WO2024037520A1 - 一种酰胺类化合物及其制备方法、药物组合物和用途 - Google Patents
一种酰胺类化合物及其制备方法、药物组合物和用途 Download PDFInfo
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- WO2024037520A1 WO2024037520A1 PCT/CN2023/113026 CN2023113026W WO2024037520A1 WO 2024037520 A1 WO2024037520 A1 WO 2024037520A1 CN 2023113026 W CN2023113026 W CN 2023113026W WO 2024037520 A1 WO2024037520 A1 WO 2024037520A1
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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- A61P31/14—Antivirals for RNA viruses
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/18—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to carbon atoms of six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
- C07D211/76—Oxygen atoms attached in position 2 or 6
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06147—Dipeptides with the first amino acid being heterocyclic and His-amino acid; Derivatives thereof
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- C07B2200/07—Optical isomers
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C2601/14—The ring being saturated
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to the fields of medicinal chemistry and drug therapy, and specifically to amide compounds as human cathepsin or RNA virus protease inhibitors, their preparation methods, pharmaceutical compositions containing such compounds and their uses.
- the pathogens of diseases such as SARS, MERS, and COVID-19 are all RNA viruses, which are highly susceptible to mutation and are likely to acquire new characteristics through frequent mutations, thus triggering uncontrollable changes in the epidemic.
- the initial symptoms of people infected with these pathogens are similar to those of a cold, but the disease progresses faster and is more harmful. There are even asymptomatic infections, making it difficult to prevent them. Ebola hemorrhagic fever can be transmitted through direct contact with blood, body fluids and tissues of patients or wild animals, as well as contaminated materials.
- Ebola virus infection is characterized by abnormal high levels of inflammatory cytokines, coagulopathy, depressed immune response, and lymphopenia, ultimately leading to septic shock and multiorgan failure, with mortality rates as high as 30-90%.
- the pathogenic mechanisms of these acute infectious diseases remain to be studied.
- the main treatment methods are symptomatic and supportive treatment, and there is a general lack of specific antiviral drugs.
- SARS-CoV-2 belongs to the genus Coronavirus of the family Coronaviridae and is an enveloped single-stranded positive-sense RNA virus. Similar to other known coronaviruses, SARS-CoV-2 coronavirus also completes the proliferation of progeny viruses through several processes such as adsorption, penetration, uncoating, biosynthesis, assembly and release of progeny viruses. Coronavirus infection of host cells begins when the spike glycoprotein on the surface of the virus envelope binds to the receptor on the surface of the host cell, followed by membrane fusion, or through the endocytic membrane fusion pathway mediated by human cathepsin L (cathepsin L).
- These two polyproteins are automatically hydrolyzed to produce 16 non-structural proteins, of which nsp3 and nsp5 have papain-like protease (PL pro ) and 3C-like protease (3CL pro ) activities respectively. Induces cleavage of progeny polyproteins, producing nonstructural proteins. Under the action of these non-binding proteins, viral RNA replicates progeny viral nucleic acid materials and translates the required structural proteins in large quantities to complete the assembly and release of progeny viruses.
- PL pro papain-like protease
- 3CL pro 3C-like protease
- Any link or key enzyme in the life cycle of cells infected by the 2019-nCoV coronavirus can be used as a research target for antiviral drugs, such as cysteine proteases PLpro and 3CLpro that hydrolyze and cleave polyprotein precursors, human cathepsin L, etc. .
- Ebola virus is an enveloped single-stranded negative-sense RNA virus belonging to the Filoviridae family. Its virions have a specific filamentous structure.
- Ebola virus was identified as the causative agent of viral hemorrhagic fever in Sudan and Congo. Since then, five different Ebola viruses have been confirmed: 1) Zaire type; 2) Sudan type; 3) Bundibugyo type; 4) Tai Forest type; 5) Reston type. Ebola hemorrhagic fever can be transmitted through direct contact with blood, body fluids and tissues of patients or wild animals, as well as contaminated materials.
- glycoprotein on the surface of Ebola virus can be directly cleaved by cathepsin under acidic conditions, which then causes the cleaved glycoprotein to undergo conformational changes to generate a 19kDa fusion form, thereby inducing interaction between the virus and the host cell. Fusion. Inhibiting cathepsin B/L can effectively prevent EBOV from invading host cells, so cathepsin B/L is an ideal target for the development of anti-EBOV drugs.
- Human cathepsin L belongs to the lysosomal papain-like protease family cysteine protease. It first exists in the cell as an inactive zymogen and needs to be cleaved by itself in the acidic environment of endosomes or lysosomes, or through Activation of other proteases leads to the formation of mature enzymes with catalytic activity. Studies have shown that human cathepsin L is closely related to the occurrence of various tumors and also plays an important role in heart disease.
- human cathepsin L is also involved in the infection of host cells by pathogenic microorganisms, so these host proteases can Acts as an entry inhibitor for coronaviruses and other viruses that invade host cells. Inhibiting human cathepsin L can effectively prevent coronavirus, EBOV and other RNA viruses from invading host cells. Therefore, human cathepsin L inhibitors are ideal targets for the development of anti-coronavirus, EBOV and other RNA viruses, and are expected to solve the problem of antiviral drugs targeting viruses. Potential risks and issues with mutational resistance.
- the object of the present invention is to provide a protease inhibitor.
- the chiral carbon atoms C* and C* 2 are each independently S-type or R-type;
- X is selected from the following group: O, NR 4 ';
- R 4 ' is selected from the following group: hydrogen, C 1 -C 6 linear or branched alkyl;
- Ra is selected from the following group: -(CH 2 ) m R 4 ; wherein, m is 0 or 1;
- Rb is H or C1-C4 alkyl
- R 1 is selected from the following group:
- R 6 is hydrogen, or a group selected from the following group substituted by 1 to 3 substituents: C 1 to C 6 linear or branched alkyl, C 1 to C 6 linear or branched alkoxy base, C 3 -C 7 cycloalkyl group, C 6 to C 12 aryl group or 5 to 12 membered heteroaryl group;
- Y is selected from the following group: O, S;
- Z is selected from the following group: O, NH, N-Boc;
- R 7 is selected from the following group: H, F, Br, Cl, CN;
- R 8 and R 9 are each independently selected from the group consisting of hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C 1 to C 10 alkyl, substituted or unsubstituted C 3 to C 10 cycloalkyl, Substituted or unsubstituted C 3 to C 10 cycloalkyl C 1 to C 4 alkylene, substituted or unsubstituted C 3 to C 10 heterocycloalkyl, substituted or unsubstituted C 3 to C 10 heterocycloalkyl C 1 to C 4 alkylene group, substituted or unsubstituted C 6 to C 12 aryl group, substituted or unsubstituted C 5 to C 12 heteroaryl group, substituted or unsubstituted C 6 to C 12 aryl group C 1 to C 4 alkylene group, substituted or unsubstituted C 5 to C 12 heteroaryl group, C 1 to C 4 alkylene group;
- R 10 is hydrogen or a group selected from the following group substituted by 1 to 2 substituents: C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, C 2 to C 10 epoxyalkyl;
- R 11 is selected from the group consisting of: hydroxyl, halogen
- R 12 and R 13 are each independently selected from the following group: a 6- to 12-membered aryl group that is unsubstituted or substituted with 1 to 3 substituents, or a 5- to 12-membered aryl group that is unsubstituted or substituted with 1 to 3 substituents. metaheteroaryl;
- R 14 and R 15 are each independently selected from the following group: hydrogen, or a group selected from the following group that is unsubstituted or substituted by 1 to 3 substituents: C 1 to C 4 linear or branched alkane, C 2 ⁇ C 6 linear or branched alkenes, C 2 ⁇ C 6 linear or branched alkynes, C 6 ⁇ C 12 aryl C 1 ⁇ C 4 alkylene;
- R 14 and R 15 are connected with the adjacent -OCO- structure to form a 5-8 membered heterocyclic ring, and the ring contains 2-3 heteroatoms selected from oxygen, sulfur and nitrogen;
- R 16 is selected from the following group: hydrogen, or C 1 to C 6 linear or branched alkylcarbonyloxy;
- R 17 is selected from metal ions, such as Na + ;
- R 2 and R 3 are each independently selected from the following group: hydrogen, C 1 to C 6 linear or branched alkyl, C 2 to C 6 linear or branched alkenyl, C 2 to C 6 linear or branched alkynyl,
- R 2 and R 3 and the carbon atoms to which they are connected together form a C 3 to C 7 cycloalkyl group that is unsubstituted or substituted by 1 to 3 substituents; wherein the substituents are each independently selected from the following Group: Halogen, C 1 to C 4 linear or branched alkyl, C 2 to C 4 linear or branched alkenyl, C 2 to C 4 linear or branched alkynyl, C 1 to C 4 linear Or branched alkoxy, C 1 to C 4 linear or branched alkyl carbonyloxy, cyano, nitro, hydroxyl, amino, hydroxymethyl, trifluoromethyl, carboxyl, mercapto, C 1 to C 4 acyl group, amide group, sulfonyl group, aminosulfonyl group, C 1 to C 4 alkyl substituted sulfonyl group, or a 5 to 7-membered ring composed of two adjacent substituents together with the carbon
- n is selected from 0, 1 or 2;
- the heteroaryl group contains 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen; the substituents are each independently selected from the following group: halogen, C 1 to C 4 linear or branched alkyl, C 2 to C 4 linear or branched alkenyl, C 2 to C 4 linear or branched alkynyl, C 1 to C 4 linear or branched alkoxy, C 1 to C 4 linear or branched alkyl Carbonyloxy, cyano, nitro, hydroxyl, amino, hydroxymethyl, trifluoromethyl, carboxyl, mercapto, C 1 to C 4 acyl, amide, sulfonyl, aminosulfonyl, C 1 to C 4 Alkyl-substituted sulfonyl group
- Chiral carbon atoms C* 3 and C* 4 are each independently S-type or R-type;
- R 4 is selected from the following group: hydrogen, or a group selected from the following group that is unsubstituted or substituted by 1 to 3 substituents: C 1 to C 6 linear or branched alkyl, C 3 to C 7 ring Alkyl, trifluoromethyl, C 2 to C 6 alkynyl, 4 to 7 membered heterocyclyl, C 5 to C 7 aryl, 5 to 7 membered heteroaryl; each of the heterocyclyl and heteroaryl Contains 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen; the substituents are each independently selected from the following group: halogen, C 1 to C 4 straight chain or branched alkyl, C 2 to C 4 straight chain Chain or branched alkenyl, C 2 to C 4 linear or branched alkynyl, C 1 to C 4 linear or branched alkoxy, C 1 to C 4 linear or branched alkylcarbonyloxy, Cyano group, nitro group, hydroxyl group, amino group, hydroxy
- R 4 and R 4 '' and their connected carbon atoms and nitrogen atoms together form a 5-10 membered cyclic structure that is unsubstituted or substituted with 1 to 3 substituents.
- R 1 is selected from the following group:
- R 8 and R 9 are each independently selected from the following group: hydrogen, deuterium, substituted or unsubstituted C 1 to C 4 linear or branched alkyl, substituted or unsubstituted C 3 to C 6 cycloalkyl , substituted or unsubstituted C 3 ⁇ C 6 cycloalkyl C 1 ⁇ C 2 alkylene, substituted or unsubstituted C 6 ⁇ C 12 aryl, substituted or unsubstituted C 6 ⁇ C 12 aryl C 1 ⁇ C 2 alkylene;
- R 11 is selected from the group consisting of: hydroxyl and halogen atoms
- R 12 is a group selected from the following group that is unsubstituted or substituted by 1 to 3 substituents: phenyl, pyrimidinyl, and pyridyl.
- R 18 and R 19 are each independently selected from the following group: halogen, amino, hydroxyl, carboxyl, substituted or unsubstituted C 1 to C 6 alkyl, substituted or unsubstituted C 3 to C 6 cycloalkyl, substituted or Unsubstituted C 1 to C 6 alkoxy group, substituted or unsubstituted C 1 to C 6 aldehyde group, substituted or unsubstituted C 2 to C 6 acyl group, substituted or unsubstituted C 2 to C 6 ester group, Substituted or unsubstituted phenyl, substituted or unsubstituted phenyl C 1 to C 4 alkylene.
- R 2 and R 3 are independently selected from the following group: hydrogen, Or a substituted or unsubstituted group selected from the following group: C 1 to C 6 linear or branched alkyl, benzyl, phenethyl, C 3 to C 6 cycloalkyl, C 3 to C 6 cycloalkyl methylene; or, R 2 and R 3 are connected to form a substituted or unsubstituted C 3 to C 5 cycloalkyl group;
- the chiral carbon atoms C* 3 and C* 4 are S-type.
- R 4 is selected from the following group: unsubstituted or substituted by 1 to 3 substituents, selected from the following group: C 1 to C 6 linear or branched alkyl, C 3 ⁇ C 7 cycloalkyl, trifluoromethyl, C 2 ⁇ C 6 alkynyl, 4-7 membered heterocyclyl, C 5 ⁇ C 7 aryl, 5-7 membered heteroaryl;
- R 4 ' is selected from the following group: hydrogen, C 1 -C 6 linear or branched alkyl
- R 4 and R 4 ' and their connected carbon atoms and nitrogen atoms together form a 5-6-membered cyclic or 6-10-membered bicyclic structure that is unsubstituted or substituted with 1 to 3 substituents, so
- the cyclic or bicyclic structures include the following structures:
- R 4 is hydrogen, or a group selected from the following group that is unsubstituted or substituted by 1 to 3 substituents: C 1 to C 4 linear or branched alkyl, C 3 ⁇ C 7 cycloalkyl, trifluoromethyl, C 5 ⁇ C 7 aryl; the substituents are each independently selected from the following group: halogen, C 1 ⁇ C 4 linear or branched alkyl, C 1 ⁇ C 4 linear or branched alkyl carbonyloxy, cyano, nitro, hydroxyl, amino, hydroxymethyl, trifluoromethyl, carboxyl, mercapto, C 1 to C 4 acyl, amide, sulfonyl, amino Sulfonyl group, C 1 to C 4 alkyl-substituted sulfonyl group, or a 5- to 7-membered ring composed of two adjacent substituents together with the carbon atoms connected to them;
- R 4 ' is selected from the following group: hydrogen, C1-C4 linear or branched alkyl
- R 4 is connected to R 4 ', the ⁇ carbon atom connected to R 4 , the ⁇ carbon atom connected to R 4 , and the ⁇ nitrogen atom connected to R 4 ' are unsubstituted or substituted with 1 to 3 substituents.
- n 1;
- R 4 is selected from the following groups that are unsubstituted or substituted by 1 to 3 substituents: isopropyl, cyclohexyl, cyclopentyl, phenyl; the substituents are each independently selected from the following group: halogen , C1 ⁇ C4 linear or branched alkyl group, cyano group, nitro group, hydroxyl group, trifluoromethyl group.
