WO2022256622A1 - N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels - Google Patents

N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels Download PDF

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Publication number
WO2022256622A1
WO2022256622A1 PCT/US2022/032116 US2022032116W WO2022256622A1 WO 2022256622 A1 WO2022256622 A1 WO 2022256622A1 US 2022032116 W US2022032116 W US 2022032116W WO 2022256622 A1 WO2022256622 A1 WO 2022256622A1
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Prior art keywords
pain
compound
pharmaceutically acceptable
acceptable salt
trifluoromethyl
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English (en)
French (fr)
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Beck Mary ELIZABETH
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Vertex Pharmaceuticals Inc
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Vertex Pharmaceuticals Inc
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Priority to IL308953A priority Critical patent/IL308953A/en
Priority to EP22740607.1A priority patent/EP4347031B1/en
Priority to LTEPPCT/US2022/032116T priority patent/LT4347031T/lt
Priority to ES22740607T priority patent/ES3058787T3/es
Priority to MX2023014378A priority patent/MX2023014378A/es
Priority to HRP20251504TT priority patent/HRP20251504T1/hr
Priority to MA64853A priority patent/MA64853B1/fr
Priority to CA3221259A priority patent/CA3221259A1/en
Priority to EP25210969.9A priority patent/EP4699607A2/en
Priority to SI202230218T priority patent/SI4347031T1/sl
Priority to CN202280054039.4A priority patent/CN117794920A/zh
Priority to RS20251262A priority patent/RS67577B1/sr
Priority to PL22740607.1T priority patent/PL4347031T3/pl
Priority to MDE20240380T priority patent/MD4347031T2/ro
Priority to AU2022284886A priority patent/AU2022284886A1/en
Application filed by Vertex Pharmaceuticals Inc filed Critical Vertex Pharmaceuticals Inc
Priority to CR20230586A priority patent/CR20230586A/es
Priority to KR1020247000231A priority patent/KR20240031300A/ko
Priority to PE2023003208A priority patent/PE20241335A1/es
Priority to SM20250481T priority patent/SMT202500481T1/it
Priority to FIEP22740607.1T priority patent/FI4347031T3/fi
Priority to JP2023574395A priority patent/JP2024522292A/ja
Priority to DK22740607.1T priority patent/DK4347031T3/da
Publication of WO2022256622A1 publication Critical patent/WO2022256622A1/en
Priority to JOJO/P/2023/0316A priority patent/JOP20230316B1/ar
Priority to DO2023000267A priority patent/DOP2023000267A/es
Anticipated expiration legal-status Critical
Priority to ECSENADI202395485A priority patent/ECSP23095485A/es
Priority to CONC2023/0017899A priority patent/CO2023017899A2/es
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom

Definitions

  • Neuropathic pain is a form of chronic pain caused by an injury to the sensory nerves (Dieleman, J.P., et al., Incidence rates and treatment of neuropathic pain conditions in the general population. Pain, 2008.137(3): p.681-8). Neuropathic pain can be divided into two categories, pain caused by generalized metabolic damage to the nerve and pain caused by a discrete nerve injury.
  • the metabolic neuropathies include post-herpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy.
  • Discrete nerve injury indications include post-amputation pain, post-surgical nerve injury pain, and nerve entrapment injuries like neuropathic back pain.
  • Voltage-gated sodium channels Na V s are involved in pain signaling.
  • Na V s are biological mediators of electrical signaling as they mediate the rapid upstroke of the action potential of many excitable cell types (e.g. neurons, skeletal myocytes, cardiac myocytes).
  • excitable cell types e.g. neurons, skeletal myocytes, cardiac myocytes.
  • the evidence for the role of these channels in normal physiology, the pathological states arising from mutations in sodium channel genes, preclinical work in animal models, and the clinical pharmacology of known sodium channel modulating agents all point to the central role of Na V s in pain sensation (Rush, A.M. and T.R. Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Na V 1.8 Sodium Channels. Mol.
  • the Na V s form a subfamily of the voltage-gated ion channel super-family and comprises 9 isoforms, designated Na V 1.1 – Na V 1.9.
  • the tissue localizations of the nine isoforms vary.
  • Na V 1.4 is the primary sodium channel of skeletal muscle
  • Na V 1.5 is primary sodium channel of cardiac myocytes.
  • Na V s 1.7, 1.8 and 1.9 are primarily localized to the peripheral nervous system, while Na V s 1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the central and peripheral nervous systems.
  • the functional behaviors of the nine isoforms are similar but distinct in the specifics of their voltage-dependent and kinetic behavior (Catterall, W.
  • Na V 1.8 channels were identified as likely targets for analgesia (Akopian, A.N., L. Sivilotti, and J.N. Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996.379(6562): p.257-62).
  • Na V 1.8 has been shown to be a carrier of the sodium current that maintains action potential firing in small dorsal root ganglia (DRG) neurons (Blair, N.T. and B.P. Bean, Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na + current, and Ca 2+ current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002. 22(23): p.10277-90).
  • DRG dorsal root ganglia
  • TTX tetrodotoxin
  • Na V 1.8 is involved in spontaneous firing in damaged neurons, like those that drive neuropathic pain (Roza, C., et al., The tetrodotoxin-resistant Na + channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003.550(Pt 3): p. 921-6; Jarvis, M.F., et al., A-803467, a potent and selective Na V 1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc. Natl. Acad. Sci.
  • the small DRG neurons where Na V 1.8 is expressed include the nociceptors involved in pain signaling.
  • Na V 1.8 mediates large amplitude action potentials in small neurons of the dorsal root ganglia (Blair, N.T. and B.P. Bean, Roles of tetrodotoxin (TTX)-sensitive Na + current, TTX-resistant Na + current, and Ca 2+ current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002.22(23): p.10277-90).
  • Na V 1.8 is necessary for rapid repetitive action potentials in nociceptors, and for spontaneous activity of damaged neurons. (Choi, J.S.
  • Na V 1.8 appears to be a driver of hyper-excitablility (Rush, A.M., et al., A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc. Natl. Acad. Sci. USA, 2006.103(21): p.8245-50).
  • Na V 1.8 mRNA expression levels have been shown to increase in the DRG (Sun, W., et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats.
  • the invention relates to a compound described herein, or a pharmaceutically acceptable salt thereof.
  • the invention relates to a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.
  • the invention relates to a method of inhibiting a voltage gated sodium channel in a subject by administering the compound, pharmaceutically acceptable salt, or pharmaceutical composition to the subject.
  • the invention relates to a method of treating or lessening the severity in a subject of a variety of diseases, disorders, or conditions, including, but not limited to, chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomy pain, herniorrhaphy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, and cardiac arrhythmia, by administering the compound, pharmaceutically acceptable salt, or pharmaceutical composition to the subject.
  • diseases, disorders, or conditions including, but not limited to, chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (
  • Figure 1 depicts an XRPD pattern characteristic of amorphous Compound 1.
  • Figure 2 depicts an XRPD pattern characteristic of amorphous Compound 7.
  • Figure 3 depicts an XRPD pattern characteristic of amorphous Compound 8.
  • Figure 4 depicts an XRPD pattern characteristic of Compound 16 in crystalline form.
  • Figure 5 depicts an XRPD pattern characteristic of amorphous Compound 21.
  • Figure 6 depicts an XRPD pattern characteristic of amorphous Compound 35.
  • the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: X 2a is N, N + -O-, or C-R 2a ; X 3a is N or N + -O-; X 5a is N, N + -O-, or C-R 5a ; X 6a is N, N + -O-, or C-R 6a ; R d is (CH 2 ) m (CHR e ) n (CH 2 ) p H; m, n, and p are each independently 0 or 1; R e is H, OH, halo, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 2a and R 6a are each independently H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 5a is H, halo, CH
  • the term “compounds of the invention” refers to the compounds of formula (I), and all of the embodiments thereof (e.g., formulas (I-A), etc.), as described herein, and to the compounds identified in Table A.
  • the compounds of the invention comprise multiple variable groups (e.g., R 1 , X 3a , R 5b , etc.).
  • variable groups e.g., R 1 , X 3a , R 5b , etc.
  • stable in this context, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 ⁇ C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • formulas (I), (I-A), (I-B), and (I-C) X 2a and X 3a are connected by a single bond, X 5a and X 6a are connected by a double bond, and X 4c and X 5c are connected by a single bond, even though the bonds between these groups may be obscured by the atom labels in the chemical structures.
  • formula (I) could be drawn as follows to show the bonds in question:
  • a substituent depicted as “CF 3 ” or “F 3 C” in a chemical structure refers to a trifluoromethyl substituent, regardless of which depiction appears in the chemical structure.
  • alkyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having the specified number of carbon atoms, which is attached to the rest of the molecule by a single bond.
  • a “C 1 -C 6 alkyl” group is an alkyl group having between one and six carbon atoms.
  • alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds, and having the specified number of carbon atoms, which is attached to the rest of the molecule by a single bond.
  • a “C 2 -C 6 alkenyl” group is an alkenyl group having between two and six carbon atoms.
