WO2022169882A1 - Procédés et traitement d'une infection virale provoquée par le sars-cov-2 - Google Patents

Procédés et traitement d'une infection virale provoquée par le sars-cov-2 Download PDF

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WO2022169882A1
WO2022169882A1 PCT/US2022/014954 US2022014954W WO2022169882A1 WO 2022169882 A1 WO2022169882 A1 WO 2022169882A1 US 2022014954 W US2022014954 W US 2022014954W WO 2022169882 A1 WO2022169882 A1 WO 2022169882A1
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4alkyl
optionally substituted
phenyl
independently
monocyclic
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PCT/US2022/014954
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English (en)
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Jane RHODES
Michelle MIGHDOLL
Irene CHOI
Brian KOPEC
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Verge Analytics, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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

Definitions

  • SARS-CoV-2 which is responsible for the COVID-19 (2019 novel coronavirus (2019-nCoV) disease, global pandemic is an enveloped, positive-sense, RNA virus that belongs to the Betacoronavirus genus. Bouhaddou et al, Cell 182: 1-28 (2020). Improved understanding of key steps in viral entry and ways to disrupt them can lead to the development of effective antiviral drugs, not only for COVID-19, but for future viral outbreaks as well. Treatments for COVID-19 are greatly needed.
  • Embodiment 1 is a method of blocking SARS-CoV-2 entry into a host cell and preventing an infection caused by SARS-CoV-2, comprising administering to a subject in need thereof a compound of:
  • R b is -L-R c ; wherein L is a bond, -C(O)-, -C(O)O-, or -Ci-4alkylene-;
  • R g and R h are each independently H or Ci-4alkyl
  • R 2 and R 3 taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl, optionally substituted with one, two, or three R j substituents; wherein each R j substituent is independently Ci-4alkyl, -OH, -NR’T , halo, halo-Ci-4alkyl, -O-Ci-4alkyl, or -O-Ci-4-haloalkyl; where R k and R 1 are each independently H or Ci-4alkyl; and
  • R 52 is H or -C2-3-alkylene-NR m2 R n2 ; wherein R m2 and R 112 are each independently H or methyl, or R m2 and R 112 taken together with the nitrogen to which they are attached form pyrrolidine, piperidine, piperazine, or morpholine, each optionally substituted with methyl; wherein
  • R d3 is (a) methyl, ethyl, isopropyl, -CF3, -OCH3, or -OCF3, or (b) phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, thiophenyl, or pyridyl, wherein the phenyl, benzyl, each optionally substituted with one or two substituents independently selected from methyl, fluoro, chloro, -CF3, -OCH3, and -OCF3; or a pharmaceutically acceptable salt thereof.
  • Embodiment 3 is the method of embodiment 1 or 2, wherein R 1 is -NR a R b .
  • Embodiment 5 is the method of any one of embodiments 1-3, wherein R a is Ci-4alkyl.
  • Embodiment 6 is the method of any one of the preceding embodiments, wherein L is a bond.
  • Embodiment 8 is the method of any one of embodiments 1-5, wherein L is -Ci-4alkylene-.
  • Embodiment 9 is the method of any one of embodiments 1-5, wherein L is methylene or ethylene.
  • Embodiment 11 is the method of any one of embodiments 1-9, wherein R c is optionally substituted monocyclic cycloalkyl.
  • Embodiment 12 is the method of any one of embodiments 1-9, wherein R c is optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • Embodiment 16 is the method of any one of embodiments 1-9, wherein R c is optionally substituted monocyclic heteroaryl.
  • Embodiment 20 is the method of any one of the preceding embodiments, wherein each R c is optionally substituted with one or two R d substituents.