- the amide compound is selected from the following group:
- Ha is halogen
- the halogen-substituted compound of formula Ia and the compound of formula Ib undergo a substitution reaction to obtain a compound of formula Ic.
- the base is preferably selected from triethylamine, diisopropylethylamine, cesium carbonate, potassium carbonate, 1 ,8-diazabis Cycl[5.4.0]undec-7-ene;
- the compound of formula Ic is dissolved in an organic solvent.
- an alkaline solution the compound of formula Ic is hydrolyzed to generate the compound Id.
- the organic solvent is preferably methanol, ethanol, tetrahydrofuran, dioxane, or a combination thereof.
- the alkaline solution is preferably hydrogen Sodium oxide aqueous solution, lithium hydroxide aqueous solution, potassium hydroxide aqueous solution;
- the compound of formula Id is dissolved in an organic solvent, and in the presence of a condensing agent and a base, it undergoes a condensation reaction with a compound of formula Ie to generate an If compound.
- the organic solvent is preferably selected from dichloromethane, ethyl acetate, dichloroethane, N, N Dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, dioxane, or combinations thereof
- the base is preferably selected from triethylamine, diisopropylethylamine
- the condensation agent is preferably selected from 2-(7 -Azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 1-ethyl-(3-dimethylaminopropyl)carbodiimide salt acid salt;
- the compound of formula If is dissolved in an organic solvent, and a reducing agent is used to perform a reduction reaction to obtain a compound of formula Ig.
- the organic solvent is selected from a mixed solvent of dichloromethane and methanol, a mixed solvent of tetrahydrofuran and methanol, and the reducing agent is preferably sodium borohydride. ;
- the compound of formula Ig undergoes an oxidation reaction to obtain the compound of formula Ih, that is, the aldehyde compound of formula (I).
- the solvent is preferably selected from dichloromethane, dimethyl sulfoxide, tetrahydrofuran, and ethyl acetate.
- the oxidizing agent Preferably from pyridine sulfur trioxide, Desmartin oxidant or a combination of oxalyl chloride and dimethyl sulfoxide;
- the compound of formula Ih reacts with an isonitrile compound under acidic conditions to obtain a compound of formula II.
- the solvent is preferably selected from dichloromethane, dimethyl sulfoxide, tetrahydrofuran, and ethyl acetate, and the acid is preferably selected from acetic acid. , trifluoroacetic acid, hydrochloric acid;
- the compound of formula II is dissolved in an organic solvent. In the presence of an alkaline solution, the compound of formula II is hydrolyzed to generate the compound Ij.
- the organic solvent is preferably selected from methanol, ethanol, tetrahydrofuran, dioxane, or a combination thereof.
- the alkali solution is preferably selected from Sodium hydroxide aqueous solution, lithium hydroxide aqueous solution, potassium hydroxide aqueous solution;
- the compound of formula Ij undergoes an oxidation reaction to obtain the compound of formula Ik, that is, the ketoamide compound of formula (I).
- the solvent is preferably selected from dichloromethane, dimethyl sulfoxide, tetrahydrofuran, and ethyl acetate.
- the oxidizing agent Preferably from sulfur trioxide pyridine, Desmartin oxidant or oxalyl chloride and dimethyl sulfoxide;
- the compound of formula If and ammonia are reacted through amine transesterification to obtain the compound of formula Il, and the solvent is preferably selected from methanol, ethanol, tetrahydrofuran, and ethyl acetate;
- the compound of formula Il is subjected to a dehydration reaction in the presence of a dehydrating agent to obtain a compound of formula Im, that is, a cyano compound of formula (I).
- the solvent is preferably selected from dichloromethane, dimethyl sulfoxide, tetrahydrofuran, and acetic acid.
- the dehydrating agent is preferably selected from phosphorus oxychloride, trifluoroacetic anhydride, Burgess reagent, etc.
- the third aspect of the present invention provides a pharmaceutical composition, which includes: a therapeutically effective amount of one or more compounds represented by the general formula (I) described in the first aspect of the present invention, or their Pharmaceutically acceptable salts, enantiomers, diastereomers or racemates.
- the fourth aspect of the present invention provides a compound represented by the general formula (I) as described in the first aspect of the present invention, or a pharmaceutically acceptable salt, enantiomer, diastereomer or The racemate, or the use of the pharmaceutical composition according to the third aspect of the present invention, for the preparation of treatment or prevention of coronaviruses such as SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV, and /or pharmaceutical compositions for related diseases caused by RNA virus infection such as EV71 and/or EV68 and/or norovirus and/or EBOV;
- coronaviruses such as SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV
- RNA virus infection such as EV71 and/or EV68 and/or norovirus and/or EBOV
- the coronavirus includes: SARS-CoV-2, SARS-CoV, MERS-CoV;
- the RNA viruses include: EV71, EV68, norovirus, and EBOV.
- the related diseases caused by coronavirus infection such as SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV are selected from the following group: respiratory tract infection, pneumonia and its complications, or its combination.
- the related diseases caused by RNA virus infection such as EV71 and/or EV68 and/or norovirus are selected from the following group: hand, foot and mouth disease, central nervous system infection, diarrhea and its complications, or its combination.
- the related diseases caused by RNA virus infection such as EBOV are selected from the following group: hemorrhagic fever, central nervous system infection and its complications, or a combination thereof.
- an amide compound as described in the first aspect of the present invention or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof body, or the use of the pharmaceutical composition according to the third aspect of the present invention, which is characterized in that it is used to treat, prevent, and/or alleviate related diseases caused by coronavirus and/or RNA virus infection, including the steps of: giving The subject in need is administered a safe and effective amount of the amide compound represented by the general formula (I) as described in the first aspect of the present invention, or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof. Or the racemate, or the pharmaceutical composition as described in the third aspect of the present invention;
- the coronavirus includes: SARS-CoV-2, SARS-CoV, MERS-CoV;
- the RNA viruses include: EV71, EV68, norovirus, and EBOV.
- the subject is a primate mammal, such as a human.
- a method for treating, preventing, and/or alleviating coronaviruses caused by SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV, and/or EV71 and/or EV68 and/or related diseases caused by RNA virus infection such as norovirus and/or EBOV including the step of administering a safe and effective amount of an amide compound represented by the general formula (I) to a subject in need, or a pharmaceutically acceptable amount thereof.
- the subject is a primate mammal, such as a human.
- Figure 1 shows a bar graph of the inhibitory effect of the ketoamide compound of the present invention on SARS-CoV-2 replication in Activity Test Example 4.
- RNA viruses such as EV68 and/or norovirus and/or EBOV, that is, the compound represented by general formula I or its pharmaceutically acceptable salts, enantiomers, and diastereomers Or racemate.
- Tests have shown that the active ingredient of the present invention can effectively inhibit the activity of human cathepsin L, thereby inhibiting the replication and activity of related viruses. On this basis, the present invention was completed.
- substituted means that one or more hydrogen atoms on the group are replaced by a substituent selected from the following group: C 1 to C 10 alkyl, C 3 to C 10 cycloalkyl group, C 1 to C 10 alkoxy group, halogen, hydroxyl group, carboxyl group (-COOH), C 1 to C 10 aldehyde group, C 2 to C 10 acyl group, C 2 to C 10 ester group, amino group, phenyl group; so
- the above-mentioned phenyl group includes unsubstituted phenyl group or substituted phenyl group with 1-3 substituents, and the substituent groups are selected from: halogen, C 1 -C 10 alkyl group, cyano group, OH, nitro group, C 3 ⁇ C 10 cycloalkyl group, C 1 ⁇ C 10 alkoxy group, amino group.
- each chiral carbon atom may optionally be in R configuration or S configuration, or a mixture of R configuration and S configuration.
- C1-C6 alkyl refers to a straight-chain or branched alkyl group with 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.
- 3-8 membered heterocyclyl refers to a group formed by losing one hydrogen atom from a 3-8 membered saturated ring with 1-3 heteroatoms selected from the following group: N, S, O; for example, pyrrolidinyl, Piperidinyl, piperazinyl, morpholinyl, or similar groups.
- 6- to 10-membered aryl group refers to a group formed by losing one hydrogen atom from a 6- to 10-membered aryl group; such as phenyl, naphthyl, or similar groups.
- 5-10 membered heteroaryl refers to a group formed by losing one hydrogen atom from a 5-8 membered aryl group having 1-3 heteroatoms selected from the following group: N, S, O, where each heteroaryl
- the cyclic system of the base may be monocyclic or polycyclic; for example, pyrrolyl, pyridyl, thienyl, furyl, imidazolyl, pyrimidinyl, benzothienyl, indolyl, imidazopyridyl, quinolyl or similar groups.
- C 1 to C 6 alkoxy refers to a straight or branched chain alkoxy group with 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy , isobutoxy, sec-butoxy, tert-butoxy, or similar groups.
- C 2 -C 6 alkenyl refers to a group formed by losing one or two hydrogen atoms from an alkene having 2 to 6 carbon atoms.
- halogen refers to F, Cl, Br and I.
- the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers): for example, containing asymmetric centers R, S configuration, double bond (Z), (E) isomers and (Z), (E) conformational isomers. Therefore, the single stereochemical isomers of the compounds of the present invention or their enantiomers Mixtures of isomers, diastereomers or geometric isomers (or conformational isomers) are within the scope of the invention.
- tautomers means that structural isomers with different energies can cross a low energy barrier and thus interact with each other. Transformation.
- proton tautomers i.e. proton transfer
- interconversion through proton migration such as 1H-indazole and 2H-indazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole
- valency tautomers include interconversion through some bonding electron recombination.
- C 1 to C 6 means that the group may have 1 to 6 carbon atoms, such as 1, 2, 3, 4 or 5.
- a method that can effectively inhibit coronaviruses such as SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV, and/or EV71 and/or EV68 and/or norovirus and/or Active ingredient for infection and replication of RNA viruses such as EBOV.
- the active ingredient is a compound represented by general formula I, and the active ingredient can effectively prevent, treat and/or alleviate related diseases.
- the active ingredients of the present invention include amide compounds represented by general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers or racemates thereof, or their prodrug. It should be understood that the active ingredient of the present invention also includes the crystalline form, amorphous compound, deuterated compound and other forms of the compound of general formula (I).
- the "pharmaceutically acceptable salt” is a conventional non-toxic salt formed by the reaction of a compound of general formula (I) with an inorganic acid or organic acid.
- conventional non-toxic salts can be prepared by reacting compounds of general formula (I) with inorganic acids or organic acids.
- the inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid and phosphoric acid, etc.
- Organic acids include citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, propylene glycol Acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, parapic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzene Sulfonic acid, 2-acetoxybenzoic acid, isethionic acid, etc.; or compounds of general formula (I) with propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid,
- Amine salt, ethylamine salt or ethanolamine salt; or the compound of general formula (I) forms ester with lysine, arginine or ornithine and then forms ester with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid
- the corresponding inorganic acid salt or the corresponding organic acid salt formed with formic acid, acetic acid, picric acid, methanesulfonic acid or ethanesulfonic acid.
- the present invention also provides one of the amide compounds represented by the general formula (I), or their pharmaceutically acceptable salts, enantiomers, diastereomers or racemates and prodrugs.
- a mixture of one or more species is an active ingredient in the preparation for the treatment or prevention of coronaviruses caused by SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV, and/or EV71 and/or EV68 and/or norovirus and/or use in medicines for related diseases caused by RNA virus infection such as EBOV.
- the pharmaceutical composition provided by the present invention preferably contains active ingredients in a weight ratio of 0.001-99wt%.
- the preferred ratio is that the compound of general formula I as the active ingredient accounts for 0.1wt%-90wt% of the total weight, and the remainder is pharmaceutically acceptable.
- the carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption accelerators, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field.
- the compounds and pharmaceutical compositions provided by the present invention can be in various forms, such as tablets, capsules, powders, syrups, Solution, suspension, aerosol, etc., and may be present in a suitable solid or liquid carrier or diluent and in a suitable sterile device for injection or infusion.
- the unit dosage of the preparation formula usually contains 0.05-500 mg of the compound of general formula I.
- the unit dosage of the preparation formula contains 1 mg-500 mg of the compound of general formula I.
- the compounds and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, through oral, nasal, skin, lung, gastrointestinal tract or intravenous administration routes. Most preferred are veins.
- the most preferred daily dose is 0.01-400 mg/kg body weight, taken at one time, or 0.01-200 mg/kg body weight taken in divided doses. Regardless of the method of administration, the optimal dose for the individual will depend on the specific treatment. Usually, you start with a small dose and gradually increase the dose until you find the most suitable dose.
- the drugs or inhibitors of the present invention can be administered in various ways, for example, through injection, spray, nasal drop, eye drop, penetration, absorption, physical or chemical mediated method, such as muscle, intradermal, subcutaneous, intravenous introduction into the body. , mucosal tissue; or mixed or wrapped with other substances and introduced into the body.
- the analysis data of the samples were measured by the following instruments: NMR was measured by GEMINI-300, Bruker AMX-400 and INVOA-600 NMR instruments, TMS (tetramethylsilane) was used as the internal standard, the chemical shift unit was ppm, and the coupling The constant unit is Hz; the mass spectrum was measured by Finnigan MAT-711, MAT-95 and LCQ-DECA mass spectrometers and IonSpec 4.7 Tesla mass spectrometer.
- the silica gel used for column chromatography is 200-300 mesh (produced by Qingdao Ocean Chemical Plant); the TLC silica gel plate is a HSGF-254 thin layer chromatography prefabricated plate produced by Yantai Chemical Plant; the boiling range of petroleum ether is 60-90°C; a UV lamp is used , iodine cylinder color development.
- the conventional reagents and drugs used in the following examples were purchased from Sinopharm Group. The reagents and solvents used in the experiment were handled according to the specific conditions of the reaction.
- Dissolve compound 1-3 (1.57g, 4.85mmol) in a mixture of methanol and water (10:1, 44mL), add lithium hydroxide monohydrate (0.81g, 19.42mmol), stir at room temperature, and monitor the reaction with TLC after completion , add 1M HCl to adjust the pH to neutral, extract with dichloromethane, separate the liquids, dry the organic phase over anhydrous sodium sulfate and concentrate to obtain 1-4 1.3g, with a yield of 89%.
- Dissolve compound 1-4 (1.3g, 4.2mmol) in dichloromethane (50mL), cool the reaction solution to -20°C, then add HATU (2.40g, 6.3mmol) to the reaction solution, and stir for 20 minutes. 1-5 (0.74g, 5.04mmol) was added to the reaction solution, stirred again at -20°C for 30 minutes, and then DIPEA (1.63g, 12.61mmol) was added dropwise to the reaction solution. Maintain -20°C, stir for 12 hours, extract with ammonium chloride (60mL 1.31g of compound 1-6 was obtained by chromatography, with a yield of 76%.