  • cycloalkyl refers to a stable, non-aromatic, mono- or bicyclic (fused, bridged, or spiro) saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, having the specified number of carbon ring atoms, and which is attached to the rest of the molecule by a single bond.
  • a “C 3 -C 8 cycloalkyl” group is a cycloalkyl group having between three and eight carbon atoms.
  • haloalkyl refers to an alkyl group having the specified number of carbon atoms, wherein one or more of the hydrogen atoms of the alkyl group are replaced by halo groups.
  • a “C 1 -C 6 haloalkyl” group is an alkyl group having between one and six carbon atoms, wherein one or more of the hydrogen atoms of the alkyl group are replaced by halo groups.
  • alkoxy refers to a radical of the formula -OR a where R a is an alkyl group having the specified number of carbon atoms.
  • a “C 1 -C 6 alkoxy” group is a radical of the formula -OR a where R a is an alkyl group having the between one and six carbon atoms.
  • the term “haloalkoxy” refers to an alkoxy group having the specified number of carbon atoms, wherein one or more of the hydrogen atoms of the of the alkyl group are replaced by halo groups.
  • the term “alkylene” refers to a divalent, straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having the specified number of carbon atoms, which is attached to the rest of the molecule by two single bonds.
  • a “C 1 -C 6 alkylene” group is an alkylene group having between one and six carbon atoms.
  • the term “optionally substituted” refers to a group that is either unsubstituted or substituted with the subsequently identified substituents.
  • a group that is “optionally substituted with 1-2 halo” is either unsubstituted, substituted with 1 halo group, or substituted with 2 halo groups.
  • “*2” and “*3” in the following structure designate the carbon atoms to which the R 2c and R 3c groups, respectively, are attached.
  • the compounds of the invention include all stereoisomers (e.g., enantiomers and diastereomers), double bond isomers (e.g., (Z) and (E)), conformational isomers, and tautomers of the compounds identified by the chemical names and chemical structures provided herein.
  • stereoisomers e.g., enantiomers and diastereomers
  • double bond isomers e.g., (Z) and (E)
  • conformational isomers e.g., (Z) and (E)
  • tautomers e.g., tautomers of the compounds identified by the chemical names and chemical structures provided herein.
  • single stereoisomers, double bond isomers, conformational isomers, and tautomers as well as mixtures of stereoisomers, double bond isomers, conformational isomers, and tautomers are within the scope of the invention.
  • a non-bold, straight bond attached to a stereocenter of a compound such as in denotes that the configuration of the stereocenter is unspecified.
  • the compound may have any configuration, or a mixture of configurations, at the stereocenter.
  • a bold or hashed straight bond attached to a stereocenter of a compound such as in denotes the relative stereochemistry of the stereocenter, relative to other stereocenter(s) to which bold or hashed straight bonds are attached.
  • a bold or hashed wedge bond attached to a stereocenter of a compound such as in denotes the absolute stereochemistry of the stereocenter, as well as the relative stereochemistry of the stereocenter, relative to other stereocenter(s) to which bold or hashed wedge bonds are attached.
  • the prefix “rac-,” when used in connection with a chiral compound refers to a racemic mixture of the compound. In a compound bearing the “rac-” prefix, the (R)- and (S)- designators in the chemical name reflect the relative stereochemistry of the compound.
  • the prefix “rel-,” when used in connection with a chiral compound, refers to a single enantiomer of unknown absolute configuration.
  • the (R)- and (S)- designators in the chemical name reflect the relative stereochemistry of the compound, but do not necessarily reflect the absolute stereochemistry of the compound. Where the relative stereochemistry of a given stereocenter is unknown, no stereochemical designator is provided. In some instances, the absolute configuration of some stereocenters is known, while only the relative configuration of the other stereocenters is known.
  • the stereochemical designators associated with the stereocenters of known absolute configuration are marked with an asterisk (*), e.g., (R*)- and (S*)-, while the stereochemical designators associated with stereocenters of unknown absolute configuration are not so marked.
  • the unmarked stereochemical designators associated with the stereocenters of unknown absolute configuration reflect the relative stereochemistry of those stereocenters with respect to other stereocenters of unknown absolute configuration, but do not necessarily reflect the relative stereochemistry with respect to the stereocenters of known absolute configuration.
  • the term “compound,” when referring to the compounds of the invention, refers to a collection of molecules having identical chemical structures, except that there may be isotopic variation among the constituent atoms of the molecules.
  • the term “compound” includes such a collection of molecules without regard to the purity of a given sample containing the collection of molecules.
  • the term “compound” includes such a collection of molecules in pure form, in a mixture (e.g., solution, suspension, colloid, or pharmaceutical composition, or dosage form) with one or more other substances, or in the form of a hydrate, solvate, or co-crystal.
  • amorphous refers to a solid material having no long-range order in the position of its molecules. Amorphous solids are generally glasses or supercooled liquids in which the molecules are arranged in a random manner so that there is no well-defined arrangement, e.g., molecular packing, and no long-range order.
  • Amorphous solids are generally rather isotropic, i.e., exhibit similar properties in all directions and do not have definite melting points. Instead, they typically exhibit a glass transition temperature which marks a transition from glassy amorphous state to supercooled liquid amorphous state upon heating.
  • an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid.
  • a solid material may comprise an amorphous compound, and the material may, for example, be characterized by a lack of sharp characteristic crystalline peak(s) in its XRPD spectrum (i.e., the material is not crystalline, but is amorphous, as determined by XRPD). Instead, one or several broad peaks (e.g., halos) may appear in the XRPD pattern of the material. See US 2004/0006237 for a representative comparison of XRPDs of an amorphous material and crystalline material.
  • a solid material comprising an amorphous compound
  • Other techniques such as, for example, solid state NMR may also be used to characterize crystalline or amorphous forms.
  • crystalline refers to a crystal structure (or polymorph) having a particular molecular packing arrangement in the crystal lattice.
  • Crystalline forms can be identified and distinguished from each other by one or more characterization techniques including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, and solid state nuclear magnetic resonance (e.g., 13 C, 19 F, 15 N, and 31 P SSNMR).
  • XRPD X-ray powder diffraction
  • single crystal X-ray diffraction e.g., single crystal X-ray diffraction
  • solid state nuclear magnetic resonance e.g., 13 C, 19 F, 15 N, and 31 P SSNMR
  • the term “stable,” when referring to an isotope, means that the isotope is not known to undergo spontaneous radioactive decay. Stable isotopes include, but are not limited to, the isotopes for which no decay mode is identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).
  • H refers to hydrogen and includes any stable isotope of hydrogen, namely 1 H and D.
  • an atom is designated as “H”
  • 1 H refers to protium. Where an atom in a compound of the invention, or a pharmaceutically acceptable salt thereof, is designated as protium, protium is present at the specified position at at least the natural abundance concentration of protium.
  • the compounds of the invention, and pharmaceutically acceptable salts thereof include each constituent atom at approximately the natural abundance isotopic composition of the specified element.
  • the compounds of the invention, and pharmaceutically acceptable salts thereof include one or more atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the most abundant isotope of the specified element (“isotope-labeled” compounds and salts).
  • stable isotopes which are commercially available and suitable for the invention include without limitation isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, for example 2 H, 13 C, 15 N, 18 O, 17 O, and 31 P, respectively.
  • the isotope-labeled compounds and salts can be used in a number of beneficial ways, including as medicaments.
  • the isotope-labeled compounds and salts are deuterium ( 2 H)- labeled.
  • Deuterium ( 2 H)-labeled compounds and salts are therapeutically useful with potential therapeutic advantages over the non- 2 H-labeled compounds.
  • deuterium ( 2 H)-labeled compounds and salts can have higher metabolic stability as compared to those that are not isotope-labeled owing to the kinetic isotope effect described below. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which under most circumstances would represent a preferred embodiment of the present invention.
  • the isotope-labeled compounds and salts can usually be prepared by carrying out the procedures disclosed in the synthesis schemes, the examples and the related description, replacing a non-isotope-labeled reactant by a readily available isotope-labeled reactant.
  • the deuterium ( 2 H)-labeled compounds and salts can manipulate the rate of oxidative metabolism of the compound by way of the primary kinetic isotope effect.
  • the primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies of the covalent bonds involved in the reaction.
  • Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially.
  • the concentration of an isotope (e.g., deuterium) incorporated at a given position of an isotope- labeled compound of the invention, or a pharmaceutically acceptable salt thereof, may be defined by the isotopic enrichment factor.
  • isotopic enrichment factor means the ratio between the abundance of an isotope at a given position in an isotope-labeled compound (or salt) and the natural abundance of the isotope.
  • the isotopic enrichment factor is at least 3500 ( ⁇ 52.5% deuterium incorporation), at least 4000 ( ⁇ 60% deuterium incorporation), at least 4500 ( ⁇ 67.5% deuterium incorporation), at least 5000 ( ⁇ 75% deuterium incorporation), at least 5500 ( ⁇ 82.5% deuterium incorporation), at least 6000 ( ⁇ 90% deuterium incorporation), at least 6333.3 ( ⁇ 95% deuterium incorporation), at least 6466.7 ( ⁇ 97% deuterium incorporation), at least 6600 ( ⁇ 99% deuterium incorporation), or at least 6633.3 ( ⁇ 99.5% deuterium incorporation).
