WO2022010948A1 - Novel cell metabolism modulating compounds and uses thereof for the treatment of viral diseases - Google Patents

Novel cell metabolism modulating compounds and uses thereof for the treatment of viral diseases Download PDF

Info

Publication number
WO2022010948A1
WO2022010948A1 PCT/US2021/040584 US2021040584W WO2022010948A1 WO 2022010948 A1 WO2022010948 A1 WO 2022010948A1 US 2021040584 W US2021040584 W US 2021040584W WO 2022010948 A1 WO2022010948 A1 WO 2022010948A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
methyl
acetic acid
alkyl
quinolin
Prior art date
Application number
PCT/US2021/040584
Other languages
English (en)
French (fr)
Inventor
Emre Koyuncu
Hahn Kim
Gokhan Hotamisligil
Original Assignee
Crescenta Biosciences
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Crescenta Biosciences filed Critical Crescenta Biosciences
Priority to JP2023500381A priority Critical patent/JP2023532998A/ja
Priority to CN202180054153.2A priority patent/CN116615189A/zh
Priority to EP21838930.2A priority patent/EP4281054A1/de
Publication of WO2022010948A1 publication Critical patent/WO2022010948A1/en

Links

Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the field of the embodiments of the present invention relate to antiviral therapies for treatment or prophylaxis of diseases caused by coronavirus infections.
  • Compounds in this invention particularly interact with fatty acid binding protein 4 (FABP4) and inhibit the growth of coronaviruses in cells.
  • FABP4 fatty acid binding protein 4
  • FABPs are a family of proteins that reversibly bind free fatty acids and other lipid molecules and facilitate their transport in cells. To date, nine different FABP isoforms have been identified in mammals. FABP isoforms display differential expression patterns in different tissues. Fatty acid binding protein 4 (FABP4), also often referred to as aP2 in literature, is primarily expressed in adipocytes and macrophages, and mediates key metabolic and inflammatory pathways in these cells such as lipid storage and degradation, signaling and eicosanoid production. In addition, FABP4 is also secreted to plasma and has been proposed to act as an adipose-derived factor regulating systemic glucose homeostasis.
  • Fatty acid binding protein 4 FABP4
  • aP2 Fatty acid binding protein 4
  • FABP4 is also secreted to plasma and has been proposed to act as an adipose-derived factor regulating systemic glucose homeostasis.
  • the present invention relates to the pharmaceutical industry and medicines and presents a new therapy for the treatment and prevention of acute viral infections, particularly acute respiratory viral infections and more particularly to therapy for coronavirus and severe acute respiratory syndrome (SARS) diseases, comprising the administration of a therapeutically effective dose of a compound described herein to a subject in need thereof.
  • acute viral infections particularly acute respiratory viral infections and more particularly to therapy for coronavirus and severe acute respiratory syndrome (SARS) diseases
  • SARS severe acute respiratory syndrome
  • Acute respiratory viral infections are a group of infectious diseases of viral etiology and characterized by damage to the respiratory tract and exhibiting common clinical symptoms.
  • the successes achieved by medicine in the field of infectious pathology have contributed to the development and improvement of methods for the prevention and treatment of diseases, but acute respiratory viral infections continue to be a serious public health problem due to extremely high rates of incidence and the occurrence of epidemics and pandemics.
  • Acute respiratory viral infections are polyetiological. Currently, more than 200 relevant pathogens are known with rhinoviruses, coronaviruses, and influenza viruses frequently seen causing a high outbreak in the autumn and winter. Other viruses causing acute respiratory viral infections at relatively higher rates include respiratory syncytial viruses (RSVs), parainfluenza, adenoviruses, Human metapneumovirus (HMPV), Human Bocavirus (HBoV) along with unidentified viruses responsible for the remainder of acute infections of the respiratory tract of viral and unspecified etiology.
  • RSVs respiratory syncytial viruses
  • HMPV Human metapneumovirus
  • HBPV Human Bocavirus
  • SARS a form of acute respiratory viral infection
  • SARS a form of acute respiratory viral infection
  • the high incidence of SARS is associated with significant economic losses due to indirect costs associated with disability and compounded by societal and economic damage from governmentally imposed lockdowns instituted to prevent viral spread.
  • Most seasonal morbidity is affected by children, the elderly, people with concomitant diseases (various immunodeficiencies, diseases of the lungs, cardiovascular system, liver, kidneys, diabetes, etc.).
  • Acute respiratory diseases of coronavirus etiology can be severe and cause extensive damage to lung tissue as well as other organs.
  • Common human coronaviruses cause varying levels of acute respiratory infections.
  • Viruses HCoV-OC43, and HCoV-HKUl, HCoV-229E, and HCoV-NL63 cause common colds and self-limiting upper respiratory infections in immunocompetent individuals. In immunocompromised subjects and the elderly, lower respiratory tract infections can occur.
  • Other coronaviruses can cause more severe form of acute respiratory disease and include SARS-CoV, SARS-CoV-2, and MERS-CoV. These coronaviruses can cause epidemics and pandemics with variable clinical severity featuring respiratory and extra-respiratory manifestations.
  • the invention and embodiments thereof disclosed herein describes a novel class of antiviral agents that interact with fatty acid binding protein 4 (FABP4) and inhibit viral replication in human cells.
  • FABP4 is a key mediator of fatty acid metabolism and inflammation, two pathways that have been implicated in the life cycle of many viral pathogens.
  • FABP4 has been particularly associated with the development of a number of metabolic conditions such as diabetes, cardiovascular disease, and airway inflammation that are known to confer susceptibility to coronavirus, influenza virus and certain other virus infections.
  • the compounds described in this invention present a universally applicable treatment for disease caused by known viruses and variants that emerge in future. Summary of the Embodiments
  • the invention is a method for treating a viral disease in a subject comprising administering to said subject a therapeutically effective dose of one or more of the compounds described in Formula (I):
  • each of R 1 and R 6 -R 9 are independently -H, -CN, -COOH, -CONH 2 , B(OR a ) 2 , an acid isostere, a halo, C n alkyl, C n alkenyl, C n alkynyl, C n aryl, C n aminoalkyl, C n haloalkyl, C n heteroaryl, C n cycloalkyl, or C n heterocycloalkyl, wherein R a of the B(OR a ) 2 is H or an alkyl, wherein B of the B(OR a ) 2 is boron, wherein n of the C n is 1 — 10, wherein each of R 2 - R 5 are independently -H, -CN, -COOH, -COOMe, -CONH2, B(OR a ) 2 , the acid isostere, a halo, C n alkyl,
