WO2022148434A1 - 吡啶酮多并环类衍生物及其应用 - Google Patents
吡啶酮多并环类衍生物及其应用 Download PDFInfo
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- WO2022148434A1 WO2022148434A1 PCT/CN2022/070733 CN2022070733W WO2022148434A1 WO 2022148434 A1 WO2022148434 A1 WO 2022148434A1 CN 2022070733 W CN2022070733 W CN 2022070733W WO 2022148434 A1 WO2022148434 A1 WO 2022148434A1
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Classifications
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D517/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having selenium, tellurium, or halogen atoms as ring hetero atoms
- C07D517/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having selenium, tellurium, or halogen atoms as ring hetero atoms in which the condensed system contains three hetero rings
- C07D517/14—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D517/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having selenium, tellurium, or halogen atoms as ring hetero atoms
- C07D517/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having selenium, tellurium, or halogen atoms as ring hetero atoms in which the condensed system contains two hetero rings
- C07D517/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention relates to a class of pyridone polycyclic derivatives and applications thereof, in particular to compounds represented by formula (VI) and pharmaceutically acceptable salts thereof.
- Influenza virus namely influenza virus (IFV) is a segmented single-stranded antisense RNA virus that can cause influenza in humans and animals. Influenza viruses can cause very high morbidity and mortality, especially influenza A viruses can cause global pandemics, such as "Spanish flu” (H1N1 subtype) in 1918-1920, "Asian flu” in 1957-1958 “(H2N2 subtype), 1968 to 1969 "Asian flu” (H3N2 subtype), 1977 to 1978 "Hong Kong flu” (H1N1 subtype) and the first outbreak of influenza A H1N1 in Mexico in March 2009. Influenza outbreaks killed thousands of people, caused huge social panic and increased social instability.
- IMV influenza virus
- Influenza A virus is a single negative-stranded RNA virus with a genome of 8 segments encoding 8 proteins.
- the 5' and 3' ends of influenza virus genome fragments are highly conserved, and the sequences of the two ends are complementary to form a handle loop structure, which plays an important role in initiating viral RNA replication.
- the proteins encoded by each gene segment of the virus are different in size and play different roles in the life cycle of influenza virus.
- the basic functions of several main proteins are introduced as follows.
- HA of influenza virus is a ligand for influenza virus to recognize host receptors, bind to virus-specific receptors on the cell surface, mediate the fusion of the viral outer membrane and the intracellular body membrane, and release the viral nucleocapsid into the cytoplasm.
- the receptor of influenza virus is specific, and the receptor of influenza A virus is sialoglycoprotein.
- the NA protein of influenza virus can remove sialic acid on the surface of virus particles during replication, so that virus particles cannot continue to aggregate on the surface of host cells, which is conducive to the release of virions and further infection of more host cells.
- M2 protein of influenza virus binds to sialic acid, and influenza virus is endocytosed by host cells.
- the acidity and alkalinity in phagosomes play a crucial role in virus uncoating.
- the ion channel of M2 protein on the viral membrane can gradually reduce the pH of phagosomes. When the pH value drops to 5.0-6.0, HA2
- the protein allosteric shifts the fusion peptide located at the amino terminus of the HA2 protein, which activates the fusion process, resulting in the fusion of the double lipid membrane of the virus and the cell membrane, releasing the RNPs inside the virus particle to the host cytoplasm.
- the M2 protein is a transmembrane ion channel found only in influenza A virus, and it partially extends to the surface of the viral outer membrane.
- influenza virus proteins also utilizes the host cell translation mechanism, and even the virus can suspend the translation of host proteins and accelerate the synthesis of its own proteins.
- the polyadenylation of host cell mRNA is completed by a specific adenylase, unlike the adenylate tail of viral mRNA, which is formed by the transcription of 5-7 consecutive uracils on the negative-strand vRNA. of.
- mRNAs viral individual messenger RNAs
- PA and PB2 proteins grab the 5' capping primer of the host pre-mRNA transcript and in turn initiate viral mRNA synthesis, a process known as "cap” snatching", which is mainly accomplished by the virus' RNA-dependent RNA polymerase (RdRp), whose PA subunit has RNA endonuclease activity and is responsible for severing host mRNA.