  • the invention relates to a compound of formula (I-A) or a pharmaceutically acceptable salt thereof, wherein X 2a , X 3a , X 5a , X 6a , R d , R 4b1 , R 4b2 , R 5b1 , R 5b2 , X 3c , X 4c , X 5c , X 6c , and R 2c are defined as set forth above in connection with formula (I).
  • the invention relates to a compound of formula (I-A-1) or a pharmaceutically acceptable salt thereof, wherein R d , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 2c , R 3c , and R 4c are defined as set forth above in connection with formula (I).
  • the invention relates to a compound of formula (I-A-2)
  • the invention relates to a compound of formula (I-A-3) or a pharmaceutically acceptable salt thereof, wherein R d , R 4b2 , R 2c , R 3c , and R 4c are defined as set forth above in connection with formula (I).
  • the invention relates to a compound of formula (I-B) or a pharmaceutically acceptable salt thereof, wherein X 2a , X 3a , X 5a , X 6a , R d , R 4b1 , R 4b2 , R 5b1 , R 5b2 , X 3c , X 4c , X 5c , X 6c , and R 2c are defined as set forth above in connection with formula (I). [0057] In some embodiments, the invention relates to a compound of formula (I-B-1)
  • the invention relates to a compound of formula (I-B-2) or a pharmaceutically acceptable salt thereof, wherein R d , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 2c , R 3c , and R 4c are defined as set forth above in connection with formula (I).
  • the invention relates to a compound of formula (I-B-2) or a pharmaceutically acceptable salt thereof, wherein R d , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 2c , R 3c , and R 4c are defined as set forth above in connection with formula (I).
  • the invention relates to a compound of formula (I-B-3) or a pharmaceutically acceptable salt thereof, wherein R d , R 4b2 , R 2c , R 3c , and R 4c are defined as set forth above in connection with formula (I). [0060] In some embodiments, the invention relates to a compound of formula (I-C)
  • X 2a , X 3a , X 5a , X 6a , R d , R 4b1 , R 4b2 , R 5b1 , R 5b2 , X 3c , X 4c , X 5c , X 6c , and R 2c are defined as set forth above in connection with formula (I).
  • the invention relates to a compound of formula (I-C-1) or a pharmaceutically acceptable salt thereof, wherein R d , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 2c , R 3c , and R 4c are defined as set forth above in connection with formula (I).
  • the invention relates to a compound of formula (I-C-2) or a pharmaceutically acceptable salt thereof, wherein R d , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 2c , R 3c , and R 4c are defined as set forth above in connection with formula (I).
  • the invention relates to a compound of formula (I-C-3)
  • the invention relates to a compound of any one of formulas (I), (I-A), (I- B), and (I-C), or a pharmaceutically acceptable salt thereof, wherein X 2a is C-R 2a .
  • X 2a is C-R 2a ; and R 2a is H.
  • the invention relates to a compound of any one of formulas (I), (I-A), (I- B), and (I-C), or a pharmaceutically acceptable salt thereof, wherein X 3a is N. In other embodiments, X 3a is N + -O-. [0066] In some embodiments, the invention relates to a compound of any one of formulas (I), (I-A), (I- B), and (I-C), or a pharmaceutically acceptable salt thereof, wherein X 5a is N or C-R 5a ; and R 5a is H, halo, or CH 2 OH. In other embodiments, X 5a is N. In other embodiments, X 5a is C-R 5a .
  • X 5a is C-R 5a ; and R 5a is H, halo, or CH 2 OH. In other embodiments, X 5a is C-R 5a ; and R 5a is H, F, or CH 2 OH. In other embodiments, X 5a is C-R 5a ; and R 5a is H. In other embodiments, X 5a is C-R 5a ; and R 5a is halo. In other embodiments, X 5a is C-R 5a ; and R 5a is F. In other embodiments, X 5a is C-R 5a ; and R 5a is CH 2 OH.
  • the invention relates to a compound of any one of formulas (I), (I-A), (I- B), and (I-C), or a pharmaceutically acceptable salt thereof, wherein X 6a is N or C-R 6a ; and R 6a is H. In other embodiments, X 6a is N. In other embodiments, X 6a is C-R 6a . In other embodiments, X 6a is C-R 6a ; and R 6a is H.
  • the invention relates to a compound of any one of formulas (I), (I-A), (I- A-1), (I-A-2), (I-B), (I-B-1), (I-B-2), (I-C), (I-C-1), and (I-C-2), or a pharmaceutically acceptable salt thereof, wherein R 4b1 is H or C 1 -C 6 alkyl. In other embodiments, R 4b1 is H. In other embodiments, R 4b1 is C 1 -C 6 alkyl. In other embodiments, R 4b1 is H or CH 3 . In other embodiments, R 4b1 is CH 3 .
  • the invention relates to a compound of any one of formulas (I), (I-A), (I- A-1), (I-A-2), (I-A-3), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-C), (I-C-1), (I-C-2), and (I-C-3), or a pharmaceutically acceptable salt thereof, wherein R 4b2 is H or C 1 -C 6 alkyl. In other embodiments, R 4b2 is H. In other embodiments, R 4b2 is C 1 -C 6 alkyl. In other embodiments, R 4b2 is H or CH 3 . In other embodiments, R 4b2 is CH 3 .
  • the invention relates to a compound of any one of formulas (I), (I-A), (I- A-1), (I-A-2), (I-B), (I-B-1), (I-B-2), (I-C), (I-C-1), and (I-C-2), or a pharmaceutically acceptable salt thereof, wherein R 5b1 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In other embodiments, R 5b1 is C 1 -C 6 alkyl. In other embodiments, R 5b1 is C 1 -C 6 haloalkyl. In other embodiments, R 5b1 is CH 3 or CF 3 . In other embodiments, R 5b1 is CH 3 .
  • R 5b1 is CF 3 .
  • the invention relates to a compound of any one of formulas (I), (I-A), (I- A-1), (I-A-2), (I-B), (I-B-1), (I-B-2), (I-C), (I-C-1), and (I-C-2), or a pharmaceutically acceptable salt thereof, wherein R 5b2 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In other embodiments, R 5b2 is C 1 -C 6 alkyl. In other embodiments, R 5b2 is C 1 -C 6 haloalkyl.
  • R 5b2 is CH 3 or CF 3 . In other embodiments, R 5b2 is CH 3 . In other embodiments, R 5b2 is CF 3 . [0072] In some embodiments, the invention relates to a compound of any one of formulas (I), (I-A), (I- A-1), (I-A-2), (I-A-3), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-C), (I-C-1), (I-C-2), and (I-C-3), or a pharmaceutically acceptable salt thereof, wherein R 2c is OH, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy.
  • R 2c is OH. In other embodiments, R 2c is halo. In other embodiments, R 2c is C 1 -C 6 alkyl. In other embodiments, R 2c is C 1 -C 6 alkoxy. In other embodiments, R 2c is C 1 -C 6 haloalkoxy. In other embodiments, R 2c is OH, Cl, CH 3 , OCH 3 , OCD 3 , OCH 2 CH 3 , OCH(CH 3 ) 2 , OCH 2 CH 2 F, or OCH 2 CHF 2 . In other embodiments, R 2c is Cl. In other embodiments, R 2c is CH 3 . In other embodiments, R 2c is OCH 3 .
  • R 2c is OCD 3 . In other embodiments, R 2c is OCH 2 CH 3 . In other embodiments, R 2c is OCH(CH 3 ) 2 . In other embodiments, R 2c is OCH 2 CH 2 F. In other embodiments, R 2c is OCH 2 CHF 2 . [0073] In some embodiments, the invention relates to a compound of any one of formulas (I), (I-A), (I- B), and (I-C), or a pharmaceutically acceptable salt thereof, wherein X 3c is N or C-R 3c ; and R 3c is H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • X 3c is N. In other embodiments, X 3c is C-R 3c . In other embodiments, X 3c is C-R 3c ; and R 3c is H. In other embodiments, X 3c is C-R 3c ; and R 3c is halo. In other embodiments, X 3c is C-R 3c ; and R 3c is C 1 -C 6 alkyl. In other embodiments, X 3c is C-R 3c ; and R 3c is C 1 -C 6 haloalkyl. In other embodiments, X 3c is C-R 3c ; and R 3c is H, F, CH 3 , CHF 2 , or CF 3 .
  • X 3c is C-R 3c ; and R 3c is F. In other embodiments, X 3c is C-R 3c ; and R 3c is CH 3 . In other embodiments, X 3c is C-R 3c ; and R 3c is CHF 2 . In other embodiments, X 3c is C-R 3c ; and R 3c is CF 3 .
  • the invention relates to a compound of any one of formulas (I-A-1), (I-A- 2), (I-A-3), (I-B-1), (I-B-2), (I-B-3), (I-C-1), (I-C-2), and (I-C-3), or a pharmaceutically acceptable salt thereof, wherein R 3c is H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In other embodiments, R 3c is H. In other embodiments, R 3c is halo. In other embodiments, R 3c is C 1 -C 6 alkyl. In other embodiments, R 3c is C 1 -C 6 haloalkyl.
