CN110590768B - Heterocyclic compounds, compositions thereof and their use as anti-influenza virus agents - Google Patents
Heterocyclic compounds, compositions thereof and their use as anti-influenza virus agents Download PDFInfo
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- CN110590768B CN110590768B CN201810605064.2A CN201810605064A CN110590768B CN 110590768 B CN110590768 B CN 110590768B CN 201810605064 A CN201810605064 A CN 201810605064A CN 110590768 B CN110590768 B CN 110590768B
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- 150000002391 heterocyclic compounds Chemical class 0.000 title claims abstract description 24
- 206010022000 influenza Diseases 0.000 title claims description 34
- 241000700605 Viruses Species 0.000 title abstract description 18
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- 150000001875 compounds Chemical class 0.000 claims abstract description 75
- 238000002360 preparation method Methods 0.000 claims abstract description 28
- 239000003814 drug Substances 0.000 claims abstract description 26
- 239000003112 inhibitor Substances 0.000 claims abstract description 23
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- -1 fluoro-n-propyl Chemical group 0.000 claims description 46
- 239000002911 sialidase inhibitor Substances 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 229940042406 direct acting antivirals neuraminidase inhibitors Drugs 0.000 claims description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 230000003612 virological effect Effects 0.000 claims description 8
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- 239000001257 hydrogen Substances 0.000 claims description 7
- 208000015181 infectious disease Diseases 0.000 claims description 6
- 208000035473 Communicable disease Diseases 0.000 claims description 5
- 230000000840 anti-viral effect Effects 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
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- 125000006425 chlorocyclopropyl group Chemical group 0.000 claims description 2
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 claims description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 2
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 2
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- 125000000217 alkyl group Chemical group 0.000 description 17
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Classifications
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention provides a heterocyclic compound shown as a formula (I) or a pharmaceutically acceptable salt thereof, a preparation method thereof and application thereof in preparing a medicament for treating or preventing influenza virus. As a novel virus polymerase inhibitor, the compounds can inhibit the transcription and synthesis of influenza A virus RNA, and compared with the existing virus polymerase inhibitors, the compounds have the advantages of remarkably better activity, better water solubility and simpler structure.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a heterocyclic compound, a heterocyclic compound salt, a preparation method of the heterocyclic compound and an application of the heterocyclic compound salt as a medicament for treating and preventing influenza viruses.
Background
Influenza is a contagious disease that can be fatal, with high morbidity and mortality. 5-20% of people are infected with influenza virus every year, and other complications such as respiration or heart are caused, hundreds of thousands of people die each year worldwide, millions of people may die when influenza is pandemic, and tens of millions of people die after a major outbreak of influenza in the 20 th century. These pandemic influenza are caused by the mutation of influenza virus in animals and the transmission of the influenza virus from animal species to humans.
Influenza viruses belong to the orthomyxoviridae (orthomyxoviridae) family of antisense RNA viruses, including 5 species: type A viruses, type B viruses, type C viruses, Isavirus, and Thogoto viruses. Type a virus is a virus that is transmitted from birds to humans, has a high pathogenic rate, and is prevalent in large numbers with serious consequences. Different influenza viruses are classified according to the different serotypes of influenza a. For example, H1N1 caused spanish influenza in 1918, H2N2 caused asian influenza in 1957, H3N2 caused hong kong influenza in 1968, and H5N1 was the type of influenza between 2007 and 2008. Other examples include H1N2, H7N7, H9N2, H7N2, H7N3, and H10N 7.
The size of the influenza A virus particle is 80-120 nm. Its genome is not a single fragment of nucleic acid, but 8 fragments of antisense RNA. The 8 genomes of influenza a encode 11 proteins: hemagglutinin (HA), Neuraminidase (NA), Nucleoprotein (NP), M1, M2, NS1, NS2, PA, PB1, PB1-F2 and PB 2. HA and NA are macromolecular proteins outside the viral particle. HA is a lectin that mediates binding of the virus to target cells and entry of the viral genome into target cells, and NA is involved in the release of progeny viruses, so these proteins can all be targeted proteins for the development of influenza inhibitors.
The method of treating influenza is a vaccine or an antiviral drug. Since the vaccine is a main strain in the year every season, it is weak to infect patients other than the main strain or the elderly. In addition, influenza viruses mutate very quickly and vaccines need to be updated every year. If influenza is pandemic, it is a great challenge to be able to produce enough vaccines or to develop the right vaccine.
The standard antiviral drugs today are neuraminidase inhibitors, such as Oseltamivir (Oseltamivir) and Zanamivir (Zanamivir). These drugs can be used to treat influenza a and influenza B infected patients, but neuraminidase inhibitors must be treated within 48 hours of infection and may not be clinically effective in critically ill patients. In addition, influenza virus is highly mutated, and it has been reported that influenza H5N1 has resistance to neuraminidase inhibitors. The anti-influenza drugs have the function of preventing virus from spreading among human cells, and the drugs have no effect of preventing virus proliferation. Therefore, there is a need to develop new mechanisms and anti-influenza drugs with high efficacy, low toxicity and high mutation threshold to meet the needs of clinical and potential influenza outbreaks.
The polymerase of influenza viruses comprises three subunits: PB1, PB2 and PA, these three subunits being responsible for the replication and transcription of 8 RNA fragments. These three subunits are all targets for drug development. In the synthesis of viral mRNA, viral polymerase utilizes the host pre-mRNA as a primer for transcription by the "cap-snatchinging" mechanism, and the region of this mechanism is contained in the PB2 subunit for binding m7GTP of the m-RNA precursor. The PB2 inhibitor aiming at the region is an anti-influenza virus compound with a brand-new mechanism, and has great clinical application value.
