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WO2025252600A1 - Activating compounds of potassium channels kv7.2/kv7.3 - Google Patents

Activating compounds of potassium channels kv7.2/kv7.3

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Publication number
WO2025252600A1
WO2025252600A1 PCT/EP2025/064958 EP2025064958W WO2025252600A1 WO 2025252600 A1 WO2025252600 A1 WO 2025252600A1 EP 2025064958 W EP2025064958 W EP 2025064958W WO 2025252600 A1 WO2025252600 A1 WO 2025252600A1
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WIPO (PCT)
Prior art keywords
group
disorders
spiro
pharmaceutically acceptable
compound
Prior art date
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Pending
Application number
PCT/EP2025/064958
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French (fr)
Inventor
Barbara Garofalo
Rosella Ombrato
Federica PRATI
Prashant Bhimrao Kapadnis
Alan Haughan
Jamie Knight
Simon CRUMPLER
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Angelini Pharma SpA
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Angelini Pharma SpA
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Publication of WO2025252600A1 publication Critical patent/WO2025252600A1/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Voltage-gated potassium (Kv) channels conduct potassium (K+) ions across cell membranes in response to changes in membrane potential and can therefore regulate cellular excitability by modulating (increasing or decreasing) the cell's electrical activity.
  • Functional Kv channels exist as multimeric structures formed by the association of four alpha and four beta subunits.
  • Alpha subunits comprise six transmembrane domains, a poreforming loop, and a voltage sensor and are arranged symmetrically around a central pore.
  • Beta or auxiliary subunits interact with alpha subunits and can modify the properties of the channel complex to include, but not limited to, alterations in electrophysiological or biophysical properties of the channel, levels, or expression patterns.
  • Kv1 -Kv9 Nine families of Kv channel alpha subunits have been identified, referred to as Kv1 -Kv9.
  • the Kv7 channel family consists of at least five members including Kv7.1 , Kv7.2, Kv7.3, Kv7.4, and Kv7.5.
  • the members of this family are referred to by the gene names KCNQ1 , KCNQ2, KCNQ3, KCNQ4, and KCNQ5, respectively (Dalby-Brown et al., Current Topics in Medicinal Chemistry, 2006, 6(10), 999-1023).
  • Kv7 potassium channels play a role in the control of neuronal excitation.
  • Kv7 channels particularly the Kv7.2/Kv7.3 heterotetramers, underlie the M- current (Wang et al Science. 1998 Dec 4;282(5395): 1890-1893).
  • the M current has a characteristic time and voltage dependence that results in the stabilization of the membrane potential in response to multiple excitatory stimuli.
  • M current is involved in the control of neuronal excitability (Delmas & Brown, Nature, 2005, 6, 850-862).
  • the M current is a noninactivating potassium current found in many neuronal cell types. In each cell type, it is dominant in the control of membrane excitability being the only sustained current in the range of action potential initiation (Marrion, Annual Review Physiology 1997, 59, 483-504).
  • Kv7.1 is restricted to the heart, peripheral epithelium, and smooth muscle
  • Kv7.2, Kv7.3, Kv7.4, and Kv7.5 appears to be dominant in the nervous system that includes the hippocampus, cortex, ventral tegmental area, and dorsal root ganglion neurons.
  • Kv7.4 is a subtype selectively expressed in the auditory pathway including hair cells of the inner ear.
  • Kv7.4 and Kv7.5 are also expressed in various smooth muscle cells (Greene & Hoshi, Cellular and Molecular Life Sciences, 2017, 74(3), 495-508).
  • the KCNQ2 and KCNQ3 genes appear to be mutated in an inherited form of epilepsy known as benign familial neonatal seizures (Rogawski, Trends in Neuroscience 2000, 23, 393-398). Proteins encoded by the KCNQ2 and KCNQ3 genes are localized in pyramidal neurons of the human cortex and hippocampus, regions of the brain associated with seizure generation and propagation (Cooper et al., Proceedings National Academy of Science U S A, 2000, 97(9), 4914-4919).
  • Kv7.2, Kv7.3, and Kv7.5 are expressed in astrocytes and glial cells.
  • Kv7.2, Kv7.3, and Kv7.5 channels may help modulate synaptic activity in the CNS and contribute to the neuroprotective effects of KCNQ channel activators (Noda, et al., Society for Neuroscience Abstracts 2003, 53.9), which would be relevant to the treatment of neurodegenerative disorders such as, but not limited to, Alzheimer's disease, Parkinson's disease, and Huntington's chorea.
  • mRNAs for Kv7.2 and Kv7 are expressed in astrocytes and glial cells.
  • 3 are found in regions of the brain associated with anxiety and emotional behaviors such as depression and bipolar disorder, for example the hippocampus, ventral tegmental area, and amygdala (Saganich, et al., Journal of Neuroscience 2001 , 21 (13), 4609-4624; Friedman et al., Nat Commun., 2016, 7, 11671 ).
  • Kv7.2/Kv7.3 channels have also been reported to be upregulated in models of neuropathic pain (Wickenden, et al, Society for Neuroscience Abstracts 2002, 454.7), and modulators of potassium channels have been hypothesized to be active in both neuropathic pain and epilepsy (Schroder et al., Neuropharmacology 2001 , 40(7), 888-898).
  • mRNA expression for Kv7.2-5 in the trigeminal and dorsal root ganglia and in the trigeminal caudal nucleus implies that activators of these channels may also influence sensory processing of migraine pain (Goldstein, et al. Society for Neuroscience Abstracts 2003, 53.8).
  • Retigabine and flupirtine are known Kv7.2/Kv7.3 potassium channel activating compounds that have been used in the treatment of epilepsy, migraine, neuropathic pain, acute pain, and tinnitus.
  • Retigabine has been withdrawn from the market because of its adverse side effects, particularly urinary retention and changes in retinal and skin pigmentation.
  • Flupirtine should be used by individuals who do not respond to other analgesic treatments and for no longer than two weeks because of its hepatic toxicity.
  • the Applicant has addressed the problem of providing novel therapies for the treatment of disorders of the central nervous system (CNS), e.g., epilepsy and neurodegenerative disorders, and the peripheral nervous system (PNS), e.g., chronic and neuropathic pain.
  • CNS central nervous system
  • PNS peripheral nervous system
  • the Applicant focused its attention on potassium channel activating compounds Kv7.2/7.3, initiating research work that could provide alternative compounds to retigabine and flupirtine.
  • the Applicant has identified a number of compounds capable of acting as activators of Kv7.2/7.3 potassium channels.
  • CNS central nervous system
  • PNS peripheral nervous system
  • the present invention relates to a Kv7.2/Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, having the following general formula (I) wherein
  • R 1 is represented by A1 — L1 — , wherein
  • R 2 is a ring selected from:
  • monocyclic aliphatic ring having three to six members, optionally substituted by a halogen atom, an optionally halogenated C1 -3 alkyl group or an optionally halogenated C1 -3 alkoxy group, and g. aryl group, optionally substituted by a halogen atom, an optionally halogenated C1 -3 alkyl group or an optionally halogenated C1 -3 alkoxy group.
  • the present invention relates to a Kv7.2/Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to the first aspect of the present invention for use as a drug.
  • the present invention relates to a Kv7.2/Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to the first aspect of the present invention, for use in the treatment of disorders that are modulated by Kv7.2/Kv7.3 potassium channels, preferably in the treatment of central nervous system (CNS) and peripheral nervous system (PNS) disorders.
  • CNS central nervous system
  • PNS peripheral nervous system
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising (i) a Kv7.2/7.3 potassium channel activating compound, or a pharmaceutically acceptable salt thereof, according to the first aspect of the present invention, and (ii) at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition according to the fourth aspect of the present invention can be used in the treatment of disorders that are modulated by Kv7.2/7.3 potassium channels, preferably in the treatment of central nervous system (CNS) and peripheral nervous system (PNS) disorders.
  • CNS central nervous system
  • PNS peripheral nervous system
  • the present invention relates to a method for treating disorders that are modulated by Kv7.2/7.3 potassium channels in a subject in need thereof comprising administering a therapeutically effective amount of a Kv7.2/7.3 potassium channel activating compound, or a pharmaceutically acceptable salt thereof, according to the first aspect of the present invention.
  • pharmaceutically acceptable is intended to define, without any particular limitation, any material suitable for the preparation of a pharmaceutical composition to be administered to a living being.
  • terapéuticaally effective amount means an amount of compound sufficient to alleviate, arrest, partially arrest, remove or delay the clinical manifestations of a certain disease and its complications in a therapeutic treatment comprising the administration of said compound.
  • treatment means the management and care of a patient for the purpose of alleviating, arresting, partially arresting, removing or delaying the progress of the clinical manifestation of disease.
  • the patient to be treated is preferably a mammal, particularly a human being.
  • Kv7.2/7.3 potassium channel activator refers to a compound that causes a shift in voltage dependence for channel opening to more negative potentials, meaning that the Kv7.2/7.3 potassium channels open to more negative potentials in the presence of said compound, facilitating the transmission of ions through them.
  • L1 is an unsubstituted methylene group (-CH2- ) ⁇
  • L1 is a methylene group substituted with a - CR’R”R”’ group.
  • at least one of R’, R” and R’” is a hydrogen atom.
  • At least two of R', R" and R'" are hydrogen atoms.
  • all R', R" and R'" are hydrogen atoms.
  • At least one of R’, R” and R’” is a hydroxy group.
  • At least one of R’, R” and R’” is a CN group.
  • At least one of R’, R” and R’” is a C1-3 alkyl group, optionally substituted by one or more fluorine or chlorine atom.
  • At least one of R’, R” and R’” is a Ci alkyl group, optionally substituted by one or more fluorine or chlorine atom.
  • At least one of R’, R” and R’” is selected from the group consisting of -CH3, -CH2F, -CHF2, and -CF3.
  • At least one of R’, R” and R’” is a C1-3 alkoxy group, optionally substituted by one or more fluorine or chlorine atom.
  • At least one of R’, R” and R’” is a C1-2 alkoxy group, optionally substituted by one or more fluorine or chlorine atom.
  • At least one of R’, R” and R’” is a Ci alkoxy group, optionally substituted by one or more fluorine or chlorine atom.
  • At least one of R’, R” and R’” is selected from the group consisting of -OCH3, -OCH2F, -OCHF2, and -OCF3.
  • At least one of R’, R” and R’” is tetrahydrofuran.
  • any two of R’, R” and R’” together form an aliphatic ring having 3 carbon atoms.
  • any two of R’, R” and R’” together form an aliphatic ring having 4 carbon atoms.
  • any two of R’, R” and R’” together form an aliphatic ring having 5 carbon atoms.
  • any two of R’, R” and R’” together form an aliphatic ring having 6 carbon atoms.
  • A1 is an aromatic ring selected from the group consisting of pyrrole, pyridine, pyridazine, pyrimidine, and pyrazine.
  • A1 is substituted by one or more halogen atoms selected from fluoride, chloride, bromide, and iodide, preferably fluoride and chloride.
  • A1 is substituted by a linear or branched C1 -C3 alkyl chain substituted by one or more halogen atoms selected from fluoride, chloride, bromide, and iodide, preferably fluoride and chloride.
  • A1 is substituted by a linear or branched C1 -C3 alkoxy chain substituted by one or more halogen atoms selected from fluoride, chloride, bromide, and iodide, preferably fluoride and chloride.
  • A1 is substituted by a linear or branched C1 -C3 alkoxy chain substituted by a cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein one or more carbon atom is optionally substituted by a heteroatom selected from 0, N and S, such as for example, oxirane, aziridine, oxetane, azetidine, thietane, tetrahydrofuran, pyrrolidine, pyrazolidine, imidazoline, thiolane, oxazolidine, isoxazolidine, thiazolidine, 1 ,3-oxathiolane, piperidine, oxane, thiane, piperazine, morpholine, and thiomorpholine.
  • a cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cycl
  • A1 is substituted by one or more substituent selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, wherein one or more hydrogen atoms is substituted by a halogen atom, preferably fluoride and chloride, more preferably fluoride.
  • A1 is substituted by one or more substituent selected from methoxy, ethoxy, propoxy, and isopropoxy, wherein one or more hydrogen atoms is substituted by a halogen atom, preferably fluoride and chloride, more preferably fluoride.
  • A1 is substituted by one or more substituent selected from CF3-CH2-O- or CF3-CH(CH3)-O-
  • R1 is represented by any one of the following structural formulas (a) to (e): wherein L1 has the meaning described above, and G1 is a C1-3 alkoxy group, optionally substituted by one or more halogen atoms.