  • R 3c is H, F, CH 3 , CHF 2 , or CF 3 . In other embodiments, R 3c is F. In other embodiments, R 3c is CH 3 . In other embodiments, R 3c is CHF 2 . In other embodiments, R 3c is CF 3 .
  • the invention relates to a compound of any one of formulas (I), (I-A), (I- B), and (I-C), or a pharmaceutically acceptable salt thereof, wherein X 3c is C-R 3c ; and R 2c and R 3c , together with the carbon atoms to which they are attached, form a ring of formula:
  • the ring is of formula: [0076]
  • the invention relates to a compound of any one of formulas (I-A-1), (I-A- 2), (I-A-3), (I-B-1), (I-B-2), (I-B-3), (I-C-1), (I-C-2), and (I-C-3), or a pharmaceutically acceptable salt thereof, wherein R 2c and R 3c , together with the carbon atoms to which they are attached, form a ring of formula:
  • the ring is of formula: [0077]
  • the invention relates to a compound of any one of formulas (I), (I-A), (I- B
  • X 4c is C-R 4c . In other embodiments, X 4c is C-R 4c ; and R 4c is H. In other embodiments, X 4c is C-R 4c ; and R 4c is halo. In other embodiments, X 4c is C-R 4c ; and R 4c is C 1 -C 6 haloalkyl. In other embodiments, X 4c is C-R 4c ; and R 4c is C 1 - C 6 alkoxy. In other embodiments, X 4c is C-R 4c ; and R 4c is C 1 -C 6 haloalkoxy.
  • X 4c is C-R 4c ; and R 4c is H, F, CHF 2 , OCH 2 CH 3 , OCHF 2 , OCF 3 .
  • X 4c is C-R 4c ; and R 4c is F.
  • X 4c is C-R 4c ; and R 4c is CHF 2 .
  • X 4c is C-R 4c ; and R 4c is OCH 2 CH 3 .
  • X 4c is C-R 4c ; and R 4c is OCHF 2 .
  • X 4c is C-R 4c ; and R 4c is OCF 3 .
  • the invention relates to a compound of any one of formulas (I-A-1), (I-A- 2), (I-A-3), (I-B-1), (I-B-2), (I-B-3), (I-C-1), (I-C-2), and (I-C-3), or a pharmaceutically acceptable salt thereof, wherein R 4c is H, halo, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 4c is H. In other embodiments, R 4c is halo. In other embodiments, R 4c is C 1 -C 6 haloalkyl.
  • R 4c is C 1 -C 6 alkoxy. In other embodiments, R 4c is C 1 -C 6 haloalkoxy. In other embodiments, R 4c is H, F, CHF 2 , OCH 2 CH 3 , OCHF 2 , OCF 3 . In other embodiments, R 4c is F. In other embodiments, R 4c is CHF 2 . In other embodiments, R 4c is OCH 2 CH 3 . In other embodiments, R 4c is OCHF 2 . In other embodiments, R 4c is OCF 3 .
  • the invention relates to a compound of any one of formulas (I), (I-A), (I- B), and (I-C), or a pharmaceutically acceptable salt thereof, wherein X 5c is C-R 5c ; and R 5c is H.
  • the invention relates to a compound of any one of formulas (I), (I-A), (I- B), and (I-C), or a pharmaceutically acceptable salt thereof, wherein X 6c is C-R 6c ; and R 6c is H.
  • the invention relates to a compound of any one of formulas (I), (I-A), (I- A-1), (I-A-2), (I-A-3), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-C), (I-C-1), (I-C-2), and (I-C-3), or a pharmaceutically acceptable salt thereof, wherein R d is (CH 2 ) p H. In other embodiments, R d is H or CH 3 . In other embodiments, R d is (CHR e ) n (CH 2 ) p H. In other embodiments, R d is CH 2 F, CH 2 OH, or CH(OH)CH 3 .
  • R d is (CH 2 ) m (CHR e ) n H. In other embodiments, R d is CH 2 OCH 3 or CH 2 CH 2 OCH 3 .
  • the invention relates to a compound of any one of formulas (I), (I-A), (I- A-1), (I-A-2), (I-A-3), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-C), (I-C-1), (I-C-2), and (I-C-3), or any embodiment thereof, i.e., the compound in non-salt form.
  • the invention relates to a compound selected from Table A, or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to a compound selected from Table A, i.e., the compound in non-salt form. [0084] Table A. Compound Structures and Names.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein. [0086] In some embodiments, the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute and relative stereochemistry corresponding to the first eluting isomer when the two diastereoisomers of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide are separated by SFC as described in Example 1, Step 15.
  • the invention relates to the foregoing compound in non-salt form.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute and relative stereochemistry corresponding to the second eluting isomer when the two diastereoisomers of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide are separated by SFC as described in Example 1, Step 15.
  • the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof.
  • the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof.
  • the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute and relative stereochemistry of the first eluting isomer when rac-(2R,3S,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2- methoxyphenyl)-N-(6-(hydroxymethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide is separated by SFC as described in Example 6.
  • the invention relates to the foregoing compound in non-salt form.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute and relative stereochemistry of the second eluting isomer when rac-(2R,3S,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2- methoxyphenyl)-N-(6-(hydroxymethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide is separated by SFC as described in Example 6.
  • the invention relates to the foregoing compound in non-salt form.
  • Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein. [0094] In some embodiments, the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein. [0095] In some embodiments, the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof.
  • the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute and relative stereochemistry corresponding to the first eluting isomer when the two enantiomers of rac-(5- ((2R,3S,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamido)pyrimidin-2-yl)methyl benzoate are separated by SFC as described in Example 6.
  • the invention relates to the foregoing compound in non- salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute and relative stereochemistry corresponding to the second eluting isomer when the two enantiomers of rac-(5- ((2R,3S,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamido)pyrimidin-2-yl)methyl benzoate are separated by SFC as described in Example 6.
  • the invention relates to the foregoing compound in non- salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein. [0099] In some embodiments, the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein. [00100] In some embodiments, the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof.
  • the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof.
  • the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound rel-(2S,3R,4R,5S)-N-(6-((R*)- 1,2-dihydroxyethyl)pyridin-3-yl)-3-(4-fluoro-2-methoxy-3-methylphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute and relative stereochemistry corresponding tothe first eluting isomer when the two diastereoisomers rel-(2S,3R,4R,5S)-N-(6-((R*)- 2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-3- (4-fluoro-2-methoxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide and rel
  • the invention relates to the foregoing compound in non- salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein. [00103] In some embodiments, the invention relates to a compound rel-(2R,3S,4S,5R)-N-(6-((R*)- 1,2-dihydroxyethyl)pyridin-3-yl)-3-(4-fluoro-2-methoxy-3-methylphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute and relative stereochemistry of the second eluting isomer when the two diastereoisomers rel-(2S,3R,4R,5S)-N-(6-((R*)- 2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-3-(4-flu
  • the invention relates to the foregoing compound in non- salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof.
  • the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof.
  • the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute and relative stereochemistry corresponding to the first eluting isomer when the two enantiomers of rac- (2R,3S,4S,5R)-N-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)-3-(3,4-difluoro-2-methylphenyl)- 4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide are separated by SFC as described in Example 9.
  • the invention relates to the foregoing compound in non-salt form.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute and relative stereochemistry corresponding to the second eluting isomer when the two enantiomers of rac- (2R,3S,4S,5R)-N-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)-3-(3,4-difluoro-2-methylphenyl)- 4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide are separated by SFC as described in Example 9.
  • the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof.
  • the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof.
  • the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute and relative stereochemistry corresponding to the first eluting isomer when the two diastereoisomers of (2R,3S,4S,5R)-N-(6-(1-((tert-butyldimethylsilyl)oxy)-2-methoxyethyl)pyridin-3-yl)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide are separated by SFC as described in Example 2, Step 2.
  • the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof, wherein the compound had the absolute and relative stereochemistry corresponding to the second eluting isomer when the two diastereoisomers of (2R,3S,4S,5R)-N-(6-(1-((tert-butyldimethylsilyl)oxy)-2-methoxyethyl)pyridin-3-yl)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide are separated by SFC as described in Example 2, Step 2.
  • the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof.
  • the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof.