The existing PB2 inhibitor is effective for influenza A virus, and can effectively inhibit known clinical serotype viruses, such as H1N1, H5N1 and the like. The PB2 inhibitor can effectively inhibit the transcription and synthesis of virus RNA, while the neuraminidase inhibitor has no effect on the synthesis of RNA. In addition, the neuraminidase inhibitor is effective for people with low virus infection, and the PB2 inhibitor has a protection effect on all MIOs, which indicates that the PB2 inhibitor has a good protection effect on severe patients. Unlike neuraminidase inhibitors which are only effective within 48 hours, PB2 inhibitors are still effective at 120 hours. Particularly, the combined medication of the PB2 inhibitor and the neuraminidase inhibitor greatly improves the clinical effect and prolongs the treatment time after the infection of the virus. The PB2 inhibitor and the PA endonuclease inhibitor are combined, and the animal model shows that the curative effect is better than that of a single medicament. In the future, the PB2 inhibitor, neuraminidase, PA endonuclease inhibitor and the like are combined, so that the rehabilitation of patients can be accelerated, and the survival rate of clinical patients can be improved.
Although some PB2 inhibitors have been reported in the prior art, the structures of the inhibitors are complex, the water solubility is poor, and the activity needs to be further improved. The development of novel PB2 inhibitors, either as replacements for or in combination with existing neuraminidase inhibitors and other anti-influenza drugs, is a clinically urgent need.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a novel heterocyclic compound which is a novel PB2 inhibitor, has remarkably stronger in-vitro activity for inhibiting influenza viruses and has more excellent pharmacokinetic properties.
In order to solve the technical problems, the invention adopts the following technical scheme:
the invention describes a heterocyclic compound shown in a formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate or a crystal thereof. In some embodiments of the invention described herein, isomers and other chemically protected forms having the structure represented by formula (I) are also provided, for example prodrug forms, esters and other prodrugs that include chemical hydrolysis or biodegradation to the acid. The heterocyclic compound provided by the invention has a structure shown in a formula (I),
wherein,
R1selected from F or Cl;
R2the compound is selected from C1-C8 alkyl, C3-C6 cycloalkyl, substituted C1-C8 alkyl and substituted C3-C6 cycloalkyl, wherein the substituent of the substituted alkyl and the substituted cycloalkyl is one or more independently selected from fluorine, chlorine, C1-C8 alkyl and C1-C8 alkoxy;
R3selected from hydrogen, hydrocarbyl carbonyl oxygen of C1-C8, hydrocarbyl of C1-C4, hydrocarbyl oxygen carbonyl oxygen of C1-C8, hydrocarbyl-of C1-C4;
z is selected from N or CH.
According to a preferred aspect of the present invention, in the formula (I), R2Is selected from C1-C8 alkyl, C3-C6 cycloalkyl, substituted C1-C8 alkyl and substituted C3-C6 cycloalkyl, wherein the substituent groups in the substituted alkyl and the substituted cycloalkyl are independently one or more selected from fluorine, chlorine, C1-C8 alkyl and C1-C8 alkoxy. More preferably, in formula (I), R2Is selected from C1-C6 alkyl, C3-C6 cycloalkyl, substituted C1-C6 alkyl and substituted C3-C6 cycloalkyl, wherein the substituent groups in the substituted alkyl and the substituted cycloalkyl are independently one or more selected from fluorine, chlorine, C1-C3 alkyl and C1-C3 alkoxy.
According to some particularly preferred embodiments of the invention, in formula (I), R2Selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoro-isopropyl, fluoro-cyclopropyl, fluoro-cyclobutyl, fluoro-cyclopentyl, fluoro-cyclohexyl, chloromethyl, chloroethyl, chloro-n-propyl, chloro-isopropyl, chloro-cyclopropyl, chloro-cyclobutyl, chloro-cyclopentyl, chloro-cyclohexyl, methoxy-substituted methyl, methoxy-substituted ethyl, methoxy-substituted cyclopropyl, methoxy-substituted cyclobutyl, ethoxy-substituted methylEthyl, ethoxy-substituted cyclopropyl, ethoxy-substituted cyclobutyl.
According to the invention, when the other groups constituting the compound are the same, for example, R as defined above2Replacement of a group with other possible groups, such as a thiophene ring or the like that forms an annulated structure with a pyrimidine ring, will result in a significant decrease in the water solubility of the compound, unstable metabolism, and in many cases a decrease in the activity of the compound.
According to still another preferred aspect of the present invention, in the formula (I), R3Selected from hydrogen, alkyl carbonyl oxygen of C1-C8, alkyl of C1-C4 and alkoxy carbonyl oxygen of C1-C8, and alkyl of C1-C4. More preferably, in formula (I), R3Selected from hydrogen, alkyl carbonyl oxygen of C1-C4, alkyl of C1-C2 and alkoxy carbonyl oxygen of C1-C4, and alkyl of C1-C2.
According to some particularly preferred embodiments of the invention, R3Selected from the group consisting of hydrogen, methylcarbonyloxymethyl-, methylcarbonyloxy 1-ethyl-, ethylcarbonyloxymethyl-, isopropylcarbonyloxymethyl-, tert-butylcarbonyloxymethyl-, methoxycarbonyloxymethyl-, methoxycarbonyloxy 1-ethyl-, ethoxycarbonyloxymethyl-, isopropoxycarbonyloxymethyl-, n-butyloxycarbonyloxymethyl-, isopropyloxycarbonyloxy 1-ethyl-.