  • R1 is represented by any one of the following structural formulas (f), (g), (h) and (i): wherein L1 has the meaning described above, and G1 is a C1-3 alkoxy group, optionally substituted by one or more halogen atoms.
  • G1 is a C2-3 alkoxy group, optionally substituted by one or more fluorine or chlorine atoms.
  • G1 is a C2-3 alkoxy group, optionally substituted by one or more fluorine atoms.
  • G1 is CF3-CH2-O- or CF3-CH(CH3)-O-.
  • R 2 is a monocyclic aliphatic ring selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahydrofuran, piperidine, and tetrahydropyran, preferably cyclopropane, cyclobutane, and tetrahydropyran, more preferably cyclopropane.
  • R 2 is a condensed bicyclic ring selected from the group consisting of bicyclo(3.1 ,0)hexane, 1 ,2,3,4-tetrahydroisoquinoline, 2,3- dihydrobenzofuran (coumaran), and 3, 4-dihydro-2H-1 -benzopyran (chromane), preferably bicyclo(3.1 ,0)hexane, 2,3-dihydrobenzofuran (coumaran), and 3,4-dihydro-2H-1 - benzopyran (chromane).
  • R 2 is a bridged bicyclic ring selected from the group consisting of bicyclo(1 .1 ,1 )pentane, bicyclo(2.1 ,1 )hexane, 2-oxabicyclo[2.1 ,1 ]hexane, bicyclo[2.2.1 ]heptane (norbornane), 2-oxa-5-azabicyclo[2.2.1 ]heptane, bicyclo[2.2.2]octane, preferably bicyclo(1 .1 ,1 )pentane, bicyclo(2.1.1 )hexane, 2- oxabicyclo[2.1 ,1 ]hexane, bicyclo[2.2.1 ]heptane (norbornane), bicyclo[2.2.2]octane, more preferably bicyclo(1.1.1 )pentane, bicyclo[2.2.1 ]heptane (norbornane), and bicyclo[2.
  • R 2 is a spiro residue selected from the group consisting of spiro[2.2]pentane, spiro[2,3]hexane, spiro[2.4]heptane, spiro[2.5]octane, spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane, wherein one carbon atom is optionally replaced by one heteroatom selected from the group consisting of N and 0, such as, for example 1 -oxaspiro[3.4]octane, 5-oxaspiro[3.4]octane, 2-azaspiro[3.4]octane, 6-azaspiro[3.4]octane, and 2-oxa-6- azaspiro[3.4]oc
  • any one of such rings (i), (ii) and (iii) representing R 2 is unsubstituted.
  • any one of such rings (i), (ii) and (iii) representing R 2 is substituted with one or more halogen atoms, preferably with one or more halogen atoms selected from fluorine or chlorine atoms, preferably with one or more fluorine atom, more preferably with one or two fluorine atoms.
  • any one of such rings (i), (ii) and (iii) representing R 2 is substituted with one or more hydroxyl group (-0H).
  • any one of such rings (i), (ii) and (iii) representing R 2 is substituted with one or more hydroxy C1-C3 alkyl group, preferably -CH2OH, -C2H5OH or -C3H7OH, more preferably -CH2OH.
  • any one of such rings (i), (ii) and (iii) representing R 2 is substituted with one or more C1-3 alkyl groups, optionally substituted by one or more fluorine or chlorine atom.
  • any one of such rings (i), (ii) and (iii) representing R 2 is substituted with one or more C1-2 alkyl groups, optionally substituted by one or more fluorine or chlorine atom.
  • any one of such rings (i), (ii) and (iii) representing R 2 is substituted with one or more Ci alkyl groups, optionally substituted by one or more fluorine or chlorine atom.
  • any one of such rings (i), (ii) and (iii) representing R 2 is substituted with one or more substituents selected from the group consisting of -CH3, -CH2F, -CHF2, and -CF3, preferably -CF3.
  • any one of such rings (i), (ii) and (iii) representing R 2 is substituted with one or more C1-3 alkoxy groups, optionally substituted by one or more fluorine or chlorine atom.
  • any one of such rings (i), (ii) and (iii) representing R 2 is substituted with one or more C1-2 alkoxy groups, optionally substituted by one or more fluorine or chlorine atom.
  • any one of such rings (i), (ii) and (iii) representing R 2 is substituted with one or more Ci alkoxy groups, optionally substituted by one or more fluorine or chlorine atom.
  • any one of such rings (i), (ii) and (iii) representing R 2 is substituted with one or more substituents selected from the group consisting of -OCH3, -OCH2F, -OCHF2, and -OCF3.
  • any one of such rings (i), (ii) and (iii) representing R 2 is substituted with one or more cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted by a halogen atom, an optionally halogenated C1 -3 alkyl group or an optionally halogenated C1 -3 alkoxy group.
  • any one of such rings (i), (ii) and (iii) representing R 2 is substituted with one or more phenyl, tolyl, xylyl, naphthyl, anthryl, phenanthryl, pyrenyl, biphenylyl, terphenylyl, benzyl, phenethyl, styryl, cinnamyl, furanyl, thienyl, or pyridyl, optionally substituted by a halogen atom, an optionally halogenated C1 -3 alkyl group or an optionally halogenated C1 -3 alkoxy group.
  • the first aspect of the present invention relates to a Kv7.2/Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the compounds of the following Table A:
  • Some compounds of the present invention may exist in tautomeric forms, and the invention includes all tautomeric forms of such compounds unless otherwise noted.
  • the structures depicted herein are also intended to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center.
  • Individual stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the compounds according to the present invention are within the scope of the invention.
  • the present invention includes any diastereomer or enantiomer substantially free of other isomers (>90%, and preferably >95%, free of other stereoisomers on a molar basis), as well as a mixture of such isomers.
  • optical isomers can be obtained by resolution of racemic mixtures according to conventional processes, for example, by formation of diastereomeric salts, by treatment with an optically active acid or base and subsequent separation of the mixture of diastereomers by crystallization of the corresponding salt followed finally by liberation of the optically active bases from such salts.
  • appropriate acids include tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorosulfonic acids.
  • a different process for the separation of optical isomers involves the use of a chiral chromatographic column optimally chosen to maximize the separation of enantiomers.
  • Still another method involves the synthesis of covalent diastereomers by reacting the compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate.
  • the synthesized diastereomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to provide the enantiomerically pure compound.
  • the optically active compounds of the invention can be obtained using active starting materials. These isomers may be in the form of a free acid, a free base, an ester, or a salt.
  • Radioisotopes of hydrogen, carbon, phosphorus, fluorine, and chlorine include 3 H, 14 C, 32 P, 35 S, 18 F and 36 CI, respectively.
  • Compounds of the present invention that contain these radioisotopes and/or other radioisotopes of other atoms are within the scope of the present invention.
  • the triziated radioisotopes, i.e., 3 H, and carbon-14, i.e., 14 C, are particularly preferred because of their ease of preparation and detectability.
  • radiolabeled compounds of this invention can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by performing the procedures described herein by substituting a non-radiolabeled reagent for a readily available non-radiolabeled reagent.
  • Compounds according to the present invention are preferably used as salts with pharmaceutically acceptable organic and inorganic acids or bases.
  • the pharmaceutically acceptable organic acids are chosen from the group consisting of oxalic, maleic, methanesulfonic, paratoluenesulfonic, succinic, citric, malic, tartaric and lactic acids.
  • pharmaceutically acceptable organic bases are selected from the group consisting of tromethamine, lysine, arginine, glycine, alanine and ethanolamine.
  • the pharmaceutically acceptable inorganic acids are chosen from the group consisting of hydrochloric, hydrobromic, phosphoric and sulfuric acids.
  • the pharmaceutically acceptable inorganic bases are chosen from the group consisting of hydroxide or carbonate of alkaline or alkaline-earth metals, such as sodium, potassium and calcium.
  • the compounds of the present invention can be prepared by a variety of procedures known to a man skilled in the art, some of which are described in the preparations illustrated in the examples of the experimental part. Intermediates and final compounds may be recovered by conventional methods well known in the art, such as, for example, extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. Reagents and starting materials are known and readily available to the man skilled in the art.
  • the compounds of the present invention are used as a drug, particularly in the treatment of disorders that are modulated by Kv7.2/Kv7.3 potassium channels, preferably in the treatment of central nervous system (CNS) and peripheral nervous system (PNS) disorders.
  • CNS central nervous system
  • PNS peripheral nervous system
  • Central nervous system (CNS) disorders that are preferably treated with the compounds of the present invention are, for example, epilepsy, epileptic syndromes, epileptic symptoms, epilepsy resistant or refractory to treatment, seizures, bipolar disorder, bipolar depression, schizophrenia, psychosis, mania, stress-related disorders, acute stress reactions, major depressive disorder, anxiety, panic attacks, social phobia, sleep disorders, attention deficit hyperactivity disorder, post-traumatic stress disorder, obsessive-compulsive disorder, impulsivity disorders, personality disorders, Huntington's disease, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, tinnitus, and so on.
  • the central nervous system (CNS) disorders that are preferably treated with the compounds of the present invention are epilepsy, epileptic syndromes, epileptic symptoms, epilepsy resistant or refractory to treatment, seizures, bipolar disorder, bipolar depression, schizophrenia, and amyotrophic lateral sclerosis.
  • PNS disorders that are preferably treated with the compounds of the present invention are, for example, migraine, chronic pain, acute pain, neuropathic pain, visceral pain, inflammatory pain, muscle pain, and so forth.
  • peripheral nervous system (PNS) disorders that are preferably treated with the compounds of the present invention are neuropathic pain, chronic pain, visceral pain, and inflammatory pain.
  • the compounds of the present invention are administered in the form of a pharmaceutical composition comprising a pharmaceutically acceptable excipient.
  • one aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising (i) a Kv7.2/Kv7.3 potassium channel activating compound, or a pharmaceutically acceptable salt thereof, according to the first aspect of the present invention, and (ii) at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition according to the present invention is for systemic use.
  • composition according to the present invention can be administered orally, parenterally, inhaled (spray, powder or aerosol), rectally, nasally, buccally, vaginally or via an implanted device.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical composition according to the present invention is formulated for oral or parenteral administration.
  • the pharmaceutical composition according to the present invention is prepared in suitable dosage forms comprising an effective amount of at least one compound according to the first aspect of the present invention, a salt thereof with a pharmaceutically acceptable organic or inorganic acid or base, and at least one pharmaceutically acceptable excipient.
  • suitable dosage forms include tablets, capsules, coated tablets, granules and solutions and syrups for oral administration; suppositories for rectal or vaginal administration; and solutions, suspensions, dispersions or emulsions for administration by injection or infusion.
  • Preferred dosage forms include tablets, coated tablets, capsules and solutions for oral administration, and aqueous to non-aqueous sterile solutions for administration by injection or infusion.
  • the amount of compound according to the first aspect of the present invention, or a pharmacologically acceptable salt thereof, present in the pharmaceutical composition of the present invention may vary over a wide range depending on known factors, for example, the type of disease, the seventy of the disease, the body weight of the patient, the dosage form, the route of administration chosen, the number of administrations per day, and the efficacy of the compound itself. However, a person skilled in the art can determine the optimal amount easily and routinely.
  • the amount of compound according to the first aspect of the present invention or a pharmacologically acceptable salt thereof in the pharmaceutical composition of the present invention will be such as to provide a level of administration from 0.0001 to 100 mg/kg/day.
  • the level of administration is from 0.001 to 50 mg/kg/day, and even more preferably from 0.01 to 10 mg/kg/day.
  • the dosage forms of the pharmaceutical composition of the present invention can be prepared according to techniques well known to a man skilled in the pharmaceutical art, including mixing, granulation, compression, dissolution, sterilization, and the like.
  • dosage forms are formulated to provide controlled release of the active ingredient over time.
  • the required release time may be very short, normal or long.
  • the pharmaceutical composition of the present invention is contained in a single dosage form, to be administered once a day, or several times (two, three or four) a day.
  • the pharmaceutically acceptable excipient may be selected from the group consisting of thickeners, glidants, binders, disintegrants, fillers, diluents, preservatives, stabilizers, surfactants, buffers, flu idizers, lubricants, humectants, absorbents, salts to regulate osmotic pressure, emulsifiers, flavorings, colorants, sweeteners, and the like.