  • the invention comprises the compound of Formula I where at least one of R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , R 4 and R 5 , R 6 and R 7 , R 7 and R 8 , R 8 and R 9 are bonded forming a fused heteroaryl or fused heterocycloalkyl.
  • the invention is a method for treating a viral disease in a subject comprising administering to said subject a therapeutically effective dose of one or more of the compounds described in Formula II: or pharmaceutically acceptable salts or esters thereof wherein: wherein R 1 and R 6 -R 9 is independently -H, -CN, -COOH, -CONH 2 , B(OR a ) 2 , an acid isostere, a halo, C n alkyl, C n alkenyl, C n alkynyl, C n aryl, C n aminoalkyl, C n haloalkyl, C n heteroaryl, C n cycloalkyl, or C n heterocycloalkyl, wherein R a of the B(OR a ) 2 is H or an alkyl, wherein B of the B(OR a ) 2 is boron, wherein n of the C n is 1 — 10, wherein each of R 2
  • the invention includes compounds of Formula II, wherein a heterocycloalkyl group is formed by bonding two of R 7 , R 8 , or R 9 to form:
  • R 1 is selected from the group consisting of: -CN, alkyl, -H, halo, 2 H, amino, alkoxy, aminoalkyl, (amino)alkoxy, alkenyl, alkynyl, alkoxy, hydroxy, alkylhydroxy, aryloxy, alkyl(aryl), (alkoxyalkyl)amino, aryl, aryl(halo), heteroaryl, hydroxyl-alkyl, hydroxyl-aryl, (aryl)alkyl, C(0)OH, -S(0) 2 -alkyl, -S(0) 2 -aryl, -C(0)alkyl, and C(0)NH 2 , wherein each of R 3 and R 4 are independently -H, the halo, C n alkyl, C n alkyl, C n alkenyl, C n alkynyl, C n aryl, C n amino
  • Another embodiment of the invention includes compounds of Formula III wherein X is N.
  • An embodiment the invention includes compounds of Formula III wherein R 6 is hydrogen and X is N.
  • a further embodiment the invention includes compounds of Formula III wherein R 3 is alkyl and R 1 is cyano.
  • FABP4 fatty acid binding protein
  • Yet another object of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compounds herein as active ingredient, in combination with a pharmaceutically acceptable diluent or carrier for use in the treatment of viral disorders by acting on FABP4.
  • the pharmaceutical composition can further comprise an additional therapeutically active agent.
  • Yet another object of the present invention is a method for the treatment of viral disorders by acting on the FABP4, which comprises administering to a subject in need of such treatment (preferably, a human) an effective amount of the compounds herein, including, optionally, the co-administration with other therapeutic agents, either as a single (or multiple) dosing, and either simultaneously or sequentially.
  • Yet another object of the present invention is the use of the compounds herein for the manufacture of a medicament for use in the treatment of viral disorders by acting on the fatty acid binding protein FABP4.
  • disorders include common cold, SARS, and COVID-19.
  • FIG. 1 depicts a graphical chart showing a virus yield obtained from cells treated with corresponding compounds and vehicle control (DMSO), according to at least some embodiments disclosed herein. Description of the Preferred Embodiments
  • acid isostere includes, but is not limited to, the following functional groups, where R is H or alkyl.
  • alkyl refers to a saturated, straight- or branched-chain hydrocarbon group having from 1 to 20 carbon atoms.
  • Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl- 1 -propyl, 2-methyl-2-propyl, 2-methyl- 1 -butyl, 3- methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl- 1 -propyl, 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-l-butyl, 2-ethyl- 1 -butyl, butyl, isobutyl, t-butyl, n-pentyl,
  • alkoxy as used herein includes -O-(alkyl), wherein alkyl is defined above.
  • amino refers to an -NH2 group.
  • aryl means a mono-, bi-, or tricyclic aromatic group, wherein all rings of the group are aromatic and all ring atoms are carbon atoms. For bi- or tricyclic systems, the individual aromatic rings are fused to one another. Examples of aryl groups are 6 and 10 membered aryls. Further examples of aryl groups include, but are not limited to, phenyl, naphthalene, and anthracene.
  • cyano as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond.
  • deuterium as used herein means a stable isotope of hydrogen having one proton and one neutron.
  • halo represents chloro, fluoro, bromo, or iodo. In some embodiments, halo is chloro, fluoro, or bromo.
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • hydroxy means an -OH group.
  • N-oxide refers to the oxidized form of a nitrogen atom.
  • cycloalkyl refers to a saturated or partially saturated, monocyclic, fused polycyclic, bridged polycyclic, or spiro polycyclic carbocycle having from 3 to 15 carbon ring atoms.
  • a non limiting category of cycloalkyl groups are saturated or partially saturated, monocyclic carbocycles having from 3 to 6 carbon atoms.
  • Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties:
  • heterocycloalkyl refers to a monocyclic, or fused, bridged, or spiro polycyclic ring structure that is saturated or partially saturated and has from three to 12 ring atoms selected from carbon atoms and up to three heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the ring structure may optionally contain up to two oxo groups on carbon or sulfur ring members, or an N-oxide.
  • Illustrative heterocycloalkyl entities include, but are not limited to:
  • heteroaryl refers to a monocyclic, or fused polycyclic, aromatic heterocycle having from three to 15 ring atoms that are selected from carbon, oxygen, nitrogen, and sulfur. Suitable heteroaryl groups do not include ring systems that must be charged to be aromatic, such as pyrylium. Suitable 5-membered heteroaryl rings (as a monocyclic heteroaryl or as part of a polycyclic heteroaryl) have one oxygen, sulfur, or nitrogen ring atom, or one nitrogen plus one oxygen or sulfur, or 2, 3, or 4 nitrogen ring atoms.
  • Suitable 6-membered heteroaryl rings (as a monocyclic heteroaryl or as part of a polycyclic heteroaryl) have 1, 2, or 3 nitrogen ring atoms.
  • heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl
  • fused heteroaryl refers to a heteroaryl as defined above, having two constituent aromatic rings, wherein the two rings are fused to one another and at least one of the rings is a heteroaryl as defined above.
  • Fused heteroaryls include fused heteroaryl groups comprising 1, 2, 3, or 4 heteroatom ring atoms selected from O, N or S. In certain embodiments, wherein the heteroatom is N it can be an N-oxide.
  • Fused heteroaryls also include 8-, 9-, or 10- membered fused heteroaryl groups.
  • Fused heteroaryls also include 8-, 9-, or 10-membered fused heteroaryl groups that have 1, 2, 3, or 4 heteroatom ring atoms selected from O, N or S.
  • Illustrative examples of fused heteroaryls include, but are not limited to:
  • heteroaryl, cycloalkyl, and heterocycloalkyl groups listed or illustrated above are not exhaustive, and that additional species within the scope of these defined terms may also be selected.
  • substituted means that the specified group or moiety bears one or more suitable substituents.
  • unsubstituted means that the specified group bears no substituents.
  • optionally substituted means that the specified group is unsubstituted or substituted by the specified number of substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system.
  • any atom that is represented herein with an unsatisfied valence is assumed to have the sufficient number of hydrogen atoms to satisfy the atom’s valence.
  • any variable e.g ., alkyl, R a , R 1 , etc.
  • the definition of that variable on each occurrence is independent of its definition at every other occurrence.
  • Numerical ranges are intended to include sequential whole numbers. For example, a range expressed as “from 0 to 4” or “0-4” includes 0, 1, 2, 3 and 4.
  • the point of attachment to the remainder of the formula can be at any point on the multifunctional moiety.
  • the point of attachment is indicated by a line or hyphen.
  • aryloxy- refers to a moiety in which an oxygen atom is the point of attachment to the core molecule while aryl is attached to the oxygen atom.
  • the term “subject” encompasses mammals and non-mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans; non human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; and laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • non-mammals include, but are not limited to, birds, fish and the like.
  • the mammal is a human.
  • patient includes both human and animals.
  • an “effective amount” or “therapeutically effective amount” refer to a sufficient amount of the agent to provide the desired biological result. That result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease or medical condition, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic use is the amount of a compound, or of a composition comprising the compound, that is required to provide a clinically relevant change in a disease state, symptom, or medical condition.
  • An appropriate “effective” amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • the expression “effective amount” generally refers to the quantity for which the active substance has a therapeutically desired effect.
  • treat encompass both “preventative” and “curative” treatment.
  • Preventative treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom.
  • “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition.
  • treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.
  • the invention is a method for treating a viral disease in a subject comprising administering to said subject a therapeutically effective dose of one or more of the compounds described in Formula (I):
  • each of R 1 and R 6 -R 9 are independently -H, -CN, -COOH, -CONH2, B(OR a )2, an acid isostere, a halo, C n alkyl, C n alkenyl, C n alkynyl, C n aryl, C n aminoalkyl, C n haloalkyl, C n heteroaryl, C n cycloalkyl, or C n heterocycloalkyl, wherein R a of the B(OR a )2 is H or an alkyl, wherein B of the B(OR a )2 is boron, wherein n of the C n is 1 - 10, wherein each of R 2 - R 5 are independently -H, -CN, -COOH, -COOMe, -CONH2, B(OR a ) 2 , the acid isostere, the halo, -CONHOH, -NH
  • each Ri of N(Ri)(Ri) is independently hydrogen, the C n alkyl, the C n alkenyl, the C n alkynyl, the C n aryl, the C n aminoalkyl, the C n haloalkyl, the C n heteroaryl, the C n cycloalkyl, or the C n heterocycloalkyl, wherein each Ri of N(Ri)(Ri) is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents which can be the same or different and are independently selected from the group consisting of: H, 2 H, halo
  • the invention comprises the compound of Formula I where at least one of R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , R 4 and R 5 , R 6 and R 7 , R 7 and R 8 , R 8 and R 9 are bonded forming a fused heteroaryl or fused heterocycloalkyl.
  • the invention may be a compound of Formula II or pharmaceutically acceptable salts or esters thereof:
  • R 1 and R 6 -R 9 is independently -H, -CN, -COOH, -CONH 2 , B(OR a ) 2 , an acid isostere, a halo, C n alkyl, C n alkenyl, C n alkynyl, C n aryl, C n aminoalkyl, C n haloalkyl, C n heteroaryl, C n cycloalkyl, or C n heterocycloalkyl, wherein R a of the B(OR a )2 is H or an alkyl, wherein B of the B(OR a )2 is boron, wherein n of the C n is 1 - 10, wherein each of R 2 - R 5 are independently -H, -CN, -COOH, -COOMe, -COMB, B(OR a )2, the acid isostere, the halo, -CONHOH, -NH-
  • the invention includes compounds of Formula II, wherein a heterocycloalkyl group is formed by bonding two of R 7 , R 8 , or R 9 to form:
  • R 1 is selected from the group consisting of: -CN, alkyl, -H, halo, 2 H, amino, alkoxy, aminoalkyl, (amino)alkoxy, alkenyl, alkynyl, alkoxy, hydroxy, alkylhydroxy, aryloxy, alkyl(aryl), (alkoxyalkyl)amino, aryl, aryl(halo), heteroaryl, hydroxyl-alkyl, hydroxyl-aryl, (aryl)alkyl, C(0)OH, -S(0) 2 -alkyl, -S(0) 2 -aryl, -C(0)alkyl, and C(0)NH 2 , wherein each of R 3 and R 4 are independently -H, the halo, C n alkyl, C n alkyl, C n alkenyl, C n alkynyl, C n
  • Another embodiment of the invention includes compounds of Formula III wherein X is N.
  • An embodiment the invention includes compounds of Formula III wherein R 6 is hydrogen and X is N.
  • a further embodiment the invention includes compounds of Formula III wherein R 3 is alkyl and R 1 is cyano.
  • a method of inhibiting the fatty acid binding protein FABP4 in a mammal which comprises administering to a mammal an effective amount of a compound of Formula (I).
  • the subject is a human.
  • the disorders are selected from common cold, SARS, and COVID-19.
  • composition comprising a compound according to Formula (I) as the active ingredient.
  • composition further comprising at least one additional active ingredient or a pharmaceutically acceptable carrier.
  • a method for the prophylaxis or treatment of disorders acting on the fatty acid binding protein FABP4 which comprises administering to a subject in need of such treatment an effective amount of a compound according to Formula (I).
  • any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms.
  • compounds of any formula given herein may have asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomers, including optical isomers, enantiomers, (+)-isomers, and diastereomers, of the compounds of the general formula, and mixtures thereof, are considered to fall within the scope of the formula.
  • certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. All such isomeric forms, and mixtures thereof, are contemplated herein as part of the present invention.
  • any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more tautomeric or atropisomeric forms, and mixtures thereof.