- compound 1 (0.2g, 0.53mmol) was dissolved in dichloromethane (10ml), then acetic acid (180 ⁇ L) was added, and compound 3-1 (180 ⁇ L) was stirred and reacted at room temperature for 24h. After TLC monitoring the completion of the reaction, it was separated by column chromatography, and a total of 0.21g of compound 3-2 was synthesized with a yield of 70%.
- the synthesis method refers to the synthesis of compound 3, and compound 9 is obtained with ESI-MS m/z 462.26[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 10 is obtained, with ESI-MS m/z 448.25[M+H] + .
- the synthesis method refers to the synthesis of compound 2, and compound 11 is obtained with ESI-MS m/z 445.25[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 12 is obtained, with ESI-MS m/z 531.29[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 13 is obtained, with ESI-MS m/z 581.30[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 14 is obtained, with ESI-MS m/z 462.26[M+H] + .
- the synthesis method refers to the synthesis of compound 2, and compound 15 is obtained, with ESI-MS m/z 459.26[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 16 is obtained, with ESI-MS m/z 545.30[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 17 is obtained, with ESI-MS m/z 595.32[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 18 is obtained, with ESI-MS m/z 432.22[M+H] + .
- the synthesis method refers to the synthesis of compound 2, and compound 19 is obtained with ESI-MS m/z 429.22[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 20 is obtained, with ESI-MS m/z 515.25[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 21 is obtained, ESI-MS m/z 565.27[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 22 is obtained, with ESI-MS m/z 579.29[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 23 is obtained, with ESI-MS m/z 529.27[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 24 is obtained, with ESI-MS m/z 446.23[M+H] + .
- the synthesis method refers to the synthesis of compound 2, and compound 25 is obtained, with ESI-MS m/z 560.29[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 26 is obtained, with ESI-MS m/z 563.29[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 27 is obtained, with ESI-MS m/z 646.33[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 28 is obtained, ESI-MS m/z 549.27[M+H] + .
- the synthesis method refers to the synthesis of compound 2, and compound 29 is obtained, ESI-MS m/z 546.28[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 30 is obtained, with ESI-MS m/z 632.32[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 31 is obtained, with ESI-MS m/z 682.33[M+H] + .
- the synthesis method refers to the synthesis of compound 2, and compound 32 is obtained, with ESI-MS m/z 382.20[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 33 is obtained with ESI-MS m/z 468.24[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 34 is obtained, with ESI-MS m/z 387.19[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 35 is obtained with ESI-MS m/z 470.23[M+H] + .
- the synthesis method refers to the synthesis of compound 2, and compound 36 is obtained, with ESI-MS m/z 384.19[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 37 is obtained, with ESI-MS m/z 520.25[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 38 is obtained, ESI-MS m/z 518.23[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 39 is obtained, with ESI-MS m/z 596.28[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 40 is obtained, with ESI-MS m/z 614.27[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 41 is obtained, with ESI-MS m/z 548.28[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 43 is obtained.
- ESI-MS m/z 589.27[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 43 is obtained, with ESI-MS m/z 539.25[M+H] + .
- the synthesis method refers to the synthesis of compound 2, and compound 44 is obtained, with ESI-MS m/z 453.21[M+H] + .
- the synthesis method refers to the synthesis of compound 2, and compound 45 is obtained, with ESI-MS m/z 467.23[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 46 is obtained, with ESI-MS m/z 470.23[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 47 is obtained, with ESI-MS m/z 523.22[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 48 is obtained, with ESI-MS m/z 535.30[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 49 is obtained, with ESI-MS m/z 521.28[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 50 is obtained, ESI-MS m/z 539.27[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 51 is obtained, with ESI-MS m/z 551.29[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 52 is obtained, with ESI-MS m/z 557.27[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 53 is obtained, with ESI-MS m/z 546.28[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 54 is obtained, ESI-MS m/z 601.21[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 55 is obtained, with ESI-MS m/z 619.20[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 56 is obtained, with ESI-MS m/z 549.24[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 57 is obtained, ESI-MS m/z 535.22[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 58 is obtained, with ESI-MS m/z 432.22[M+H] + .
- the synthesis method refers to the synthesis of compound 2, and compound 59 is obtained, with ESI-MS m/z 429.22[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 60 is obtained, with ESI-MS m/z 565.27[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 61 is obtained, ESI-MS m/z 529.27[M+H] + .
- the synthesis method refers to the synthesis of compound 7, and compound 62 is obtained with ESI-MS m/z 494.21[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 63 is obtained with ESI-MS m/z 428.17[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 64 is obtained, with ESI-MS m/z 442.18[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 65 is obtained, ESI-MS m/z 561.22[M+H] + .
- the synthesis method refers to the synthesis of compound 8, and compound 66 is obtained, ESI-MS m/z 601.21[M+H] + .
- the synthesis method refers to the synthesis of compound 2, and compound 67 is obtained with ESI-MS m/z 432.18[M+H] + .
- the synthesis method refers to the synthesis of compound 2, and compound 68 is obtained, with ESI-MS m/z 436.19[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 69 is obtained, with ESI-MS m/z 544.21[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 71 is obtained, with ESI-MS m/z 437.17[M+H] + .
- the synthesis method refers to the synthesis of compound 4, and compound 71 is obtained, with ESI-MS m/z 449.17[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 73 is obtained, with ESI-MS m/z 601.27[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 73 is obtained, ESI-MS m/z 565.27[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 74 is obtained, with ESI-MS m/z 482.23[M+H] + .
- the synthesis method refers to the synthesis of compound 7, and compound 75 is obtained with ESI-MS m/z 447.17[M+H] + .
- the synthesis method refers to the synthesis of compound 8, and compound 76 is obtained, with ESI-MS m/z 615.17[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 77 is obtained, with ESI-MS m/z 570.30[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 78 is obtained, with ESI-MS m/z 437.25[M+H] + .
- the synthesis method refers to the synthesis of compound 7, and compound 79 is obtained with ESI-MS m/z 499.24[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 80 is obtained, with ESI-MS m/z 588.23[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 81 is obtained, with ESI-MS m/z 586.28[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 82 is obtained, with ESI-MS m/z 587.28[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 83 is obtained, with ESI-MS m/z 518.26[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 84 is obtained, with ESI-MS m/z 551.28[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 85 is obtained, with ESI-MS m/z 383.19[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 86 is obtained, ESI-MS m/z 601.29[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 87 is obtained, with ESI-MS m/z 558.30[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 88 is obtained, with ESI-MS m/z 439.26[M+H] + .
- the synthesis method refers to the synthesis of compound 2, and compound 89 is obtained with ESI-MS m/z 470.22[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 90 is obtained, with ESI-MS m/z 504.28[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 91 is obtained with ESI-MS m/z 437.25[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 92 is obtained, with ESI-MS m/z 574.28[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 93 is obtained, with ESI-MS m/z 602.29[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 94 is obtained, with ESI-MS m/z 552.29[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 95 is obtained, with ESI-MS m/z 549.26[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 96 is obtained with ESI-MS m/z 469.25[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 97 is obtained with ESI-MS m/z 419.24[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 98 is obtained, with ESI-MS m/z 487.24[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 99 is obtained, with ESI-MS m/z 505.23[M+H] + .
- the synthesis method refers to the synthesis of compound 42, and compound 100 is obtained, with ESI-MS m/z 588.27[M+H] + .
- R-cyclohexylalanine was used to replace S-cyclohexylalanine, and the synthesis method was as described in compound 42, to obtain compound 110, ESI-MS m/z 589.27[M+H] + .
- the synthesis method was as follows: compound 110, and compound 111 was obtained, with ESI-MS m/z 589.27[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 114 is obtained, with ESI-MS m/z 579.29[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 115 is obtained, with ESI-MS m/z 446.23[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 116 is obtained, with ESI-MS m/z 515.25[M+H] + .
- the synthesis method refers to the synthesis of compound 2, and compound 117 is obtained, with ESI-MS m/z 443.23[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 118 is obtained, with ESI-MS m/z 456.21[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 119 is obtained, with ESI-MS m/z 553.27[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 120 is obtained, with ESI-MS m/z 603.28[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 121 is obtained, with ESI-MS m/z 456.21[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 122 is obtained, with ESI-MS m/z 696.34[M+H] + .
- the synthesis method refers to the synthesis of compound 2, and compound 123 is obtained, with ESI-MS m/z 453.21[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 124 is obtained, with ESI-MS m/z 539.25[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 125 is obtained, with ESI-MS m/z 589.27[M+H] + .
- the synthesis method refers to the synthesis of compound 2, and compound 126 is obtained, with ESI-MS m/z 467.23[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 127 is obtained, with ESI-MS m/z470.23[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 128 is obtained, with ESI-MS m/z 553.27[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 129 is obtained, with ESI-MS m/z 603.28[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 130 is obtained, with ESI-MS m/z 581.30[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 131 is obtained, with ESI-MS m/z 373.18[M+H] + .
- the synthesis method refers to the synthesis of compound 2, and compound 132 is obtained, with ESI-MS m/z 370.18[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 133 is obtained, with ESI-MS m/z 456.21[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 134 is obtained, with ESI-MS m/z 506.23[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 135 is obtained, with ESI-MS m/z 463.22[M+H] + .
- the synthesis method refers to the synthesis of compound 2, and compound 136 is obtained, with ESI-MS m/z 460.22[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 129 is obtained, with ESI-MS m/z 546.26[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 138 is obtained, with ESI-MS m/z 596.28[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 139 is obtained, with ESI-MS m/z 537.24[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 140 is obtained, with ESI-MS m/z 587.25[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 141 is obtained, with ESI-MS m/z 454.20[M+H] + .
- the synthesis method refers to the synthesis of compound 2, and compound 142 is obtained with ESI-MS m/z 451.20[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 143 is obtained, with ESI-MS m/z 440.18[M+H] + .
- the synthesis method refers to the synthesis of compound 2, and compound 144 is obtained, with ESI-MS m/z 437.18[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 145 is obtained, with ESI-MS m/z 573.24[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 146 is obtained, with ESI-MS m/z 523.22[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 147 is obtained with ESI-MS m/z 447.20[M+H] + .
- the synthesis method refers to the synthesis of compound 2, and compound 148 is obtained, with ESI-MS m/z 444.19[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 149 is obtained, with ESI-MS m/z 530.23[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 150 is obtained, with ESI-MS m/z 580.25[M+H] + .
- the synthesis method refers to the synthesis of compound 1, and compound 151 is obtained, with ESI-MS m/z 357.15[M+H] + .
- the synthesis method refers to the synthesis of compound 2, and compound 152 is obtained, with ESI-MS m/z 354.15[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 153 is obtained.
- ESI-MS m/z 440.18[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 154 is obtained, with ESI-MS m/z 490.20[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 155 is obtained, with ESI-MS m/z 571.30[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 156 is obtained, with ESI-MS m/z 521.28[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 157 is obtained, with ESI-MS m/z 585.31[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 158 is obtained, with ESI-MS m/z 535.30[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 159 is obtained, with ESI-MS m/z 578.31[M+H] + .
- the synthesis method refers to the synthesis of compound 3, and compound 160 is obtained, with ESI-MS m/z 528.29[M+H] + .
- Activity test example 1 Evaluation of human cathepsin L protease inhibitory activity
- test compounds had excellent inhibitory activity against human cathepsin L.
- the IC 50 of several compounds reached the nanomolar level, and the IC 50 of 5 compounds was less than 1 nM.
- the enzyme level inhibitory activity of inhibitors against Cat B was determined using fluorescence resonance energy transfer FRET technology.
- test compounds have excellent inhibitory activity against human cathepsin B.
- the IC 50 of several compounds reaches the nanomolar level, and the IC 50 of two compounds is less than 100 nM.
- Fluorescence resonance energy transfer (FRET) technology was used to determine the enzyme level inhibitory activity of inhibitors against 3CL protease.
- the volume of the entire enzymatic reaction system is 120 ⁇ L, the final concentration of protease is 30 nM, and the final concentration of substrate is 20 ⁇ M.
- the buffer of the reaction system includes 50mM Tris pH7.3, 1mM EDTA.
- the excitation light and emission light are 320nm and 405nm respectively.
- test time 10 minutes, and the fluorescence value is read every 30 seconds.
- the final results were taken from the readings of the first 2 minutes to fit the reaction rate, and compared with the control group (DMSO) to calculate the inhibition rate.
- the experimental results are shown in Table 3.
- Activity test example 4 Evaluation of compound’s inhibitory activity against 2019 novel coronavirus (SARS-CoV-2) replication
- Vero E6 cells (50,000 cells/well) to a 96-well plate, add 100 ⁇ L/well of culture medium containing gradient concentrations of compounds, and then add 2019 novel coronavirus (SARS-CoV-2) at a multiplicity of infection (MOI) of 0.05 . After incubation for 1 hour, aspirate the supernatant, wash and re-add 200 ⁇ L/well of culture medium containing compounds with gradient concentrations, and incubate at 37°C for 24 hours. After 24 hours, the cell supernatant was collected, the viral RNA of the supernatant was extracted, and the virus copy number of the supernatant was detected using real-time fluorescence quantitative PCR. The compound inhibition rate was calculated based on the virus copy number.