- RdRp virus' RNA-dependent RNA polymerase
- the mRNA of the virus exits the nucleus, enters the cytoplasm, and is translated like the mRNA of the host cell.
- the nuclear export of the viral vRNA fragment is mediated by the M1 and NS2 proteins of the virus.
- M1 protein when M1 protein can interact with vRNA and NP protein, it also interacts with nuclear export protein NS2; thus, nuclear export protein NS2 mediates the export of M1-RNP as a nuclear protein into the cytoplasm of host cells.
- Influenza has direct costs due to lost productivity and associated healthcare resources and indirect costs of preventive measures.
- influenza cumulatively costs approximately $10 billion annually, and future influenza pandemics are estimated to have direct and indirect costs in the hundreds of billions of dollars.
- Prevention costs are also very high, with governments around the world spending billions of dollars to prepare for and plan for a possible H5N1 avian influenza pandemic, costs associated with purchasing drugs and vaccines, and developing strategies for disaster drills and improved border controls.
- Influenza vaccine against influenza is often recommended for high-risk groups, such as children and the elderly, or people with asthma, diabetes, or heart disease, but even vaccination does not completely prevent the flu. Vaccines for some specific influenza strains are recreated each season, but it is impossible to cover the various strains that actively infect people globally during that season. In addition, because influenza viruses undergo a certain degree of antigenic drift, if more than one virus infects a single cell, the 8 separate vRNA segments in the genome mix or reassort, resulting in rapid changes in viral genetics that can produce The antigenic shift enables the virus to infect new host species and rapidly overcome protective immunity.
- Antiviral drugs can also be used to treat influenza.
- neuraminidase inhibitors such as oseltamivir (Tamiflu)
- Tamiflu oseltamivir
- Drug-resistant virus strains have emerged.
- anti-influenza virus there is an urgent need for anti-influenza virus drugs with a new mechanism of action, which can support the use of single drugs for the treatment of influenza A, or can be used in combination with other anti-influenza virus drugs with other mechanisms of action that have been marketed for influenza A.
- Influenza prevention and treatment Among them, WO2016175224 reported RNA polymerase PA subunit inhibitors, such as S-033447 and its prodrug S-033188:
- the present invention provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof,
- R 7 is selected from H and
- R 8 is selected from C 1-3 alkyl and The C 1-3 alkyl and optionally substituted with 1, 2 or 3 Ra ;
- R 9 is selected from H
- E 1 is selected from Se
- X 1 is selected from CR 10 R 11 , R 10 and R 11 together with the atoms to which they are commonly attached form a C 3-5 cycloalkyl
- X1 and R9 are formed together with the atoms to which they are attached p is selected from 0 and 1, one of E 1 and E 2 is selected from Se, and the other is selected from S and O;
- R 12 is selected from H, F, Cl, Br, I, OH, NH 2 , -COOH, C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino, the C 1-3 Alkyl, C 1-3 alkoxy and C 1-3 alkylamino are each independently optionally substituted with 1 , 2 or 3 R b ;
- T 1 , T 2 , T 3 and T 4 are each independently selected from CH and N;
- q is selected from 0 and 1;
- t is selected from 0, 1, 2, 3 and 4;
- each R a and R b are independently selected from H, F, Cl, Br and I;
- each R12 is independently selected from OH and NH2 .
- each R 12 is independently selected from F, and other variables are as defined in the present invention.
- the R 8 is selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and The CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and Optionally substituted with 1, 2 or 3 Ra , other variables are as defined herein.
- the R 8 is selected from CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 and Other variables are as defined in the present invention.
- the R8 is selected from CH3 and Other variables are as defined in the present invention.
- the R is selected from H, Other variables are as defined in the present invention.
- the R is selected from H, Other variables are as defined in the present invention.
- the R is selected from H and Other variables are as defined in the present invention.
- the E 1 is selected from Se
- E 2 is selected from O
- other variables are as defined in the present invention.
