[go: up one dir, main page]

WO2021191872A1 - Inhibiteurs macrocycliques d'endonucléase de la grippe substitués par hétéroaryle - Google Patents

Inhibiteurs macrocycliques d'endonucléase de la grippe substitués par hétéroaryle Download PDF

Info

Publication number
WO2021191872A1
WO2021191872A1 PCT/IB2021/052544 IB2021052544W WO2021191872A1 WO 2021191872 A1 WO2021191872 A1 WO 2021191872A1 IB 2021052544 W IB2021052544 W IB 2021052544W WO 2021191872 A1 WO2021191872 A1 WO 2021191872A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
mmol
alkyl
synthesis
mixture
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2021/052544
Other languages
English (en)
Inventor
Robert Than Hendricks
Antitsa Dimitrova Stoycheva
Jean-François BONFANTI
Pierre Jean-Marie Bernard Raboisson
Jèrôme Michel Claude Fortin
Guillaume Jean Maurice Mercey
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Biopharma Inc
Original Assignee
Janssen Biopharma Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Janssen Biopharma Inc filed Critical Janssen Biopharma Inc
Publication of WO2021191872A1 publication Critical patent/WO2021191872A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C07D498/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • the present invention relates to macrocyclic compounds, in particular heteroaryl- substituted macrocyclic derivatives and the prodrugs thereof, to methods to prevent or treat influenza viral infections by using said compounds and to said compounds for use as a medicine, more preferably for use as a medicine to treat or prevent influenza viral infections.
  • the present invention also relates to pharmaceutical compositions or combination preparations of the compounds, to the compositions or preparations for use as a medicine, more preferably for the prevention or treatment of influenza viral infections.
  • Influenza is a serious public health problem with high incidence in the human population resulting in regular large-scale morbidity and mortality.
  • WHO the average global burden of annual epidemics may be on the order of 1 billion cases, 3 to 5 million cases of severe illness and 290,000 to 650,000 deaths annually.
  • annual influenza epidemics lead to approximately 30 million outpatient visits, resulting in medical costs of $10 billion annually.
  • Lost earnings due to illness and loss of life represent a cost of over $15 billion annually and the total US economic burden of annual influenza epidemics amounts to over $85 billion.
  • Influenza A viruses are the most common form and can spread in mammals and birds.
  • the subtypes of influenza A are named by the types of surface proteins hemagglutinin (H) and neuraminidase (N). There are 18 different hemagglutinin and 11 known neuraminidases.
  • Seasonal influenza viruses found in human are mainly the H1N1 and H3N2 subtypes.
  • Influenza B viruses are usually found only in humans. They are not divided into subtypes but can be further broken down into different strains. Circulating influenza viruses are highly variable each year, and both influenza A and B cause seasonal epidemics all over the world. Influenza C viruses give much milder symptoms and do not cause epidemics.
  • the genome comprises eight segments, encoding 9 to 11 proteins, depending on the type.
  • Influenza A encodes 11 proteins, including the surface proteins hemagglutinin (HA) and neuraminidase (NA), the polymerase complex, nucleoprotein (NP), membrane proteins (Ml and M2), and other proteins (NS1, NS2, NEP).
  • the polymerase complex is a heterotrimer composed of three subunits: polymerase acid (PA), polymerase basic 1 (PB1) and polymerase basic 2 (PB2). This polymerase is responsible for replication and transcription of the viral RNA in the nuclei of infected cells.
  • the PA subunit contains the endonuclease active site. The endonuclease activity of the PA cleaves the cellular mRNA, which is then used by the PB 1 subunit as a primer for the viral mRNA synthesis.
  • influenza vaccine may be less effective in preventing illness among the elderly and may only reduce severity of disease and incidence of complications and deaths.
  • influenza vaccination is most effective when circulating viruses are well-matched with vaccine viruses, and the success of vaccination is largely dependent on the accuracy of the prediction of the most prevalent virus type of the season. Rapid and continual evolution of influenza viral strains through antigenic drift, coupled with the short-lived nature of vaccine-induced immune responses to current influenza vaccines, means that vaccination with seasonally appropriate strains is required every year for prevention.
  • vaccine effectivess is typically only 20 to 60%.
  • influenza antiviral drugs There are two classes of influenza antiviral drugs available on the market: neuraminidase inhibitors and M2 channel inhibitors. Neuraminidase inhibitors oseltamivir or zanamivir are the primary antiviral agents recommended for the prevention and treatment of influenza. These medications are effective against both influenza type A and B viruses. Development of resistance to these antiviral drugs has been identified during treatment of seasonal influenza and in sporadic oseltamivir-resistant 2009 H1N1 virus, but the public health impact has been limited to date.
  • M2 channel inhibitors such as amantadine and rimantadine (adamantanes) are active against influenza A strains, but not influenza B strains.
  • Amantadine and rimantadine are active against influenza A strains, but not influenza B strains.
  • Adamantane resistance among circulating influenza A viruses increased rapidly worldwide during the 2003-2004 season. Therefore, amantadine and rimantadine are not recommended for antiviral treatment or chemoprophylaxis of currently circulating influenza A virus strains.
  • the novel swine H1N1 strain caused an unexpected influenza pandemic as a result of reassortment of genes from human, pig, and bird H1N1 viruses.
  • This past pandemic together with the ongoing circulation of highly pathogenic avian H5N1 strains and the recent emergence of the H7N9 virus (a new reassortant of avian origin isolated in China that is associated with severe respiratory disease with 40% of mortality, which could potentially adapt for human-to-human transmission), highlighted the vulnerability of the world population to novel influenza strains.
  • the present invention provides heteroaryl-substituted macrocyclic compounds, and pharmaceutically acceptable salts and solvates thereof, having activity against influenza virus, in particular influenza A and/or B strains.