  • Embodiment 21 is the method of any one of the preceding embodiments, wherein each R d substituent is independently Ci-4alkyl, Ci-4alkenyl, Ci-4alkynyl, -O-Ci-4alkyl, halo, cyano,
  • Embodiment 24 is the method of any one of embodiments 1-22, wherein each R d substituent is independently methyl, ethyl isopropyl, -CF3, phenyl, pyridyl, thiophenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclobutylmethyl, or cyclopentylmethyl, wherein each phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclobutylmethyl, or cyclopentylmethyl is optionally substituted with one or two substituents R e , wherein each R e is independently methyl, -CF3, fluoro, chloro, -OCH3, or -OCF3.
  • Embodiment 30 is the method of any one of the preceding embodiments, wherein R 2 and R 3 taken together with the nitrogen to which they are attached form pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, or thiomorpholine-l,l-dioxide, each optionally substituted with one, two, or three R 1 substituents.
  • Embodiment 32 is the method of any one of the preceding embodiments, wherein each R 1 substituent is independently methyl, hydroxy, -OCH3, halo, -CF3, or -OCF3.
  • Embodiment 33 is the method of any one of the preceding embodiments, wherein R k and R 1 are each independently H or methyl.
  • Embodiment 34 is the method of any one of the preceding embodiments, wherein R 4 and R 5 are each H.
  • Embodiment 35 is the method of any one of embodiments 1-33, wherein one of R 4 and R 5 is H and the other is Ci-4alkyl, halo, -OH, or -OCi-4alkyl, wherein each alkyl is optionally substituted with -NR m R n .
  • Embodiment 36 is the method of any one of embodiments 1-33, wherein one of R 4 and R 5 is H and the other is -OH, halo, or -OCH3.
  • Embodiment 37 is the method of any one of embodiments 1-33, wherein one of R 4 and R 5 is H and the other is C2-3alkyl substituted with -NR m R n .
  • Embodiment 38 is the method of any one of the preceding embodiments, wherein R m and R n are each independently H or Ci-4alkyl.
  • Embodiment 39 is the method of any one of the preceding embodiments, wherein R m and R n are each methyl.
  • Embodiment 40 is the method of any one of embodiments 1-37, wherein R m and R n taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl, optionally substituted with one or two R° substituents.
  • Embodiment 41 is the method of any one of embodiments 1-37, wherein R m and R n taken together with the nitrogen to which they are attached form pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, or thiomorpholine-l,l-dioxide, each optionally substituted with one or two R° substituents.
  • Embodiment 42 is the method of any one of embodiments 1-37, wherein R m and R n taken together with the nitrogen to which they are attached form pyrrolidine, piperidine, piperazine, or morpholine, each optionally substituted with one or two R° substituents.
  • Embodiment 44 is the method of any one of the preceding embodiments, wherein R p and R q are each independently H or methyl.
  • Embodiment 45 is the method of any one of the preceding embodiments, wherein R b2 is pyrazole, optionally substituted with methyl, -CF3, fluoro, chloro, -OCH3, -OCF3, or phenyl.
  • Embodiment 46 is the method of any one of the preceding embodiments where the compound is chosen from any of the compounds in Table 1, and pharmaceutically acceptable salts thereof.
  • Embodiment 47 is the method of any of the preceding embodiments, wherein the compound and/or the pharmaceutically acceptable salt is in a pharmaceutical composition.
  • Embodiment 48 is the method of embodiment 47, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
  • Figure 1 shows antiviral effect and cell toxicity data for Compound 9 in Vero-E6 cells. Concentration-dependent antiviral effect (i.e., antiviral activity) is shown as percent inhibition on the left axis (data represented by circles with a solid line). Concentration-dependent cell toxicity is shown as toxicity on the right axis (data represented by squares with a dotted line).
  • Figure 2 shows antiviral effect of Compound 9 in A549-ACE2 cells. Viral titer is shown as Logio of plaque forming units per mL (PFU/mL) on the left axis (data represented by circles). Percent cell viability is shown on the right axis (data represented by squares).