- the structural unit selected from R 5 and R 6 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , -COOH, C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino,
- the C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino groups are each independently optionally substituted with 1, 2 or 3 R b , and other variables are as defined in the present invention.
- said R5 is selected from F, and other variables are as defined herein.
- said R6 is selected from F, and other variables are as defined herein.
- the compound, or a pharmaceutically acceptable salt thereof is selected from,
- R 5 and R 6 are each independently selected from H, F, Cl, Br, I, OH and NH 2 ;
- R 7 is selected from H and
- R 8 is selected from C 1-3 alkyl and The C 1-3 alkyl and optionally substituted with 1, 2 or 3 Ra ;
- R 9 is selected from H
- E 1 is selected from Se
- X 1 is selected from CR 10 R 11 , R 10 and R 11 together with the atoms to which they are commonly attached form a C 3-5 cycloalkyl
- X1 and R9 are formed together with the atoms to which they are attached
- One of E 1 and E 2 is selected from Se, and the other is selected from S and O;
- T 1 is selected from CH and N;
- p and q are independently selected from 0 and 1, respectively;
- each R a is independently selected from H, F, Cl, Br and I;
- T1 is selected from CH
- E1 is selected from Se
- E2 is selected from O
- p is selected from 1
- q is selected from 1
- R5 and R6 are independently selected from OH and NH2 , respectively ;
- the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
- the compound, or a pharmaceutically acceptable salt thereof is selected from,
- the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
- the compound, or a pharmaceutically acceptable salt thereof is selected from,
- the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
- the compound, or a pharmaceutically acceptable salt thereof is selected from,
- the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
- the compound, or a pharmaceutically acceptable salt thereof is selected from,
- R 1 and R 2 are each independently selected from H, F, Cl, Br, I, OH and NH 2 ;
- n is selected from 0 and 1;
- R 5 , R 6 , R 7 and R 8 are as defined in the present invention.
- said R 1 and R 2 are each independently selected from F, and other variables are as defined in the present invention.
- said R 5 and R 6 are each independently selected from F, and other variables are as defined in the present invention.
- the compound, or a pharmaceutically acceptable salt thereof is selected from,
- R 1 , R 2 , R 5 , R 6 , R 7 and R 8 are as defined in the present invention.
- the compound, or a pharmaceutically acceptable salt thereof is selected from,
- R 1 , R 2 , R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH and NH 2 ;
- n and m are independently selected from 0 and 1, respectively;
- R 1 and R 2 are independently selected from OH and NH 2 respectively; q, R 5 , R 6 and R 8 as defined in the present invention.
- said R 1 and R 2 are each independently selected from F, and other variables are as defined in the present invention.
- said R 3 and R 4 are each independently selected from F, and other variables are as defined in the present invention.
- the compound, or a pharmaceutically acceptable salt thereof is selected from,
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in the present invention.
- the present invention provides a compound represented by formula (V) or a pharmaceutically acceptable salt thereof,
- R 5 and R 6 are each independently selected from H, F, Cl, Br, I, OH and NH 2 ;
- R 7 is selected from H and
- R 8 is selected from C 1-3 alkyl and The C 1-3 alkyl and optionally substituted with 1, 2 or 3 Ra ;
- R is selected from H;
- X 1 is selected from CR 10 R 11 , R 10 and R 11 together with the atoms to which they are commonly attached form a C 3-5 cycloalkyl;
- E 1 is selected from S and Se;
- E 2 is selected from O and Se, and at least one of E 1 and E 2 is selected from Se;
- T 1 is selected from CH and N;
- p and q are independently selected from 0 and 1, respectively;
- each R a is independently selected from H, F, Cl, Br and I;
- T1 is selected from CH
- E1 is selected from Se
- E2 is selected from O
- p is selected from 1
- q is selected from 1
- R5 and R6 are independently selected from OH and NH2 , respectively ;
- the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
- the present invention provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof,
- T 1 is selected from CH and N;
- E 1 is selected from S and Se;
- E 2 is selected from O and Se, and at least one of E 1 and E 2 is selected from Se;
- R 5 and R 6 are each independently selected from H, F, Cl, Br, I, OH and NH 2 ;
- R 7 is selected from H and
- R 8 is selected from C 1-3 alkyl and The C 1-3 alkyl and optionally substituted with 1, 2 or 3 Ra ;
- p and q are independently selected from 0 and 1, respectively;
- each R a is independently selected from H, F, Cl, Br and I;
- T 1 is selected from CH, and E 1 is selected from Se, E 2 is selected from O, p is selected from 1, and q is selected from 1, R 5 and R 6 are independently selected from OH and NH 2 respectively;
- the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
- the compound, or a pharmaceutically acceptable salt thereof is selected from,
- the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
- the present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
- T 1 is selected from CH and N;
- R 1 is selected from H, F, Cl, Br, I, OH and NH 2 ;
- R 2 is selected from H, F, Cl, Br, I, OH and NH 2 ;
- n is selected from 0 and 1;
- the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
- the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
- R3 is selected from H, F, Cl, Br, I, OH and NH2 ;
- R4 is selected from H, F, Cl, Br, I, OH and NH2 ;
- n is selected from 0 and 1;
- the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- R 1 , R 2 and m are as defined in the present invention.