  • Diastereomeric mixtures may be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers may be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride, or formation of a mixture of diastereomeric salts), separating the diastereomers and converting (e.g., hydrolyzing or de-salting) the individual diastereomers to the corresponding pure enantiomers.
  • Enantiomers may also be separated by use of chiral HPLC column.
  • the chiral centers of compounds of the present invention may be designated as “R” or “S” as defined by the IUPAC 1974 Recommendations.
  • the compounds of the invention can form pharmaceutically acceptable salts, which are also within the scope of this invention.
  • a “pharmaceutically acceptable salt” refers to a salt of a free acid or base of a compound of Formula I, II, or III that is non-toxic, is physiologically tolerable, is compatible with the pharmaceutical composition in which it is formulated, and is otherwise suitable for formulation and/or administration to a subject.
  • Reference to a compound herein is understood to include reference to a pharmaceutically acceptable salt of said compound unless otherwise indicated.
  • Compound salts include acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • a given compound contains both a basic moiety, such as, but not limited to, a pyridine or imidazole, and an acidic moiety, such as, but not limited to, a carboxylic acid
  • a zwitterion inner salt
  • such salts are included within the term “salt” as used herein.
  • Salts of the compounds of the invention may be prepared, for example, by reacting a compound with an amount of a suitable acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate (“mesylate”), ethanesulfonate, benzenesulfonate, / oluenesulfonate, and pamoate (i.e., l,r-methylene-bis(2-hydroxy-3-naphthoate)) salts.
  • sulfate citrate, acetate, oxalate
  • a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counterion.
  • the counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counterions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • alkali metal salts such as sodium, lithium, and potassium salts
  • alkaline earth metal salts such as calcium and magnesium salts
  • salts with organic bases for example, organic amines
  • organic amines such as dicyclohexylamines, t-butyl amines
  • salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quartemized with agents such as lower alkyl halides (e.g, methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g, dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g, decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g, benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g, methyl, ethyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g, dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g, decyl, lauryl, and stearyl chlorides
  • any compound described herein is intended to refer also to any unsolvated form, or a hydrate, solvate, or polymorph of such a compound, and mixtures thereof, even if such forms are not listed explicitly.
  • “Solvate” means a physical association of a compound of the invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution- phase and isolatable solvates. Suitable solvates include those formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. In some embodiments, the solvent is water and the solvates are hydrates.
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Methods for the preparation of solvates are generally known.
  • M. Caira et al ., J. Pharm. Sci ., 93(3), 601-611 (2004) describes the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
  • Similar preparations of solvates, hemisolvate, hydrates, and the like are described by E. C. van Tonder et al ., AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al., Chem. Commun., 603-604 (2001).
  • a typical, non limiting process involves dissolving the inventive compound in a suitable amounts of the solvent (organic solvent or water or a mixture thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example, infrared spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • the invention also relates to pharmaceutically acceptable prodrugs of the compounds of Formula I, II, or III, and treatment methods employing such pharmaceutically acceptable prodrugs.
  • prodrug means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula I).
  • a “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise suitable for formulation and/or administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
  • prodrugs include pharmaceutically acceptable esters of the compounds of the invention, which are also considered to be part of the invention.
  • Pharmaceutically acceptable esters of the present compounds include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, Ci-4alkyl, Ci-4alkoxy, or amino); (2) sulfonate esters, such as alkyl- or aralkyl sulfonyl (for example, methanesulfonyl
  • the phosphate esters may be further esterified by, for example, a Ci-20 alcohol or reactive derivative thereof, or by a 2,3-di(C 6-24 )acyl glycerol. Additional discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-Cs)alkyl, (C2-Ci2)alkanoyloxymethyl, 1- (alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, l-(N-(alkoxycarbonyl)amino)ethyl
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Ci-C 6 )alkanoyloxymethyl, l-((Ci-C 6 )alkanoyloxy)ethyl, 1-methyl- l-((Ci-C 6 )alkanoyloxy)ethyl, (Ci-C 6 )alkoxycarbonyloxymethyl, N-(Ci- C 6 )alkoxycarbonylaminom ethyl, succinoyl, (Ci-C 6 )alkanoyl, a-amino(Ci-C4)alkanyl, arylacyl and a-aminoacyl, or a-aminoacyl- a-aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids,
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R”-carbonyl, R”0-carbonyl, NR”R'-carbonyl where R” and R' are each independently (Ci-C2o)alkyl, (C3-C7) cycloalkyl, benzyl, or R”-carbonyl is a natural a-aminoacyl or natural a-aminoacyl, -C(OH)C(0)OY 1 wherein Y 1 is H, (Ci-C 6 )alkyl or benzyl, -C(OY 2 )Y 3 wherein Y 2 is (C1-C4) alkyl and Y 3 is (Ci-C 6 )alkyl, carboxy(Ci-C 6 )alkyl, amino(Ci-C4)alkyl or mono-N- or di-
  • the present invention also relates to pharmaceutically active metabolites of compounds of Formula I, II, or III, and uses of such metabolites in the methods of the invention.
  • a “pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula I, II, or III, or salt thereof.
  • Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al ., J. Med. Chem. 1997, 40, 2011-2016; Shan et al, J Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res.
  • any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, n C, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, 36 C1, and 125 I, respectively.
  • Such isotopically labelled compounds are useful in metabolic studies (for example with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or U C labeled compound may be particularly suitable for PET or SPECT studies.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
  • the embodiments of the present invention can also include a compound from PCT/US21/14250 filed on January 20, 2021, the entire contents of which are hereby incorporated by reference in their entirety.
