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WO2023244672A1 - 2-(imidazo[1, 2-a]1,8-naphthyridin-8-yl)-1,3,4-oxadiazole derivatives as enhancers of innate immune response for the treatment of viral infections - Google Patents

2-(imidazo[1, 2-a]1,8-naphthyridin-8-yl)-1,3,4-oxadiazole derivatives as enhancers of innate immune response for the treatment of viral infections Download PDF

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Publication number
WO2023244672A1
WO2023244672A1 PCT/US2023/025312 US2023025312W WO2023244672A1 WO 2023244672 A1 WO2023244672 A1 WO 2023244672A1 US 2023025312 W US2023025312 W US 2023025312W WO 2023244672 A1 WO2023244672 A1 WO 2023244672A1
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WIPO (PCT)
Prior art keywords
mmol
imidazo
pharmaceutically acceptable
acceptable salt
naphthyridin
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PCT/US2023/025312
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French (fr)
Inventor
Jian Zhang
Michael Walker
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Assembly Biosciences, Inc.
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Publication of WO2023244672A1 publication Critical patent/WO2023244672A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses

Definitions

  • Antiviral drugs can work by interacting with the virus to reduce its pathogenicity or by targeting the host to improve the host's defense against the virus.
  • Most antiviral drugs on the market e.g., zanamivir for treating influenza, zidovudine for treating HIV, acyclovir for treating HSV, and entecavir for treating HBV
  • viruses can mutate and, thereby, develop resistance to these types of antiviral drugs. Consequently, antiviral drugs aimed at directly targeting a virus are prone to decreased efficacy over time.
  • antiviral drugs aimed at directly targeting a virus are prone to decreased efficacy over time.
  • IFN is one of the cytokines secreted by immune cells, which activates immune cells and acts on various points in the virus life cycle to suppress the growth of viruses.
  • injectable pegylated interferon (Peg-IFN) is available for general clinical use. A significant number of patients with Peg-IFN have a therapeutic effect regardless of whether they are HBe antigen positive or negative, and various side effects have been reported.
  • WO2013/059559 to Glaxo SmithKline, LLC discloses non-nucleic acid, low-molecular-weight, antiviral therapeutics suitable for oral administration.
  • imidazonaphthyridine compound RO8191 and related compounds are reported as IFN mimetic drugs using HCV replicon cells.
  • WO2018043747 to Kyoto University discloses imidazonaphthyridine compounds for treatment of HBV.
  • the present disclosure provides, in part, imidazonaphthyridine compounds and pharmaceutical compositions thereof, useful for treatment of viral infections.
  • the disclosure provides a compound of Formula I: Formula I or a pharmaceutically acceptable salt thereof, where the variables are described in the detailed description.
  • the disclosure provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the disclosure provides a method of treating a viral infection in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the disclosure provides a method of treating a viral infection in a subject in need thereof, comprising: administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • alkyl refers to a saturated straight or branched hydrocarbon.
  • exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6 or 1-4 carbon atoms, referred to herein as C1-6 alkyl and C1-4 alkyl, respectively.
  • Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2- butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2- pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.
  • alkylene refers to a biradical alkyl group.
  • alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond.
  • exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 carbon atoms, referred to herein as C2-6alkenyl. Examples include, but are not limited to, vinyl, allyl, butenyl, and pentenyl.
  • alkenylene refers to a biradical alkenyl group.
  • alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond.
  • exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6 carbon atoms, referred to herein as C2-6alkynyl. Examples include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and methylpropynyl.
  • alkoxy refers to a straight or branched alkyl group attached to oxygen (i.e., alkyl-O-).
  • alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 1-4 carbon atoms, referred to herein as C1-6alkoxy and C1-4alkoxy, respectively. Examples include, but are not limited to, methoxy, ethoxy, and isopropoxy.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group.
  • Exemplary alkoxyalkyl groups include, but are not limited to, a C1-6alkyl group substituted with a C1-3alkoxy or C1-4alkoxy group, referred to herein as C1-3alkoxyC1-6alkyl and C 1-4 alkoxyC 1-6 alkyl, respectively.
  • alkoxyalkenyl refers to an alkenyl group substituted with an alkoxy group.
  • alkoxyalkenyl groups include, but are not limited to, a C 2-6 alkenyl group substituted with a C1-3alkoxy or C1-4alkoxy group, referred to herein as C1-3alkoxyC2- 6alkenyl and C1-4alkoxyC2-6alkenyl, respectively.
  • haloalkyl refers to an alkyl group substituted with one or more halogen atoms.
  • haloalkyl groups include, but are not limited to, a C 1-6 alkyl or C1-4alkyl substituted with one or more halo groups, referred to herein as haloC1-6alkyl and haloC1-4alkyl, respectively. Examples include, but are not limited to, -CH2F, -CHCl2, -CHF2, - CF 3 , CF 3 CH 2 -, CH 3 CF 2 -, CF 3 CCl 2 - and CF 3 CF 2 -.
  • haloalkenyl refers to an alkenyl group substituted with one or more halogen atoms.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms.
  • alkoxy groups include, but are not limited to, a C1-6alkoxy or C 1-4 alkoxy substituted with one or more halo groups, referred to herein as haloC 1-6 alkoxy and haloC1-4alkoxy, respectively. Examples include, but are not limited to, CCl3O-, CF3O-, CHF2O- CF3CH2O-, and CF3CF2O-.
  • haloalkoxyalkyl refers to an alkoxyalkyl group substituted with one of more halogen atoms.
  • haloalkoxyalkyl groups include, but are not limited to, a C1-3alkoxyC1-6alkyl or C1-4alkoxyC1-5alkyl group substituted with one or more halogen atoms, herein referred to as haloC1-3alkoxyC1-6alkyl and haloC1-4alkoxyC1-5alkyl. Examples include, but are not limited to, CF 3 CH 2 OCH 2 -, CH 3 OCH 2 CF 2 - and CH 3 OCFH-. [0027]
  • haloalkoxyalkenyl refers to an alkoxyalkenyl group substituted with one of more halogen atoms.
  • haloalkoxyalkenyl groups include, but are not limited to, a C 1-3 alkoxyC 2-6 alkenyl or C 1-4 alkoxyC 2-4 alkenyl group substituted with one or more halogen atoms, herein referred to as haloC1-3alkoxyC2-6alkenyl and haloC1-4alkoxyC2- 4alkenyl.
  • hydroxy and “hydroxyl” as used herein refer to OH.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups.
  • exemplary hydroxyalkyl groups include, but are not limited to, a C1-6alkyl or C 1-4 alkyl substituted with one or more hydroxy groups, referred to herein as hydroxyC 1-6 alkyl and hydroxyC1-4alkyl, respectively. Examples include, but are not limited to, HOCH2-, HOCH2CH2-, CH3CH(OH)CH2-, (CH3)2C(OH)CH2-, and HOCH2CH(OH)CH2-.
  • hydroxyalkenyl refers to an alkenyl group substituted with one or more hydroxy groups.
  • hydroxyalkoxy refers to an alkoxy group substituted with one or more hydroxy groups.
  • hydroxyalkoxy groups include, but are not limited to, a C1- 6alkoxy or C1-4alkoxy substituted with one or more hydroxy groups, referred to herein as hydroxyC1-6alkoxy and hydroxyC1-4alkoxy, respectively. Examples include, but are not limited, to HOCH 2 O-, HOCH 2 CH 2 O-, CH 3 CH(OH)CH 2 O-, (CH 3 ) 2 C(OH)CH 2 O-, and HOCH2CH(OH)CH2O-.
  • hydroxyhaloalkyl refers to an haloalkyl group substituted with one or more hydroxy groups.
  • hydroxyalkyl groups include, but are not limited to, a haloC 1-6 alkyl or haloC 1-4 alkyl substituted with one or more hydroxy groups, referred to herein as hydroxyhaloC1-6alkyl and hydroxyhaloC1-4alkyl, respectively.
  • hydroxyhaloC1-6alkyl and hydroxyhaloC1-4alkyl respectively.
  • examples include, but are not limited to, HOCFH-, HOCH2CF2-, CF3CH(OH)CH2-, (CH3)2C(OH)CFH-, and HOCH 2 CH(OH)CF 2 -.
  • the term “monocycloalkyl” as used herein refers to a saturated monocyclic hydrocarbon group of, for example, 3-6 carbons, referred to herein as monoC3-6cycloalkyl.
  • Examples include, but are not limited to, cyclooctyl, cycloheptyl. cyclohexyl, cyclopentenyl, cyclobutyl and cyclopropyl.
  • the term “monocycloalkenyl” as used herein refers to a partially unsaturated monocyclic hydrocarbon group of, for example, 4-7 carbons, referred to herein as monoC 4- 7 cycloalkenyl.
  • Exemplary monocyclic cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.
  • monoheterocycloalkyl refers to a monocycloalkyl group, for example a monoC 3-7 cycloalkyl, wherein 1-3 of the carbon atoms are replaced with independently selected heteroatoms, such as nitrogen, oxygen, and sulfur (including its oxidation states: S(O) and SO2), herein referred to as mono3-7heterocycloalkyl.
  • Examples of mono3-7heterocycloalkyl groups include, but are not limited to, aziridinyl, oxiranyl, thiarinyl 1,1-dioxide, oxetanyl, azetidinyl, thietanyl 1,1-dioxide, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydro-2H-pyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl 1,1,dioxide, and piperazinyl.
  • the term “monoheterocycloalkenyl” refers to a monocycloalkyl group, for example a monoC 4-7 cycloalkenyl, wherein 1-3 of the carbon atoms are replaced with independently selected heteroatoms, such as nitrogen, oxygen, and sulfur (including its oxidation states: S(O) and SO2), herein referred to as mono4-7heterocycloalkenyl.
  • Examples of mono4-7heterocycloalkenyl groups include, but are not limited to, 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl, 4,5-dihydro- 1H-pyrazolyl, 2,3-dihydro-1H-pyrazolyl, 4,5-dihydro-1H-imidazolyl, 2,3-dihydro-1H- imidazolyl, 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl, 4,5-dihydrothiazolyl, 2,3- dihydrothiazolyl, 4,5-dihydroisothiazolyl, 2,3-dihydroisothiazolyl, 2,3-dihydrofuranyl, 2,5- dihydrofuranyl, 4,5-dihydrooxazolyl, 2,3-dihydrooxazolyl, 4,5-dihydroisoxazolyl,
  • bicyclic ring when a bicyclic ring is shown with a floating point of attachment and/or floating substituents, for example signifies that the bicyclic ring can be attached via a carbon atom on either ring, and that the substituents (e.g., the R 33 group(s)) can be independently attached to either or both rings.
  • the terms “Individual,” “patient,” and “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the compounds or pharmaceutical compositions of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, and the like).
  • veterinary treatment e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, and the like).
  • the mammal treated in the methods of the disclosure is desirably a mammal in which treatment of HBV infection is desired.
  • the term “Pharmaceutically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, fillers, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art.
  • compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • pharmaceutical composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable excipients.
  • pharmaceutically acceptable salt(s) refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-
  • Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids.
  • the compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.
  • terapéuticaally effective amount refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the compounds or pharmaceutical compositions of the disclosure are administered in therapeutically effective amounts to treat a disease.
  • a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect.
  • treating as used herein includes any effect, e.g., lessening, reducing, modulating, or eliminating, a viral infection, that results in the improvement of the disease.
  • the compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers.
  • stereoisomers when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “ ” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • the present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “( ⁇ )” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • the compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon- carbon double bond.
  • the symbol denotes a bond that may be a single, double or triple bond as described herein.
  • Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers.
  • Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
  • Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring.
  • the arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards.
  • structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers.
  • Substituents around a carbocyclic or heterocyclic ring may also be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring.
  • Stereoselective syntheses a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre- existing one, are well known in the art.
  • Stereoselective syntheses encompass both enantiomeric and diastereoselective transformations and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.
  • the compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms.
  • the compound is amorphous.
  • the compound is a single polymorph.
  • the compound is a mixture of polymorphs.
  • the compound is in a crystalline form.
  • the disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • a compound of the disclosure may have one or more H atom replaced with deuterium.
  • Certain isotopically-labeled disclosed compounds e.g., those labeled with 3 H and 14 C are useful in compound and/or substrate tissue distribution assays.
  • Tritiated (i.e., 3 H) and carbon- 14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. II.
  • R a and R b are independently selected for each occurrence from the group consisting of hydrogen and C1-4alkyl;
  • R 1 is acetyl, C 1-5 alkyl, haloC 1 - 5 alkyl, hydroxyC 1-5 alkyl, hydroxyhaloC 1-5 alkyl, C 1- 3 alkoxyC 1-5 alkyl, haloC 1-3 alkoxyC 1-5 alkyl, C 2-5 alkenyl, haloC 1 - 5 alkenyl, hydroxyC 1-5 alkenyl, C 1- 3alkoxyC2-5alkenyl, haloC1-3alkoxyC2-5alkenyl, monoC3-7cycloalkyl, monoC4-7cycloalkenyl, mono3-7heterocycloalkyl,
  • Formula II or a pharmaceutically acceptable salt thereof, wherein: X 1 is CH or N; and R 1 , R 2 , R 3 and R 4 are as described herein with respect to Formula I.
  • the present disclosure provides a compound of Formula III Formula III , or a pharmaceutically acceptable salt thereof, wherein: R x is hydrogen or C 1-4 alkyl; and R 1 , R 2 , R 3 and R 4 are as described herein with respect to Formula I.
  • the present disclosure provides a compound of Formula IV
  • Formula IV or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , R 3 and R 4 are as described herein with respect to Formula I.
  • the present disclosure provides a compound of Formula V Formula V , or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , R 3 and R 4 are as described herein with respect to Formula I.
  • the following embodiments further describe a compound of Formula I, II, III, IV or V, or a pharmaceutically acceptable salt thereof. It will be appreciated that all chemically allowable combinations of the embodiments described herein are envisioned as further embodiments of the invention.
  • R 1 is haloC1-5alkyl having 4 or more halo atoms, C2-5alkenyl, haloC 2 - 5 alkenyl, hydroxyC 2-5 alkenyl, C 1-3 alkoxyC 2-5 alkenyl, C 1-3 alkoxyhaloC 2-5 alkenyl, monoC 4- 7 cycloalkenyl, or mono 4-7 heterocycloalkenyl, wherein the monoC 4-7 cycloalkenyl or mono 4- 7heterocycloalkenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of NRaR b , CN, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-3alkoxyC1- 5alkyl , and tert-butyloxycarbonyl.
  • R 1 is haloC 1 - 5 alkyl having 4 or more halo atoms, C 2-5 alkenyl, haloC2-5alkenyl, hydroxyC2-5alkenyl, C1-3alkoxyC2-5alkenyl, C1-3alkoxyhaloC2-5alkenyl, monoC4- 7cycloalkenyl, or mono4-7heterocycloalkenyl, wherein the monoC4-7cycloalkenyl or mono4- 7 heterocycloalkenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of NRaR b , CN, halo, C 1-4 alkyl, hydroxyC 1-4 alkyl, C 1-4 alkoxy, C 1-3 alkoxyC 1- 5alkyl , and tert-butyloxycarbonyl; and [0068] R 2 is haloC1-5alkyl having 4 or more halo atoms, C
  • R 1 is C1-5alkyl. [0070] In certain embodiments, R 1 is haloC1-5alkyl. [0071] In certain embodiments, R 1 is CF 3 . [0072] In certain embodiments, R 1 is haloC 2 - 5 alkyl having 4 or more halo atoms. [0073] In certain embodiments, R 1 is CF3CF2 or CF3CF2CF2. [0074] In certain embodiments, R 1 is C2-5alkenyl, haloC2-5alkenyl, hydroxyC2-5alkenyl, C1- 3 alkoxyC 2-5 alkenyl or haloC 1-3 alkoxyC 2-5 alkenyl.
  • R 1 is monoC3-7cycloalkyl optionally substituted with 1-3 substituents independently selected from the group consisting of NRaR b , CN, halo, C1-4alkyl, hydroxyC 1-4 alkyl, C 1-4 alkoxy, C 1-3 alkoxyC 1-5 alkyl, and tert-butyloxycarbonyl. [0076] In certain embodiments, R 1 is monoC3-7cycloalkyl.
  • R 1 is monoC4-7cycloalkenyl or mono4-7heterocycloalkenyl, wherein the monoC 4-7 cycloalkenyl or mono 4-7 heterocycloalkenyl is optionally substituted with 1- 3 substituents independently selected from the group consisting of NR a R b , CN, halo, C 1-4 alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-3alkoxyC1-5alkyl, and tert-butyloxycarbonyl.
  • R 2 is haloC1-5alkyl having 4 or more halo atoms, C2-5alkenyl, haloC2-5alkenyl, monoC4-7cycloalkenyl, or mono4-7heterocycloalkenyl, wherein the monoC4- 7 cycloalkenyl or mono 4-7 heterocycloalkenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of NR a R b , CN, halo, C1-4alkyl, hydroxyC1- 4alkyl, C1-4alkoxy, C1-3alkoxyC1-5alkyl and monoC3-7cycloalkyl.
  • R 2 is C 1-5 alkyl. [0080] In certain embodiments, R 2 is haloC 1 - 5 alkyl. [0081] In certain embodiments, R 2 is CF3. [0082] In certain embodiments, R 2 is haloC1-5alkyl having 4 or more halo atoms, C2-5alkenyl or haloC 2 - 5 alkenyl. [0083] In certain embodiments, R 2 is haloC2-5alkyl having 4 or more halo atoms. [0084] In certain embodiments, R 2 is CF3CF2 or CF3CF2CF2.
  • R 2 is C 2-5 alkenyl or haloC 2 - 5 alkenyl.
  • R 2 is monoC3-7cycloalkyl.
  • R 2 is monoC4-7cycloalkenyl or mono4-7heterocycloalkenyl, wherein the monoC 4-7 cycloalkenyl or mono 4-7 heterocycloalkenyl is optionally substituted with 1- 3 substituents independently selected from the group consisting of NR a R b , CN, halo, C 1-4 alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-3alkoxyC1-5alkyl and monoC3-7cycloalkyl.
  • R 3 is hydrogen. [0089] In certain embodiments, R 3 is halo. [0090] In certain embodiments, R 4 is hydrogen. [0091] In certain embodiments, R 4 is halo or cyano. III. Methods of Use [0092] Without being bound by any theory, since the compounds of the present disclosure behave as interferon mimicking agents (IFN mimetic agents), it is believed that may exhibit their antiviral activity through a variety of mechanisms.
  • IFN mimetic agents interferon mimicking agents
  • ISGs interferon-stimulated genes
  • JK/STAT janus kinase/signal transducer and activator
  • the compounds of the present disclosure may also function as protease or polymerase inhibitors, disrupt the viral replication machinery or have general anti-viral activity against viral components. The presence of these mechanisms in a broad group of viruses suggest the compounds disclosed herein may provide therapeutic anti-viral activity against a diverse group of viruses.
  • one aspect described herein is a method of treating a hepatitis B infection (HBV) in a patient in need thereof is provided, comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s).
  • a method for treating a hepatitis B infection in a patient in need thereof comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient.
  • HDV hepatitis D
  • the present disclosure also contemplates a method of treating an HBV or HDV infection, or HBV/HDV coinfection, in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s).
  • a method for treating an HBV or HDV infection or HBV/HDV coinfection in a patient in need thereof comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient.
  • the disclosure provides a method of treating a hepatitis B infection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, in combination with one or more other HBV agents each selected from the group consisting of HBV capsid assembly promoters, HBV viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors, disruptors of nucleocapsid formation, cccDNA formation inhibitors, antiviral core protein mutant, HBc directed transbodies, RNAi targeting HBV RNA, immunostimulants, TLR-7/9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimetics, epigenetic modulators, kinase inhibitors, and STING agonists.
  • HBV agents each selected from the group consisting of HBV capsid assembly promoters, HBV viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors,
  • the disclosure provides a method of treating a hepatitis B infection in a patient in need thereof, comprising administering an amount of a disclosed compound, and administering another HBV capsid assembly promoter therapeutic.
  • Other combinations contemplated herein include administering a first compound selected from any one of the disclosed compounds, in combination with any available HBV treatment, including not limited to, entecavir, tenofovir, Baraclude, Viread, lamivudine, Vemlidy, Hepsera, Epivir-HBV, adefovir, epivir tenofovir alafenamide, and other suitable HBV drugs.
  • the disclosure further provides a method of treating HBV or HDV infection or HBV/HDV coinfection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, and one or more other additional antivirals, the one or more additional antivirals include HDV therapies, such as lonafarnib, and one or more of HBV agents each selected from the group consisting of HBV capsid assembly promoters, HBV viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors, disruptors of nucleocapsid formation, cccDNA formation inhibitors, antiviral core protein mutant, HBc directed transbodies, RNAi targeting HBV RNA, immunostimulants, TLR-7/9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimetics, epigenetic modulators, kinase inhibitors, and STING agonists.
  • HDV therapies such as lonafarnib
  • the disclosure provides a method of treating a HBV or HDV infection or HBV/HDV coinfection in a patient in need thereof, comprising administering an amount of a disclosed compound, and administering another HBV therapeutic or an HDV therapeutic.
  • HCV hepatitis C virus
  • Corona viruses WO2022/049521
  • ZIKV Zika virus
  • the compounds of the instant disclosure are also IFN mimicking agents anti-viral activity against HCV, Corona virus and Zika virus is also contemplated herein.
  • a method of treating a hepatitis C infection (HCV) in a patient in need thereof comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s).
  • a method for treating a hepatitis C infection in a patient in need thereof comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient.
  • the disclosure provides a method of treating a hepatitis C infection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, in combination with suitable treatments for HCV including, but not limited to, lbasvir/Grazoprevir (Zepatier), Glecaprevir/Pibrentasvir (Mavyret), Sofosbuvir/Ledipasvir (Harvoni), Sofosbuvir/Velpatasvir (Epclusa), second line hepatitis C medications such as Sofosbuvir/Velpatasvir/Voxelaprevir (Vosevi), and other suitable HCV drugs.
  • suitable treatments for HCV including, but not limited to, lbasvir/Grazoprevir (Zepatier), Glecaprevir/Pibrentasvir (Mavyret), Sofosbuvir/Ledipasvir (Harvoni), Sofosbuvir/Velpat
  • Coronaviruses are another possible viral target for the compounds of the present disclosure (See, for example, WO2022/049521).
  • another aspect of the present disclosure provides methods for treating viral infection, wherein said viral infection comprises one or more viruses from the Coronaviridae family including human coronavirus, Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), Middle East Respiratory Syndrome coronavirus (MERS- CoV) and Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV- 2).
  • the disease caused by these viruses are SARS (SARS-CoV), MERS (MERS-CoV) and COVID-19 (SARS- CoV-2).
  • the disclosure provides a method of treating any Coronaviridae viral infection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, in combination with suitable treatments for Coronavirus infection including, but not limited to, nirmatrelvir, ritonavir, Lüvrio (molnupiravir), baricitinib, and the various coronavirus vaccines and other suitable Coronavirus drugs.
  • Another aspect described herein is a method of treating a Zika virus (ZIKV) viral infection in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s).
  • a method for treating a ZIKV infection in a patient in need thereof comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient.
  • the disclosure provides a method of treating a Zika virus infection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, in combination with suitable treatments for ZIKV infection.
  • suitable drugs for combining administration of the compounds of the instant disclosure include acetaminophen, ibuprofen, non-steroidal anti-inflammatory drugs and hydration therapies.
  • HPV Human papillomavirus
  • another aspect described herein is a method of treating HPV infection in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s).
  • a method for treating a HPV infection in a patient in need thereof comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient.
  • Combination therapy with the compounds disclosed herein, and known HPV drugs are also contemplated herein.
  • the disclosure provides a method of treating any HPV viral infection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, in combination with suitable treatments for HPV infection including, but not limited to, condylax (podofilox), trichloroacetic acid, aldara (imiquimod), zyclara, keratoyltic agents, immune response modifiers, and various commonly used HPV vaccines.
  • suitable treatments for HPV infection including, but not limited to, condylax (podofilox), trichloroacetic acid, aldara (imiquimod), zyclara, keratoyltic agents, immune response modifiers, and various commonly used HPV vaccines.
  • one aspect described herein is a method of treating prion infection in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s).
  • a method for treating a prion infection in a patient in need thereof comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient.
  • Chikungunya virus (CHIKV) and Dengue virus are both related mosquito-borne viruses with no approved therapies.
  • CHIKV replication has been found to be inhibited by an agonist of Liver X receptor (LXR-623) by activation of the interferon signaling pathway (Hwang et al., 2019), and halofuginone has been found to work synergistically with another IFN mimicking agent.
  • LXR-623 Liver X receptor
  • halofuginone has been found to work synergistically with another IFN mimicking agent.
  • both CHIKV and Dengue virus represents yet another group of viruses ideally suited for therapy with the compounds described herein.
  • the compounds of the present disclosure could demonstrate a synergistic effect with LXR-623 agonists for the treatment of CHIKV and/or with halofuginone for the treatment of both CHIV and Dengue virus.
  • another embodiment described herein is a method of treating CHIKV by administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s).
  • a method of treatment would include administering any of the disclosed compounds in combination with LXR-623.
  • a method of treating CHIKV virus comprising administering to a subject in need thereof, a combination of the compounds disclosed herein and LXR-623 or halofuginone.
  • a method of treating Dengue virus comprising administering to a subject in need thereof, a combination of the compounds disclosed herein and halofuginone.
  • HNV human norovirus
  • EMCV encephalomyocarditis virus
  • another aspect described herein is a method of treating HNV infection in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s).
  • a method for treating a EMCV infection in a patient in need thereof comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s).
  • a method for treating any of the viral infections described herein, in a subject that has been diagnosed with said viral infection or is at risk of developing said viral infection comprising administering to said subject, any one of the compounds described herein.
  • Another aspect described herein is a method for enhancing the immune response to a viral infection from any of the viruses described herein, in a subject that is immunocompromised or is at risk of developing an immunocompromised immune system, comprising administering to said subject, any of the compound as described herein.
  • IV. Administration and Formulations [0112]
  • a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the chemical entities are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease.
  • the compounds of the present invention can also be supplied in the form of a pharmaceutically acceptable salt.
  • compositions prepared from pharmaceutically acceptable inorganic and organic acids and bases include metallic ions. More preferred metallic ions include, but are not limited to, appropriate alkali metal salts, alkaline earth metal salts and other physiological acceptable metal ions.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like and in their usual valences.
  • Exemplary salts include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, including in part, trimethylamine, diethylamine, N, N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine; substituted amines including naturally occurring substituted amines; cyclic amines; quaternary ammonium cations; and basic ion exchange resins, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ -dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine,
  • Illustrative pharmaceutically acceptable acid addition salts of the compounds of the present invention can be prepared from the following acids, including, without limitation formic, acetic, propionic, benzoic, succinic, glycolic, gluconic, lactic, maleic, malic, tartaric, citric, nitic, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, hydrochloric, hydrobromic, hydroiodic, isocitric, trifluoroacetic, pamoic, propionic, anthranilic, mesylic, oxalacetic, oleic, stearic, salicylic, p-hydroxybenzoic, nicotinic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, phosphoric, phosphonic, ethanesulfonic, benzenesulfonic, pantothenic, tol
  • Preferred pharmaceutically acceptable salts include the salts of hydrochloric acid and trifluoroacetic acid. All of the above salts can be prepared by those skilled in the art by conventional means from the corresponding compound of the present invention.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization in the salt may vary from completely ionized to almost non-ionized.
  • Lists of suitable salts are found in Remington's Pharmaceutical Sciences. 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418, the disclosure of which is hereby incorporated by reference only with regards to the lists of suitable salts. [0117]
  • the chemical entities provided will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • the actual amount of the chemical entity i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the chemical entity used, the route and form of administration, and other factors.
  • the drug can be administered more than once a day, such as once or twice or three times a day.
  • Therapeutically effective amounts of the chemical entities described herein may range from approximately 0.01 to 200 mg per kilogram body weight of the recipient per day; [0119] such as about 0.01-100 mg/kg/day, for example, from about 0.1 to 50 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range may be about 7-3500 mg per day.
  • the amount of the chemical entity in a composition can vary within the full range employed by those skilled in the art.
  • the composition will contain, on a weight percent (wt%) basis, from about 0.01-99.99 wt% of at least one chemical entity described herein based on the total composition, with the balance being one or more suitable pharmaceutical excipients.
  • the at least one chemical entity described herein is present at a level of about 1-80 wt%.
  • the chemical entities will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), sublingually, subcutaneously, topically, intrapulmonarilly, vaginally, rectally, or intraocularly, or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • oral administration with a convenient daily dosage regimen that can be adjusted according to the degree of disorder or disease may be used.
  • the choice of administration route and/or formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance.
  • the compounds of the present invention may be administered topically to the diseased area on the skin or mucous membranes of a subject. In another embodiment, the compounds of the present invention may be administered topically to the diseased area on the skin or mucous membranes of a subject so that the topical administration allows for the compound to penetrate into the subject's skin layer keratinocyte cells.
  • the compositions are comprised of, in general, at least one chemical entity described herein in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of at least one chemical entity described herein.
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, [0124] glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Liquid carriers, for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Pharmaceutical compositions or formulations include solid, semi-solid, liquid and aerosol dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols or the like.
  • the chemical entities can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.
  • the compositions are provided in unit dosage forms suitable for single administration of a precise dose.
  • the chemical entities described herein can be administered either alone or more typically in combination with a conventional pharmaceutical carrier, excipient or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like).
  • the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).
  • auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).
  • the pharmaceutical composition will contain about 0.005% to 95%; in certain embodiments, about 0.5% to 50% by weight of a chemical entity.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.
  • the compositions will take the form of a pill or tablet and thus the composition will contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.
  • a powder, marume, solution or suspension e.g., in propylene carbonate, vegetable oils or triglycerides
  • a gelatin capsule e.g., in propylene carbonate, vegetable oils or triglycerides
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. at least one chemical entity and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension.
  • a carrier e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like
  • injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection.
  • the percentage of chemical entities contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the chemical entities and the needs of the subject.