  • the present invention provides compounds of Formula (I): which includes all possible stereoisomeric forms thereof, wherein:
  • A is a five-membered heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, wherein the five-membered heteroaryl is optionally fused to a phenyl ring, and wherein A is optionally substituted with one or more substituents independently selected from C 1-4 alkyl, halogen, C 3-6 Cyeloalkyl, and C 1-3 -fluoroalkyl;
  • X 1 to X 4 are each independently N or CR X , wherein each R x is independently selected from H, C 1-4 alkyl, C 3-6 Cyeloalkyl, and halogen;
  • R 1 is C 1-4 alkyl or C 3-6 Cyeloalkyl, each optionally substituted by one or more substituents independently selected from C 1-4 alkyl;
  • R 2 is C 2-6 alkenyl or C 1-6 alkyl, each optionally substituted by one or more substituents independently selected from C 1-4 alkyl and C 1-4 alkoxy; and
  • R 3 is O or CH 2 ; and the pharmaceutically acceptable salts, polymorphs and solvates thereof.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount, in particular an anti-virally effective amount, of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, and one or more pharmaceutically acceptable excipient, diluent, or carrier.
  • the invention further relates to a compound of Formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, for use as a medicament, in particular for use in the treatment or in the prevention of Orthomyxoviridae or influenza viral infections, particularly influenza A and/or influenza B viral infections.
  • the invention relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, in combination with an additional pharmaceutical agent, in particular an additional antiviral, for use in the treatment or prevention of an Orthomyxoviridae viral infection, particularly an influenza viral infection, more particularly an influenza A and/or influenza B viral infection.
  • an additional pharmaceutical agent in particular an additional antiviral
  • the invention also relates to a method of treating an Orthomyxoviridae viral infection, particularly an influenza viral infection, in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, or a pharmaceutical composition comprising such compound, particularly an influenza A and/or influenza B viral infection.
  • the invention also relates to a product comprising a compound of Formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, and an additional pharmaceutical agent, in particular an additional antiviral, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of an Orthomyxoviridae viral infection, particularly an influenza viral infection, more particularly an influenza A and/or influenza B viral infection.
  • the term “about” has the meaning known to the person skilled in the art. In certain embodiments, the term “about” may be left out and the exact amount is meant. In other embodiments the term “about” means that the numerical following the term “about” is in the range of ⁇ 15%, or of ⁇ 10%, or of ⁇ 5%, or of ⁇ 1%, of said numerical value.
  • C x-y refers to the number of carbon atoms in a given group.
  • a C 1-6 alkyl group contains from 1 to 6 carbon atoms
  • a C 1-4 alkyl group contains from 1 to 4 carbon atoms
  • a C 1-3 alkyl group contains from 1 to 3 carbon atoms
  • a C 3-6 Cyeloalkyl group contains from 3 to 6 carbon atoms, and so on.
  • alkyl refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon containing the specified number of carbon atoms.
  • alkenyl refers to a straight or branched chain unsaturated hydrocarbon radical having at least one double bond, and preferably having one double bond, and respectively from 2 to 6 and 2 to 8 carbon atoms.
  • alkenyl groups include ethenyl, propenyl, buten-1-yl, buten-2-yl, penten-1-yl, penten-2-yl, hexen-1-yl, hexen-2-yl, hexen-3- yl, 2-methylbuten-1-yl, hepten-1-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, 2-methylhexen-1- yl, octen-1-yl, octen-2-yl, octen-3-yl, octen-4-yl, 2-methylhepten-1-yl and the like.
  • alkoxy refers to an -O-alkyl group.
  • cycloalkyl refers to a carbocyclic ring containing the specified number of carbon atoms, e.g., C 3-6 cycloalkyl.
  • exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • fluoroalkyl refers to an alkyl group substituted with one, two, or three fluoro groups.
  • exemplary fluoroalkyl groups include -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, and - CH 2 CF 3 .
  • halo or “halogen” is generic to fluoro, chloro, bromo, and iodo.
  • heteroaryl refers to a monocyclic or polycyclic aromatic ring system comprising at least one ring member selected from N, O, and S.
  • exemplary monocyclic heteroaryl groups include pyrrole, imidazole, triazole, tetrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, furan, and thiophene.
  • Exemplary bicyclic or polycyclic heteroaryl groups include indole, benzofuran, benzothiophene, benzimidazole, quinoline, isoqunioline, and the like.
  • radical positions on any molecular moiety used in the definitions may be anywhere on such moiety as long as it is chemically stable. Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated. [0029] When any variable occurs more than one time in any constituent, each definition is independent.
  • salt refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • the salt is an acid addition salt of the compound.
  • Pharmaceutical salts can be obtained by reacting a compound, such as a compound with a basic nitrogen, with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, or phosphoric acid.
  • Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as an aliphatic or aromatic carboxylic acid or a sulfonic acid, for example, formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic, or naphthalenesulfonic acid.
  • an organic acid such as an aliphatic or aromatic carboxylic acid or a sulfonic acid
  • Pharmaceutical salts can also be obtained by reacting a compound, such as a compound with a carboxylic acid, with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C 1-7 alkylamine, cyclohexylamine, triethanolamine, ethyienediamine, and salts with amino acids such as arginine and lysine.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C 1-7
  • prodrug of a compound of the invention includes any compound that when administered to a biological system, generates the biologically active agent having the desired pharmacological effect, e.g., the antiviral activity, as a result of a biotransformation or chemical transformation (e.g., spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s)).
  • the prodrug is pharmacologically inactive.
  • General information on prodrugs may be found, e.g., in Bundegaard, H. “Design of Prodrugs” p. 1-92, Elsevier, New York-Oxford (1985).