  • Such compounds may include: 3- ⁇ [6-butyl-4-(4- fluorophenyl)quinolin-2-yl](methyl)amino ⁇ -2-methylpropanoic acid, 3- ⁇ [4-(4-fluorophenyl)-6- hexylquinolin-2-yl](methyl)amino ⁇ -2-methylpropanoic acid, 2- ⁇ [4-(4-fluorophenyl)-6- pentylquinolin-2-yl](methyl)amino ⁇ acetic acid, 2- ⁇ [4-(4-fluorophenyl)-6-hexylquinolin-2- yl](methyl)amino ⁇ acetic acid, 2- ⁇ [6-hexyl-3-methyl-4-(morpholin-4-yl)quinolin-2- yl]
  • FABP4 fatty acid binding protein
  • Yet another object of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compounds herein as active ingredient, in combination with a pharmaceutically acceptable diluent or carrier for use in the treatment of viral disorders by acting on FABP4.
  • the pharmaceutical composition can further comprise an additional therapeutically active agent.
  • Yet another object of the present invention is a method for the treatment of viral disorders by acting on the FABP4, which comprises administering to a subject in need of such treatment (preferably, a human) an effective amount of the compounds herein, including, optionally, the co-administration with other therapeutic agents, either as a single (or multiple) dosing, and either simultaneously or sequentially.
  • Yet another embodiment is a method for administering a compound of the instant invention to a subject (e.g., a human) in need thereof by administering to the subject the pharmaceutical formulation of the present invention.
  • a subject e.g., a human
  • Yet another embodiment is a method of preparing a pharmaceutical formulation of the present invention by mixing at least one pharmaceutically acceptable compound of the present invention, and, optionally, one or more pharmaceutically acceptable additives or excipients.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
  • Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.
  • compositions and formulations of the invention can be administered as sterile compositions and sterile formulations.
  • Sterile pharmaceutical formulations are compounded or manufactured according to pharmaceutical -grade sterilization standards (e.g., United States Pharmacopeia Chapters 797, 1072, and 1211; California Business & Professions Code 4127.7;
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
  • a pharmaceutically acceptable carrier such as an inert compressed gas, e.g. nitrogen.
  • Bioadhesives have been described for facilitating transport of medicaments across endothelial mucosa.
  • U.S. Patent No. 6,228,383 teaches use of bioadhesive fatty acid esters for facilitating transport of drug substances across mucosa in the lung, nose and other tissues.
  • Penetration enhancers have been described in, for example, U.S. Patent Application 09/315,298, filed on May 20, 1999. Penetration enhancers facilitate the penetration of mucosa, including pulmonary and nasal mucosa.
  • the present invention provides, inter alia, compositions formulated for pulmonary or nasal administration of antiviral compounds, especially compounds capable of attenuating, mitigating or preventing viral infections, and especially coronavirus.
  • viral infections are treated by administering an antiviral compound of the present invention to a patient in need thereof.
  • viral infection is treated by administering an antiviral small molecule to a patient in need thereof.
  • an antiviral agent is administered by pulmonary or intranasal means to a patient in need thereof.
  • the antiviral agent is a compound of the invention.
  • the antiviral agent is a mixture of antiviral compounds.
  • the invention comprises a molecule of the invention in combination therapy, for example with one or more additional antiviral agents.
  • the inventive composition comprises, in addition to one or more antiviral agents, a therapeutically acceptable agent for intrapulmonary or intranasal administration.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
  • the compounds of the invention may also be deliverable transdermally.
  • the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the compounds of this invention may also be delivered subcutaneously.
  • the compound can be administered orally or intravenously.
  • the pharmaceutical preparation can be in a unit dosage form.
  • the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 1000 mg, for example from about 1 mg to about 500 mg, in particular from about 1 mg to about 250 mg, or from about 1 mg to about 25 mg, according to the particular application.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
  • a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.
  • the compounds of the invention are useful in human and veterinary medicine for treating or preventing a viral infection in a patient.
  • the compounds of the invention are inhibitors of viral replication.
  • the compounds of the invention can be inhibitors of influenza, rhinovirus or coronavirus replication. Accordingly, the compounds of the invention are useful for treating viral infections, such as coronavirus.
  • the compounds of the invention can be administered to a patient in need of treatment or prevention of a viral infection.
  • the invention provides methods for treating a viral infection in a patient comprising administering to the patient an effective amount of at least one compounds of the invention or a pharmaceutically acceptable salt thereof.
  • the compounds of the invention are useful in the inhibition of viruses, the treatment of viral infection and/or reduction of the likelihood or severity of symptoms of viral infection and the inhibition of viral replication and/or viral production in a cell-based system.
  • the compounds of the invention are useful in treating infection by viruses after suspected past exposure to viruses by such means as airborne transmission, blood transfusion, exchange of body fluids, etc.
  • the viral infection is acute respiratory viral infection. In another embodiment, the viral infection is chronic viral infection.
  • the invention provides methods for treating viral infection in a patient, the methods comprising administering to the patient an effective amount of at least one the invention or a pharmaceutically acceptable salt thereof.
  • the amount administered is effective to treat or prevent a viral infection in a patient.
  • the amount administered is effective to inhibit viral replication and/or viral production in the patient.
  • the viral infection is caused by influenza, coronavirus, rhinovirus, respiratory syncytial viruses (RSVs), parainfluenza, adenoviruses, Human metapneumovirus (HMPV) or Human Bocavirus (HBoV).
  • RSVs respiratory syncytial viruses
  • HMPV Human metapneumovirus
  • HoV Human Bocavirus