  • the compounds of the present invention can be formulated into dermatological topical delivery formulations.
  • Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations may be applied as a topical ointment or cream.
  • the active ingredient When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • the compositions herein may additionally include an organic solvent, an adhesive, plasticizer, and a water swellable polymer.
  • the organic solvent may be one or more of dimethylsulfoxide (DMSO), N,N'-dimethylacetamide (DMA), N',N'-dimethylformamide (DMF), dioxane, tetraglycol, or the like.
  • Appropriate adhesives for use in the invention include, but are not limited to, polyvinyl alcohol, polyethylene oxides, polyethylene glycols of molecular weight 3350 and higher, hydroxypropylcellulose, and povidone. Polyvinyl alcohol is preferred. The adhesive is typically present in an amount from about 10 to 75% by weight, preferably about 45-55% by weight, and most preferably about 50% by weight of the composition. [0132] The compositions herein may optionally also include a plasticizer. Suitable plasticizers are typically high-boiling, water-soluble organic compounds containing hydroxyl, amide, or amino groups.
  • plasticizers include, but are not limited to, soy, egg or synthetic lecithin, ethylene glycol, tetraethylene, hexamethylene, nonaethylene glycol, formamide, ethanolamine salts, water, glycerin, or combinations thereof. Such plasticizers are well known in the art. A plasticizer is therefore preferably included in the formulation to provide these benefits.
  • the plasticizer is typically present in the composition in an amount ranging from about 0.4-2.0% by weight, with about 1-2% by weight being preferred, and about 0.9% by weight being most preferred.
  • the composition may also include a water swellable polymer which acts as an extender and serves to thicken the composition.
  • Such water swellable polymers are well known in the art and include, but are not limited to, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, methyl ethyl cellulose, sodium carboxymethylcellulose, gums, carboxyvinyl polymer, hydroxyethyl cellulose, cornstarch, casein, urea, dextrin, and fume silica.
  • the filler is typically present in an amount from about 1- 10% by weight, preferably about 3-6% by weight, with about 4.67% by weight being most preferred.
  • the present invention is further directed to a method of treating warts by applying the pharmaceutical composition(s) topically to the location on the skin where the warts are present.
  • the method of the invention comprises topically applying to a wart on an individual a therapeutically effective amount of the compositions of the invention.
  • the composition may be applied using an applicator, for example, a swab, sponge, finger cot or a toothpick.
  • an applicator for example, a swab, sponge, finger cot or a toothpick.
  • the method further comprises occluding the wart with an occluding agent to aid the composition's absorption into the wart, protect the composition from rubbing off, and also further keratolytic activity.
  • Many occluding agents are known to those skilled in the art. These include, but are not limited to, bandages, plastic wrap, and adhesive tape, for example, duct tape.
  • compositions of the invention may further include a variety of substances, including suitable stabilizers, buffers, thickeners, lubricants, wetting, and dissolving agents as well as colorings, moisturizers, preservatives, and fragrances.
  • suitable stabilizers, buffers, thickeners, lubricants, wetting, and dissolving agents as well as colorings, moisturizers, preservatives, and fragrances.
  • These minors are added in small amounts and are conventionally known in pharmaceutical formulation work to enhance elegance. Such minors typically comprise less than about 1% of the overall composition.
  • the compounds of the present invention can be formulated into dermatological delivery formulations, such as a stick-gel, which can be used to target the delivery of the compound directly onto the site of action.
  • the compound(s) may be formulated into a stick-gel that can apply the compounds in a formulation directly to the surface of the wart.
  • the stick-gel application formulation can be based on a PSAs (Pressure Sensitive Adhesives) concept.
  • PSAs unlike structural adhesives or sealants, differ in that the adhesive-substrate interface does not resist separation when the adhesive is peeled off. In other words, PSAs are intended to show adhesive failure, especially when skin is the substrate, whereas this would be a major fatal flaw for cement and glue.
  • Developing a suitable PSA-GeI for a targeted adherend to treat a skin common wart takes the following two critical adhesive attributes into consideration: surface activity and visco-elastic properties. [0137] As such, these attributes are associated to the three steps of adhesion process.
  • the first step involves contact between the adhesive and the surface. This dynamic step is known as “bonding or sticking” and is dependent on wetting behavior and quick spreadability of the adhesive composition.
  • the second step “adhering” relies on the capacity of the adhesive to remain in contact with surface. This is important for treating warts where the active should be adherent to the warts long enough to exert its intended action. Flowability and creep resistance are the physical characteristics that contribute to maintain the established bond and stick.
  • the third step “debonding” is also dynamic. It consists in separating the adhesive-stick from the surface by means of a peel release process. The peel adhesion property of the adhesive composition will direct the force required to break the bond in an adhesive failure mode.
  • the formulation composition to achieve all these attributes can comprise suitable hydrophilic polymers incorporated into a gel matrix containing the active drug in solution.
  • hydrophilic polymers e.g., hydroxy propyl methyl cellulose, ethyl cellulose, etc.
  • hydrophilic polymers e.g., hydroxy propyl methyl cellulose, ethyl cellulose, etc.
  • organogel nonaqueous solvent
  • gels prepared with hydroxyethyl cellulose containing water are hydrogels
  • gels prepared with polyethylene-containing mineral oil (PIastibase) are organogels.
  • thermally sensitive gels are prepared from poloxamers.
  • silicones are versatile materials permitting the design of various transdermal and topical drug delivery forms.
  • the substantivity to skin can be adjusted from hours to one week in duration.
  • the hydrophobic, highly open, and mobile dimethylsiloxane network allows for the preparation of semi-occlusive matrices, permeable to many molecules including the compound(s) of the present invention.
  • sustained release of certain compounds described herein from silicone pressure sensitive adhesive matrices This capability can also be expanded to other types of silicone matrices including fillerless or reinforced elastomers. As such, modulation of the release of certain compounds of the present invention could enhance drug targeting and therapeutic effectiveness.
  • the silicone formulations could include a loosely cross-linked fillerless elastomer dispersion (Dow Corning® 9040 Silicone Elastomer Blend), a fully cross-linked fillerless elastomer (Dow Corning® 7-9800 A&B Soft Skin Adhesive), a rubber film-forming dispersion (Dow Corning® 7-5300 Film-In-Place Coating), and/or a visco-elastic system (Dow Corning® PSA 7-4502 and 7-4602 pressure sensitive adhesive.
  • a loosely cross-linked fillerless elastomer dispersion (Dow Corning® 9040 Silicone Elastomer Blend)
  • a fully cross-linked fillerless elastomer Dow Corning® 7-9800 A&B Soft Skin Adhesive
  • a rubber film-forming dispersion Dow Corning® 7-5300 Film-In-Place Coating
  • a visco-elastic system Dow Corning® PSA 7-4502 and 7-
  • the compound(s) of the present invention could be formulated in the different silicone and polymer matrices along with the following excipients: surfactants, citric-sodium bicarbonates, and/or carbomer 974.
  • Pharmaceutical compositions of the chemical entities described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of the pharmaceutical composition have diameters of less than 50 microns, in certain embodiments, less than 10 microns.
  • the chemical entity can be formulated as liquid solution, suspensions, aerosol propellants or dry powder and loaded into a suitable dispenser for administration.
  • suitable dispenser for administration.
  • inhalation devices metered dose inhalers (MDI) and dry powder inhalers (DPI).
  • MDIs typically are formulation packaged with a compressed gas. Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent.
  • DPI dispenses therapeutic agents in the form of a free-flowing powder that can be dispersed in the patient's inspiratory air stream during breathing by the device.
  • the therapeutic agent is formulated with an excipient such as lactose.
  • a measured amount of the therapeutic agent is stored in a capsule form and is dispensed with each actuation.
  • compressed gases may be used to disperse a chemical entity described herein in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
  • compositions have been developed for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area, i.e., decreasing particle size.
  • U.S. Patent No.4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a cross-linked matrix of macromolecules.
  • U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability. V.
  • Step 3 Synthesis of 5,7-dibromo-1,8-naphthyridin-2-amine (3-4).
  • N-(5-hydroxy-7-oxo-8H-1,8-naphthyridin-2-yl)acetamide (3-3) (20.00 g, 91.24 mmol) in toluene (200 mL) was added POBr 3 (209.26 g, 729.9 mmol) and the reaction mixture was stirred at 105 °C for 2 h under nitrogen atmosphere.
  • Example 3 (10.00 mg, 13.98%) as an off-white solid.
  • Step 1 Synthesis of ethyl 4-chloro-2-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridine-8-carboxylate (4-2).
  • Step 3 Synthesis of 2-(1,1,2,2,2-pentafluoroethyl)-4-(prop-1-en-2-yl)imidazo[1,2- a]1,8-naphthyridine-8-carbohydrazide (4-4).
  • Example 6 (25 mg, 18.76%) as a white solid. MS calcd. for C18H12F5N5O: 409.1; Found: 410.1 [M + 1] + .
  • Step 1 Synthesis of N,N-diisopropylcyanamide (9-2).
  • diisopropylamine (9-1) 50 g, 494.10 mmol
  • Acetonitrile 750 mL
  • Na 2 CO 3 104.74 g, 988.21 mmol
  • cyanogen bromide 54.95 g, 518.81 mmol
  • Step 4 Synthesis of 2,4-bis(perfluoroethyl)pyrido[2,3-d]pyrimidin-7-amine (9-5).
  • 2,4,6-tris(perfluoroethyl)-1,3,5-triazine (9-4) (2 g, 4.60 mmol)
  • acetic acid (20 mL
  • 2,6-diaminopyridine (0.75 g, 6.90 mmol)
  • the resulting mixture was stirred for 24 h at 80 °C under N2 atmosphere.
  • the mixture was allowed to cool down to room temperature.
  • the resulting mixture was diluted with water (50 mL).
  • the mixture was basified to pH 8 with NaHCO 3 Solution.
  • Example 9 (10 mg, 24.47%) as a white solid.
  • Step 1 Synthesis of ethyl 4-(1-methyl-1H-pyrazol-3-yl)-2- (perfluoroethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxylate (10-1).
  • the resulting mixture was filtered, the filter cake was washed with ethyl acetate and water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated salt solution, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • Step 1 Synthesis of tert-butyl 3-[8-(ethoxycarbonyl)-2-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-4-yl]-2,5-dihydropyrrole-1-carboxylate (11-1).
  • Step 2 Synthesis of tert-butyl 3-[8-(ethoxycarbonyl)-2-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-4-yl]pyrrolidine-1-carboxylate (11-2).
  • Step 5 Synthesis of 2-[2-(1,1,2,2,2-pentafluoroethyl)-4-(pyrrolidin-3-yl)imidazo[1,2- a]1,8-naphthyridin-8-yl]-1,3,4-oxadiazole (11-5).
  • Step 7 Synthesis of 2- ⁇ 3-[8-(1,3,4-oxadiazol-2-yl)-2-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-4-yl]pyrrolidin-1-yl ⁇ ethanol (Example 11).
  • Step 2 Synthesis of ethyl 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4- (perfluoroethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxylate (12-2).
  • Step 5 Synthesis of 2-(4-(perfluoroethyl)-2-(pyrrolidin-3-yl)imidazo[1,2- a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (12-5).
  • Example 12 (7 mg, 8.47%) as a light-yellow solid.
  • reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were, dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was purified by CombiFlash chromatography (using a gradient method of 15% EtOAc in heptane) to afford an inseparable mixture of ethyl 2-(perfluoroethyl)-4- (trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxylate (14-3a) and ethyl 4- (perfluoroethyl)-2-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxylate (14-3b) (a mixture of regioisomers) (0.55 g, 55%) as an off-white solid.
  • reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organic layers were, dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure.
  • the crude compound was purified by silica gel column chromatography (100-200 mesh, using a gradient method of 30-40% EtOAc in heptane) to afford 2-(9-bromo-2-(perfluoroethyl)-4- (trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (14-7) and 2-(9-bromo- 4-(perfluoroethyl)-2-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (14-8) as a mixture of regioisomers (0.24 g, 51.06%) as
  • reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were, dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure.
  • the crude compound was purified by preparative SFC [Column; CHIRAL PAK IC (250*30mm, 5um)/Mobile Phase A: MTBE: n-Hexane (50:50); Mobile Phase B: EtOH/ A:B: 50:50/ Flow: 30 ml/min/ UV: 254nm/ Diluent: DCM:MEOH(50:50)] to afford Example 14 (11 mg, 7.7%) as an off-white solid. MS calcd.
  • Step 1 Synthesis of 2-(2-bromo-4-(trifluoromethyl)imidazo[1,2- a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (16-2).
  • 8-(1,3,4-oxadiazol- 2-yl)-4-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-2(1H)-one (16-1) (5 g, 15.58 mmol) in DMF/ DCE (1/1 (v/v), 60 mL) was added POBr 3 (8 mL, 77.88 mmol) and then resulting reaction mixture was heated at 90 °C for 4 h.
  • reaction mixture was cooled to 0 °C and diluted with ice cold water, extracted with EtOAc. The combined organic layers were, washed with water, dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure.
  • the crude compound was purified by column chromatography on silica gel (100-200 mesh, using a gradient method of 40-50% EtOAc in hexane) to afford 2-(2-bromo-4-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)-1,3,4- oxadiazole (16-2) (2.1 g, 35.23%) as a yellow solid.
  • Step 4 Synthesis of 1-(8-(1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)imidazo[1,2- a][1,8]naphthyridin-2-yl)-2-methylpropan-1-ol (16-5).
  • reaction mixture was slowly warmed to room temperature and allowed to stir for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • reaction mixture was cooled to room temperature and the resulting solution was diluted with water and extracted with EtOAc. The combined organic layers were, dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure.
  • the crude compound obtained was purified by Column chromatography on silica gel (100-200 mesh, using a gradient method of 15-30% EtOAc in heptane) to afford 4-bromo-7-(perfluoroethyl)-5-(trifluoromethyl)- 1,8-naphthyridin-2-amine (17-2) (0.85 g, 25.83%) as an off-white solid.
  • TLC 50% EtOAc/Heptane (Rf: 0.7). MS calcd.
  • Step 4 Synthesis of 2-(5-bromo-2-(perfluoroethyl)-4-(trifluoromethyl)imidazo[1,2- a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (Example 17).
  • Example 17 The crude compound obtained was purified by column chromatography on silica gel (100-200 mesh, using a gradient method of 15-20% EtOAc in heptane) to afford Example 17 (25 mg, 34.24%) as a yellow solid. TLC: 50% EtOAc/heptane (Rf: 0.5). MS calcd. for C15H4BrF8N5O: 503.0, Found: 504.0 [M+1] + .
  • 1 H NMR 400 MHz, CD3OD: ⁇ 9.28 (s, 1H), 9.11 (s, 1H), 8.50 (s, 1H), 8.30 (s, 1H) ppm. [0248]
  • Example 18 Example 18
  • Step 1 Synthesis of ethyl 4-(dimethylamino)-2-(perfluoroethyl)imidazo[1,2- a][1,8]naphthyridine-8-carboxylate (18-1).
  • reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluting with 1-2% MeOH- in DCM to afford Example 18 (40 mg, 26.14%) as an off-white solid.
  • TLC 5% MeOH/DCM (R f : 0.5). MS calcd. for C 16 H 11 F 5 N 6 O: 398.1; Found: 399.0 [M + 1].
  • Step 1 Synthesis of ethyl 2-[(6-bromopyridin-2-yl)(hydroxy)methyl]prop-2-enoate (82-2).
  • Step 1 Synthesis of ethyl 4-((tert-butoxycarbonyl)amino)-1H-indole-2-carboxylate (83-2).
  • ethyl 4-bromo-1H-indole-2-carboxylate (83-1) (2 g, 7.46 mmol) in 1, 4-dioxane (50 mL) were added tert-butyl carbamate (1.30 g, 11.19 mmol) and Cs 2 CO 3 (6.06 g, 18.66 mmol), and the reaction mixture was purged under nitrogen for 10 min.
  • Step 4 Synthesis of ethyl 7-methyl-2-(perfluoroethyl)-4-(trifluoromethyl)-7H- pyrrolo[2,3-h]quinoline-8-carboxylate (83-5a) and ethyl 7-methyl-4-(perfluoroethyl)-2- (trifluoromethyl)-7H-pyrrolo[2,3-h]quinoline-8-carboxylate (83-5b).
  • methyl iodide 35 ⁇ L, 0.56 mmol was added at 0 °C and then the reaction mixture was slowly warmed to room temperature. The reaction was then stirred at room temperature under a nitrogen atmosphere for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, and concentrated under reduced pressure.
  • Step 5 Synthesis of 7-methyl-2-(perfluoroethyl)-4-(trifluoromethyl)-7H- pyrrolo[2,3-h]quinoline-8-carbohydrazide (83-6a) and 7-methyl-4-(perfluoroethyl)-2- (trifluoromethyl)-7H-pyrrolo[2,3-h]quinoline-8-carbohydrazide (83-6b).
  • Example 83 MS calcd. for C17H8F8N4O: 436.1; Found: 436.8 [M + 1].
  • Example 85 2-(4-(perfluoroethyl)-2-(trifluoromethyl)pyrazolo[1,5-h][1,7]naphthyridin- 9-yl)-1,3,4-oxadiazole
  • Example 86.2 2-(perfluoroethyl)-4-(trifluoromethyl)pyrazolo[1,5-h][1,7]naphthyridin- 9-yl)-1,3,4-oxadiazole
  • Step 1 Synthesis of methyl (Z)-2-azido-3-(3-bromopyridin-2-yl) acrylate (85-2).
  • 3-bromopicolinaldehyde (85-1) 5 g, 27.03 mmol
  • sodium methoxide solution 30% w/w in methanol, 11.26 mL, 67.57 mmol
  • methyl 2-azidoacetate 8.78 g, 67.57 mmol
  • reaction mixture was heated at 110 °C for 3 h in a sealed tube. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of Celite and washed with EtOAc (50 mL). The filtrate was diluted with water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na 2 SO 4 .
  • Step 6 Synthesis of 4-(perfluoroethyl)-2-(trifluoromethyl)pyrazolo[1,5- h][1,7]naphthyridine-9-carbohydrazide (85-7a) and 2-(perfluoroethyl)-4- (trifluoromethyl)pyrazolo[1,5-h][1,7]naphthyridine-9-carbohydrazide (85-7b).
  • Step 7 Synthesis of 2-(4-(perfluoroethyl)-2-(trifluoromethyl)pyrazolo[1,5- h][1,7]naphthyridin-9-yl)-1,3,4-oxadiazole (Example 85) and 2-(2-(perfluoroethyl)-4- (trifluoromethyl)pyrazolo[1,5-h][1,7]naphthyridin-9-yl)-1,3,4-oxadiazole (Example 86).
  • Example 85 MS calcd. for C15H5F8N5O: 423.0; Found: 424.1 [M + 1] + .
  • Example 86 Example 86.
  • Step 1 Synthesis of ethyl 2-[(3-bromopyridin-2-yl)(hydroxy)methyl]prop-2-enoate (87-2).
  • Table 2 shows structures and analytical data for representative Examples of the present invention. These compounds can be prepared according to the synthetic schemes described above and using procedures known to those of ordinary skill in the art. [0296] Table 2: Analytical data of representative compounds.
  • HEK293 cells expressing the firefly luciferase gene under the control of ISRE stably integrated into HEK293 cells were obtained from BPS Bioscience.
  • ISRE reporter was used to measure IFN ⁇ pathway induction.
  • pospho-STAT1 and phosphor-STAT2 form a complex with IRF9, named as ISGF3, which translocates to the nucleus and activates the transcription of interferon inducible genes (ISGs) through binding to ISRE in the promoter region of ISGs.
  • ISGs interferon inducible genes
  • the cells were culture in MEM medium (Corning) supplemented with 10% FBS, 1% non-essential amino acids, 1 mM sodium pyruvate, 1% Penicillin/Streptomycin plus 400 ⁇ g/ml of Geneticin. Sub-confluent culture is passaged and split twice a week, not exceeding 30 passages. Cells are detached using 0.05% Trypsin/0.53mM EDTA solution (Corning). [0299] For testing the compound effect on IFN ⁇ pathway, HEK293 ISRE reporter cells were seeded in 96-well plate at density of 50,000 cells/well 24 hours before treatment in a black clear bottom plate (Corning).
  • HCV replicon assay [0300] HCV 1b replicon (NanoLuc luciferase) cell line was generated in Huh7-Lunet cells.
  • HCV replicon cells were cultured in DMEM medium (Cytiva) supplemented with 10% FBS, 1% Penicillin/Streptomycin plus 250 ⁇ g/ml of Geneticin. Sub-confluent culture of HCV replicon is passaged and split twice a week, not exceeding 40 passages. Cells are detached using 0.25% Trypsin/2.21 mM EDTA solution (Corning).
  • HCV 1b replicon cells were seeded in DMEM medium supplemented with 5% FBS and 1% % Penicillin/Streptomycin at a density of 5,000 cells/well in a black clear bottom half-well 96-well plate (Corning), following by the addition of compounds in a three-fold serial dilution. The final DMSO concentration in each well is normalized to 1%. After 48-hour incubation, the luciferase activity was measured using Nano- Glo luciferase substrate (Promega) on a Tecan Infinite M1000 Pro plate reader. The antiviral activity of compound was calculated from the percentage of luciferase signals relative to DMSO treated cells.
  • Table 3 provides assay data for exemplified compounds of the invention.
  • the antiviral activity of the exemplified compounds at 20 uM is grouped in the following ranges: A indicates ⁇ 25%; B indicates 25% to 50%; C indicates > 50%.
  • Table 3 Assay data for exemplified compounds of the invention. INCORPORATION BY REFERENCE [0304] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference.