  • prodrug forming strategies are available in the field of antivirals and are known to the skilled person. Such prodrug strategies have been reviewed, for instance, in Jones RJ and Bischofberger N, Antiviral Research 1995, 27, 1-17; Sofia, MJ, Antivir Chem Chemother 2011, 22, 23-49; Bobeck DR et al. Antiviral Therapy 2010, 15, 935-950; Sofia MJ, Adv Pharmacol 2013, 67, 39-73; Schultz C, Bioorg Med Chem 2003, 11, 885-898; Pertusati F et al. Antivir Chem Chemother 2012, 22, 181-203; Sofia MJ et al. J Med Chem 2012, 55(6), 2481-2531; Coats SJ et al. Antiviral Res 2014, 102, 119-147; Meier C and Balzarini J, Antiviral Res 2006, 71 (2-3), 282-292, incorporated by reference herein in their entirety.
  • Prodrugs may be prepared by modifying functional groups present on the compound in such a way that the modified functional groups are cleaved, in vivo when such prodrug is administered to a subject. The modifications typically are achieved by synthesising the parent compound with a prodrug substituent.
  • prodrugs include compounds of the invention wherein a hydroxyl, amino or phosphate group on the active compound is modified.
  • a prodrug of a compound of Formula (I) has an -O-C(O)-C 1- 6 alkyl group (such as an -O-C(O)-isopropyl group) or an -O-C 1-3 alkyl-OC(O)O-C 1-6 alkyl group (such as an -OCH 2 O-C(O)OCH 3 group) in place of the -OH group in the structure of Formula (I).
  • the present disclosure relates to prodrugs of compounds of Formula (I), pharmaceutical compositions comprising such prodrugs, and methods of treatment and uses as described herein for compounds of Formula (I), including the particular embodiments of Formula (I) described herein.
  • polymorph refers to the ability of the compound of the invention to exist in more than one solid form or crystal structure.
  • solvate refers to any pharmaceutically acceptable solvate that a compound of Formula (I), as well as the prodrugs and the salts thereof, are able to form.
  • solvates are for example hydrates, alcoholates, e.g., ethanolates, propanolates, and the like.
  • stereochemical configuration for centres in some compounds may be designated “A” or “A’ when the mixture(s) was separated; for some compounds, the stereochemical configuration at indicated centres has been designated as “R*”, “S*”, “*R” or “*S” when the absolute stereochemistry is undetermined although the compound itself has been isolated as a single stereoisomer and is enantiomerically or diastereomerically pure.
  • E*”, “Z*”, “*E” or “*E” when shown in a compound containing a double bond refer to a double bond for which the configuration is undetermined although the compound itself has been isolated as a single stereoisomer.
  • stereoisomerically pure concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e., minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e., 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%, or of 98% up to 100%.
  • enantiomerically pure and “diastereomerically pure” should be understood in a similar way, but then having regard to the enantiomeric excess, and the
  • stereoisomeric forms of the compounds and intermediates of this invention may be obtained by the application of art-known procedures.
  • enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid.
  • enantiomers may be separated by chromatographic techniques using chiral stationary layers.
  • Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • said compound is synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • the diastereomeric racemates of the compounds of Formula (I) can be obtained separately by conventional methods.
  • Appropriate physical separation methods that may advantageously be employed are, for example, selective crystallization and chromatography, e.g., column chromatography.
  • composition is intended to encompass a product comprising the specified ingredients in any amounts, and in some embodiments in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients, optionally in the specified amounts.
  • subject refers to a warm-blooded animal, preferably a mammal (e.g., cat, dog, primate or human), more preferably a human, who is or has been the object of treatment, observation or experiment.
  • a mammal e.g., cat, dog, primate or human
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medicinal doctor or other clinician, which includes alleviation or reversal of the symptoms of the disease or disorder being treated.
  • treatment is intended to refer to all processes wherein there may be a slowing, interrupting, arresting or stopping of the progression of a disease, but does not necessarily indicate a total elimination of all symptoms.
  • treatment or “treating” is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired results in treating a viral infection include, but are not limited to, one or more of the following: eliminating or lessening the severity of one or more symptoms resulting from the viral infection (such as but not limited to coughing, sneezing, runny nose, sore throat, fever, decrease of appetite, irritability, decreased activity, apnea, and wheezing), increasing the quality of life of those suffering from the viral infection, decreasing the dose of other medications required to treat the viral infection, delaying the progression of the viral infection, and/or prolonging survival of an individual.
  • eliminating or lessening the severity of one or more symptoms resulting from the viral infection such as but not limited to coughing, sneezing, runny nose, sore throat, fever, decrease of appetite, irritability, decreased activity, apnea, and wheezing
  • increasing the quality of life of those suffering from the viral infection decreasing the dose of other medications required to treat the viral infection, delaying the progression of the viral infection, and/or prolonging survival
  • preventing is an approach for eliminating or reducing the risk of developing a viral infection or delaying the onset of a viral infection, including biochemical, histological and/or behavioral symptoms of a viral infection. Prevention may be in the context of an individual at risk of developing the viral infection, such as where the “at risk” individual does not develop the viral infection over a period of time, such as during a viral season or during a period of exposure to the virus, which may be days to weeks to months.
  • An individual “at risk” of developing a viral infection is an individual with one or more risk factors for developing the viral infection but who has not been diagnosed with and does not display symptoms consistent with a viral infection.