  • the present disclosure provides methods and compositions for blocking SARS-CoV-2 entry into a host cell; and ii) preventing an infection caused by SARS-CoV-2.
  • the term “about” refers to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system.
  • “about” or “approximately” can mean within one or more than one standard deviation per the practice in the art.
  • “about” or “approximately” can mean a range of up to 10% (i.e., ⁇ 10%) or more depending on the limitations of the measurement system.
  • about 5 mg can include any number between 4.5 mg and 5.5 mg.
  • subject and patient refers to human and non-human animals, including vertebrates, mammals and non-mammals.
  • the subject can be human, non-human primates, simian, ape, murine (e.g., mice and rats), bovine, porcine, equine, canine, feline, caprine, lupine, ranine or piscine.
  • administering refers to the physical introduction of an agent to a subject, using any of the various methods and delivery systems known to those skilled in the art.
  • exemplary routes of administration for the formulations disclosed herein include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion.
  • non-parenteral routes include a topical, epidermal or mucosal route of administration, for example, intranasally, vaginally, rectally, sublingually or topically.
  • Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
  • treatment refers to ameliorating or slowing the progression of a disease or disorder, such as a coronavirus infection, in a human or animal subject.
  • a disease or disorder such as a coronavirus infection
  • the terms “treatment” and “treating” also refers to attenuating symptoms associated with a viral infection (e.g., respiratory syndrome, kidney failure, fever, and other symptoms relating to virus infections).
  • ⁇ ективное amount refers to an amount of a described PIKfyve inhibitor that when administered to a subject, is sufficient to affect a measurable improvement or prevention of a disease or disorder associated with a virus infection.
  • a “pharmaceutically acceptable vehicle” for therapeutic purposes is a physical embodiment that can be administered to a subject.
  • Pharmaceutically acceptable vehicles include pills, capsules, caplets, tablets, oral fluids, injection fluids, sprays, aerosols, troches, dietary supplements, creams, lotions, oils, solutions, pastes, powders, steam, or it may be a liquid, but is not limited to these.
  • An example of a pharmaceutically acceptable vehicle is a buffered isotonic solution such as phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • Alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.
  • Alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1 -methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
  • Alkyl sulfonyl means a -SO2R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethyl sulfonyl, and the like.
  • Amino means a -NH2.
  • Alkoxy means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or Zc/V-butoxy, and the like.
  • Alkoxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with an alkoxy group, (in one embodiment one or two alkoxy groups), as defined above, e.g., 2- methoxy ethyl, 1-, 2-, or 3 -methoxypropyl, 2-ethoxy ethyl, and the like.
  • “Acyl” means a -COR radical where R is alkyl, haloalkyl, or cycloalkyl, e.g., acetyl, propionyl, cyclopropylcarbonyl, and the like. When R is alkyl, the radical is also referred to herein as alkylcarbonyl.
  • “Cycloalkyl” means a cyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms wherein one or two carbon atoms may be replaced by an oxo group, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the like.
  • Carboxy means -COOH.
  • coronavirus refers to a virus belonging to the family Coronaviridae.
  • Coronaviruses are enveloped, positive-sense RNA viruses of approximately 31 Kb, making these viruses the largest known RNA viruses.
  • Coronaviruses infect a variety of host species, including humans and several other vertebrates. These viruses predominantly cause respiratory and intestinal tract infections and induce a wide range of clinical manifestations.
  • coronaviruses can be classified into low pathogenic CoVs (including human CoVs (hCoVs)) and highly pathogenic CoVs, such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV).
  • SARS-CoV severe acute respiratory syndrome CoV
  • MERS-CoV Middle East respiratory syndrome CoV
  • hCoV low pathogenic hCoV infect upper airways and cause seasonal mild to moderate cold-like respiratory illnesses in healthy individuals.
  • highly pathogenic hCoVs pathogenic hCoV infect the lower respiratory tract and cause severe pneumonia, which sometimes leads to fatal acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), resulting in high morbidity and mortality.