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Abstract

The present invention relates to 2-(imidazo[l,2-a]l,8-naphthyridin-8- yl)-l,3,4-oxadiazole derivatives of formula (I) as enhancers of innate immune response for the treatment of viral infections

Description

IMIDAZONAPHTHYRIDINE COMPOUNDS USEFUL FOR ENHANCING INNATE IMMUNE RESPONSES CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims benefit of U.S. Provisional Application No.63/352,130, filed June 14, 2022, the contents of which are hereby incorporated by reference. FIELD OF THE INVENTION [0002] Provided are compounds, pharmaceutical compositions, methods for their preparation, and methods for their use in treating and/or preventing viral infections, and in particular, to certain compounds that can enhance one or more innate immune responses within a subject. BACKGROUND [0003] Antiviral drugs can work by interacting with the virus to reduce its pathogenicity or by targeting the host to improve the host's defense against the virus. Most antiviral drugs on the market (e.g., zanamivir for treating influenza, zidovudine for treating HIV, acyclovir for treating HSV, and entecavir for treating HBV) interact directly with the virus to reduce pathogenicity. However, viruses can mutate and, thereby, develop resistance to these types of antiviral drugs. Consequently, antiviral drugs aimed at directly targeting a virus are prone to decreased efficacy over time. [0004] As a result, there is an unmet need for an antiviral drug that targets the host rather than the virus directly. Therapeutic agents that bolster existing host immune mechanisms of viral defense, specifically the host innate immune response to infection, hold potential for treatment of multiple infections with a single agent. [0005] IFN is one of the cytokines secreted by immune cells, which activates immune cells and acts on various points in the virus life cycle to suppress the growth of viruses. Currently, injectable pegylated interferon (Peg-IFN) is available for general clinical use. A significant number of patients with Peg-IFN have a therapeutic effect regardless of whether they are HBe antigen positive or negative, and various side effects have been reported. To address these issues, WO2013/059559 to Glaxo SmithKline, LLC discloses non-nucleic acid, low-molecular-weight, antiviral therapeutics suitable for oral administration. For example, imidazonaphthyridine compound RO8191 and related compounds are reported as IFN mimetic drugs using HCV replicon cells. WO2018043747 to Kyoto University discloses imidazonaphthyridine compounds for treatment of HBV. [0006] There is a long-felt and unmet need for new non-nucleic acid, low-molecular-weight, antiviral therapeutics, that are not only suitable for oral administration, but have increased efficacy, safety, and pharmacokinetic profiles. SUMMARY [0007] The present disclosure provides, in part, imidazonaphthyridine compounds and pharmaceutical compositions thereof, useful for treatment of viral infections. [0008] In one aspect, the disclosure provides a compound of Formula I:
Figure imgf000003_0001
Formula I or a pharmaceutically acceptable salt thereof, where the variables are described in the detailed description. [0009] In another aspect, the disclosure provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0010] In another aspect, the disclosure provides a method of treating a viral infection in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of compound of Formula I, or a pharmaceutically acceptable salt thereof. [0011] In another aspect, the disclosure provides a method of treating a viral infection in a subject in need thereof, comprising: administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. DETAILED DESCRIPTION [0012] The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. I. Definitions [0013] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6 or 1-4 carbon atoms, referred to herein as C1-6 alkyl and C1-4 alkyl, respectively. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2- butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2- pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl. [0014] The term “alkylene” as used herein refers to a biradical alkyl group. [0015] The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 carbon atoms, referred to herein as C2-6alkenyl. Examples include, but are not limited to, vinyl, allyl, butenyl, and pentenyl. [0016] The term “alkenylene” as used herein refers to a biradical alkenyl group. [0017] The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6 carbon atoms, referred to herein as C2-6alkynyl. Examples include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and methylpropynyl. [0018] The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (i.e., alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 1-4 carbon atoms, referred to herein as C1-6alkoxy and C1-4alkoxy, respectively. Examples include, but are not limited to, methoxy, ethoxy, and isopropoxy. [0019] The term “alkoxyalkyl” as used herein refers to an alkyl group substituted with an alkoxy group. Exemplary alkoxyalkyl groups include, but are not limited to, a C1-6alkyl group substituted with a C1-3alkoxy or C1-4alkoxy group, referred to herein as C1-3alkoxyC1-6alkyl and C1-4alkoxyC1-6alkyl, respectively. Examples include, but are not limited to, CH3CH2OCH2-, CH3OCH2CH2- and CH3OCH2-. [0020] The term “alkoxyalkenyl” as used herein refers to an alkenyl group substituted with an alkoxy group. Exemplary alkoxyalkenyl groups include, but are not limited to, a C2-6alkenyl group substituted with a C1-3alkoxy or C1-4alkoxy group, referred to herein as C1-3alkoxyC2- 6alkenyl and C1-4alkoxyC2-6alkenyl, respectively. Examples include, but are not limited to, CH3CH2OCH2CH=CH-, CH3OCH=CH2- and CH3OCH2CH=CHCH2-. [0021] The term “cyano” as used herein refers to CN. [0022] The terms “halo” or “halogen” as used herein refer to F, Cl, Br or I. [0023] The term “haloalkyl” as used herein refers to an alkyl group substituted with one or more halogen atoms. Exemplary haloalkyl groups include, but are not limited to, a C1-6alkyl or C1-4alkyl substituted with one or more halo groups, referred to herein as haloC1-6alkyl and haloC1-4alkyl, respectively. Examples include, but are not limited to, -CH2F, -CHCl2, -CHF2, - CF3, CF3CH2-, CH3CF2-, CF3CCl2- and CF3CF2-. [0024] The term “haloalkenyl” as used herein refers to an alkenyl group substituted with one or more halogen atoms. Exemplary haloalkenyl groups include, but are not limited to, a C2-66alkenyl or C2-4alkenyl substituted with one or more halo groups, referred to herein as haloC2-6alkenyl and haloC2-4alkenyl, respectively. Examples include, but are not limited to, CH2=CHCF2CF2-, CF3CH2CH=CH- and CH2=CHCH2CHF-. [0025] The term “haloalkoxy” as used herein refers to an alkoxy group substituted with one or more halogen atoms. Exemplary alkoxy groups include, but are not limited to, a C1-6alkoxy or C1-4alkoxy substituted with one or more halo groups, referred to herein as haloC1-6alkoxy and haloC1-4alkoxy, respectively. Examples include, but are not limited to, CCl3O-, CF3O-, CHF2O- CF3CH2O-, and CF3CF2O-. [0026] The term “haloalkoxyalkyl” as used herein refers to an alkoxyalkyl group substituted with one of more halogen atoms. Exemplary haloalkoxyalkyl groups include, but are not limited to, a C1-3alkoxyC1-6alkyl or C1-4alkoxyC1-5alkyl group substituted with one or more halogen atoms, herein referred to as haloC1-3alkoxyC1-6alkyl and haloC1-4alkoxyC1-5alkyl. Examples include, but are not limited to, CF3CH2OCH2-, CH3OCH2CF2- and CH3OCFH-. [0027] The term “haloalkoxyalkenyl” as used herein refers to an alkoxyalkenyl group substituted with one of more halogen atoms. Exemplary haloalkoxyalkenyl groups include, but are not limited to, a C1-3alkoxyC2-6alkenyl or C1-4alkoxyC2-4alkenyl group substituted with one or more halogen atoms, herein referred to as haloC1-3alkoxyC2-6alkenyl and haloC1-4alkoxyC2- 4alkenyl. Examples include, but are not limited to, CF3CF2OCH2CH=CH-, CH3OCF=CH2- and CH3OCH2CH=CHCF2-. [0028] The terms “hydroxy” and “hydroxyl” as used herein refer to OH. [0029] The term “hydroxyalkyl” as used herein refers to an alkyl group substituted with one or more hydroxy groups. Exemplary hydroxyalkyl groups include, but are not limited to, a C1-6alkyl or C1-4alkyl substituted with one or more hydroxy groups, referred to herein as hydroxyC1-6alkyl and hydroxyC1-4alkyl, respectively. Examples include, but are not limited to, HOCH2-, HOCH2CH2-, CH3CH(OH)CH2-, (CH3)2C(OH)CH2-, and HOCH2CH(OH)CH2-. [0030] The term “hydroxyalkenyl” as used herein refers to an alkenyl group substituted with one or more hydroxy groups. Exemplary hydroxyalkenyl groups include, but are not limited to, a C2-6alkenyl or C2-4alkenyl substituted with one or more hydroxy groups, referred to herein as hydroxyC2-6alkenyl and hydroxyC2-4alkenyl, respectively. Examples include, but are not limited to, CH2=CHCH(OH)CH2-, CH3CH(OH)CH=CH- and HOCH2CH2CH2=CHCH2-. [0031] The term “hydroxyalkoxy” as used herein refers to an alkoxy group substituted with one or more hydroxy groups. Exemplary hydroxyalkoxy groups include, but are not limited to, a C1- 6alkoxy or C1-4alkoxy substituted with one or more hydroxy groups, referred to herein as hydroxyC1-6alkoxy and hydroxyC1-4alkoxy, respectively. Examples include, but are not limited, to HOCH2O-, HOCH2CH2O-, CH3CH(OH)CH2O-, (CH3)2C(OH)CH2O-, and HOCH2CH(OH)CH2O-. [0032] The term “hydroxyhaloalkyl” as used herein refers to an haloalkyl group substituted with one or more hydroxy groups. Exemplary hydroxyalkyl groups include, but are not limited to, a haloC1-6alkyl or haloC1-4alkyl substituted with one or more hydroxy groups, referred to herein as hydroxyhaloC1-6alkyl and hydroxyhaloC1-4alkyl, respectively. Examples include, but are not limited to, HOCFH-, HOCH2CF2-, CF3CH(OH)CH2-, (CH3)2C(OH)CFH-, and HOCH2CH(OH)CF2-. [0033] The term “monocycloalkyl” as used herein refers to a saturated monocyclic hydrocarbon group of, for example, 3-6 carbons, referred to herein as monoC3-6cycloalkyl. Examples include, but are not limited to, cyclooctyl, cycloheptyl. cyclohexyl, cyclopentenyl, cyclobutyl and cyclopropyl. [0034] The term “monocycloalkenyl” as used herein refers to a partially unsaturated monocyclic hydrocarbon group of, for example, 4-7 carbons, referred to herein as monoC4- 7cycloalkenyl. Exemplary monocyclic cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. [0035] The term “monoheterocycloalkyl” refers to a monocycloalkyl group, for example a monoC3-7cycloalkyl, wherein 1-3 of the carbon atoms are replaced with independently selected heteroatoms, such as nitrogen, oxygen, and sulfur (including its oxidation states: S(O) and SO2), herein referred to as mono3-7heterocycloalkyl. Examples of mono3-7heterocycloalkyl groups include, but are not limited to, aziridinyl, oxiranyl, thiarinyl 1,1-dioxide, oxetanyl, azetidinyl, thietanyl 1,1-dioxide, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydro-2H-pyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl 1,1,dioxide, and piperazinyl. [0036] The term “monoheterocycloalkenyl” refers to a monocycloalkyl group, for example a monoC4-7cycloalkenyl, wherein 1-3 of the carbon atoms are replaced with independently selected heteroatoms, such as nitrogen, oxygen, and sulfur (including its oxidation states: S(O) and SO2), herein referred to as mono4-7heterocycloalkenyl. Examples of mono4-7heterocycloalkenyl groups include, but are not limited to, 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl, 4,5-dihydro- 1H-pyrazolyl, 2,3-dihydro-1H-pyrazolyl, 4,5-dihydro-1H-imidazolyl, 2,3-dihydro-1H- imidazolyl, 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl, 4,5-dihydrothiazolyl, 2,3- dihydrothiazolyl, 4,5-dihydroisothiazolyl, 2,3-dihydroisothiazolyl, 2,3-dihydrofuranyl, 2,5- dihydrofuranyl, 4,5-dihydrooxazolyl, 2,3-dihydrooxazolyl, 4,5-dihydroisoxazolyl, 2,3- dihydroisoxazolyl, 3,4-dihydropyridinyl, 2,3-dihydropyridinyl, 2,3,4,5-tetrahydropyridinyl, 1,6- dihydropyridazinyl, 4,5-dihydropyridazinyl, 3,4,5,6-tetrahydropyridazinyl, 4,5- dihydropyrimidinyl, 1,2,5,6-tetrahydropyrimidinyl, 1,2-dihydropyrimidinyl, 1,2- dihydropyrazinyl, 2,3-dihydropyrazinyl, 1,2,3,6-tetrahydropyrazinyl, 4H-1,4-oxazinyl, 3,4- dihydro-2H-1,4-oxazinyl, 4H-1,4-thiazinyl, and 3,4-dihydro-2H-1,4-thiazinyl. [0037] As used herein, when a bicyclic ring is shown with a floating point of attachment and/or floating substituents, for example
Figure imgf000008_0001
signifies that the bicyclic ring can be attached via a carbon atom on either ring, and that the substituents (e.g., the R33 group(s)) can be independently attached to either or both rings. [0038] The terms “Individual,” “patient,” and “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds or pharmaceutical compositions of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, and the like). The mammal treated in the methods of the disclosure is desirably a mammal in which treatment of HBV infection is desired. [0039] The term “Pharmaceutically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards. [0040] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, fillers, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions. [0041] The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable excipients. [0042] The term "pharmaceutically acceptable salt(s)" as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3- naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt. [0043] The term “therapeutically effective amount” or “effective amount” as used herein refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds or pharmaceutical compositions of the disclosure are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect. [0044] The term “treating” as used herein includes any effect, e.g., lessening, reducing, modulating, or eliminating, a viral infection, that results in the improvement of the disease. [0045] The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “
Figure imgf000010_0001
” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. [0046] The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon- carbon double bond. The symbol denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond. [0047] Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents around a carbocyclic or heterocyclic ring may also be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.” [0048] Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral- phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre- existing one, are well known in the art. Stereoselective syntheses encompass both enantiomeric and diastereoselective transformations and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009. [0049] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form. [0050] The disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium. [0051] Certain isotopically-labeled disclosed compounds (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon- 14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. II. Imidazonaphthyridine Compounds [0052] In one aspect, the present disclosure provides a compound of Formula I
Figure imgf000012_0001
Formula I , or a pharmaceutically acceptable salt thereof, wherein: [0053] Ra and Rb are independently selected for each occurrence from the group consisting of hydrogen and C1-4alkyl; [0054] R1 is acetyl, C1-5alkyl, haloC1-5alkyl, hydroxyC1-5alkyl, hydroxyhaloC1-5alkyl, C1- 3alkoxyC1-5alkyl, haloC1-3alkoxyC1-5alkyl, C2-5alkenyl, haloC1-5alkenyl, hydroxyC1-5alkenyl, C1- 3alkoxyC2-5alkenyl, haloC1-3alkoxyC2-5alkenyl, monoC3-7cycloalkyl, monoC4-7cycloalkenyl, mono3-7heterocycloalkyl, mono4-7heterocycloalkenyl, phenyl or pyridyl, wherein the monoC3- 7cycloalkyl, monoC4-7cycloalkenyl, mono3-7heterocycloalkyl, mono4-7heterocycloalkenyl, phenyl or pyridyl is optionally substituted with 1-3 substituents independently selected from the group consisting of NRaRb, CN, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-3alkoxyC1-5alkyl, and tert-butyloxycarbonyl; [0055] R2 is halo, OH, acetyl, C1-5alkyl, haloC1-5alkyl, C2-5alkenyl, haloC2-5alkenyl, hydroxyC1- 4alkyl, C1-3alkoxyC1-5alkyl, monoC3-7cycloalkyl-alkylene-, monoC3-7cycloalkyl-alkenylene-, monoC3-7cycloalkyl, monoC4-7cycloalkenyl, mono3-7heterocycloalkyl, mono4- 7heterocycloalkenyl, phenyl, pyridyl, or pyrazolyl, wherein the monoC3-7cycloalkyl, monoC4- 7cycloalkenyl, mono3-7heterocycloalkyl, mono4-7heterocycloalkenyl, phenyl, pyridyl, or pyrazolyl is optionally substituted with 1-3 substituents independently selected from the group consisting of NRaRb, CN, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-3alkoxyC1-5alkyl and monoC3-7cycloalkyl; [0056] R3 is hydrogen or halo; and [0057] R4 is hydrogen, halo or cyano; [0058] with the proviso that: [0059] R1 is haloC1-5alkyl having 4 or more halo atoms, C2-5alkenyl, haloC2-5alkenyl, hydroxyC2-5alkenyl, C1-3alkoxyC2-5alkenyl, C1-3alkoxyhaloC2-5alkenyl, monoC4-7cycloalkenyl, or mono4-7heterocycloalkenyl, wherein the monoC4-7cycloalkenyl or mono4-7heterocycloalkenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of NRaRb, CN, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-3alkoxyC1-5alkyl , and tert- butyloxycarbonyl; or [0060] R2 is haloC1-5alkyl having 4 or more halo atoms, C2-5alkenyl, haloC2-5alkenyl, monoC4- 7cycloalkenyl, or mono4-7heterocycloalkenyl, wherein the monoC4-7cycloalkenyl or mono4- 7heterocycloalkenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of NRaRb, CN, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-3alkoxyC1- 5alkyl and monoC3-7cycloalkyl. [0061] In another aspect, the present disclosure provides a compound of Formula II
Figure imgf000014_0002
Formula II , or a pharmaceutically acceptable salt thereof, wherein: X1 is CH or N; and R1, R2, R3 and R4 are as described herein with respect to Formula I. [0062] In another aspect, the present disclosure provides a compound of Formula III
Figure imgf000014_0001
Formula III , or a pharmaceutically acceptable salt thereof, wherein: Rx is hydrogen or C1-4alkyl; and R1, R2, R3 and R4 are as described herein with respect to Formula I. [0063] In another aspect, the present disclosure provides a compound of Formula IV
Figure imgf000015_0001
Formula IV , or a pharmaceutically acceptable salt thereof, wherein: R1, R2, R3 and R4 are as described herein with respect to Formula I. [0064] In another aspect, the present disclosure provides a compound of Formula V
Figure imgf000015_0002
Formula V , or a pharmaceutically acceptable salt thereof, wherein: R1, R2, R3 and R4 are as described herein with respect to Formula I. [0065] The following embodiments further describe a compound of Formula I, II, III, IV or V, or a pharmaceutically acceptable salt thereof. It will be appreciated that all chemically allowable combinations of the embodiments described herein are envisioned as further embodiments of the invention. [0066] In certain embodiments, R1 is haloC1-5alkyl having 4 or more halo atoms, C2-5alkenyl, haloC2-5alkenyl, hydroxyC2-5alkenyl, C1-3alkoxyC2-5alkenyl, C1-3alkoxyhaloC2-5alkenyl, monoC4- 7cycloalkenyl, or mono4-7heterocycloalkenyl, wherein the monoC4-7cycloalkenyl or mono4- 7heterocycloalkenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of NRaRb, CN, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-3alkoxyC1- 5alkyl , and tert-butyloxycarbonyl. [0067] In certain embodiments, R1 is haloC1-5alkyl having 4 or more halo atoms, C2-5alkenyl, haloC2-5alkenyl, hydroxyC2-5alkenyl, C1-3alkoxyC2-5alkenyl, C1-3alkoxyhaloC2-5alkenyl, monoC4- 7cycloalkenyl, or mono4-7heterocycloalkenyl, wherein the monoC4-7cycloalkenyl or mono4- 7heterocycloalkenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of NRaRb, CN, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-3alkoxyC1- 5alkyl , and tert-butyloxycarbonyl; and [0068] R2 is haloC1-5alkyl having 4 or more halo atoms, C2-5alkenyl, haloC2-5alkenyl, monoC4- 7cycloalkenyl, or mono4-7heterocycloalkenyl, wherein the monoC4-7cycloalkenyl or mono4- 7heterocycloalkenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of NRaRb, CN, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-3alkoxyC1- 5alkyl and monoC3-7cycloalkyl. [0069] In certain embodiments, R1 is C1-5alkyl. [0070] In certain embodiments, R1 is haloC1-5alkyl. [0071] In certain embodiments, R1 is CF3. [0072] In certain embodiments, R1 is haloC2-5alkyl having 4 or more halo atoms. [0073] In certain embodiments, R1 is CF3CF2 or CF3CF2CF2. [0074] In certain embodiments, R1 is C2-5alkenyl, haloC2-5alkenyl, hydroxyC2-5alkenyl, C1- 3alkoxyC2-5alkenyl or haloC1-3alkoxyC2-5alkenyl. [0075] In certain embodiments, R1 is monoC3-7cycloalkyl optionally substituted with 1-3 substituents independently selected from the group consisting of NRaRb, CN, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-3alkoxyC1-5alkyl, and tert-butyloxycarbonyl. [0076] In certain embodiments, R1 is monoC3-7cycloalkyl. [0077] In certain embodiments, R1 is monoC4-7cycloalkenyl or mono4-7heterocycloalkenyl, wherein the monoC4-7cycloalkenyl or mono4-7heterocycloalkenyl is optionally substituted with 1- 3 substituents independently selected from the group consisting of NRaRb, CN, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-3alkoxyC1-5alkyl, and tert-butyloxycarbonyl. [0078] In certain embodiments, R2 is haloC1-5alkyl having 4 or more halo atoms, C2-5alkenyl, haloC2-5alkenyl, monoC4-7cycloalkenyl, or mono4-7heterocycloalkenyl, wherein the monoC4- 7cycloalkenyl or mono4-7heterocycloalkenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of NRaRb, CN, halo, C1-4alkyl, hydroxyC1- 4alkyl, C1-4alkoxy, C1-3alkoxyC1-5alkyl and monoC3-7cycloalkyl. [0079] In certain embodiments, R2 is C1-5alkyl. [0080] In certain embodiments, R2 is haloC1-5alkyl. [0081] In certain embodiments, R2 is CF3. [0082] In certain embodiments, R2 is haloC1-5alkyl having 4 or more halo atoms, C2-5alkenyl or haloC2-5alkenyl. [0083] In certain embodiments, R2 is haloC2-5alkyl having 4 or more halo atoms. [0084] In certain embodiments, R2 is CF3CF2 or CF3CF2CF2. [0085] In certain embodiments, R2 is C2-5alkenyl or haloC2-5alkenyl. [0086] In certain embodiments, R2 is monoC3-7cycloalkyl. [0087] In certain embodiments, R2 is monoC4-7cycloalkenyl or mono4-7heterocycloalkenyl, wherein the monoC4-7cycloalkenyl or mono4-7heterocycloalkenyl is optionally substituted with 1- 3 substituents independently selected from the group consisting of NRaRb, CN, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-3alkoxyC1-5alkyl and monoC3-7cycloalkyl. [0088] In certain embodiments, R3 is hydrogen. [0089] In certain embodiments, R3 is halo. [0090] In certain embodiments, R4 is hydrogen. [0091] In certain embodiments, R4 is halo or cyano. III. Methods of Use [0092] Without being bound by any theory, since the compounds of the present disclosure behave as interferon mimicking agents (IFN mimetic agents), it is believed that may exhibit their antiviral activity through a variety of mechanisms. One such mechanism involves modulating the expression of interferon-stimulated genes (ISGs) through the janus kinase/signal transducer and activator (JAK/STAT) pathway, a common target for attack by a variety of viruses (Fleming, 2016, herein incorporated by reference with regard to such background teaching). Like other antiviral agents – the compounds of the present disclosure may also function as protease or polymerase inhibitors, disrupt the viral replication machinery or have general anti-viral activity against viral components. The presence of these mechanisms in a broad group of viruses suggest the compounds disclosed herein may provide therapeutic anti-viral activity against a diverse group of viruses. [0093] Thus, one aspect described herein is a method of treating a hepatitis B infection (HBV) in a patient in need thereof is provided, comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s). In another embodiment, a method for treating a hepatitis B infection in a patient in need thereof is provided, comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient. [0094] With regard to HBV/hepatitis D (HDV) coinfection or superinfection, HDV encodes HDAg, the HDV protein responsible for HDV RNA replication. HDV infection is facilitated by the interaction of HDAg with HBV viral envelope protein HBsAg, for both entry into the hepatocytes and assembly and release of the HDV virions (Negro, 2014). Thus, because HDV infection is dependent on the presence of an existing HBV infection, strategies for treating HBV/HDV coinfection may focus on targeting HBV alone, HDV alone or both viruses together. [0095] Thus, the present disclosure also contemplates a method of treating an HBV or HDV infection, or HBV/HDV coinfection, in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s). In another embodiment, a method for treating an HBV or HDV infection or HBV/HDV coinfection in a patient in need thereof is provided, comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient. [0096] In some aspects, the disclosure provides a method of treating a hepatitis B infection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, in combination with one or more other HBV agents each selected from the group consisting of HBV capsid assembly promoters, HBV viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors, disruptors of nucleocapsid formation, cccDNA formation inhibitors, antiviral core protein mutant, HBc directed transbodies, RNAi targeting HBV RNA, immunostimulants, TLR-7/9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimetics, epigenetic modulators, kinase inhibitors, and STING agonists. In some embodiments, the disclosure provides a method of treating a hepatitis B infection in a patient in need thereof, comprising administering an amount of a disclosed compound, and administering another HBV capsid assembly promoter therapeutic. Other combinations contemplated herein include administering a first compound selected from any one of the disclosed compounds, in combination with any available HBV treatment, including not limited to, entecavir, tenofovir, Baraclude, Viread, lamivudine, Vemlidy, Hepsera, Epivir-HBV, adefovir, epivir tenofovir alafenamide, and other suitable HBV drugs. [0097] In some aspects, the disclosure further provides a method of treating HBV or HDV infection or HBV/HDV coinfection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, and one or more other additional antivirals, the one or more additional antivirals include HDV therapies, such as lonafarnib, and one or more of HBV agents each selected from the group consisting of HBV capsid assembly promoters, HBV viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors, disruptors of nucleocapsid formation, cccDNA formation inhibitors, antiviral core protein mutant, HBc directed transbodies, RNAi targeting HBV RNA, immunostimulants, TLR-7/9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimetics, epigenetic modulators, kinase inhibitors, and STING agonists. In some embodiments, the disclosure provides a method of treating a HBV or HDV infection or HBV/HDV coinfection in a patient in need thereof, comprising administering an amount of a disclosed compound, and administering another HBV therapeutic or an HDV therapeutic. [0098] Another IFN mimetic, RO 8191 has demonstrated antiviral activity against hepatitis C virus (HCV) (Wang et al., 2015), Corona viruses (WO2022/049521), and Zika virus (ZIKV) (Fernandes et al., 2021). Given that the compounds of the instant disclosure are also IFN mimicking agents anti-viral activity against HCV, Corona virus and Zika virus is also contemplated herein. [0099] Thus, another aspect described herein is a method of treating a hepatitis C infection (HCV) in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s). In another embodiment, a method for treating a hepatitis C infection in a patient in need thereof is provided, comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient. [0100] In some aspects, the disclosure provides a method of treating a hepatitis C infection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, in combination with suitable treatments for HCV including, but not limited to, lbasvir/Grazoprevir (Zepatier), Glecaprevir/Pibrentasvir (Mavyret), Sofosbuvir/Ledipasvir (Harvoni), Sofosbuvir/Velpatasvir (Epclusa), second line hepatitis C medications such as Sofosbuvir/Velpatasvir/Voxelaprevir (Vosevi), and other suitable HCV drugs. [0101] Coronaviruses are another possible viral target for the compounds of the present disclosure (See, for example, WO2022/049521). Thus, another aspect of the present disclosure provides methods for treating viral infection, wherein said viral infection comprises one or more viruses from the Coronaviridae family including human