  • the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound rel-(2R*,3S*,4S*,5R*)-3- (3,4-difluoro-2-methoxyphenyl)-N-(6-((1R,2R)-1,2-dihydroxypropyl)pyridin-3-yl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute and relative stereochemistry corresponding to the first eluting isomer when the two diastereoisomers rel-(2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl- 5-(trifluoromethyl)-N-(6-((4R,5R)-2,2,5-trimethyl-1,3-dioxolan-4-yl)pyridin-3-yl
  • the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound rel-(2R*,3S*,4S*,5R*)-3- (3,4-difluoro-2-methoxyphenyl)-N-(6-((1S,2S)-1,2-dihydroxypropyl)pyridin-3-yl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute and relative stereochemistry corresponding to the second eluting isomer when the two diastereoisomers rel-(2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl- 5-(trifluoro
  • the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein. [00118] In some embodiments, the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • the invention relates to a compound rel-(2S,3R,5S)-3-(2-chloro-4- (trifluoromethoxy)phenyl)-N-(6-((R*)-1,2-dihydroxyethyl)pyridin-3-yl)-5-methyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute and relative stereochemistry corresponding to the first eluting isomer when the two diastereomers rel-(2R,3S,5R)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-N-(6-((R*)-2,2- dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide and rel-(2S,3R,5S)-3-(2-chloro-4-
  • the invention relates to the foregoing compound in non- salt form. Such compound is considered to be a “compound of the invention,” as that term is used herein. [00120] In some embodiments, the invention relates to a compound rel-(2R,3S,5R)-3-(2-chloro-4- (trifluoromethoxy)phenyl)-N-(6-((R*)-1,2-dihydroxyethyl)pyridin-3-yl)-5-methyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute and relative stereochemistry corresponding to the second eluting isomer when the two diastereomers rel-(2R,3S,5R)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-N-(6-((R*)-2,2- dimethyl-1,3-dioxolan-4-yl)pyri
  • the invention relates to the foregoing compound in non- salt form.
  • Such compound is considered to be a “compound of the invention,” as that term is used herein.
  • Salts, Compositions, Uses, Formulation, Administration and Additional Agents Pharmaceutically acceptable salts and compositions [00121]
  • the invention provides compounds, and pharmaceutically acceptable salts thereof, that are inhibitors of voltage-gated sodium channels, and thus the present compounds, and pharmaceutically acceptable salts thereof, are useful for the treatment of diseases, disorders, and conditions including, but not limited to chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomy pain, herniorrhaphy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia.
  • diseases, disorders, and conditions including, but not limited to chronic pain, gut pain, n
  • compositions comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • these compositions optionally further comprise one or more additional therapeutic agents.
  • the additional therapeutic agent is a sodium channel inhibitor.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • a “pharmaceutically acceptable salt” of a compound of this invention includes any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • the salt may be in pure form, in a mixture (e.g., solution, suspension, or colloid) with one or more other substances, or in the form of a hydrate, solvate, or co-crystal.
  • the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of a voltage- gated sodium channel.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al.
  • Pharmaceutically acceptable salts of the compound of this invention include those derived from suitable inorganic and organic acids and bases.
  • suitable inorganic and organic acids and bases include those derived from suitable inorganic and organic acids and bases.
  • pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • the pharmaceutically acceptable compositions of the invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier, adjuvant, or vehicle which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known
  • any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc
  • the invention features a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the invention features a pharmaceutical composition comprising a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.
  • Uses of Compounds and Pharmaceutically Acceptable Salts and Compositions features a method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject a compound of the invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the voltage-gated sodium channel is Na V 1.8.
  • the invention features a method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomy pain, herniorrhaphy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • postsurgical pain e.g., bunionectomy pain, herniorrhaphy pain or abdominoplasty pain
  • visceral pain e.g., multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia
  • administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the invention features a method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the invention features a method of treating or lessening the severity in a subject of gut pain, wherein gut pain comprises inflammatory bowel disease pain, Crohn’s disease pain or interstitial cystitis pain wherein said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the invention features a method of treating or lessening the severity in a subject of neuropathic pain comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the neuropathic pain comprises post-herpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small-fiber neuropathy.
  • the neuropathic pain comprises diabetic neuropathy (e.g., diabetic peripheral neuropathy).
  • diabetic neuropathy e.g., diabetic peripheral neuropathy.
  • idiopathic small- fiber neuropathy shall be understood to include any small fiber neuropathy.
  • the invention features a method of treating or lessening the severity in a subject of neuropathic pain, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton’s neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia; post spinal cord injury pain, small fiber neuropathy, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia wherein said method comprises administering an effective amount of a compound of
  • the invention features a method of treating or lessening the severity in a subject of musculoskeletal pain comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the musculoskeletal pain comprises osteoarthritis pain.
  • the invention features a method of treating or lessening the severity in a subject of musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain wherein said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the invention features a method of treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain or vulvodynia wherein said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the invention features a method of treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain wherein said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the invention features a method of treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain wherein said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • idiopathic pain comprises fibromyalgia pain
  • the invention features a method of treating or lessening the severity in a subject of pathological cough wherein said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the invention features a method of treating or lessening the severity in a subject of acute pain comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the acute pain comprises acute post-operative pain.
  • the invention features a method of treating or lessening the severity in a subject of postsurgical pain (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain) comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • postsurgical pain e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain
  • the invention features a method of treating or lessening the severity in a subject of bunionectomy pain comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the invention features a method of treating or lessening the severity in a subject of herniorrhaphy pain comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the invention features a method of treating or lessening the severity in a subject of abdominoplasty pain comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the invention features a method of treating or lessening the severity in a subject of visceral pain comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the visceral pain comprises visceral pain from abdominoplasty.
  • the invention features a method of treating or lessening the severity in a subject of a neurodegenerative disease comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the neurodegenerative disease comprises multiple sclerosis.
  • the neurodegenerative disease comprises Pitt Hopkins Syndrome (PTHS).
  • the invention features a method wherein the subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with an effective amount of the compound, pharmaceutically acceptable salt or pharmaceutical composition.
  • the additional therapeutic agent is a sodium channel inhibitor.
  • the invention features a method of inhibiting a voltage-gated sodium channel in a biological sample comprising contacting the biological sample with an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the voltage-gated sodium channel is Na V 1.8.
  • the invention features a method of treating or lessening the severity in a subject of acute pain, sub-acute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, nociplastic pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain of multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, unspecific chronic back pain, head pain, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain (e.g., joint replacement pain, soft
  • the invention features a method of treating or lessening the severity in a subject of femur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headaches; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy induced neuropathic pain; radiotherapy-induced neuropathic pain; persistent/chronic post-surgical pain (e.g., post amputation, post-t
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use as a medicament.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting a voltage-gated sodium channel in a subject.
  • the voltage-gated sodium channel is Na V 1.8.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., herniorrhaphy pain, bunionectomy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia.
  • postsurgical pain e.g., herniorrhaphy pain, bunionectomy pain or abdominoplasty pain
  • visceral pain e.g., multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of gut pain, wherein gut pain comprises inflammatory bowel disease pain, Crohn’s disease pain or interstitial cystitis pain.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of neuropathic pain.
  • the neuropathic pain comprises post-herpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small-fiber neuropathy.
  • the neuropathic pain comprises diabetic neuropathy (e.g., diabetic peripheral neuropathy).
  • the phrase “idiopathic small-fiber neuropathy” shall be understood to include any small fiber neuropathy.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of neuropathic pain, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton’s neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neural
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of musculoskeletal pain.
  • the musculoskeletal pain comprises osteoarthritis pain.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain or vulvodynia.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of pathological cough.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of acute pain.
  • the acute pain comprises acute post-operative pain.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of postsurgical pain (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain).
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of bunionectomy pain.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of herniorrhaphy pain.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of abdominoplasty pain.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of visceral pain.
  • the visceral pain comprises visceral pain from abdominoplasty.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of a neurodegenerative disease.
  • the neurodegenerative disease comprises multiple sclerosis.
  • the neurodegenerative disease comprises Pitt Hopkins Syndrome (PTHS).
  • PTHS Pitt Hopkins Syndrome
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method wherein the subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with an effective amount of the compound, pharmaceutically acceptable salt or pharmaceutical composition.
  • the additional therapeutic agent is a sodium channel inhibitor.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting a voltage-gated sodium channel in a biological sample comprising contacting the biological sample with an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the voltage-gated sodium channel is Na V 1.8.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of acute pain, sub-acute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, nociplastic pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain of multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, unspecific chronic back pain, head pain, neck pain, moderate pain, severe pain, intractable pain, no
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of femur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headaches; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy induced neuropathic pain; radiotherapy-induced neuropathic pain;
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of trigeminal neuralgia, migraines treated with botox, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbrosacral radiculopathy, iliolingual neuralgia, pudendal neuralgia, femoral neuropathy, meralgia paresthetica, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain or postamputation pain.
  • the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in inhibiting a voltage-gated sodium channel.
  • the voltage-gated sodium channel is Na V 1.8.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., herniorrhaphy pain, bunionectomy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia.
  • postsurgical pain e.g., herniorrhaphy pain, bunionectomy pain or abdominoplasty pain
  • visceral pain e.g., multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia.
  • the invention provides the use of the compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity in a subject of gut pain, wherein gut pain comprises inflammatory bowel disease pain, Crohn’s disease pain or interstitial cystitis pain.
  • the invention provides a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of neuropathic pain.
  • the neuropathic pain comprises post-herpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small- fiber neuropathy.
  • the neuropathic pain comprises diabetic neuropathy (e.g., diabetic peripheral neuropathy).
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in a treating or lessening the severity in a subject of neuropathic pain, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton’s neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti- retroviral therapy induced neuralgia; post
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of musculoskeletal pain.
  • the musculoskeletal pain comprises osteoarthritis pain.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain or vulvodynia.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of pathological cough.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of acute pain.