  • excipients include water, ethanol, propylene glycol, glycerol, polyethylene glycols, polyoxamers, mono-, di- and tri-glycerides, coconut oil, palm oil, sodium carbonate, magnesium carbonate, magnesium stearate, stearic acid, talc, sugars, lactose, mannitol, sorbitol, polysorbate, povidone, pectin, dextrin, starch (especially corn starch), sodium starch glycolate, croscarmellose sodium, sucrose, cyclodextrin, gelatin, microcrystalline cellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, povidone, glyceryl monostearate, hypromellose, cocoa butter, titanium dioxide (E171 ), red iron oxide and yellow iron oxide (E172), and the like.
  • water ethanol, propylene glycol, glycerol, polyethylene glycols, polyoxamers, mono-, di
  • intermediate and final compounds may be purified by any technique or combination of techniques known to one skilled in the art. Some examples that are not limiting include:
  • Isolute SPE Si II cartridge refers to a pre-packed polypropylene column containing unbonded activated silica with irregular particles with average size of 50 pm and nominal 60A porosity), and a solvent or combination of solvents (cyclohexane, EtOAc, DCM, MeOH, MeCN, water, etc.) that elutes the desired compounds; • RP-HPLC purification performed on Waters Mass Directed FractionLynx systems (2767 autosampler, System Fluidics Organiser, 2998 Photodiode array, 2545 pump, 3x515 pump, QDa mass spectrometer), Gilson system (GX281 autosampler, 322 pump, 155 UV/vis detector), Interchim PuriFlash 4125 coupled to a UV DAD (see Table 2 for some non-limiting conditions);
  • a reaction vessel was charged with 3,3-difluoro-cyclobutanecarboxylic acid (244 mg, 1.79 mmol, CAS: 107496-54-8) and solvated in DCM (10.0 mL).
  • CDI 290 mg, 1.79 mmol
  • triethylamine (1 .0 mL, 7.17 mmol
  • [2-(2,2,2-trifluoroethoxy)-4-pyridyl]methanamine dihydrochloride 500 mg, 1.79 mmol, CAS: 2460508-43-2
  • a reaction vessel was charged with 6-chloropyrimidine-4-carbonitrile (5.00 g, 35.8 mmol, CAS: 939986-65-9) and solvated in MeCN (150 mL).
  • (R)-1 ,1 ,1 -Trifluoro-2-propanol (4.70 g, 41.2 mmol, CAS: 75-89-8) was added, and the solution was stirred at RT until dissolution had occurred.
  • 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (6.2 mL, 41.2 mmol, 1.15 eq) was added dropwise and the reaction was stirred at RT for 24 h. The reaction was concentrated in vacuo.
  • reaction vessel was charged with (R)-6-((1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyrimidine-4- carbonitrile (2.6 g, 12.0 mmol) and di-tert-butyl decarbonate (6.9 mL, 29.9 mmol) and solvated in IMS (148 mL).
  • the reaction was evacuated and placed under an argon atmosphere.
  • 10% palladium on carbon (637 mg, 0.05 mmol) was added and the reaction was evacuated and placed under a hydrogen atmosphere (x3).
  • the reaction was stirred at RT under a hydrogen atmosphere for 12 h.
  • the reaction was evacuated and purged with argon (x3).
  • reaction vessel was charged with te/Y-butyl (R)-((6-((1 ,1 ,1 -trifluoropropan-2- yl)oxy)pyrimidin-4-yl)methyl)carbamate (2.0 g, 6.22 mmol) and dissolved in DCM (40 mL). To the reaction was added 4 M hydrogen chloride in dioxane (16.0 mL, 62.2 mmol) dropwise and the mixture was stirred at RT for 24 h. The reaction suspension was filtered in vacuo, washed with DCM and dried in vacuo to afford the title compound as a white solid (1.8 g, 98%).
  • the title compound was prepared using an analogous reaction protocol to that described for Example 1 : 3,3-Difluoro-N-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)cyclobutane-1 - carboxamide, from the appropriate starting materials (R)-(6-((1 ,1 ,1 -trifluoropropan-2- yl)oxy)pyrimidin-4-yl)methanamine dihydrochloride and 3,3-dimethylcyclobutane-1 - carboxylic acid (CAS: 34970-18-8).
  • the title compound was purified by reverse phase HPLC (Table 2, Method 1 ) to afford an off-white solid (58 mg, 57%).
  • reaction vessel was charged with (R)-2-((1 ,1 ,1 -trifluoropropan-2-yl)oxy)isonicotinonitrile (3.3 g, 15.3 mmol) and solvated in THF (50.0 mL). The reaction was set to stir at RT and next cooled to 0 °C. Cyclopropylmagnesium bromide solution (0.5M in THF, 64 mL, 32.1 mmol) was added dropwise at 0 °C. The reaction was stirred at 0 °C for 1 h. 6M HCI (10 mL) was added at 0 °C and the reaction was allowed to warm to RT and stirred at RT for 15 mins.
  • a reaction vessel was charged with cyclopropyl (2-(((R)-1 ,1 ,1 -trifluoropropan-2- yl)oxy)pyridin-4-yl)methanamine (1.48 g, 5.69 mmol) and di-tert-butyl decarbonate (2.0 mL, 8.53 mmol) and solvated in DCM (30.0 mL) at RT. Triethylamine (2.4 mL, 17.1 mmol) was added dropwise and the reaction was stirred at RT for 4 h. The reaction was next concentrated in vacuo and partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound as an off-white solid (1 .58 g, 77%).
  • a reaction vessel was charged with te/Y-butyl (cyclopropyl(2-(((R)-1 ,1 ,1 -trifluoropropan-2- yl)oxy)pyridin-4-yl)methyl)carbamate (isomer 2, 720 mg, 2.0 mmol) and dissolved in DCM (15.0 mL). 3M Hydrogen chloride in CPME (13.0 mL, 40.0 mmol) was added dropwise at RT. The reaction was stirred at RT for 18 h. The reaction was concentrated in vacuo to afford the title compound (625 mg, 94%) as an off-white solid which was use directly in the subsequent reaction without further purification.
  • the title compound was prepared using an analogous reaction protocol to that described for Example 1 : 3,3-Difluoro-/V-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)cyclobutane-1 - carboxamide, from the appropriate starting materials cyclopropyl(2-(((R)-1 ,1 ,1 - trifluoropropan-2-yl)oxy)pyridin-4-yl)methanamine dihydrochloride and 3,3- difluorocyclobutane-1 -carboxylic acid (CAS: 107496-54-8).
  • the crude reaction was purified by flash column chromatography (cyclohexane to EtOAc gradient elution) to afford the title compound as a white solid (53.9 mg, 39%).
  • reaction vessel was charged with ((R)-6-((1 ,1 ,1-trifluoropropan-2-yl)oxy)pyrimidine-4- carbonitrile (Example 2, step (i), 2.87 g, 13.2 mmol) and solvated in THF (40 mL). The reaction was set to stir at RT and next cooled to 0 °C. Cyclopropylmagnesium bromide solution (0.5M in THF, 56 mL, 27.8 mmol) was added dropwise at 0 °C. The reaction was stirred at 0 °C for 1 hour. 6M HCI (10 mL) was added at 0 °C and the reaction was allowed to warm to RT and stirred at RT for 15 mins.
  • a reaction vessel was charged with cyclopropyl(6-(((R)-1 ,1 ,1-trifluoropropan-2- yl)oxy)pyrimidin-4-yl)methanamine (1.60 g, 6.12 mmol) and di-tert-butyl decarbonate (2.1 mL, 9.19 mmol) and solvated in DCM (35.0 mL) at RT. Triethylamine (2.6 mL, 18.4 mmol) was added dropwise and the reaction was stirred at RT for 24 h. The reaction was next concentrated in vacuo and partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound as an off-white solid (1 .23 g, 56%).
  • a reaction vessel was charged with te/Y-butyl (cyclopropyl(6-(((R)-1 ,1 ,1 -trifluoropropan-2- yl)oxy)pyrimidin-4-yl)methyl)carbamate (isomer 2, 105 mg, 0.29 mmol) and dissolved in DCM (3.0 mL). 3M Hydrogen chloride in CPME (1.9 mL, 5.81 mmol) was added dropwise at RT. The reaction was stirred at RT for 20 h. The reaction was concentrated in vacuo to afford the title compound (82 mg, 85%) as an off-white solid which was use directly in the subsequent reaction without further purification.
  • the title compound was prepared using an analogous reaction protocol to that described for Example 1 : 3,3-Difluoro-/V-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)cyclobutane-1 - carboxamide, from the appropriate starting materials cyclopropyl(6-(((R)-1 ,1 ,1 - trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methanamine dihydrochloride and 3,3- difluorocyclobutane-1 -carboxylic acid (CAS: 107496-54-8).
  • the crude reaction was purified by flash column chromatography (cyclohexane to EtOAc gradient elution) to afford the title compound as a white solid (59.8 mg, 64%).
  • the cell line used was a stably transfected CH0-K1 cell line with constitutive Kv7.2/7.3 expression.
  • CHO-K1/KV7.2/KV7.3 cells were maintained in the following culture media:
  • intracellular solution 120 KCI, 5.74 CaCI2, 1.75 MgCI2, 10 EGTA, 10 HEPES, 5 Na2ATP, pH 7.2, adjusted to 315 mOsm with sucrose.
  • Data were reviewed in Sophion Analyser version 6.5.2 (Sophion Bioscience) for recording quality and filters were applied to remove any failed wells. Leak subtraction was applied to all recordings. Data filters for multihole QChips were typically: seal resistance >4 MQ, capacitance >20 pF, baseline VHalf between 0 to -40 mV, baseline holding current between -2 to 2 nA, baseline steady state current at 20 mV >4 nA unless otherwise stated.

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Abstract

The present invention relates to compounds of formula (I) as defined in the specification capable of promoting the opening of Kv7.2/Kv7.3 potassium channels, a pharmaceutical composition comprising them, and their use as a drug, particularly in the treatment of disorders of the central nervous system (CNS), such as, for example, epilepsy and neurodegenerative disorders, and of the peripheral nervous system (PNS), such as, for example, chronic and neuropathic pain.

Description

“Activating compounds of potassium channels KV7.2/KV7.3”
FIELD OF THE INVENTION
The present invention relates to compounds capable of promoting the opening of Kv7.2/7.3 potassium channels and their use as a drug, particularly in the treatment of disorders of the central nervous system (CNS), e.g., epilepsy and neurodegenerative disorders, and of the peripheral nervous system (PNS), e.g., chronic and neuropathic pain.
STATE OF THE ART
Voltage-gated potassium (Kv) channels conduct potassium (K+) ions across cell membranes in response to changes in membrane potential and can therefore regulate cellular excitability by modulating (increasing or decreasing) the cell's electrical activity.
Functional Kv channels exist as multimeric structures formed by the association of four alpha and four beta subunits. Alpha subunits comprise six transmembrane domains, a poreforming loop, and a voltage sensor and are arranged symmetrically around a central pore. Beta or auxiliary subunits interact with alpha subunits and can modify the properties of the channel complex to include, but not limited to, alterations in electrophysiological or biophysical properties of the channel, levels, or expression patterns.
Nine families of Kv channel alpha subunits have been identified, referred to as Kv1 -Kv9. The Kv7 channel family consists of at least five members including Kv7.1 , Kv7.2, Kv7.3, Kv7.4, and Kv7.5. Alternatively, the members of this family are referred to by the gene names KCNQ1 , KCNQ2, KCNQ3, KCNQ4, and KCNQ5, respectively (Dalby-Brown et al., Current Topics in Medicinal Chemistry, 2006, 6(10), 999-1023).
As mentioned above, neuronal Kv7 potassium channels play a role in the control of neuronal excitation. Kv7 channels, particularly the Kv7.2/Kv7.3 heterotetramers, underlie the M- current (Wang et al Science. 1998 Dec 4;282(5395): 1890-1893).
The M current has a characteristic time and voltage dependence that results in the stabilization of the membrane potential in response to multiple excitatory stimuli. Thus, M current is involved in the control of neuronal excitability (Delmas & Brown, Nature, 2005, 6, 850-862).
The M current is a noninactivating potassium current found in many neuronal cell types. In each cell type, it is dominant in the control of membrane excitability being the only sustained current in the range of action potential initiation (Marrion, Annual Review Physiology 1997, 59, 483-504).