coronavirus, Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), Middle East Respiratory Syndrome coronavirus (MERS- CoV) and Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV- 2). The disease caused by these viruses are SARS (SARS-CoV), MERS (MERS-CoV) and COVID-19 (SARS- CoV-2). Another aspect described herein, are methods for treating viral infections, and the disease caused by such viral infection, wherein said viral infection is SARS-CoV, and the resulting disease is SARS, MERS-CoV, and the resulting disease is MERS, or SARS-CoV-2, and the disease is COVID-19. [0102] In some aspects, the disclosure provides a method of treating any Coronaviridae viral infection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, in combination with suitable treatments for Coronavirus infection including, but not limited to, nirmatrelvir, ritonavir, Lagevrio (molnupiravir), baricitinib, and the various coronavirus vaccines and other suitable Coronavirus drugs. [0103] Another aspect described herein, is a method of treating a Zika virus (ZIKV) viral infection in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s). In another embodiment, a method for treating a ZIKV infection in a patient in need thereof is provided, comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient. [0104] In some aspects, the disclosure provides a method of treating a Zika virus infection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, in combination with suitable treatments for ZIKV infection. Although there are no medications to treat ZIKV, because treatment includes over the counter use of pain, anti-inflammatory drugs, suitable drugs for combining administration of the compounds of the instant disclosure include acetaminophen, ibuprofen, non-steroidal anti-inflammatory drugs and hydration therapies. [0105] Human papillomavirus (HPV) is another common sexually transmitted virus with more than 100 known varieties. Interferons have been successfully used to treat HPV infections, making this virus an ideal candidate for treatment by the compounds of the present disclosure. Thus, another aspect described herein, is a method of treating HPV infection in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s). In another embodiment, a method for treating a HPV infection in a patient in need thereof is provided, comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient. [0106] Combination therapy with the compounds disclosed herein, and known HPV drugs are also contemplated herein. In some aspects, the disclosure provides a method of treating any HPV viral infection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, in combination with suitable treatments for HPV infection including, but not limited to, condylax (podofilox), trichloroacetic acid, aldara (imiquimod), zyclara, keratoyltic agents, immune response modifiers, and various commonly used HPV vaccines. [0107] Prion infection results in fatal brain diseases and encephalopathies in both humans and animals. Recombinant and IFN mimicking interferon therapy have both been found to possible protect neurons from prion infections (Ishibashi, 2019). Thus, one aspect described herein is a method of treating prion infection in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s). In another embodiment, a method for treating a prion infection in a patient in need thereof is provided, comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient. [0108] Chikungunya virus (CHIKV) and Dengue virus are both related mosquito-borne viruses with no approved therapies. Studies have demonstrated that CHIKV replication has been found to be inhibited by an agonist of Liver X receptor (LXR-623) by activation of the interferon signaling pathway (Hwang et al., 2019), and halofuginone has been found to work synergistically with another IFN mimicking agent. Thus, both CHIKV and Dengue virus represents yet another group of viruses ideally suited for therapy with the compounds described herein. Without being bound by any theory, it is possible the compounds of the present disclosure could demonstrate a synergistic effect with LXR-623 agonists for the treatment of CHIKV and/or with halofuginone for the treatment of both CHIV and Dengue virus. Thus, another embodiment described herein is a method of treating CHIKV by administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s). In one aspect, a method of treatment would include administering any of the disclosed compounds in combination with LXR-623. In another aspect described herein is a method of treating CHIKV virus comprising administering to a subject in need thereof, a combination of the compounds disclosed herein and LXR-623 or halofuginone. In yet another aspect, is a method of treating Dengue virus comprising administering to a subject in need thereof, a combination of the compounds disclosed herein and halofuginone. [0109] Without being bound by any theory, it is further understood that the compounds of the present disclosure may be useful for the treatment of human norovirus (HNV) and encephalomyocarditis virus (EMCV) – both of which have been found to be respond to interferon-mediated antiviral therapy (de Graff et al., 2016; Campillay-Veliz et al., 2020)). Thus, another aspect described herein is a method of treating HNV infection in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s). In another embodiment, a method for treating a EMCV infection in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s). [0110] Further contemplated herein is a method for treating any of the viral infections described herein, in a subject that has been diagnosed with said viral infection or is at risk of developing said viral infection comprising administering to said subject, any one of the compounds described herein. [0111] Another aspect described herein, is a method for enhancing the immune response to a viral infection from any of the viruses described herein, in a subject that is immunocompromised or is at risk of developing an immunocompromised immune system, comprising administering to said subject, any of the compound as described herein. IV. Administration and Formulations [0112] In further embodiments, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The chemical entities are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease. [0113] The compounds of the present invention can also be supplied in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable inorganic and organic acids and bases. [0114] Pharmaceutically acceptable inorganic bases include metallic ions. More preferred metallic ions include, but are not limited to, appropriate alkali metal salts, alkaline earth metal salts and other physiological acceptable metal ions. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like and in their usual valences. Exemplary salts include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. [0115] Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, including in part, trimethylamine, diethylamine, N, N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine; substituted amines including naturally occurring substituted amines; cyclic amines; quaternary ammonium cations; and basic ion exchange resins, such as arginine, betaine, caffeine, choline, Ν,Ν-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. [0116] Illustrative pharmaceutically acceptable acid addition salts of the compounds of the present invention can be prepared from the following acids, including, without limitation formic, acetic, propionic, benzoic, succinic, glycolic, gluconic, lactic, maleic, malic, tartaric, citric, nitic, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, hydrochloric, hydrobromic, hydroiodic, isocitric, trifluoroacetic, pamoic, propionic, anthranilic, mesylic, oxalacetic, oleic, stearic, salicylic, p-hydroxybenzoic, nicotinic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, phosphoric, phosphonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, sulfuric, salicylic, cyclohexylaminosulfonic, algenic, β-hydroxybutyric, galactaric and galacturonic acids. Preferred pharmaceutically acceptable salts include the salts of hydrochloric acid and trifluoroacetic acid. All of the above salts can be prepared by those skilled in the art by conventional means from the corresponding compound of the present invention. For example, the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized. Lists of suitable salts are found in Remington's Pharmaceutical Sciences. 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418, the disclosure of which is hereby incorporated by reference only with regards to the lists of suitable salts. [0117] In general, the chemical entities provided will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the chemical entity, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the chemical entity used, the route and form of administration, and other factors. The drug can be administered more than once a day, such as once or twice or three times a day. [0118] Therapeutically effective amounts of the chemical entities described herein may range from approximately 0.01 to 200 mg per kilogram body weight of the recipient per day; [0119] such as about 0.01-100 mg/kg/day, for example, from about 0.1 to 50 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range may be about 7-3500 mg per day. [0120] In addition, the amount of the chemical entity in a composition can vary within the full range employed by those skilled in the art. Typically, the composition will contain, on a weight percent (wt%) basis, from about 0.01-99.99 wt% of at least one chemical entity described herein based on the total composition, with the balance being one or more suitable pharmaceutical excipients. In certain embodiments, the at least one chemical entity described herein is present at a level of about 1-80 wt%. [0121] In certain embodiments, the chemical entities will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), sublingually, subcutaneously, topically, intrapulmonarilly, vaginally, rectally, or intraocularly, or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. In other embodiments, oral administration with a convenient daily dosage regimen that can be adjusted according to the degree of disorder or disease may be used. The choice of administration route and/or formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance. [0122] In one embodiment, the compounds of the present invention may be administered topically to the diseased area on the skin or mucous membranes of a subject. In another embodiment, the compounds of the present invention may be administered topically to the diseased area on the skin or mucous membranes of a subject so that the topical administration allows for the compound to penetrate into the subject's skin layer keratinocyte cells. [0123] In some embodiments, the compositions are comprised of, in general, at least one chemical entity described herein in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of at least one chemical entity described herein. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art. Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, [0124] glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Liquid carriers, for injectable solutions, include water, saline, aqueous dextrose, and glycols. [0125] Pharmaceutical compositions or formulations include solid, semi-solid, liquid and aerosol dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols or the like. The chemical entities can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for prolonged and/or timed, pulsed administration at a predetermined rate. In certain embodiments, the compositions are provided in unit dosage forms suitable for single administration of a precise dose. [0126] The chemical entities described herein can be administered either alone or more typically in combination with a conventional pharmaceutical carrier, excipient or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like). If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like). Generally, depending on the intended mode of administration, the pharmaceutical composition will contain about 0.005% to 95%; in certain embodiments, about 0.5% to 50% by weight of a chemical entity. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania. [0127] In certain embodiments, the compositions will take the form of a pill or tablet and thus the composition will contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides) is encapsulated in a gelatin capsule. [0128] Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. at least one chemical entity and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of chemical entities contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the chemical entities and the needs of the subject. However, percentages of active ingredient of 0.01% to 10% in solution are employable and will be higher if the composition is a solid which will be subsequently diluted to the above percentages. In certain embodiments, the composition will comprise from about 0.2 to 2% of the active agent in solution. [0129] In one embodiment, the compounds of the present invention can be formulated into dermatological topical delivery formulations. Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For treatments of external tissues, such as skin, the formulations may be applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base. [0130] In addition to the compounds of the present invention, the compositions herein may additionally include an organic solvent, an adhesive, plasticizer, and a water swellable polymer. The organic solvent may be one or more of dimethylsulfoxide (DMSO), N,N'-dimethylacetamide (DMA), N',N'-dimethylformamide (DMF), dioxane, tetraglycol, or the like. [0131] Appropriate adhesives for use in the invention include, but are not limited to, polyvinyl alcohol, polyethylene oxides, polyethylene glycols of molecular weight 3350 and higher, hydroxypropylcellulose, and povidone. Polyvinyl alcohol is preferred. The adhesive is typically present in an amount from about 10 to 75% by weight, preferably about 45-55% by weight, and most preferably about 50% by weight of the composition. [0132] The compositions herein may optionally also include a plasticizer. Suitable plasticizers are typically high-boiling, water-soluble organic compounds containing hydroxyl, amide, or amino groups. Such plasticizers include, but are not limited to, soy, egg or synthetic lecithin, ethylene glycol, tetraethylene, hexamethylene, nonaethylene glycol, formamide, ethanolamine salts, water, glycerin, or combinations thereof. Such plasticizers are well known in the art. A plasticizer is therefore preferably included in the formulation to provide these benefits. The plasticizer is typically present in the composition in an amount ranging from about 0.4-2.0% by weight, with about 1-2% by weight being preferred, and about 0.9% by weight being most preferred. [0133] The composition may also include a water swellable polymer which acts as an extender and serves to thicken the composition. Such water swellable polymers are well known in the art and include, but are not limited to, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, methyl ethyl cellulose, sodium carboxymethylcellulose, gums, carboxyvinyl polymer, hydroxyethyl cellulose, cornstarch, casein, urea, dextrin, and fume silica. The filler is typically present in an amount from about 1- 10% by weight, preferably about 3-6% by weight, with about 4.67% by weight being most preferred. [0134] The present invention is further directed to a method of treating warts by applying the pharmaceutical composition(s) topically to the location on the skin where the warts are present. The method of the invention comprises topically applying to a wart on an individual a therapeutically effective amount of the compositions of the invention. The composition may be applied using an applicator, for example, a swab, sponge, finger cot or a toothpick. While some compositions of this invention can be adhesive in and of themselves, in another embodiment of the invention, the method further comprises occluding the wart with an occluding agent to aid the composition's absorption into the wart, protect the composition from rubbing off, and also further keratolytic activity. Many occluding agents are known to those skilled in the art. These include, but are not limited to, bandages, plastic wrap, and adhesive tape, for example, duct tape. [0135] The compositions of the invention may further include a variety of substances, including suitable stabilizers, buffers, thickeners, lubricants, wetting, and dissolving agents as well as colorings, moisturizers, preservatives, and fragrances. These minors are added in small amounts and are conventionally known in pharmaceutical formulation work to enhance elegance. Such minors typically comprise less than about 1% of the overall composition. [0136] In still other embodiments, the compounds of the present invention can be formulated into dermatological delivery formulations, such as a stick-gel, which can be used to target the delivery of the compound directly onto the site of action. For example, if the compounds of the present invention are intended to be used as a treatment for papillomavirus induced warts, then the compound(s) may be formulated into a stick-gel that can apply the compounds in a formulation directly to the surface of the wart. In still other embodiments, the stick-gel application formulation can be based on a PSAs (Pressure Sensitive Adhesives) concept. PSAs, unlike structural adhesives or sealants, differ in that the adhesive-substrate interface does not resist separation when the adhesive is peeled off. In other words, PSAs are intended to show adhesive failure, especially when skin is the substrate, whereas this would be a major fatal flaw for cement and glue. Developing a suitable PSA-GeI for a targeted adherend to treat a skin common wart, takes the following two critical adhesive attributes into consideration: surface activity and visco-elastic properties. [0137] As such, these attributes are associated to the three steps of adhesion process. The first step involves contact between the adhesive and the surface. This dynamic step is known as "bonding or sticking" and is dependent on wetting behavior and quick spreadability of the adhesive composition. The second step "adhering" relies on the capacity of the adhesive to remain in contact with surface. This is important for treating warts where the active should be adherent to the warts long enough to exert its intended action. Flowability and creep resistance are the physical characteristics that contribute to maintain the established bond and stick. During this more static phase, the adhesion will build up if the adhesive-to-surface interactions increase (e.g., interpenetration). The third step "debonding" is also dynamic. It consists in separating the adhesive-stick from the surface by means of a peel release process. The peel adhesion property of the adhesive composition will direct the force required to break the bond in an adhesive failure mode. [0138] The formulation composition to achieve all these attributes can comprise suitable hydrophilic polymers incorporated into a gel matrix containing the active drug in solution. Large organic macromolecules that are either natural or synthetic hydrophilic polymers (e.g., hydroxy propyl methyl cellulose, ethyl cellulose, etc.) on the other hand, exist as randomly coiled chains that entangle with each other to form the gel structure. The nature of the solvent determines whether the gel is a hydrogel (water based) or an organogel (nonaqueous solvent). For example, gels prepared with hydroxyethyl cellulose containing water are hydrogels, whereas gels prepared with polyethylene-containing mineral oil (PIastibase) are organogels. Another class of gels, called thermally sensitive gels, are prepared from poloxamers. In addition to hydrophilic polymers, silicones are versatile materials permitting the design of various transdermal and topical drug delivery forms. The substantivity to skin can be adjusted from hours to one week in duration. Moreover, the hydrophobic, highly open, and mobile dimethylsiloxane network allows for the preparation of semi-occlusive matrices, permeable to many molecules including the compound(s) of the present invention. [0139] In other embodiments of the present invention, there is provided sustained release of certain compounds described herein from silicone pressure sensitive adhesive matrices. This capability can also be expanded to other types of silicone matrices including fillerless or reinforced elastomers. As such, modulation of the release of certain compounds of the present invention could enhance drug targeting and therapeutic effectiveness. The silicone formulations could include a loosely cross-linked fillerless elastomer dispersion (Dow Corning® 9040 Silicone Elastomer Blend), a fully cross-linked fillerless elastomer (Dow Corning® 7-9800 A&B Soft Skin Adhesive), a rubber film-forming dispersion (Dow Corning® 7-5300 Film-In-Place Coating), and/or a visco-elastic system (Dow Corning® PSA 7-4502 and 7-4602 pressure sensitive adhesive. In certain embodiments, the compound(s) of the present invention could be formulated in the different silicone and polymer matrices along with the following excipients: surfactants, citric-sodium bicarbonates, and/or carbomer 974. [0140] Pharmaceutical compositions of the chemical entities described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the pharmaceutical composition have diameters of less than 50 microns, in certain embodiments, less than 10 microns. [0141] For delivery via inhalation the chemical entity can be formulated as liquid solution, suspensions, aerosol propellants or dry powder and loaded into a suitable dispenser for administration. There are several types of pharmaceutical inhalation devices-nebulizer inhalers, metered dose inhalers (MDI) and dry powder inhalers (DPI). Nebulizer devices produce a stream of high velocity air that causes the therapeutic agents (which are formulated in a liquid form) to spray as a mist that is carried into the patient's respiratory tract. MDIs typically are formulation packaged with a compressed gas. Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent. DPI dispenses therapeutic agents in the form of a free-flowing powder that can be dispersed in the patient's inspiratory air stream during breathing by the device. To achieve a free-flowing powder, the therapeutic agent is formulated with an excipient such as lactose. A measured amount of the therapeutic agent is stored in a capsule form and is dispensed with each actuation. Likewise, compressed gases may be used to disperse a chemical entity described herein in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990). [0142] Recently, pharmaceutical compositions have been developed for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area, i.e., decreasing particle size. For example, U.S. Patent No.4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a cross-linked matrix of macromolecules. U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability. V. Examples [0143] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials. [0144] At least some of the compounds identified as “intermediates” herein are contemplated as compounds of the disclosure. Abbreviations:
Figure imgf000032_0001
Figure imgf000033_0001
[0145] Example 1. 2-[2-Isopropyl-4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridin-8-yl]-1,3,4- oxadiazole
Figure imgf000034_0001
[0146] Step 1. Synthesis of 1,1,1,2,2-pentafluoro-6-methylheptane-3,5-dione (1-2). A solution of ethyl pentafluoropropionate (10 g, 52.06 mmol), methyl isopropyl ketone (6.73 g, 78.09 mmol) and NaH (2.50 g, 104.12 mmol) in THF (200 mL) was stirred for 2 h at 70 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 1,1,1,2,2-pentafluoro-6-methylheptane-3,5-dione (1-2) (6 g, 49.65%) as a red oil. MS calcd. for C8H9F5O2: 232.1; Found: 233.1 [M + 1]+. [0147] Step 2. Synthesis of 7-isopropyl-5-(1,1,2,2,2-pentafluoroethyl)-1,8-naphthyridin-2- amine (1-3). A mixture of 1,1,1,2,2-pentafluoro-6-methylheptane-3,5-dione (1-2) (6 g, 25.85 mmol) and 2,6-diaminopyridine (4.23 g, 38.77 mmol) in PPA (60 mL) was stirred for 4 h at 120 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (200 mL). The mixture was basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (2:1). Then the residue was diluted with hexane (100 mL). The precipitated solids were collected by filtration to give 7- isopropyl-5-(1,1,2,2,2-pentafluoroethyl)-1,8-naphthyridin-2-amine (1-3) (1.4 g, 17.75%) as a white solid. MS calcd. for C13H12F5N3: 305.1; Found: 306.1 [M + 1]+. [0148] Step 3. Synthesis of ethyl 2-isopropyl-4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2- a]1,8-naphthyridine-8-carboxylate (1-4). A solution of 7-isopropyl-5-(1,1,2,2,2- pentafluoroethyl)-1,8-naphthyridin-2-amine (1-3) (500 mg, 1.64 mmol), ethyl 3-bromo-2- oxopropanoate (1.12 g, 5.73 mmol) and TEA (497.26 mg, 4.91 mmol) in THF (20 mL) was stirred for 16 h at 70 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL) then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (3:1) to afford ethyl 2-isopropyl-4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridine-8-carboxylate (1-4) (350 mg, 53.24%) as a yellow oil. MS calcd. for C18H16F5N3O2: 401.1; Found: 402.1 [M + 1]+. [0149] Step 4. Synthesis of 2-isopropyl-4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridine-8-carbohydrazide (1-5). A solution of ethyl 2-isopropyl-4-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridine-8-carboxylate (1-4) (200 mg, 0.50 mmol) and hydrazine (79.85 mg, 2.49 mmol) in EtOH (4 mL) was stirred for 4 h at 70 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography, eluted with CH3CN/H2O (4:1) to afford 2-isopropyl-4-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridine-8-carbohydrazide (1-5) (30 mg, 15.54%) as a yellow solid. MS calcd. for C16H14F5N5O: 387.1; Found: 388.0 [M + 1]+. [0150] Step 5. Synthesis of 2-[2-isopropyl-4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridin-8-yl]-1,3,4-oxadiazole (Example 1). A solution of 2-isopropyl-4-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridine-8-carbohydrazide (30 mg, 0.08 mmol) and p- toluenesulfonic acid (6.67 mg, 0.04 mmol) in CH(OMe)3 (1.5 mL) was stirred for 4 h at 70 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (5 mL). The mixture was basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL) then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC to afford Example 1 (26 mg, 84.49%) as a white solid. MS calcd. for C17H12F5N5O: 397.1; Found: 398.1 [M + 1]+.1H NMR (400 MHz, DMSO-d6): δ 9.42 (s, 1H), 9.23 (s, 1H), 8.00 (s, 1H), 7.93 ‒ 7.87 (m, 2H), 3.48 ‒ 3.41 (m, J = 6.8 Hz, 1H), 1.43 (d, J = 6.8 Hz, 6H) ppm. [0151] Example 2. 2-[4-Isopropyl-2-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridin-8-yl]-1,3,4-oxadiazole
Figure imgf000036_0001