  • the acute pain comprises acute post-operative pain.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of postsurgical pain (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain).
  • postsurgical pain e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of herniorrhaphy pain.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of bunionectomy pain.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of abdominoplasty pain.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of visceral pain.
  • the visceral pain comprises visceral pain from abdominoplasty.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or lessening the severity in a subject of a neurodegenerative disease.
  • the neurodegenerative disease comprises multiple sclerosis.
  • the neurodegenerative disease comprises Pitt Hopkins Syndrome (PTHS).
  • PTHS Pitt Hopkins Syndrome
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in combination with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.
  • the additional therapeutic agent is a sodium channel inhibitor.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity of acute pain, sub-acute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, nociplastic pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain of multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, unspecific chronic back pain, head pain, neck pain, moderate pain, severe pain, intrac
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity of femur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headaches; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy induced neuropathic pain; radiotherapy-induced n
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity of trigeminal neuralgia, migraines treated with botox, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbrosacral radiculopathy, iliolingual neuralgia, pudendal neuralgia, femoral neuropathy, meralgia paresthetica, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain or postamputation pain.
  • an “effective amount” of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is that amount effective for treating or lessening the severity of one or more of the conditions recited above.
  • the compounds, salts, and compositions, according to the method of the invention may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the pain or non-pain diseases recited herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition, the particular agent, its mode of administration, and the like.
  • the compounds, salts, and compositions of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compounds, salts, and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound or salt employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound or salt employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound or salt employed, and like factors well known in the medical arts.
  • subject or “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the condition being treated.
  • the compound, salts, and compositions of the invention may be administered orally or parenterally at dosage levels of about 0.001 mg/kg to about 1000 mg/kg, one or more times a day, effective to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compound or salt of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound or salt is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cety
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions examples include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. [00209]
  • the active compound or salt can also be in microencapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound or salt may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Dosage forms for topical or transdermal administration of a compound or salt of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
  • the invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the compounds of the invention are useful as inhibitors of voltage-gated sodium channels.
  • the compounds are inhibitors of Na V 1.8 and thus, without wishing to be bound by any particular theory, the compounds, salts, and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of Na V 1.8 is implicated in the disease, condition, or disorder.
  • the disease, condition, or disorder may also be referred to as a “Na V 1.8-mediated disease, condition or disorder.” Accordingly, in another aspect, the invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of Na V 1.8 is implicated in the disease state.
  • the activity of a compound utilized in this invention as an inhibitor of Na V 1.8 may be assayed according to methods described generally in International Publication No. WO 2014/120808 A9 and U.S.
  • compositions of the invention can be employed in combination therapies, that is, the compounds, salts, and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • therapies therapeutics or procedures
  • the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.
  • additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.”
  • additional therapeutic agents include, but are not limited to: non-opioid analgesics (indoles such as Etodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such as Nabumetone; oxicams such as Piroxicam; para-aminophenol derivatives, such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylates such as Aspirin
  • nondrug analgesic approaches may be utilized in conjunction with administration of one or more compounds of the invention.
  • anesthesiologic intraspinal infusion, neural blockade
  • neurosurgical neurolysis of CNS pathways
  • neurostimulatory transcutaneous electrical nerve stimulation, dorsal column stimulation
  • physiatric physical therapy, orthotic devices, diathermy
  • psychologic psychologic
  • additional appropriate therapeutic agents are selected from the following: [00215] (1) an opioid analgesic, e.g.
  • NSAID nonsteroidal antiinflammatory drug
  • a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone
  • a skeletal muscle relaxant e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine
  • an NMDA receptor antagonist e.g.
  • dextromethorphan (+)-3-hydroxy-N- methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2- piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g.
  • doxazosin tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-l, 2,3,4- tetrahydroisoquinolin-2-yl)-5- (2-pyridyl) quinazoline;
  • a tricyclic antidepressant e.g. desipramine, imipramine, amitriptyline or nortriptyline
  • an anticonvulsant e.g.
  • a tachykinin (NK) antagonist particularly an NK-3, NK-2 or NK-1 antagonist, e.g.
  • a Na V 1.8 blocker such as PF-04531083, PF-06372865 and such as those disclosed in WO2008/135826 (US2009048306), WO2006/011050 (US2008312235), WO2013/061205 (US2014296313), US20130303535, WO2013131018, US8466188, WO2013114250 (US2013274243), WO2014/120808 (US2014213616), WO2014/120815 (US2014228371) WO2014/120820 (US2014221435), WO2015/010065 (US20160152561), WO2015/089361 (US20150166589), WO2019/014352 (US20190016671), WO2018/213426, WO2020/146682, WO2020/146612, WO2020/014243, WO2020/014246, WO2020/092187, WO2020/092667 (US2020140411), WO2020
  • the additional appropriate therapeutic agents are selected from V- 116517, Pregabalin, controlled release Pregabalin, Ezogabine (Potiga®). Ketamine/amitriptyline topical cream (Amiket®), AVP-923, Perampanel (E-2007), Ralfinamide, transdermal bupivacaine (Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561 or ARC-4558.
  • the additional appropriate therapeutic agents are selected from N-(6- amino-5-(2,3,5-trichlorophenyl)pyridin-2-yl)acetamide; N-(6-amino-5-(2-chloro-5- methoxyphenyl)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; or 3-((4-(4- (trifluoromethoxy)phenyl)-1H-imidazol-2-yl)methyl)oxetan-3-amine.
  • the additional therapeutic agent is selected from a GlyT2/5HT2 inhibitor, such as Operanserin (VVZ149), a TRPV modulator such as CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101, MDR16523, or MDR652, a EGR1 inhibitor such as Brivoglide (AYX1), an NGF inhibitor such as Tanezumab, Fasinumab, ASP6294, MEDI7352, a Mu opioid agonist such as Cebranopadol, NKTR181 (oxycodegol), a CB-1 agonist such as NEO1940 (AZN1940), an imidazoline 12 agonist such as CR4056 or a p75NTR-Fc modulator such as LEVI-04.
  • a GlyT2/5HT2 inhibitor such as Operanserin (VZ149), a TRPV modulator such as CA008, CMX-020, NEO6860, FTABS,
  • the additional therapeutic agent is oliceridine or ropivacaine (TLC590).
  • the additional therapeutic agent is a Na V 1.7 blocker such as ST-2427 or ST-2578 and those disclosed in WO2010129864, WO2015157559, WO2017059385, WO2018183781, WO2018183782, WO2020072835, and WO2022036297 the entire contents of each application hereby incorporated by reference.
  • the additional therapeutic agent is a Na V 1.7 blocker disclosed in WO2020072835.
  • the additional therapeutic agent is a Na V 1.7 blocker disclosed in WO2022036297.
  • the additional therapeutic agent is ASP18071, CC-8464, ANP-230, ANP-231, NOC-100, NTX-1175, ASN008, NW3509, AM-6120, AM-8145, AM-0422, BL-017881, NTM-006, Opiranserin (Unafra TM ), brivoligide, SR419, NRD.E1, LX9211, LY3016859, ISC-17536, NFX-88, LAT-8881, AP-235, NYX 2925, CNTX-6016, S-600918, S-637880, RQ-00434739, KLS-2031, MEDI 7352, or XT-150.
  • the additional therapeutic agent is Olinvyk, Zynrelef, Seglentis, Neumentum, Nevakar, HTX-034, CPL-01, ACP-044, HRS-4800, Tarlige, BAY2395840, LY3526318, Eliapixant, TRV045, RTA901, NRD1355-E1, MT-8554, LY3556050, AP-325, tetrodotoxin, Otenaproxesul, CFTX-1554, Funapide, iN1011-N17, JMKX000623, ETX-801, or ACD440.
  • the additional therapeutic agent is a compound disclosed in WO2021257490, WO2021257420, WO2021257418, WO2020014246, WO2020092187, WO2020092667, WO2020261114, CN112457294, CN112225695, CN111808019, WO2021032074, WO2020151728, WO2020140959, WO2022037641, WO2022037647, CN112300051, CN112300069, WO2014120808, WO2015089361, WO2019014352, WO2021113627, WO2013086229, WO2013134518, WO2014211173, WO2014201206, WO2016141035, WO2021252818, WO2021252822, and WO2021252820.
  • the additional therapeutic agent is a compound disclosed in WO2013086229. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2013134518. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2014211173. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2014201206. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2016141035. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2021252818. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2021252822. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2021252820.
  • the additional therapeutic agent is a compound disclosed in WO2020072835. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2022036297. [00276] In another embodiment, the additional therapeutic agent is a sodium channel inhibitor (also known as a sodium channel blocker), such as the Na V 1.7 and Na V 1.8 blockers identified above. [00277]
  • the amount of additional therapeutic agent present in the compositions of this invention may be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. The amount of additional therapeutic agent in the presently disclosed compositions may range from about 10% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • the invention in another aspect, includes a composition for coating an implantable device comprising a compound or salt of the invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.
  • the invention includes an implantable device coated with a composition comprising a compound or salt of the invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.
  • Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121.