  • Risk factors for developing an influenza infection include but are not limited to an individual’s age (young children under age 5 such as children between about 0 and about 2 years of age, including infants, and individuals greater than 65 years of age), premature birth, co-morbidities associated with influenza and individuals who are immune- compromised.
  • a “prophylactically effective dosage” or “prophylactically effective amount” is an amount sufficient to effect the preventative result of eliminating or reducing the risk of developing a viral infection or delaying the onset of a viral infection, including biochemical, histological and/or behavioral symptoms of a viral infection.
  • a prophylactically effective amount or a prophylactically effective dosage can be administered in one or more administrations and over a period of time in which such prevention is desired.
  • the present invention provides pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
  • a “therapeutically effective dosage” or “therapeutically effective amount” of compound or salt thereof or pharmaceutical composition is an amount sufficient to produce a desired therapeutic outcome.
  • a therapeutically effective amount or a therapeutically effective dosage can be administered in one or more administrations.
  • a therapeutically effective amount or dosage may be considered in the context of administering one or more therapeutic agents (e.g., a compound, or pharmaceutically acceptable salt thereof), and a single agent may be considered to be given in a therapeutically effective amount if, in conjunction with one or more other agents, a desired therapeutic outcome is achieved.
  • Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
  • A is a five-membered heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, wherein the five- membered heteroaryl is optionally fused to a phenyl ring, and the resulting monocyclic or bicyclic heteroaryl is optionally substituted as indicated herein.
  • A has one or two heteroatoms.
  • A is thiophene, oxazole, thiazole, imidazole, isothiazole, or benzothiophene.
  • A is a five-membered monocyclic heteroaryl group comprising one, two or three heteroatoms independently selected from N, O and S, and optionally substituted as indicated herein.
  • A is substituted with one or more substituents independently selected from C 1-4 alkyl, halogen, C 3-6 Cyeloalkyl, and C 1-3 fluoroalkyl.
  • A is optionally substituted with one or more substituents independently selected from C 1-3 alkyl, C 3-4 Cyeloalkyl, -CHF 2 , -CF 3 , and Cl.
  • A is optionally substituted with one or more, or one or two, methyl groups.
  • A is optionally substituted with methyl.
  • each of X 1 to X 4 is CR X , wherein each R x is independently selected from H, C 1-4 alkyl, C 3-6 Cyeloalkyl, and halogen. In some embodiments, each R x is H or F. In some embodiments, X 1 is CH or CF. In some embodiments, X 2 is CH or CF. In some embodiments, X3 is CH. In some embodiments, X 4 is CH. In some embodiments, X 1 and X2 are each CF. In some embodiments, X 1 and X2 are each CF and X 3 and X 4 are each CH. In some embodiments, one of X 1 to X 4 is N. In some embodiment, X 1 is N.
  • R 1 is C 1-4 alkyl. In some embodiments, R 1 is -CH 2 -. In some embodiments, R 1 is -CH(CH 2 CH 3 )-. In some embodiments, R 1 is 1,1 -cyclopropyl or 1,1- cyclobutyl.
  • R 3 is O. In some embodiments, R 3 is CH 2 .
  • X 1 to X 4 are each CR X wherein each R x is independently selected from H, C 1-4 alkyl, C 3-6 Cyeloalkyl, and halogen;
  • R 1 is selected from the group consisting of C 1-4 alkyl and C 3-6 Cyeloalkyl optionally substituted by one or more substituents independently selected from C 1-4 alkyl;
  • R 2 is selected from the group consisting of C 2-6 alkenyl and C 1-6 alkyl optionally substituted by one or more substituents independently selected from C 1-4 alkyl and C 1-4 alkoxy;
  • R 3 is selected from the group consisting of O and CH 2 .
  • X 1 to X 4 are each CR X , wherein each R x is independently selected from C 1-4 alkyl, C3- 6Cyeloalkyl, or halogen; R 1 is selected from the group consisting of C 1-4 alkyl and C 3-6 Cyeloalkyl optionally substituted by one or more substituents independently selected from C 1-4 alkyl;
  • R 2 is C 2-6 alkenyl optionally substituted by one or more substituents independently selected from C 1-4 alkyl and C 1-4 alkoxy;
  • R 3 is selected from the group consisting of O and CH 2 .
  • X 1 to X 4 are each CR X , wherein each R x is independently selected from C 1-4 alkyl, C 3 - 6 Cyeloalkyl, and halogen;
  • R 1 is selected from the group consisting of C 1-4 alkyl and C 3-6 Cyeloalkyl optionally substituted by one or more substituents independently selected from and C 1-4 alkyl;
  • R 2 is C 2-6 alkenyl optionally substituted by one or more substituents independently selected from C 1-4 alkyl and C 1-4 alkoxy;
  • R 3 is O.
  • A is a 5-membered monocyclic heteroaryl optionally substituted with one or more substituents selected from C 1-3 alkyl, C 1-3 fluoroalkyl, and C 3-6 Cyeloalkyl, or two adjacent substituents taken together with the carbons to which they are attached form a fused phenyl ring;
  • R a and R b are each H, methyl, or ethyl, or R a and R b are taken together with the carbon to which they are attached to form cyclopropyl or cyclobutyl; each R x is independently H or F; and the pharmaceutically acceptable salts, solvates, and polymorphs thereof.
  • A is thiophene, oxazole, thiazole, imidazole, isothiazole, or benzothiophene.
  • A is a five-membered monocyclic heteroaryl group comprising one, two or three heteroatoms independently selected from N, O and S, and optionally substituted as indicated herein.
  • A is substituted with one or more substituents independently selected from C 1-4 alkyl, C 3-6 Cyeloalkyl, and C 1-3 - fluoroalkyl.
  • A is optionally substituted with one or more substituents independently selected from C 1-3 alkyl, C 3-4 Cyeloalkyl, -CHF 2 , and -CF 3 . In some embodiments, A is optionally substituted with one or more, or one or two, methyl groups. In some embodiments, A is optionally substituted with methyl.
  • R a and R b are each H, methyl, or ethyl. In some embodiments, R a and R b are taken together with the carbon to which they are attached to form cyclopropyl or cyclobutyl.
  • each R x is H. In some embodiments, each R x is F.
  • the compound of Formula (I) is selected from the compounds in Table 1A below including stereoisomers, and pharmaceutically acceptable salts, solvates, and polymorphs thereof.
  • compounds of Formula (I) are selected from:
  • compositions comprising a pharmaceutically acceptable carrier, a therapeutically active amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and another antiviral agent, in particular an influenza inhibiting compound.
  • the combination of another antiviral agent and a compound of Formula (I) can be used as a medicine.
  • the present invention also relates to a product containing (a) a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and (b) another antiviral compound, as a combined preparation for simultaneous, separate or sequential use in antiviral treatment.
  • the different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers.
  • Other antiviral compounds (b) to be combined with a compound of Formula (I) for use in the treatment of influenza include, but are not limited to, influenza polymerase inhibitors, neuraminidase inhibitors, and M2 channel inhibitors.
  • the compound of Formula (I) or form thereof is combined with one or more other agents that reduce or treat symptoms of the viral infection.
  • compositions of this invention an effective amount of the particular compound, in free base or acid form or acid or base addition salt form, as appropriate, as the active ingredient is combined in intimate admixture with at least one pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for oral administration, rectal administration, percutaneous administration, parenteral or intramuscular injection.
  • any of the usual liquid pharmaceutical carriers may be employed, such as for instance water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid pharmaceutical carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their easy administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
  • the pharmaceutical carrier will mainly comprise sterile water, although other ingredients may be included in order to improve solubility of the active ingredient.
  • Injectable solutions may be prepared for instance by using a pharmaceutical carrier comprising a saline solution, a glucose solution or a mixture of both. Injectable suspensions may also be prepared by using appropriate liquid carriers, suspending agents and the like.
  • the pharmaceutical carrier may optionally comprise a penetration enhancing agent and/or a suitable wetting agent, optionally combined with minor proportions of suitable additives which do not cause a significant deleterious effect to the skin. Said additives may be selected in order to facilitate administration of the active ingredient to the skin and/or be helpful for preparing the desired compositions.
  • These topical compositions may be administered in various ways, e.g., as a transdermal patch, a spot-on or an ointment. Addition salts of the compounds of Formula (I), due to their increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions.
  • Dosage unit form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
  • the pharmaceutical compositions of the present invention may take the form of solid dose forms, for example, tablets (both swallowable and chewable forms), capsules or gelcaps, prepared by conventional means with pharmaceutically acceptable excipients and carriers such as binding agents, fillers, lubricants, disintegrating agents, wetting agents and the like. Such tablets may also be coated by methods well known in the art.
  • Liquid preparations for oral administration may take the form of e.g. solutions, syrups or suspensions, or they may be formulated as a dry product for admixture with water and/or another suitable liquid carrier before use.
  • Such liquid preparations may be prepared by conventional means, optionally with other pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous carriers, sweeteners, flavours, masking agents and preservatives.
  • the compounds of Formula (I) or pharmaceutically acceptable salts, solvates, and polymorphs thereof may be formulated for parenteral administration by injection, conveniently intravenous, intramuscular or subcutaneous injection, for example by bolus injection or continuous intravenous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or multi-dose containers, including an added preservative. They may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as isotonizing, suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be present in powder form for mixing with a suitable vehicle, e.g., sterile pyrogen free water, before use.
  • the compounds of Formula (I) or pharmaceutically acceptable salts, solvates, or polymorphs thereof may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter and/or other glycerides.
  • an antivirally effective daily amount would be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from 0.1 mg/kg to 50 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub- doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
  • the exact dosage and frequency of administration depends on the particular compound of Formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines.
  • Compounds of Formula (I) may be prepared by the methods described below, using synthetic methods known in the art of organic chemistry, or modifications and derivatisations that are familiar to those of skilled in the art.
  • the starting materials used herein are commercially available or may be prepared by routine methods known in the art such as those methods disclosed in standard reference books. Preferred methods include, but are not limited to, those described below.
  • HPLC High Performance Liquid Chromatography
  • MS Mass Spectrometer
  • the HPLC measurement was performed using Analytical system from Waters comprises a modules pump-autosampler alliance 2695 and a diode array detector 996. Data acquisition and reprocess was performed with a Waters-Micromass MassLynx data system.
  • DSC823e (indicated as DSC): For some compounds, melting points were determined with a DSC823e (Mettler- Toledo). Melting points were measured with a temperature gradient of 10°C/minute. Maximum temperature was 300°C.
  • Example 1 Synthesis of (18*R, *Z)-12-hydroxy-18-(thiophen-2-yl)-6,9-dihydro-18H- 10,17 -methanobenzo [b]
  • the enantiomers (610 mg) were separated via chiral SFC (Stationary phase: Chiralcel ® OD-H 5 pm 250 x 21.2 mm, Mobile phase: 63% CO 2 , 37% MeOH) to give the first eluted enantiomer lhA (220 mg) and the second eluted enantiomer lhB (258mg).
  • Example 2 Synthesis of ( 18 *R. *Z)- 12-hydroxy- 18-(3-methylthiophen-2-yl)-6.9- dihydro- 18H- 10, 17-methanobenzo [b]pyrido[1,2- ⁇ ] [ 1] oxa[5 ,6,9]triazacyclotridecine- 11 , 13 - dione (Compound 2A) and ( 18 *,V, *Z)- 12-hydroxy- 18-(3-methylthiophen-2-yl)-6.9-dihydro- 18H- 10, 17 -methanobenzo [b]pyrido [1,2- ⁇ ] [ 1 ]oxa[5,6,9]triazacyclotridecine- 11,13 -dione (Compound 2B).