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • Halo means fluoro, chloro, bromo, or iodo.
  • Haloalkyl means alkyl radical as defined above, which is substituted with one or one to five halogen atoms (in one embodiment fluorine or chlorine,) including those substituted with different halogens, e.g., -CH2CI, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, and the like.
  • halogen atoms in one embodiment fluorine or chlorine,
  • fluoroalkyl alkyl radical as defined above, which is substituted with one or one to five halogen atoms (in one embodiment fluorine or chlorine,) including those substituted with different halogens, e.g., -CH2CI, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, and the like.
  • fluoroalkyl When the alkyl is substituted with only fluoro, it can be referred to in this disclosure as fluoroalkyl.
  • Haloalkoxy means a -OR radical where R is haloalkyl as defined above e.g., -OCF3, -OCHF2, and the like.
  • R is haloalkyl where the alkyl is substituted with only fluoro, it can be referred to in this disclosure as fluoroalkoxy.
  • Hydroalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom.
  • Representative examples include, but are not limited to, hydroxymethyl, 2- hydroxy ethyl, 2-hydroxypropyl, 3 -hydroxypropyl, l-(hydroxymethyl)-2-m ethylpropyl, 2- hydroxybutyl, 3 -hydroxybutyl, 4-hydroxybutyl, 2,3 -dihydroxypropyl, l-(hydroxymethyl)-2- hydroxy ethyl, 2,3 -dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl.
  • Heterocyclyl means a saturated or unsaturated monovalent monocyclic or bi-cyclic group (fused bi-cyclic or bridged bi-cyclic or spiro compounds) of 4 to 10 ring atoms in which one or two ring atoms are heteroatom selected from N, O, and S(O)n, where n is an integer from 0 to 2, the remaining ring atoms being C.
  • heterocyclyl includes, but is not limited to, oxetanyl, pyrrolidino, piperidino, homopiperidino, 2- oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, hexahydropyrrolo[l,2-a]pyrazin-6(2H)-one-yl, tetrahydro-lH-oxazolo[3,4-a]pyrazin-3(5H)-one- yl, 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine-yl, 3-oxa-8-azabicyclo[3.2.1]octane-yl, 6- oxa-l-
  • Heterocyclylalkyl or “heterocycloalkyl” means a -(alkylene)-R radical where R is heterocyclyl ring as defined above e.g., tetraydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like.
  • Heterocycloaminoalkyl means a -(alkylene)-R radical where R is heterocycloamino as described above.
  • Heteroaryl means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms where one or more, (in one embodiment one, two, or three), ring atoms are heteroatom selected from N, O, and S, the remaining ring atoms being carbon.
  • Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.
  • heterocyclyl group optionally substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heterocyclyl group is substituted with an alkyl group and situations where the heterocyclyl group is not substituted with alkyl.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • phrases “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • salt or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, /?-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington ’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference.
  • the disclosure relates to a method for treating or preventing COVID-19 or a SARS-CoV-2 infection comprising administering to the subject a compound of Formula (I) or any of the embodiments thereof described herein.
  • the disclosure relates to a method for preventing SARS- CoV-2 entry into a host cell comprising administering to the subject a compound of Formula (I) or any of the embodiments thereof described herein.
  • a method of inhibiting SARS-CoV-2 viral membrane fusion with an early endosomal membrane in a host cell comprising administering a compound of Formula (I) or any of the embodiments thereof (e.g., compounds of Table 1) described herein.
  • a method of inhibiting SARS-CoV-2 viral membrane fusion with a maturing endosomal membrane comprising administering a compound of Formula (I) or any of the embodiments thereof (e.g., compounds of Table 1) described herein.
  • a method of inhibiting SARS-CoV-2 viral membrane fusion with a late endosomal membrane comprising administering a compound of Formula (I) or any of the embodiments thereof (e.g., compounds of Table 1) described herein.