In some embodiments according to the invention, R in formula (I)1Is Cl; r2Selected from methyl or cyclopropyl; r3Selected from alkyl carbonyl oxygen of H, C1-C8, alkyl of C1-C4, alkoxy carbonyl oxygen of C1-C8, and alkyl of C1-C4; z is selected from N or CH.
In still other embodiments according to the present invention, R in formula (I)1Is F; r2Selected from methyl or cyclopropyl; r3Selected from alkyl carbonyl oxygen of H, C1-C8, alkyl of C1-C4, alkoxy carbonyl oxygen of C1-C8, and alkyl of C1-C4; z is selected from N or CH.
In still other embodiments according to the invention, R in formula (I)1Is F; r2Is methyl; r3Is H; z is selected from CH or N.
In still other embodiments according to the present invention, R in formula (I)1Is F; r2Is cyclopropylA group; r3Is H; z is selected from CH or N.
According to a preferred aspect of the present invention, in formula (I), Z is N.
According to the present invention, typical heterocyclic compounds represented by the general formula (I) are those represented by the following formula (I-1), formula (I-2), formula (I-3), formula (I-4), formula (I-5), formula (I-6), formula (I-7), formula (I-8), formula (I-9), formula (I-10), formula (I-11), formula (I-12), formula (I-13), formula (I-14), formula (I-15), formula (I-16), formula (I-17), formula (I-18), formula (I-19), formula (I-20), formula (I-21), formula (I-22), formula (I-23), formula (I-24), formula (I-25), formula (I-26), A compound represented by the formula (I-27), the formula (I-28), the formula (I-29), the formula (I-30), the formula (I-31), the formula (I-32), the formula (I-33), the formula (I-34), the formula (I-35), the formula (I-36), the formula (I-37), the formula (I-38), the formula (I-39) or the formula (I-40).
The present invention also provides a process for producing the heterocyclic compound represented by the general formula (I) of the present invention, which comprises:
(1) the compound A and the compound B are subjected to coupling reaction in the presence of a transition metal catalyst to obtain a compound C, and R related in the compound A, B, C1、R2、R3And Z is as defined above, P in compound A, C represents an amino protecting group; .
(2) Subjecting the compound C to basic hydrolysis and removal of the amino-protecting group to give a heterocyclic compound represented by the formula (I).
In the step (1), the transition metal catalyst may specifically be, for example, a palladium catalyst. A classical palladium catalyst is Pd (PPh)3)4(Ph＝phenyl),Pd(PPh3)2Cl2,Pd(dppf)2Cl2(dppf＝1,1’-Bis(diphenylphosphino)-ferrocene),Pd(acac)2(acac＝acetylacetonate),PdCl2(PCy3)2(PCy＝cyclohexyl),Pd2(dba)3(dba ═ dibenzylideneacetone), etc., these palladium catalysts are preferably used in combination with a phosphorus reagent for the coupling reaction.
The above-mentioned amino protecting group may be those known in the art, and is not particularly limited, and specifically, for example, p-toluenesulfonyl, 2- (trimethylsilyl) ethoxymethyl, tetrahydropyranyl or trityl, etc.
According to some embodiments of the invention, where formula A, C, (I) is where Z is CH and P is P-toluenesulfonyl, an exemplary implementation of step (2) is as follows: alkaline hydrolysis is carried out in the presence of inorganic base, and p-toluenesulfonyl and ethyl ester are sequentially removed to obtain the target product.
According to other embodiments of the present invention, in formula A, C, (I) where Z is N and P is tetrahydropyranyl or trityl, one exemplary implementation of step (2) is as follows: tetrahydropyranyl or trityl groups were removed with trifluoroacetic acid (TFA) and then basic hydrolysis was performed in the presence of an inorganic base.
The inorganic base is not particularly limited, and examples thereof include lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like.
The invention also provides a prodrug of anti-influenza, which has a structure shown in a formula (II),
wherein R is1、R2Z is as defined above，R4Is selected from alkyl carbonyl-of C1-C8 or alkoxy carbonyl-of C1-C8. The prodrug design improves the physicochemical properties of the compound, enhances absorption, increases the bioavailability of the compound, and reduces the possible clinical dose. Prodrugs may in particular be, for example, the following compounds:
the heterocyclic compound and the salt thereof have strong activity of inhibiting influenza viruses, are about 4-10 times higher than the activity of the similar compound clinically at present, have excellent pharmacokinetic characteristics and have strong drug forming property. The introduction of hydrophobic substituent groups such as methyl and cyclopropyl can effectively enhance the interaction with a hydrophobic cavity of a PB2 subunit, and the activity of the compound is improved; meanwhile, the pyrimidine ring can be shielded, the site of oxidation of pyrimidine heterocycle by P450 oxidase is blocked, and the instability of compound metabolism is reduced. The high-activity compound or prodrug can be combined with neuraminidase inhibitor, PA endonuclease inhibitor or other anti-influenza drugs to provide drugs for preventing or rapidly curing influenza virus infection clinically.
The invention further provides a pharmaceutical composition containing the heterocyclic compound provided by the invention, an isomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition further comprises one or more therapeutic agents selected from neuraminidase inhibitors, PA endonuclease inhibitors, or other anti-influenza drugs.
The invention provides application of the heterocyclic compound or an isomer, a pharmaceutically acceptable salt, a hydrate, a solvate, a crystal or a pharmaceutical composition containing the heterocyclic compound in preparation of a medicament for treating or preventing influenza virus.
Preferably, the invention provides the application of the heterocyclic compound or the isomer, the pharmaceutically acceptable salt, the hydrate, the solvate, the crystal or the pharmaceutical composition containing the heterocyclic compound in preparing anti-influenza medicaments such as PB2 inhibitors and the like.