  • the enantiomers (750 mg) were separated via chiral SFC (Stationary phase: Chiralpak ® AD- IT 5 pm 250 x 30 mm, Mobile phase: 70% CO 2 , 30% EtOH) to give the first eluted enantiomer 2dA (287 mg) and the second eluted enantiomer 2dB (270 mg).
  • Example 3 Synthesis of ( 18 *R. *Z)- 12-hydroxy- 18-(2-methylthiophen-3-yl)-6.9- dihydro- 18H- 10, 17-methanobenzo [b]pyrido [1,2- ⁇ ] [ 1 ]oxa[5 ,6,9]triazacyclotridecine- 11 , 13 - dione (Compound 3A) ( 18 *S. *Z)- 12-hydroxy- 18-(2-methylthiophen-3-yl)-6.9-dihydro- 18H- 10, 17-methanobenzo [b]pyrido [1,2- ⁇ ] [ 1 ]oxa[5,6,9]triazacyclotridecine- 11, 13-dione (Compound 3B).
  • Example 4 Synthesis of ( 18 *R. *Z)- 18-(3-cyclopropylthiophen-2-yl)- 12-hydroxy- 6,9-dihydro- 18H- 10, 17-methanobenzo [b]pyrido [1,2- ⁇ ] [ 1 ]oxa[5 ,6,9]triazacyclotridecine- 11, 13 -dione (Compound 4A) and ( 18*,S,*Z)- 18-(3-cyclopropylthiophen-2-yl)- 12-hydroxy- 6, 9-dihydro- 18H- 10, 17-methanobenzo [b]pyrido [1,2- ⁇ ] [ 1 ]oxa[5 ,6,9]triazacyclotridecine- 11,13 -dione (Compound 4B).
  • the enantiomers (1.1 g) were separated via chiral SFC (Stationary phase: Chiralpak ® AD-H 5 pm 250 x 30 mm, Mobile phase: 60% CO 2 , 40% EtOH) to give the first eluted enantiomer 4dA (418 mg) and the second eluted enantiomer 4dB (411 mg).
  • the enantiomers (180 mg) were separated via chiral SFC (Stationary phase: Chiralpak ® IG 5 pm 250 x 20 mm, Mobile phase: 55% CO 2 , 45% MeOH) to give the first eluted enantiomer 5dA (79 mg) and the second eluted enantiomer 5dB (72 mg).
  • Example 6 Synthesis ( 18*/7*Z)- 12-hydroxy- 18-( 1 -methyl- 1H-imidazol-2-yl)-6.9- dihydro- 18H- 10, 17-methanobenzo [b]pyrido [1,2- ⁇ ] [ 1 ]oxa[5 ,6,9]triazacyclotridecine- 11 , 13 - dione (Compound 6A) and of ( 18 *S.
  • the enantiomers (410 mg) were separated via chiral SFC (Stationary phase: Chiralpak ® AD-H 5 pm 250 x 30 mm, Mobile phase: 50% CO 2 , 50% EtOH) to give the first eluted enantiomer 6dA (125 mg) and the second eluted enantiomer 6dB (125 mg).
  • the enantiomers (618 mg) were separated via chiral SFC (Stationary phase: Chiralpak ® IC 5 pm 250 x 30 mm, Mobile phase: 45% CO 2 , 55% mixture of MeOH/ CH 2 CI 2 90/10) to give the first eluted enantiomer 7dA (267 mg) and the second eluted enantiomer 7dB (256 mg).
  • Example 8 Synthesis of (9*R, 18*R,E)-9-ethyl- 12-hydroxy- 18-(thiophen-2-yl)-6.9- dihydro- 18H- 10, 17-methanobenzo [b]pyrido [1,2- ⁇ ] [ 1 ]oxa[5 ,6,9]triazacyclotridecine- 11 , 13 - dione (Compound 8A) and (9*R, 18*S,E)- 9-ethyl-l 2-hydroxy- 18-(thiophen-2-yl)-6, 9-dihydro- 18H- 10, 17 -methanobenzo [b]pyrido [1,2- ⁇ ] [ 1 ]oxa[5,6,9]triazacyclotridecine- 11,13 -dione (Compound 8B).
  • Example 9 Synthesis of ( 18 *R. *Z)- 12-hydroxy- 18-(thiophen-3-yl)-6.9-dihydro- 187/- 10,17-methanobenzo [b]pyrido [1,2- ⁇ ] [ 1 ]oxa[5,6,9]triazacyclotridecine- 11,13-dione (Compound 9A) ( 18 *S, *Z)- 12-hydroxy- 18-(thiophen-3-yl)-6, 9-dihydro- 18 H- 10,17- methanobenzo [b]pyrido [1,2- ⁇ ] [ 1 ]oxa[5,6,9]triazacyclotridecine- 11,13-dione (Compound 9B).
  • the enantiomers (1.55 g) were separated via chiral SFC (Stationary phase: Chiralcel ® OJ-H 5 pm 250 x 30 mm, Mobile phase: 80% CO 2 , 20% MeOH (0.3% iPrNH 2 )) to give the first eluted enantiomer 9dA (693 mg) and the second eluted enantiomer 9dB (692 mg).
  • Example 10 Synthesis of (9*S, 18*R,E)-9-ethyl- 12-hydroxy- 18-(3 -methylthiophen-2- yl)-6, 9-dihydro- 18 H- 10, 17 -methanobenzo [b]pyrido [1,2- ⁇ ] [ 1 ]oxa[5 ,6,9]triazacyclotridccinc- 11,13-dione (Compound 10A), (9*R, 18*S,E)-9-ethyl - 12-hydroxy- 18-(3-methylthiophen-2- yl)-6, 9-dihydro- 18 H- 10, 17 -methanobenzo [b]pyrido [1,2- ⁇ ] [ 1 ]oxa[5 ,6,9]triazacyclotridccinc- 11,13-dione (Compound 10B) and (9*S, 18*S,*E) -9-cthyl-3.4-difluoro- 12-hydroxy- 18-(3
  • the major isomers (337 mg) were separated via chiral SFC (Stationary phase: Whelk-01 ® (S,S) 5 ⁇ m 250 x 30 mm, Mobile phase: 40% CO 2 , 60% mixture of iPrOH/CH 2 CI 2 80/20; +0.3% iPrNH 2 ) to give the first eluted isomer 10bA (107 mg), the second eluted isomer lObB (106 mg) and the third eluted isomer lObC (70 mg)
  • Example 11 Synthesis of (18*R,*Z)-18-(2,4-dimethylthiazol-5-yl)-3,4-difluoro-12- hydroxy-6, 9-dihydro- 18H- 10, 17 -methanobenzo [b]pyrido [1,2- f][l]oxa[5,6,9]triazacyclotridecine- 11,13-dione (Compound 11A) and (18*S,*Z)-18-(2,4- dimethylthiazol-5-yl)-3,4-difluoro-12-hydroxy-6, 9-dihydro- 18H-10,17- methanobenzo[b]pyrido [1,2- ⁇ ] [ 1 ]oxa[5,6,9]triazacyclotridecine- 11,13-dione (Compound 11A) and (18*S,*Z)-18-(2,4- dimethylthiazol-5-yl)-3,4-difluoro-12-hydroxy-6, 9-dihydro- 18H
  • reaction mixture was quenched by addition of a saturated aqueous solution of NH 4 Cl and the mixture was extracted three times with EtOAc. The combined organic layers were washed with water then brine, dried (MgSCft), filtered and concentrated. The residue was purified by flash column chromatography on silica gel (GraceResolv® 80 g, eluent PE/EtOAc 100:0 to 90: 10) to give intermediate 11a as yellow oil (2.24 g, 95%).
  • lid was purified by chiral SFC (Stationary phase: CHIRALPAK IC 5 ⁇ m 250*30mm, Mobile phase: 45% CO 2 , 55% MeOH) to lldB (656 mg) and lldA (808 mg).
  • Example 12 Synthesis of (18*R,Z)-3,4-difluoro-12-hydroxy-18-(2-methylthiazol-5- yl)-6, 9-dihydro- 18H- 10, 17-methanobenzo [b]pyrido [1,2- ⁇ ] [ 1 ]oxa[5 ,6,9]triazacyclotridecine- 11,13-dione (Compound 12A) and (18*S,Z)-3,4-difluoro-12-hydroxy-18-(2-methylthiazol-5- yl)-6, 9-dihydro- 18H- 10, 17-methanobenzo [b]pyrido [1,2- ⁇ ] [ 1 ]oxa[5 ,6,9]triazacyclotridecine- 11,13-dione (Compound 12B).
  • Example 13 Synthesis of (18*R, *Z)-18-(benzo[b]thiophen-2-yl)-3, 4-difluoro-12- hydroxy-6, 9-dihydro- 18H- 10, 17 -methanobenzo [b]pyrido [1,2- f][l]oxa[5,6,9]triazacyclotridecine- 11,13-dione (Compound 13A) and (18*S,*Z)-18- (benzo [b]thiophen-2-yl)-3 ,4-difluoro- 12-hydroxy-6, 9-dihydro- 18H- 10,17- methanobenzo[b]pyrido[l,2-f][l]oxa[5,6,9]triazacyclotridecine- 11,13-dione (Compound 13B).
  • Example 14 Synthesis of (18*R,*Z)-3,4-difluoro-12-hydroxy-18-(5-methylthiophen- 2-yl)-6, 9-dihydro- 18H-10,17-methanobenzo[b]pyrido[ 1,2- f][l]oxa[5,6,9]triazacyclotridecine- 11,13-dione (Compound 14A) and (18*S,*Z)-3,4- difluoro- 12-hydroxy- 18-(5 -methylthiophen-2-yl)-6, 9-dihydro- 18H- 10,17- methanobenzo[b]pyrido[l,2-f][l]oxa[5,6,9]triazacyclotridecine- 11,13-dione (Compound 14A) and (18*S,*Z)-3,4- difluoro- 12-hydroxy- 18-(5 -methylthiophen-2-yl)-6, 9-dihydro- 18H- 10,17- methano