  • the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
  • the coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
  • Another aspect of the invention relates to inhibiting Na V 1.8 activity in a biological sample or a subject, which method comprises administering to the subject, or contacting said biological sample with a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • Inhibition of Na V 1.8 activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art.
  • the compounds of the invention can be prepared from known materials by the methods described in the Examples, other similar methods, and other methods known to one skilled in the art.
  • the functional groups of the intermediate compounds in the methods described below may need to be protected by suitable protecting groups.
  • Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art. The use of protecting groups is described in detail in T.G.M. Wuts et al., Greene’s Protective Groups in Organic Synthesis (4th ed.2006).
  • Radiolabeled Analogs of the Compounds of the Invention relates to radiolabeled analogs of the compounds of the invention.
  • the term “radiolabeled analogs of the compounds of the invention” refers to compounds that are identical to the compounds of the invention, as described herein, including all embodiments thereof, except that one or more atoms has been replaced with a radioisotope of the atom present in the compounds of the invention.
  • the term “radioisotope” refers to an isotope of an element that is known to undergo spontaneous radioactive decay.
  • radioisotopes examples include 3 H, 14 C, 32 P, 35 S, 18 F, 36 Cl, and the like, as well as the isotopes for which a decay mode is identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).
  • the radiolabeled analogs can be used in a number of beneficial ways, including in various types of assays, such as substrate tissue distribution assays.
  • tritium ( 3 H)- and/or carbon-14 ( 14 C)-labeled compounds may be useful for various types of assays, such as substrate tissue distribution assays, due to relatively simple preparation and excellent detectability.
  • the invention relates to pharmaceutically acceptable salts of the radiolabeled analogs, in accordance with any of the embodiments described herein in connection with the compounds of the invention.
  • the invention relates to pharmaceutical compositions comprising the radiolabeled analogs, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle, in accordance with any of the embodiments described herein in connection with the compounds of the invention.
  • the invention relates to methods of inhibiting voltage-gated sodium channels and methods of treating or lessening the severity of various diseases and disorders, including pain, in a subject comprising administering an effective amount of the radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, in accordance with any of the embodiments described herein in connection with the compounds of the invention.
  • the invention relates to radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use, in accordance with any of the embodiments described herein in connection with the compounds of the invention.
  • the invention relates to the use of the radiolabeled analogs, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments, in accordance with any of the embodiments described herein in connection with the compounds of the invention.
  • the radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof can be employed in combination therapies, in accordance with any of the embodiments described herein in connection with the compounds of the invention.
  • ENUMERATED EMBODIMENTS [00291] Further embodiments of the disclosure are set out in the following numbered clauses: 1.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein: X 2a is N, N + -O-, or C-R 2a ; X 3a is N or N + -O-; X 5a is N, N + -O-, or C-R 5a ; X 6a is N, N + -O-, or C-R 6a ; R d is (CH 2 ) m (CHR e ) n (CH 2 ) p H; m, n, and p are each independently 0 or 1; R e is H, OH, halo, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 2a and R 6a are each independently H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 5a is H, halo, CH 2 OH, C 1 -C 6 alkyl, or C 1 -C 6
  • a method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject the compound of any one of clauses 1-39, or a pharmaceutically acceptable salt thereof, the compound of clause 40, or the pharmaceutical composition of clause 41 or 42. 44. The method of clause 43, wherein the voltage-gated sodium channel is Na V 1.8. 45.
  • a method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia comprising administering to the subject an effective amount of the compound of any one of clauses 1-39, or a pharmaceutically acceptable salt thereof, the compound of clause 40, or the pharmaceutical composition of clause 41 or 42.
  • 47. The method of clause 46, wherein the neuropathic pain comprises post-herpetic neuralgia.
  • neuropathic pain comprises small-fiber neuropathy. 49. The method of clause 46, wherein the neuropathic pain comprises idiopathic small-fiber neuropathy. 50. The method of clause 46, wherein the neuropathic pain comprises diabetic neuropathy. 51. The method of clause 50, wherein the diabetic neuropathy comprises diabetic peripheral neuropathy. 52. The method of clause 45, wherein the method comprises treating or lessening the severity in the subject of musculoskeletal pain. 53. The method of clause 52, wherein the musculoskeletal pain comprises osteoarthritis pain. 54. The method of clause 45, wherein the method comprises treating or lessening the severity in the subject of acute pain. 55.
  • the method of clause 54, wherein the acute pain comprises acute post-operative pain.
  • 56. The method of clause 45, wherein the method comprises treating or lessening the severity in the subject of postsurgical pain.
  • the postsurgical pain comprises bunionectomy pain.
  • the method of clause 56, wherein the postsurgical pain comprises abdominoplasty pain.
  • the method of clause 56, wherein the postsurgical pain comprises herniorrhaphy pain.
  • the method comprises treating or lessening the severity in the subject of visceral pain. 61.
  • LC/MS analysis was conducted using an Acquity UPLC BEH C 8 column (50 ⁇ 2.1 mm, 1.7 ⁇ m particle) made by Waters (pn: 186002877) with a (2.1 ⁇ 5 mm, 1.7 ⁇ m particle) guard column (pn: 186003978), and a dual gradient run from 2-98% mobile phase B over 4.45 minutes.
  • Mobile phase A H 2 O (10 mM ammonium formate with 0.05 % ammonium hydroxide).
  • Mobile phase B acetonitrile.
  • X-ray powder diffraction analysis Method A X-ray powder diffraction (XRPD) analysis was performed at room temperature in transmission mode using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel 1D Medipix-2 detector (Malvern PANalytical Inc, Westborough, Massachusetts). The X-Ray generator operated at a voltage of 45 kV and a current of 40 mA with copper radiation (1.54060 ⁇ ). The powder sample was placed on a 96 well sample holder with mylar film and loaded into the instrument.
  • XRPD X-ray powder diffraction
  • X-ray powder diffraction analysis Method B X-ray powder diffraction (XRPD) analysis was performed at room temperature in transmission mode using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel 3D Medipix-3 detector (Malvern PANalytical Inc, Westborough, Massachusetts). The X-Ray generator operated at a voltage of 45 kV and a current of 40 mA with copper radiation (1.54060 ⁇ ).
  • Trimethylsilyl trifluoromethanesulfonate (8.5 mL, 47.0 mmol) was added dropwise over 5 min and the mixture was stirred for a further 30 min at 0 °C.
  • the reaction mixture was diluted with pentane (100 mL), the layers separated and the organic phase washed with dilute aqueous sodium bicarbonate (100 mL) and brine (100 mL).
  • the organic layer was dried (MgSO 4 ), and concentrated in vacuo to give ethyl (Z)-2-diazo-3- trimethylsilyloxy-pent-3-enoate (9.4 g, 99%) as a red oil.
  • Step 2 [00301] To a stirred solution of 1,1,1-trifluoropropan-2-one (8 mL, 89.4 mmol) in DCM (80 mL) at -78 oC was added TiCl 4 (70 mL of 1 M in DCM, 70.00 mmol) via cannula.
  • Step 3 A solution of rhodium tetraacetate (245 mg, 0.55 mmol) in benzene (32 mL) was heated at reflux for 10 min before a solution of ethyl rac-(4R,5R)-2-diazo-6,6,6-trifluoro-5-hydroxy-4,5- dimethyl-3-oxohexanoate (10 g, 35.4 mmol) in benzene (13 mL) was added slowly via addition funnel while refluxing for 60 min.
  • Step 4 [00305] To a stirred solution of ethyl rac-(4R,5R)-4,5-dimethyl-3-oxo-5- (trifluoromethyl)tetrahydrofuran-2-carboxylate (48 g, 188.83 mmol) in DCM (400 mL) at -78 °C was added DIPEA (29.680 g, 40 mL, 229.64 mmol). A solution of trifluoromethylsulfonyl trifluoromethanesulfonate (53.440 g, 32 mL, 189.41 mmol) in DCM (200 mL) was added to the reaction mixture at the same temperature over 1h.
  • Step 5 [00307] To stirred a solution of ethyl rac-(4R,5R)-2,3-dimethyl-2-(trifluoromethyl)-4- (trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (26 g, 67.311 mmol) in toluene (130.00 mL) was added (3,4-difluoro-2-methoxy-phenyl)boronic acid (14 g, 74.5 mmol) followed by K 3 PO 4 (100 mL of 2 M, 200.00 mmol) under an argon atmosphere.
  • the reaction was degassed before tetrakis(triphenylphosphine)palladium (0) (4 g, 3.46 mmol) was added. After further degassing, the reaction was heated at 100 °C for 2 h. The reaction was diluted in water and the aqueous layer extracted with EtOAc (2 x 100 mL). The combined organic layers were concentrated in vacuo.
  • Step 6 [00309] To an ice-cooled solution of ethyl rac-(4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-2,3- dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (110 g, 243.0 mmol) in DCM (360 mL) was added BBr 3 (370 mL of 1 M, 370.0 mmol) dropwise. Upon addition completion, the mixture was quenched by addition of water and aqueous sodium bicarbonate solution. The aqueous layer was extracted with DCM and the combined organic layers were dried (MgSO 4 ), filtered and concentrated in vacuo.