  • one or more compounds of the present invention are administered with one or more additional therapeutic agents selected from: an interferon, an immunomodulator, a viral replication inhibitor, an antisense agent, a therapeutic vaccine, a viral polymerase inhibitor, a nucleoside inhibitor, a viral protease inhibitor, a viral helicase inhibitor, a viral polymerase inhibitor a virion production inhibitor, a viral entry inhibitor, a viral assembly inhibitor, an antibody therapy (monoclonal or polyclonal), and any agent useful for treating an RNA-dependent polymerase-related disorder.
  • additional therapeutic agents selected from: an interferon, an immunomodulator, a viral replication inhibitor, an antisense agent, a therapeutic vaccine, a viral polymerase inhibitor, a nucleoside inhibitor, a viral protease inhibitor, a viral helicase inhibitor, a viral polymerase inhibitor a virion production inhibitor, a viral entry inhibitor, a viral assembly inhibitor, an antibody therapy (monoclonal or polyclonal), and any agent useful for treating
  • the present methods for treating or preventing viral infection can further comprise the administration of one or more additional therapeutic agents.
  • the additional therapeutic agent is an antiviral agent.
  • the additional therapeutic agent is an immunomodulatory agent, such as an immunosuppressive agent.
  • the present invention provides methods for treating a viral infection in a patient, the method comprising administering to the patient: a compound of the invention or a pharmaceutically acceptable salt thereof, and (ii) at least one additional therapeutic agent that is other than a compound of the invention, wherein the amounts administered are together effective to treat or prevent a viral infection.
  • therapeutic agents in the combination may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like.
  • the amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts).
  • a compound of the invention and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single dosage unit (e.g., a capsule, a tablet and the like).
  • the at least one a compound of the invention is administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.
  • the at least one a compound of the invention and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating a viral infection.
  • the at least one a compound of the invention and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a viral infection.
  • the at least one a compound of the invention and the additional therapeutic agent(s) act synergistically and are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a viral infection.
  • the at least one a compound of the invention and the additional therapeutic agent(s) are present in the same composition.
  • this composition is suitable for oral administration.
  • this composition is suitable for intravenous administration.
  • this composition is suitable for subcutaneous administration.
  • this composition is suitable for parenteral administration.
  • Viral infections and virus-related disorders that can be treated or prevented using the combination therapy methods of the present invention include, but are not limited to, those listed above.
  • the at least one a compound of the invention and the additional therapeutic agent(s) can act additively or synergistically.
  • a synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy.
  • a lower dosage or less frequent administration of one or more agents may lower toxicity of therapy without reducing the efficacy of therapy.
  • the administration of at least one 5 a compound of the invention and the additional therapeutic agent(s) may inhibit the resistance of a viral infection to these agents.
  • Non-limiting examples of additional therapeutic agents useful in the present compositions and methods include an interferon, an immunomodulator, a viral replication inhibitor, an antisense agent, a therapeutic vaccine, a viral polymerase inhibitor, a nucleoside inhibitor, a viral protease inhibitor, a viral helicase inhibitor, a virion production inhibitor, a viral entry inhibitor, a viral assembly inhibitor, an antibody therapy (monoclonal or polyclonal), and any agent useful for treating an RNA-dependent polymerase-related disorder.
  • the additional therapeutic agent is a viral protease inhibitor.
  • the additional therapeutic agent is a viral replication inhibitor.
  • the compounds of the invention are in substantially purified form.
  • compositions comprising an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • composition of (b), wherein the antiviral agent is an antiviral selected from the group consisting of protease inhibitors, polymerase inhibitors and other viral inhibitors.
  • a pharmaceutical combination that is (i) a compound of the invention and (ii) a second therapeutic agent selected from the group consisting of antiviral agents, immunomodulators, and anti-infective agents; wherein the compound of the invention and the second therapeutic agent are each employed in an amount that renders the combination effective for inhibiting viral replication or disease, or for treating viral infection and/or reducing the likelihood or severity of symptoms of viral infection.
  • a method of treating viral infection and/or reducing the likelihood or severity of symptoms of viral infection in a subject in need thereof which comprises administering to the subject an effective amount of a compound of the invention).
  • (j) A method of inhibiting viral replication in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b) or (c) or the combination of (d) or (e).
  • (k) A method of treating viral infection and/or reducing the likelihood or severity of symptoms of viral infection in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b) or (c) or the combination of (d) or (e).
  • the present invention also includes a compound of the present invention for use (i) in, (ii) as a medicament for, or (iii) in the preparation of a medicament for: (a) medicine, (b) inhibiting viral replication or (c) treating viral infection and/or reducing the likelihood or severity of symptoms of viral infection.
  • the compounds of the present invention can optionally be employed in combination with one or more second therapeutic agents selected from antiviral agents, anti-infective agents, and immunomodulators.
  • Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(k) above and the uses set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, aspects, classes, sub-classes, or features of the compounds described above.
  • the compound may optionally be used in the form of a pharmaceutically acceptable salt or hydrate as appropriate. It is understood that references to compounds would include the compound in its present form as well as in different forms, such as polymorphs, solvates and hydrates, as applicable.
  • compositions and methods provided as (a) through (k) above are understood to include all embodiments of the compounds, including such embodiments as result from combinations of embodiments.
  • Bicyclic beta-keto amide (3.5g, 14.285mmol) in 15mL of DMF was cooled to 0°C and triethylamine (2.48mL, 17.142mmol) was added and stirred for 5 min.