[0152] Step 1. Synthesis of 7-amino-2-(1,1,2,2,2-pentafluoroethyl)-1H-1,8-naphthyridin-4- one (2-2). A solution of 2,6-diaminopyridine (6 g, 54.98 mmol) and ethyl 4,4,5,5,5-pentafluoro- 3-oxopentanoate (19.31 g, 82.47 mmol) in phosphoric acid (30 mL) was stirred for 120 °C at 16 h under nitrogen atmosphere. The mixture was allowed to cool down to rt. The resulting mixture was diluted with H2O (50 mL). The mixture was neutralized to pH 8-9 with NaHCO3 aq. solution. The precipitated solids were collected by filtration and washed with H2O (50 mL). The residue was purified by silica gel column chromatography, eluted with DCM/MeOH = 2/1 (v/v) to afford 7-amino-2-(1,1,2,2,2-pentafluoroethyl)-1H-1,8-naphthyridin-4-one (2-2) (3 g, 19.55%) as a yellow solid. MS calcd. for C10H6F5N3O: 279.0; Found: 280.1 [M + 1]+. [0153] Step 2. Synthesis of ethyl 4-oxo-2-(1,1,2,2,2-pentafluoroethyl)-1H-imidazo[1,2-a]1,8- naphthyridine-8-carboxylate (2-3). A solution of 7-amino-2-(1,1,2,2,2-pentafluoroethyl)-1H- 1,8-naphthyridin-4-one (2-2) (3 g, 10.75 mmol) and ethyl 3-bromo-2-oxopropanoate (4.19 g, 21.49 mmol) in THF (30 mL) was stirred for 70 °C at 10 h under nitrogen atmosphere. The mixture was allowed to cool down to rt. The resulting mixture was diluted with H2O (30 mL). The aqueous layer was extracted with EA (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/THF = 1/10 (v/v) to ethyl 4-oxo-2-(1,1,2,2,2- pentafluoroethyl)-1H-imidazo[1,2-a]1,8-naphthyridine-8-carboxylate (2-3) (1.5 g, 37.20%) as a yellow solid. MS calcd. for C15H10F5N3O3: 375.0; Found: 376.1 [M + 1]+. [0154] Step 3. Synthesis of 4-oxo-2-(1,1,2,2,2-pentafluoroethyl)-1H-imidazo[1,2-a]1,8- naphthyridine-8-carbohydrazide (2-4). A solution of ethyl 4-oxo-2-(1,1,2,2,2- pentafluoroethyl)-1H-imidazo[1,2-a]1,8-naphthyridine-8-carboxylate (2-3) (1.5 g, 4.00 mmol) and hydrazine (1.5 mL) in EtOH (15 mL) was stirred for 70°C at 4h under nitrogen atmosphere. The mixture was allowed to cool down to rt. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash column chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 30% gradient over 15 min; detector, UV 254 nm to give 4-oxo-2-(1,1,2,2,2-pentafluoroethyl)-1H- imidazo[1,2-a]1,8-naphthyridine-8-carbohydrazide (2-4) (0.5 g, 34.63%) as a yellow solid. MS calcd. for C13H8F5N5O2: 361.0; Found: 362.1 [M + 1]+. [0155] Step 4. Synthesis of 8-(1,3,4-oxadiazol-2-yl)-2-(1,1,2,2,2-pentafluoroethyl)-1H- imidazo[1,2-a]1,8-naphthyridin-4-one (2-5). A solution of 4-oxo-2-(1,1,2,2,2- pentafluoroethyl)-1H-imidazo[1,2-a]1,8-naphthyridine-8-carbohydrazide (2-4) (500 mg, 1.38 mmol) and p-toluenesulfonic acid (357.53 mg, 2.08 mmol) in trimethyl orthoformate (5 mL) was stirred for 70 °C at 4h under nitrogen atmosphere. The mixture was allowed to cool down to rt. The resulting mixture was diluted with H2O (30 mL). The resulting mixture was extracted with EA (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE: THF (1:1) to afford 8-(1,3,4-oxadiazol-2-yl)-2-(1,1,2,2,2-pentafluoroethyl)-1H- imidazo[1,2-a]1,8-naphthyridin-4-one (2-5) (200 mg, 38.92%) as a brown solid. MS calcd. for C14H6F5N5O2: 371.0; Found: 372.1 [M + 1]+.1H NMR (300 MHz, DMSO-d6): δ 9.39 (s, 1H), 8.87 (s, 1H), 8.00 ‒ 7.97 (d, J = 9.9 Hz, 1H), 7.73 ‒ 7.70 (d, J = 9.9 Hz, 1H), 7.32 (s, 1H) ppm. [0156] Step 5. Synthesis of 2-[4-chloro-2-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridin-8-yl]-1,3,4-oxadiazole (2-6). A solution of 8-(1,3,4-oxadiazol-2-yl)-2-(1,1,2,2,2- pentafluoroethyl)-1H-imidazo[1,2-a]1,8-naphthyridin-4-one (2-5) (200 mg, 0.54 mmol) and phosphorus oxychloride (413.01 mg, 2.70 mmol) in dimethylformamide (2 mL) and DCE (2 mL) was stirred for 4hat 90 °C under nitrogen atmosphere. The mixture was allowed to cool to rt. The residue was purified by reversed-phase flash column chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 20% to 60% gradient in 10 min; detector, UV 254 nm to give 2-[4-chloro-2-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridin-8-yl]-1,3,4-oxadiazole (2-6) (20 mg, 9.53%) as a white solid. MS calcd. for C13H8F5N5OCl: 389.0; Found: 390.1 [M + 1]+. [0157] Step 6. Synthesis of 2-[2-(1,1,2,2,2-pentafluoroethyl)-4-(prop-1-en-2-yl)imidazo[1,2- a]1,8-naphthyridin-8-yl]-1,3,4-oxadiazole (2-7). A solution of 2-[4-chloro-2-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-8-yl]-1,3,4-oxadiazole (2-6) (60 mg, 0.15 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (77.62 mg, 0.46 mmol), potassium carbonate (42.87 mg, 0.31 mmol), Pd(dppf)Cl2 (5.63 mg, 0.008 mmol) in water (0.6 mL) and dioxane (0.6 mL ) was stirred for 4h at 100°C under nitrogen atmosphere. The mixture was allowed to cool to rt. The residue was purified by reversed-phase flash column chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 20% to 60% gradient in 10 min; detector, UV 254 nm to give 2-[2-(1,1,2,2,2- pentafluoroethyl)-4-(prop-1-en-2-yl)imidazo[1,2-a]1,8-naphthyridin-8-yl]-1,3,4-oxadiazole (2-7) (24 mg, 39.43%) as a white solid. MS calcd. for C17H10F5N5O1: 395.0; Found: 396.1 [M + 1]+. [0158] Step 7. Synthesis of 2-[4-isopropyl-2-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridin-8-yl]-1,3,4-oxadiazole (Example 2). To a solution of 2-[2-(1,1,2,2,2- pentafluoroethyl)-4-(prop-1-en-2-yl)imidazo[1,2-a]1,8-naphthyridin-8-yl]-1,3,4-oxadiazole (2-7) (24 mg, 0.06 mmol) in 2 mL MeOH was added Pd/C (10%, 0.013 g) in a high pressure vessel. The mixture was hydrogenated at room temperature under 30 psi of hydrogen pressure for 0.5 h thenfiltered through a Celite®545 pad and concentrated under reduced pressure. The residue was purified by reversed-phase flash column chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 20% to 50% gradient in 10 min; detector, UV 254 nm to give Example 2 (0.9 mg, 3.73%) as a white solid. MS calcd. for C17H12F5N5O1: 397.0; Found: 398.1
Figure imgf000039_0001
NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1H), 8.99 (s, 1H), 8.25 ‒ 8.23 (d, J = 10.0 Hz, 1H), 8.05 (s, 1H), 7.94 ‒ 7.92 (d, J = 10.0 Hz, 1H), 3.94 (p, J = 6.8 Hz, 1H), 1.41 (d, J = 6.8 Hz, 6H) ppm. [0159] Example 3. 2-(2,4-Bis(perfluoroethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)-1,3,4- oxadiazole
Figure imgf000039_0002
[0160] Step 1. Synthesis of 7-amino-4-hydroxy-1H-1,8-naphthyridin-2-one (3-2). A mixture of 2,6-diaminopyridine (20.00 g, 183.26 mmol) and diethyl malonate (3-1) (29.35 g, 183.26 mmol) in diphenyl ether (200 mL) was stirred for 2 h at 220 °C under nitrogen atmosphere. After completion of the reaction (monitored by LCMS), the mixture was allowed to cool to room temperature and 1 L petroleum ether was added. The precipitate was filtered and washed with PE/EA = 3/1 (v/v) (1 L) to afford 7-amino-4-hydroxy-1H-1,8-naphthyridin-2-one (3-2) (30.00 g, 92.40%) as a light brown solid. MS calcd. for C8H7N3O2: 177.1; Found: 178.2 [M + 1]+. [0161] Step 2. Synthesis of N-(5-hydroxy-7-oxo-8H-1,8-naphthyridin-2-yl)acetamide (3-3). 7-Amino-4-hydroxy-1H-1,8-naphthyridin-2-one (3-2) (30.0 g, 169.33 mmol) was dissolved in acetic anhydride (150 mL) and the reaction mixture stirred at 120 °C for 18 h. After completion of the reaction (monitored by LCMS), the mixture was allowed to cool to room temperature and quenched with ice water (1500 mL). The precipitate was filtered and dried to provide the crude product N-(5-hydroxy-7-oxo-8H-1,8-naphthyridin-2-yl)acetamide (3-3) (33.00 g, 88.90%) as a light brown solid. MS calcd. for C10H9N3O3: 219.1; Found: 220.0 [M + 1]+. [0162] Step 3. Synthesis of 5,7-dibromo-1,8-naphthyridin-2-amine (3-4). To a stirred mixture of N-(5-hydroxy-7-oxo-8H-1,8-naphthyridin-2-yl)acetamide (3-3) (20.00 g, 91.24 mmol) in toluene (200 mL) was added POBr3 (209.26 g, 729.9 mmol) and the reaction mixture was stirred at 105 °C for 2 h under nitrogen atmosphere. After completion of the reaction (monitored by LCMS), the mixture was allowed to cool to room temperature, the reaction mixture was quenched with water 400 mL. The mixture was warmed to 105 °C and stirred for further 3 h. Then, the reaction mixture was basified with Sat. NaHCO3 solution to pH > 7. Then the getting precipitate was filtered and dried to give the crude 5,7-dibromo-1,8-naphthyridin-2- amine (3-4) (15.00 g, 54.27%) as a brown solid. MS calcd. for C8H5Br2N3: 302.9; Found: 303.9 [M + 1]+. [0163] Step 4. Synthesis of ethyl 2,4-dibromoimidazo[1,2-a]1,8-naphthyridine-8- carboxylate (3-5). To a stirred solution of 5,7-dibromo-1,8-naphthyridin-2-amine (3-4) (5.00 g, 16.50 mmol) in THF (80 mL) was added ethyl 3-bromo-2-oxopropanoate (6.44 g, 33.00 mmol) and DIEA (4.27 g, 33.00 mmol). The reaction mixture was stirred at 80 °C for 16 h. After completion of the reaction (monitored by LCMS), the mixture was allowed to cool down to room temperature, the reaction mixture was concentrated in vacuo. The residue was diluted with ice water 80 mL extracted with (EA / EtOH = 5/1 (v/v), 3 x 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to get a residue. The residue was purified by column flash (PE/EA = 1:1 to 0:1 (v/v)) to give ethyl 2,4-dibromoimidazo[1,2- a]1,8-naphthyridine-8-carboxylate (3-5) (1.50 g, 22.78%) as a brown solid. 1H NMR (400 MHz, CDCl3): δ 9.04 (s, 1H), 7.96 (s, 1H), 7.88 (d, J = 9.6 Hz, 1H), 7.79 (d, J = 9.6 Hz, 1H), 4.51 (q, J = 7.2 Hz, 2H), 1.48 (t, J = 7.2 Hz, 3H) ppm. [0164] Step 5. Synthesis of ethyl 2,4-bis(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridine-8-carboxylate (3-6). A solution of ethyl 2,4-dibromoimidazo[1,2-a]1,8- naphthyridine-8-carboxylate (3-5) (200.00 mg, 0.50 mmol) and trimethyl(1,1,2,2,2- pentafluoroethyl)silane (289.00 mg, 1.50 mmol), potassium fluoride (116.47 mg, 2.00 mmol) and copper(I) iodide (214.77 mg, 1.13 mmol) in DMF was stirred for overnight at 150 °C under nitrogen atmosphere. After completion of the reaction (monitored by LCMS), the mixture was allowed to cool down to room temperature. Then the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford ethyl 2,4- bis(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridine-8-carboxylate (3-6) (70.00 mg, 29.26%) as an off-white solid. MS calcd. for C17H9F10N3O2: 477.1; Found: 477.9 [M + 1]+.1H NMR (300 MHz, CDCl3): δ 9.14 (s, 1H), 8.12 (s, 1H), 8.03 – 7.86 (m, 2H), 7.28 (s, 1H), 4.55 (q, J = 7.2 Hz, 2H), 1.51 (t, J = 7.2 Hz, 3H) ppm. [0165] Step 6. Synthesis of 2,4-bis(perfluoroethyl)imidazo[1,2-a][1,8]naphthyridine-8- carbohydrazide (3-7). A mixture of ethyl 2,4-bis(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridine-8-carboxylate (3-6) (70.00 mg, 0.15 mmol) and hydrazine (47.00 mg, 1.47 mmol) in ethanol was stirred for 4 h at 70 °C. After completion of the reaction (monitored by LCMS), the mixture was allowed to cool down to room temperature. Then the resulting mixture was concentrated under reduced pressure to give crude 2,4-bis(perfluoroethyl)imidazo[1,2- a][1,8]naphthyridine-8-carbohydrazide (3-7), which was used in the next step directly without further purification. MS calcd. for C15H7F10N5O: 463.0; Found: 463.9 [M + 1]+. [0166] Step 7. Synthesis of 2-(2,4-bis(perfluoroethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)- 1,3,4-oxadiazole (Example 3). A mixture of crude 2,4-bis(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridine-8-carbohydrazide (3-7) (70.00 mg, 0.15 mmol) and p-toluenesulfonic acid (13.01 mg, 0.08 mmol) in CH(OMe)3 was stirred for 4 h at 70 °C. After completion of the reaction (monitored by LCMS), the resulting solution was cooled to room temperature. The residue was purified by Pre-HPLC Column, XBridge Shield RP18 OBD Column, 19*150 mm, 5µm; mobile phase, Water (0.5% NH3·H2O) and ACN (5% ACN up to 95% in 3 min) to afford Example 3 (10.00 mg, 13.98%) as an off-white solid. MS calcd. for C16H5F10N5O: 473.0; Found: 474.1 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 9.25 (s, 1H), 9.12 (s, 1H), 8.34 (s, 1H), 8.17 (d, J = 9.9 Hz, 1H), 8.00 (d, J = 9.9 Hz, 1H) ppm. [0167] Example 4. 2-[4-(2-Fluoropropan-2-yl)-2-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2- a]1,8-naphthyridin-8-yl]-1,3,4-oxadiazole
Figure imgf000042_0001
[0168] Step 1. Synthesis of ethyl 4-chloro-2-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridine-8-carboxylate (4-2). A solution of ethyl 4-oxo-2-(1,1,2,2,2-pentafluoroethyl)- 1H-imidazo[1,2-a]1,8-naphthyridine-8-carboxylate (4-1) (9.5 g, 25.32 mmol) and phosphorus oxychloride (19.41 g, 126.58 mmol) in a mixed solvent of DMF (50 mL) and DCE (50 mL) was stirred at 90 °C for 4 hrs under nitrogen gas atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with H2O (100 mL). The aqueous layer was extracted with EA (3X100 mL). The organic phase was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography, eluted with (EA:PE =1:2) to afford ethyl 4-chloro-2-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridine-8-carboxylate (4-2) (7.3 g, 73.24%) as a yellow solid. MS calcd. for C15H9ClF5N3O2: 393.0; Found: 394.1 [M + 1]+. 1H NMR (300 MHz, DMSO-d6): δ 8.82 (s, 1H), 8.50 (s, 1H), 8.06 ‒ 8.03 (d, J = 9.9 Hz, 1H), 7.99 ‒ 7.95 (d, J = 9.9 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H) ppm. [0169] Step 2. Synthesis of ethyl 2-(1,1,2,2,2-pentafluoroethyl)-4-(prop-1-en-2- yl)imidazo[1,2-a]1,8-naphthyridine-8-carboxylate (4-3). A solution of ethyl 4-chloro-2- (1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridine-8-carboxylate (4-2) (550 mg, 1.40 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (469.50 mg, 2.79 mmol), K2CO3 (386.15 mg, 2.79 mmol), Pd(dppf)Cl2 (51.11 mg, 0.07 mmol) in water (2 mL) and dioxane (8 mL) was stirred for 100 °C at 3 h under nitrogen atmosphere. The mixture was allowed to cool down to rt. The resulting mixture was diluted with H2O (30 mL). The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography, eluted with EA:PE (1:2) to afford ethyl 2-(1,1,2,2,2-pentafluoroethyl)-4-(prop-1-en-2-yl)imidazo[1,2-a]1,8- naphthyridine-8-carboxylate (4-3) (400 mg, 71.70%) as a yellow oil. MS calcd. for C18H14F5N3O2: 399.0; Found: 400.1 [M + 1]+. [0170] Step 3. Synthesis of 2-(1,1,2,2,2-pentafluoroethyl)-4-(prop-1-en-2-yl)imidazo[1,2- a]1,8-naphthyridine-8-carbohydrazide (4-4). A solution of ethyl 2-(1,1,2,2,2- pentafluoroethyl)-4-(prop-1-en-2-yl)imidazo[1,2-a]1,8-naphthyridine-8-carboxylate (4-3) (400 mg, 1.00 mmol) and hydrazine (0.5 mL) in ethyl alcohol (4 mL) was stirred for 3 h at 70 °C under nitrogen atmosphere. The mixture was allowed to cool to rt. The resulting mixture was concentrated under reduced pressure to give 2-(1,1,2,2,2-pentafluoroethyl)-4-(prop-1-en-2- yl)imidazo[1,2-a]1,8-naphthyridine-8-carbohydrazide (4-4) (350 mg, 90.68%) as a yellow oil. MS calcd. for C16H12F5N5O: 385.0; Found: 386.1 [M + 1]+. [0171] Step 4. Synthesis of 2-[2-(1,1,2,2,2-pentafluoroethyl)-4-(prop-1-en-2-yl)imidazo[1,2- a]1,8-naphthyridin-8-yl]-1,3,4-oxadiazole (4-5). A solution of 2-(1,1,2,2,2-pentafluoroethyl)-4- (prop-1-en-2-yl)imidazo[1,2-a]1,8-naphthyridine-8-carbohydrazide (4-4) (350 mg, 0.91 mmol) and p-toluenesulfonic acid (78.21 mg, 0.45 mmol) in trimethyl orthoformate (3.5 mL) was stirred for 4h at 70 °C under nitrogen atmosphere. The mixture was allowed to cool down to rt. The reaction was quenched with H2O (10 mL) at rt. The aqueous layer was extracted with EA (3x10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 10 min; detector, UV 254 nm to give 2- [2-(1,1,2,2,2-pentafluoroethyl)-4-(prop-1-en-2-yl)imidazo[1,2-a]1,8-naphthyridin-8-yl]-1,3,4- oxadiazole (4-5) (250 mg, 69.62%) as a white solid. MS calcd. for C17H10F5N5O: 395.0; Found: 396.1 [M + 1]+. 1H NMR (300 MHz, DMSO-d6): δ 9.41 (s, 1H), 9.01 (s, 1H), 8.09 (s, 1H), 7.99 ‒ 42 7.96 (d, J = 9.9 Hz, 1H), 7.92 ‒ 7.89 (d, J = 9.9 Hz, 1H), 5.71 (s, 1H), 5.25 (s, 1H), 2.27 (s, 3H) ppm. [0172] Step 5. Synthesis of 1-[8-(1,3,4-oxadiazol-2-yl)-2-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-4-yl]ethanone (4-6). A solution of 2-[2- (1,1,2,2,2-pentafluoroethyl)-4-(prop-1-en-2-yl)imidazo[1,2-a]1,8-naphthyridin-8-yl]-1,3,4- oxadiazole (4-5) (240 mg, 0.61 mmol) and tetraoxodipotassioosmium (20.18 mg, 0.06 mmol), sodium periodate (454.52 mg, 2.12 mmol) in water (0.7 mL) and ACN (2.4 mL) was stirred for 3 h at 0 °C under nitrogen atmosphere. The resulting mixture was diluted with H2O (10 mL). The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography, eluted with EA:PE (1:1) to afford 1-[8-(1,3,4-oxadiazol-2-yl)-2-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-4-yl]ethanone (4-6) (200 mg, 82.92%) as a yellow solid. MS calcd. for C16H8F5N5O2: 397.0; Found: 398.1 [M + 1]+.1H NMR (300 MHz, DMSO-d6): δ 9.42 (s, 1H), 9.03 (s, 1H), 8.56 (s, 1H), 8.15 ‒ 8.12 (d, J = 9.9 Hz, 1H), 8.01 ‒ 7.98 (d, J = 9.9 Hz, 1H), 2.85 (s, 3H) ppm. [0173] Step 6. Synthesis of 2-[8-(1,3,4-oxadiazol-2-yl)-2-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-4-yl]propan-2-ol (4-7). A solution of 1-[8- (1,3,4-oxadiazol-2-yl)-2-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-4- yl]ethanone (4-6) (200 mg, 0.50 mmol) and bromo(methyl)magnesium (120.06 mg, 1.0 mmol) in THF (2 mL) was stirred for 1h at 0 °C under nitrogen atmosphere. The resulting mixture was diluted with H2O (10 mL). The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 70% gradient in 10 min; detector, UV 254 nm. This resulted in 2-[8-(1,3,4- oxadiazol-2-yl)-2-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-4-yl]propan-2-ol (4-7) (120 mg, 57.67%) as a white solid. MS calcd. for C17H12F5N5O2: 413.0; Found: 414.1 [M + 1]+.1H NMR (300 MHz, DMSO-d6): δ 9.41 (s, 1H), 9.00 (s, 1H), 8.75 ‒ 8.72 (d, J = 10.2 Hz, 1H), 8.12 (s, 1H), 7.91 ‒ 7.88 (d, J = 10.2 Hz, 1H), 6.03 (s, 1H), 1.76 (s, 6H) ppm. [0174] Step 7. Synthesis of 2-[4-(2-fluoropropan-2-yl)-2-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-8-yl]-1,3,4-oxadiazole (Example 4). A solution of 2-[8-(1,3,4-oxadiazol-2-yl)-2-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridin-4-yl]propan-2-ol (4-7) (100 mg, 0.24 mmol) and diethylaminosulfur trifluoride (46.80 mg, 0.29 mmol) in DCM (1 mL) was stirred for 1h at 0 °C under nitrogen atmosphere. The resulting mixture was diluted with H2O (10 mL). The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 40% to 80% gradient in 10 min; detector, UV 254 nm to give Example 4 (4.4 mg, 4.38%) as a white solid. MS calcd. for C17H11F6N5O: 415.0; Found: 416.1 [M + 1]+.1H NMR (300 MHz, DMSO-d6): δ 9.42 (s, 1H), 9.02 (s, 1H), 8.33 ‒ 8.30 (d, J = 10.2 Hz, 1H), 8.07 (s, 1H), 7.96 ‒ 7.93 (d, J = 10.2 Hz, 1H), 2.02 (s, 3H), 1.94 (s, 3H) ppm. [0175] Example 5. 2-(4-Cyclobutyl-2-(perfluoroethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)- 1,3,4-oxadiazole
Figure imgf000045_0001
[0176] Step 1. Synthesis of ethyl 4-cyclobutyl-2-(perfluoroethyl)imidazo[1,2- a][1,8]naphthyridine-8-carboxylate (5-1). A mixture of ethyl 4-chloro-2-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridine-8-carboxylate (4-2) (350.00 mg, 0.89 mmol) and Xphos (84.76 mg, 0.18 mmol) in DMA/THF (1/1 (v/v), 8.00 mL) was stirred for 3 h at 80 °C under nitrogen atmosphere. After completion of the reaction (monitored by LCMS), the mixture was allowed to cool down to room temperature, the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA = 1/1 (v/v) to afford ethyl 4- cyclobutyl-2-(perfluoroethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxylate (5-1) (110.00 mg, 29.93%) as a light-yellow solid. MS calcd. for C19H16F5N3O2: 413.1.0; Found: 414.1 [M + 1]+. 1H NMR (300 MHz, CDCl3): δ 9.11 (s, 1H), 8.05 – 7.90 (m, 1H), 7.84 (d, J = 7.2 Hz, 2H), 4.54 (q, J = 7.2 Hz, 2H), 4.29 – 4.13 (m, 1H), 2.66 (d, J = 9.3 Hz, 2H), 2.51 – 2.23 (m, 3H), 2.11 – 2.00 (m, 1H), 1.51 (t, J = 7.2 Hz, 3H) ppm. [0177] Step 2. Synthesis of 4-cyclobutyl-2-(perfluoroethyl)imidazo[1,2- a][1,8]naphthyridine-8-carbohydrazide (5-2). A mixture of ethyl 4-cyclobutyl-2- (perfluoroethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxylate (5-1) (110.00 mg, 0.27 mmol) and NH2NH2 (266.44 mg, 5.32 mmol) in dioxane (2.5 mL) was stirred for 16 h at 80 °C. After completion of the reaction (monitored by LCMS), the mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure to give crude 4- cyclobutyl-2-(perfluoroethyl)imidazo[1,2-a][1,8]naphthyridine-8-carbohydrazide (5-2), which was used in the next step directly without further purification. MS calcd. for C17H14F5N5O: 399.1; Found: 400.1 [M + 1]+. [0178] Step 3. Synthesis of 2-(4-cyclobutyl-2-(perfluoroethyl)imidazo[1,2- a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (Example 5). A mixture of 4-cyclobutyl-2- (perfluoroethyl)imidazo[1,2-a][1,8]naphthyridine-8-carbohydrazide (5-2) (110.00 mg, 0.28 mmol) and p-toluenesulfonic acid (23.72 mg, 0.14 mmol) in trimethyl orthoformate (2.5 mL) was stirred for 4 h at 70 °C. After completion of the reaction (monitored by LCMS), the mixture was allowed to cool down to room temperature. The crude product was purified by Pre-HPLC Column, XBridge Shield RP18 OBD Column, 19*150 mm, 5µm; mobile phase, Water (0.5% NH3·H2O) and ACN (5% ACN up to 95% in 3 min) to afford Example 5 (11.00 mg, 9.76%) as an off-white solid. MS calcd. for C18H12F5N5O: 409.1; Found: 410.1 [M + 1]+.1H NMR (300 MHz, DMSO-d6): δ 9.41 (s, 1H), 8.98 (s, 1H), 8.03 – 7.92 (m, 3H), 4.41 – 4.30 (m, 1H), 2.61 – 2.56 (m, 2H), 2.43 – 2.31 (m, 2H), 2.24 – 2.12 (m, 1H), 1.95 –1.86 (m, 1H) ppm. [0179] Example 6. 2-[2-Cyclobutyl-4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridin-8-yl]-1,3,4-oxadiazole
Figure imgf000047_0001
[0180] Step 1. Synthesis of 7-amino-4-(perfluoroethyl)-1,8-naphthyridin-2(1H)-one (6-1). A solution of ethyl 4,4,5,5,5-pentafluoro-3-oxopentanoate (2-1) (30 g, 128.14 mmol) and 2,6- diaminopyridine (13.98 g, 128.14 mmol) in toluene (300 mL) was stirred for 10 h at 100°C under nitrogen gas atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with MTBE (200 mL). The precipitated solids were collected by filtration to give 7-amino-4-(1,1,2,2,2-pentafluoroethyl)-1H-1,8-naphthyridin-2-one (6-1) (27 g, 75.48%) as a yellow solid. MS calcd. for C10H6F5N3O: 279.0; Found: 280.1 [M + 1]+. [0181] Step 2. Synthesis of ethyl 2-oxo-4-(perfluoroethyl)-1,2-dihydroimidazo[1,2- a][1,8]naphthyridine-8-carboxylate (6-2). A solution of 7-amino-4-(1,1,2,2,2- pentafluoroethyl)-1H-1,8-naphthyridin-2-one (6-1) (27 g, 96.71 mmol) and ethyl 3-bromo-2- oxopropanoate (37.72 g, 193.43 mmol) in DMF (300 mL) was stirred for 10 hrs at 70°C under nitrogen gas atmosphere. The reaction mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (500 mL). The aqueous layer was extracted with EtOAc (2 x 300 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuum to give the crude product which was directly purified by flash chromatography (PE/ THF = 1/1 (v/v)) mixture to afford ethyl 2-oxo-4-(1,1,2,2,2-pentafluoroethyl)-1H-imidazo[1,2- a]1,8-naphthyridine-8-carboxylate (6-2) (13 g, 35.82%) as a yellow solid. MS calcd. for C15H10F5N3O3: 375.0; Found: 376.1 [M + 1]+. [0182] Step 3. Synthesis of ethyl 2-chloro-4-(perfluoroethyl)imidazo[1,2- a][1,8]naphthyridine-8-carboxylate (6-3). A solution of ethyl 2-oxo-4-(1,1,2,2,2- pentafluoroethyl)-1H-imidazo[1,2-a]1,8-naphthyridine-8-carboxylate (6-2) (13 g, 34.64 mmol) and phosphorus oxychloride (26.56 g, 173.21 mmol) in a mixed solvent of DCE (70 mL) and DMF (70 mL) was stirred for 4 hrs at 90°C under nitrogen gas atmosphere. The resulting mixture was concentrated under reduced pressure and then diluted with water (200 mL). The aqueous layer was extracted with EtOAc (2X300 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuum to give the crude product which was directly purified by flash chromatography (PE/THF = 3/1 (v/v)) mixture to afford ethyl 2-chloro-4-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridine-8-carboxylate (6-3) (7.2 g, 52.79%) as a yellow solid. MS calcd. for C15H9ClF5N3O2: 393.0; Found: 394.1 [M + 1]+.1H NMR (400 MHz, CDCl3): δ 9.08 (s, 1H), 7.86 (d, J = 10.0 Hz, 1H), 7.80 (d, J = 10.0 Hz, 1H), 7.77 (s, 1H), 4.51 (q, J = 7.1 Hz, 2H), 1.48 (t, J = 7.1 Hz, 3H) ppm. [0183] Step 4. Synthesis of ethyl 2-cyclobutyl-4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2- a]1,8-naphthyridine-8-carboxylate (6-4). A solution of ethyl 2-chloro-4-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridine-8-carboxylate (6-3) (350 mg, 0.889 mmol), bromo(cyclobutyl)zinc (534.41 mg, 2.66 mmol), Pd2(dba)3 (81.41 mg, 0.09 mmol) and X-Phos (157.42 mg, 0.33 mmol) in DMA (3 mL) and THF (3 mL) was stirred for 3 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/THF = 3/1(v/v) to afford ethyl 2- cyclobutyl-4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridine-8-carboxylate (6-4) (170 mg, 46.26%) as a yellow solid. MS calcd. for C19H16F5N3O2: 413.1; Found: 414.2 [M + 1]+. [0184] Step 5. Synthesis of 2-cyclobutyl-4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridine-8-carbohydrazide (6-5). A solution of ethyl 8-cyclobutyl-6-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]quinoline-2-carboxylate (6-4) (170 mg, 0.41 mmol) and NH2NH2•H2O (0.6 mL, 12.35 mmol) in dioxane (3 mL) was stirred for 6 h at 80 °C. The resulting mixture was concentrated under vacuum to give 2-cyclobutyl-4-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridine-8-carbohydrazide (6-5) (130 mg, 78.97%) as a yellow solid. MS calcd. for C17H14F5N5O: 399.1; Found: 400.2 [M + 1]+. [0185] Step 6. Synthesis of 2-[2-cyclobutyl-4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridin-8-yl]-1,3,4-oxadiazole (Example 6). A solution of 2-cyclobutyl-4-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridine-8-carbohydrazide (6-5) (130 mg, 0.33 mmol) and p-toluenesulfonic acid (28.03 mg, 0.16 mmol) in Trimethyl orthoformate (3 mL) was stirred for 2 h at 70 °C. The mixture was allowed to cool down to room temperature. The mixture was basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC to afford Example 6 (25 mg, 18.76%) as a white solid. MS calcd. for C18H12F5N5O: 409.1; Found: 410.1 [M + 1]+. 1H NMR (300 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.27 (s, 1H), 7.91 (d, J = 3.9 Hz, 3H), 4.08 ‒ 4.00 (m, 1H), 2.61 ‒ 2.50 (m, 2H), 2.45 ‒ 2.38 (m, 2H), 2.16 ‒ 1.98 (m, 2H) ppm. [0186] Example 7. (S)-2-(2-(2-fluoro-3-methylbutan-2-yl)-4-(perfluoroethyl)imidazo[1,2- a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole [0187] Example 8. (R)-2-(2-(2-fluoro-3-methylbutan-2-yl)-4-(perfluoroethyl)imidazo[1,2- a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole
Figure imgf000050_0001
[0188] Step 1. Synthesis of ethyl 4-(1,1,2,2,2-pentafluoroethyl)-2-(prop-1-en-2- yl)imidazo[1,2-a]1,8-naphthyridine-8-carboxylate (7-1). To a solution of ethyl 2-chloro-4- (1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridine-8-carboxylate (6-3) (3.5 g, 8.89 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (2.24 g, 13.33 mmol) in dioxane (35 mL) and H2O (7 mL) was added K2CO3 (3.69 g, 26.67 mmol,) and Pd(dppf)Cl2 (0.65 g, 0.88 mmol). After stirring for 3h at 100°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA = 2/1 (v/v) to afford ethyl 4-(1,1,2,2,2-pentafluoroethyl)-2- (prop-1-en-2-yl)imidazo[1,2-a]1,8-naphthyridine-8-carboxylate (7-1) (3 g, 84.51%) as a yellow solid. MS calcd. for C14H8F6N4O2: 399.1; Found: 400.1 [M + 1]+. [0189] Step 2. Synthesis of 4-(1,1,2,2,2-pentafluoroethyl)-2-(prop-1-en-2-yl)imidazo[1,2- a]1,8-naphthyridine-8-carboxylic acid (7-2). A solution of ethyl 4-(1,1,2,2,2-pentafluoroethyl)- 2-(prop-1-en-2-yl)imidazo[1,2-a]1,8-naphthyridine-8-carboxylate (5.2 g, 13.02 mmol) (7-1) and lithium hydroxide (1.25 g, 52.08 mmol) in MeOH (2 mL), H2O (50 mL) was stirred for 3h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The mixture residue was acidified to pH 2 with citric acid. The precipitated solids were collected by filtration and dried in vacuo to give 4-(1,1,2,2,2-pentafluoroethyl)-2- (prop-1-en-2-yl)imidazo[1,2-a]1,8-naphthyridine-8-carboxylic acid (7-2) (4 g, 82.74%) as a yellow solid. MS calcd. for C16H10F5N3O2: 371.1; Found: 372.1 [M + 1]+. [0190] Step 3. Synthesis of N'-(tert-butoxycarbonyl)-4-(1,1,2,2,2-pentafluoroethyl)-2- (prop-1-en-2-yl)imidazo[1,2-a]1,8-naphthyridine-8-carbohydrazide (7-3). A solution of 4- (1,1,2,2,2-pentafluoroethyl)-2-(prop-1-en-2-yl)imidazo[1,2-a]1,8-naphthyridine-8-carboxylic acid (7-2) (4 g, 10.77 mmol) and tert-butoxycarbohydrazide (2.14 g, 16.16 mmol), HATU (4.92 g, 12.92 mmol) , TEA (3.27 g, 32.32 mmol) in DMA (80 mL) was stirred for 3 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (200 mL). The precipitated solids were collected by filtration and dried in vacuo to give N'-(tert- butoxycarbonyl)-4-(1,1,2,2,2-pentafluoroethyl)-2-(prop-1-en-2-yl)imidazo[1,2-a]1,8- naphthyridine-8-carbohydrazide (7-3) (4.2 g, 80.31%) as a yellow oil. MS calcd. for C21H20F5N5O3:485.1; Found: 486.1 [M + 1]+. [0191] Step 4. Synthesis of 4-(1,1,2,2,2-pentafluoroethyl)-2-(prop-1-en-2-yl)imidazo[1,2- a]1,8-naphthyridine-8-carbohydrazide (7-4). A solution of N'-(tert-butoxycarbonyl)-4- (1,1,2,2,2-pentafluoroethyl)-2-(prop-1-en-2-yl)imidazo[1,2-a]1,8-naphthyridine-8- carbohydrazide (7-3) (4.2 g, 8.65 mmol) and trifluoroacetic acid (50 mL, 510.07 mmol) in DCM (50 mL) was stirred for 4 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the residue was dried in vacuo to give 4- (1,1,2,2,2-pentafluoroethyl)-2-(prop-1-en-2-yl)imidazo[1,2-a]1,8-naphthyridine-8- carbohydrazide (7-4) (3.1 g, 92.99%) as a yellow solid. MS calcd. for C16H12F5N5O: 385.1; Found: 386.1 [M + 1]+. [0192] Step 5. Synthesis of 2-[4-(1,1,2,2,2-pentafluoroethyl)-2-(prop-1-en-2-yl)imidazo[1,2- a]1,8-naphthyridin-8-yl]-1,3,4-oxadiazole (7-5). A solution of 4-(1,1,2,2,2-pentafluoroethyl)-2- (prop-1-en-2-yl)imidazo[1,2-a]1,8-naphthyridine-8-carbohydrazide (7-4) (3.1 g, 8.04 mmol) and p-toluenesulfonic acid (0.14 g, 0.81 mmol) in CH(OMe)3 (50 mL) was stirred for 4h at 70°C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with water (50 mL). The aqueous layer was extracted with EtOAc (3 x 30 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA = 1/1 (v/v) to afford 2-[4-(1,1,2,2,2- pentafluoroethyl)-2-(prop-1-en-2-yl)imidazo[1,2-a]1,8-naphthyridin-8-yl]-1,3,4-oxadiazole (7-5) (1.5 g, 47.16%) as a yellow solid. MS calcd. for C17H10F5N5O: 395.1; Found: 396.2 [M + 1]+. [0193] Step 6. Synthesis of 1-[8-(1,3,4-oxadiazol-2-yl)-4-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-2-yl]ethanone (7-6). A solution of 2-[4- (1,1,2,2,2-pentafluoroethyl)-2-(prop-1-en-2-yl)imidazo[1,2-a]1,8-naphthyridin-8-yl]-1,3,4- oxadiazole (7-5) (1.5 g, 3.79 mmol) in acetone (60 mL), H2O (20 mL) was treated K2OsO4•2H2O (0.14 g, 0.38 mmol) for 5 min at 0°C under nitrogen atmosphere followed by the addition of NaIO4 (1.99 g, 13.28 mmol) in portions at 0°C. The resulting mixture was stirred for 2 h at RT under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (4 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA = 1/1 (v/v) to afford 1-[8- (1,3,4-oxadiazol-2-yl)-4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-2- yl]ethanone (7-6) (1 g, 66.34%) as a yellow solid. MS calcd. for C16H8F5N5O2: 397.1; Found: 398.1 [M + 1]+. 1H NMR (300 MHz, DMSO-d6): δ 9.54 (s, 1H), 9.45 (s, 1H), 8.30 (s, 1H), 8.09 (d, J = 9.9 Hz, 1H), 8.01 ((d, J = 9.9 Hz, 1H), 2.92 (s, 3H) ppm. [0194] Step 7. Synthesis of 3-methyl-2-[8-(1,3,4-oxadiazol-2-yl)-4-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-2-yl]butan-2-ol (7-7). To a degassed solution of isopropylmagnesium bromide, 1 M solution in THF (1.5 mL, 1.51 mmol) in THF (5 mL) was added tetrabutylammonium chloride (27.98 mg, 0.11 mmol), 1-methoxy-2-(2- methoxyethoxy)ethane (202.65 mg, 1.51 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 h then added 1-[8-(1,3,4-oxadiazol-2-yl)-4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridin-2-yl]ethanone (7-6) (400 mg, 1.01 mmol) in THF (5 mL) at -40°C. The reaction mixture was stirred at -40°C for 1h. After completion of the reaction, the reaction mixture was quenched with H2O (50 mL). The aqueous layer was extracted three times with ethyl acetate (30 mL). Then, the combined organic phase was washed with brine, dried over anhydrous Na2SO4. Purified by column chromatography on silica gel (Combiflash) (THF/PE = 1/1 (v/v)) to afford 3- methyl-2-[8-(1,3,4-oxadiazol-2-yl)-4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridin-2-yl]butan-2-ol (7-7) (300 mg, 67.51%). MS calcd. for C16H8F5N5O2: 441.1; Found: 442.2