  • Example 15 Synthesis of (18*R,*Z)-3,4-difluoro-12-hydroxy-18-(4-methylthiophen- 2-yl)-6, 9-dihydro- 18H- 10, 17-methanobenzo[b]pyrido[ 1,2- f][l]oxa[5,6,9]triazacyclotridecine-11,13-dione (Compound 15A) and (18*S,*Z)-3,4- difluoro-12-hydroxy-18-(4-methylthiophen-2-yl)-6,9-dihydro-18H-10,17- methanobenzo[b]pyrido [1,2- ⁇ ] [ 1 ]oxa[5,6,9]triazacyclotridecine- 11,13-dione (Compound 15A) and (18*S,*Z)-3,4- difluoro-12-hydroxy-18-(4-methylthiophen-2-yl)-6,9-dihydro-18H-10,17- methanobenzo[b]pyr
  • 15d was purified via chiral SFC (Stationary phase: CHIRACEL OJ-H 5 ⁇ m 250*30mm, Mobile phase: 80% CO 2 , 20% EtOH) giving 308 mg of 15dA and 330 mg of 15dB.
  • Example 16 Synthesis of (18*R,*Z)-18-(5-(difluoromethyl)tliioplien-2-yl)-3, 4- difluoro-12-hydroxy-6, 9-dihydro- 18H-10,17-methanobenzo[b]pyrido[ 1,2- f][l]oxa[5,6,9]triazacyclotridecine-11,13-dione (Compound 16A) and (18*S,*Z)-18-(5- (difluoromethyl)thiophen-2-yl)-3 ,4-difluoro- 12-hydroxy-6, 9-dihydro- 18H- 10,17- methanobenzo[b]pyrido [1,2- ⁇ ] [ 1 ]oxa[5,6,9]triazacyclotridecine- 11,13-dione (Compound 16 B)
  • Example 17 Synthesis of (18*S,*Z)-3, 4-difluoro-12-hydroxy-18-(5- (trifluoromethyl)thiophen-2-yl)-6, 9-dihydro- 18H- 10,17 -methanobenzo [b]pyrido [1,2- f][l]oxa[5,6,9]triazacyclotridecine- 11,13-dione (Compound 17A).
  • 17d was purified via chiral SFC (Stationary phase: CHIRACEL OJ-H 5 ⁇ m 250*20mm, Mobile phase: 90% CO 2 , 10% MeOH) giving 37 mg (17dB) and 38 mg (17dA).
  • Example 18 Synthesis of (18*R,*Z)-18-(4,5-dimethylthiophen-3-yl)-3,4-difluoro- 12-hydroxy-6, 9-dihydro- 18H- 10,17 -methanobenzo [b]pyrido [1,2- f][l]oxa[5,6,9]triazacyclotridecine-11,13-dione (Compound 18B) and (18*S,*Z)-18-(4,5- dimethylthiophen-3-yl)-3,4-difluoro-12-hydroxy-6,9-dihydro-18H-10,17- methanobenzo [b]pyrido [1,2- ⁇ ] [ 1 ]oxa[5,6,9]triazacyclotridecine- 11,13-dione (Compound 18 A)
  • Example 19 Synthesis of (18*S,*Z)-3,4-difluoro-12-hydroxy-18-(2-methylthiazol-4- yl)-6, 9-dihydro- 18H- 10, 17-methanobenzo [b]pyrido [1,2- ⁇ ] [ 1 ]oxa[5 ,6,9]triazacyclotridecine- 11,13-dione (Compound 19A).
  • Example 20 synthesis of (18'*S,*E)-18'-(5-chloro-3-methylthiophen-2-yl)-3',4'- difluoro- 12'-hydroxy-6H, 18'H-spiro [cyclobutane- 1 ,9'-[ 10, 17]methanobenzo [b]pyrido [1,2- f][l]oxa[5,6,9]triazacyclotridecine]- 11',13'-dione (Compound 20A) and (18'*R,*E)-18'-(5- chloro-3-methylthiophen-2-yl)-3',4'-difluoro-12'-hydroxy-6H,18H-spiro[cyclobutane-1,9'- [10,17]methanobenzo [b]pyrido [1,2- ⁇ ] [ 1 ]oxa[5 ,6,9]triazacyclotridecine] - 11',13'-dione (Compound 20A) and (18
  • Example 21 Synthesis of (18'*R,*E)-3',4'-difluoro-12'-hydroxy-18'-(3- methylthiophen-2-yl)-6H, 18H-spiro[cyclobutane- 1 ,9'-[ 10, 17]methanobenzo [b]pyrido [1,2- f][l]oxa[5,6,9]triazacyclotridecine]- 11',13'-dione (Compound 21A) and (18'*S,*E)-3',4'- difluoro- 12'-hydroxy- 18'-(3-methylthiophen-2-yl)-6H, 18 ⁇ -spiro [cyclobutane- 1 ,9'- [10,17]methanobenzo [b]pyrido [1,2- ⁇ ] [ 1 ]oxa[5 ,6,9]triazacyclotridecine] - 11',13'-dione (Compound 2 IB).
  • Example 23 synthesis of (18'*S,*E)-3',4'-difluoro-12'-hydroxy-18'-(4- methylisothiazol-5-yl)-6'H,18H-spiro[cyclobutane-1,9'-[10,17]methanobenzo[b]pyrido[l,2- f][l]oxa[5,6,9]triazacyclotridecine]- 11',13'-dione (Compound 23A), (18'*R,*E)-3',4'- difluoro-12'-hydroxy-18'-(4-methylisothiazol-5-yl)-6'H,18'H-spiro[cyclobutane-1,9'- [10,17]methanobenzo [b]pyrido [1,2- ⁇ ] [ 1 ]oxa[5 ,6,9]triazacyclotridecine] - 11',13'-dione (Compound 23B), (18'
  • Example A Influenza Antiviral Assay.
  • Human lung carcinoma A549 cells (ATCC, Manassas, VA) were plated at a density of 5 x 10 4 cells/mL (10 x 10 3 cells/well) in assay media (Ham’s F12 media supplemented with 0.3% FBS, 1% penicillin/streptomycin, 1% L-Glutamine, and 1% non-essential amino acids (all Mediatech, Manassas, VA) and 1% DMSO (Sigma- Aldrich, St Louis, MO)) in white 96-well plates.
  • assay media Ham’s F12 media supplemented with 0.3% FBS, 1% penicillin/streptomycin, 1% L-Glutamine, and 1% non-essential amino acids (all Mediatech, Manassas, VA) and 1% DMSO (Sigma- Aldrich, St Louis, MO)
  • Example B EN PA FRET Inhibition Assay.
  • EN PA FRET inhibition assay was performed using a 19-nucleotide synthetic oligoribonucleotide substrate: 5’-FAM- AUUUUGUUUUUAAUAUUUC-BHQ-3 ’ (Integrated DNA Technologies, Inc., Coralville, IA) (SEQ. ID. NO. 1). Upon RNA cleavage, the fluorescent FAM group is released from the BHQ quencher.
  • the PA sequence used to produce active enzyme is derived from any one of multiple influenza A virus strains (e.g., A/goose/Nanchang/3- 120/01 (H 3 N 2 ), A/Victoria/3/1975 (H 3 N 2 ), A/Brisbane/ 10/2007 (H 3 N 2 ), AAVSN/33 (H1N1), A/CA/4/2009 (H1N1), A/CA/5/2009 (H1N1), A/Shanghai/1/2013 (H7N9), A/Guizhou/1/2009 (H5N1)).
  • multiple influenza A virus strains e.g., A/goose/Nanchang/3- 120/01 (H 3 N 2 ), A/Victoria/3/1975 (H 3 N 2 ), A/Brisbane/ 10/2007 (H 3 N 2 ), AAVSN/33 (H1N1), A/CA/4/2009 (H1N1), A/CA/5/2009 (H1N1),
  • the full length recombinant protein was expressed from a baculovirus vector in insect cells.
  • Full length EN PA was used in this assay at an effective concentration of 1 to 10 nM, together with 50 nM FRET probe with a final volume of 20 ml cleavage buffer (20 mM Tris Ph8, 100 mM NaCl, 5% Glycerol, 10 mM ⁇ -ME, 0.0003% Tween-20, 5 mM MgCI 2 ).
  • IC 50 is defined as the concentration at which fluorescence is 50% that of the uninhibited control (DMSO).
  • Y corresponds to the percent relative enzyme activity
  • Max is the maximum enzyme activity in the presence of DMSO
  • Min is the inhibited activity at saturating concentration of compound
  • X corresponds to the compound concentration.
  • the IC 50 values were derived from the mean of a minimum of two independent experiments.
  • Table 1A shows the antiviral data obtained against influenza A H1N1 strain and cellular toxicity.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés macrocycliques substitués par hétéroaryle et des promédicaments associés ainsi que des sels, solvates et polymorphes pharmaceutiquement acceptables associés, et l'utilisation de tels composés en tant que médicament, en particulier dans la prévention et/ou le traitement d'infections virales provoquées par des virus appartenant à la famille des Orthomyxoviridae. La présente invention concerne en outre des compositions pharmaceutiques ou des préparations combinées de composés, et des compositions ou des préparations destinées à être utilisées en tant que médicament, plus préférentiellement pour la prévention ou le traitement d'infections virales provoquées par des virus appartenant à la famille des Orthomyxoviridae.
PCT/IB2021/052544 2020-03-26 2021-03-26 Inhibiteurs macrocycliques d'endonucléase de la grippe substitués par hétéroaryle Ceased WO2021191872A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202063000345P 2020-03-26 2020-03-26
US63/000,345 2020-03-26
EP20172175.0 2020-04-29
EP20172175 2020-04-29