- SARS-CoV-2 2019 novel coronavirus
- MOI multiplicity of infection
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Abstract
本发明公开了通式I所示的一种新化合物及其药学上可接受的盐、对映异构体、非对映异构体、外消旋体以及含有所述化合物的药物组合物,R1、R2、R3、R4、R4'A环等具有在说明书中给出的含义。本发明还涉及此类化合物的制备方法,并且还涉及该类化合物其药学上可接受的盐、溶剂化物、各种比例混合物在内的立体异构体的用途,特别是在制备抗病毒类药物中的用途。
Description
本发明涉及药物化学和药物治疗学领域,具体涉及作为人组织蛋白酶或RNA病毒蛋白酶抑制剂的酰胺类化合物、其制备方法、含此类化合物的药物组合物及用途。
突发传染病特别是病毒感染性疾病依然是人类健康的严重威胁。世界卫生组织(WHO)自2007年颁布《国际卫生条例》以来,已宣布了甲型H1N1流感(2009年)、脊髓灰质炎(2014年)、西非埃博拉(2014年)、“寨卡”(2015-2016年)、刚果(金)埃博拉(2018年)、COVID-19(2019-2020年)等6次“国际公共卫生紧急事件”(均是病毒引起)。在急性传染病中,绝大部分都是病毒性传染病,病毒性传染病的发病率高,死亡率也很高。由于检测和诊断手段有限,导致新病毒引发的新疫情爆发往往具有突发性、随机性和不可预测性等特点,一旦爆发,如无有效的防治手段,极易造成大规模流行,严重威胁人民健康生命安全。SARS、MERS和COVID-19等疾病的病原体均为RNA病毒,极易发生变异,很可能会在频繁的变异中获得新的特性,从而引发疫情不可控制的变化。这些病原体感染者初期症状与感冒类似,但病程发展更快,危害更大,甚至存在无症状感染者,让人难以防范。埃博拉出血热可通过与患者或野生动物的血液、体液和组织以及被污染的物料直接接触而传播。埃博拉病毒感染的特点是高水平炎性细胞因子异常、凝血障碍、低下的免疫反应和淋巴细胞减少症,最终导致败血病休克和多器官衰竭,其死亡率高达30-90%。这些急性传染病的致病机制还有待研究,目前主要的治疗方法是以对症支持治疗为主,普遍缺乏抗病毒特效药物。
SARS-CoV-2属于冠状病毒科冠状病毒属,为具有包膜的单链正义RNA病毒。和其他已知冠状病毒类似,SARS-CoV-2冠状病毒也经过吸附、穿入、脱壳、生物合成、子代病毒的组装与释放等几个过程完成子代病毒的增殖。冠状病毒感染宿主细胞起始于病毒包膜表面的刺突糖蛋白与宿主细胞表面的受体结合,随后发生膜融合,或者经由人组织蛋白酶L(cathepsin L)介导的内吞膜融合途径,病毒进入宿主细胞,释放遗传物质,其基因组作为mRNA直接翻译产生多聚蛋白pp1a和pp1ab。这两个多聚蛋白自动水解,产生16个非结构蛋白,其中nsp3和nsp5分别具有木瓜样蛋白酶(papain-like protease,PLpro)和3C样蛋白酶(3C-like protease,3CLpro)活性,可诱导子代多聚蛋白的切割,产生非结构蛋白。在这些非结够蛋白的作用下,病毒RNA复制出子代病毒核酸物质,并大量翻译出所需的结构蛋白,完成子代病毒的组装和释放。2019-nCoV冠状病毒感染细胞的生命周期的任何环节或关键酶均可以作为抗病毒药物的研究靶点,如水解切割多聚蛋白前体的半胱氨酸蛋白酶PLpro和3CLpro,人组织蛋白酶L等。
埃博拉病毒(Ebola virus,EBOV)是具包膜的单链负义RNA病毒,属于丝状病毒科(Filoviridae),其病毒粒子为特异性的丝状结构。1976年,埃博拉病毒被确定为引起苏丹和刚果地区病毒性出血热的病原体。此后陆续有五种不同的埃博拉病毒被确认:1)扎伊尔型;2)苏丹型;3)本迪布焦型;4)塔伊森林型;5)莱斯顿型。埃博拉出血热可通过与患者或野生动物的血液、体液和组织以及被污染的物料直接接触而传播。
研究表明埃博拉病毒表面的糖蛋白(glycoprotein)在酸性条件下能够直接被需首先被组织蛋白酶裂解,进而导致裂解的糖蛋白发生构象变化生成19kDa的融合形式,从而诱导了病毒与宿主细胞的融合。抑制组织蛋白酶B/L可以有效阻止EBOV侵入宿主细胞,因此组织蛋白酶B/L是抗EBOV药物研发的理想靶标。
人组织蛋白酶L属于溶酶体木瓜样蛋白酶家族半胱氨酸蛋白酶,在胞内首先以无活性的酶原形式存在,需要在胞内体或者溶酶体的酸性环境下自行剪切,或者通过其他蛋白酶活化才能形成具有催化活性的成熟酶。研究表明,人组织蛋白酶L与多种肿瘤的发生有着密切关系,且在心脏疾病中也发挥重要作用,此外,研究还发现人组织蛋白酶还参与病原微生物侵染宿主细胞,因此这些宿主蛋白酶均可作为冠状病毒等侵入宿主细胞的进入抑制剂。抑制人组织蛋白酶L可以有效阻止冠状病毒、EBOV等RNA病毒侵入宿主细胞,因此人组织蛋白酶L抑制剂是抗冠状病毒、EBOV等RNA病毒研发的理想靶标,有望解决靶向病毒的抗病毒药物出现突变耐药的潜在风险和问题。
目前,针对SARS-CoV-2、EBOV等高致病性RNA病毒感染导致的急性传染病尚无特效的抗病毒药物,这些感染性疾病严重影响了人们的生命健康,研发效果好的小分子抗病毒药物迫在眉睫。针对冠状病毒3CLpro和/或人组织蛋白酶L开发出结构新颖、低毒高效且具有自主知识产权的抗病毒药物,以满足国内外SARS-CoV-2、EBOV等高致病性RNA病毒感染患者的临床需求,具有重大的社会意义。
综上所述,本领域迫切需要开发针对冠状病毒3CL蛋白酶的抑制剂和/或人组织蛋白酶L用于治疗SARS-CoV-2、EBOV等高致病性RNA病毒感染导致的急性传染病。
发明内容
本发明的目的是提供一种蛋白酶抑制剂。
在本发明第一方面,提供了一种通式(I)所示的酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体:
其中,
手性碳原子C*、C*2各自独立地为S型或R型;
X选自下组:O、N-R4’;
其中,R4
’选自下组:氢、C1-C6直链或支链烷基;
Ra选自下组:-(CH2)mR4;其中,m为0或1;
Rb为H或C1-C4烷基;
选自下组:取代或未取代的5-12元芳基、取代或未取代的5-12元杂环基、取代或未取代的5-12元杂芳基;
R1选自下组:
其中,R6为氢,或者被1~3个取代基取代的选自下组的基团:C1~C6直链或支链烷基、C1~C6直链或支链烷氧基、C3-C7环烷基、C6~C12芳基或5~12元杂芳基;
Y选自下组:O、S;
Z选自下组:O、NH、N-Boc;
R7选自下组:H、F、Br、Cl、CN;
R8和R9各自独立地选自下组:氢、氘、氚、氨基、羟基、取代或未取代的C1~C10烷基、取代或未取代的C3~C10环烷基、取代或未取代的C3~C10环烷基C1~C4亚烷基、取代或未取代的C3~C10杂环烷基、取代或未取代的C3~C10杂环烷基C1~C4亚烷基、取代或未取代的C6~C12芳基、取代或未取代的C5~C12杂芳基、取代或未取代的C6~C12芳基C1~C4亚烷基、取代或未取代的C5~C12杂芳基C1~C4亚烷基;
R10为氢或者被1~2个取代基取代的选自下组的基团:C2~C6烯基、C2~C6炔基、C2~C10环氧烷基;
R11选自下组:羟基、卤素;
R12、R13各自独立地选自下组:未被取代或者被1~3个取代基取代的6~12元芳基、或者未被取代或者被1~3个取代基取代的5~12元杂芳基;
R14与R15各自独立地选自下组:氢,或未取代或者被1~3个取代基取代的选自下组的基团:C1~C4直链或支链烷烃、C2~C6直链或支链烯烃、C2~C6直链或支链炔烃、C6~C12芳基C1~C4亚烷基;
或者,其中R14与R15与相邻的-O-C-O-结构连接成5~8元杂环,且所述的环上含有2~3个选自氧、硫和氮的杂原子;
R16选自下组:氢、或C1~C6直链或支链烷基羰基氧基;
R17选自金属离子,如Na+;
R2与R3各自独立地选自下组:氢、C1~C6直链或支链烷基、C2~C6直链或支链烯基、C2~C6直链或支链炔基、
或者,R2与R3及其相连的碳原子共同形成未被取代或者被1~3个取代基取代的C3~C7环烷基;其中,所述的取代基各自独立地选自下组:卤素、C1~C4直链或支链烷基、C2~C4直链或支链烯基、C2~C4直链或支链炔基、C1~C4直链或支链烷氧基、C1~C4直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、C1~C4酰基、酰胺基、磺酰基、氨基磺酰基、C1~C4烷基取代的磺酰基,或者两个相邻的取代基连同与其连接的碳原子构成的5~7元环;
其中:n选自0、1或2;
选自未被取代或者被1~3个取代基取代的选自下组的基团:C3~C7环烷基、C5~C7芳基、或C5~C7杂芳基;所述杂芳基含有1~3个选自氧、硫和氮的杂原子;所述的取代基各自独立地选自下组:卤素、C1~C4直链或支链烷基、C2~C4直链或支链烯基、C2~C4直链或支链炔基、C1~C4直链或支链烷氧基、C1~C4直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、C1~C4酰基、酰胺基、磺酰基、氨基磺酰基、C1~C4烷基取代的磺酰基,或者两个相邻的取代基连同与其连接的碳原子构成的5~7元环;
手性碳原子C*3、C*4各自独立地为S型或R型;
R4选自下组:氢、或者未被取代或被1~3个取代基取代的选自下组的基团:C1~C6直链或支链烷基、C3~C7环烷基、三氟甲基、C2~C6炔基、4~7元杂环基、C5~C7芳基、5-7元杂芳基;所述杂环基和杂芳基各自含有1~3个选自氧、硫和氮的杂原子;所述的取代基各自独立地选自下组:卤素、C1~C4直链或支链烷基、C2~C4直链或支链烯基、C2~C4直链或支链炔基、C1~C4直链或支链烷氧基、C1~C4直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、C1~C4酰基、酰胺基、磺酰基、氨基磺酰基、C1~C4烷基取代的磺酰基,或者两个相邻的取代基连同与其连接的碳原子构成的5~7元环;
或者,R4与R4
’‘及其相连的碳原子和氮原子共同组成未被取代或者被1~3个取代基取代的5-10元环状结构
除特别说明之处,所述“取代”指基团上的一个或多个氢原子被选自下组的取代基取代:氰基、氧代(=O)、C1~C10烷基、C1~C10卤代烷基、C3~C10环烷基、C1~C10烷氧基、卤素、羟基、羧基(-COOH)、C1~C10醛基、C2~C10酰基、C2~C10酯基、氨基、苯基、苄基;所述的苯基或苄基包括未取代的苯基或具有1-3个取代基的取代苯基或苄基,所述取代基选自:卤素、C1-C10烷基、氰基、OH、硝基、C3~C10环烷基、C1~C10烷氧基、氨基。
在另一例优选例中,R1选自下组:
其中,R8和R9各自独立地选自下组:氢、氘、取代或未取代的C1~C4直链或支链烷基、取代或未取代的C3~C6环烷基、取代或未取代的C3~C6环烷基C1~C2亚烷基、取代或未取代的C6~C12芳基、取代或未取代的C6~C12芳基C1~C2亚烷基;
R11选自下组:羟基、卤素原子;
R12为未被取代或者被1~3个取代基取代的选自下组的基团:苯基、嘧啶基、吡啶基。
在另一例优选例中,选自或者取代或未取代的选自下组的基团:苯基、嘧啶基、吡啶基、吲哚基、苯并咪唑基、苯并呋喃基、喹啉基或喹
唑啉酮基;
R18和R19各自独立地选自下组:卤素、氨基、羟基、羧基、取代或未取代的C1~C6烷基、取代或未取代的C3~C6环烷基、取代或未取代的C1~C6烷氧基、取代或未取代的C1~C6醛基、取代或未取代的C2~C6酰基、取代或未取代的C2~C6酯基、取代或未取代的苯基、取代或未取代的苯基C1~C4亚烷基。
在另一例优选例中,R2与R3分别独立地选自下组:氢、或者取代或未取代的选自下组的基团:C1~C6直链或支链烷基、苄基、苯乙基、C3~C6环烷基、C3~C6环烷基亚甲基;或者,R2与R3连接,组成取代或未取代的C3~C5环烷基;
其中,手性碳原子C*3、C*4为S型。
在另一例优选例中,R4选自下组:未被取代或被1~3个取代基取代的选自下组的基团:C1~C6直链或支链烷基、C3~C7环烷基、三氟甲基、C2~C6炔基、4~7元杂环基、C5~C7芳基、5-7元杂芳基;
R4'选自下组:氢、C1-C6直链或支链烷基;
或者,R4与R4'及其相连的碳原子和氮原子共同组成未被取代或者被1~3个取代基取代的5-6元环状、或6~10元双环状结构,所述环状或双环状结构包括以下结构:
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代:氧代(=O)、C1~C4烷基、C1~C4卤代烷基、C3~C6环烷基、C1~C6烷氧基、卤素、羟基、羧基(-COOH)、C2~C6醛基氨基、苯基、苄基;所述的苯基或苄基包括未取代的苯基或具有1-3个取代基的取代苯基或苄基,所述取代基选自:卤素、C1-C6烷基、氰基、OH、硝基、C3~C6环烷基、C1~C6烷氧基、氨基。
在另一优选例中,R4为氢,或者未被取代或者被1~3个取代基取代的选自下组的基团:C1~C4直链或支链烷基、C3~C7环烷基、三氟甲基、C5~C7芳基;所述的取代基各自独立地选自下组:卤素、C1~C4直链或支链烷基、C1~C4直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、C1~C4酰基、酰胺基、磺酰基、氨基磺酰基、C1~C4烷基取代的磺酰基,或者两个相邻的取代基连同与其连接的碳原子构成的5~7元环;
R4'选自下组:氢、C1-C4直链或支链烷基;
或者,R4与R4'连接,同R4相连的α碳原子,R4相连的β碳原子,以及R4'相连的α氮原子组成未被取代或者被1~3个取代基取代的以下环状结构:
在另一例优选例中,n=1;
R4选自未被取代基或者被1~3个取代基取代的以下基团:异丙基、环己基、环戊基、苯基;所述的取代基各自独立地选自下组:卤素、C1~C4直链或支链烷基、氰基、硝基、羟基、三氟甲基。
在另一优选例中,所述酰胺类化合物选自下组:
在本发明的第二方面,提供了一种如本发明第一方面所述通式(Ⅰ)所示的化合物的制备方法,包括步骤:
(1)
其中,Ha为卤素;
在惰性溶剂中,在碱存在下,式卤素取代化合物Ia与式Ib化合物进行取代反应得到式Ic化合物,所述碱优选自三乙胺、二异丙基乙胺、碳酸铯、碳酸钾、1,8-二氮杂二
环[5.4.0]十一碳-7-烯;
(2)
式Ic化合物溶于有机溶剂中,在碱溶液存在下,式Ic化合物水解生成Id化合物所述有机溶剂优选自甲醇、乙醇、四氢呋喃、二氧六环、或其组合,所述碱溶液优选自氢氧化钠水溶液、氢氧化锂水溶液、氢氧化钾水溶液;
(3)
式Id化合物溶于有机溶剂中,在缩合剂和碱存在下,与式Ie化合物进行缩合反应生成If化合物,所述有机溶剂优选自二氯甲烷、乙酸乙酯、二氯乙烷、N,N二甲基甲酰胺、四氢呋喃、二甲基亚砜、二氧六环、或其组合,所述碱优选自三乙胺、二异丙基乙基胺,所述缩合剂优选自2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐;
(4)
a.