Figure imgf000053_0001
NMR (300 MHz, DMSO-d6): δ 9.42 (s, 1H), 9.36 (s, 1H), 8.16 (s, 1H), 7.93 -7.92(m, 2H), 5.57 (s, 1H), 2.26 (q, J = 6.6 Hz, 1H), 1.63 (s, 3H), 0.94 (d, J = 6.9 Hz, 3H), 0.71 (d, J = 6.9 Hz, 3H) ppm. [0195] Step 8. Synthesis of 2-[2-(2-fluoro-3-methylbutan-2-yl)-4-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-8-yl]-1,3,4-oxadiazole (7-8). To a stirred solution of 3-methyl-2-[8-(1,3,4-oxadiazol-2-yl)-4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2- a]1,8-naphthyridin-2-yl]butan-2-ol (7-7) (290 mg, 0.66 mmol) in anhydrous DCM (5 mL) was added DAST (127.09 mg, 0.78 mmol) at -60°C and stirred for 1h. The reaction progress was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure to give crude product which was further purified by column chromatography using PE/THF = 1/1 (v/v) gradient to afford 2-[2-(2-fluoro-3-methylbutan-2-yl)-4-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-8-yl]-1,3,4-oxadiazole (7-8) (60 mg, 20.60%). MS calcd. for C19H15F6N5O: 443.1; Found: 444.2 [M + 1]+.1H NMR (300 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.36 (s, 1H), 7.96 ‒ 7.92 (m, 3H), 2.49 ‒ 2.38 (m, 1H), 1.85 (d, J = 23.1 Hz, 3H), 1.01(d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H) ppm. [0196] Step 9. Synthesis of 2-{2-[(2S)-2-fluoro-3-methylbutan-2-yl]-4-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-8-yl}-1,3,4-oxadiazole (Example 7) and 2- {2-[(2R)-2-fluoro-3-methylbutan-2-yl]-4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridin-8-yl}-1,3,4-oxadiazole (Example 8). 2-[2-(2-fluoro-3-methylbutan-2-yl)-4- (1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-8-yl]-1,3,4-oxadiazole (7-8) (55 mg, 0.12 mmol) was purified by Prep-SFC with the following conditions Column: CHIRAL ART Cellulose-SZ, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: ETOH(0.1% 2M NH3- MEOH); Flow rate: 80 mL/min; Gradient: isocratic 25% B; Column Temperature(℃): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT1(min): 3.2; RT2(min): 3.7; Sample Solvent: EtOH; to afford Example 7 (13 mg, 23.64%) as a white solid and Example 8 (12 mg, 21.82%) as a white solid. The stereochemistry of these two pure enantiomers was arbitrarily assigned. [0197] Example 7. MS calcd. for C19H15F6N5O: 443.1; Found: 444.2 [M + 1]+. 1H NMR (300 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.36 (s, 1H), 7.96 ‒ 7.92 (m, 3H), 2.49 ‒ 2.38 (m, 1H), 1.85 (d, J = 23.1 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H) ppm. [0198] Example 8. MS calcd. for C19H15F6N5O: 443.1; Found: 444.2 [M + 1]+. 1H NMR (300 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.36 (s, 1H), 7.96 ‒ 7.92 (m, 3H), 2.49 ‒ 2.38 (m, 1H), 1.85 (d, J = 23.1 Hz, 3H), 1.01(d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H) ppm. [0199] Example 9. 2-(2,4-Bis(perfluoroethyl)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-8-yl)- 1,3,4-oxadiazole
Figure imgf000054_0001
[0200] Step 1. Synthesis of N,N-diisopropylcyanamide (9-2). In a 2000 mL round bottom flask, to a solution of diisopropylamine (9-1) (50 g, 494.10 mmol) in Acetonitrile (750 mL) was added Na2CO3 (104.74 g, 988.21 mmol) and cyanogen bromide (54.95 g, 518.81 mmol) at room temperature. The reaction mixture was stirred for 24 h at room temperature. The reaction was quenched with water (1000 mL), and then the mixture was extracted with EA (3 x 750 mL). The combined organic extracts were washed with brine (2 x 750 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with EA/PE =1/10 (v/v) to afford N,N-diisopropylcyanamide (9-2) (58 g, 93.01%) as light-yellow oil. MS calcd. for C7H14N2: 126.1; Found: 127.3 [M+1]+. [0201] Step 2. Synthesis of (Z)-2,2,3,3,3-pentafluoropropanoic (Z)-N- (diisopropylcarbamoyl)-2,2,3,3,3-pentafluoropropanimidic anhydride (9-3). A solution of N,N-diisopropylcyanamide (9-2) (3.0 g, 23.77 mmol) and 2,2,3,3,3-pentafluoropropanoic anhydride (7.37 g, 23.77 mmol) in Et2O (30 mL) was stirred for 2 h at -20 °C-rt under N2 atmosphere. The resulting mixture was concentrated under reduced pressure and the residue was dried in vacuo to give (Z)-2,2,3,3,3-pentafluoropropanoic (Z)-N-(diisopropylcarbamoyl)- 2,2,3,3,3-pentafluoropropanimidic anhydride (9-3) (10 g, crude) as light-yellow oil. MS calcd. for C13H14F10N2O3: 436.1; Found: 437.1 [M+1]+. [0202] Step 3. Synthesis of 2,4,6-tris(perfluoroethyl)-1,3,5-triazine (9-4). (Z)-2,2,3,3,3- pentafluoropropanoic (Z)-N-(diisopropylcarbamoyl)-2,2,3,3,3-pentafluoropropanimidic anhydride (9-3) (10 g, 22.92 mmol) mixture of was stirred for 3 h at 110 °C under N2 atmosphere. The crude product was purified by distillation under 760 Torr and the fraction was collected at 110 °C to give 2,4,6-tris(perfluoroethyl)-1,3,5-triazine (9-4) (2 g, 20.05%) as a colorless oil. MS calcd. for C9F15N3: 435.0; Found: 436.1 [M+1]+. [0203] Step 4. Synthesis of 2,4-bis(perfluoroethyl)pyrido[2,3-d]pyrimidin-7-amine (9-5). Into a 40 mL vessel were added 2,4,6-tris(perfluoroethyl)-1,3,5-triazine (9-4) (2 g, 4.60 mmol), acetic acid (20 mL) and 2,6-diaminopyridine (0.75 g, 6.90 mmol) at room temperature. The resulting mixture was stirred for 24 h at 80 °C under N2 atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (50 mL). The mixture was basified to pH 8 with NaHCO3 Solution. The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with Brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE = 1/3 (v/v) to afford 2,4-bis(perfluoroethyl)pyrido[2,3-d]pyrimidin-7-amine (9-5) (120 mg, 6.83%) as an off- white solid. MS calcd. for C11H4F10N4: 382.0; Found: 383.0 [M+1]+. [0204] Step 5. Synthesis of ethyl 2,4-bis(perfluoroethyl)imidazo[1',2':1,6]pyrido[2,3- d]pyrimidine-8-carboxylate (9-6). Into a 20 mL vessel were added 2,4- bis(perfluoroethyl)pyrido[2,3-d]pyrimidin-7-amine (9-5) (120 mg, 0.31 mmol), DMF (6 mL) and ethyl 3-bromo-2-oxopropanoate (122.47 mg, 0.63 mmol) at room temperature. The resulting mixture was stirred for 24 h at 80 °C under N2 atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with Brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE = 1/3 (v/v) to afford ethyl 2,4-bis(perfluoroethyl)imidazo[1',2':1,6]pyrido[2,3- d]pyrimidine-8-carboxylate (9-6) (60 mg, 39.95%) as a yellow solid. MS calcd. for C16H8F10N4O2: 478.0; Found: 489.0 [M+1]+. [0205] Step 6. Synthesis of 2,4-bis(perfluoroethyl)imidazo[1',2':1,6]pyrido[2,3- d]pyrimidine-8-carbohydrazide (9-7). Into a 40 mL vial were added ethyl 2,4- bis(perfluoroethyl)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-8-carboxylate (9-6) (80 mg, 0.17 mmol), EtOH (4 mL) and NH2NH2•H2O (98.52 mg, 1.67 mmol, 85%) at room temperature. The resulting mixture was stirred for 4 h at 70 °C under N2 atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure and the residue was dried in vacuo to give 2,4-bis(perfluoroethyl)imidazo[1',2':1,6]pyrido[2,3- d]pyrimidine-8-carbohydrazide (9-7) (40 mg, 51.51%) as a yellow solid. MS calcd. for C14H6F10N6O: 464.0; Found: 465.0 [M+1]+. [0206] Step 7. Synthesis of 2-(2,4-bis(perfluoroethyl)imidazo[1',2':1,6]pyrido[2,3- d]pyrimidin-8-yl)-1,3,4-oxadiazole (Example 9). Into a 8 mL vial were added 2,4- bis(perfluoroethyl)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-8-carbohydrazide (9-7) (40 mg, 0.086 mmol), CH(OCH3)3 (2 mL) and p-toluenesulfonic acid (7.42 mg, 0.043 mmol) at room temperature. The resulting mixture was stirred for 4 h at 70 °C under N2 atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with H2O (0.5 mL). The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase, Water (0.05% FA) and ACN (45% Phase B up to 75% in 7 min); Detector, UV 254 nm. to afford Example 9 (10 mg, 24.47%) as a white solid. MS calcd. for C15H4F10N6O: 474.0; Found: 475.1 [M+1]+. 1H NMR (300 MHz, CD3OD): δ 9.32 (s, 1H), 9.14 (s, 1H), 8.22 (d, J = 9.9 Hz, 1H), 8.08 (d, J = 10.0 Hz, 1H) ppm. [0207] Example 10.2-(4-(1-Methyl-1H-pyrazol-3-yl)-2-(perfluoroethyl)imidazo[1,2- a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole
Figure imgf000057_0001
[0208] Step 1. Synthesis of ethyl 4-(1-methyl-1H-pyrazol-3-yl)-2- (perfluoroethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxylate (10-1). A mixture of ethyl 4- chloro-2-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridine-8-carboxylate (4-2) (220 mg, 0.56 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (237 mg, 1.15 mmol), potassium carbonate (234.3 mg, 1.68 mmol) and Pd(dppf)Cl2 (40.92 mg, 0.056 mmol) was stirred in dioxane and water (5:1) for 3 h at 100 °C under N2 atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with ethyl acetate and water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated salt solution, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE = 1/3 (v/v) to afford ethyl 4-(1-methyl-1H-pyrazol-3-yl)-2-(perfluoroethyl)imidazo[1,2-a][1,8]naphthyridine-8- carboxylate (10-1) (200 mg, 81.46%) as a light-yellow solid. MS calcd. for C19H14F5N5O2: 439.1; Found: 440 [M+1]+. [0209] Step 2. Synthesis of 4-(1-methyl-1H-pyrazol-3-yl)-2-(perfluoroethyl)imidazo[1,2- a][1,8]naphthyridine-8-carbohydrazide (10-2). A solution of ethyl 4-(1-methyl-1H-pyrazol-3- yl)-2-(perfluoroethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxylate (10-1) (200 mg, 0.45 mmol) and hydrazine hydrate(228 mg, 4.44 mmol) in EtOH (5 mL) was refluxed for 4 h. The resulting mixture was concentrated under reduced pressure and the residue was dried in vacuo to give 4-(1-methyl-1H-pyrazol-3-yl)-2-(perfluoroethyl)imidazo[1,2-a][1,8]naphthyridine-8- carbohydrazide (10-2) (172 mg, crude) as brown solid. MS calcd. for C17H12F5N7O:425.1; Found: 426.0 [M+1]+. [0210] Step 3. Synthesis of 2-(4-(1-methyl-1H-pyrazol-3-yl)-2-(perfluoroethyl)imidazo[1,2- a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (Example 10). A solution of 4-(1-methyl-1H- pyrazol-3-yl)-2-(perfluoroethyl)imidazo[1,2-a][1,8]naphthyridine-8-carbohydrazide (10-2) (172 mg, 0.40 mmol), p-TsOH (696 mg, 4.04 mmol) in CH(OMe)3 (3 mL) was stirred for 4 h at 70 ℃. The mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column, XBridge Shield RP18 OBD Column, 5um,19*150mm; mobile phase, Water (0.05% FA) and ACN (45% Phase B up to 75% in 7 min); Detector, UV 254 nm.) to afford Example 10 (34 mg, 19.31%) as yellow solid. MS calcd. for C24H36FN3O5S2: 529.2; Found: 530.1 [M+1]+.1H NMR (400 MHz, CDCl3): δ 9.27 (s, 1H), 8.83 (d, J = 9.9 Hz, 1H), 8.57 (s, 1H), 8.11 (s, 1H), 7.83 (d, J = 9.9 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 6.83 (d, J = 2.3 Hz, 1H), 4.13 (s, 3H) ppm. [0211] Example 11.2-{3-[8-(1,3,4-Oxadiazol-2-yl)-2-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2- a]1,8-naphthyridin-4-yl]pyrrolidin-1-yl}ethanol
Figure imgf000059_0001
[0212] Step 1. Synthesis of tert-butyl 3-[8-(ethoxycarbonyl)-2-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-4-yl]-2,5-dihydropyrrole-1-carboxylate (11-1). A solution of ethyl 4-chloro-2-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridine-8-carboxylate (4-2) (400 mg, 1.02 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (599.83 mg, 2.03 mmol), potassium carbonate (282.88 mg, 2.03 mmol), Pd(dppf)Cl2 (37.17 mg, 0.05 mmol) in water (1 mL) and dioxane (3 mL) was stirred for 3 h at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to rt. The resulting mixture was diluted with H2O (30 mL). The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography, eluted with EA:PE (2:1) to afford tert-butyl 3-[8-(ethoxycarbonyl)-2-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-4-yl]-2,5-dihydropyrrole-1-carboxylate (11-1) (350 mg, 65.43%) as a yellow oil. MS calcd. for C24H23F5N4O: 526.0; Found: 527.1 [M + 1]+. [0213] Step 2. Synthesis of tert-butyl 3-[8-(ethoxycarbonyl)-2-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-4-yl]pyrrolidine-1-carboxylate (11-2). To a solution of tert-butyl 3-[8-(ethoxycarbonyl)-2-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridin-4-yl]-2,5-dihydropyrrole-1-carboxylate (11-1) (350 mg, 0.67 mmol) in MeOH (7 mL) was added Pd/C (10%, 100 mg) in a pressure tank. The mixture was hydrogenated at room temperature under 30 psi of hydrogen pressure for 24 h, filtered through a Celite pad and concentrated under reduced pressure to give tert-butyl 3-[8-(ethoxycarbonyl)-2-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-4-yl]pyrrolidine-1-carboxylate (11-2) (280 mg, 79.69%) as a brown oil. MS calcd. for C24H25F5N4O: 528.0; Found: 529.1 [M + 1]+. [0214] Step 3. Synthesis of tert-butyl 3-[8-(hydrazinecarbonyl)-2-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-4-yl]pyrrolidine-1-carboxylate (11-3). A solution of tert-butyl 3-[8-(ethoxycarbonyl)-2-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridin-4-yl]pyrrolidine-1-carboxylate (11-2) (280 mg, 0.53 mmol) and hydrazine (0.3 mL) in ethyl alcohol (2.8 mL) was stirred for 3h at 70 °C under nitrogen atmosphere. The mixture was allowed to cool down to rt. The resulting mixture was concentrated under reduced pressure and the residue was dried in vacuo to give tert-butyl 3-[8-(hydrazinecarbonyl)-2-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-4-yl]pyrrolidine-1-carboxylate (11-3) (260 mg, 95.39%) as a yellow oil. MS calcd. for C22H23F5N6O3: 514.0; Found: 515.1 [M + 1]+. [0215] Step 4. Synthesis of tert-butyl 3-[8-(1,3,4-oxadiazol-2-yl)-2-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-4-yl]pyrrolidine-1-carboxylate (11-4). A solution of tert-butyl 3-[8-(hydrazinecarbonyl)-2-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridin-4-yl]pyrrolidine-1-carboxylate (11-3) (260 mg, 0.51 mmol) and p-toluenesulfonic acid (43.51 mg, 0.25 mmol) in trimethyl orthoformate (2.6 mL) was stirred for 4 h at 70 °C under nitrogen atmosphere. The mixture was allowed to cool down to rt. The reaction was quenched with H2O (10 mL) at rt. The aqueous layer was extracted with EA (3 x 10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm to give tert-butyl 3-[8-(1,3,4-oxadiazol-2-yl)-2-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-4- yl]pyrrolidine-1-carboxylate (11-4) (220 mg, 83.00%) as a white solid. MS calcd. for C23H21F5N6O3: 524.0; Found: 525.1 [M + 1]+. [0216] Step 5. Synthesis of 2-[2-(1,1,2,2,2-pentafluoroethyl)-4-(pyrrolidin-3-yl)imidazo[1,2- a]1,8-naphthyridin-8-yl]-1,3,4-oxadiazole (11-5). A solution of tert-butyl 3-[8-(1,3,4- oxadiazol-2-yl)-2-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-4-yl]pyrrolidine-1- carboxylate (11-4) (215 mg, 0.41 mmol) and trifluoroacetic acid (200.93 mg, 2.05 mmol) in DCM (2 mL) was stirred for 10h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with H2O (30 mL). The mixture was basified to pH 7-8 NaHCO3 (aq). The aqueous layer was extracted with EA (3 x 30 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 50% to 80% gradient in 10 min; detector, UV 254 nm to give 2-[2-(1,1,2,2,2-pentafluoroethyl)-4-(pyrrolidin- 3-yl)imidazo[1,2-a]1,8-naphthyridin-8-yl]-1,3,4-oxadiazole (11-5) (170 mg, 97.73%) as a white solid. MS calcd. for C18H13F5N6O3: 424.0; Found: 425.1 [M + 1]+. [0217] Step 6. Synthesis of 2-[4-(1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyrrolidin-3-yl)- 2-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-8-yl]-1,3,4-oxadiazole (11-6). A solution of 2-[2-(1,1,2,2,2-pentafluoroethyl)-4-(pyrrolidin-3-yl)imidazo[1,2-a]1,8- naphthyridin-8-yl]-1,3,4-oxadiazole (11-5) (165 mg, 0.39 mmol) and 2-[(tert- butyldimethylsilyl)oxy]acetaldehyde (135.56 mg, 0.78 mmol), acetic acid (2.34 mg, 0.04 mmol), sodium triacetoxyborohydride (247.23 mg, 1.17 mmol) in methanol (2 mL) was stirred at rt for 3h under nitrogen atmosphere. The resulting mixture was diluted with H2O (30 mL). The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4. The solvent was removed and the residue was dried in vacuo to give 2- [4-(1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyrrolidin-3-yl)-2-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-8-yl]-1,3,4-oxadiazole (11-6) (60 mg, 26.48%) as a yellow solid. MS calcd. for C26H31F5N6O2Si: 582.0; Found: 583.1 [M + 1]+. [0218] Step 7. Synthesis of 2-{3-[8-(1,3,4-oxadiazol-2-yl)-2-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-4-yl]pyrrolidin-1-yl}ethanol (Example 11). A solution of 2-[4-(1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyrrolidin-3-yl)-2-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-8-yl]-1,3,4-oxadiazole (11-6) (60 mg, 0.10 mmol) and cesium fluoride (46.93 mg, 0.31 mmol) in water (1 mL) and tetrahydrofuran (1 mL) was stirred for 6 h at 85 °C under nitrogen atmosphere. The mixture was allowed to cool down to rt. The resulting mixture was diluted with H2O (30 mL). The resulting mixture was extracted with EA (3 x 30 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 70% gradient in 10 min; detector, UV 254 nm to give Example 11 (24.1 mg, 49.97%) as a white solid. MS calcd. for C20H17F5N6O2: 468.0; Found: 469.1 [M + 1]+. 1H NMR (300 MHz, DMSO-d6): δ 9.41 (s, 1H), 8.97 (s, 1H), 8.41 ‒ 8.31 (m, 1H), 8.18 (s, 1H), 7.92 ‒ 7.89 (m, 1H), 4.60 (s, 1H), 4.22 (s, 1H), 3.58 (m, 2H), 3.07 (m, 2H), 2.85 (m, 1H), 2.71 (m, 2H), 2.51 ‒ 2.43 (m, 2H), 1.87 ‒ 1.75 (m, 1H) ppm. [0219] Example 12.2-(2-(1-Methylpyrrolidin-3-yl)-4-(perfluoroethyl)imidazo[1,2- a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole
Figure imgf000062_0001
[0220] Step 1. Synthesis of ethyl 2-(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)-4- (perfluoroethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxylate (12-1).To a solution of ethyl 2-chloro-4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridine-8-carboxylate (6-3) (500 mg, 1.27 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5- dihydropyrrole-1-carboxylate (562.34 mg, 1.90 mmol) in dioxane (5 mL) and H2O (1 mL) were added K2CO3 (526.56 mg, 3.81 mmol) and Pd(dppf)Cl2 (92.93 mg, 0.12 mmol) . After stirring for 3 h at 100°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with THF/PE = 1/1 (v/v) to afford tert-butyl 3-[8-(ethoxycarbonyl)-4-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-2-yl]-2,5-dihydropyrrole-1-carboxylate (12-1) (400 mg, 59.83%) as a yellow solid. MS calcd. for C24H23F5N4O4: 526.2; Found:527.2[M + 1]+. [0221] Step 2. Synthesis of ethyl 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4- (perfluoroethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxylate (12-2). To a solution of tert- butyl 3-[8-(ethoxycarbonyl)-4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-2-yl]- 2,5-dihydropyrrole-1-carboxylate (12-1) (400 mg, 0.76 mmol) in MeOH (10 mL) was added Pd/C (10%, 20 mg) in a pressure tank. The mixture was hydrogenated at room temperature under 30 psi of hydrogen pressure for overnight, then filtered through a Celite®545 pad. The filtrate was concentrated under reduced pressure and the residue was dried in vacuo to give tert-butyl 3- [8-(ethoxycarbonyl)-4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-2- yl]pyrrolidine-1-carboxylate (12-2) (400 mg, 99.62%) as a yellow solid. MS calcd. for C24H25F5N4O4: 528.2; Found: 529.3 [M + 1]+. [0222] Step 3. Synthesis of tert-butyl 3-(8-(hydrazinecarbonyl)-4- (perfluoroethyl)imidazo[1,2-a][1,8]naphthyridin-2-yl)pyrrolidine-1-carboxylate (12-3). A solution of tert-butyl 3-[8-(ethoxycarbonyl)-4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridin-2-yl]pyrrolidine-1-carboxylate (12-2) (400 mg, 0.75 mmol) and NH2NH2•H2O (189.45 mg, 3.78 mmol) in dioxane (2 mL) was stirred for 3 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure and the residue was dried in vacuo to give tert-butyl 3- [8-(hydrazinecarbonyl)-4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-2- yl]pyrrolidine-1-carboxylate (12-3) (280 mg, 71.91%) as a yellow solid. MS calcd. for C22H23F5N6O3: 514.2; Found: 515.1 [M + 1]+. [0223] Step 4. Synthesis of tert-butyl 3-(8-(1,3,4-oxadiazol-2-yl)-4- (perfluoroethyl)imidazo[1,2-a][1,8]naphthyridin-2-yl)pyrrolidine-1-carboxylate (12-4). A solution of tert-butyl 3-[8-(hydrazinecarbonyl)-4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8- naphthyridin-2-yl]pyrrolidine-1-carboxylate (12-3) (280 mg, 0.54 mmol) and p-toluenesulfonic acid (46.86 mg, 0.27 mmol) in CH(OMe)3 (5 mL) was stirred for 4 h at 70 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (10 mL). The mixture was basified to pH = 8 with saturated NaHCO3 (aq). The aqueous layer was extracted with EtOAc (3 x 20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA = 3/1 (v/v) to afford tert-butyl 3-[8-(1,3,4-oxadiazol-2-yl)- 4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-2-yl]pyrrolidine-1-carboxylate (12-4) (240 mg, 84.08%) as a yellow oil. MS calcd. for C23H21F5N6O3: 524.2; Found: 525.3 [M + 1]+. [0224] Step 5. Synthesis of 2-(4-(perfluoroethyl)-2-(pyrrolidin-3-yl)imidazo[1,2- a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (12-5). A solution of tert-butyl 3-[8-(1,3,4- oxadiazol-2-yl)-4-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridin-2-yl]pyrrolidine-1- carboxylate (12-4) (240 mg, 0.46 mmol) and trifluoroacetic acid (448.58 mg, 4.58 mmol) in DCM (5 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The mixture was basified to pH 8 with saturated Na2CO3 (aq.). The aqueous layer was extracted with EtOAc (3 x 30 mL). The resulting mixture was concentrated under reduced pressure and the residue was dried in vacuo to give 2-[4-(1,1,2,2,2-pentafluoroethyl)-2-(pyrrolidin-3-yl)imidazo[1,2-a]1,8- naphthyridin-8-yl]-1,3,4-oxadiazole (12-5) (160 mg, 82.40%) as a yellow solid. MS calcd. for C18H13F5N6O: 424.1; Found: 425.2 [M + 1]+. [0225] Step 6. Synthesis of 2-(2-(1-methylpyrrolidin-3-yl)-4-(perfluoroethyl)imidazo[1,2- a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (Example 12). A solution of 2-[4-(1,1,2,2,2- pentafluoroethyl)-2-(pyrrolidin-3-yl)imidazo[1,2-a]1,8-naphthyridin-8-yl]-1,3,4-oxadiazole (12- 5) (80 mg, 0.18 mmol) and HCHO (56.61 mg, 1.89 mmol), AcOH (1.13 mg, 0.019 mmol), NaBH(AcO)3 (79.91 mg, 0.37 mmol) in MeOH (2 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The mixture was basified to pH 8 with saturated NaHCO3 (aq.). The aqueous layer was extracted with EtOAc (2 x 40 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions, XBridge Shield RP18 OBD Column, 19*150 mm, 5µm; mobile phase, Water (0.05%NH3H2O) and ACN (26% ACN up to 40% in 8 min) to afford Example 12 (7 mg, 8.47%) as a light-yellow solid. MS calcd. for C19H15F5N6O: 438.1; Found: 439.1 [M + 1]+. 1H NMR (400 MHz, CD3OD): δ 9.44 (s, 1H), 9.11 (s, 1H), 8.05 (d, J = 10.0 Hz, 1H), 7.94 (s, 1H), 7.78 (d, J = 10.0 Hz, 1H), 4.03 – 3.91 (m, 1H), 3.17 (dd, J = 9.8, 8.4 Hz, 1H), 3.07 (dd, J = 9.8, 6.8 Hz, 1H), 2.97 (m, 1H), 2.87 (m, 1H), 2.51 ‒ 2.52 (m, 4H), 2.39 – 2.26 (m, 1H) ppm. [0226] Example 13.2-(2-(Prop-1-en-2-yl)-4-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin- 8-yl)-1,3,4-oxadiazole
Figure imgf000065_0001
[0227] Step 1. Synthesis of 2-(2-(prop-1-en-2-yl)-4-(trifluoromethyl)imidazo[1,2- a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole. To a stirred solution of 2-(2-chloro-4- (trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (13-1) (1 g, 2.95 mmol) in 1, 4-dioxane and water (4:1 (v/v), 10 mL) were added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)- 1,3,2-dioxaborolane (0.99 g, 5.90 mmol) and K3PO4 (1.56 g, 7.37 mmol) and the reaction mixture was purged under nitrogen for 10 min. To this resulting solution, PdCl2(PPh3)2 (0.20 g, 0.29 mmol) was added under nitrogen atmosphere. The reaction mixture was heated at 100 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water and, extracted with EtOAc followed by brine. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by CombiFlash chromatography (eluting with 60-70% EtOAc in heptane) to afford Example 13 (0.45 g, 45%) as a yellow solid. TLC: 50% EtOAc/Heptane (Rf: 0.5). MS calcd. for C16H10F3N5O: 345.1; Found: 346.0 [M + 1]+. 1H NMR (400 MHz, DMSO-d6): δ 9.42 (s, 1H), 9.30 (s, 1H), 8.27 (s, 1H), 7.94 ‒ 7.90 (m, 2H), 6.49 (s, 1H), 5.74 (s, 1H), 2.36 (s, 3H) ppm. [0228] Example 14.8-(1,3,4-Oxadiazol-2-yl)-2-(perfluoroethyl)-4- (trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-9-carbonitrile [0229] Example 15.8-(1,3,4-Oxadiazol-2-yl)-4-(perfluoroethyl)-2- (trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-9-carbonitrile
Figure imgf000066_0001
[0230] Step 1. Synthesis of 7-(perfluoroethyl)-5-(trifluoromethyl)-1,8-naphthyridin-2- amine (14-2a) and 5-(perfluoroethyl)-7-(trifluoromethyl)-1,8-naphthyridin-2-amine (14-2b). To a stirred solution of 2,6-diaminopyridine (0.8 g, 7.34 mmol) in AcOH (6.5 mL) was added 1,1,1,5,5,6,6,6-octafluorohexane-2,4-dione (14-1) (1.9 g, 7.34 mmol). The reaction mixture was heated at 120 °C for 16 h in a sealed tube. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by CombiFlash chromatography (using a gradient method of 40-60% EtOAc in heptane) to afford an inseparable mixture of 7- (perfluoroethyl)-5-(trifluoromethyl)-1,8-naphthyridin-2-amine (14-2a) and 5-(perfluoroethyl)-7- (trifluoromethyl)-1,8-naphthyridin-2-amine (14-2b) (a mixture of regioisomers) (0.8 g, 33%) as a pale-yellow solid. TLC: 60% EtOAc/Heptane (Rf: 0.5). MS calcd. for C11H5F8N3: 331.04; Found: 332.0
Figure imgf000067_0001