The invention also provides application of the pharmaceutical composition in preparing a medicament for treating or preventing influenza virus infection and a method for treating or preventing diseases of patients infected by the influenza virus by using the pharmaceutical composition.
The pharmaceutical composition according to the invention, wherein the compound of the invention is preferably present in a therapeutically effective amount.
The pharmaceutically acceptable carrier in the pharmaceutical composition may be, for example, pharmaceutically acceptable diluents, excipients, fillers, binders, disintegrants, absorption enhancers, surfactants, lubricants, flavoring agents, sweeteners, etc.
The medicine prepared by taking the compound of the invention as an active ingredient can be various forms such as tablets, powder, capsules, granules, oral liquid, injection preparations and the like. The dosage form of the pharmaceutical composition is preferably tablets, capsules or injections.
The medicaments in various dosage forms can be prepared by the conventional method in the pharmaceutical field.
The invention also provides the use of a compound of the invention in the preparation of a medicament for the prophylaxis or treatment of a viral infectious disease, preferably wherein the viral infectious disease is an influenza virus infection.
In one specific aspect of the present invention, the pharmaceutical composition of the present invention may comprise:
due to the implementation of the technical scheme, compared with the prior art, the invention has the following advantages:
the invention provides a novel heterocyclic compound, which has great advantages compared with the existing neuraminidase inhibitor widely used, and the compounds are shown as a strong influenza A virus inhibitor and effectively inhibit the replication and synthesis of virus RNA. These compounds still have potent protective effects against both severe cases and those with influenza infection for 120 hours, whereas neuraminidase inhibitors are effective only for 48 hours and are not effective in cases with severe influenza infection. The heterocyclic compound has strong PB2 inhibitory activity, excellent pharmacokinetic properties and strong drug forming property.
Further, according to the compound of the present invention, the hydrogen atom adjacent to the nitrogen atom of the pyrimidine ring structure is substituted by methyl, cyclopropyl and the like, compared with other substituents such as thiophene ring and the like, the substituents can block the oxidation of P450 better, reduce the metabolic instability of the compound, and facilitate the improvement of the bioavailability of the drug and the reduction of the dosage of the clinical drug.
Further, based on the structural analysis of the co-crystal, R is on the pyrimidine ring structure2The substituted position is a hydrophobic cavity, and the newly generated hydrophobic effect reduces the binding energy of the compound, so that the inhibitory activity of the compound is greatly improved.
The compound of the invention is used for treating clinical influenza patients or used as stock drugs for preventing large influenza by being used alone or being combined with neuraminidase inhibitors, PA endonuclease inhibitors or other anti-influenza drugs.
Furthermore, the heterocyclic compound provided by the invention is simple in structure and can be prepared at a lower cost.
Detailed Description
Definition of terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The term "isomer" refers to isomers resulting from the difference in the arrangement of atoms in a molecule in space. Including cis-trans isomers, enantiomers, and conformers. All stereoisomers are within the scope of the present invention. The compounds of the invention may be individual stereoisomers or mixtures of other isomers, such as racemates, or mixtures of all other stereoisomers.
The term "salt" refers to a pharmaceutically acceptable salt of a compound of the invention with an acid, which may be an organic or inorganic acid, and is specifically selected from: phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid, or the like.
The term "solvate" refers to a form of a compound of the present invention that forms a solid or liquid complex by coordination with a solvent molecule. Hydrates are a special form of solvates in which coordination occurs with water. Within the scope of the present invention, the solvate is preferably a hydrate.
The term "crystalline" refers to the various solid forms formed by the compounds of the present invention, including crystalline forms, amorphous forms.
The term "hydrocarbyl" refers to a straight, branched, or cyclic, saturated or unsaturated substituent consisting essentially of carbon and hydrogen. Preferably 1 to 20 carbon atoms, more preferably 1 to 12 carbon atoms. The term "alkyl" refers to a straight, branched, saturated hydrocarbon group. Alkyl includes in particular methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, n-hexyl, isohexyl, 2, -methylbutyl and 2, 3-dimethylbutyl, 16-alkyl, 18-alkyl. The term "C1-20 alkyl" refers to straight chain, branched chain saturated hydrocarbon radicals containing from 1 to 20 carbon atoms. Substituted alkyl refers to alkyl substituted with a substituent. When the alkyl group is substituted, the substituent may be substituted at any available point of attachment, and the substituent may be mono-or poly-substituted. The substituents are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxy, nitro, carboxy, ester, cyano, cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, oxo, the substituents usually preceded by alkyl when named.
The term "cycloalkyl" refers to a saturated and/or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group. A single ring may comprise 3-10 carbon atoms. Non-limiting examples of monocyclocycloalkane groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl and the like. Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl includes unsubstituted and substituted. The substituent is selected from one or more substituent groups, including but not limited to the following groups, independently selected from alkyl, cycloalkyl, alkoxy, halogen, carboxyl, ester group, amino, amido, hydroxyl, cyano, nitro, aryl, heteroaryl.
The term "halogen" means fluorine, chlorine, bromine, iodine, preferably fluorine, chlorine, bromine.
The term "haloalkyl" refers to an alkyl group substituted with at least one halogen atom.
The following examples are presented to enable one of ordinary skill in the art to more fully understand the present invention and are not intended to limit the invention in any way. All compounds have the structure1H NMR or MS.