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- R 1 is selected from H, F, Cl, Br, I, OH and NH 2 ;
- R 2 is selected from H, F, Cl, Br, I, OH and NH 2 ;
- n is selected from 0 and 1;
- the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
- said R1 is selected from F , and other variables are as defined herein.
- said R 2 is selected from F, and other variables are as defined herein.
- said R3 is selected from F, and other variables are as defined herein.
- said R4 is selected from F, and other variables are as defined herein.
- the present invention provides a compound of the formula or a pharmaceutically acceptable salt thereof,
- the present invention also provides the use of the compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating influenza virus-related diseases.
- the compound of the present invention exhibits a positive effect in the test of inhibiting influenza virus replication at the cellular level, and exhibits excellent body weight protection in an animal in vivo pharmacodynamic model, and has an early recovery time.
- the plasma protein binding rate test The results show that the compound of the present invention has a moderate plasma protein binding rate in plasma, and the PK results show that it has good pharmacokinetic properties and good drug-forming properties.
- FIG. 1 3D binding mode of S-033447 to the protein (PDB ID: 6FS6).
- the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
- base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
- acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
- the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
- the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
- Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
- the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
- compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
- deuterated drugs can be formed by replacing hydrogen with deuterium, and the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
- substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
- oxygen it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
- optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
- any variable eg, R
- its definition in each case is independent.
- the group may optionally be substituted with up to two Rs, with independent options for R in each case.
- combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
- the direction of attachment is arbitrary, for example,
- the linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
- Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- any one or more sites in the group can be linked to other groups by chemical bonds.
- connection method of the chemical bond is not positioned and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to the corresponding valence. the group.
- the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines express.
- a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
- the straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
- the wavy line in the phenyl group indicates that it is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
- C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
- the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) .
- Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
- C1-3alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom.
- the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy and the like.
- Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
- C 1-3 alkylamino refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an amino group.
- the C 1-3 alkylamino groups include C 1-2 , C 3 and C 2 alkylamino groups and the like.
- Examples of C 1-3 alkylamino include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , - NHCH 2 (CH 3 ) 2 and the like.
- C 3-5 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic ring system, said C 3-5 cycloalkyl including C 3 -4 and C 4-5 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent.
- Examples of C3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
- Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+ m , eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membere
- leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, a nucleophilic substitution reaction).
- a substitution reaction eg, a nucleophilic substitution reaction
- representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy, such as acetoxy, trifluoroacetoxy, and the like.
- protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
- amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
- Representative amino protecting groups include, but are not limited to: formyl; acyl groups, such as alkanoyl groups (eg, acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
- hydroxy protecting group refers to a protecting group suitable for preventing hydroxyl side reactions.
- Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (eg acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
- alkyl groups such as methyl, ethyl and tert-butyl
- acyl groups such as alkanoyl (eg acetyl)
- arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenyl
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
- the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
- SXRD single crystal X-ray diffraction method
- the cultured single crystal is collected by Bruker D8 venture diffractometer
- the light source is CuK ⁇ radiation
- the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
- the present invention adopts the following abbreviations: DMAC: N,N-dimethylacetamide, PG: propylene glycol, HP- ⁇ -CD: hydroxypropyl- ⁇ -cyclodextrin, Solutol HS-15 stands for polyethylene glycol (15)-Hydroxystearate.
- the solvent used in the present invention is commercially available.
- Compounds are named according to conventional nomenclature in the art or are used Software naming, commercially available compounds use supplier catalog names.
- the low-energy conformation of S-033447 was calculated by the Macromodel module of the Maestro software of Schrodinger Company.
- the dihedral angle (dehidal 1) of pyridohexahydropyrimidine hereinafter referred to as the parent nucleus
- the dihedral angle between the parent nucleus and 2,5-dihydrothiophene is 56.8° ( See Figure 3).
- the smaller the energy barrier difference between the lowest energy barrier conformation (low energy conformation) of a small molecule and its binding mode conformation in the protein (active conformation) the smaller the energy barrier difference means that the small molecule switches from the low energy conformation to binding to the protein.
- Dihedral 1 is the dihedral angle of pyridohexahydropyrimidine
- Dihedral 2 is the dihedral angle of pyridohexahydropyrimidine and 2,5-dihydrothiophene
- ⁇ E is the protein binding mode from the low-energy conformation transition to S-033447 The energy barrier required to consume the active conformation (-153.7° for Dihedral 1 and 55.0° for Dihedral 2).
- Dihedral 1 is the dihedral angle of pyridohexahydropyrimidine
- Dihedral 2 is the dihedral angle of pyridohexahydropyrimidine and 2,5-dihydroselenothiophene.
- the reaction solution was filtered, the filter cake was washed with ethyl acetate (10 mL ⁇ 2), the layers were separated, the aqueous phase was extracted with ethyl acetate (10 mL ⁇ 2), the organic phases were combined, washed with saturated brine (20 mL), anhydrous sulfuric acid Dry over sodium, filter, and concentrate the filtrate to dryness under reduced pressure.
- the crude product reaction solution was separated and purified by preparative high performance liquid chromatography (column: Xtimate C18 100*30mm*3 ⁇ m; mobile phase: [A: water (0.225% formic acid); B: acetonitrile]; gradient: acetonitrile%: 40%-60 %, 8 minutes) to obtain compound 2 (retention time 3.205 minutes) and compound 2' (retention time 3.301 minutes).
- the obtained crude product was added with dichloromethane (460 mL), triethylamine (77.60 g, 766.87 mmol, 106.74 mL) and N,O-dimethylhydroxylamine hydrochloride (37.40 g, 383.43 mmol, ) were added under stirring, and the reaction solution was Stir at 20°C for 1 hour. Water (100 mL) was added, the layers were separated, and the aqueous phase was extracted with dichloromethane (50 mL ⁇ 2).
- the reaction solution was cooled to room temperature, water (10 mL) was added, extracted with ethyl acetate (10 mL ⁇ 2), the organic phase was washed with saturated brine (10 mL ⁇ 4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure .
- Compound 6-9 was detected by supercritical fluid chromatography (analysis method: column model: CHIRALCEL OD-3 (100mm ⁇ 4.6mm, 3 ⁇ m); mobile phase: [A: carbon dioxide, B: 0.05% diethylamine/ethanol]; Gradient: B%: increase from 5% to 40% in 4min, then hold for 2.5min; then hold 5% for 1.5min) analysis as a racemic compound by chiral separation (column type: DAICEL CHIRALCEL OD-H (25mm x 30mm) , 5 ⁇ m); mobile phase: [A: carbon dioxide, B: 0.1% ammonia water/ethanol]; gradient: B%: 40%-40%) to obtain compound 6-9A (retention time 4.024min) and compound 6-9B (retention time 4.024min) time 4.447min).
- the antiviral activity of the compounds against Influenza virus (IFV) was evaluated by determining the half effective concentration (EC 50 ) value of the compounds. Cytopathic assays are widely used to measure the protective effect of compounds on virus-infected cells to reflect the antiviral activity of compounds.