NMR (400 MHz, DMSO-d6): δ 8.18 (m, 1H), 7.81 ‒ 7.75 (m, 1H), 7.60 (br s, 2H), 7.18-7.14 (m, 1H) ppm. [0231] Step 2. Synthesis of ethyl 2-(perfluoroethyl)-4-(trifluoromethyl)imidazo[1,2- a][1,8]naphthyridine-8-carboxylate (14-3a) and ethyl 4-(perfluoroethyl)-2- (trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxylate (14-3b). To a stirred solution of 7-(perfluoroethyl)-5-(trifluoromethyl)-1,8-naphthyridin-2-amine (14-2a) and 5- (perfluoroethyl)-7-(trifluoromethyl)-1,8-naphthyridin-2-amine (14-2b) (a mixture of regioisomers) (a mixture of regioisomers) (0.78 g, 2.36 mmol) in DMF (10 mL) was added ethyl 3-bromo-2-oxopropanoate (0.68 g, 3.53 mmol). The resulting reaction mixture was heated at 110 °C for 16 h. After completion of the reaction (monitored by TLC), reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by CombiFlash chromatography (using a gradient method of 15% EtOAc in heptane) to afford an inseparable mixture of ethyl 2-(perfluoroethyl)-4- (trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxylate (14-3a) and ethyl 4- (perfluoroethyl)-2-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxylate (14-3b) (a mixture of regioisomers) (0.55 g, 55%) as an off-white solid. TLC: 60% EtOAc/Heptane (Rf: 0.7). MS calcd. for C16H9F8N3O2: 427.1; Found: 428.3 [M + 1]+.1H NMR (400 MHz, DMSO- d6): δ 8.99 ‒ 8.90 (m, 1H), 8.48 ‒ 8.45 (m, 1H), 8.08 ‒ 7.97 (m, 2H), 4.37 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H) ppm. [0232] Step 3. Synthesis of 2-(perfluoroethyl)-4-(trifluoromethyl)imidazo[1,2- a][1,8]naphthyridine-8-carbohydrazide (14-4a) and 4-(perfluoroethyl)-2- (trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-8-carbohydrazide (14-4b). To a stirred solution of ethyl 2-(perfluoroethyl)-4-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-8- carboxylate (14-3a) and ethyl 4-(perfluoroethyl)-2-(trifluoromethyl)imidazo[1,2- a][1,8]naphthyridine-8-carboxylate (14-3b) (a mixture of regioisomers) (0.55 g, 1.29 mmol) in ethanol (8 mL) was added hydrazine hydrate (1 mL) and the reaction mixture was heated at 60 °C for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness. The crude compound obtained was triturated with heptane. The obtained solid was filtered off and dried in vacuo to afford 2-(perfluoroethyl)-4- (trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-8-carbohydrazide (14-4a) and 4- (perfluoroethyl)-2-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-8-carbohydrazide (14-4b) (a mixture of regioisomers) (0.44 g, 82.86) as an off-white solid. TLC: 40% EtOAc/heptane (Rf: 0.3), which was used in the next step without further purification. MS calcd. for C14H7F8N5O: 413.1; Found: 414.1 [M + 1]+. [0233] Step 4. Synthesis of 2-(2-(perfluoroethyl)-4-(trifluoromethyl)imidazo[1,2- a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (14-5) and 2-(4-(perfluoroethyl)-2- (trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (14-6). To a stirred solution of 2-(perfluoroethyl)-4-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-8- carbohydrazide (14-4a) and 4-(perfluoroethyl)-2-(trifluoromethyl)imidazo[1,2- a][1,8]naphthyridine-8-carbohydrazide (14-4b) (a mixture of regioisomers) (0.43 g, 1.05 mmol) in triethyl orthoformate (5 mL) was added p-TsOH (0.17 g) and the reaction mixture was then stirred at 100 °C for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude product was purified by SFC [SFC purification method: Column- CHIRAL PAK IC (250*30mm,5um)/ Mobile Phase A: 0.1%DEA in n-Hexane; Mobile Phase B: DCM:MEOH(80:20)/ A:B: 60:40/ Flow rate: 32 ml/min/ UV :254nm/ Diluent: DCM:MEOH(50:50)] to afford 2-(2-(perfluoroethyl)-4- (trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (14-5) (46 mg, 10.33%) as an off-white solid. MS calcd. for C15H5F8N5O: 423.0; Found: 423.9 [M + 1]+. 1H NMR (400 MHz, DMSO-d6): δ 9.44 (s, 1H), 9.11 (s, 1H), 8.50 (s, 1H), 8.14 (d, J = 10 Hz, 1H), 8.01 (dd, J = 10 Hz, 2 Hz, 1H) ppm and 2-(4-(perfluoroethyl)-2-(trifluoromethyl)imidazo[1,2- a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (14-6) (23 mg, 5.16%) as an off-white solid. MS calcd. for C15H5F8N5O: 423.0; Found: 423.9 [M + 1]+. NMR (400 MHz, DMSO-d6): δ 9.32 (s, 1H), 9.11 (s, 1H), 8.34 (s, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.99 (d, J = 10 Hz, 1H) ppm. [0234] Step 5. Synthesis of 2-(9-bromo-2-(perfluoroethyl)-4-(trifluoromethyl)imidazo[1,2- a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (14-7) and 2-(9-bromo-4-(perfluoroethyl)-2- (trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (14-8). To a stirred solution of 2-(2-(perfluoroethyl)-4-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)-1,3,4- oxadiazole (14-5) and 2-(4-(perfluoroethyl)-2-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin- 8-yl)-1,3,4-oxadiazole (14-6) (a mixture of regioisomers) (0.4 g, 0.95 mmol) in DMF (8 mL) was added NBS (0.34 g, 1.89 mmol) and the reaction mixture was then stirred at 60 °C for 2 h. After completion of the reaction (monitored by TLC), reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organic layers were, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (100-200 mesh, using a gradient method of 30-40% EtOAc in heptane) to afford 2-(9-bromo-2-(perfluoroethyl)-4- (trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (14-7) and 2-(9-bromo- 4-(perfluoroethyl)-2-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (14-8) as a mixture of regioisomers (0.24 g, 51.06%) as a yellow solid. From which 60 mg of mixture was purified by preparative SFC [Column: CHIRAL PAK IG (250*30mm,5um)/ Mobile Phase A: n-Hexane; Mobile Phase B: IPA/ A:B: 50:50/ Flow: 30 ml/min/ UV: 254 nm/ Diluent: IPA] to afford 2-(9-bromo-2-(perfluoroethyl)-4-(trifluoromethyl)imidazo[1,2- a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (14-7) (9 mg, 12.6%) as a yellow solid. MS calcd. for C15H4BrF8N5O: 503.0; Found: 504.0 [M + 1]+.1H NMR (400 MHz, CD3OD): δ 8.37 (s, 1H), 7.59 (s, 1H), 7.32 (dd, J = 10 Hz, 2 Hz, 1H), 7.19 (d, J = 9.6 Hz, 1H) ppm and 2-(9-bromo-4- (perfluoroethyl)-2-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (14- 8) (5 mg, 7.04%) as a yellow solid. TLC: 60% EtOAc/heptane (Rf: 0.5) MS calcd. for C15H4BrF8N5O: 503.0; Found: 504.0 [M + 1]+.1H NMR (400 MHz, CD3OD): δ 9.18 (s, 1H), 8.35 (s, 1H), 8.17 ‒ 7.90 (m, 2H) ppm. The remaining 160 mg of mixture of isomers was used for the next step without further purification. [0235] Step 6. Synthesis of 8-(1,3,4-oxadiazol-2-yl)-2-(perfluoroethyl)-4- (trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-9-carbonitrile (Example 14) and 8- (1,3,4-oxadiazol-2-yl)-4-(perfluoroethyl)-2-(trifluoromethyl)imidazo[1,2- a][1,8]naphthyridine-9-carbonitrile (Example 15). To a stirred solution of 2-(9-bromo-2- (perfluoroethyl)-4-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (14- 7) and 2-(9-bromo-4-(perfluoroethyl)-2-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)- 1,3,4-oxadiazole (14-8) (a mixture of regioisomers) (0.16 g, 0.32 mmol) in DMF (3 mL) was added CuCN (0.086 g, 0.96 mmol) and the reaction mixture was then stirred at 135 °C for 1 h in microwave. After completion of the reaction (monitored by TLC), reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by preparative SFC [Column; CHIRAL PAK IC (250*30mm, 5um)/Mobile Phase A: MTBE: n-Hexane (50:50); Mobile Phase B: EtOH/ A:B: 50:50/ Flow: 30 ml/min/ UV: 254nm/ Diluent: DCM:MEOH(50:50)] to afford Example 14 (11 mg, 7.7%) as an off-white solid. MS calcd. for C16H4F8N6O: 448.0; Found: 449.1 [M + 1]+. 1H NMR (400 MHz, DMSO-d6): δ 9.60 (s, 1H), 8.63 (s, 1H), 8.31 ‒ 8.23 (m, 2H) ppm and Example 15 (3.4 mg, 2.14%) as an off-white solid. TLC: 50% EtOAc/heptane (Rf: 0.5). MS calcd. for C16H4F8N6O: 448.0; Found: 449.1 [M + 1]+. 1H NMR (400 MHz, DMSO-d6): δ 9.61 (s, 1H), 8.65 (s, 1H), 8.27 (s, 2H) ppm. [0236] Example 16.2-(2-(1,1-Difluoro-2-methylpropyl)-4-(trifluoromethyl)imidazo[1,2- a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole
Figure imgf000071_0001
[0237] Step 1. Synthesis of 2-(2-bromo-4-(trifluoromethyl)imidazo[1,2- a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (16-2). To a stirred solution of 8-(1,3,4-oxadiazol- 2-yl)-4-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-2(1H)-one (16-1) (5 g, 15.58 mmol) in DMF/ DCE (1/1 (v/v), 60 mL) was added POBr3 (8 mL, 77.88 mmol) and then resulting reaction mixture was heated at 90 °C for 4 h. After completion of the reaction (monitored by TLC), reaction mixture was cooled to 0 °C and diluted with ice cold water, extracted with EtOAc. The combined organic layers were, washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel (100-200 mesh, using a gradient method of 40-50% EtOAc in hexane) to afford 2-(2-bromo-4-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)-1,3,4- oxadiazole (16-2) (2.1 g, 35.23%) as a yellow solid.1H NMR (400 MHz, DMSO-d6): δ 9.42 (s, 1H), 9.11 (s, 1H), 8.26 (s, 1H), 7.98 (d, J = 9.6 Hz, 1H), 7.88 (dd, J = 10 Hz, 1.6 Hz, 1H) ppm. [0238] Step 2. Synthesis of 2-(4-(trifluoromethyl)-2-vinylimidazo[1,2-a][1,8]naphthyridin- 8-yl)-1,3,4-oxadiazole (16-3). To a stirred solution of 2-(2-bromo-4- (trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (16-2) (1 g, 2.61 mmol) in a mixture of 1, 4-dioxane and water (16:4 mL) were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2- dioxaborolane (0.80 g, 5.22 mmol) and K3PO4 (1.66 g, 7.83 mmol) and the resulting reaction mixture was purged under nitrogen for 10 min. To this solution Pd (dppf)Cl2 (0.382 g, 0.52 mmol) was added under nitrogen atmosphere. The resulting reaction mixture was heated at 100 °C for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of Celite and washed with ethyl acetate. The filtrate was diluted with water and, extracted with EtOAc followed by brine. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by CombiFlash chromatography (using a gradient method of 60-80% EtOAc in hexane) to afford 2-(4-(trifluoromethyl)-2-vinylimidazo[1,2- a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (16-3) (0.7 g, 81.39%) as a brown colored solid. TLC: 50% EtOAc/hexane (Rf: 0.5).1H NMR (400 MHz, DMSO-d6): δ 8.98 (s, 1H), 8.27 (s, 1H), 7.94 ‒ 7.87 (m, 2H), 7.53 ‒ 7.51 (m, 2H), 7.44 ‒ 7.37 (m, 2H) ppm. [0239] Step 3. Synthesis of 8-(1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)imidazo[1,2- a][1,8]naphthyridine-2-carbaldehyde (16-4). To a stirred solution of 2-(4-(trifluoromethyl)-2- vinylimidazo[1,2-a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (16-3) (0.7 g, 2.114 mmol) in acetone/water (15 mL/5 mL) was added NaIO4 (1.35 g, 6.34 mmol) followed by K2OsO4 (77.9 mg, 0.21 mmol) at 0 °C. The resulting reaction mixture was slowly warmed to room temperature and stirred for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of Celite and washed with ethyl acetate. The filtrate was diluted with water and, extracted with EtOAc followed by brine. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by CombiFlash chromatography (using a gradient method of 60-80% EtOAc in hexane) to afford 8-(1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine- 2-carbaldehyde (16-4) (0.45 g, 63%) as a yellow solid. TLC: 50% EtOAc/hexane (Rf: 0.3). MS calcd. for C14H6F3N5O2: 333.0; Found: 334.0 [M + 1]+. [0240] Step 4. Synthesis of 1-(8-(1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)imidazo[1,2- a][1,8]naphthyridin-2-yl)-2-methylpropan-1-ol (16-5). To a stirred solution of 8-(1,3,4- oxadiazol-2-yl)-4-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-2-carbaldehyde (16-4) (0.2 g, 0.60 mmol) in dry THF (5 mL) at 0 °C under an Argon atmosphere, Isopropyl magnesium bromide solution (2.9 M in 2-methyltetrahydrofuran, 0.41 mL, 1.20 mmol) was added drop wise. The resulting reaction mixture was slowly warmed to room temperature and stirred for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by CombiFlash chromatography (using a gradient method of 60-80% EtOAc in hexane) to afford 1-(8-(1,3,4-oxadiazol-2-yl)-4- (trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-2-yl)-2-methylpropan-1-ol (16-5) (25 mg, 11%) as an off-white solid. TLC: 60% EtOAc/hexane (Rf: 0.5). MS calcd. for C17H14F3N5O2: 377.1, Found: 378.1 [M+1]+.1H NMR (400 MHz, DMSO-d6): δ 9.42 (s, 1H), 9.30 (s, 1H), 8.08 (s, 1H), 7.96 ‒ 7.92 (m, 2H), 5.81 (d, J = 6.0 Hz, 1H), 4.72 ‒ 4.69 (m, 1H), 2.33 ‒ 2.27 (m, 1H), 1.02 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 7.2 Hz, 3H) ppm. [0241] Step 5. Synthesis of 1-(8-(1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)imidazo[1,2- a][1,8]naphthyridin-2-yl)-2-methylpropan-1-one (16-6). To a stirred solution of 1-(8-(1,3,4- oxadiazol-2-yl)-4-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-2-yl)-2-methylpropan-1-ol (16-5) (15 mg, 0.039 mmol) in DCM (2 mL) at 0 °C, Dess–Martin periodinane (33 mg, 0.079 mmol) was added. Then the resulting reaction mixture was slowly warmed to room temperature and allowed to stir for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by CombiFlash chromatography (using a gradient method of 30-40% EtOAc in hexane) to afford 1-(8-(1,3,4- oxadiazol-2-yl)-4-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-2-yl)-2-methylpropan-1-one (16-6) (12 mg, 80%) as a pale-yellow solid. TLC: 50% EtOAc/hexane (Rf: 0.5). MS calcd. for C17H12F3N5O2: 375.1, Found: 375.9 [M+1]+. [0242] Step 6. Synthesis of 2-(2-(1,1-difluoro-2-methylpropyl)-4- (trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (Example 16). To a stirred solution of 1-(8-(1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)imidazo[1,2- a][1,8]naphthyridin-2-yl)-2-methylpropan-1-one (16-6) (12 mg, 0.032 mmol) in DCM (1 mL) at 0 °C, DAST (9 µL, 0.064 mmol) was added. Then the resulting reaction mixture was slowly warmed to room temperature and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated NaHCO3 solution and extracted with DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by CombiFlash chromatography (using a gradient method of 30-40% EtOAc in hexane) to afford Example 16 (3.7 mg, 29%) as an off-white solid. TLC: 50% EtOAc/hexane (Rf: 0.5). MS calcd. for C17H12F5N5O: 397.1, Found: 398.0 [M+1]+.1H NMR (400 MHz, DMSO-d6): δ 9.45 ‒ 9.43 (m, 1H), 9.33 ‒ 9.30 (m, 1H), 8.20 ‒ 8.16 (m, 1H), 8.10 ‒ 8.03 (m, 1H), 8.00 ‒ 7.93 (m, 1H), 3.17 ‒ 3.06 (m, 1H), 1.05 (d, J = 6.8 Hz, 6H) ppm. [0243] Example 17.2-(5-Bromo-2-(perfluoroethyl)-4-(trifluoromethyl)imidazo[1,2- a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole
Figure imgf000074_0001
[0244] Step 1. Synthesis of 4-bromo-7-(perfluoroethyl)-5-(trifluoromethyl)-1,8- naphthyridin-2-amine (17-2). To a mixture 4-bromopyridine-2,6-diamine (17-1) (1.5 g, 8.02 mmol) and 1,1,1,5,5,6,6,6-octafluorohexane-2,4-dione (5.17 g, 20.05 mmol) at 0 °C, Eaton’s reagent (15 mL) was added. The resulting reaction mixture was slowly warmed to room temperature and heated at 100 °C for 16 h in a sealed tube. After completion of the reaction (monitored by TLC), reaction mixture was cooled to room temperature and the resulting solution was diluted with water and extracted with EtOAc. The combined organic layers were, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound obtained was purified by Column chromatography on silica gel (100-200 mesh, using a gradient method of 15-30% EtOAc in heptane) to afford 4-bromo-7-(perfluoroethyl)-5-(trifluoromethyl)- 1,8-naphthyridin-2-amine (17-2) (0.85 g, 25.83%) as an off-white solid. TLC: 50% EtOAc/Heptane (Rf: 0.7). MS calcd. for C11H4BrF8N3: 411.0; Found: 412.0 [M + 1]+ [0245] Step 2. Synthesis of ethyl 5-bromo-2-(perfluoroethyl)-4- (trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxylate (17-3). To a stirred solution of 4-bromo-7-(perfluoroethyl)-5-(trifluoromethyl)-1,8-naphthyridin-2-amine (17-2) (0.8 g, 1.96 mmol) in DMF (15 mL) was added ethyl 3-bromo-2-oxopropanoate (0.57 g, 2.93 mmol). The resulting reaction mixture was heated at 80 °C for 16 h. After completion of the reaction (monitored by TLC), reaction mixture was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography on silica gel (100-200 mesh, using a gradient method of 40-50% EtOAc in heptane) to afford ethyl 5-bromo-2-(perfluoroethyl)-4- (trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxylate (17-3) (0.23 g, 23.3%) as an off-white solid. TLC: 40% EtOAc/Heptane (Rf: 0.7). MS calcd. for C16H8BrF8N3O2: 505.0; Found: 506.1 [M + 1]+.1H NMR (400 MHz, DMSO-d6): δ 8.96 (s, 1H), 8.65 (s, 1H), 8.31 (s, 1H), 4.37 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 6.8 Hz, 3H) ppm. [0246] Step 3. Synthesis of 5-bromo-2-(perfluoroethyl)-4-(trifluoromethyl)imidazo[1,2- a][1,8]naphthyridine-8-carboxylic acid (17-4). A suspension of ethyl 5-bromo-2- (perfluoroethyl)-4-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxylate (17-3) (0.23 g, 0.45 mmol) in concd. HCl (2.3 mL) was heated at 120 °C for 12 h. After completion of the reaction (monitored by TLC), reaction mixture was cooled to room temperature and the resulting solution was diluted with water and extracted with EtOAc. The combined organic layers were, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound obtained was purified by column chromatography on silica gel (100-200 mesh, using a gradient method of 5-7% MeOH in DCM) to afford 5-bromo-2-(perfluoroethyl)-4- (trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxylic acid (17-4) (90 mg, 42.85%) as a brown colored solid. TLC: 10% MeOH/DCM (Rf: 0.2). MS calcd. for C14H4BrF8N3O2: 479.0; Found: 480.0 [M + 1]+.1H NMR (400 MHz, DMSO-d6): δ 13.1 (br. s, 1H), 8.91 (s, 1H), 8.62 (s, 1H), 8.30 (s, 1H) ppm. [0247] Step 4. Synthesis of 2-(5-bromo-2-(perfluoroethyl)-4-(trifluoromethyl)imidazo[1,2- a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole (Example 17). To a stirred solution of 5-bromo-2- (perfluoroethyl)-4-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxylic acid (17-4) (70 mg, 0.15 mmol) in DCM (1.5 mL) and THF (1.5 mL) was added (N- isocyanoimino)triphenylphosphorane (88 mg, 0.29 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 12 h. After completion of the reaction (monitored by TLC), the resulting reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound obtained was purified by column chromatography on silica gel (100-200 mesh, using a gradient method of 15-20% EtOAc in heptane) to afford Example 17 (25 mg, 34.24%) as a yellow solid. TLC: 50% EtOAc/heptane (Rf: 0.5). MS calcd. for C15H4BrF8N5O: 503.0, Found: 504.0 [M+1]+.1H NMR (400 MHz, CD3OD): δ 9.28 (s, 1H), 9.11 (s, 1H), 8.50 (s, 1H), 8.30 (s, 1H) ppm. [0248] Example 18. N,N-dimethyl-8-(1,3,4-oxadiazol-2-yl)-2-(perfluoroethyl)imidazo[1,2- a][1,8]naphthyridin-4-amine.
Figure imgf000076_0001
[0249] Step 1. Synthesis of ethyl 4-(dimethylamino)-2-(perfluoroethyl)imidazo[1,2- a][1,8]naphthyridine-8-carboxylate (18-1). A stirred solution of 4-chloro-2-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]1,8-naphthyridine-8-carboxylate (4-2) (0.1 g, 0.25 mmol) in dimethyl amine (50% in THF, 1 mL) was stirred at 50 °C for 6 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness to afford ethyl 4-(dimethylamino)-2-(perfluoroethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxylate (18-1) (0.41 g, crude) as a yellow solid. TLC: 50% EtOAc/heptane (Rf: 0.2). MS calcd. for C17H15F5N4O2: 402.11; Found: 403.1 [M + 1].1H NMR (400 MHz, DMSO-d6) δ = 8.70 (s, 1H), 8.48 (br s, 3H), 7.99 (d, J = 10.3 Hz, 1H), 7.58 (d, J = 9.8 Hz, 1H), 7.29 (s, 1H), 4.35 (q, J = 7.0 Hz, 2H), 3.25 (s, 6H), 1.35 (t, J = 6.8 Hz, 3H) ppm. [0250] Step 2. Synthesis of 4-(dimethylamino)-2-(perfluoroethyl)imidazo[1,2- a][1,8]naphthyridine-8-carbohydrazide (18-2). To a stirred solution of ethyl 4- (dimethylamino)-2-(perfluoroethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxylate (18-1) (0.4 g, 1.0 mmol) in ethanol (5 mL) was added hydrazine hydrate (0.5 g, 9.95 mmol) and the reaction mixture was stirred at 80 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness. The crude residue obtained was purified by trituration with diethyl ether. The obtained solid was filtered off and dried in vacuo to afford 4- (dimethylamino)-2-(perfluoroethyl)imidazo[1,2-a][1,8]naphthyridine-8-carbohydrazide (18-2) (0.38 g, crude) as a yellow solid. TLC: 70% EtOAc/heptane (Rf: 0.5). MS calcd. for C15H13F5N6O: 388.11; Found: 389.1 [M + 1]. [0251] Step 3. Synthesis of N,N-dimethyl-8-(1,3,4-oxadiazol-2-yl)-2- (perfluoroethyl)imidazo[1,2-a][1,8]naphthyridin-4-amine (Example 18). To a stirred solution of 4-(dimethylamino)-2-(perfluoroethyl)imidazo[1,2-a][1,8]naphthyridine-8-carbohydrazide (18- 2) (0.15 g, 0.39 mmol) in triethyl orthoformate (5 mL) was added p-TsOH (51.41 mg, 0.27 mmol) and the reaction mixture was then stirred at 110 °C for 16 h. After completion of the reaction (monitored by TLC), reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluting with 1-2% MeOH- in DCM to afford Example 18 (40 mg, 26.14%) as an off-white solid. TLC: 5% MeOH/DCM (Rf: 0.5). MS calcd. for C16H11F5N6O: 398.1; Found: 399.0 [M + 1].1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.85 (s, 1H), 8.05 (d, J = 10.0 Hz, 1H), 7.66 (d, J = 9.9 Hz, 1H), 7.31 (s, 1H), 3.30 (s, 3H), 3.27 (s, 3H) ppm. [0252] Table 1 shows structures and analytical data for representative Examples of the present invention. These compounds can be prepared according to the synthetic schemes described above and using procedures known to those of ordinary skill in the art. The stereochemistry of these pure enantiomers was arbitrarily assigned. [0253] Table 1: Analytical data of representative compounds
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
[0255] Example 82.5-[2-(1,1,2,2,2-Pentafluoroethyl)-4-(trifluoromethyl)pyrrolo[1,2-a]1,8- naphthyridin-8-yl]-1,3-oxazole
Figure imgf000092_0001
[0256] Step 1. Synthesis of ethyl 2-[(6-bromopyridin-2-yl)(hydroxy)methyl]prop-2-enoate (82-2). A solution of 6-bromopyridine-2-carbaldehyde (82-1) (11 g, 59.14 mmol), ethyl acrylate (11.84 g, 118.27 mmol) and DABCO (0.66 g, 5.91 mmol) in dioxane (90 mL) and H2O (30 mL) was stirred at room temperature for 3 h. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (6:1) to afford ethyl 2-[(6-bromopyridin-2- yl)(hydroxy)methyl]prop-2-enoate (82-2) (13 g, 76.83%) as a light yellow oil. MS calcd. for C11H12BrNO3: 285.0; Found: 286.1 [M + 1]+. [0257] Step 2. Synthesis of ethyl 2-[(acetyloxy)(6-bromopyridin-2-yl)methyl]prop-2-enoate (82-3). A solution of ethyl 2-[(6-bromopyridin-2-yl)(hydroxy)methyl]prop-2-enoate (82-2) (13 g, 45.44 mmol) and Ac2O (50 mL) was stirred at 100 °C for 3 h. The mixture was basified to pH 8 with saturated NaHCO3 (aq.), diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (3:1) to afford ethyl 2-[(acetyloxy)(6-bromopyridin-2-yl)methyl]prop-2-enoate (82-3) (13 g, 87.19%) as a black oil. MS calcd. for C13H14BrNO4: 327.0; Found: 328.1 [M + 1]+. [0258] Step 3. Synthesis of ethyl 5-bromoindolizine-2-carboxylate (82-4). A solution of ethyl 2-[(acetyloxy)(6-bromopyridin-2-yl)methyl]prop-2-enoate (82-3) (13 g, 39.62 mmol) in Xylene (100 mL) was stirred for 6 h at 120 °C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature and diluted with water (100 mL). The mixture was basified to pH 8 with saturated Na2CO3 (aq.), and then extracted with EtOAc (3 x 70 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (5:1) to afford ethyl 5-bromoindolizine-2- carboxylate (82-4) (2.8 g, 26.36%) as a red oil. MS calcd. for C11H10BrNO2: 267.0; Found: 268.1 [M + 1]+. [0259] Step 4. Synthesis of ethyl 5-[(diphenylmethylidene)amino]indolizine-2-carboxylate (82-5). A solution of ethyl 5-bromoindolizine-2-carboxylate (82-4) (2.8 g, 10.44 mmol), benzenemethanimine, α-phenyl- (1.89 g, 10.44 mmol), Xantphos-Pd-G4 (502.53 mg, 0.52 mmol), XantPhos (302.15 mg, 0.52 mmol) and Cs2CO3 (8.51 g, 26.11 mmol) in dioxane (30 mL) was stirred for 4 h at 100 °C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (5:1) to afford ethyl 5-[(diphenylmethylidene)amino]indolizine-2-carboxylate (82-5) (1.8 g, 46.78%) as a red oil. MS calcd. for C24H20N2O2: 368.2; Found: 369.3 [M + 1]+. [0260] Step 5. Synthesis of ethyl 5-aminoindolizine-2-carboxylate (82-6). A solution of ethyl 5-[(diphenylmethylidene)amino]indolizine-2-carboxylate (82-5) (1.8 g, 4.89 mmol) and HCl (6 M) (6 mL, 197.48 mmol) in THF (20 mL) was stirred for 6 h at room temperature. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). And the aqueous layer was basified to pH = 8 with saturated NaHCO3 (aq.) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (3:1) to afford ethyl 5-aminoindolizine-2-carboxylate (82-6) (700 mg, 70.16%) as a black solid. MS calcd. for C11H12N2O2: 204.1; Found: 205.2 [M + 1]+. [0261] Step 6. Synthesis of ethyl 2-(1,1,2,2,2-pentafluoroethyl)-4- (trifluoromethyl)pyrrolo[1,2-a]1,8-naphthyridine-8-carboxylate (82-7). A solution of ethyl 5- aminoindolizine-2-carboxylate (82-6) (620 mg, 3.04 mmol) and sodium (Z)-1,1,1,2,2,6,6,6- octafluoro-5-oxohex-3-en-3-olate (4.25 g, 15.18 mmol) in AcOH (10 mL) was stirred at room temperature for 1 h and then at 80 °C for 3 h . The mixture was allowed to cool down to room temperature and diluted with water (30 mL). The residue was basified to pH 8 with saturated NaHCO3 (aq.) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography, eluted with CH3CN / H2O (12:1) to afford ethyl 2-(1,1,2,2,2-pentafluoroethyl)-4- (trifluoromethyl)pyrrolo[1,2-a]1,8-naphthyridine-8-carboxylate (82-7) (150 mg, 11.59%) as a green solid. MS calcd. for C17H10F8N2O2: 426.1; Found: 427.1 [M + 1]+. [0262] Step 7. Synthesis of [2-(1,1,2,2,2-pentafluoroethyl)-4-(trifluoromethyl)pyrrolo[1,2- a]1,8-naphthyridin-8-yl]methanol (82-8). A solution of ethyl 2-(1,1,2,2,2-pentafluoroethyl)-4- (trifluoromethyl)pyrrolo[1,2-a]1,8-naphthyridine-8-carboxylate (82-7) (240 mg, 0.56 mmol) and DIBAL-H (0.23 mL, 1.13 mmol) in DCM (3 mL) was stirred at -78 °C under a nitrogen atmosphere for 1 h. The mixture was allowed to return to room temperature. The reaction was quenched with Na2SO4·10H2O at room temperature. Then the resulting mixture was filtered and the filter cake was washed with DCM (5 x 10 mL). The filtrate was concentrated under reduced pressure to offer [2-(1,1,2,2,2-pentafluoroethyl)-4-(trifluoromethyl)pyrrolo[1,2-a]1,8- naphthyridin-8-yl]methanol (82-8) (210 mg, 97.07%) as a brown yellow solid. MS calcd. for C15H8F8N2O: 384.1; Found: 385.2 [M + 1]+. [0263] Step 8. Synthesis of 2-(1,1,2,2,2-pentafluoroethyl)-4-(trifluoromethyl)pyrrolo[1,2- a]1,8-naphthyridine-8-carbaldehyde (82-9). A solution of [2-(1,1,2,2,2-pentafluoroethyl)-4- (trifluoromethyl)pyrrolo[1,2-a]1,8-naphthyridin-8-yl]methanol (82-8) (210 mg, 0.55 mmol) and Dess–Martin periodinane (278.18 mg, 0.66 mmol) in DCM (3 mL) was stirred for 3 h at 0 °C. The mixture was allowed to return to room temperature. The reaction was quenched with sat. NaHSO3 (aq.) at room temperature. The resulting mixture was diluted with water (20 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to offer 2-(1,1,2,2,2-pentafluoroethyl)-4-(trifluoromethyl)pyrrolo[1,2-a]1,8- naphthyridine-8-carbaldehyde (82-9) (200 mg, 95.74%) as a brown yellow solid. MS calcd. for C15H6F8N2O: 382.0; Found: 383.2 [M + 1]+. [0264] Step 9. Synthesis of 5-[2-(1,1,2,2,2-pentafluoroethyl)-4- (trifluoromethyl)pyrrolo[1,2-a]1,8-naphthyridin-8-yl]-1,3-oxazole (Example 82). A solution of 2-(1,1,2,2,2-pentafluoroethyl)-4-(trifluoromethyl)pyrrolo[1,2-a]1,8-naphthyridine-8- carbaldehyde (82-9) (200 mg, 0.52 mmol), toluenesulfonylmethyl isocyanide (112.38 mg, 0.58 mmol) and K2CO3 (79.55 mg, 0.58 mmol) in MeOH (2 mL) was stirred for at 70 °C 2 h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (20 mL). The residue was basified to pH = 8 with saturated NaHCO3 (aq.) and extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC to afford Example 82 (40 mg, 18.15%) as a yellow solid. MS calcd. for C17H7F8N3O: 421.0; Found: 422.1 [M + 1]+.1H NMR (300 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.45 (s, 1H), 8.22 (s, 1H), 7.91 (d, J = 9.6 Hz, 1H), 7.70 (s, 1H), 7.33 (d, J = 9.6 Hz, 1H), 7.21 (d, J = 1.5 Hz, 1H). [0265] Example 83.2-(7-methyl-2-(perfluoroethyl)-4-(trifluoromethyl)-7H-pyrrolo[2,3- h]quinolin-8-yl)-1,3,4-oxadiazole [0266] Example 84.2-(7-methyl-4-(perfluoroethyl)-2-(trifluoromethyl)-7H-pyrrolo[2,3- h]quinolin-8-yl)-1,3,4-oxadiazole
Figure imgf000096_0001