The compound names used in the examples are abbreviated as follows:
DCM: dichloromethane; EtOAc: ethyl acetate; THF, tetrahydrofuran; DME: ethylene glycol dimethyl ether; 1, 4-Dioxane: 1, 4-dioxane; pd2(dba)3: tris (dibenzylideneacetone) dipalladium; xantphos: 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene; tBuONa: sodium tert-butoxide; TsCl: p-toluenesulfonyl chloride; DIPEA: diisopropylethylamine; pd (dppf) Cl2: [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride; mCPBA: m-chloroperoxybenzoic acid; x-phos: 2-dicyclohexylphosphonium-2, 4, 6-triisopropylbiphenyl.
The preparation methods of compound Int-1 and compound Int-2 in the following examples are as follows.
Preparation of (1S, 2S, 3S, 4R) -3-aminobicyclo [2.2.2]Oct-5-ene-2-carboxylic acid ethyl ester trifluoroacetate salt (Compound No.)
Substance Int-1)
Preparation of compound 2:
maleic anhydride (10g,0.1mol) was dissolved in chloroform (100mL), cooled to 0 ℃ and 1, 3-cyclohexadiene (11.2mL,0.11mol) was added dropwise to the reaction mixture, and after the addition, the temperature was slowly raised to room temperature and the mixture was stirred overnight in the absence of light. The reaction was concentrated, methanol (70mL) was added, heated to 50 ℃, stirred for 10min, ice-cooled to 0 ℃, stirred for 30min, filtered and dried to give compound 2(14g, 71%) as a white solid.1H NMR(400MHz,CDCl3):δ6.31-6.32(m,2H),3.21-3.22(m,2H),3.14-3.16(m，2H),1.60-1.64(m,2H),1.59-1.60(m,2H).13C NMR(100MHz,CDCl3)δ:172.9,133.1,44.6,31.6,22.8.
Preparation of compound 3:
compound 2(24.6g,138.0mmol) and quinine (49.2g,151.6mmol) were suspended in anhydrous toluene (92mL), the reaction was cooled to-16 deg.C, anhydrous ethanol (52.4mL,898.6mmol) was added dropwise, the reaction was allowed to react at-20 deg.C for 20h, filtered, the filter cake was washed with a small amount of cooled toluene and dried at room temperature to give compound 3(57g, 75%) as a white solid.
Preparation of compound 4:
suspending compound 3(5.77g, 10.5mmol) in toluene (29mL), adding 6N hydrochloric acid (3.9mL) under ice bath, heating to room temperature, stirring below 25 ℃ until the solid becomes liquid completely, standing for about 1 hour, separating the organic phase, washing the aqueous phase with toluene (10mLx2), combining the organic phases, adding anhydrous sodium sulfate (6g), stirring in a refrigerator below 5 ℃ for 8-12 hours under sealed conditions, filtering the reaction solution through a funnel filled with anhydrous sodium sulfate, washing a small amount of toluene, cooling the obtained toluene solution to-20 ℃, slowly adding potassium tert-amylate (1.7M, 8mL), strongly stirring, adding dropwise, stirring at-20 ℃ for 30-40 minutes, adding acetic acid (0.3mL), adding 2N hydrochloric acid (8.1mL), stirring at about 5 ℃ for 30 minutes, standing, separating the aqueous phase, washing the organic phase with a buffer solution (2mL x3) (the preparation of the buffer solution is 7.9g of sodium dihydrogen phosphate and 1.3g of phosphorus phosphate and the organic phase is prepared by 7.9g Disodium hydrogen acid and 143mL of purified water), toluene was distilled off to obtain an oily liquid, heptane (2mL) was added, and the mixture was stirred at 40 ℃ for 30 minutes and placed in a 0 ℃ freezer overnight, and the resulting crystals were washed with a small amount of heptane to obtain 1.5g of colorless crystals (64%).
1H NMR(400MHz,CDCl3):δ11.74(brs,1H),6.37(t,J＝7.2Hz,1H),6.22(t,J＝7.2Hz,1H),4.14-4.22(m,2H),3.20(dd,J＝2.4Hz,J＝5.6Hz,1H),3.05-3.07(m,1H),2.95-2.97(m,1H),2.83-2.85(m,1H),1.61-1.67(m,1H),1.45-1.52(m,1H),1.30-1.34(m,1H),1.25(t,J＝7.2Hz,3H),1.09-1.17(m,1H).13C NMR(100MHz,CDCl3):δ180.4,173.7,134.6,132.5,60.9,45.8,45.1,32.5,32.3,24.3,20.2,14.2.
Preparation of compound 5:
triethylamine (5.8mL,41.6mmol) was slowly added to a solution of Compound 4(4.3g,19.1mmol) in toluene (50mL), then warmed to 95 deg.C, DPPA (diphenylphosphoryl azide) (4.1mL,19.0mmol) was added dropwise, reacted at 96 deg.C for 1 hour, t-butanol (3.6mL,38.2mmol) was added, reacted at 96 deg.C overnight, cooled to room temperature, Boc was added2O (4.1g,19.0mmol), stirred overnight, poured into saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated brine, concentrated, and purified by column chromatography to give 1.1g of compound 5.
Preparation of Compound Int-1:
trifluoroacetic acid (5mL) was added dropwise to an ice-cooled solution of compound 5(2g,6.7mmol) in dichloromethane (10mL) over 5 minutes, stirring was continued for 30 minutes while cooling, TLC showed almost complete consumption of starting material, dichloromethane and trifluoroacetic acid were evaporated under reduced pressure, diethyl ether (5mL) was added, stirring was carried out, diethyl ether was evaporated under reduced pressure, and the resulting solid was washed twice with diethyl ether to give a white solid, compound Int-1, 1.5g, 78%.