式If化合物溶于有机溶剂中,用还原剂进行还原反应得到式Ig化合物,所述有机溶剂有选自二氯甲烷与甲醇混合溶剂、四氢呋喃与甲醇混合溶剂,所述还原剂优选为硼氢化钠;
在有机溶剂中,式Ig化合物进行氧化反应得到式Ih化合物,即式(I)醛基类化合物,所述溶剂优选自二氯甲烷、二甲基亚砜、四氢呋喃、乙酸乙酯,所述氧化剂优选自三氧化硫吡啶、戴斯马丁氧化剂或草酰氯和二甲基亚砜的组合物;
b.
在有机溶剂中,式Ih化合物于酸性条件下与异腈类化合物反应得到式Ii化合物,所述溶剂优选自二氯甲烷、二甲基亚砜、四氢呋喃、乙酸乙酯,所述酸优选自醋酸、三氟乙酸、盐酸;
式Ii化合物溶于有机溶剂中,在碱溶液存在下,式Ii化合物水解生成Ij化合物,所述有机溶剂优选自甲醇、乙醇、四氢呋喃、二氧六环、或其组合,所述碱溶液优选自氢氧化钠水溶液、氢氧化锂水溶液、氢氧化钾水溶液;
在有机溶剂中,式Ij化合物进行氧化反应得到式Ik化合物,即式(I)酮酰胺类化合物,所述溶剂优选自二氯甲烷、二甲基亚砜、四氢呋喃、乙酸乙酯,所述氧化剂优选自三氧化硫吡啶、戴斯马丁氧化剂或草酰氯和二甲基亚砜;
c.
在有机溶剂中,式If化合物与氨通过胺酯交换反应得到式Il化合物,所述溶剂优选自甲醇、乙醇、四氢呋喃、乙酸乙酯;
在有机溶剂中,式Il化合物在脱水剂存在下,通过脱水反应得到式Im化合物,即式(I)氰基类化合物,所述溶剂优选自二氯甲烷、二甲基亚砜、四氢呋喃、乙酸乙酯,所述脱水剂优选自三氯氧磷、三氟乙酸酐、伯吉斯试剂等。
本发明的第三方面,提供了一种药物组合物,所述的药物组合物包括:治疗有效量的一种或多种本发明第一方面所述通式(I)所示化合物,或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体。
本发明的第四方面,提供了一种如本发明第一方面所述通式(I)所示化合物,或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,或者如本发明第三方面所述的药物组合物的用途,用于制备治疗或预防由SARS-CoV-2和/或SARS-CoV和/或MERS-CoV等冠状病毒,和/或EV71和/或EV68和/或诺如病毒和/或EBOV等RNA病毒感染引起的相关疾病的药物组合物;
其中,所述冠状病毒包括:SARS-CoV-2、SARS-CoV、MERS-CoV;
所述RNA病毒包括:EV71、EV68、诺如病毒、EBOV。
在另一优选例中,所述由SARS-CoV-2和/或SARS-CoV和/或MERS-CoV等冠状病毒感染引起的相关疾病选自下组:呼吸道感染、肺炎及其并发症、或其组合。
在另一优选例中,所述由EV71和/或EV68和/或诺如病毒等RNA病毒感染引起的相关疾病选自下组:手足口病、中枢神经系统感染、腹泻及其并发症、或其组合。
在另一优选例中,所述由EBOV等RNA病毒感染引起的相关疾病选自下组:出血热、中枢神经系统感染及其并发症、或其组合。
在本发明的第五方面,提供了一种如本发明第一方面所述的酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,或如本发明第三方面所述的药物组合物的用途,其特征在于,用于治疗、预防、和/或缓解由冠状病毒和/或RNA病毒感染引起的相关疾病,包括步骤:给需要的对象施用安全有效量的如本发明第一方面所述的通式(I)所示的酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,或者如本发明第三方面所述的药物组合物;
其中,所述冠状病毒包括:SARS-CoV-2、SARS-CoV、MERS-CoV;
所述RNA病毒包括:EV71、EV68、诺如病毒、EBOV。
在另一优选例中,所述的对象为灵长目哺乳动物,如人。
在本发明的第六方面,提供了一种治疗、预防、和/或缓解由SARS-CoV-2和/或SARS-CoV和/或MERS-CoV等冠状病毒,和/或EV71和/或EV68和/或诺如病毒和/或EBOV等RNA病毒感染引起的相关疾病的方法,包括步骤:给需要的对象施用安全有效量的通式(I)所示的酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体或者如本发明第三方面所述的药物组合物,其中所述的通式(I)所示的酰胺类化合物如上所述。
在另一优选例中,所述的对象为灵长目哺乳动物,如人。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
图1显示了活性测试例4中本发明酮酰胺类化合物对SARS-CoV-2复制的抑制效果的柱状图。
本发明人经过广泛而深入的研究,通过大量筛选,首次意外地开发了一类可有效抑制SARS-CoV-2和/或SARS-CoV和/或MERS-CoV等冠状病毒,和/或EV71和/或EV68和/或诺如病毒和/或EBOV等RNA病毒的活性成分,即通式I所示的化合物或或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体。试验表明,本发明的活性成分可高效地抑制人组织蛋白酶L的活性,从而抑制相关病毒的复制和活力。在此基础上完成了本发明。
术语
在本文中,除特别说明之处,术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代:C1~C10烷基、C3~C10环烷基、C1~C10烷氧基、卤素、羟基、羧基(-COOH)、C1~C10醛基、C2~C10酰基、C2~C10酯基、氨基、苯基;所述的苯基包括未取代的苯基或具有1-3个取代基的取代苯基,所述取代基选自:卤素、C1-C10烷基、氰基、OH、硝基、C3~C10环烷基、C1~C10烷氧基、氨基。
除特别说明之处,本发明的所有化合物之中,各手性碳原子可以任选地为R构型或S构型,或R构型和S构型的混合物。
术语“C1~C6烷基”指具有1~6个碳原子的直链或支链烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
术语“3-8元杂环基”指具有选自下组的1-3个杂原子的3~8元饱和环失去一个氢原子形成的基团:N、S、O;例如吡咯烷基、哌啶基、哌嗪基、吗啉基、或类似基团。
术语“6-10元芳基”指6~10元芳基失去一个氢原子形成的基团;例如苯基、萘基,或类似基团。
术语“5-10元杂芳基”指具有选自下组的1-3个杂原子的5~8元芳基失去一个氢原子形成的基团:N、S、O,其中每个杂芳基的环状体系可以是单环或多环的;例如吡咯基、吡啶基、噻吩基、呋喃基、咪唑基、嘧啶基、苯并噻吩基、吲哚基、咪唑并吡啶基、喹啉基或类似基团。
术语“C1~C6烷氧基”指具有1-6个碳原子的直链或支链烷氧基,例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、或类似基团。
术语“C2-C6酯基”指具有2-6个碳原子的R-O-C(=O)-基团,如-COOCH3、-COOC2H5、-COOC3H7、-COOC4H9,或类似基团。
术语“C2-C6烯基”指具有2-6个碳原子的烯烃失去一个或两个氢原子所形成的基团,所述的烯烃可以是单烯烃、二烯烃或三烯烃,例如-CH=CH2、-C2H4=CH2、-CH=C2H4,或类似基团。
术语“卤素”指F、Cl、Br和I。
除非特别说明,本发明所描述的结构式意在包括所有的同分异构形式(如对映异构,非对映异构和几何异构体(或构象异构体):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体和(Z)、(E)的构象异构体。因此本发明的化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒,从而互相
转化。比如,质子互变异构体(即质子移变)包括通过质子迁移进行互变,如1H-吲唑与2H-吲唑、1H-苯并[d]咪唑与3H-苯并[d]咪唑,化合价互变异构体包括通过一些成键电子重组而进行互变。
在本文中,形如“C1~C6”,表示该基团可以具有1个至6个碳原子,例如1个、2个、3个、4个或5个。
活性成分
在本发明中,提供了一种可有效抑制SARS-CoV-2和/或SARS-CoV和/或MERS-CoV等冠状病毒,和/或EV71和/或EV68和/或诺如病毒和/或EBOV等RNA病毒感染复制的活性成分。该活性成分为通式I所示的化合物,该活性成分可有效预防、治疗和/或缓解相关疾病。
应理解,本发明的活性成分包括通式(I)所示的酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体、或其前药。应理解,本发明的活性成分还包括通式(I)化合物的晶型、无定形化合物、以及氘代化合物等形式。
所述“药学上可接受的盐”为通式(I)化合物与无机酸或有机酸反应形成常规的无毒盐。例如,常规的无毒盐可通过通式(I)化合物与无机酸或有机酸反应制得,所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等,所述有机酸包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等;或者通式(I)化合物与丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、天冬氨酸或谷氨酸形成酯后再与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐;或者通式(I)化合物与有机碱形成的甲胺盐、乙胺盐或乙醇胺盐;或者通式(I)化合物与赖氨酸、精氨酸、鸟氨酸形成酯后再与盐酸、氢溴酸、氢氟酸、硫酸、硝酸或磷酸形成的对应的无机酸盐或与甲酸、乙酸、苦味酸、甲磺酸或乙磺酸形成的对应的有机酸盐。
药物组合物和应用
本发明还提供了以通式(I)所示的酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体及前药中的一种或多种的混合物为有效成分在制备治疗或预防由SARS-CoV-2和/或SARS-CoV和/或MERS-CoV等冠状病毒,和/或EV71和/或EV68和/或诺如病毒和/或EBOV等RNA病毒感染引起的相关疾病的药物中的用途。
本发明所提供的药物组合物优选含有重量比为0.001-99wt%的活性成份,优选的比例是通式I化合物作为活性成分占总重量的0.1wt%~90wt%,其余部分为药学可接受的载体、稀释液或溶液或盐溶液。
需要的时候,在本发明药物中还可以加入一种或多种药学上可接受的载体。所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂等。
本发明所提供的化合物和药物组合物可以是多种形式,如片剂、胶囊、粉剂、糖浆、
溶液状、悬浮液和气雾剂等,并可以存在于适宜的固体或液体的载体或稀释液中和适宜的用于注射或滴注的消毒器具中。
本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。其制剂配方的单位计量中通常包含0.05-500mg通式I化合物,优选地,制剂配方的单位计量中包含1mg-500mg通式I化合物。
本发明的化合物和药物组合物可对哺乳动物临床使用,包括人和动物,可以通过口、鼻、皮肤、肺、胃肠道或者静脉等的给药途径。最优选为静脉。最优选日剂量为0.01-400mg/kg体重,一次性服用,或0.01-200mg/kg体重分次服用。不管用何种服用方法,个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始,逐渐增加剂量一直到找到最适合的剂量。
本发明的药物或抑制剂可通过各种不同方式施用,例如可通过注射、喷射、滴鼻、滴眼、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮内、皮下、静脉、粘膜组织;或是被其他物质混合或包裹导入机体。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
样品的分析数据由以下仪器测定:核磁共振由GEMINI-300型、Bruker AMX-400型和INVOA-600型核磁共振仪测定,TMS(四甲基硅烷)为内标,化学位移单位为ppm,耦合常数单位为Hz;质谱由Finnigan MAT-711型,MAT-95和LCQ-DECA型质谱仪以及IonSpec 4.7Tesla质谱仪测定。
柱层析用硅胶200-300目(青岛海洋化工厂生产);TLC硅胶板为烟台化工厂生产的HSGF-254型薄层层析预制板;石油醚沸程为60-90℃;采用紫外灯,碘缸显色。除另有说明外,以下实施例中所用常规试剂、药品均购自国药集团。实验中所用试剂及溶剂均按反应具体情况处理。
实施例1:化合物1的合成
合成路线:
化合物1-3的合成:
化合物1-1(10.0g,57.28mmol)溶于1,4-二氧六环(500ml)中,加入1-2(12.7g,57.28mmol),随后加入N,N-二异丙基乙胺(14.81g,114.56mmol),110℃油浴下搅拌48h,TLC监测反应后,柱层析分离1-3共1.57g,收率8%。
化合物1-4的合成:
将化合物1-3(1.57g,4.85mmol)溶于甲醇和水混合液(10:1,44mL)中,加入一水合氢氧化锂(0.81g,19.42mmol),室温搅拌,TLC监测反应完全后,加1M HCl调节pH至中性后,二氯甲烷萃取,分液,有机相无水硫酸钠干燥后浓缩得1-4 1.3g,收率89%。
化合物1-6的合成:
将化合物1-4(1.3g,4.2mmol)溶于二氯甲烷(50mL),将反应液冷却至-20℃,然后将HATU(2.40g,6.3mmol)加入反应液,搅拌二十分钟后将1-5(0.74g,5.04mmol)加入反应液,再次在-20℃搅拌30分钟,随后将DIPEA(1.63g,12.61mmol)滴加入反应液。保持-20℃,搅拌12h后,分别用氯化铵(60mL×3)、碳酸氢钠(60mL)以及氯化钠(60mL)萃取,合并有机相,无水硫酸钠干燥后减压蒸馏,柱层析分离得化合物1-6 1.31g,产率76%。
化合物1-7的合成:
将化合物1-6(1.31g,3.21mmol)溶于四氢呋喃(30ml)中,分批缓慢加入硼氢化钠(728mg,19.24mmol),随后逐滴加入甲醇6ml,室温下搅拌约2小时反应完全。待反应完毕后,加入约40ml饱和氯化铵淬灭反应,加入乙酸乙酯萃取。有机相经饱和食盐水洗涤、无水硫酸钠干燥后,柱层析分离得到1-7 0.83g,产率68%。
化合物1的合成:
冰盐浴下将化合物1-7(0.83g,2.18mmol)溶于20ml无水二氯甲烷与无水DMSO(1:1)中,氮气保护下加入DIPEA(1.69g,13.09mmol),随后滴加三氧化硫吡啶的DMSO溶液(2.07g/8mL),加完后搅拌1h,TLC监测反应完全后,加入水淬灭反应,萃取分液,有机相经1M盐酸,饱和食盐水,饱和碳酸氢钠,饱和食盐水洗涤、无水硫酸钠干燥后,柱层析分离,得到化合物1共0.45g,产率55%。ESI-MS m/z 379.23[M+H]+。
实施例2:化合物2的合成
合成路线:
化合物2-7的合成:
将化合物1-6(0.5g,1.22mmol)溶于氨水与甲醇(1:1)中,室温搅拌反应24h。TLC监测反应完全后,乙酸乙酯萃取分液,有机相经饱和食盐水洗涤、无水硫酸钠干燥后,柱层析分离,得到化合物2-1共0.36g,产率74%。