  • a method of inhibiting SARS-CoV-2 viral membrane fusion with an endo- lysosomal membrane comprising administering a compound of Formula (I) or any of the embodiments thereof (e.g., compounds of Table 1) described herein.
  • a method of inhibiting SARS-CoV-2 viral membrane fusion with a lysosomal membrane comprising administering a compound of Formula (I) or any of the embodiments thereof (e.g., compounds of Table 1) described herein.
  • a method of inhibiting SARS-CoV-2 viral membrane fusion with an early macropinosomal membrane comprising administering a compound of Formula (I) or any of the embodiments thereof (e.g., compounds of Table 1) described herein.
  • a method of inhibiting SARS-CoV-2 viral membrane fusion with a macropinosomal membrane comprising administering a compound of Formula (I) or any of the embodiments thereof (e.g., compounds of Table 1) described herein.
  • a method of inhibiting SARS- CoV-2 viral membrane fusion with a late macropinosomal membrane comprising administering a compound of Formula (I) or any of the embodiments thereof (e.g., compounds of Table 1) described herein.
  • R 1 is -NR a R b . In some embodiments, R 1 is H. In some embodiments, R 1 is Ci-4alkyl. In some embodiments, R 1 is methyl. [0134] In some embodiments, R a is H. In some embodiments, R a is Ci-4alkyl. In some embodiments, R a is methyl.
  • R b2 is pyrazole, optionally substituted with methyl, -CF3, fluoro, chloro, -OCH3, -OCF3, or phenyl.
  • Example 2 N-Benzyl-4-morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-amine.
  • Step B 4-Morpholinobenzofuro[3,2-d]pyrimidin-2-amine.
  • a solution of N-(2, 4- dimethoxybenzyl)-4-morpholinobenzofuro[3,2-d]pyrimidin-2-amine (183 mg, 0.43 mmol) in TFA (5 mL) was heated to 60 °C for 1 h.
  • a saturated aq. NaHCOs solution was added to adjust the pH to 9.
  • the aqueous solution was extracted with MeOH/DCM (1/15, 3 x 10 mL).
  • Step A 2-Chloro-4-morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidine 6-oxide.
  • 2-chloro-4-morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidine 5 g, 3.45 mmol
  • urea hydrogen peroxide 8 g, 17.24 mmol
  • TFA 6.5 mL, 17.24 mmol
  • the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated, and the aqueous phase was extracted with DCM (5 x 50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
  • Step E 5-((7-(2-(Dimethylamino)ethoxy)-4-morpholinopyrido[3',2':4,5]furo[3,2- d]pyrimidin-2-yl)amino)-N,N-dimethyl-3-phenyl-lH-pyrazole-l-sulfonamide.
  • Step F To a solution of 5-((7-(2-(dimethylamino)ethoxy)-4- morpholinopyrido[3',2':4,5]furo[3,2-d] pyrimidin-2-yl)amino)-N,N-dimethyl-3-phenyl-lH- pyrazole-1 -sulfonamide (39 mg, 0.06 mmol) in DCM (2 mL) was added a solution of HCl/Et2O (1 mL). The reaction was stirred at rt for 2 h.
  • Example 5 4-Morpholino-2-((3-phenyl-lH-pyrazol-5- yl)amino)pyrido[3',2':4,5]furo[3,2-d]pyrimidin-7-ol hydrochloride.
  • Step A 7-(Benzyloxy)-2-chloro-4-morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidine.
  • THF 2,7-dichloro-4-morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidine (150 mg, 0.46 mmol) in THF (30 mL) at 0 °C was added NaH (92 mg, 2.3 mmol). The mixture was stirred at 0 °C for 20 min.
  • To the reaction mixture was added a solution of phenylmethanol (60 mg, 0.56 mmol) in THF.
  • Step B 5-((7-(benzyloxy)-4-morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidin-2- yl)amino)-N,N-dimethyl-3-phenyl-lH-pyrazole-l-sulfonamide.