1H NMR(400MHz,DMSO-d6):δ7.95(brs,3H),6.50(t,J＝7.2Hz,1H),6.17(t,J＝7.2Hz,1H),4.09-4.19(m,2H,3.66(m,1H),2.87-32.89(m,1H),2.80-2.81(m,1H),2.30(m,1H),1.48-1.53(m,1H),1.20-1.35(m,5H),1.02-1.09(m,1H).13C NMR(100MHz,DMSO-d6):δ172.1,136.2,130.4,61.2,51.4,48.8,33.0,32.9,22.7,19.5，14.4.
Preparation of 5-fluoro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-
1H-pyrrolo [2,3-b]Pyridine (Compound Int-2)
Preparation of compound 7: n-bromosuccinimide (NBS,5.29g,29.7mmol) was added to a solution of Compound 6(4.50g,33mmol) in dichloromethane (100mL) and reacted at room temperature for 19 hours, after completion of the reaction, a saturated sodium bisulfite solution (200mL) was added, the organic layer was separated, washed with 20% sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give crude 4.62 g.
Preparation of compound 8: compound 7(4.40g, 20.4mmol) was dissolved in 30mL dry DMF and sodium hydride (1.30g,32.6mol) was added and stirred for 30 min. Then p-toluenesulfonyl chloride (5.78g,30.6mmol) was added and reacted for 4 hours. After the reaction, the mixture was poured into an ice-water mixture to precipitate a solid, which was filtered, the filter cake was washed with petroleum ether, and the crude product was recrystallized from ethyl acetate to give 3.10g of Compound 8. Yield: 42.1 percent.
Preparation of compound int-2: compound 8(1.50g,4.05mmol), bis-pinacolato borate (3.089g,12.16mmol), Pd (dppf) Cl2(0.296g,0.41mmol) and potassium acetate (1.193g,12.16mmol) were added to 25mL of 1,4-dioxane, nitrogen was bubbled through to remove oxygen from the system, the mixture was heated under reflux for 19 hours, spun dry, the crude product was dissolved in ethyl acetate (150mL), filtered through a silica gel pad, and the product was recrystallized from methyl tert-butyl ether (4.5mL) and petroleum ether (15mL) to give 0.605g of product. Yield: 35.9 percent.
The invention will be further described with reference to specific examples:
example 1: preparation of (2S, 3S) -3- ((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -6-methylpyrimidin-4-yl) amino) bicyclo [2.2.2] oct-5-ene-2-carboxylic acid (I-1)
Preparation of compound 1 b:
methyl magnesium bromide (27mL,0.027mol,1M tetrahydrofuran solution) was added to a three-necked flask, cooled to 0 deg.C, added with a tetrahydrofuran solution (10mL) of Compound 1a (2.990g,0.018mol), and stirred at 10-15 deg.C for 1 h; cooled to 0 ℃ and triethylamine (2.5mL,0.018mol) and I were added dropwise in that order2(4.960g,0.018mol) in THF (60mL), after addition the temperature was maintained for 1h and then overnight at room temperature. The mixture was washed with sodium hydrogen sulfite solution, extracted with ethyl acetate (150mL) 3 times, and the ethyl acetate layers were combined, washed with water (200mL) and saturated brine (200mL) in this order, dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by silica gel column chromatography (PE/EA ═ 100/5) to give 1.010g of pale yellow oil, which was compound 1 b.
Preparation of compound 1 c:
compound 1b (0.130g,0.718mmol), compound Int-1(0.204g,0.718mmol) and DIPEA (0.401g,2.730mmol) were added sequentially to tetrahydrofuran (30mL) and absolute ethanol (2mL), heated to reflux and stirred for 12 h. After quenching with water, ethyl acetate (30mL) was extracted 2 times, the ethyl acetate layers were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (PE/EA ═ 20/1 to 10/1) to obtain 0.115g of a pale yellow oil, which was compound 1 c.
Preparation of compound 1 d:
compound 1c (0.115g,0.338mmol), compound Int-2(0.311g,0.745mmol) and sodium carbonate (0.110g,1.02mmol) were charged into a 100mL single-neck flask, replaced with nitrogen three times, and Pd was added2(dba)3(0.016g,0.016mmol) and X-phos (0.040g,0.085mmol) were purged with nitrogen three times, 2-methyltetrahydrofuran (5mL) and water (1mL) were added, purged with nitrogen three times again, and heated to reflux for 7 h. Cooling to room temperature, directly stirring the crude product with silica gel column chromatography (PE: EA is 15:1) to purify to obtain light yellow solid 0.199g,i.e. compound 1 d.
1HNMR(400MHz,CDCl3)δ:8.63(dd,1H,J1＝2.8Hz,J2＝8.4Hz),8.59(s,1H),8.32(d,1H,J＝2.0Hz),8.15(d,2H,J＝8.4Hz),7.31(s,1H),6.61(t,1H,J1＝7.2Hz,J2＝7.6Hz),6.32(t,1H,J1＝6.8Hz,J2＝7.6Hz),4.89-4.80(m,2H),4.32-4.17(m,2H),2.99-2.96(m,1H),2.93-2.90(m,1H),2.41(d,3H,J＝2.8Hz),2.40(s,3H),2.25-2.23(m,1H),1.91-1.85(m,1H),1.73-1.72(m,1H),1.57-1.46(m,1H),1.38-1.33(m,1H),1.26-1.15(m,4H).