  • Comin’s reagent (3.78g, 17.142mmol) was added and the reaction mixture was stirred for 2h at room temperature. Reaction mixture was then poured into ice and pale yellow solid was formed which was filtered and dried to yield 3.0g of the desired product, as determined by LCMS and HNMR.
  • Bicyclic triflate (0.3g, 0.797mmol), 3-cyano-phenyl boronic acid (0.177g, 1.196mmol) andNa 2 CC> 3 (0.168g, 1.594mmol) was added in DMF+H2O (lOmL :2mL) solution.
  • Argon gas was bubbled and Pd(dppf)Cl2 (0.058g, 0.0797mmol) was added at which point the reaction was moved to pre-heated 100 °C oil bath and stirred for lh.
  • Reaction mixture was diluted with water, resulting in formation of brown precipitation which was then filtered and dried to yield the desired product, as determined by LCMS and HNMR.
  • Tricyclic amide (0.2g, 0.606mmol) in toluene was added POBr3 (0.52g, 1.818mmol) and stirred for 3h at 140 °C.
  • the reaction mixture was poured into ice and the aqueous layer was extract with EtOAc (x2). The organic layer was then dried over NaiSCri and concentrated.
  • Bicyclic beta-keto amide (3.5g, 14.285mmol) in 15mL of DMF was cooled to 0 °C and triethylamine (2.48mL, 17.142mmol) was added and stirred for 5 min.
  • Comin’s reagent (3.78g, 17.142mmol) was added and the reaction mixture was stirred for 2h at room temperature. Reaction mixture was then poured into ice and pale yellow solid was formed which was filtered and dried to yield 3.0g of the desired product, as determined by LCMS and HNMR.
  • Tricyclic amide (0.4g, 1.212mmol) in DMF (5mL) was cooled to 0°C and NaH (60% in Mineral Oil, 0.145g, 3.636mmol) was added portion wise and stirred for 30 minutes.
  • Bromo- methyl acetate (0.1303g, 1.818mmol) was added at 0 °C and the reaction mixture, after removal of ice bath, was stirred for 4h. Reaction was quenched with ice and organic layer was extracted with EtOAc (x2), dried over Na 2 S0 4 and concentrated by flash column chromatography gave the desired bromide product as determined by LCMS and HNMR.
  • Synthetic method C Representative example: 2- ⁇ [6-hexyl-4-(morpholin-4-yl)quinolin-2- yl](methyl)amino ⁇ acetic acid 4-hexyl aniline (5g, 28.24 mmol) in CH2CI2 (50mL) was cooled to 0°C and then 2 was added at stirred for 2h at room temperature. Reaction mixture was quenched with ice and neutralized with saturated NaHCCb solution. Resulting solution was then extracted with CH2CI2 (x2) then dried over Na 2 SC> 4 and concentrated. 5g of desired ester amide product was obtained by purification by flash column chromatography which was taken to next step. 5g of ester amide in PolyPhosphoricAcid (50mL) was heated to 150 °C and stirred. After
  • Morpholino amide (O.lg, 0.3184mmol) in toluene (3mL) was added POBr3 (0.273g, 0.955mmol) and stirred for 3h at 140°C.
  • the reaction mixture was poured into ice and the aqueous layer was extract with EtOAc (x2). The organic layer was then dried over Na 2 S0 4 and concentrated. Purification by flash column chromatography gave the desired bromide product as determined by LCMS and HNMR.
  • Morpholino bromide (0.08g, 0.212mmol) in DMSO (3mL) was added N-Methyl glycine methyl ester (0.145g, 1.063 mmol) and K2CO3 (0.090g, 0.636mmol). Reaction mixture was then stirred at 100°C for 16h before quenched with H2O. The mixture was acidified with IN HC1 to adjust the pH ⁇ 6 before being extracted with EtOAc (x2). Organic layer was dried over Na 2 S0 4 and concentrated before purification by reverse phase prep-HPLC to yield 2- ⁇ [6-hexyl-4- (morpholin-4-yl)quinolin-2-yl](methyl)amino ⁇ acetic acid as confirmed by H-NMR and LCMS.
  • 3T3-L1 preadipocytes were routinely cultured in a growth medium composed of DMEM high-glucose (Sigma), 10% FBS (Gibco), 10 U/ml penicillin and 10 pg/ml streptomycin (P/S; Gibco) in a standard cell culture incubator at 37°C.
  • a confluent layer of 3T3-L1 cells were incubated with the growth medium containing 2 mM rosiglitazone, 1 mM dexamethasone, 500 pM IBMX, and 1 pg/ml insulin (Sigma). Forty-eight (48) hours later (on day 2) and on days 4 and 6, medium of the cells was replaced with fresh medium containing 1 pg/ml insulin. On days 8 and 10, the medium was refreshed with regular growth medium and addition of insulin was omitted.
  • the cells were infected with human coronavirus OC43 (ATCC) at a multiplicity of 0.05 TCID50 (tissue-culture infectious-dose 50) per cell in DMEM containing 2% heat-inactivated FBS and P/S.
  • TCID50 tissue-culture infectious-dose 50
  • DMEM fresh medium containing either the indicated FABP4 modulating compounds or the vehicle in which the compounds were dissolved
  • the final compound concentration was 10 pM and final concentration of DMSO was 0.1% (v/v).
  • the cells were incubated at 35°C during the course of infection and compound treatment. Twenty -four hours after infection, medium of the cells was collected, cleared by centrifugation at 2,000g for 5 minutes, and frozen at -80 degrees C until further processing.
  • the viral titers in the samples were determined by TCID50 assay in MRC5 cells (ATCC) using Reed-Munch method and median fold reduction of virus titers in compound treated cells compared to vehicle control was calculated.
  • Table 2 shown below depicts the antiviral activity of the FABP4 modulating compounds.
  • the compounds were categorized based on the magnitude of their antiviral activity.
  • the compounds reduced virus titers > 100-fold, between 10- to 99-fold, and between 2- to 9-fold compared to vehicle control were represented as “A”, “B” and “C”, respectively.
  • FIG. 1 depicts graphical charts showing the virus yield obtained from cells treated with the corresponding compounds and vehicle control (DMSO). More specifically, Figure 1 includes a graph for the vehicle control (DMSO) and different FABP4 modulating compounds and include an x-axis associated with compound ID and a y-axis associated with a viral titer in TCID50/ml. Data are shown as mean ( ⁇ standard deviation) of two or three biological replicates.
  • DMSO vehicle control
  • FIG. 1 includes a graph for the vehicle control (DMSO) and different FABP4 modulating compounds and include an x-axis associated with compound ID and a y-axis associated with a viral titer in TCID50/ml. Data are shown as mean ( ⁇ standard deviation) of two or three biological replicates.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/US2021/040584 2020-07-06 2021-07-06 Novel cell metabolism modulating compounds and uses thereof for the treatment of viral diseases WO2022010948A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2023500381A JP2023532998A (ja) 2020-07-06 2021-07-06 新規細胞代謝調節化合物およびそのウイルス性疾患の治療のための使用
CN202180054153.2A CN116615189A (zh) 2020-07-06 2021-07-06 新型细胞代谢调节化合物及其用于治疗病毒疾病的用途
EP21838930.2A EP4281054A1 (de) 2020-07-06 2021-07-06 Neuartige verbindungen zur modulation des zellmetabolismus und verwendungen davon zur behandlung von virenerkrankungen