The five members of this family of ion channels differ in their expression patterns. Expression of Kv7.1 is restricted to the heart, peripheral epithelium, and smooth muscle, whereas expression of Kv7.2, Kv7.3, Kv7.4, and Kv7.5 appears to be dominant in the nervous system that includes the hippocampus, cortex, ventral tegmental area, and dorsal root ganglion neurons. Kv7.4 is a subtype selectively expressed in the auditory pathway including hair cells of the inner ear. In addition to neurons, Kv7.4 and Kv7.5 are also expressed in various smooth muscle cells (Greene & Hoshi, Cellular and Molecular Life Sciences, 2017, 74(3), 495-508).
The KCNQ2 and KCNQ3 genes appear to be mutated in an inherited form of epilepsy known as benign familial neonatal seizures (Rogawski, Trends in Neuroscience 2000, 23, 393-398). Proteins encoded by the KCNQ2 and KCNQ3 genes are localized in pyramidal neurons of the human cortex and hippocampus, regions of the brain associated with seizure generation and propagation (Cooper et al., Proceedings National Academy of Science U S A, 2000, 97(9), 4914-4919).
In addition, mRNAs for Kv7.2, Kv7.3, and Kv7.5 are expressed in astrocytes and glial cells. Thus, Kv7.2, Kv7.3, and Kv7.5 channels may help modulate synaptic activity in the CNS and contribute to the neuroprotective effects of KCNQ channel activators (Noda, et al., Society for Neuroscience Abstracts 2003, 53.9), which would be relevant to the treatment of neurodegenerative disorders such as, but not limited to, Alzheimer's disease, Parkinson's disease, and Huntington's chorea. mRNAs for Kv7.2 and Kv7. 3 are found in regions of the brain associated with anxiety and emotional behaviors such as depression and bipolar disorder, for example the hippocampus, ventral tegmental area, and amygdala (Saganich, et al., Journal of Neuroscience 2001 , 21 (13), 4609-4624; Friedman et al., Nat Commun., 2016, 7, 11671 ).
Kv7.2/Kv7.3 channels have also been reported to be upregulated in models of neuropathic pain (Wickenden, et al, Society for Neuroscience Abstracts 2002, 454.7), and modulators of potassium channels have been hypothesized to be active in both neuropathic pain and epilepsy (Schroder et al., Neuropharmacology 2001 , 40(7), 888-898). In addition to a role in neuropathic pain, mRNA expression for Kv7.2-5 in the trigeminal and dorsal root ganglia and in the trigeminal caudal nucleus implies that activators of these channels may also influence sensory processing of migraine pain (Goldstein, et al. Society for Neuroscience Abstracts 2003, 53.8).
Retigabine and flupirtine are known Kv7.2/Kv7.3 potassium channel activating compounds that have been used in the treatment of epilepsy, migraine, neuropathic pain, acute pain, and tinnitus. Retigabine has been withdrawn from the market because of its adverse side effects, particularly urinary retention and changes in retinal and skin pigmentation. Flupirtine should be used by individuals who do not respond to other analgesic treatments and for no longer than two weeks because of its hepatic toxicity. SUMMARY OF THE INVENTION
The Applicant has addressed the problem of providing novel therapies for the treatment of disorders of the central nervous system (CNS), e.g., epilepsy and neurodegenerative disorders, and the peripheral nervous system (PNS), e.g., chronic and neuropathic pain.
The Applicant focused its attention on potassium channel activating compounds Kv7.2/7.3, initiating research work that could provide alternative compounds to retigabine and flupirtine.
After extensive experimentation, the Applicant identified a number of novel compounds capable of acting as drugs, particularly for the treatment of disorders that are modulated by Kv7.2/7.3 potassium channels.
In particular, as demonstrated in the examples in the following experimental portion, the Applicant has identified a number of compounds capable of acting as activators of Kv7.2/7.3 potassium channels.
Based on the information known to the man skilled in the art, Applicant believes that these compounds may be effective in the treatment of a variety of disorders of the central nervous system (CNS), e.g., epilepsy and neurodegenerative disorders, and the peripheral nervous system (PNS), e.g., chronic and neuropathic pain.
Thus, in a first aspect, the present invention relates to a Kv7.2/Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, having the following general formula (I) wherein
R1 is represented by A1 — L1 — , wherein
L1 is a methylene group, optionally substituted with a CR’R”R”’, wherein R’, R” and R’”, equal or different each other, are hydrogen atom, OH, CN, optionally halogenated C1-6 linear or branched alkyl group, optionally halogenated C1-3 alkoxy group, five to six membered heterocycle comprising one oxygen atom, or R’ and R” together form an aliphatic ring having 3 to 6 carbon atoms,
A1 is an aromatic ring comprising one or two nitrogen atoms, optionally substituted by one or more substituents selected from
(i) a halogen atom,
(ii) a linear or branched C1 -C6 alkyl chain, optionally substituted with one or more halogen atoms, and
(iii) a linear or branched C1 -C6 alkoxy chain, optionally substituted with one or more halogen atoms, or with C3-C6 cycloalkyl, or with 3-6 members heterocycloalkyl, R2 is a ring selected from:
(i) a monocyclic aliphatic ring having three to six members, optionally containing one or more heteroatoms selected from the group consisting of N and 0,
(ii) a condensed or bridged bicyclic ring having five to ten members, optionally containing one or more heteroatoms selected from the group consisting of N and 0, and
(iii) a spiro residue comprising two aliphatic rings, wherein each of said two aliphatic rings has three to six members, and optionally contains one or more heteroatoms selected from the group consisting of N and 0, wherein any one of such rings (i), (ii) and (iii) are unsubstituted or substituted with one or more substituents selected from the group consisting of a. halogen atom, b. hydroxy group, c. hydroxy C1 -C3 alkyl group, d. optionally halogenated C1 -3 alkyl group, e. optionally halogenated C1 -3 alkoxy group, f. monocyclic aliphatic ring having three to six members, optionally substituted by a halogen atom, an optionally halogenated C1 -3 alkyl group or an optionally halogenated C1 -3 alkoxy group, and g. aryl group, optionally substituted by a halogen atom, an optionally halogenated C1 -3 alkyl group or an optionally halogenated C1 -3 alkoxy group.
In a second aspect, the present invention relates to a Kv7.2/Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to the first aspect of the present invention for use as a drug.
In a third aspect, the present invention relates to a Kv7.2/Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to the first aspect of the present invention, for use in the treatment of disorders that are modulated by Kv7.2/Kv7.3 potassium channels, preferably in the treatment of central nervous system (CNS) and peripheral nervous system (PNS) disorders.
In a fourth aspect, the present invention relates to a pharmaceutical composition comprising (i) a Kv7.2/7.3 potassium channel activating compound, or a pharmaceutically acceptable salt thereof, according to the first aspect of the present invention, and (ii) at least one pharmaceutically acceptable excipient.
Advantageously, the pharmaceutical composition according to the fourth aspect of the present invention can be used in the treatment of disorders that are modulated by Kv7.2/7.3 potassium channels, preferably in the treatment of central nervous system (CNS) and peripheral nervous system (PNS) disorders.
In a fifth aspect, the present invention relates to a method for treating disorders that are modulated by Kv7.2/7.3 potassium channels in a subject in need thereof comprising administering a therapeutically effective amount of a Kv7.2/7.3 potassium channel activating compound, or a pharmaceutically acceptable salt thereof, according to the first aspect of the present invention.
For the purposes of this description and the claims that follow, the phrase "pharmaceutically acceptable" is intended to define, without any particular limitation, any material suitable for the preparation of a pharmaceutical composition to be administered to a living being.
For the purposes of this description and the claims that follow, the phrase "therapeutically effective amount" means an amount of compound sufficient to alleviate, arrest, partially arrest, remove or delay the clinical manifestations of a certain disease and its complications in a therapeutic treatment comprising the administration of said compound.
For the purposes of this description and the claims that follow, the term "treatment" or "treating" means the management and care of a patient for the purpose of alleviating, arresting, partially arresting, removing or delaying the progress of the clinical manifestation of disease. The patient to be treated is preferably a mammal, particularly a human being.
For the purposes of the present description and the following claims, the expression "for example" and the terms "preferably", "advantageously", "particularly", and the like are used to better illustrate the invention without adding any limitation to the scope of the invention, unless otherwise indicated.
For the purposes of the present description and the claims that follow, the phrase " Kv7.2/7.3 potassium channel activator" refers to a compound that causes a shift in voltage dependence for channel opening to more negative potentials, meaning that the Kv7.2/7.3 potassium channels open to more negative potentials in the presence of said compound, facilitating the transmission of ions through them.
DETAILED DESCRIPTION OF THE INVENTION
A first aspect of the present invention relates to a Kv7.2/Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, having the general formula (I) described above.
In an embodiment of the present invention, L1 is an unsubstituted methylene group (-CH2- )■
In an embodiment of the present invention, L1 is a methylene group substituted with a - CR’R”R”’ group. In an embodiment of the present invention, at least one of R’, R” and R’” is a hydrogen atom.
In an embodiment of the present invention, at least two of R', R" and R'" are hydrogen atoms.
In an embodiment of the present invention, all R', R" and R'" are hydrogen atoms.
In an embodiment of the present invention, at least one of R’, R” and R’” is a hydroxy group.
In an embodiment of the present invention, at least one of R’, R” and R’” is a CN group.
In an embodiment of the present invention, at least one of R’, R” and R’” is a C1-3 alkyl group, optionally substituted by one or more fluorine or chlorine atom.
In an embodiment of the present invention, at least one of R’, R” and R’” is a C1-2 alkyl group, optionally substituted by one or more fluorine or chlorine atom.
In an embodiment of the present invention, at least one of R’, R” and R’” is a Ci alkyl group, optionally substituted by one or more fluorine or chlorine atom.
In an embodiment of the present invention, at least one of R’, R” and R’” is selected from the group consisting of -CH3, -CH2F, -CHF2, and -CF3.
In an embodiment of the present invention, at least one of R’, R” and R’” is a C1-3 alkoxy group, optionally substituted by one or more fluorine or chlorine atom.
In an embodiment of the present invention, at least one of R’, R” and R’” is a C1-2 alkoxy group, optionally substituted by one or more fluorine or chlorine atom.
In an embodiment of the present invention, at least one of R’, R” and R’” is a Ci alkoxy group, optionally substituted by one or more fluorine or chlorine atom.
In an embodiment of the present invention, at least one of R’, R” and R’” is selected from the group consisting of -OCH3, -OCH2F, -OCHF2, and -OCF3.
In an embodiment of the present invention, at least one of R’, R” and R’” is tetrahydrofuran.
In an embodiment of the present invention, at least one of R’, R” and R’” is tetrahydropyran.
In an embodiment of the present invention, any two of R’, R” and R’” together form an aliphatic ring having 3 carbon atoms.
In an embodiment of the present invention, any two of R’, R” and R’” together form an aliphatic ring having 4 carbon atoms.
In an embodiment of the present invention, any two of R’, R” and R’” together form an aliphatic ring having 5 carbon atoms.
In an embodiment of the present invention, any two of R’, R” and R’” together form an aliphatic ring having 6 carbon atoms.
In an embodiment of the present invention, A1 is an aromatic ring selected from the group consisting of pyrrole, pyridine, pyridazine, pyrimidine, and pyrazine. In an embodiment of the present invention, A1 is substituted by one or more halogen atoms selected from fluoride, chloride, bromide, and iodide, preferably fluoride and chloride.
In an embodiment of the present invention, A1 is substituted by a linear or branched C1 -C3 alkyl chain substituted by one or more halogen atoms selected from fluoride, chloride, bromide, and iodide, preferably fluoride and chloride.
In an embodiment of the present invention, A1 is substituted by a linear or branched C1 -C3 alkoxy chain substituted by one or more halogen atoms selected from fluoride, chloride, bromide, and iodide, preferably fluoride and chloride.
In an embodiment of the present invention, A1 is substituted by a linear or branched C1 -C3 alkoxy chain substituted by a cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein one or more carbon atom is optionally substituted by a heteroatom selected from 0, N and S, such as for example, oxirane, aziridine, oxetane, azetidine, thietane, tetrahydrofuran, pyrrolidine, pyrazolidine, imidazoline, thiolane, oxazolidine, isoxazolidine, thiazolidine, 1 ,3-oxathiolane, piperidine, oxane, thiane, piperazine, morpholine, and thiomorpholine.