化合物2的合成:
将化合物2-1(0.36g,0.91mmol)溶于无水四氢呋喃(20ml),加入伯吉斯试剂(1.10g,4.57mmol)室温搅拌反应1h。TLC监测反应完全后,加入乙酸乙酯萃取分液,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥后,柱层析分离,得到化合物2共0.14g,产率40%。ESI-MS m/z 376.23[M+H]+。
实施例3:化合物3的合成
合成路线:
化合物3-1的合成
参考化合物1的合成,将化合物1(0.2g,0.53mmol)溶于二氯甲烷(10ml),随后加入乙酸(180μL),化合物3-1(180μL)室温搅拌反应24h。TLC监测反应完成后,经柱层析分离,合成化合物3-2共0.21g,产率70%。
化合物3-3的合成
将化合物3-2(0.21g,0.38mmol)溶于甲醇和水混合液(10:1,22ml),随后加入一水合氢氧化锂(0.095g,2.27mmol)室温搅拌,TLC监测反应完全后,二氯甲烷萃取,分液,有机相无水硫酸钠干燥后浓缩得3-3共0.18g,收率90%。
化合物3的合成
将化合物3-3(0.18g,0.35mmol)溶于二氯甲烷(20ml)中,加入戴斯马丁氧化剂(0.22g,0.53mmol),室温搅拌反应,TLC监测反应完全后,加入二氯甲烷萃取分液,有机相经硫代硫酸钠、饱和碳酸氢钠、、饱和氯化钠溶液洗涤,无水硫酸钠干燥后,柱层析分离得到化合物3共0.11g,产率60%。ESI-MS m/z 512.28[M+H]+。
实施例4:化合物4的合成
合成路线:
化合物4的合成:
将化合物1(0.2g,0.53mmol)溶于10mL无水二氯甲烷中,加入三苯基膦(0.15g,0.58mmol),化合物4-1(0.65mg,0.58mmol),室温下搅拌24h。TLC检测反应完全后,反应液浓缩,柱层析分离得到化合物4 0.2g,产率80%。ESI-MS m/z474.26[M+H]+。
实施例5:化合物5的合成
合成路线:
化合物5的合成:
将化合物1(0.2g,0.53mmol)溶于6mL无水二氯甲烷,室温搅拌状态下滴加化合物5-1(0.66g,0.58mmol),哌啶(0.05g,0.53mmol),室温反应4小时,减压浓缩。柱层析分离得化合物5共0.15g,产率60%。ESI-MS m/z 474.26[M+H]+。
实施例6:化合物6的合成
用化合物6-1替换实施例5中的5-1,合成方法参考化合物5的合成,得到化合物6。ESI-MS m/z 449.27[M+H]+。
实施例7:化合物7的合成
合成路线:
化合物7的合成:
将化合物1-6(0.2g,0.49mmol)溶于无水四氢呋喃(20ml)中,加入氯碘甲烷(0.35g,1.96mmol),冷却至-78℃,随后通过恒压漏斗缓慢滴加LDA(0.31g,2.94mmol),搅拌1h。随后加入乙酸(3ml)、四氢呋喃(20ml)搅拌10min,转移至室温,加入乙酸乙酯萃取分液,有机相经水、碳酸氢钠、饱和氯化钠洗涤,无水硫酸钠干燥后,柱层析分离得到化合物7共0.11g,产率54%。ESI-MS m/z 427.20[M+H]+。
实施例8:化合物8的合成
合成路线:
化合物8-2的合成:
将化合物8-1(1.0g,3.33mmol)溶于二氯甲烷(40ml),在0℃条件下加入4M HCl二氧六环溶液(9ml,35mmol),反应在室温下搅拌12h,将溶液蒸干得到中间体8-2,直接进行下一步反应无需纯化。
化合物8-3的合成:
将化合物1-4(1.1g,3.56mmol)溶于二氯甲烷(50mL),将反应液冷却至-20℃,然后将HATU(2.03g,5.33mmol)加入反应液,搅拌二十分钟后将8-2加入反应液,再次在-20
℃搅拌30分钟,随后将DIPEA(1.38g,10.67mmol)滴加入反应液。保持-20℃,搅拌12h后,分别用氯化铵(60mL×3)、碳酸氢钠(60mL)以及氯化钠(60mL)萃取,合并有机相,无水硫酸钠干燥后减压蒸馏,柱层析分离得化合物1-6 1.40g,产率80%。
化合物8-4的合成
将化合物8-3(1.4g,2.85mmol)溶于无水四氢呋喃(60ml)中,加入氯碘甲烷(2.01g,11.39mmol),冷却至-78℃,随后通过恒压漏斗缓慢滴加LDA(1.83g,17.09mmol),搅拌1h。随后加入乙酸(9ml)、四氢呋喃(60ml)搅拌10min,转移至室温,加入乙酸乙酯萃取分液,有机相经水、碳酸氢钠、饱和氯化钠洗涤,无水硫酸钠干燥后,柱层析分离得到化合物8-4共0.87g,产率60%。
化合物8的合成:
将化合物8-4(0.87g,1.71mmol)于DMF(5ml)溶解,加入苯甲酸(0.27g,2.22mmol),氮气保护,随后加入氟化铯(0.466mg,3.07mmol)65℃搅拌反应3h。TLC监测反应完全后,冷却至室温,反应液用水稀释,并用二氯甲烷萃取分液,有机相用水、饱和氯化钠洗涤、无水硫酸钠干燥后,经柱层析分离得到化合物8共0.51g,产率50%。ESI-MS m/z 664.22[M+H]+。
实施例9:化合物9的合成
合成方法参考化合物3的合成,得到化合物9,ESI-MS m/z 462.26[M+H]+。
实施例10:化合物10的合成
合成方法参考化合物1的合成,得到化合物10,ESI-MS m/z 448.25[M+H]+。
实施例11:化合物11的合成
合成方法参考化合物2的合成,得到化合物11,ESI-MS m/z 445.25[M+H]+。
实施例12:化合物12的合成
合成方法参考化合物3的合成,得到化合物12,ESI-MS m/z 531.29[M+H]+。
实施例13:化合物13的合成
合成方法参考化合物1的合成,得到化合物13,ESI-MS m/z 581.30[M+H]+。
实施例14:化合物14的合成
合成方法参考化合物1的合成,得到化合物14,ESI-MS m/z 462.26[M+H]+。
实施例15:化合物15的合成
合成方法参考化合物2的合成,得到化合物15,ESI-MS m/z 459.26[M+H]+。
实施例16:化合物16的合成
合成方法参考化合物3的合成,得到化合物16,ESI-MS m/z 545.30[M+H]+。
实施例17:化合物17的合成
合成方法参考化合物3的合成,得到化合物17,ESI-MS m/z 595.32[M+H]+。
实施例18:化合物18的合成
合成方法参考化合物1的合成,得到化合物18,ESI-MS m/z 432.22[M+H]+。
实施例19:化合物19的合成
合成方法参考化合物2的合成,得到化合物19,ESI-MS m/z 429.22[M+H]+。
实施例20:化合物20的合成
合成方法参考化合物3的合成,得到化合物20,ESI-MS m/z 515.25[M+H]+。
实施例21:化合物21的合成
合成方法参考化合物3的合成,得到化合物21,ESI-MS m/z 565.27[M+H]+。
实施例22:化合物22的合成
合成方法参考化合物3的合成,得到化合物22,ESI-MS m/z 579.29[M+H]+。
实施例23:化合物23的合成
合成方法参考化合物3的合成,得到化合物23,ESI-MS m/z 529.27[M+H]+。
实施例24:化合物24的合成
合成方法参考化合物3的合成,得到化合物24,ESI-MS m/z 446.23[M+H]+。
实施例25:化合物25的合成
合成方法参考化合物2的合成,得到化合物25,ESI-MS m/z 560.29[M+H]+。
实施例26:化合物26的合成
合成方法参考化合物1的合成,得到化合物26,ESI-MS m/z 563.29[M+H]+。
实施例27:化合物27的合成
合成方法参考化合物3的合成,得到化合物27,ESI-MS m/z 646.33[M+H]+。
实施例28:化合物28的合成
合成方法参考化合物1的合成,得到化合物28,ESI-MS m/z 549.27[M+H]+。
实施例29:化合物29的合成
合成方法参考化合物2的合成,得到化合物29,ESI-MS m/z 546.28[M+H]+。
实施例30:化合物30的合成
合成方法参考化合物3的合成,得到化合物30,ESI-MS m/z 632.32[M+H]+。
实施例31:化合物31的合成
合成方法参考化合物3的合成,得到化合物31,ESI-MS m/z 682.33[M+H]+。
实施例32:化合物32的合成
合成方法参考化合物2的合成,得到化合物32,ESI-MS m/z 382.20[M+H]+。
实施例33:化合物33的合成
合成方法参考化合物3的合成,得到化合物33,ESI-MS m/z 468.24[M+H]+。
实施例34:化合物34的合成
合成方法参考化合物1的合成,得到化合物34,ESI-MS m/z 387.19[M+H]+。
实施例35:化合物35的合成
合成方法参考化合物3的合成,得到化合物35,ESI-MS m/z 470.23[M+H]+。
实施例36:化合物36的合成
合成方法参考化合物2的合成,得到化合物36,ESI-MS m/z 384.19[M+H]+。
实施例37:化合物37的合成
合成方法参考化合物3的合成,得到化合物37,ESI-MS m/z 520.25[M+H]+。
实施例38:化合物38的合成
合成方法参考化合物3的合成,得到化合物38,ESI-MS m/z 518.23[M+H]+。
实施例39:化合物39的合成
合成方法参考化合物3的合成,得到化合物39,ESI-MS m/z 596.28[M+H]+。
实施例40:化合物40的合成
合成方法参考化合物3的合成,得到化合物40,ESI-MS m/z 614.27[M+H]+。
实施例41:化合物41的合成
合成方法参考化合物3的合成,得到化合物41,ESI-MS m/z 548.28[M+H]+。
实施例42:化合物42的合成
合成方法参考化合物3的合成,得到化合物43,ESI-MS m/z 589.27[M+H]+。
实施例43:化合物43的合成
合成方法参考化合物3的合成,得到化合物43,ESI-MS m/z 539.25[M+H]+。
实施例44:化合物44的合成
合成方法参考化合物2的合成,得到化合物44,ESI-MS m/z 453.21[M+H]+。
实施例45:化合物45的合成
合成方法参考化合物2的合成,得到化合物45,ESI-MS m/z 467.23[M+H]+。
实施例46:化合物46的合成
合成方法参考化合物1的合成,得到化合物46,ESI-MS m/z 470.23[M+H]+。
实施例47:化合物47的合成
合成方法参考化合物3的合成,得到化合物47,ESI-MS m/z 523.22[M+H]+。
实施例48:化合物48的合成
合成方法参考化合物3的合成,得到化合物48,ESI-MS m/z 535.30[M+H]+。
实施例49:化合物49的合成
合成方法参考化合物3的合成,得到化合物49,ESI-MS m/z 521.28[M+H]+。
实施例50:化合物50的合成
合成方法参考化合物3的合成,得到化合物50,ESI-MS m/z 539.27[M+H]+。
实施例51:化合物51的合成
合成方法参考化合物3的合成,得到化合物51,ESI-MS m/z 551.29[M+H]+。
实施例52:化合物52的合成
合成方法参考化合物3的合成,得到化合物52,ESI-MS m/z 557.27[M+H]+。
实施例53:化合物53的合成
合成方法参考化合物3的合成,得到化合物53,ESI-MS m/z 546.28[M+H]+。
实施例54:化合物54的合成
合成方法参考化合物3的合成,得到化合物54,ESI-MS m/z 601.21[M+H]+。
实施例55:化合物55的合成
合成方法参考化合物3的合成,得到化合物55,ESI-MS m/z 619.20[M+H]+。
实施例56:化合物56的合成
合成方法参考化合物3的合成,得到化合物56,ESI-MS m/z 549.24[M+H]+。
实施例57:化合物57的合成
合成方法参考化合物3的合成,得到化合物57,ESI-MS m/z 535.22[M+H]+。
实施例58:化合物58的合成
合成方法参考化合物1的合成,得到化合物58,ESI-MS m/z 432.22[M+H]+。
实施例59:化合物59的合成
合成方法参考化合物2的合成,得到化合物59,ESI-MS m/z 429.22[M+H]+。
实施例60:化合物60的合成
合成方法参考化合物3的合成,得到化合物60,ESI-MS m/z 565.27[M+H]+。
实施例61:化合物61的合成
合成方法参考化合物3的合成,得到化合物61,ESI-MS m/z 529.27[M+H]+。
实施例62:化合物62的合成
合成方法参考化合物7的合成,得到化合物62,ESI-MS m/z 494.21[M+H]+。
实施例63:化合物63的合成
合成方法参考化合物1的合成,得到化合物63,ESI-MS m/z 428.17[M+H]+。
实施例64:化合物64的合成
合成方法参考化合物3的合成,得到化合物64,ESI-MS m/z 442.18[M+H]+。
实施例65:化合物65的合成
合成方法参考化合物3的合成,得到化合物65,ESI-MS m/z 561.22[M+H]+。
实施例66:化合物66的合成
合成方法参考化合物8的合成,得到化合物66,ESI-MS m/z 601.21[M+H]+。
实施例67:化合物67的合成
合成方法参考化合物2的合成,得到化合物67,ESI-MS m/z 432.18[M+H]+。
实施例68:化合物68的合成
合成方法参考化合物2的合成,得到化合物68,ESI-MS m/z 436.19[M+H]+。
实施例69:化合物69的合成
合成方法参考化合物3的合成,得到化合物69,ESI-MS m/z 544.21[M+H]+。
实施例70:化合物70的合成
合成方法参考化合物3的合成,得到化合物71,ESI-MS m/z 437.17[M+H]+。
实施例71:化合物71的合成
合成方法参考化合物4的合成,得到化合物71,ESI-MS m/z 449.17[M+H]+。
实施例72:化合物72的合成
合成方法参考化合物3的合成,得到化合物73,ESI-MS m/z 601.27[M+H]+。
实施例73:化合物73的合成
合成方法参考化合物3的合成,得到化合物73,ESI-MS m/z 565.27[M+H]+。
实施例74:化合物74的合成
合成方法参考化合物1的合成,得到化合物74,ESI-MS m/z 482.23[M+H]+。
实施例75:化合物75的合成
合成方法参考化合物7的合成,得到化合物75,ESI-MS m/z 447.17[M+H]+。
实施例76:化合物76的合成
合成方法参考化合物8的合成,得到化合物76,ESI-MS m/z 615.17[M+H]+。
实施例77:化合物77的合成
合成方法参考化合物3的合成,得到化合物77,ESI-MS m/z 570.30[M+H]+。
实施例78:化合物78的合成
合成方法参考化合物1的合成,得到化合物78,ESI-MS m/z 437.25[M+H]+。
实施例79:化合物79的合成
合成方法参考化合物7的合成,得到化合物79,ESI-MS m/z 499.24[M+H]+。
实施例80:化合物80的合成