  • Step C 5-((7-Hydroxy-4-morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidin-2- yl)amino)-N,N-dimethyl-3-phenyl-lH-pyrazole-l-sulfonamide.
  • Example 6 4-Morpholino-N-(3-(pyridin-2-yl)-lH-pyrazol-5- yl)pyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-amine hydrochloride.
  • Step A 3-(Pyridin-2-yl)-lH-pyrazol-5-amine. To a solution of 3-oxo-3-(pyridin-2- yl)propanenitrile (1 g, 6.84 mmol) and hydrazine (513 mg, 10.24 mmol, 99%) in EtOH (35 mL) was added two drops of AcOH. The reaction was heated to 80 °C for 5 h.
  • Step B 5-Amino-N,N-dimethyl-3-(pyridin-2-yl)-lH-pyrazole-l-sulfonamide.
  • 3-(pyridin-2-yl)-lH-pyrazol-5-amine 630 mg, 3.94 mmol
  • NaH 315 mg, 7.88 mmol
  • dimethyl sulfamoyl chloride 676 mg, 4.72 mmol
  • the reaction mixture was quenched with saturated aq. NH4Q.
  • the aqueous solution was extracted with ethyl acetate (3 x 50 mL).
  • Step C N,N-Dimethyl-5-((4-morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidin-2- yl)amino)-3-(pyridin-2-yl)-lH-pyrazole-l-sulfonamide.
  • Step D To a solution of N,N-dimethyl-5-((4-morpholinopyrido[3',2':4,5]furo[3,2- d]pyrimidin-2-yl) amino)-3-(pyridin-2-yl)-lH-pyrazole-l-sulfonamide (70 mg, 0.13 mmol) in DCM (2 mL) was added a solution of HCl/Et2O (2 mL). The reaction was stirred at rt for 2 h. The reaction mixture was concentrated directly and the resulting residue was slurried in MeOH/Et2O (1/20, 5 mL) to provide the title compound (40.7 mg, 0.1 mmol) as a white solid.
  • Example 7 N-(3-(4-Methylpyridin-2-yl)-lH-pyrazol-5-yl)-4- morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-amine hydrochloride.
  • Step A 3-(4-Methylpyridin-2-yl)-3-oxopropanenitrile.
  • methyl 4- methylpicolinate 900 mg, 5.95 mmol
  • anhydrous acetonitrile 367 mg, 8.93 mmol
  • NaHMDS 4.5 mL, 8.9 mmol
  • the reaction mixture was warmed to rt and stirred at rt for 0.5 h.
  • the reaction mixture was quenched with saturated aq. NH4Q and extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated, and concentrated.
  • Step B The title compound was prepared as described in Example 6, using 3-(4- methylpyridin-2-yl)-3-oxopropanenitrile in Step A.
  • Example 8 N-(3-Methyl-lH-pyrazol-5-yl)-4-morpholinopyrido[3',2':4,5]furo[3,2- d]pyrimidin-2-amine.
  • Trifluoracetic acid 25.8 mL, 337 mmol was added to a mixture of 2-chloro-4- morpholinopyrido[3',2':4,5]furo[3,2-J]pyrimidine (WO2011/021038; 4.9 g, 16.9 mmol), 3- amino-5-methylpyrazole (2.80 g, 28.7 mmol), and zPrOH (25 mL) at 23 °C.
  • Example 9 4-Morpholino-N-(3-phenyl-lH-pyrazol-5-yl)pyrido[3',2':4,5]furo[3,2- d]pyrimidin-2-amine.
  • Example 10 4-Morpholino-N-(3-(pyridin-4-yl)-lH-pyrazol-5- yl)pyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-amine.
  • Example 11 A-(l,5-Dimethyl-l//-pyrazol-3-yl)-A-methyl-4- morpholinopyrido[3',2':4,5]furo[3,2-J]pyrimidin-2-amine.