According to an embodiment of the present invention, A1 is substituted by one or more substituent selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, wherein one or more hydrogen atoms is substituted by a halogen atom, preferably fluoride and chloride, more preferably fluoride.
According to an embodiment of the present invention, A1 is substituted by one or more substituent selected from methoxy, ethoxy, propoxy, and isopropoxy, wherein one or more hydrogen atoms is substituted by a halogen atom, preferably fluoride and chloride, more preferably fluoride.
According to a preferred embodiment of the present invention, A1 is substituted by one or more substituent selected from CF3-CH2-O- or CF3-CH(CH3)-O-
In an embodiment of the present invention, R1 is represented by any one of the following structural formulas (a) to (e): wherein L1 has the meaning described above, and G1 is a C1-3 alkoxy group, optionally substituted by one or more halogen atoms.
In a preferred embodiment of the present invention R1 is represented by any one of the following structural formulas (f), (g), (h) and (i): wherein L1 has the meaning described above, and G1 is a C1-3 alkoxy group, optionally substituted by one or more halogen atoms.
In an embodiment of the present invention, G1 is a C2-3 alkoxy group, optionally substituted by one or more fluorine or chlorine atoms.
In an embodiment of the present invention, G1 is a C2-3 alkoxy group, optionally substituted by one or more fluorine atoms.
In an embodiment of the present invention, G1 is a C3 alkoxy group, optionally substituted by one or more fluorine atoms.
In an embodiment of the present invention, G1 is a C2 alkoxy group, optionally substituted by one or more fluorine atoms.
In a preferred embodiment of the present invention G1 is CF3-CH2-O- or CF3-CH(CH3)-O-.
In an embodiment of the present invention, R2 is a monocyclic aliphatic ring selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahydrofuran, piperidine, and tetrahydropyran, preferably cyclopropane, cyclobutane, and tetrahydropyran, more preferably cyclopropane.
In an embodiment of the present invention, R2 is a condensed bicyclic ring comprising at least one aliphatic cycle. In this embodiment, the condensed bicyclic ring can have one aliphatic cycle condensed with an aromatic cycle, or two condensed aliphatic cycles. Preferably, R2 is a condensed bicyclic ring comprising two condensed aliphatic cycles.
In an embodiment of the present invention, R2 is a condensed bicyclic ring selected from the group consisting of bicyclo(3.1 ,0)hexane, 1 ,2,3,4-tetrahydroisoquinoline, 2,3- dihydrobenzofuran (coumaran), and 3, 4-dihydro-2H-1 -benzopyran (chromane), preferably bicyclo(3.1 ,0)hexane, 2,3-dihydrobenzofuran (coumaran), and 3,4-dihydro-2H-1 - benzopyran (chromane).
In an embodiment of the present invention, R2 is a bridged bicyclic ring selected from the group consisting of bicyclo(1 .1 ,1 )pentane, bicyclo(2.1 ,1 )hexane, 2-oxabicyclo[2.1 ,1 ]hexane, bicyclo[2.2.1 ]heptane (norbornane), 2-oxa-5-azabicyclo[2.2.1 ]heptane, bicyclo[2.2.2]octane, preferably bicyclo(1 .1 ,1 )pentane, bicyclo(2.1.1 )hexane, 2- oxabicyclo[2.1 ,1 ]hexane, bicyclo[2.2.1 ]heptane (norbornane), bicyclo[2.2.2]octane, more preferably bicyclo(1.1.1 )pentane, bicyclo[2.2.1 ]heptane (norbornane), and bicyclo[2.2.2]octane. In an embodiment of the present invention, R2 is a spiro residue selected from the group consisting of spiro[2.2]pentane, spiro[2,3]hexane, spiro[2.4]heptane, spiro[2.5]octane, spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane, wherein one carbon atom is optionally replaced by one heteroatom selected from the group consisting of N and 0, such as, for example 1 -oxaspiro[3.4]octane, 5-oxaspiro[3.4]octane, 2-azaspiro[3.4]octane, 6-azaspiro[3.4]octane, and 2-oxa-6- azaspiro[3.4]octane, preferably spiro[2.2]pentane, spiro[2,3]hexane, spiro[2.5]octane, spiro[3.3]heptane, and 5-oxaspiro[3.4]octane.
In an embodiment of the present invention, any one of such rings (i), (ii) and (iii) representing R2 is unsubstituted.
In an embodiment of the present invention, any one of such rings (i), (ii) and (iii) representing R2 is substituted with one or more halogen atoms, preferably with one or more halogen atoms selected from fluorine or chlorine atoms, preferably with one or more fluorine atom, more preferably with one or two fluorine atoms.
In an embodiment of the present invention, any one of such rings (i), (ii) and (iii) representing R2 is substituted with one or more hydroxyl group (-0H).
In an embodiment of the present invention, any one of such rings (i), (ii) and (iii) representing R2 is substituted with one or more hydroxy C1-C3 alkyl group, preferably -CH2OH, -C2H5OH or -C3H7OH, more preferably -CH2OH.
In an embodiment of the present invention, any one of such rings (i), (ii) and (iii) representing R2 is substituted with one or more C1-3 alkyl groups, optionally substituted by one or more fluorine or chlorine atom.
In an embodiment of the present invention, any one of such rings (i), (ii) and (iii) representing R2 is substituted with one or more C1-2 alkyl groups, optionally substituted by one or more fluorine or chlorine atom.
In an embodiment of the present invention, any one of such rings (i), (ii) and (iii) representing R2 is substituted with one or more Ci alkyl groups, optionally substituted by one or more fluorine or chlorine atom.
In an embodiment of the present invention, any one of such rings (i), (ii) and (iii) representing R2 is substituted with one or more substituents selected from the group consisting of -CH3, -CH2F, -CHF2, and -CF3, preferably -CF3.
In an embodiment of the present invention, any one of such rings (i), (ii) and (iii) representing R2 is substituted with one or more C1-3 alkoxy groups, optionally substituted by one or more fluorine or chlorine atom.
In an embodiment of the present invention, any one of such rings (i), (ii) and (iii) representing R2 is substituted with one or more C1-2 alkoxy groups, optionally substituted by one or more fluorine or chlorine atom. In an embodiment of the present invention, any one of such rings (i), (ii) and (iii) representing R2 is substituted with one or more Ci alkoxy groups, optionally substituted by one or more fluorine or chlorine atom.
In an embodiment of the present invention, any one of such rings (i), (ii) and (iii) representing R2 is substituted with one or more substituents selected from the group consisting of -OCH3, -OCH2F, -OCHF2, and -OCF3.
In an embodiment of the present invention, any one of such rings (i), (ii) and (iii) representing R2 is substituted with one or more cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted by a halogen atom, an optionally halogenated C1 -3 alkyl group or an optionally halogenated C1 -3 alkoxy group.
In an embodiment of the present invention, any one of such rings (i), (ii) and (iii) representing R2 is substituted with one or more phenyl, tolyl, xylyl, naphthyl, anthryl, phenanthryl, pyrenyl, biphenylyl, terphenylyl, benzyl, phenethyl, styryl, cinnamyl, furanyl, thienyl, or pyridyl, optionally substituted by a halogen atom, an optionally halogenated C1 -3 alkyl group or an optionally halogenated C1 -3 alkoxy group.
Advantageously, the first aspect of the present invention relates to a Kv7.2/Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the compounds of the following Table A:
Some compounds of the present invention may exist in tautomeric forms, and the invention includes all tautomeric forms of such compounds unless otherwise noted.
Unless otherwise stated, the structures depicted herein are also intended to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Individual stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the compounds according to the present invention are within the scope of the invention. The present invention includes any diastereomer or enantiomer substantially free of other isomers (>90%, and preferably >95%, free of other stereoisomers on a molar basis), as well as a mixture of such isomers.
Particular optical isomers can be obtained by resolution of racemic mixtures according to conventional processes, for example, by formation of diastereomeric salts, by treatment with an optically active acid or base and subsequent separation of the mixture of diastereomers by crystallization of the corresponding salt followed finally by liberation of the optically active bases from such salts. Examples of appropriate acids include tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorosulfonic acids.
A different process for the separation of optical isomers involves the use of a chiral chromatographic column optimally chosen to maximize the separation of enantiomers. Still another method involves the synthesis of covalent diastereomers by reacting the compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to provide the enantiomerically pure compound. The optically active compounds of the invention can be obtained using active starting materials. These isomers may be in the form of a free acid, a free base, an ester, or a salt. Compounds of the present invention may exist in radiolabeled form, i.e., said compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Radioisotopes of hydrogen, carbon, phosphorus, fluorine, and chlorine include 3H, 14C, 32P, 35S, 18F and 36CI, respectively. Compounds of the present invention that contain these radioisotopes and/or other radioisotopes of other atoms are within the scope of the present invention. The triziated radioisotopes, i.e., 3H, and carbon-14, i.e., 14C, are particularly preferred because of their ease of preparation and detectability.
The radiolabeled compounds of this invention can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by performing the procedures described herein by substituting a non-radiolabeled reagent for a readily available non-radiolabeled reagent.
Compounds according to the present invention are preferably used as salts with pharmaceutically acceptable organic and inorganic acids or bases.
Preferably, the pharmaceutically acceptable organic acids are chosen from the group consisting of oxalic, maleic, methanesulfonic, paratoluenesulfonic, succinic, citric, malic, tartaric and lactic acids.
Preferably, pharmaceutically acceptable organic bases are selected from the group consisting of tromethamine, lysine, arginine, glycine, alanine and ethanolamine.
Preferably, the pharmaceutically acceptable inorganic acids are chosen from the group consisting of hydrochloric, hydrobromic, phosphoric and sulfuric acids.
Preferably, the pharmaceutically acceptable inorganic bases are chosen from the group consisting of hydroxide or carbonate of alkaline or alkaline-earth metals, such as sodium, potassium and calcium.
The compounds of the present invention, or pharmaceutically acceptable salts thereof, can be prepared by a variety of procedures known to a man skilled in the art, some of which are described in the preparations illustrated in the examples of the experimental part. Intermediates and final compounds may be recovered by conventional methods well known in the art, such as, for example, extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. Reagents and starting materials are known and readily available to the man skilled in the art.
Advantageously, the compounds of the present invention are used as a drug, particularly in the treatment of disorders that are modulated by Kv7.2/Kv7.3 potassium channels, preferably in the treatment of central nervous system (CNS) and peripheral nervous system (PNS) disorders.
Central nervous system (CNS) disorders that are preferably treated with the compounds of the present invention are, for example, epilepsy, epileptic syndromes, epileptic symptoms, epilepsy resistant or refractory to treatment, seizures, bipolar disorder, bipolar depression, schizophrenia, psychosis, mania, stress-related disorders, acute stress reactions, major depressive disorder, anxiety, panic attacks, social phobia, sleep disorders, attention deficit hyperactivity disorder, post-traumatic stress disorder, obsessive-compulsive disorder, impulsivity disorders, personality disorders, Huntington's disease, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, tinnitus, and so on.
Advantageously, the central nervous system (CNS) disorders that are preferably treated with the compounds of the present invention are epilepsy, epileptic syndromes, epileptic symptoms, epilepsy resistant or refractory to treatment, seizures, bipolar disorder, bipolar depression, schizophrenia, and amyotrophic lateral sclerosis.
Peripheral nervous system (PNS) disorders that are preferably treated with the compounds of the present invention are, for example, migraine, chronic pain, acute pain, neuropathic pain, visceral pain, inflammatory pain, muscle pain, and so forth.
Advantageously, the peripheral nervous system (PNS) disorders that are preferably treated with the compounds of the present invention are neuropathic pain, chronic pain, visceral pain, and inflammatory pain.
Typically, the compounds of the present invention are administered in the form of a pharmaceutical composition comprising a pharmaceutically acceptable excipient.
Thus, one aspect of the present invention relates to a pharmaceutical composition comprising (i) a Kv7.2/Kv7.3 potassium channel activating compound, or a pharmaceutically acceptable salt thereof, according to the first aspect of the present invention, and (ii) at least one pharmaceutically acceptable excipient.
Preferably, the pharmaceutical composition according to the present invention is for systemic use.
The pharmaceutical composition according to the present invention can be administered orally, parenterally, inhaled (spray, powder or aerosol), rectally, nasally, buccally, vaginally or via an implanted device.
The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
More preferably, the pharmaceutical composition according to the present invention is formulated for oral or parenteral administration.