Publications (1)

Publication Number Publication Date
WO2021191872A1 true WO2021191872A1 (fr) 2021-09-30

Family

ID=75252602

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2021/052544 Ceased WO2021191872A1 (fr) 2020-03-26 2021-03-26 Inhibiteurs macrocycliques d'endonucléase de la grippe substitués par hétéroaryle

Country Status (1)

Country Link
WO (1) WO2021191872A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115667269A (zh) * 2020-06-12 2023-01-31 上海翰森生物医药科技有限公司 含吡啶酮稠环类衍生物抑制剂、其制备方法和应用
WO2023088370A1 (fr) * 2021-11-17 2023-05-25 辰欣药业股份有限公司 Forme cristalline de dérivé de cycle fusionné et son procédé de préparation
WO2023238065A1 (fr) * 2022-06-09 2023-12-14 Glaxosmithkline Intellectual Property Development Limited Composés de 2,3-dihydroquinazolinone condensés contenant de l'azote utilisés en tant qu'inhibiteurs de nav1.8

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130197219A1 (en) * 2010-09-24 2013-08-01 Chika Takahashi Substituted polycyclic carbamoyl pyridone derivative prodrug
WO2020075080A1 (fr) * 2018-10-10 2020-04-16 Janssen Biopharma, Inc. Inhibiteurs macrocycliques d'endonucléase de la grippe

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130197219A1 (en) * 2010-09-24 2013-08-01 Chika Takahashi Substituted polycyclic carbamoyl pyridone derivative prodrug
WO2020075080A1 (fr) * 2018-10-10 2020-04-16 Janssen Biopharma, Inc. Inhibiteurs macrocycliques d'endonucléase de la grippe

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
BOBECK DR ET AL., ANTIVIRAL THERAPY, vol. 15, 2010, pages 935 - 950
BUNDEGAARD, H.: "Design of Prodrugs", 1985, ELSEVIER, pages: 1 - 92
CAS, no. 1416374-23-6
COATS SJ ET AL., ANTIVIRAL RES, vol. 102, 2014, pages 119 - 147
JONES RJBISCHOFBERGER N, ANTIVIRAL RESEARCH, vol. 27, 1995, pages 1 - 17
MEIER CBALZARINI J, ANTIVIRAL RES, vol. 71, no. 2-3, 2006, pages 282 - 292
PERTUSATI F ET AL., ANTIVIR CHEM CHEMOTHER, vol. 22, 2012, pages 181 - 203
SCHULTZ C, BIOORG MED CHEM, vol. 11, 2003, pages 885 - 898
SOFIA MJ ET AL., J MED CHEM, vol. 55, no. 6, 2012, pages 2481 - 2531
SOFIA MJ, ADV PHARMACOL, vol. 67, 2013, pages 39 - 73
SOFIA, MJ, ANTIVIR CHEM CHEMOTHER, vol. 22, 2011, pages 23 - 49
T. W. GREENEP. G. M. WUTS: "Protective Groups in Organic Chemistry", 1999, JOHN WILEY & SONS

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115667269A (zh) * 2020-06-12 2023-01-31 上海翰森生物医药科技有限公司 含吡啶酮稠环类衍生物抑制剂、其制备方法和应用
CN115667269B (zh) * 2020-06-12 2024-09-17 上海翰森生物医药科技有限公司 含吡啶酮稠环类衍生物抑制剂、其制备方法和应用
WO2023088370A1 (fr) * 2021-11-17 2023-05-25 辰欣药业股份有限公司 Forme cristalline de dérivé de cycle fusionné et son procédé de préparation
WO2023238065A1 (fr) * 2022-06-09 2023-12-14 Glaxosmithkline Intellectual Property Development Limited Composés de 2,3-dihydroquinazolinone condensés contenant de l'azote utilisés en tant qu'inhibiteurs de nav1.8

Similar Documents

Publication Publication Date Title
US11104689B2 (en) Influenza virus replication inhibitor and use thereof
EP2697213B1 (fr) Inhibiteurs de réplication virale, procédé pour leur préparation et leurs utilisations thérapeutiques
EP3349581B1 (fr) Modulateurs des protéines du noyau de l'hépatite b
AU709273B2 (en) Asymmetric synthesis of (-) 6-chloro-4-cyclopropyl-ethynyl-4 -trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one
KR101535691B1 (ko) 항­인플루엔자 활성을 갖는 포스포네이트 동종체를 함유하는 오셀타미비르의 합성
WO2021191872A1 (fr) Inhibiteurs macrocycliques d'endonucléase de la grippe substitués par hétéroaryle
US9701638B2 (en) Therapeutic hydroxyquinolones
EP2864338B1 (fr) Dérivés d'acide 7-oxothiazolopyridine carbonique et leur utilisation dans le traitement, l'amélioration ou la prévention d'une maladie virale
CN113292565B (zh) 核苷类化合物及其制备方法和应用
EP3996716A1 (fr) Composés s'utilisant pour traiter les infections causées par le virus de la grippe
WO2020125729A1 (fr) Dérivés d'hétéroaryldihydropyrimidine et procédés de traitement d'infections par le virus de l'hépatite b
KR20150014506A (ko) 바이러스성 질환의 치료, 개선 또는 예방에서 유용한 7-옥소-4,7-디하이드로-피라졸로[1,5-a]피리미딘 유도체
KR102342250B1 (ko) 1,2 나프토퀴논 유도체 및 이의 제조방법
WO2020078401A1 (fr) Inhibiteur de la réplication du virus de la grippe et utilisations associées
WO2014130258A1 (fr) 5h-chromeno[3,4-c]pyridines utilisés en tant qu'inhibiteurs de la kinase 1 associée à un adaptateur (aak1)
JP2013530130A (ja) ヘテロアリール（アルキル）ジチオカルバメート化合物、その調製方法及び使用
KR101902567B1 (ko) 플루오로치환된 (3r,4r,5s)-5-구아니디노-4-아세트아미도-3-(펜탄-3-일옥시)사이클로헥센-1-카복실릭 엑시드, 이의 에스테르 및 이의 용도
WO2009059243A1 (fr) Traitement et prévention d'infections virales
HK1211288A1 (en) Naphthyridinone derivatives and their use in the treatment,amelioration or prevention of a viral disease
EP3166943A1 (fr) Composés pyridopyraziniques et leur utilisation dans le traitement, l'amélioration des symptômes ou la prévention de la grippe
WO2021249522A1 (fr) Dérivé à cycles fusionnés contenant de la pyridone comme inhibiteur, son procédé de préparation et son utilisation
US9695135B2 (en) Therapeutic catechols
KR20250118317A (ko) Pin 1의 발현 또는 활성을 억제하는 안트라닐산계 화합물의 신규한 항바이러스 제약 조성물 및 이의 용도
CN104447390B (zh) 取代环丁烷类神经氨酸酶抑制剂及其使用方法和用途
CN118420692A (zh) 4'-氟代-1,2,3-三氮唑核苷类似物及其制备方法和作为抗狂犬病毒抑制剂的用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21714692

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21714692

Country of ref document: EP

Kind code of ref document: A1