- MDCK cells were seeded in black 384-well cell culture plates at a density of 2,000 cells per well, and then placed in a 37°C, 5% CO2 incubator overnight. Compounds were diluted by Echo555 non-contact nanoliter sonic pipetting system and added to cell wells (4-fold dilution, 8 test concentration points). Influenza virus A/PR/8/34 (H1N1) strain was then added to cell culture wells at 1-2 90% tissue culture infectious dose (TCID90) per well at a final concentration of 0.5% DMSO in the medium. Virus control wells (DMSO added and virus added, no compound added), cell control wells (DMSO added, no compound and virus added) and medium control wells (medium only, no cells) were set up.
- the cytotoxicity assay and the antiviral activity assay of the compounds were performed in parallel, except that no virus was added, other experimental conditions were the same as the antiviral activity assay.
- Cell plates were placed in a 37°C, 5% CO2 incubator for 5 days. After 5 days of culture, the cell viability was detected using the cell viability detection kit CCK8. Raw data were used for compound antiviral activity and cytotoxicity calculations.
- the antiviral activity and cytotoxicity of the compounds were expressed by the inhibition rates (%) of the compounds against virus-induced cellular viral effects, respectively. Calculated as follows:
- the compounds of the present invention exhibited positive effects in the assay of inhibiting influenza virus replication at the cellular level.
- mice were infected with influenza A virus A/PR/8/34 (H1N1) by intranasal instillation, and were treated with compounds starting 48 hours after infection and administered orally for 7 consecutive days, twice a day.
- the anti-influenza A virus H1N1 effect of the compound in this model was evaluated by observing the changes in body weight and survival rate of mice.
- mice of SPF grade, 6-7 weeks old, female were selected for the experiment.
- the mice were acclimated for at least 3 days after arriving in the BSL-2 animal room to start the experiment.
- the day of infection was set as day 0 of the experiment.
- Mice were anesthetized by intraperitoneal injection of pentobarbital sodium (75 mg/kg, 10 mL/kg). After the animals entered deep anesthesia, they were infected with A/PR/8/34 (H1N1) virus by intranasal infusion, and the infection volume was 50 ⁇ L. From day 2 to day 8, the test compound was orally administered at 5 mg/kg (administration volume 10 mL/kg) twice a day. The first dose was 48 hours after infection. The state of the mice was observed every day, and the body weight and survival rate of the mice were recorded. On day 14, all surviving animals were euthanized.
- the results are shown in Table 4: Compound 5 can protect the animals with a maximum weight loss rate of 13.77% on the 7th day, and then began to recover, and the mouse survival rate was 100% at the end of the experiment; Compound 4 can protect the animals on the 3rd day. The maximum weight loss rate was 7.03%, and then began to recover, and the mouse survival rate was 100% by the end of the experiment.
- the compounds of the present invention show excellent body weight protection and early recovery time in the animal in vivo pharmacodynamic model.
- MDCK cells were seeded in 96-well cell culture plates at a density of 15,000 cells per well and cultured overnight in a 37°C, 5% CO2 incubator.
- Compound solution (3-fold serial dilution, 8 concentration points, triple wells) and Baloxavir-resistant A/PR/8/34 (H1N1) influenza virus strain were added the next day, and the final concentration of DMSO in cell culture medium was 0.5%.
- Cells were cultured in a 5% CO2 , 37°C incubator for 5 days until 80-95% cytopathic effect was achieved in virus-infected control wells without compound. Cell viability in each well was then assayed with CCK8. If the cell viability of the compound-containing wells is higher than that of the virus-infected control wells, that is, the CPE is weakened, it indicates that the compound has an inhibitory effect on the tested virus.
- the antiviral activity of the compound was expressed by the inhibitory activity (%) of the compound against the virus-induced cellular viral effect. Calculated as follows:
- the inhibitory activity and cell viability of the compounds were analyzed by nonlinear fitting of EC 50 using GraphPad Prism (version 5) software, and the fitting method was "log(inhibitor) vs.response--Variable slope".
- the experimental results are shown in Table 5.