Preferably, the pharmaceutical composition according to the present invention is prepared in suitable dosage forms comprising an effective amount of at least one compound according to the first aspect of the present invention, a salt thereof with a pharmaceutically acceptable organic or inorganic acid or base, and at least one pharmaceutically acceptable excipient. Examples of suitable dosage forms include tablets, capsules, coated tablets, granules and solutions and syrups for oral administration; suppositories for rectal or vaginal administration; and solutions, suspensions, dispersions or emulsions for administration by injection or infusion.
Preferred dosage forms include tablets, coated tablets, capsules and solutions for oral administration, and aqueous to non-aqueous sterile solutions for administration by injection or infusion.
The amount of compound according to the first aspect of the present invention, or a pharmacologically acceptable salt thereof, present in the pharmaceutical composition of the present invention may vary over a wide range depending on known factors, for example, the type of disease, the seventy of the disease, the body weight of the patient, the dosage form, the route of administration chosen, the number of administrations per day, and the efficacy of the compound itself. However, a person skilled in the art can determine the optimal amount easily and routinely.
Typically, the amount of compound according to the first aspect of the present invention or a pharmacologically acceptable salt thereof in the pharmaceutical composition of the present invention will be such as to provide a level of administration from 0.0001 to 100 mg/kg/day. Preferably, the level of administration is from 0.001 to 50 mg/kg/day, and even more preferably from 0.01 to 10 mg/kg/day.
As known to the man skilled in the art, lower or higher doses than those mentioned above may be required. The specific dosage and treatment regimens for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health status, gender, diet, time of administration, rate of excretion, combination of drugs, seventy and course of disease and the patient's disposition to the disease and the judgment of the treating physician.
The dosage forms of the pharmaceutical composition of the present invention can be prepared according to techniques well known to a man skilled in the pharmaceutical art, including mixing, granulation, compression, dissolution, sterilization, and the like.
Advantageously, such dosage forms are formulated to provide controlled release of the active ingredient over time. In particular, depending on the type of therapy, the required release time may be very short, normal or long.
Preferably, the pharmaceutical composition of the present invention is contained in a single dosage form, to be administered once a day, or several times (two, three or four) a day.
The pharmaceutically acceptable excipient may be selected from the group consisting of thickeners, glidants, binders, disintegrants, fillers, diluents, preservatives, stabilizers, surfactants, buffers, flu idizers, lubricants, humectants, absorbents, salts to regulate osmotic pressure, emulsifiers, flavorings, colorants, sweeteners, and the like. Particularly preferred excipients include water, ethanol, propylene glycol, glycerol, polyethylene glycols, polyoxamers, mono-, di- and tri-glycerides, coconut oil, palm oil, sodium carbonate, magnesium carbonate, magnesium stearate, stearic acid, talc, sugars, lactose, mannitol, sorbitol, polysorbate, povidone, pectin, dextrin, starch (especially corn starch), sodium starch glycolate, croscarmellose sodium, sucrose, cyclodextrin, gelatin, microcrystalline cellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, povidone, glyceryl monostearate, hypromellose, cocoa butter, titanium dioxide (E171 ), red iron oxide and yellow iron oxide (E172), and the like.
EXPERIMENTAL PART
The following examples are intended to further illustrate the present invention, but do not limit it.
EXAMPLE 1
Analytical Methods
Analytical data is included within the procedures below, in the illustrations of the general procedures, or in the tables of examples. Unless otherwise stated, all 1 H NMR data were collected on a Broker Avance 400 MHz equipped with 5 mm QNP probe or Broker Avance III 400 MHz, 5 mm BBFO probe or Fourier 300 MHz, 5 mm dual probe instruments and chemical shifts are quoted in parts per million (ppm). LC/MS was performed on Acquity UPLC H-Class (quaternary pump/PDA detector) coupled to QDa Mass Spectrometer or Acquity UPLC (binary pump/PDA detector) coupled to ZQ Mass Spectrometer or Acquity UPLC with Waters DAD coupled to SQD2 Mass Spectrometer. LC/MS data is referenced to LC/MS conditions using the method number provided in Table 1.
Table 1. LC/MS analysis methods
Purification Methods
For the general procedures, intermediate and final compounds may be purified by any technique or combination of techniques known to one skilled in the art. Some examples that are not limiting include:
• flash chromatography performed on the COMBIFLASH® Companion purification system or the Biotage SP1 purification system, products were purified using an Isolute® SPE Si II cartridge, (‘Isolute SPE Si cartridge’ refers to a pre-packed polypropylene column containing unbonded activated silica with irregular particles with average size of 50 pm and nominal 60A porosity), and a solvent or combination of solvents (cyclohexane, EtOAc, DCM, MeOH, MeCN, water, etc.) that elutes the desired compounds; • RP-HPLC purification performed on Waters Mass Directed FractionLynx systems (2767 autosampler, System Fluidics Organiser, 2998 Photodiode array, 2545 pump, 3x515 pump, QDa mass spectrometer), Gilson system (GX281 autosampler, 322 pump, 155 UV/vis detector), Interchim PuriFlash 4125 coupled to a UV DAD (see Table 2 for some non-limiting conditions);
• SFC purification performed on a Waters Thar PreplOO system (P200 CO2 pump, 2545 modifier pump, 2998 UV/VIS detector, 2767 liquid handler with Stacked Injection Module) or Waters Thar Investigator semi preparative system (Waters Fluid Delivery Module, 2998 UV/VIS detector, Waters Fraction Collection Module) (see Table 2 for some non-limiting conditions);
• recrystallization from an appropriate solvent (MeOH, EtOH, /-PrOH, EtOAc, toluene, etc.) or combination of solvents (EtOAc/heptane, EtOAc/MeOH, etc.);
• precipitation from a combination of solvents (DMF/water, DMSO/DCM, EtOAc/heptane, etc.);
• trituration with an appropriate solvent (EtOAc, DCM, MeCN, MeOH, EtOH, /-PrOH, n-PrOH, etc.);
• extractions by dissolving a compound in a liquid and washing with an appropriately immiscible liquid (DCM/water, EtOAc/water, DCM/saturated NaHCOs, EtOAc/saturated NaHCOs, DCM/10% aqueous HCI, EtOAc/10% aqueous HCI, etc.);
• and/or distillation (simple, fractional, Kugelrohr, etc.).
Descriptions of these techniques can be found in the following references: Gordon, A. J. and Ford, R. A. "The Chemist’s Companion”, 1972; Palleros, D. R. “Experimental Organic Chemistry”, 2000; Still, W. C., Kahn and M. Mitra, A. J. Org. Chem. 1978, 43(14), 2923- 2925; Yan, B. “Analysis and Purification Methods in Combinatorial Chemistry” 2003; Harwood, L. M., Moody, C. J. and Percy, J. M. “Experimental Organic Chemistry: Standard and Microscale, 2nd Edition”, 1999.
Table 2. RP-HPLC and SFC purification methods Preparations and Examples
Starting materials/reagents are commercially available from standard suppliers incl. but not limited to Sigma-Aldrich (including Fluka and Discovery CPR), Fluorochem, Enamine etc. Reagent/reactant names given are as named on the commercial bottle or as generated by IIIPAC conventions or ChemDraw 20.1 . None of the specific conditions and reagents noted herein is to be construed as limiting the scope of the invention and are provided for illustrative purposes only.
Abbreviations
°C Degrees Celsius
CAS Chemical Abstracts Service
CDI Carbonyldiimidazole
CPME Cyclopentyl methyl ether
DAD Diode array detector
DCM Dichloromethane
DMSO Dimethyl sulfoxide
Ee Enantiomeric excess
EtOAc Ethyl acetate
EtOH Ethanol h Hour(s)
HCI Hydrogen chloride
HCOOH Formic acid
IMS Industrial methylated spirits
LC/MS Liquid Chromatography/Mass Spectrometry m/z Mass-to-charge ratio
MeCN Acetonitrile
MeOH Methanol
MHz Megahertz
Min Minute(s)
MS Mass Spectrometer
NaHCOs Sodium hydrogen carbonate
Na2SO4 Sodium sulphate
NH4CI Ammonium chloride
NH4HCO3 Ammonium hydrogen carbonate
NMR Nuclear Magnetic Resonance
/-PrOH Propan-2-ol n-PrOH Propan-1-ol
RP-HPLC Reverse Phase-High Performance Liquid Chromatography
Rt Retention time RT Room temperature
SFC Supercritical Fluid Chromatography
THF Tetrahydrofuran
LIPLC Ultra Performance Liquid Chromatography
The synthesis of compounds 1 -94 can be accomplished as described below.
Compound 1
3,3-Difluoro-/V-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)cyclobutane-1- carboxamide
A reaction vessel was charged with 3,3-difluoro-cyclobutanecarboxylic acid (244 mg, 1.79 mmol, CAS: 107496-54-8) and solvated in DCM (10.0 mL). CDI (290 mg, 1.79 mmol) was added and the reaction was set to stir at RT. After 30 min., triethylamine (1 .0 mL, 7.17 mmol) and [2-(2,2,2-trifluoroethoxy)-4-pyridyl]methanamine dihydrochloride (500 mg, 1.79 mmol, CAS: 2460508-43-2) were added. The reaction was stirred at RT for 12 h. The reaction was next partitioned between DCM and a saturated aqueous NH4CI solution. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) and subsequently crystallised from heptane I ethyl acetate to afford the title compound a white solid (460 mg, 79%).
1H NMR (400 MHz, DMSO-de) d 8.61 (t, J=5.8 Hz, 1 H), 8.12 (d, J=5.3 Hz, 1 H), 6.98 (dd, J=1 .3, 5.3 Hz, 1 H), 6.80 (s, 1 H), 4.98 (q, J=9.1 Hz, 2H), 4.31 (d, J=6.0 Hz, 2H), 3.02-2.93 (m, 1 H), 2.77-2.68 (m, 4H).
LC/MS (Table 1 , Method A) Rt = 4.25 min; MS m/z: 325 [M+H]+.
Compound 2
(/?)-3,3-Dimethyl-/V-((6-((1,1,1 -trifluoropropan-2-yl)oxy)pyrimidin-4- yl)methyl)cyclobutane-1 -carboxamide
(i) (R)-6-((1 , 1 , 1 -T rifluoropropan-2-yl)oxy)pyrim idine-4-carbonitrile
A reaction vessel was charged with 6-chloropyrimidine-4-carbonitrile (5.00 g, 35.8 mmol, CAS: 939986-65-9) and solvated in MeCN (150 mL). (R)-1 ,1 ,1 -Trifluoro-2-propanol (4.70 g, 41.2 mmol, CAS: 75-89-8) was added, and the solution was stirred at RT until dissolution had occurred. 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (6.2 mL, 41.2 mmol, 1.15 eq) was added dropwise and the reaction was stirred at RT for 24 h. The reaction was concentrated in vacuo. The reaction was next partitioned between DCM and a saturated aqueous NH4CI solution. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound as a white solid (6.7 g, 86%). 1H NMR (400 MHz, CDCh) d 8.87 (s, 1 H), 7.19 (d, J=1 .0 Hz, 1 H), 5.85 (septet, J=6.4 Hz, 1 H), 1.55 (d, J=6.6 Hz, 3H).
LC/MS (Table 1 , Method B) Rt = 1.58 min; MS m/z: 218 [M+H]+.
(ii) Te/t-Butyl (R)-((6-((1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methyl)carbamate
A reaction vessel was charged with (R)-6-((1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyrimidine-4- carbonitrile (2.6 g, 12.0 mmol) and di-tert-butyl decarbonate (6.9 mL, 29.9 mmol) and solvated in IMS (148 mL). The reaction was evacuated and placed under an argon atmosphere. 10% palladium on carbon (637 mg, 0.05 mmol) was added and the reaction was evacuated and placed under a hydrogen atmosphere (x3). The reaction was stirred at RT under a hydrogen atmosphere for 12 h. The reaction was evacuated and purged with argon (x3). The reaction was diluted with DCM, filtered through celite and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) and crystallised from heptane to afford the title compound as a white solid (2.1 g, 55%).
1H NMR (400 MHz, DMSO-de) d 8.70 (s, 1 H), 6.78 (s, 1 H), 5.83 (septet, J=6.5 Hz, 1 H), 5.29 (s, 1 H), 4.37 (t, J=5.29 Hz, 2H), 1.50 (d, J=6.6 Hz, 3H), 1.47 (broad s, 9H).
LC/MS (Table 1 , Method B) Rt = 1.69 min; MS m/z: 322 [M+H]+.