Preparation of Compound I-1:
compound 1d (0.190g,0.320mmol) was dissolved in methanol (2mL) and dioxane (2mL), and an aqueous solution of lithium hydroxide (0.055g,1.280mmol,2mL water) was added and after the addition was complete, the reaction was heated to reflux for 3 h. Concentrated to dryness under reduced pressure, dissolved in ethyl acetate (20mL) and water (20mL), adjusted to pH 6 with 1N hydrochloric acid, extracted 3 times with ethyl acetate (20mL), combined with ethyl acetate layers, washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure, and subjected to crude silica gel column chromatography (PE/EA 5:1) to obtain 0.065g of a pale yellow solid, i.e., compound I-1.
1HNMR(400MHz,CDCl3)δ:11.68(s,1H),8.71(dd,1H,J1＝2.4Hz,J2＝8.8Hz),8.58(d,1H,J＝2.0Hz),8.01(t,1H,J1＝2.0Hz,J2＝7.2Hz),6.71(t,1H,J1＝7.2Hz,J2＝7.2Hz),6.44(t,1H,J1＝6.4Hz,J2＝8.0Hz),5.31(m,1H),4.90(m,1H),3.15-3.13(m,1H),2.85(m,1H),2.42(d,1H,J＝4.8Hz),2.35(m,1H),1.91-1.76(m,2H),1.50-1.42(m,1H),1.24-1.18(m,4H).
LC/MS m/z：412.1(M+H).
Example 2: preparation of (2S, 3S) -3- (6-cyclopropyl-5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -pyrimidin-4-yl) amino) bicyclo [2.2.2] oct-5-ene-2-carboxylic acid (I-7)
Preparation of compound 7 b:
cyclopropyl magnesium bromide (27mL,27.000mmol,1M tetrahydrofuran solution) was added to a three-necked flask, cooled to 0 deg.C, and compound 1a (2.980g,17.850mmol) was addedTetrahydrofuran solution (20mL), after dropping at 10-15 deg.C, stirring for 1h, cooling to 0 deg.C, and sequentially dropping triethylamine (2.5mL,17.850mmol) and I2(4.960g,17.850mmol) in THF (60mL) was stirred at this temperature for 1h after the addition was complete and then at room temperature overnight. The mixture was washed with sodium hydrogen sulfite solution, extracted with ethyl acetate (150mL) 3 times, and the ethyl acetate layers were combined, washed with saturated brine (200mL), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (PE/EA ═ 100/5) to give 2.310g of a pale yellow solid, i.e., compound 7 b.
Preparation of compound 7 c:
compound 7b (0.082g,0.396mmol), Int-1(0.115g,0.396mmol) and DIPEA (0.194g,1.505mmol) were added to tetrahydrofuran (15mL) and absolute ethanol (1mL) in that order, heated to reflux and stirred for 6h, and the TLC detection reaction was complete. And adding one more batch according to the feeding amount and operation, combining the two batches of reaction liquid after the second batch of reaction is finished, adding water for quenching, extracting for 2 times by using ethyl acetate (30mL), combining ethyl acetate layers, washing by using saturated saline solution (30mL), drying by using anhydrous sodium sulfate, concentrating under reduced pressure to dryness, and purifying by using silica gel column chromatography (PE/EA is 100/5) to obtain 0.154g of light yellow solid, namely the compound 7 c.
Preparation of compound 7 d:
compound 7c (0.154g,0.421mmol), int-2(0.386g,0.926mmol) and sodium carbonate (0.134g,1.260mmol) were charged into a 100mL single-necked flask, and Pd was added after three-time replacement with nitrogen2(dba)3(0.019g,0.021mmol) and X-phos (0.050g,0.105mmol), three times with nitrogen substitution; 2-methyltetrahydrofuran (5mL) and water (1mL) were added, the mixture was again replaced with nitrogen three times, and the mixture was heated to reflux for 7 h. Cooling to room temperature, and purifying the crude product by direct silica gel column chromatography (PE: EA ═ 10:1) to obtain 0.250g of a solid, i.e., compound 7 d.
1HNMR(400MHz,CDCl3)δ:8.54(s,1H),8.46(dd,1H,J1＝2.8Hz,J2＝9.2Hz),8.31(d,1H,J＝2.0Hz),8.14(d,2H,J＝8.4Hz),7.32(s,1H),6.59(t,1H,J1＝8.0Hz,J2＝7.2Hz),6.33(t,1H,J1＝6.8Hz,J2＝7.6Hz),4.87-4.78(m,2H),4.37-4.14(m,2H),2.98-2.95(m,1H),2.92-2.90(m,1H),2.39(s,3H),2.26-2.22(m,2H),1.92-1.86(m,1H),1.72-1.66(m,1H),1.46-1.39(m,1H),1.30-1.26(m,1H),1.24-1.18(m,5H),1.08-1.05(m,2H).
Preparation of Compound I-7:
compound 7d (0.240g,0.387mmol) was dissolved in methanol (2mL) and dioxane (2mL), and an aqueous solution of lithium hydroxide (0.068g,1.548mmol,2mL water) was added and after the addition was complete, the reaction was heated to reflux for 3 h. Concentrated to dryness under reduced pressure, dissolved in ethyl acetate (20mL) and water (20mL), adjusted to pH 6 with 1N hydrochloric acid, extracted 3 times with ethyl acetate (20mL), combined with ethyl acetate layers, washed with saturated brine, dried over sodium sulfate, concentrated to dryness under reduced pressure, and purified by crude thin layer chromatography (DCM: MeOH ═ 15:1) to give 0.067g of a pale yellow solid, i.e., compound I-7.