- the compounds of the present invention show a positive effect in the assay of inhibiting the replication of Baloxavir-resistant A/PR/8/34 (H1N1) influenza virus strain at the cellular level.
- mice were infected with influenza A virus Baloxavir-resistant A/PR/8/34(H1N1) I38T strain by intranasal infusion, treated with compound starting 2 hours before infection, and administered orally for 7 consecutive days, twice a day .
- the anti-influenza A virus H1N1 effect of the compound in this model was evaluated by observing the changes in body weight and survival rate of mice.
- mice of SPF grade, 6-7 weeks old, female were selected for the experiment.
- the mice were acclimated for at least 3 days after arriving in the BSL-2 animal room to start the experiment.
- the day of infection was set as day 0 of the experiment.
- Mice were deeply anesthetized by intraperitoneal injection of sutai 50/xylazine hydrochloride, and then infected with Baloxavir-resistant A/PR/8/34(H1N1) I38T virus strain by intranasal infusion, and the infection volume was 50 ⁇ L.
- test compounds were administered orally at 15 mg/kg or 50 mg/kg (administration volume 10 mL/kg) twice a day.
- the first dose was 2 hours before infection.
- the state of the mice was observed every day, and the body weight and survival rate of the mice were recorded. On day 14, all surviving animals were euthanized.
- the experimental results are shown in Table 6 below. When compound 4 was administered at a dose of 50 mg/kg, the body weight of mice hardly decreased, and the survival rate of mice was 100% at the end of the experiment.
- the compounds of the present invention show excellent body weight protection and early recovery time in an animal pharmacodynamic model.
- Test protocol The test compounds were diluted into the plasma of the above five species with dialysis buffer, respectively, to prepare a sample with a final concentration of 2 ⁇ M, and then the sample was added to a 96-well equilibrium dialysis device with phosphate at 37 °C. The buffer solution was dialyzed for 4 hours. Warfarin was used as a control compound in the experiment. The concentrations of test compounds and warfarin in plasma and buffer were determined by LC-MS/MS method.
- H stands for human
- R stands for rat
- M stands for mouse
- D stands for dog
- C stands for cynomolgus monkey
- the compounds of the present invention have moderate plasma protein binding rates in the plasma of the five species, indicating that in the plasma of the above five species, the free drug concentration ratio of the tested compounds is moderate and has good drug properties.
- mice Male SD rats, 6-8 weeks old, weighing 200-300 grams;
- mice male beagle, ⁇ 6 months old, weighing 6-12 kg;
- Plasma: dichlorvos solution 40:1, and the dichlorvos solution was 40mM dichlorvos in acetonitrile/water (1:1) solution, within half an hour, at 4°C, 3000g After centrifugation for 10 minutes, the supernatant plasma was aspirated, quickly placed in dry ice, and stored in a -80°C refrigerator for LC-MS/MS analysis.
- the compound of the present invention has low clearance rate, long half-life time, high oral plasma exposure and good pharmacokinetic properties.