(iii) (R)-(6-((1 ,1 ,1 -Trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methanamine monohydrochloride
A reaction vessel was charged with te/Y-butyl (R)-((6-((1 ,1 ,1 -trifluoropropan-2- yl)oxy)pyrimidin-4-yl)methyl)carbamate (2.0 g, 6.22 mmol) and dissolved in DCM (40 mL). To the reaction was added 4 M hydrogen chloride in dioxane (16.0 mL, 62.2 mmol) dropwise and the mixture was stirred at RT for 24 h. The reaction suspension was filtered in vacuo, washed with DCM and dried in vacuo to afford the title compound as a white solid (1.8 g, 98%).
1H NMR (400 MHz, DMSO-de) d 8.91 (d, J=1 .0 Hz, 1 H), 8.65 (s, 3H), 7.26 (d, J=1 .0 Hz, 1 H), 6.01 (septet, J=6.5 Hz, 1 H), 4.18-4.14 (q, J=5.9 Hz, 2H), 1.50 (d, J=6.5 Hz, 3H).
LC/MS (Table 1 , Method C) Rt = 1 .11 min; MS m/z: 222 [M+H]+.
(iv) (R)-3,3-Dimethyl-/V-((6-((1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methyl) cyclobutene-1 -carboxamide
The title compound was prepared using an analogous reaction protocol to that described for Example 1 : 3,3-Difluoro-N-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)cyclobutane-1 - carboxamide, from the appropriate starting materials (R)-(6-((1 ,1 ,1 -trifluoropropan-2- yl)oxy)pyrimidin-4-yl)methanamine dihydrochloride and 3,3-dimethylcyclobutane-1 - carboxylic acid (CAS: 34970-18-8). The title compound was purified by reverse phase HPLC (Table 2, Method 1 ) to afford an off-white solid (58 mg, 57%). 1 H NMR (400 MHz, DMSO-de) 5 8.77 (s, 1 H), 8.27 (dd, J=5.8, 5.8 Hz, 1 H), 6.78 (s, 1 H), 6.01 - 5.93 (m, 1 H), 4.28 (dd, J=3.9, 5.6 Hz, 2H), 3.11 -3.05 (m, 1 H), 1.97-1.82 (m, 4H), 1.47 (d, J=6.6 Hz, 3H), 1.15 (s, 3H), 1.04 (s, 3H).
LC/MS (Table 1 , Method D) Rt = 4.79 min; MS m/z: 332 [M+H]+.
Compounds 3-92
The following compounds 3-92 in Table 3 were prepared from commercial starting materials using similar methods to that described in examples 1 -2 from either [2-(2,2,2- trifluoroethoxy)-4-pyridyl]methanamine dihydrochloride (CAS: 2460508-43-2), (R -(6- ((1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methanamine monohydrochloride, (6-(2,2,2- trifluoroethoxy)pyridin-2-yl)methanamine (CAS: 1250054-65-9), 6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methanamine (CAS: 771584-26-0) or 1 -(6-(2,2,2- trifluoroethoxy)pyrimidin-4-yl)ethan-1 -amine (CAS: 2734906-84-2, WO2021219594) and a commercial acid/acid chloride derivative. The title compounds were purified by standard flash column chromatography or crystallisation unless indicated by RP-HPLC/achiral/chiral SFC purification following the methods outlined in Table 2. Absolute stereochemistry where known or relative stereochemistry as confirmed by additional 2D NMR experiments has been assigned.
An additional stereocomment (Isomer 1 , 2, Relative R*S* isomer 1 , 2, Relative R*R* isomer 1 , 2) has been assigned to a single compound where absolute/relative stereochemistry is unknown. Mixture 1 , 2 etc. has been used to denote an enriched combination of two diastereoisomers.
TABLE 3
Compound 93
/V-(Cyclopropyl(2-(((/?)-1,1,1 -trifluoropropan-2-yl)oxy)pyridin-4-yl)methyl)-3,3- difluorocyclobutane-1 -carboxamide (Isomer 2)
(i) (R)-2-((1 ,1 ,1 -trifluoropropan-2-yl)oxy)isonicotinonitrile
To a suspension of sodium hydride (60%, 721 mg, 18.0 mmol) in THF (65.0 mL) was added (R)-1 ,1 ,1 -Trifluoro-2-propanol (1.87 g, 16.4 mmol, CAS: 75-89-8) at RT and the reaction was allowed to stir at RT for 1 h. 4-Cyano-2 -fluoropyridine (2.0 g, 16.4 mmol, CAS: 3939-14-8) was next added and the reaction was stirred at RT for 24 h. The reaction was concentrated in vacuo and partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound as an off-white solid (3.3 g, 93%).
1H NMR (400 MHz, DMSO-de) d 8.46 (dd, J=1 .0, 5.1 Hz, 1 H), 7.57-7.54 (m, 2H), 5.96-5.88 (m, 1 H), 1.47 (d, J=6.5 Hz, 3H).
(ii) (R)-Cyclopropyl(2-((1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyridin-4-yl)methanone
A reaction vessel was charged with (R)-2-((1 ,1 ,1 -trifluoropropan-2-yl)oxy)isonicotinonitrile (3.3 g, 15.3 mmol) and solvated in THF (50.0 mL). The reaction was set to stir at RT and next cooled to 0 °C. Cyclopropylmagnesium bromide solution (0.5M in THF, 64 mL, 32.1 mmol) was added dropwise at 0 °C. The reaction was stirred at 0 °C for 1 h. 6M HCI (10 mL) was added at 0 °C and the reaction was allowed to warm to RT and stirred at RT for 15 mins. The reaction was next partitioned between EtOAc and a saturated NaHCOs solution. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound as a yellow oil (2.98 g, 75%).
LC/MS (Table 1 , Method C) RT 1 .57 min; MS m/z 261 [M+H]+.
(iii) Cyclopropyl(2-(((R)-1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyridin-4-yl)methanamine (2 Diastereoisomers)
To a solution of (R)-cyclopropyl(2-((1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyridin-4-yl)methanone (2.98 g, 11.5 mmol) in MeOH (80.0 mL) was added ammonium formate (8.69 g, 0.138 mol) and sodium cyanoborohydride (2.89 g, 46.0 mmol). The reaction was set to stir at RT and next heated at 60 °C for 18 h. The reaction was allowed to cool to RT and concentrated in vacuo. The reaction was partitioned between EtOAc and a 10% aqueous sodium hydroxide solution. The organic layers were separated, washed with distilled water, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to DCM:2M NH3 in MeOH (15:1 ), gradient elution) to afford the title compound as a pale yellow oil (1 .90 g, 64%). LC/MS (Table 1 , Method C) RT 1 .57 min; MS m/z 261 [M+H]+.
(iv) Te/t-Butyl (cyclopropyl(2-(((R)-1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyridin-4- yl)methyl)carbamate (Isomer 1 and Isomer 2)
A reaction vessel was charged with cyclopropyl (2-(((R)-1 ,1 ,1 -trifluoropropan-2- yl)oxy)pyridin-4-yl)methanamine (1.48 g, 5.69 mmol) and di-tert-butyl decarbonate (2.0 mL, 8.53 mmol) and solvated in DCM (30.0 mL) at RT. Triethylamine (2.4 mL, 17.1 mmol) was added dropwise and the reaction was stirred at RT for 4 h. The reaction was next concentrated in vacuo and partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound as an off-white solid (1 .58 g, 77%).
The title compound was purified by SFC (Table 2, Method 19) to afford te/Y-butyl (cyclopropyl(2-(((R)-1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyridin-4-yl)methyl)carbamate, isomer 1 (733 mg, 36%, 100% Ee) and te/Y-butyl (cyclopropyl(2-(((R)-1 ,1 ,1 -trifluoropropan-2- yl)oxy)pyridin-4-yl)methyl)carbamate, isomer 2 (723 mg, 35%, 99% Ee).
LC/MS (Table 1 , Method A) RT 5.62 min; MS m/z 361 [M+H]+.
(v) Cyclopropyl(2-(((R)-1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyridin-4-yl)methanamine dihydrochloride (Isomer 2)
A reaction vessel was charged with te/Y-butyl (cyclopropyl(2-(((R)-1 ,1 ,1 -trifluoropropan-2- yl)oxy)pyridin-4-yl)methyl)carbamate (isomer 2, 720 mg, 2.0 mmol) and dissolved in DCM (15.0 mL). 3M Hydrogen chloride in CPME (13.0 mL, 40.0 mmol) was added dropwise at RT. The reaction was stirred at RT for 18 h. The reaction was concentrated in vacuo to afford the title compound (625 mg, 94%) as an off-white solid which was use directly in the subsequent reaction without further purification.
LC/MS (Table 1 , Method C) RT 1 .58 min; MS m/z 261 [M+H]+
(vi) A/-(Cyclopropyl(2-(((R)-1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyridin-4-yl)methyl)-3,3- difluorocyclobutane-1 -carboxamide (Isomer 2)
The title compound was prepared using an analogous reaction protocol to that described for Example 1 : 3,3-Difluoro-/V-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)cyclobutane-1 - carboxamide, from the appropriate starting materials cyclopropyl(2-(((R)-1 ,1 ,1 - trifluoropropan-2-yl)oxy)pyridin-4-yl)methanamine dihydrochloride and 3,3- difluorocyclobutane-1 -carboxylic acid (CAS: 107496-54-8). The crude reaction was purified by flash column chromatography (cyclohexane to EtOAc gradient elution) to afford the title compound as a white solid (53.9 mg, 39%).
1 H NMR (400 MHz, DMSO-de) 5 8.67 (d, J=8.0 Hz, 1 H), 8.13 (d, J=5.3 Hz, 1 H), 7.06 (dd, J=1 .1 , 5.3 Hz, 1 H), 6.88 (s, 1 H), 5.94-5.81 (m, 1 H), 4.18 (t, J=8.6 Hz, 1 H), 3.03-2.92 (m, 1 H), 2.77-2.59 (m, 4H), 1.44 (d, J=6.5 Hz, 3H), 1.26-1.02 (m, 1 H), 0.53-0.43 (m, 3H), 0.35- 0.30 (m, 1 H).
LC/MS (Table 1 , Method A) Rt = 5.14 min; MS m/z: 379 [M+H]+.
Compound 94
N-(Cyclopropyl(6-(((/?)-1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methyl)-3,3- difluorocyclobutane-1 -carboxamide (Isomer 2)
(i) (R)-Cyclopropyl(6-((1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methanone
A reaction vessel was charged with ((R)-6-((1 ,1 ,1-trifluoropropan-2-yl)oxy)pyrimidine-4- carbonitrile (Example 2, step (i), 2.87 g, 13.2 mmol) and solvated in THF (40 mL). The reaction was set to stir at RT and next cooled to 0 °C. Cyclopropylmagnesium bromide solution (0.5M in THF, 56 mL, 27.8 mmol) was added dropwise at 0 °C. The reaction was stirred at 0 °C for 1 hour. 6M HCI (10 mL) was added at 0 °C and the reaction was allowed to warm to RT and stirred at RT for 15 mins. The reaction was next partitioned between EtOAc and a saturated NaHCOs solution. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound as a yellow oil (1 .57 g, 43%).
LC/MS (Table 1 , Method C) RT 165 min; MS m/z 261 [M+H]+.
(ii) Cyclopropyl(6-(((R)-1 ,1 ,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methanamine (2 Diastereoisomers)
To a solution of (R)-cyclopropyl(6-((1 ,1 ,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methanone (1.45 g, 5.57 mmol) in MeOH (40.0 mL) was added ammonium formate (4.21 g, 66.9 mol) and sodium cyanoborohydride (1.40 g, 22.3 mmol). The reaction was set to stir at RT and next heated at 60 °C for 18 h. The reaction was allowed to cool to RT and concentrated in vacuo. The reaction was partitioned between EtOAc and a 10% aqueous sodium hydroxide solution. The organic layers were separated, washed with distilled water, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to DCM:2M NH3 in MeOH (15:1 ), gradient elution) to afford the title compound as a pale yellow oil (1 .60 g, Quant.).
LC/MS (Table 1 , Method B) RT 0.92 min; MS m/z 262 [M+H]+.