[0267] Step 1. Synthesis of ethyl 4-((tert-butoxycarbonyl)amino)-1H-indole-2-carboxylate (83-2). To a stirred solution of ethyl 4-bromo-1H-indole-2-carboxylate (83-1) (2 g, 7.46 mmol) in 1, 4-dioxane (50 mL) were added tert-butyl carbamate (1.30 g, 11.19 mmol) and Cs2CO3 (6.06 g, 18.66 mmol), and the reaction mixture was purged under nitrogen for 10 min. To this resulting solution, Pd2(dba)3 (0.68 g, 0.75 mmol) and Xanthphos (0.86 g, 1.49 mmol) were subsequently added at room temperature under a nitrogen atmosphere. The reaction mixture was heated at 110 °C for 16 h in a sealed tube. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of Celite and washed with EtOAc (50 mL). The filtrate was diluted with water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. The solution was concentrated under reduced pressure to give the crude product which was purified by CombiFlash chromatography (eluting with 30-50% EtOAc in heptane) to afford ethyl 4-((tert- butoxycarbonyl)amino)-1H-indole-2-carboxylate (83-2) (1 g, 44.24%) as an off-white solid. TLC: 50% EtOAc/Heptane (Rf: 0.5). MS calcd. for Chemical Formula C16H20N2O4: 304.14; Found: 303.0 [M - 1]. [0268] Step 2. Synthesis of ethyl 4-amino-1H-indole-2-carboxylate.TFA salt (83-3). To a stirred solution of ethyl 4-((tert-butoxycarbonyl)amino)-1H-indole-2-carboxylate (83-2) (1 g, 3.29 mmol) in DCM (15 mL) at 0 °C, trifluoroacetic acid (5 mL) was added dropwise and the resulting reaction mixture was slowly warmed to room temperature. The reaction was stirred at room temperature under a nitrogen atmosphere for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness. The crude compound was triturated with diethyl ether, and the obtained solid was filtered off and dried in vacuo to afford ethyl 4-amino-1H-indole-2-carboxylate-TFA salt (83-3) (0.3 g, crude) as a brown colored solid. TLC: 50% EtOAc/heptane (Rf: 0.2). The crude product was used in the next step without further purification as a TFA salt. MS calcd. for Chemical Formula C11H12N2O2: 204.09; Found: 204.9 [M + 1]. [0269] Step 3. Synthesis of ethyl 2-(perfluoroethyl)-4-(trifluoromethyl)-7H-pyrrolo[2,3- h]quinoline-8-carboxylate (83-4a) and ethyl 4-(perfluoroethyl)-2-(trifluoromethyl)-7H- pyrrolo[2,3-h]quinoline-8-carboxylate (83-4b). To a stirred solution of ethyl 4-amino-1H- indole-2-carboxylate.TFA salt (83-3) (0.25 g, 0.78 mmol) in TFA (2.5 mL) was added 1,1,1,5,5,6,6,6-octafluorohexane-2,4-dione (0.8 g, 3.11 mmol) and the reaction mixture was heated at 140 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude residue was purified by trituration with diethyl ether. The mixture was filtered and the solid was dried in vacuo to afford the title compound mixture of ethyl 2-(perfluoroethyl)-4-(trifluoromethyl)-7H-pyrrolo[2,3-h]quinoline-8- carboxylate (83-4a) and ethyl 4-(perfluoroethyl)-2-(trifluoromethyl)-7H-pyrrolo[2,3-h]quinoline- 8-carboxylate (83-4b) (0.3 g, crude) as a brown solid. TLC: 50% EtOAc/heptane (Rf: 0.5). MS calcd. for Chemical Formula C17H10F8N2O2: 426.06; Found: 427.20 [M + 1]. [0270] Step 4. Synthesis of ethyl 7-methyl-2-(perfluoroethyl)-4-(trifluoromethyl)-7H- pyrrolo[2,3-h]quinoline-8-carboxylate (83-5a) and ethyl 7-methyl-4-(perfluoroethyl)-2- (trifluoromethyl)-7H-pyrrolo[2,3-h]quinoline-8-carboxylate (83-5b). To a stirred solution of compound mixture of ethyl 2-(perfluoroethyl)-4-(trifluoromethyl)-7H-pyrrolo[2,3-h]quinoline-8- carboxylate (83-4a) and ethyl 4-(perfluoroethyl)-2-(trifluoromethyl)-7H-pyrrolo[2,3-h]quinoline- 8-carboxylate (83-4b) (0.2 g, 0.47 mmol) in dry THF (15 mL) at 0 °C under a nitrogen atmosphere, CS2CO3 (0.3 g, 0.94 mmol) was added in small portions and the resulting reaction mixture was stirred at the same temperature for 5-10 min. To this reaction mixture, methyl iodide (35 µL, 0.56 mmol) was added at 0 °C and then the reaction mixture was slowly warmed to room temperature. The reaction was then stirred at room temperature under a nitrogen atmosphere for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluting with 20-30% EtOAc in heptane) to afford the mixture of ethyl 7-methyl-2-(perfluoroethyl)-4-(trifluoromethyl)-7H- pyrrolo[2,3-h]quinoline-8-carboxylate (83-5a) and ethyl 7-methyl-4-(perfluoroethyl)-2- (trifluoromethyl)-7H-pyrrolo[2,3-h]quinoline-8-carboxylate (83-5b) (0.15 g, 75%) as a brown colored solid. TLC: 40% EtOAc/hepatne (Rf: 0.5). MS calcd. for Chemical Formula C18H12F8N2O2: 440.08; Found: 441.1[M + 1]. [0271] Step 5. Synthesis of 7-methyl-2-(perfluoroethyl)-4-(trifluoromethyl)-7H- pyrrolo[2,3-h]quinoline-8-carbohydrazide (83-6a) and 7-methyl-4-(perfluoroethyl)-2- (trifluoromethyl)-7H-pyrrolo[2,3-h]quinoline-8-carbohydrazide (83-6b). To a stirred solution of compound mixture of ethyl 7-methyl-2-(perfluoroethyl)-4-(trifluoromethyl)-7H- pyrrolo[2,3-h]quinoline-8-carboxylate (83-5a) and ethyl 7-methyl-4-(perfluoroethyl)-2- (trifluoromethyl)-7H-pyrrolo[2,3-h]quinoline-8-carboxylate (83-5b) (0.15 g, 0.34 mmol) in ethanol (5 mL) was added hydrazine hydrate (70 mg, 1.36 mmol) and the reaction mixture was stirred at 90 °C for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness. The crude residue obtained was purified by trituration with diethyl ether. The obtained mixture was filtered and the solid was dried in vacuo to afford the mixture of 7-methyl-2-(perfluoroethyl)-4-(trifluoromethyl)-7H-pyrrolo[2,3-h]quinoline-8- carbohydrazide (83-6a) and 7-methyl-4-(perfluoroethyl)-2-(trifluoromethyl)-7H-pyrrolo[2,3- h]quinoline-8-carbohydrazide (83-6b) (0.2 g, crude) as a yellow solid. TLC: 40% EtOAc/heptane (Rf: 0.2). [0272] Step 6. Synthesis of 2-(7-methyl-2-(perfluoroethyl)-4-(trifluoromethyl)-7H- pyrrolo[2,3-h]quinolin-8-yl)-1,3,4-oxadiazole (Example 83) and 2-(7-methyl-4- (perfluoroethyl)-2-(trifluoromethyl)-7H-pyrrolo[2,3-h]quinolin-8-yl)-1,3,4-oxadiazole (Example 84). To a stirred solution of compound mixture of 7-methyl-2-(perfluoroethyl)-4- (trifluoromethyl)-7H-pyrrolo[2,3-h]quinoline-8-carbohydrazide (83-6a) and 7-methyl-4- (perfluoroethyl)-2-(trifluoromethyl)-7H-pyrrolo[2,3-h]quinoline-8-carbohydrazide (83-6b) (0.2 g, 0.47 mmol) in triethyl orthoformate (5 mL) was added p-TsOH (16.15 mg, 0.093 mmol) and the reaction mixture was then stirred at 100 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude product was purified by CombiFlash chromatography (eluting with 30-50% EtOAc in heptane) followed by preparative HPLC to afford Example 83 (9 mg, 4.5 %) as an off-white solid, and Example 84 (20 mg, 10 %) as an off-white solid. [0273] Example 83. MS calcd. for C17H8F8N4O: 436.1; Found: 436.8 [M + 1]. 1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.41 (d, J = 9.4 Hz, 1H), 8.27 (s, 1H), 8.06 (d, J = 9.5 Hz, 1H), 7.89 (s, 1H), 4.39 (s, 3H). [0274] Example 84. MS calcd. for C17H8F8N4O: 436.1; Found: 436.8 [M + 1]. 1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.38 (d, J = 9.5 Hz, 1H), 8.22 (s, 1H), 8.11 (d, J = 9.0 Hz, 1H), 7.94 (s, 1H), 4.38 (s, 3H). [0275] Example 85.2-(4-(perfluoroethyl)-2-(trifluoromethyl)pyrazolo[1,5-h][1,7]naphthyridin- 9-yl)-1,3,4-oxadiazole [0276] Example 86.2-(2-(perfluoroethyl)-4-(trifluoromethyl)pyrazolo[1,5-h][1,7]naphthyridin- 9-yl)-1,3,4-oxadiazole
Figure imgf000100_0001
[0277] Step 1. Synthesis of methyl (Z)-2-azido-3-(3-bromopyridin-2-yl) acrylate (85-2). To a stirred solution of 3-bromopicolinaldehyde (85-1) (5 g, 27.03 mmol) in methanol (70 mL) at - 15 °C, was added sodium methoxide solution (30% w/w in methanol, 11.26 mL, 67.57 mmol) followed by methyl 2-azidoacetate (8.78 g, 67.57 mmol). The resulting reaction mixture was allowed to stir at the same temperature for 1 h. Then the reaction mixture was slowly warmed to 0 °C and stirred further for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water (15 mL) and the resulting precipitated solid was filtered and dried in vacuo. The crude residue was purified by CombiFlash chromatography (using a gradient method of 40-60% EtOAc in heptane) to afford methyl (Z)-2-azido-3-(3- bromopyridin-2-yl) acrylate (85-2) (1.2 g, 15%) as an off-white solid. TLC: 50% EtOAc/heptane (Rf: 0.5). [0278] Step 2. Synthesis of methyl 4-bromopyrazolo[1,5-a] pyridine-2-carboxylate (85-3). A solution of methyl (Z)-2-azido-3-(3-bromopyridin-2-yl) acrylate (85-2) (1.2 g, 4.24 mmol) in Xylene (10 mL) was heated at 110 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness. The crude residue obtained was purified by CombiFlash chromatography (using a gradient method of 40-60% EtOAc in heptane) to afford methyl 4-bromopyrazolo[1,5-a] pyridine-2-carboxylate (85-3) (1.0 g, 93%) as an off- white solid. TLC: 50% EtOAc/heptane (Rf: 0.5). MS calcd. for Chemical Formula C9H7BrN2O2: 253.97; Found: 257.08 [M + 2].1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 0.8, 7.0 Hz, 1H), 7.68 (dd, J = 0.6, 7.4 Hz, 1H), 7.10 - 7.02 (m, 2H), 3.90 (s, 3H) [0279] Step 3. Synthesis of methyl 4-((tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyridine- 2-carboxylate (85-4). To a stirred solution of methyl 4-bromopyrazolo[1,5-a] pyridine-2- carboxylate (85-3) (1.0 g, 3.94 mmol) in 1, 4-dioxane (50 mL) were added tert-Butyl carbamate (0.69 g, 5.91 mmol) and CS2CO3 (3.19 g, 9.84 mmol) and the reaction mixture was purged under nitrogen for 10 min. To this resulting solution, Pd2(dba)3 (0.36 g, 0.39 mmol) and Xanthphos (0.45 g, 0.79 mmol) were subsequently added at room temperature under a nitrogen atmosphere. The reaction mixture was heated at 110 °C for 3 h in a sealed tube. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of Celite and washed with EtOAc (50 mL). The filtrate was diluted with water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the crude product was purified by CombiFlash chromatography (eluting with 30-50% EtOAc in heptane) to afford methyl 4-((tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyridine-2-carboxylate (85-4) (0.9 g, 81%) as an off-white solid. TLC: 50% EtOAc/Heptane (Rf: 0.5). MS calcd. for Chemical Formula C14H17N3O4: 291.12; Found: 292.1 [M + 1]. 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.43 (d, J = 6.8 Hz, 1H), 7.67 (d, J = 7.3 Hz, 1H), 7.64 - 7.60 (m, 1H), 7.01 (t, J = 7.1 Hz, 1H), 3.88 (s, 3H), 1.52 (s, 9H). [0280] Step 4. Synthesis of methyl 4-aminopyrazolo[1,5-a]pyridine-2-carboxylate-TFA salt (85-5). To a stirred solution of methyl 4-((tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyridine-2- carboxylate (85-4) (0.9 g, 3.09 mmol) in DCM (10 mL) at 0 °C under a nitrogen atmosphere, trifluoroacetic Acid (5 mL) was added dropwise and the resulting reaction mixture was slowly warmed to room temperature. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness. The crude compound obtained was purified by trituration with diethyl ether. The mixture was filtered and the solid was dried in vacuo to afford methyl 4-aminopyrazolo[1,5-a]pyridine-2-carboxylate-TFA salt (85-5) (0.35 g, crude) as an off- white solid. TLC: 50% EtOAc/heptane (Rf: 0.2). The resulting crude obtained was used in the next step without further purification as a TFA salt. MS calcd. for Chemical Formula C9H9N3O2: 191.07; Found: 191.8 [M + 1]. [0281] Step 5. Synthesis of methyl 4-(perfluoroethyl)-2-(trifluoromethyl)pyrazolo[1,5- h][1,7]naphthyridine-9-carboxylate (85-6a) and methyl 2-(perfluoroethyl)-4- (trifluoromethyl)pyrazolo[1,5-h][1,7]naphthyridine-9-carboxylate (85-6b). To a stirred solution of methyl 4-aminopyrazolo[1,5-a]pyridine-2-carboxylate-TFA salt (85-5) (0.8 g, 4.19 mmol) in TFA (10 mL) was added 1,1,1,5,5,6,6,6-octafluorohexane-2,4-dione (2.16 g, 8.38 mmol), and the reaction mixture was heated at 120 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water, brine, and dried over anhydrous Na2SO4. The solution was filtered, and the solvent was removed under reduced pressure. The crude product was purified by CombiFlash chromatography (eluting with 50-60% EtOAc in heptane) to afford the mixture of regio-isomers of methyl 4-(perfluoroethyl)- 2-(trifluoromethyl)pyrazolo[1,5-h][1,7]naphthyridine-9-carboxylate (85-6a) and methyl 2- (perfluoroethyl)-4-(trifluoromethyl)pyrazolo[1,5-h][1,7]naphthyridine-9-carboxylate (85-6b) (0.2 g, 19%) as an off-white solid. TLC: 50% EtOAc/Heptane (Rf: 0.5). MS calcd. for Chemical Formula C15H7F8N3O2: 413.04; Found: 414.1 [M + 1]. [0282] Step 6. Synthesis of 4-(perfluoroethyl)-2-(trifluoromethyl)pyrazolo[1,5- h][1,7]naphthyridine-9-carbohydrazide (85-7a) and 2-(perfluoroethyl)-4- (trifluoromethyl)pyrazolo[1,5-h][1,7]naphthyridine-9-carbohydrazide (85-7b). To a stirred solution of mixture methyl 4-(perfluoroethyl)-2-(trifluoromethyl)pyrazolo[1,5- h][1,7]naphthyridine-9-carboxylate (85-6a) and methyl 2-(perfluoroethyl)-4- (trifluoromethyl)pyrazolo[1,5-h][1,7]naphthyridine-9-carboxylate (85-6b) (0.2 g, 0.48 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.1 mL, 1.94 mmol) and the reaction mixture was heated at 100 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness. The crude compound obtained was purified by trituration with diethyl ether. The mixture was filtered and the solid was dried in vacuo to afford the mixture of regio-isomers of 4-(perfluoroethyl)-2-(trifluoromethyl)pyrazolo[1,5- h][1,7]naphthyridine-9-carbohydrazide (85-7a) and 2-(perfluoroethyl)-4- (trifluoromethyl)pyrazolo[1,5-h][1,7]naphthyridine-9-carbohydrazide (85-7b) (0.3 g, crude) as a yellow colored solid. TLC: 50% EtOAc/heptane (Rf: 0.3). The resulting crude obtained was used in the next step without further purification. [0283] Step 7. Synthesis of 2-(4-(perfluoroethyl)-2-(trifluoromethyl)pyrazolo[1,5- h][1,7]naphthyridin-9-yl)-1,3,4-oxadiazole (Example 85) and 2-(2-(perfluoroethyl)-4- (trifluoromethyl)pyrazolo[1,5-h][1,7]naphthyridin-9-yl)-1,3,4-oxadiazole (Example 86). To a stirred solution of mixture of 4-(perfluoroethyl)-2-(trifluoromethyl)pyrazolo[1,5- h][1,7]naphthyridine-9-carbohydrazide (85-7a) and 2-(perfluoroethyl)-4- (trifluoromethyl)pyrazolo[1,5-h][1,7]naphthyridine-9-carbohydrazide (85-7b) (0.2 g, 0.48 mmol) in triethyl orthoformate (10 mL) was added p-TsOH (9 mg, 0.048 mmol) and the reaction mixture was then stirred at 110 °C for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound obtained was purified by preparative HPLC to afford the title compound Example 85 (62 mg, 31%) as an off-white solid, and Example 86 (5 mg, 2.5%) as an off-white solid. [0284] Example 85. MS calcd. for C15H5F8N5O: 423.0; Found: 424.1 [M + 1]+.1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 9.04 (d, J = 8.0 Hz, 1H), 8.47 (s, 1H), 8.00 (d, J = 0.8 Hz, 1H), 7.56 (s, 1H). [0285] Example 86. MS calcd. for C15H5F8N5O: 423.0; Found: 424.2 [M + 1]+.1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 9.07 (d, J = 7.8 Hz, 1H), 8.49 (s, 1H), 7.93 (s, 1H), 7.54 (s, 1H). [0286] Example 87.2-(4-(perfluoroethyl)-2-(trifluoromethyl)pyrrolo[1,2-h][1,7]naphthyridin- 9-yl)-1,3,4-oxadiazole
Figure imgf000104_0001
[0287] Step 1. Synthesis of ethyl 2-[(3-bromopyridin-2-yl)(hydroxy)methyl]prop-2-enoate (87-2). A solution of 3-bromopyridine-2-carbaldehyde (87-1) (3.00 g, 16.13 mmol) and ethyl acrylate (3.23 g, 32.26 mmol), DABCO (0.18 g, 1.61 mmol) in water (10 mL) and dioxane (30 mL) was stirred at room temperature for 3 h under a nitrogen atmosphere. After completion of the reaction (monitored by LCMS), the resulting mixture was diluted with H2O (30 mL) and extracted with EA (3 x 40 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to offer ethyl 2-[(3- bromopyridin-2-yl)(hydroxy)methyl]prop-2-enoate (87-2) (3.00 g, 65.01%) as a yellow oil. MS calcd. for C11H12BrNO3: 285.0; Found: 286.1[M + 1]+. [0288] Step 2. Synthesis of ethyl 2-[(acetyloxy)(3-bromopyridin-2-yl)methyl]prop-2-enoate (87-3). A solution of ethyl 2-[(3-bromopyridin-2-yl)(hydroxy)methyl]prop-2-enoate (87-2) (3.00 g, 10.49 mmol) in acetic anhydride (3 mL) was stirred for 1h at 100 °C under a nitrogen atmosphere. After completion of the reaction (monitored by LCMS), the mixture was allowed to cool down to rt. The reaction was quenched with H2O (10 ml) at rt, and the aqueous layer was extracted with EA (3 x 10 ml). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to offer ethyl 2- [(acetyloxy)(3-bromopyridin-2-yl)methyl]prop-2-enoate (87-3) (2.50 g, 72.66%) as a brown oil. MS calcd. for C13H14BrNO4: 327.0; Found: 328.1[M + 1]+. [0289] Step 3. Synthesis of ethyl 8-bromoindolizine-2-carboxylate (87-4). A solution of ethyl 2-[(acetyloxy)(3-bromopyridin-2-yl)methyl]prop-2-enoate (87-3) (2.50 g, 7.62 mmol) was stirred for 2 h at 160 °C under a nitrogen atmosphere. After completion of the reaction (monitored by LCMS), the mixture was allowed to cool down to rt. The reaction was quenched with H2O (20 ml) at rt. The aqueous layer was extracted with EA (3 x 20 ml). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to offer ethyl 8-bromoindolizine-2-carboxylate (87-4) (2.00 g, 97.92%) as a yellow oil. MS calcd. for C11H10BrNO2: 267.0; Found: 268.1[M + 1]+. [0290] Step 4. Synthesis of ethyl 8-[(diphenylmethylidene)amino]indolizine-2-carboxylate (87-5). A solution of ethyl 8-bromoindolizine-2-carboxylate (87-4) (2.00 g, 7.46 mmol) and benzenemethanimine, α-phenyl- (4.06 g, 22.38 mmol), caesio methaneperoxoate caesium (7.31 g, 22.38 mmol), XantPhos (0.22 g, 0.37 mmol), Xantphos Pd G4 (0.72 g, 0.75 mmol) in dioxane (20 mL) was stirred for 4 h at 100 °C under a nitrogen atmosphere. After completion of the reaction (monitored by LCMS), the mixture was allowed to cool down to rt. The resulting mixture was diluted with H2O (30 mL) and extracted with EA (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography, eluted with EA:PE (1:2) to afford ethyl 8-[(diphenylmethylidene)amino]indolizine-2-carboxylate (87-5) (2.00 g, 72.77%) as a yellow oil. MS calcd. for C11H10BrNO2:368.0; Found: 369.1[M + 1]+. [0291] Step 5. Synthesis of ethyl 8-aminoindolizine-2-carboxylate (87-6). A solution of ethyl 8-[(diphenylmethylidene)amino]indolizine-2-carboxylate (87-5) (2.00 g, 5.43 mmol), HCl (6M) (0.99 g, 27.14 mmol) in THF (20 mL) was stirred at room temperate for 6 h under a nitrogen atmosphere. After completion of the reaction (monitored by LCMS), the resulting mixture was diluted with H2O (30 mL). The mixture was neutralized to pH 8-9 with NaHCO3(aq) and extracted with EA (3 x 40 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to offer ethyl 8- aminoindolizine-2-carboxylate (87-6) (700.00 mg, 63.14%) as a brown solid. MS calcd. for C11H12N2O2:204; Found: 205.1[M + 1]+. [0292] Step 6. Synthesis of ethyl 2-(perfluoroethyl)-4-(trifluoromethyl)pyrrolo[1,2- h][1,7]naphthyridine-9-carboxylate (87-7). A mixture of ethyl 8-aminoindolizine-2- carboxylate (87-6) (70.00 mg, 0.34 mmol) and 1,1,1,5,5,6,6,6-octafluorohexane-2,4-dione (442.27 mg, 1.71 mmol) in AcOH (2 mL) was stirred for 1 h at room temperature followed by stirred for 1 h at 80 °C. After completion of the reaction (monitored by LCMS), the resulting solution was cooled to room temperature. The residue was basified to pH = 8 with saturated NaHCO3 (aq.) and extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford ethyl 2-(perfluoroethyl)-4-(trifluoromethyl)pyrrolo[1,2- h][1,7]naphthyridine-9-carboxylate (87-7) (22.00 mg, 15.57%) as a light yellow solid. MS calcd. for C17H10F8N2O2:426.1; Found: 427.1
Figure imgf000106_0001
NMR (300 MHz, Chloroform-d) δ 8.00 – 7.85 (m, 4H), 7.09 (dd, J = 7.8, 1.8 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H). [0293] Step 7. Synthesis of 4-(perfluoroethyl)-2-(trifluoromethyl)pyrrolo[1,2- h][1,7]naphthyridine-9-carbohydrazide (87-8). A mixture of ethyl 2-(perfluoroethyl)-4- (trifluoromethyl)pyrrolo[1,2-h][1,7]naphthyridine-9-carboxylate (87-7) (65.00 mg, 0.15 mmol) and hydrazine (97.73 mg, 3.04 mmol) in ethyl alcohol (1.5 mL) was stirred for 4 h at 70 °C. After completion of the reaction (monitored by LCMS), the resulting solution was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product of 4-(perfluoroethyl)-2-(trifluoromethyl)pyrrolo[1,2-h][1,7]naphthyridine-9- carbohydrazide (87-8) was used in the next step directly without further purification. MS calcd. for C15H8F8N4O:412.1; Found: 413.0 [M + 1]+. [0294] Step 8. Synthesis of 2-(4-(perfluoroethyl)-2-(trifluoromethyl)pyrrolo[1,2- h][1,7]naphthyridin-9-yl)-1,3,4-oxadiazole (Example 87). A mixture of 4-(perfluoroethyl)-2- (trifluoromethyl)pyrrolo[1,2-h][1,7]naphthyridine-9-carbohydrazide (87-8) (65.00 mg, 0.16 mmol) and para-toluene sulfonate (13.58 mg, 0.08 mmol) in trimethyl orthoformate (1.5 mL) was stirred for 4 h at 70 °C. After completion of the reaction (monitored by LCMS), the resulting solution was cooled to room temperature, and the crude product was purified by Pre- HPLC Column, XBridge Shield RP18 OBD Column, 19*150 mm, 5µm; mobile phase, Water (0.5% NH3·H2O) and ACN (5% ACN up to 95% in 3 min) to afford Example 87 (4.80 mg, 7.21%) as a yellow solid. MS calcd. for C16H6F8N4O: 422.0; Found: 423.1 [M + 1]+.1H NMR (300 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.67 – 8.60 (m, 2H), 8.21 (s, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.28 – 7.21 (m, 1H). [0295] Table 2 shows structures and analytical data for representative Examples of the present invention. These compounds can be prepared according to the synthetic schemes described above and using procedures known to those of ordinary skill in the art. [0296] Table 2: Analytical data of representative compounds.
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
VI Biological Data IFNα pathway induction [0297] HEK293 cells expressing the firefly luciferase gene under the control of ISRE stably integrated into HEK293 cells were obtained from BPS Bioscience. ISRE reporter was used to measure IFNα pathway induction. Upon IFNα stimulation, pospho-STAT1 and phosphor-STAT2 form a complex with IRF9, named as ISGF3, which translocates to the nucleus and activates the transcription of interferon inducible genes (ISGs) through binding to ISRE in the promoter region of ISGs. [0298] The cells were culture in MEM medium (Corning) supplemented with 10% FBS, 1% non-essential amino acids, 1 mM sodium pyruvate, 1% Penicillin/Streptomycin plus 400 µg/ml of Geneticin. Sub-confluent culture is passaged and split twice a week, not exceeding 30 passages. Cells are detached using 0.05% Trypsin/0.53mM EDTA solution (Corning). [0299] For testing the compound effect on IFNα pathway, HEK293 ISRE reporter cells were seeded in 96-well plate at density of 50,000 cells/well 24 hours before treatment in a black clear bottom plate (Corning). Next day, the cells were treated with compounds in a three-fold serial dilution. The final DMSO concentration in each well is normalized to 0.5%. After 24-hour incubation, the activity of ISRE induction was measured using One-Glo luciferase substrate (Promega) on a Tecan Infinite M1000 Pro plate reader. The fold of induction was calculated by the activity of compound treated cells relative to DMSO treated cells. Cell-based HCV replicon assay [0300] HCV 1b replicon (NanoLuc luciferase) cell line was generated in Huh7-Lunet cells. HCV replicon cells were cultured in DMEM medium (Cytiva) supplemented with 10% FBS, 1% Penicillin/Streptomycin plus 250 µg/ml of Geneticin. Sub-confluent culture of HCV replicon is passaged and split twice a week, not exceeding 40 passages. Cells are detached using 0.25% Trypsin/2.21 mM EDTA solution (Corning). [0301] For testing the antiviral activity of compounds, HCV 1b replicon cells were seeded in DMEM medium supplemented with 5% FBS and 1% % Penicillin/Streptomycin at a density of 5,000 cells/well in a black clear bottom half-well 96-well plate (Corning), following by the addition of compounds in a three-fold serial dilution. The final DMSO concentration in each well is normalized to 1%. After 48-hour incubation, the luciferase activity was measured using Nano- Glo luciferase substrate (Promega) on a Tecan Infinite M1000 Pro plate reader. The antiviral activity of compound was calculated from the percentage of luciferase signals relative to DMSO treated cells. [0302] Table 3 provides assay data for exemplified compounds of the invention. The antiviral activity of the exemplified compounds at 20 uM is grouped in the following ranges: A indicates < 25%; B indicates 25% to 50%; C indicates > 50%. The ISRE induction of the exemplified compounds at 20 uM is grouped in the following ranges: A indicates greater than 2 folds; B indicates = 0.5-2 fold(s). [0303] Table 3. Assay data for exemplified compounds of the invention.
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
INCORPORATION BY REFERENCE [0304] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS [0305] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations. [0306] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

Claims

CLAIMS: 1. A compound of Formula I
Figure imgf000130_0001
Formula I , or a pharmaceutically acceptable salt thereof, wherein: Ra and Rb are independently selected for each occurrence from the group consisting of hydrogen and C1-4alkyl; R1 is acetyl, C1-5alkyl, haloC1-5alkyl, hydroxyC1-5alkyl, hydroxyhaloC1-5alkyl, C1- 3alkoxyC1-5alkyl, haloC1-3alkoxyC1-5alkyl, C2-5alkenyl, haloC1-5alkenyl, hydroxyC1-5alkenyl, C1- 3alkoxyC2-5alkenyl, haloC1-3alkoxyC2-5alkenyl, monoC3-7cycloalkyl, monoC4-7cycloalkenyl, mono3-7heterocycloalkyl, mono4-7heterocycloalkenyl, phenyl or pyridyl, wherein the monoC3- 7cycloalkyl, monoC4-7cycloalkenyl, mono3-7heterocycloalkyl, mono4-7heterocycloalkenyl, phenyl or pyridyl is optionally substituted with 1-3 substituents independently selected from the group consisting of NRaRb, CN, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-3alkoxyC1-5alkyl, and tert-butyloxycarbonyl; R2 is halo, OH, acetyl, C1-5alkyl, haloC1-5alkyl, C2-5alkenyl, haloC2-5alkenyl, hydroxyC1- 4alkyl, C1-3alkoxyC1-5alkyl, monoC3-7cycloalkyl-alkylene-, monoC3-7cycloalkyl-alkenylene-, monoC3-7cycloalkyl, monoC4-7cycloalkenyl, mono3-7heterocycloalkyl, mono4- 7heterocycloalkenyl, phenyl, pyridyl, or pyrazolyl, wherein the monoC3-7cycloalkyl, monoC4- 7cycloalkenyl, mono3-7heterocycloalkyl, mono4-7heterocycloalkenyl, phenyl, pyridyl, or pyrazolyl is optionally substituted with 1-3 substituents independently selected from the group consisting of NRaRb, CN, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-3alkoxyC1-5alkyl and monoC3-7cycloalkyl; R3 is hydrogen or halo; and R4 is hydrogen, halo or cyano; with the proviso that: R1 is haloC1-5alkyl having 4 or more halo atoms, C2-5alkenyl, haloC2-5alkenyl, hydroxyC2-5alkenyl, C1-3alkoxyC2-5alkenyl, C1-3alkoxyhaloC2-5alkenyl, monoC4-7cycloalkenyl, or mono4-7heterocycloalkenyl, wherein the monoC4-7cycloalkenyl or mono4-7heterocycloalkenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of NRaRb, CN, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-3alkoxyC1-5alkyl , and tert- butyloxycarbonyl; or R2 is haloC1-5alkyl having 4 or more halo atoms, C2-5alkenyl, haloC2-5alkenyl, monoC4- 7cycloalkenyl, or mono4-7heterocycloalkenyl, wherein the monoC4-7cycloalkenyl or mono4- 7heterocycloalkenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of NRaRb, CN, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-3alkoxyC1- 5alkyl and monoC3-7cycloalkyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R1 is haloC1-5alkyl having 4 or more halo atoms, C2-5alkenyl, haloC2-5alkenyl, hydroxyC2-5alkenyl, C1-3alkoxyC2-5alkenyl, C1-3alkoxyhaloC2-5alkenyl, monoC4-7cycloalkenyl, or mono4- 7heterocycloalkenyl, wherein the monoC4-7cycloalkenyl or mono4-7heterocycloalkenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of NRaRb, CN, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-3alkoxyC1-5alkyl , and tert- butyloxycarbonyl.
3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein: R1 is R1 is haloC2-5alkyl having 4 or more halo atoms.
4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein: R1 is CF3CF2 or CF3CF2CF2.
5. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein: R1 is C2-5alkenyl, haloC2-5alkenyl, hydroxyC2-5alkenyl, C1-3alkoxyC2-5alkenyl or haloC1-3alkoxyC2- 5alkenyl.
6. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein: R1 is monoC4-7cycloalkenyl or mono4-7heterocycloalkenyl, wherein the monoC4-7cycloalkenyl or mono4-7heterocycloalkenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of NRaRb, CN, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1- 3alkoxyC1-5alkyl, and tert-butyloxycarbonyl.
7. The compound according to any one of claims 2-6, or a pharmaceutically acceptable salt thereof, wherein R2 is C1-5alkyl.
8. The compound according to any one of claims 2-6, or a pharmaceutically acceptable salt thereof, wherein R2 is haloC1-5alkyl.
9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R2 is CF3.
10. The compound according to any one of claims 2-6, or a pharmaceutically acceptable salt thereof, wherein R2 is monoC3-7cycloalkyl.
11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is haloC1-5alkyl having 4 or more halo atoms, C2-5alkenyl, haloC2-5alkenyl, monoC4- 7cycloalkenyl, or mono4-7heterocycloalkenyl, wherein the monoC4-7cycloalkenyl or mono4- 7heterocycloalkenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of NRaRb, CN, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-3alkoxyC1- 5alkyl and monoC3-7cycloalkyl.
12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein: R2 is haloC1-5alkyl having 4 or more halo atoms, C2-5alkenyl or haloC2-5alkenyl.
13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein: R2 is haloC2-5alkyl having 4 or more halo atoms.
14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein: R2 is CF3CF2 or CF3CF2CF2.
15. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein: R2 is C2-5alkenyl or haloC2-5alkenyl.
16. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein: R2 is monoC4-7cycloalkenyl or mono4-7heterocycloalkenyl, wherein the monoC4-7cycloalkenyl or mono4-7heterocycloalkenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of NRaRb, CN, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1- 3alkoxyC1-5alkyl and monoC3-7cycloalkyl.
17. The compound according to any one of claims 11-16, or a pharmaceutically acceptable salt thereof, wherein: R1 is C1-5alkyl.
18. The compound according to any one of claims 11-16, or a pharmaceutically acceptable salt thereof, wherein: R1 is haloC1-5alkyl.
19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein: R1 is CF3.
20. The compound according to any one of claims 11-16, or a pharmaceutically acceptable salt thereof, wherein: R1 is monoC3-7cycloalkyl optionally substituted with 1-3 substituents independently selected from the group consisting of NRaRb, CN, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-3alkoxyC1-5alkyl, and tert-butyloxycarbonyl.
21. The compound according to any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen.
22. The compound according to any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein R3 is halo.
23. The compound according to any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen.
24. The compound according to any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R4 is halo or cyano.
25. A pharmaceutical composition comprising: a compound according to any one of claims 1-24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
26. A method of treating a viral infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-24, or a pharmaceutically acceptable salt thereof.
27. The method of claim 26, wherein the viral infection is an HBV infection.
28. The method of claim 26, wherein the viral infection is an HDV infection.
29. The method of claim 26, wherein the viral infection is an HSV infection.
30. A method of treating a viral infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition of claim 25.
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