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063048619P 2020-07-06 2020-07-06
US63/048,619 2020-07-06

Publications (1)

Publication Number Publication Date
WO2022010948A1 true WO2022010948A1 (en) 2022-01-13

Family

ID=79552008

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2021/040584 WO2022010948A1 (en) 2020-07-06 2021-07-06 Novel cell metabolism modulating compounds and uses thereof for the treatment of viral diseases

Country Status (4)

Country Link
EP (1) EP4281054A1 (de)
JP (1) JP2023532998A (de)
CN (1) CN116615189A (de)
WO (1) WO2022010948A1 (de)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023168367A1 (en) * 2022-03-02 2023-09-07 Immunesensor Therapeutics, Inc. QUINOLINE cGAS ANTAGONIST COMPOUNDS
WO2024008909A1 (en) 2022-07-08 2024-01-11 Janssen Pharmaceutica Nv Inhibitors of coronavirus
US11873291B2 (en) 2020-09-03 2024-01-16 Immunesensor Therapeutics, Inc. Quinoline cGAS antagonist compounds

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM Substance ANONYMOUS: "2-Ethylpyridine, 97%", XP055843371, retrieved from NCBI Database accession no. 24847096 *
JONES KEITH, ROSET XAVIER, ROSSITER SHARON, WHITFIELD PHILIP: "Demethylation of 2,4-dimethoxyquinolines: the synthesis of atanine", ORGANIC & BIOMOLECULAR CHEMISTRY, ENGLAND, 4 December 2003 (2003-12-04), England, pages 4380 - 4383, XP055898196, Retrieved from the Internet <URL:https://pubs.rsc.org/en/content/articlepdf/2003/ob/b311281k> [retrieved on 20220307], DOI: 10.1039/b311281k *
VANNELLI ET AL.: "The Antituberculosis Drug Ethionamide Is Activated by a Flavoprotein Monooxygenase", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 277, no. 15, 2002, pages 12824 - 12829, XP002283431, DOI: 10.1074/jbc.M110751200 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11873291B2 (en) 2020-09-03 2024-01-16 Immunesensor Therapeutics, Inc. Quinoline cGAS antagonist compounds
WO2023168367A1 (en) * 2022-03-02 2023-09-07 Immunesensor Therapeutics, Inc. QUINOLINE cGAS ANTAGONIST COMPOUNDS
WO2024008909A1 (en) 2022-07-08 2024-01-11 Janssen Pharmaceutica Nv Inhibitors of coronavirus

Also Published As

Publication number Publication date
JP2023532998A (ja) 2023-08-01
CN116615189A (zh) 2023-08-18
EP4281054A1 (de) 2023-11-29

Similar Documents

Publication Publication Date Title
EP4281054A1 (de) Neuartige verbindungen zur modulation des zellmetabolismus und verwendungen davon zur behandlung von virenerkrankungen
JP6516705B2 (ja) Ｈｂｖ感染に対する抗ウイルス剤としてのスルファモイルベンズアミド誘導体
US20220144834A1 (en) Chemical Compounds
AU2006212761B2 (en) Combination therapy
US20220233538A1 (en) Method for treating idiopathic pulmonary fibrosis
CN101083986A (zh) 双环杂环衍生物及其作为硬脂酰CoA去饱和酶(SCD)抑制剂的用途
JP2012519159A (ja) Ｐｄｅ４阻害剤及びｎｓａｉｄを含有する複合薬
TW201737943A (zh) 使用fasn抑制劑之方法
AU2021211437A1 (en) Novel cell metabolism modulating compounds and uses thereof
CN111499591A (zh) RORγ调节剂
EP3259256B1 (de) Verbindungen und verfahren zur induktion der bräunung von weissem fettgewebe
US20230210837A1 (en) Novel cell metabolism modulating compounds and uses thereof for the treatment of viral diseases
US20220313681A1 (en) Novel cell metabolism modulating compounds and uses thereof for the treatment of viral diseases
EP3397627B1 (de) Indolizinderivate, zusammensetzung und verfahren zur verwendung
CA3227602A1 (en) Inhibitors for coronaviruses
US20230241025A1 (en) Antiviral use of fabp4 modulating compounds
US20230255933A1 (en) Antiviral use of fabp4 modulating compounds
TW202203914A (zh) 特別用於治療b型肝炎和d型肝炎之抗病毒化合物
WO2021000527A1 (zh) 三环类xor抑制剂及其制备方法和应用
JPH01242574A (ja) 含窒素縮合環を有するピペリジン及びピペラジン誘導体、その製造方法並びにそれを含む薬学的組成物
WO2024102989A1 (en) Non-peptidic sars-cov-2 main protease inhibitors
WO2021228222A1 (zh) 用于治疗乙肝的组合
AU2019311117A1 (en) Pyrrolo(2,3-b)pyridin derivatives as inhibitors of influenza virus replication

Legal Events

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

Ref document number: 21838930

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2023500381

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2021838930

Country of ref document: EP

Effective date: 20230206

WWE Wipo information: entry into national phase

Ref document number: 202180054153.2

Country of ref document: CN