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Abstract
Description
化合物 | Dihedral 1(度) | Dihedral 2(度) | E(Kcal/mol) | ΔE(Kcal/mol) |
S-033447(活性构象) | -153.7 | 55.0 | 67.6 | 0 |
S-033447(低能构象) | -146.6 | 56.8 | 66.8 | 0.8 |
化合物A(低能构象) | 163.5 | 51.4 | 39.6 | 28 |
化合物B(低能构象) | -147.1 | 53.8 | 56.8 | 10.8 |
化合物 | Dihedral 1(度) | Dihedral 2(度) |
化合物B(低能构象) | -147.1 | 53.8 |
化合物 | EC 50(nM) |
化合物2 | 2.0 |
化合物2’ | 54.5 |
化合物3 | 2.8 |
化合物3’ | 157 |
化合物6’ | 0.75 |
化合物 | 最大体重下降率(第N天) | 存活率(百分比) |
化合物5 | 13.77%(第7天) | 100% |
化合物4 | 7.03%(第3天) | 100% |
化合物 | EC 50(nM) |
化合物2 | 133.7 |
化合物3 | 57.5 |
化合物 | 血浆蛋白结合PPB unbound(%) |
化合物3 | 25.9(H),31.3(R),13.7(M),24.6(D),31.6(C) |
化合物2 | 6.7(H),7.9(R),9.5(M),13.6(D),13.6(C) |
化合物 | Cl(mL/Kg/min) | T 1/2(h) | C max(nM) | AUC 0-last(nM·h) |
化合物3(i.v.) | 178 | 1.7 | / | 171 |
化合物4(po) | / | 2.9 | 332 | 946 |
化合物 | Cl(mL/Kg/min) | T 1/2(h) | C max(nM) | AUC 0-last(nM·h) |
化合物3(i.v.) | 36.8 | 3.7 | / | 830 |
化合物4(po) | / | 6.4 | 1100 | 3852 |
Claims (19)
- 式(VI)所示化合物或其药学上可接受的盐,其中,R 9选自H,E 1选自Se,X 1选自CR 10R 11,R 10和R 11与其共同连接的原子一起形成C 3-5环烷基;各R 12分别独立地选自H、F、Cl、Br、I、OH、NH 2、-COOH、C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基,所述C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基分别独立地任选被1、2或3个R b取代;T 1、T 2、T 3和T 4分别独立地选自CH和N;q选自0和1;t选自0、1、2、3和4;各R a和R b分别独立地选自H、F、Cl、Br和I;条件是,当T 1选自CH,且E 1选自Se,且E 2选自O,p选自1,q选自1时,各R 12分别独立地选自OH和NH 2。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,各R 12分别独立地选自F。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,E 1选自Se,E 2选自O。
- 根据权利要求1~10任意一项所述化合物或其药学上可接受的盐,其选自,其中,R 5和R 6分别独立地选自H、F、Cl、Br、I、OH和NH 2;R 9选自H,E 1选自Se,X 1选自CR 10R 11,R 10和R 11与其共同连接的原子一起形成C 3-5环烷基;E 1和E 2其中一个选自Se,另一个选自S和O;T 1选自CH和N;p和q分别独立地选自0和1;各R a分别独立地选自H、F、Cl、Br和I;条件是,当T 1选自CH,且E 1选自Se,且E 2选自O,p选自1,q选自1时,R 5和R 6分别独立地选自OH和NH 2;带“*”碳原子为手性碳原子,以(R)或(S)单一对映体形式或富含一种对映体形式存在。
- 根据权利要求14所述化合物或其药学上可接受的盐,其中,R 1和R 2分别独立地选自F。
- 根据权利要求14所述化合物或其药学上可接受的盐,其中,R 5和R 6分别独立地选自F。
- 根据权利要求1~18任意一项所述的化合物或其药学上可接受的盐在制备治疗与流感病毒相关疾病的药物中的应用。
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US18/271,162 US20240025921A1 (en) | 2021-01-08 | 2022-01-07 | Pyridone multiple-membered ring derivatives and use thereof |
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WO2024007997A1 (zh) * | 2022-07-05 | 2024-01-11 | 辉诺生物医药科技(杭州)有限公司 | 吡啶酮多并环类衍生物的晶型及其制备方法 |
WO2024074080A1 (zh) * | 2022-10-08 | 2024-04-11 | 石家庄迪斯凯威医药科技有限公司 | 一种抗流感病毒衍生物及其用途 |
CN117003771A (zh) * | 2022-11-09 | 2023-11-07 | 石家庄迪斯凯威医药科技有限公司 | 一种抗流感病毒衍生物及其用途 |
CN117003771B (zh) * | 2022-11-09 | 2024-02-02 | 石家庄迪斯凯威医药科技有限公司 | 一种抗流感病毒衍生物及其用途 |
WO2024098856A1 (zh) * | 2022-11-09 | 2024-05-16 | 石家庄迪斯凯威医药科技有限公司 | 一种抗流感病毒衍生物及其用途 |
WO2024098273A1 (zh) * | 2022-11-09 | 2024-05-16 | 石家庄迪斯凯威医药科技有限公司 | 一种抗流感病毒磷酸酯类化合物及其用途 |
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