  • the titled compound was prepared using N, l,5-trimethyl-l//-pyrazol-3-amine in a manner analogous to Example 8.
  • the crude product was chromatographed using silica gel (DCM:MeOH 100:0 to 96:4) to provide the purified compound.
  • Example 12 N-(l-Methyl-lH-imidazol-2-yl)-4-morpholinopyrido[3',2':4,5]furo[3,2- d]pyrimidin-2-amine.
  • Example 13 8-(2-(Dimethylamino)ethyl)-4-morpholino-N-(3-phenyl-lH-pyrazol-5- yl)pyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-amine.
  • Step A (£)-2-Chloro-8-(2-ethoxyvinyl)-4-morpholinopyrido[3',2':4,5]furo[3,2- ]pyrimidine.
  • a mixture of 8-bromo-2-chloro-4-morpholinopyrido[3',2':4,5]furo[3,2- Jpyrimidine (CAS # 1268241-78-6 (see WO2017/029514, WO2017/029521, WO2017/029519, WO2015/121657); 500 mg, 1.35 mmol), tetrakis(triphenylphosphine)palladium (156 mg, 0.135 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (402 mg, 0.43 mmol), Na2CCh (315 mg, 3.0 mmol), DME (8 mL), and H2O (2 mL) was heated
  • Step B A mixture of (E)-2-chloro-8-(2-ethoxyvinyl)-4- morpholinopyrido[3',2':4,5]furo[3,2-J]pyrimidine (290 mg, 0.80 mmol), THF (10 mL), and 4 M HC1 (2.75 mL) was heated to reflux for 1.5 h. The reaction mixture was allowed to cool to rt and was poured into saturated aqueous NaHCOs (20 mL). The mixture was extracted with EtOAc (3x) and the organic phases were combined, washed with brine, then dried (Na2SO4) and concentrated.
  • This material (270 mg) was taken up in DCM (5 mL) and a 2 M THF solution of dimethylamine (0.53 mL, 1.06 mmol) was added. The solution was maintained at rt for 20 min, then sodium triacetoxyborohydride (224 mg, 1.06 mmol) was added and the mixture was stirred for 90 min at rt. The mixture was poured into saturated NaHCOs and extracted with DCM (2x). The combined organic phases were dried (Na2SO4) and concentrated.
  • Example 14 4-Morpholino-N-(3-phenyl-lH-pyrazol-5-yl)-8-(2-(pyrrolidin-l- yl)ethyl)pyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-amine.
  • Example 52 4-Morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidine.
  • PIKFYVE Full length human recombinant PIKFYVE expressed in baculovirus expression system as N-terminal GST-fusion protein (265 kDa) was obtained from Cama Biosciences (Kobe, Japan).
  • the kinase substrate was prepared by mixing and sonicating fluorescently-labeled phosphatidylinositol 3-phosphate (PI3P) with phospho-L-serine (PS) at a 1 : 10 ratio in 50 mM HEPES buffer pH7.5.
  • kinase reactions were assembled in 384-well plates (Greiner) in a total volume of 20 mL as follows.
  • Kinase protein was pre-diluted in an assay buffer comprising 25 mM HEPES, pH 7.5, 1 mM DTT, 2.5 mM MgCl 2 , and 2.5 mM MnCh, and 0.005% Triton X-100, and dispensed into a 384-well plate (10 pL per well).
  • Test compounds were serially pre-diluted in DMSO and added to the protein samples by acoustic dispensing (Labcyte Echo). The concentration of DMSO was equalized to 1% in all samples. All test compounds were tested at 12 concentrations.
  • Apilimod was used as a reference compound and was tested in identical manner in each assay plate.
  • Control samples (0%-inhibition, in the absence of inhibitor, DMSO only) and 100%-inhibition (in the absence of enzyme) were assembled in replicates of four and were used to calculate %-inhibition in the presence of compounds.