1HNMR(400MHz,CDCl3)δ:11.68(s,1H),8.58(d,1H,J＝2.4Hz),8.46(dd,1H,J1＝2.8Hz,J2＝9.2Hz),7.99(t,1H,J＝2.4Hz),6.69(t,1H,J1＝4.0Hz,J2＝7.2Hz),6.44(t,1H,J1＝6.4Hz,J2＝7.2Hz),5.29(d,1H,J＝9.6Hz),4.87(d,1H,J＝9.2Hz),3.15-3.12(m,1H),2.87-2.85(m,1H),2.35-2.34(m,1H),2.28-2.25(m,1H),1.88-1.76(m,2H),1.50-1.43(m,1H),1.32-1.22(m,4H),1.08-1.06(m,2H).
LC/MS m/z：438.0(M+H).
Example 3: in vitro bioactivity and cytotoxicity studies
Test compounds: compound I-1 of the present invention, Compound I-7 of the present invention, and control compound VX-787 (Pimodivir). Test methods for in vitro bioactivity studies: MDCK cells were seeded into 384-well cell culture plates at a density of 2,000 cells per well, and then placed in a 5% CO2 incubator at 37 ℃ overnight. The next day the compounds were diluted and added to the wells individually (3 fold-rate dilution, 8 concentration points tested), and influenza a/PR/8/34(H1N1) strain was subsequently added to the cell culture wells at 2 x TCID90 per well, with a final DMSO concentration of 0.5% in the culture medium. The cell plates were incubated at 37 ℃ with 5% CO2Culturing in an incubator for 5 days. After 5 days of culture, cell viability was measured using CCK8 cell viability assay kit. Carrying out nonlinear fitting analysis on the inhibition rate and cytotoxicity of the compound by using GraphPad Prism software on the raw data to obtain EC50Values (see table 1 for results).
Study methods for cytotoxicity study: the cytotoxicity test and the antiviral activity test of the compound are carried out in parallel, and other test conditions are consistent with the antiviral activity test except that no virus is added. After 5 days of culture, cell viability was measured using CCK8 cell viability assay kit. The raw data were used for compound cytotoxicity (CC50) calculations (results see table 1).
TABLE 1 inhibitory Activity and toxicity of Compounds against influenza A/PR/8/34(H1N1)
And (4) conclusion: compounds I-1 and I-7 have excellent activity, EC, for inhibiting H1N150Less than 1nM and has very low cytotoxicity.
The other compounds of the present invention have substantially the same structures as compounds I-1 and I-7, and they are expected to have excellent activities comparable to compounds I-1 and I-7.
In addition, compared with the existing PB2 inhibitor, the compound disclosed by the invention has the advantages of simple structure, good solubility, high bioavailability, stable metabolism and the like.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (5)
1. A heterocyclic compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,
wherein R is1Selected from F or Cl;
R2selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoro-isopropyl, fluoro-cycloPropyl, chloromethyl, chloroethyl, chloro-n-propyl, chloro-isopropyl, chloro-cyclopropyl, methoxy-substituted methyl and methoxy-substituted ethyl;
R3selected from hydrogen;
z is selected from CH.
2. The heterocyclic compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is a compound represented by the formula (I-1), the formula (I-2), the formula (I-3), the formula (I-4), the formula (I-7), the formula (I-8), the formula (I-9), the formula (I-13), the formula (I-14) or the formula (I-15),
3. a pharmaceutical composition comprising the heterocyclic compound or its pharmaceutically acceptable salt according to claim 1 or 2, which is an antiviral pharmaceutical composition, optionally further comprising one or more therapeutic agents selected from the group consisting of: neuraminidase inhibitors, nucleosides, PB2 inhibitors, PB1 inhibitors or M2 inhibitors.
4. Use of the heterocyclic compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 3 for the preparation of a medicament for the prophylaxis and/or treatment of viral infectious diseases.
5. The use according to claim 4, wherein the viral infectious disease is an infectious disease caused by influenza type A or influenza type B.
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| CN102458408A (en) * | 2009-06-17 | 2012-05-16 | 沃泰克斯药物股份有限公司 | Inhibitors of influenza viruses replication |
| CN103492381A (en) * | 2010-12-16 | 2014-01-01 | 沃泰克斯药物股份有限公司 | Inhibitors of influenza viruses replication |
| WO2017097234A1 (en) * | 2015-12-09 | 2017-06-15 | Sunshine Lake Pharma Co., Ltd. | Inhibitors of influenza virus replication, application methods and uses thereof |
| WO2017133667A1 (en) * | 2016-02-05 | 2017-08-10 | Savira Pharmaceuticals Gmbh | Pyrimidine and pyridine derivatives and use in treatment, amelioration or prevention of influenza thereof |
| WO2018041263A1 (en) * | 2016-09-05 | 2018-03-08 | 广东众生药业股份有限公司 | Anti-influenza virus pyrimidine derivative |
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| CN102458408A (en) * | 2009-06-17 | 2012-05-16 | 沃泰克斯药物股份有限公司 | Inhibitors of influenza viruses replication |
| CN103492381A (en) * | 2010-12-16 | 2014-01-01 | 沃泰克斯药物股份有限公司 | Inhibitors of influenza viruses replication |
| WO2017097234A1 (en) * | 2015-12-09 | 2017-06-15 | Sunshine Lake Pharma Co., Ltd. | Inhibitors of influenza virus replication, application methods and uses thereof |
| WO2017133667A1 (en) * | 2016-02-05 | 2017-08-10 | Savira Pharmaceuticals Gmbh | Pyrimidine and pyridine derivatives and use in treatment, amelioration or prevention of influenza thereof |
| WO2018041263A1 (en) * | 2016-09-05 | 2018-03-08 | 广东众生药业股份有限公司 | Anti-influenza virus pyrimidine derivative |
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