合成方法参考化合物3的合成,得到化合物80,ESI-MS m/z 588.23[M+H]+。
实施例81:化合物81的合成
合成方法参考化合物3的合成,得到化合物81,ESI-MS m/z 586.28[M+H]+。
实施例82:化合物82的合成
合成方法参考化合物3的合成,得到化合物82,ESI-MS m/z 587.28[M+H]+。
实施例83:化合物83的合成
合成方法参考化合物3的合成,得到化合物83,ESI-MS m/z 518.26[M+H]+。
实施例84:化合物84的合成
合成方法参考化合物3的合成,得到化合物84,ESI-MS m/z 551.28[M+H]+。
实施例85:化合物85的合成
合成方法参考化合物1的合成,得到化合物85,ESI-MS m/z 383.19[M+H]+。
实施例86:化合物86的合成
合成方法参考化合物3的合成,得到化合物86,ESI-MS m/z 601.29[M+H]+。
实施例87:化合物87的合成
合成方法参考化合物3的合成,得到化合物87,ESI-MS m/z 558.30[M+H]+。
实施例88:化合物88的合成
合成方法参考化合物1的合成,得到化合物88,ESI-MS m/z 439.26[M+H]+。
实施例89:化合物89的合成
合成方法参考化合物2的合成,得到化合物89,ESI-MS m/z 470.22[M+H]+。
实施例90:化合物90的合成
合成方法参考化合物3的合成,得到化合物90,ESI-MS m/z 504.28[M+H]+。
实施例91:化合物91的合成
合成方法参考化合物3的合成,得到化合物91,ESI-MS m/z 437.25[M+H]+。
实施例92:化合物92的合成
合成方法参考化合物3的合成,得到化合物92,ESI-MS m/z 574.28[M+H]+。
实施例93:化合物93的合成
合成方法参考化合物3的合成,得到化合物93,ESI-MS m/z 602.29[M+H]+。
实施例94:化合物94的合成
合成方法参考化合物3的合成,得到化合物94,ESI-MS m/z 552.29[M+H]+。
实施例95:化合物95的合成
合成方法参考化合物3的合成,得到化合物95,ESI-MS m/z 549.26[M+H]+。
实施例96:化合物96的合成
合成方法参考化合物3的合成,得到化合物96,ESI-MS m/z 469.25[M+H]+。
实施例97:化合物97的合成
合成方法参考化合物3的合成,得到化合物97,ESI-MS m/z 419.24[M+H]+。
实施例98:化合物98的合成
合成方法参考化合物3的合成,得到化合物98,ESI-MS m/z 487.24[M+H]+。
实施例99:化合物99的合成
合成方法参考化合物3的合成,得到化合物99,ESI-MS m/z 505.23[M+H]+。
实施例100:化合物100的合成
合成方法参考化合物42的合成,得到化合物100,ESI-MS m/z 588.27[M+H]+。
实施例101:化合物101的合成
合成方法参考化合物39,得到化合物101,ESI-MS m/z 535.28[M+H]+。
实施例102:化合物102的合成
合成方法参考化合物39,得到化合物102,ESI-MS m/z 528.28[M+H]+。
实施例103:化合物103的合成
合成方法参考化合物101,得到化合物103,ESI-MS m/z 479.26[M+H]+。
实施例104:化合物104的合成
合成方法参考化合物39,得到化合物104,ESI-MS m/z 478.27[M+H]+。
实施例105:化合物105的合成
合成方法参考化合物35,得到化合物105,ESI-MS m/z 402.23[M+H]+。
实施例106:化合物106的合成
以S-叔亮氨酸替换S-环己基丙氨酸甲酯,合成方法参考化合物35,得到化合物106,ESI-MS m/z 430.20[M+H]+。
实施例107:化合物107的合成
以S-叔亮氨酸替换S-环己基丙氨酸,合成方法参考化合物43,得到化合物107,ESI-MS m/z 499.22[M+H]+。
实施例108:化合物108的合成
以108-1替换S-环己基丙氨酸,合成方法参考化合物43,得到化合物108,ESI-MS m/z534.20[M+H]+。
实施例109:化合物109的合成
以109-1替换S-环己基丙氨酸,合成方法参考化合物43,得到化合物109,ESI-MS m/z539.16[M+H]+。
实施例110:化合物110的合成
以R-环己基丙氨酸替换S-环己基丙氨酸,合成方法参考化合物42,得到化合物110,ESI-MS m/z 589.27[M+H]+。
实施例111:化合物111的合成
合成方法参考化合物110,得到化合物111,ESI-MS m/z 589.27[M+H]+。
实施例112:化合物112的合成
以环己基丙氨酸替换S-环己基丙氨酸,合成方法参考化合物111,得到化合物112,ESI-MS m/z 589.27[M+H]+。
实施例113:化合物113的合成
以S-环戊基丙氨酸替换S-环己基丙氨酸,合成方法参考化合物43的合成,得到化合物113,ESI-MS m/z 525.24[M+H]+。
实施例114:化合物114的合成
合成方法参考化合物3的合成,得到化合物114,ESI-MS m/z 579.29[M+H]+。
实施例115:化合物115的合成
合成方法参考化合物1的合成,得到化合物115,ESI-MS m/z 446.23[M+H]+。
实施例116:化合物116的合成
合成方法参考化合物3的合成,得到化合物116,ESI-MS m/z 515.25[M+H]+。
实施例117:化合物117的合成
合成方法参考化合物2的合成,得到化合物117,ESI-MS m/z 443.23[M+H]+。
实施例118:化合物118的合成
合成方法参考化合物1的合成,得到化合物118,ESI-MS m/z 456.21[M+H]+。
实施例119:化合物119的合成
合成方法参考化合物3的合成,得到化合物119,ESI-MS m/z 553.27[M+H]+。
实施例120:化合物120的合成
合成方法参考化合物3的合成,得到化合物120,ESI-MS m/z 603.28[M+H]+。
实施例121:化合物121的合成
合成方法参考化合物1的合成,得到化合物121,ESI-MS m/z 456.21[M+H]+。
实施例122:化合物122的合成
合成方法参考化合物3的合成,得到化合物122,ESI-MS m/z 696.34[M+H]+。
实施例123:化合物123的合成
合成方法参考化合物2的合成,得到化合物123,ESI-MS m/z 453.21[M+H]+。
实施例124:化合物124的合成
合成方法参考化合物3的合成,得到化合物124,ESI-MS m/z 539.25[M+H]+。
实施例125:化合物125的合成
合成方法参考化合物3的合成,得到化合物125,ESI-MS m/z 589.27[M+H]+。
实施例126:化合物126的合成
合成方法参考化合物2的合成,得到化合物126,ESI-MS m/z 467.23[M+H]+。
实施例127:化合物127的合成
合成方法参考化合物1的合成,得到化合物127,ESI-MS m/z470.23[M+H]+。
实施例128:化合物128的合成
合成方法参考化合物3的合成,得到化合物128,ESI-MS m/z 553.27[M+H]+。
实施例129:化合物129的合成
合成方法参考化合物3的合成,得到化合物129,ESI-MS m/z 603.28[M+H]+。
实施例130:化合物130的合成
合成方法参考化合物3的合成,得到化合物130,ESI-MS m/z 581.30[M+H]+。
实施例131:化合物131的合成
合成方法参考化合物1的合成,得到化合物131,ESI-MS m/z 373.18[M+H]+。
实施例132:化合物132的合成
合成方法参考化合物2的合成,得到化合物132,ESI-MS m/z 370.18[M+H]+。
实施例133:化合物133的合成
合成方法参考化合物3的合成,得到化合物133,ESI-MS m/z 456.21[M+H]+。
实施例134:化合物134的合成
合成方法参考化合物3的合成,得到化合物134,ESI-MS m/z 506.23[M+H]+。
实施例135:化合物135的合成
合成方法参考化合物1的合成,得到化合物135,ESI-MS m/z 463.22[M+H]+。
实施例136:化合物136的合成
合成方法参考化合物2的合成,得到化合物136,ESI-MS m/z 460.22[M+H]+。
实施例137:化合物137的合成
合成方法参考化合物3的合成,得到化合物129,ESI-MS m/z 546.26[M+H]+。
实施例138:化合物138的合成
合成方法参考化合物3的合成,得到化合物138,ESI-MS m/z 596.28[M+H]+。
实施例139:化合物139的合成
合成方法参考化合物3的合成,得到化合物139,ESI-MS m/z 537.24[M+H]+。
实施例140:化合物140的合成
合成方法参考化合物3的合成,得到化合物140,ESI-MS m/z 587.25[M+H]+。
实施例141:化合物141的合成
合成方法参考化合物1的合成,得到化合物141,ESI-MS m/z 454.20[M+H]+。
实施例142:化合物142的合成
合成方法参考化合物2的合成,得到化合物142,ESI-MS m/z 451.20[M+H]+。
实施例143:化合物143的合成
合成方法参考化合物1的合成,得到化合物143,ESI-MS m/z 440.18[M+H]+。
实施例144:化合物144的合成
合成方法参考化合物2的合成,得到化合物144,ESI-MS m/z 437.18[M+H]+。
实施例145:化合物145的合成
合成方法参考化合物3的合成,得到化合物145,ESI-MS m/z 573.24[M+H]+。
实施例146:化合物146的合成
合成方法参考化合物3的合成,得到化合物146,ESI-MS m/z 523.22[M+H]+。
实施例147:化合物147的合成
合成方法参考化合物1的合成,得到化合物147,ESI-MS m/z 447.20[M+H]+。
实施例148:化合物148的合成
合成方法参考化合物2的合成,得到化合物148,ESI-MS m/z 444.19[M+H]+。
实施例149:化合物149的合成
成方法参考化合物3的合成,得到化合物149,ESI-MS m/z 530.23[M+H]+。
实施例150:化合物150的合成
合成方法参考化合物3的合成,得到化合物150,ESI-MS m/z 580.25[M+H]+。
实施例151:化合物151的合成
合成方法参考化合物1的合成,得到化合物151,ESI-MS m/z 357.15[M+H]+。
实施例152:化合物152的合成
合成方法参考化合物2的合成,得到化合物152,ESI-MS m/z 354.15[M+H]+。
实施例153:化合物153的合成
合成方法参考化合物3的合成,得到化合物153,ESI-MS m/z 440.18[M+H]+。
实施例154:化合物154的合成
合成方法参考化合物3的合成,得到化合物154,ESI-MS m/z 490.20[M+H]+。
实施例155:化合物155的合成
合成方法参考化合物3的合成,得到化合物155,ESI-MS m/z 571.30[M+H]+。
实施例156:化合物156的合成
合成方法参考化合物3的合成,得到化合物156,ESI-MS m/z 521.28[M+H]+。
实施例157:化合物157的合成
合成方法参考化合物3的合成,得到化合物157,ESI-MS m/z 585.31[M+H]+。
实施例158:化合物158的合成
合成方法参考化合物3的合成,得到化合物158,ESI-MS m/z 535.30[M+H]+。
实施例159:化合物159的合成
合成方法参考化合物3的合成,得到化合物159,ESI-MS m/z 578.31[M+H]+。
实施例160:化合物160的合成
合成方法参考化合物3的合成,得到化合物160,ESI-MS m/z 528.29[M+H]+。
活性测试例1:人组织蛋白酶L蛋白酶抑制活性评价
测定化合物对人组织蛋白酶L(cathepsin L,CatL)的抑制活性:利用荧光共振能量转移(fluorescence resonance energy transfer,FRET)技术测定针对组织蛋白酶L的酶水平抑制活性。在96孔板上,每孔中加入10μL缓冲液(50mM CH3COONa,pH 5.5,1mM DTT,2mM EDTA),同时加入0.2μL化合物(最终浓度分别为100nM,10nM,1nM,0.1nM和0.01nM)和10μL组织蛋白酶L。在25℃下共孵育15min。之后加入10μL缓冲液稀释的荧光底物(Z-Phe-Arg-AMC,最终浓度20μM)。利用Tecan Infinite 200pro荧光分度计测定荧光参数,激发波长和发射波长分别为360nm和465nm,保持25℃,30min后读取数据。采用阴性对照,其中对照不加入化合物,其余相同。所得数据利用软件GraphPad Prism 8.0处理,实验结果如表1所示。
表1:人组织蛋白酶L抑制活性
实验结果显示:测试化合物对人组织蛋白酶L具有优异的抑制活性,多个化合物IC50达纳摩尔级,5个化合物IC50小于1nM。
活性测试例2:人组织蛋白酶B蛋白酶抑制活性评价
利用荧光共振能量转移(fluorescence resonance energy transfer FRET)技术测定针对Cat B的抑制剂的酶水平抑制活性。整个酶促反应体系的体积为50μL,蛋白酶的终浓度为2nM,荧光底物(Z-Arg-Arg-AMC,Z=benzyloxycarbonyl,AMC=7-amino-4-methyl-coumarin)终浓度为20μM。反应体系的缓冲液包括:100mM磷酸钾,Ph=6.5,5mM EDTA-Na,0.001%Triton x-100和5mM DDT。在96孔板中加入Cat B蛋白酶和不同浓度的化合物,室温孵育5min,加入荧光底物并迅速放入微孔板检测器中读数。激发光和发射光分别为360nm和450nm。每隔2s读一次荧光值,读取50次。根据读值拟合出不同浓度化合物下的反应Vmax,并与对照组(DMSO)比较,计算抑制率。利用软件GraphPad Prism 8拟合得到IC50值。
实验结果显示:测试化合物对人组织蛋白酶B具有优异的抑制活性,多个化合物IC50达纳摩尔级,2个化合物IC50小于100nM。
表2:人组织蛋白酶B抑制活性
活性测试例3:SARS-CoV-2 3CL蛋白酶抑制活性评价
测定化合物对SARS-CoV-2 3CL蛋白酶的抑制活性:利用荧光共振能量转移(fluorescence resonance energy transfer FRET)技术测定针对3CL蛋白酶的抑制剂的酶水平抑制活性。整个酶促反应体系的体积为120μL,蛋白酶的终浓度为30nM,底物终浓度为20μM。反应体系的缓冲液包括50mM Tris pH7.3、1mM EDTA。在96孔板中加入3CL蛋白酶和不同浓度的化合物,30℃孵育10min,加入底物并迅速放入酶标仪中读数。激发光和发射光分别为320nm和405nm。测试时间为10min,每隔30s读一次荧光值。最终结果取前2min的读值拟合出反应速率,并与对照组(DMSO)比较,计算抑制率,实验结果如表3所示。