  • the reactions were initiated by addition of 10 pL of 2x PI3P/PS substrate supplemented with ATP.
  • the final concentration of enzyme was 2 nM
  • the final concentration of ATP was 10 mM
  • the final concentration of PI3P/PS substrate was 1 pM (PI3P).
  • the kinase reactions were allowed to proceed for 3 h at room temperature.
  • Terminated plates were analyzed on a microfluidic electrophoresis instrument (Caliper LabChip® 3000,
  • Pinh (PSRo%inh - P SRcompound)/(P SRo%inh - PSR100%inh)* 100 in which PSRcompound is the product/sum ratio in the presence of compound, PSRo%inh is the product/sum ratio in the absence of compound, and the PSRioo%inh is the product/sum ratio in the absence of the enzyme.
  • IC50 of test compounds 50%-inhibition
  • %-inh cdata Pin versus compound concentration
  • IDBS XLfit software
  • CPE cytopathic effect
  • VeroE6-EGFP cells (provided by Lab of Virology & Chemotherapy, Rega Institute, KU Leuven, Leuven, Belgium) (sometimes referred to herein as VeroE6, Vero-E6, or Vero-E6- GFP) were propagated in growth medium which was prepared by supplementing DMEM (Gibco 41965-039) with 10% v/v heat-inactivated FCS and 5 mL sodium bicarbonate 7.5% (Gibco 25080-060). Cells were cultured in T150 bottles and split 1/4 twice a week. Pen-strep was added directly to the T150 bottle at a 1/100 dilution.
  • Assay medium was prepared by supplementing DMEM (Gibco 41965-039) with 2% v/v heat-inactivated FCS and 5 mL sodium bicarbonate 7.5% (Gibco 25080-060).
  • Antiviral activity is expressed as the EC50 or concentration required to rescue 50% of the GFP signal from the virus-induced cytopathogenicy.
  • the signal is provided as the logarithm of the surface of the well that is covered with fluorescent pixels which correlates with living cells.
  • cytotoxicity was assessed by growing uninfected cells in the presence of the test compound at the concentrations tested. After a 4 day incubation, cell viability was measured using a commercial kit.
  • Antiviral readout was performed using high-content imagers. Using a 5x objective, almost the entire well of a 384-well plate is captured at once (for an 96-well plate, the well is covered by 4 field of views). A GFP marker located in both the cell cytoplasm as well as the nucleus allowed for the calculation of the surface of the well that is (still) covered by cells (SpotTotalAreaCh2). The data are exported to .csv files and dose-response curves are processed in Dotmatics. [0222] Results and Discussion
  • PIKfyve inhibitors were assessed for anti-viral activity against SARS-COV-2 using A549-ACE2 cells (adenocarcinomic human alveolar basal epithelial cells) transduced to express the human Angiotensin-converting enzyme 2 (ACE2), provided by Institut Pasteur, Paris, France.
  • A549-ACE2 cells were grown in 96-well plates, and ten concentrations of each tested PIKfyve inhibitor was tested in triplicate. Concentrations of compounds tested included: 0.001 - luM (0, 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10).
  • the DMSO concentration in the final assay was ⁇ 1% (dilution of stock made in serial dilutions of media).
  • cytotoxicity was assessed by growing uninfected cells in the presence of the three tested compounds at the concentrations tested. After 48 hours of incubation, cell viability was measured using a commercial kit.
  • the tested compound, Compound 9 was provided in a 10 mM solution in 100 uL DMSO.

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Abstract

La présente divulgation concerne des composés qui sont utiles pour empêcher le SARS-CoV-2 d'entrer dans une cellule hôte et pour prévenir des maladies et des troubles provoqués par le SARS-CoV-2, comprenant la COVID-19.
PCT/US2022/014954 2021-02-03 2022-02-02 Procédés et traitement d'une infection virale provoquée par le sars-cov-2 WO2022169882A1 (fr)

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