(iii) Te/t-Butyl (cyclopropyl(6-(((R)-1 ,1 ,1-trifluoropropan-2-yl)oxy)pyrimidin-4- yl)methyl)carbamate (Isomer 1 and Isomer 2)
A reaction vessel was charged with cyclopropyl(6-(((R)-1 ,1 ,1-trifluoropropan-2- yl)oxy)pyrimidin-4-yl)methanamine (1.60 g, 6.12 mmol) and di-tert-butyl decarbonate (2.1 mL, 9.19 mmol) and solvated in DCM (35.0 mL) at RT. Triethylamine (2.6 mL, 18.4 mmol) was added dropwise and the reaction was stirred at RT for 24 h. The reaction was next concentrated in vacuo and partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound as an off-white solid (1 .23 g, 56%).
The title compound was purified by SFC (Table 2, Method 20) to afford te/Y-butyl (cyclopropyl(6-(((R)-1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methyl)carbamate, isomer 1 (112 mg, 5%, 99% Ee) and te/Y-butyl (cyclopropyl(6-(((R)-1 ,1 ,1 -trifluoropropan-2- yl)oxy)pyrimidin-4-yl)methyl)carbamate, isomer 2 (108 mg, 5%, 92% Ee).
LC/MS (Table 1 , Method A) RT 5.29 min; MS m/z 362 [M+H]+.
(iv) Cyclopropyl(6-(((R)-1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methanamine dihydrochloride (Isomer 2)
A reaction vessel was charged with te/Y-butyl (cyclopropyl(6-(((R)-1 ,1 ,1 -trifluoropropan-2- yl)oxy)pyrimidin-4-yl)methyl)carbamate (isomer 2, 105 mg, 0.29 mmol) and dissolved in DCM (3.0 mL). 3M Hydrogen chloride in CPME (1.9 mL, 5.81 mmol) was added dropwise at RT. The reaction was stirred at RT for 20 h. The reaction was concentrated in vacuo to afford the title compound (82 mg, 85%) as an off-white solid which was use directly in the subsequent reaction without further purification.
LC/MS (Table 1 , Method C) RT 1 .35 min; MS m/z 262 [M+H]+
(v) A/-(Cyclopropyl(6-(((R)-1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methyl)-3,3- difluorocyclobutane-1 -carboxamide (Isomer 2)
The title compound was prepared using an analogous reaction protocol to that described for Example 1 : 3,3-Difluoro-/V-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)cyclobutane-1 - carboxamide, from the appropriate starting materials cyclopropyl(6-(((R)-1 ,1 ,1 - trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methanamine dihydrochloride and 3,3- difluorocyclobutane-1 -carboxylic acid (CAS: 107496-54-8). The crude reaction was purified by flash column chromatography (cyclohexane to EtOAc gradient elution) to afford the title compound as a white solid (59.8 mg, 64%).
1 H NMR (400 MHz, DMSO-de) 5 8.80 (d, J=1 .0 Hz, 1 H), 8.65 (d, J=7.8 Hz, 1 H), 7.03 (d, J=0.8 Hz, 1 H), 6.02-5.90 (m, 1 H), 4.19 (t, J=8.3 Hz, 1 H), 3.07-2.96 (m, 1 H), 2.79-2.54 (m, 4H), 1.48 (d, J=6.5 Hz, 3H), 1.24-1.10 (m, 1 H), 0.53-0.32 (m, 4H).
LC/MS (Table 1 , Method A) Rt = 4.88 min; MS m/z: 380 [M+H]+.
EXAMPLE 2
Assessment of in vitro potency against Kv7.2/7.3 channels An automated patch-clamp assay on the Sophion Qube 384 was developed for potency testing to identify small molecule activators of heteromeric Kv7.2/7.3 channels (KCNQ2, Uniprot ID 043526; KCNQ3, Uniprot 043525).
The cell line used was a stably transfected CH0-K1 cell line with constitutive Kv7.2/7.3 expression.
CHO-K1/KV7.2/KV7.3 cells were maintained in the following culture media:
• DMEM/F-12 with GlutaMAX™ (Gibco 31331 -028),
• 10% Fetal clone 2 serum (Perbio Science SH30066.03),
• 1 mg/ml Geneticin™ selective antibiotic (G418, Invitrogen 1013027), and
• 5 pg/ml BlasticidinS HCI (Invivogen Ant-bl-5).
On the day of the experiment, cells were resuspended in serum free media, counted and diluted to a final concentration of 3.5x106 cells per ml of media.
Cells were then placed onto the Sophion Qube 384 and rested for a minimum of 1 hour.
The following solutions were used for recording:
• extracellular solution (in mM): 145 NaCI, 4 KCI, 1 MgCI2, 2 CaCI2, 10 HEPES, 10 glucose, pH 7.4, 315-320 mOsm.
• intracellular solution (in mM): 120 KCI, 5.74 CaCI2, 1.75 MgCI2, 10 EGTA, 10 HEPES, 5 Na2ATP, pH 7.2, adjusted to 315 mOsm with sucrose.
After establishing the whole-cell configuration, cells were held at -80 mV throughout the experiment. A current-voltage (l-V) protocol stepping from -100 to +20 mV for 1 second was applied to measure Kv7.2/7.3 currents, each step was followed by a 200 ms pulse to 0 mV to measure the tail currents. From the l-V protocol a Boltzmann fit was applied to generate activation curves. Data were sampled at 25 kHz and filtered at 5 kHz (Bessel). Data were produced using multihole QChips. The l-V protocol was applied several times to establish the response in control conditions (typically 0.3% DMSO) and in the presence of the test compound.
Data were reviewed in Sophion Analyser version 6.5.2 (Sophion Bioscience) for recording quality and filters were applied to remove any failed wells. Leak subtraction was applied to all recordings. Data filters for multihole QChips were typically: seal resistance >4 MQ, capacitance >20 pF, baseline VHalf between 0 to -40 mV, baseline holding current between -2 to 2 nA, baseline steady state current at 20 mV >4 nA unless otherwise stated.
Analysis of data for assessment of potency
10 concentrations of test compounds were applied to individual wells in quadruplicate to assess potency as a 1 in 3 dilution series from the maximal concentration of 30 mM. The average shift in the voltage for half activation (Vhaif) for each concentration was used to generate concentration-response curves fitted with a 4-parameter logistic model to estimate the ECso from the point of inflection of the curve and the maximal shift in the Vhaif from the top of the curve.
The results of the tested compounds are summarized in Table 4 below. The lower the ECso value, the higher the activity of the analyzed compound.
TABLE 4
The obtained EC50 values showed that all the tested compounds have an ability to activate Kv7.2/7.3 potassium channels.

Claims

1. A Kv7.2/7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, having the following general formula (I) wherein
R1 is represented by A1 — L1 — , wherein
L1 is a methylene group, optionally substituted with a CR’R”R”’, wherein R’, R” and R’”, equal or different each other, are hydrogen atom, OH, CN, optionally halogenated C1-6 linear or branched alkyl group, optionally halogenated C1-3 alkoxy group, five to six membered heterocycle comprising one oxygen atom, or R’ and R” together form an aliphatic ring having 3 to 6 carbon atoms,
A1 is an aromatic ring comprising one or two nitrogen atoms, optionally substituted by one or more substituents selected from a linear or branched C1 -C6 alkoxy chain, optionally substituted with one or more halogen atoms,
R2 is a ring selected from:
(i) a monocyclic aliphatic ring having three to six members, optionally containing one or more oxygen atoms,
(ii) a condensed or bridged bicyclic ring having five to ten members, optionally containing one or more oxygen atoms, wherein said bicyclic ring comprises at least one aliphatic cycle, and
(iii) a spiro residue comprising two aliphatic rings, wherein each of said two aliphatic rings has three to six members, and optionally contains one or more oxygen atoms, wherein any one of such rings (i), (ii) and (iii) are unsubstituted or substituted with one or more substituents selected from the group consisting of a. halogen atom, b. hydroxy group, c. hydroxy C1-C3 alkyl group, d. optionally halogenated C1 -3 alkyl group, e. optionally halogenated C1 -3 alkoxy group, and f. monocyclic aliphatic ring having three to six members, optionally substituted by a halogen atom, an optionally halogenated C1 -3 alkyl group or an optionally halogenated C1 -3 alkoxy group.
2. The Kv7.2/Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein L1 is a methylene group, said methylene group being unsubstituted or substituted with a CR’R”R”’, wherein R’, R” and R’”, equal or different each other, are hydrogen atom, optionally halogenated C1-3 linear or branched alkyl group, optionally halogenated C1-3 alkoxy group, or R’ and R” together form an aliphatic ring having 3 to 6 carbon atoms.
3. The Kv7.2/Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein L1 is a methylene group, said methylene group being unsubstituted or substituted with one or more substituent selected from -CH3, -CH2F, -CHF2, -CF3, -OCH3, -OCH2F, -OCHF2, -OCF3, cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
4. The Kv7.2/Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein A1 is an aromatic ring selected from the group consisting of pyrrole, pyridine, pyridazine, pyrimidine, and pyrazine.
5. The Kv7.2/Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein A1 is substituted by one or more substituents selected from methoxy, ethoxy, propoxy, and isopropoxy, wherein one or more hydrogen atoms is substituted by a halogen atom, preferably fluoride and chloride, more preferably fluoride.
6. The Kv7.2/Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein said (i) monocyclic aliphatic ring having three to six members is selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, tetrahydrofuran, and tetrahydropyran.
7. The Kv7.2/Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein said (ii-a) condensed or (ii-b) bridged bicyclic ring having five to ten members is selected from the group consisting of (ii-a) bicyclo(3.1 .0)hexane, coumaran, chromane, and (ii-b) bicyclo(1.1.1 )pentane, bicyclo(2.1.1 )hexane, 2-oxabicyclo[2.1.1]hexane, norbornane, bicyclo[2.2.2]octane.
8. The Kv7.2/Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein said (iii) spiro residue comprising two aliphatic rings is selected from the group consisting of spiro[2.2]pentane, spiro[2,3]hexane, spiro[2.4]heptane, spiro[2.5]octane, spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[4.5]decane, and spiro[5.5]undecane, wherein one carbon atom is optionally replaced by one oxygen atom.
9. The Kv7.2/Kv7.3 potassium channel activator compound according to claim 1 , wherein said compound is selected from the group consisting of the compounds of the following Table A, or a pharmaceutically acceptable salt thereof
Table A
10. The compound according to any one of claims 1 to 9, wherein said pharmaceutically acceptable salt is chosen from the group consisting of salts with organic acids, preferably oxalic, maleic, methanesulfonic, paratoluenesulfonic, succinic, citric, malic, tartaric and lactic acids, salts with organic bases, preferably thromethamine, lysine, arginine, glycine, alanine and ethanolamine, salts with inorganic acids, preferably hydrochloric, hydrobromic, phosphoric and sulfuric acids, and salts with inorganic bases, preferably hydroxide or carbonate of alkaline or alkaline-earth metals, such as sodium, potassium and calcium.
11 . The compound according to any one of claims 1 to 10 for use as a drug.
12. A pharmaceutical composition comprising (i) the Kv7.2/Kv7.3 potassium channel activating compound according to any one of claims 1 to 10, and (ii) at least one pharmaceutically acceptable excipient.
13. The compound according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 12, for use in treating disorders that are modulated by Kv7.2/Kv7.3 potassium channels.
14. The compound or pharmaceutical composition for use according to claim 13, wherein said disorders that are modulated by Kv7.2/Kv7.3 potassium channels are central nervous system (CNS) and peripheral nervous system (PNS) disorders.
15. The compound or pharmaceutical composition for use according to claim 14, wherein said central nervous system (CNS) disorders are selected from the group consisting of epilepsy, epileptic syndromes, epileptic symptoms, epilepsy resistant or refractory to treatment, seizures, bipolar disorder, bipolar depression, schizophrenia, psychosis, mania, stress-related disorders, acute stress reactions, major depressive disorder, anxiety, panic attacks, social phobia, sleep disorders, attention deficit hyperactivity disorder, post- traumatic stress disorder, obsessive-compulsive disorder, impulsivity disorders, personality disorders, Huntington's disease, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and tinnitus.
16. The compound or pharmaceutical composition for use according to claim 14, wherein said peripheral nervous system (PNS) disorders are selected from the group consisting of migraine, chronic pain, acute pain, neuropathic pain, visceral pain, inflammatory pain, and muscle pain.
17. A method of treatment of disorders that are modulated by Kv7.2/Kv7.3 potassium channels, selected from the group consisting of central nervous system (CNS) and peripheral nervous system (PNS) disorders, by the administration to a human being in need thereof of an effective amount of a compound according to any one of claims 1 to 10.
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