表3:SARS-CoV-2 3CL蛋白酶抑制活性
实验结果显示:多数化合物在10μM的条件下对SARS-CoV-2 3CL蛋白酶具有较好的抑制活性。
活性测试例4:化合物对2019新型冠状病毒(SARS-CoV-2)复制抑制活性评价
在96孔板中加入Vero E6细胞(50000个细胞/孔),加入100μL/孔含梯度浓度化合物的培养基,随后加入2019新型冠状病毒(SARS-CoV-2),感染复数(MOI)为0.05。共孵育1小时后,吸走上清,清洗并重新加入200μL/孔含梯度浓度化合物的培养基,37℃培养24小时。24小时后,收集细胞上清,提取上清病毒RNA并利用实时荧光定量PCR的方法检测上清病毒拷贝数,根据病毒拷贝数算出化合物抑制率。
试验结果如表4、表5所示。
表4:SARS-CoV-2抑制活性
结果表明,本发明的酰胺类化合物可有效地抑制SARS-CoV-2的复制(表4),化合物127、128、129和138在80nM浓度下对SARS-CoV-2的抑制活性仍大于50%。
表5:SARS-CoV-2Delta毒株抑制活性
结果表明,本发明的酰胺类化合物可有效地抑制SARS-CoV-2Delta毒株的复制(表5)。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (15)
- 一种通式(I)所示的酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体:
其中,手性碳原子C*、C*2各自独立地为S型或R型;X选自下组:O、N-R4’;其中,R4’选自下组:氢、C1-C6直链或支链烷基;Ra选自下组:-(CH2)mR4;其中,m为0或1;Rb为H或C1-C4烷基;选自下组:取代或未取代的5-12元芳基、取代或未取代的5-12元杂环基、取代或未取代的5-12元杂芳基;R1选自下组:
其中,R6为氢,或者被1~3个取代基取代的选自下组的基团:C1~C6直链或支链烷基、C1~C6直链或支链烷氧基、C3-C7环烷基、C6~C12芳基或5~12元杂芳基;Y选自下组:O、S;Z选自下组:O、NH、N-Boc;R7选自下组:H、F、Br、Cl、CN;R8和R9各自独立地选自下组:氢、氘、氚、氨基、羟基、取代或未取代的C1~C10烷基、取代或未取代的C3~C10环烷基、取代或未取代的C3~C10环烷基C1~C4亚烷基、取代或未取代的C3~C10杂环烷基、取代或未取代的C3~C10杂环烷基C1~C4亚烷基、取代或未取代的C6~C12芳基、取代或未取代的C5~C12杂芳基、取代或未取代的C6~C12芳基C1~C4亚烷基、取代或未取代的C5~C12杂芳基C1~C4亚烷基;R10为氢或者被1~2个取代基取代的选自下组的基团:C2~C6烯基、C2~C6炔基、C2~C10环氧烷基;R11选自下组:羟基、卤素;R12、R13各自独立地选自下组:未被取代或者被1~3个取代基取代的6~12元芳基、或者未被取代或者被1~3个取代基取代的5~12元杂芳基;R14与R15各自独立地选自下组:氢,或未取代或者被1~3个取代基取代的选自下组的基团:C1~C4直链或支链烷烃、C2~C6直链或支链烯烃、C2~C6直链或支链炔烃、C6~C12芳基C1~C4亚烷基;或者,其中R14与R15与相邻的-O-C-O-结构连接成5~8元杂环,且所述的环上含有2~3个选自氧、硫和氮的杂原子;R16选自下组:氢、或C1~C6直链或支链烷基羰基氧基;R17选自金属离子,如Na+;R2与R3各自独立地选自下组:氢、C1~C6直链或支链烷基、C2~C6直链或支链烯基、C2~C6直链或支链炔基、或者,R2与R3及其相连的碳原子共同形成未被取代或者被1~3个取代基取代的C3~C7环烷基;其中,所述的取代基各自独立地选自下组:卤素、C1~C4直链或支链烷基、C2~C4直链或支链烯基、C2~C4直链或支链炔基、C1~C4直链或支链烷氧基、C1~C4直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、C1~C4酰基、酰胺基、磺酰基、氨基磺酰基、C1~C4烷基取代的磺酰基,或者两个相邻的取代基连同与其连接的碳原子构成的5~7元环;其中:n选自0、1或2;选自未被取代或者被1~3个取代基取代的选自下组的基团:C3~C7环烷基、C5~C7芳基、或C5~C7杂芳基;所述杂芳基含有1~3个选自氧、硫和氮的杂原子;所述的取代基各自独立地选自下组:卤素、C1~C4直链或支链烷基、C2~C4直链或支链烯基、C2~C4直链或支链炔基、C1~C4直链或支链烷氧基、C1~C4直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、C1~C4酰基、酰胺基、磺酰基、氨基磺酰基、C1~C4烷基取代的磺酰基,或者两个相邻的取代基连同与其连接的碳原子构成的5~7元环;手性碳原子C*3、C*4各自独立地为S型或R型;R4选自下组:氢、或者未被取代或被1~3个取代基取代的选自下组的基团:C1~C6直链或支链烷基、C3~C7环烷基、三氟甲基、C2~C6炔基、4~7元杂环基、C5~C7芳基、5-7元杂芳基;所述杂环基和杂芳基各自含有1~3个选自氧、硫和氮的杂原子;所述的取代基各自独立地选自下组:卤素、C1~C4直链或支链烷基、C2~C4直链或支链烯基、C2~C4直链或支链炔基、C1~C4直链或支链烷氧基、C1~C4直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、C1~C4酰基、酰胺基、磺酰基、氨基磺酰基、C1~C4烷基取代的磺酰基,或者两个相邻的取代基连同与其连接的碳原子构成的5~7元环;或者,R4与R4’‘及其相连的碳原子和氮原子共同组成未被取代或者被1~3个取代基取代的5-10元环状结构除特别说明之处,所述“取代”指基团上的一个或多个氢原子被选自下组的取代基取代:氰基、氧代(=O)、C1~C10烷基、C1~C10卤代烷基、C3~C10环烷基、C1~C10烷氧基、卤素、羟基、羧基(-COOH)、C1~C10醛基、C2~C10酰基、C2~C10酯基、氨基、苯基、苄基;所述的苯基或苄基包括未取代的苯基或具有1-3个取代基的取代苯基或苄基,所述取代基选自:卤素、C1-C10烷基、氰基、OH、硝基、 C3~C10环烷基、C1~C10烷氧基、氨基。 - 如权利要求1所述的酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,其特征在于,R1选自下组:
其中,R8和R9各自独立地选自下组:氢、氘、取代或未取代的C1~C4直链或支链烷基、取代或未取代的C3~C6环烷基、取代或未取代的C3~C6环烷基C1~C2亚烷基、取代或未取代的C6~C12芳基、取代或未取代的C6~C12芳基C1~C2亚烷基;R11选自下组:羟基、卤素原子;R12为未被取代或者被1~3个取代基取代的选自下组的基团:苯基、嘧啶基、吡啶基。 - 如权利要求1所述的酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,其特征在于,选自或者取代或未取代的选自下组的基团:苯基、嘧啶基、吡啶基、吲哚基、苯并咪唑基、苯并呋喃基、喹啉基或喹唑啉酮基;R18和R19各自独立地选自下组:卤素、氨基、羟基、羧基、取代或未取代的C1~C6烷基、取代或未取代的C3~C6环烷基、取代或未取代的C1~C6烷氧基、取代或未取代的C1~C6醛基、取代或未取代的C2~C6酰基、取代或未取代的C2~C6酯基、取代或未取代的苯基、取代或未取代的苯基C1~C4亚烷基。
- 如权利要求1所述的酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,其特征在于,R2与R3各自独立地选自下组:氢、 或者取代或未取代的选自下组的基团:C1~C6直链或支链烷基、苄基、苯乙基、C3~C6环烷基、C3~C6环烷基亚甲基;或者,R2与R3连接,组成取代或未取代的C3~C5环烷基;其中,手性碳原子C*3、C*4为S型。
- 如权利要求1所述的酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,其特征在于,R4选自下组:未被取代或被1~3个取代基取代的选自下组的基团:C1~C6直链或支链烷基、C3~C7环烷基、三氟甲基、C2~C6炔基、4~7元杂环基、C5~C7芳基、5-7元杂芳基;R4'选自下组:氢、C1-C6直链或支链烷基;或者,R4与R4'及其相连的碳原子和氮原子共同组成未被取代或者被1~3个 取代基取代的5-6元环状、或6~10元双环状结构,所述环状或双环状结构包括以下结构:
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代:氧代(=O)、C1~C4烷基、C1~C4卤代烷基、C3~C6环烷基、C1~C6烷氧基、卤素、羟基、羧基(-COOH)、C2~C6醛基氨基、苯基、苄基;所述的苯基或苄基包括未取代的苯基或具有1-3个取代基的取代苯基或苄基,所述取代基选自:卤素、C1-C6烷基、氰基、OH、硝基、C3~C6环烷基、C1~C6烷氧基、氨基。 - 如权利要求1所述的酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,其特征在于,R4为氢,或者未被取代或者被1~3个取代基取代的选自下组的基团:C1~C4直链或支链烷基、C3~C7环烷基、三氟甲基、C5~C7芳基;所述的取代基各自独立地选自下组:卤素、C1~C4直链或支链烷基、C1~C4直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、C1~C4酰基、酰胺基、磺酰基、氨基磺酰基、C1~C4烷基取代的磺酰基,或者两个相邻的取代基连同与其连接的碳原子构成的5~7元环;R4'选自下组:氢、C1-C4直链或支链烷基;或者,R4与R4'连接,同R4相连的α碳原子,R4相连的β碳原子,以及R4'相连的α氮原子组成未被取代或者被1~3个取代基取代的以下环状结构:
- 如权利要求1所述的酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,其特征在于,n=1;R4为未被取代基或者被1~3个取代基取代的选自下组的基团:异丙基、环己基、环戊基、苯基;所述的取代基各自独立地选自下组:卤素、C1~C4直链或支链烷基、氰基、硝基、羟基、三氟甲基。
- 如权利要求1所述的酰胺类化合物、或其药学上可接受的盐、对映异构体、 非对映异构体或外消旋体,其特征在于,所述酰胺类化合物选自下组:
- 一种如权利要求1所述的酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体的制备方法,包括步骤:(1)
其中,Ha为卤素;在惰性溶剂中,在碱存在下,式Ia卤素取代化合物与式Ib化合物进行取代 反应得到式Ic化合物;所述碱包括三乙胺、二异丙基乙胺、碳酸铯、碳酸钾、1,8-二氮杂二环[5.4.0]十一碳-7-烯;(2)
式Ic化合物溶于有机溶剂中,在碱溶液存在下,式Ic化合物水解生成Id化合物;所述有机溶剂包括甲醇、乙醇、四氢呋喃、二氧六环、或其组合;所述碱溶液包括氢氧化钠水溶液、氢氧化锂水溶液、氢氧化钾水溶液;(3)
式Id化合物溶于有机溶剂中,在缩合剂和碱存在下,与式Ie化合物进行缩合反应生成If化合物;所述有机溶剂包括二氯甲烷、乙酸乙酯、二氯乙烷、N,N二甲基甲酰胺、四氢呋喃、二甲基亚砜、二氧六环、或其组合;所述碱包括三乙胺、二异丙基乙基胺,所述缩合剂包括2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐;(4)a.
式If化合物溶于有机溶剂中,用还原剂进行还原反应得到式Ig化合物,所述有机溶剂包括二氯甲烷与甲醇混合溶剂、四氢呋喃与甲醇混合溶剂;所述还原剂包括硼氢化钠;
在有机溶剂中,式Ig化合物进行氧化反应得到式Ih化合物,即式(I)醛基类化合物;所述溶剂包括二氯甲烷、二甲基亚砜、四氢呋喃、乙酸乙酯;所述氧化剂包括三氧化硫吡啶、戴斯马丁氧化剂、或草酰氯和二甲基亚砜的组合物;b.
在有机溶剂中,式Ih化合物于酸性条件下与异腈类化合物反应得到式Ii化合物;所述溶剂包括二氯甲烷、二甲基亚砜、四氢呋喃、乙酸乙酯;所述酸包括醋酸、三氟乙酸、盐酸;
式Ii化合物溶于有机溶剂中,在碱溶液存在下,式Ii化合物水解生成Ij化合物;所述有机溶剂包括甲醇、乙醇、四氢呋喃、二氧六环、或其组合;所述碱溶液包括氢氧化钠水溶液、氢氧化锂水溶液、氢氧化钾水溶液;
在有机溶剂中,式Ij化合物进行氧化反应得到式Ik化合物,即式(I)酮酰胺类化合物;所述溶剂包括二氯甲烷、二甲基亚砜、四氢呋喃、乙酸乙酯;所述氧化剂包括三氧化硫吡啶、戴斯马丁氧化剂、或草酰氯和二甲基亚砜的组合物;c.
在有机溶剂中,式If化合物与氨通过胺酯交换反应得到式Il化合物;所述溶剂草酰氯和二甲基亚砜甲醇、乙醇、四氢呋喃、乙酸乙酯;
在有机溶剂中,式Il化合物在脱水剂存在下,通过脱水反应得到式Im化合物,即式(I)氰基类化合物;所述溶剂包括二氯甲烷、二甲基亚砜、四氢呋喃、乙酸乙酯;所述脱水剂包括三氯氧磷、三氟乙酸酐、伯吉斯试剂。 - 一种药物组合物,其特征在于,包括:治疗有效量的一种或多种如权利要求1所述通式(I)所示酰胺类化合物,或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体。
- 一种如权利要求1所述通式(I)所示酰胺类化合物,或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,或者如权利要求9所述的药物组合物的用途,其特征在于,用于制备治疗或预防由一种或多种冠状病毒和/或RNA病毒感染引起的相关疾病的药物组合物;其中,所述的冠状病毒包括:SARS-CoV-2、SARS-CoV、MERS-CoV;所述的RNA病毒包括:EV71、EV68、诺如病毒、EBOV。
- 如权利要求10所述的用途,其特征在于,所述由冠状病毒感染引起的相关疾病选自下组:呼吸道感染、肺炎及其并发症、或其组合。
- 如权利要求10所述的用途,其特征在于,所述由RNA病毒感染引起的相关疾病选自下组:手足口病、中枢神经系统感染、腹泻及其并发症、出血热、中枢神经系统感染及其并发症、或其组合。
- 一种如权利要求1所述的酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,或如权利要求9所述的药物组合物的用途,其特征在于,用于治疗、预防、和/或缓解由冠状病毒和/或RNA病毒感染引起的相关疾病,包括步骤:给需要的对象施用安全有效量的权利要求1所述的通式(I)所示的酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,或者如权利要求9所述的药物组合物;其中,所述冠状病毒包括:SARS-CoV-2、SARS-CoV、MERS-CoV;所述RNA病毒包括:EV71、EV68、诺如病毒、EBOV。
- 如权利要求13所述的用途,其特征在于,所述的对象为灵长目哺乳动物,如人。
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