  • Step 8 [00315] A solution of (1S,2R)-6,7-Difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H- furo[2,3-c]chromen-4-one (0.89 kg, 2.78 mol) and 20% palladium hydroxide on carbon (50% wet, 0.39 kg, 0.278 mol) in MeOH (12 L) was stirred under a 40 psi pressure of hydrogen overnight. An increase in the reaction temperature to 37 °C was observed after reacting overnight and the mixture was cooled to 24 °C.
  • Step 9 [00317] Potassium carbonate (2.0 kg, 14.4 mol) and iodomethane (800 mL, 12.8 mol) were sequentially added to a solution of methyl (2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl- 5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.0 kg, 2.82 mol) in acetonitrile (10 L) under nitrogen stirring at ambient temperature. After stirring overnight, additional iodomethane (120 mL, 2 mmol) was added.
  • Steps 10 and 11 [00319] Sodium methoxide (25% in methanol, 65 mL, 0.28 mol) was added to a solution of methyl (2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carboxylate (0.98 kg, 2.66 mol) in THF (10 L) stirring at ambient temperature under nitrogen. After 5 h, MeOH (1 L), water (1 L) and lithium hydroxide monohydrate (0.168 kg, 4.0 mol) were sequentially added and the mixture was stirred overnight.
  • reaction mixture was poured into 1M HCl (4.4 L, 4.4 mol) then extracted with MTBE (20 L).
  • the aqueous layer was further extracted with MTBE (2 x 5 L), and the combined organic layers were washed with brine (2 L), dried (Na 2 SO 4 ), filtered, and then treated with activated carbon (50 g, 5% w/w) with stirring for 1 h.
  • the mixture was filtered through celite, washing with MTBE (2 x 4 L), and the filtrate was concentrated in vacuo.
  • Step 12 [00321] Crude (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (2.09 kg at 77% purity, 4.54 mol) was dissolved in MTBE (25 L) in a 100 L Chemglass reactor then stirred at 84 rpm at ambient temperature. A mixture of (R)-1-phenylethylamine (0.704 kg, 5.81 mol) and MTBE (2 L) was added to the reactor, followed by additional MTBE to give a total volume of 30 L in the reactor.
  • Step 13 To a suspension of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1R)-1-phenylethanamine salt (10.6 g, 22.29 mmol) in MTBE (250 mL) was added HCl (200 mL of 2 M, 400.0 mmol).
  • Steps 14 and 15 [00325] Oxalyl chloride (738 ⁇ L, 8.460 mmol) was added dropwise to a solution of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxylic acid (1.5 g, 4.234 mmol) and DMF (31 ⁇ L, 0.4004 mmol) in dichloromethane (10 mL). After stirring for 30 min at ambient temperature, the solution was concentrated in vacuo.
  • Step 16 [00330] TFA (1.743 mL, 22.62 mmol) was added to a solution of (2R,3S,4S,5R)-3-(3,4-difluoro- 2-methoxyphenyl)-N-(6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (600 mg, 1.112 mmol) (First Eluting Isomer from SFC separation) in DCM (20 mL) and the mixture stirred for 2 h at ambient temperature.
  • step 15 The following compounds were made using the method described in Example 1, except that rac-6-((4R,5R)-2,2,5-trimethyl-1,3-dioxolan-4-yl)pyridin-3-amine was used in place of rac-6-(2,2- Dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine in the amide coupling step 14.
  • step 15 purification was performed by chiral SFC using a Chiralcel OD-H column, 5 ⁇ ⁇ m particle size, 25 cm x 10 mm from Daicel Corporation (Mobile phase: 12 % MeOH (containing 20 mM Ammonia), 88 % CO 2 .
  • the SFC separation step 15 was not required: [00336] The following compounds were made using the method described in Example 1, except that ethyl iodide was used in place of methyl iodide in the alkylation step 9. The conditions used for the epimerization/hydrolysis steps 10 and 11 followed the first part of the conditions described in Example 5 step 4. In step 14, (S)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine and (R)-6-(2,2-dimethyl-1,3- dioxolan-4-yl)pyridin-3-amine were respectively used as the coupling partner for compounds 6 and 7. The SFC separation step 15 was not required:
  • Compound 7 was analyzed by X-ray powder diffraction analysis Method B and determined to be amorphous (see Fig.2).
  • the following compound was made using a method similar to that described in Example 1 except that iodomethane-d 3 was used in place of methyl iodide in the alkylation step 9 and the conditions carried out for the amide coupling step 14 followed the conditions described in Example 2 step 1 using (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine as the coupling partner.
  • the SFC separation step 15 was not required: C C C/ S ( if i ) [00339] Compound 8 was analyzed by X-ray powder diffraction analysis Method B and determined to be amorphous (see Fig.3). [00340] The following compounds were made using the method described in Example 1, except that 2-iodopropane was used in place of methyl iodide in step 9 and the reaction was carried out at 75 °C. The epimerization/hydrolysis steps 10 and 11 were carried out in one step following the conditions described in Example 6 step 3.
  • Steps 12 and 13 were omitted and, in the amide coupling step 14, 2-(2,2- dimethyl-1,3-dioxolan-4-yl)pyrimidin-5-amine was used as the coupling partner.
  • step 15 purification was performed by chiral SFC using a Chiralpak IB column, 5um particle size, 25 cm x 20 mm from Daicel Corporation (Mobile phase: 20 % MeOH (containing 20 mM Ammonia), 80 % CO 2 . Flow: 100 mL/min.) on a Minigram SFC instrument from Berger Instruments:
  • step 15 The following compounds were made using the method described in Example 1, except that steps 12 and 13 were omitted and, in the amide coupling step 14, 2-(2,2-dimethyl-1,3-dioxolan-4- yl)pyrimidin-5-amine was used as the coupling partner.
  • step 15 purification was performed by chiral SFC using a Chiralcel OD-H column, 5um particle size, 25 cm x 10 mm from Daicel Corporation (Mobile phase: 22 % MeOH (containing 20 mM Ammonia), 78 % CO 2 .
  • the compound did not require the chiral SFC separation step 15: [00343] The following compound was made using the method described in Example 1, except that 6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-amine was used as the coupling partner in the amide coupling step 14. The SFC separation step 15 was not required and the deprotection step 16 was carried out at ambient temperature over 3 days using an excess of HCl (37% w/v) in MeOH as the solvent: C C C/ S ( if i ) [00344] The following compound was made using the method described in Example 1, except that (5-aminopyrimidin-2-yl)methyl benzoate was used as the coupling partner in the amide coupling step 14.
  • the SFC separation step 15 was not required and the deprotection step 16 was carried out overnight at ambient temperature using a 2 M solution of sodium hydroxide in excess and 1,4-dioxane as the solvent: [00345]
  • the following compounds were made using the method described in Example 1, except that 6-(1-((tert-butyldimethylsilyl)oxy)-2-fluoroethyl)pyridin-3-amine was used as the coupling partner in the amide coupling step 14.
  • the chiral SFC separation step 15 was carried out using a Chiralpak IB column, 5 ⁇ m particle size, 25 cm x 20 mm from Daicel (Mobile phase: 5 % IPA (containing 20 mM Ammonia), 95 % CO 2 .
  • Step 2 [00350] The 2 diastereoisomers of (2R,3S,4S,5R)-N-(6-(1-((tert-butyldimethylsilyl)oxy)-2- methoxyethyl)pyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (210 mg, 0.3191 mmol) were separated by using a Chiralcel OD-H column, 5 ⁇ ⁇ m particle size, 25 cm x 10 mm from Daicel (Mobile phase: 15 % MeOH (containing 20 mM Ammonia), 85 % CO 2 .
  • Step 3 [00354] A THF solution of TBAF (650 ⁇ L of 1 M, 0.6500 mmol) was added to a stirred solution of rel-(2R*,3S*,4S*,5R*)-N-(6-(1-((tert-butyldimethylsilyl)oxy)-2-methoxyethyl)pyridin-3-yl)-3-(3,4- difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (80 mg, 0.1293 mmol) (First Eluting Isomer from SFC separation) in 2-MeTHF (4 mL) at 0 °C.
  • reaction was stirred at ambient temperature over the weekend (convenience).
  • the reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL), stirred for 10 min and extracted with ethyl acetate (2 x 10 mL).
  • the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo.
  • step 2 purification was performed by chiral SFC using a Chiralpak IB column, 5 ⁇ m particle size, 25 cm x 20 mm from Daicel (Mobile phase: 5 % MeOH (containing 20 mM Ammonia), 95 % CO 2 . Flow: 100 mL/min.) on a Prep-100 SFC instrument from Waters:
  • Step 2 A solution of 1,1,1-trifluoropropan-2-one (33.8 g, 27 mL, 301.2 mmol) in DCM (150 mL) was cooled down to -78 °C. TiCl 4 (56.8 g, 33 mL, 299.2 mmol) was added dropwise to the stirred reaction mixture. The reaction was kept at -78 °C for 10 min before a solution of ethyl 3-((tert- butyldimethylsilyl)oxy)-2-diazobut-3-enoate (64 g, 236.7 mmol) in DCM (150 mL) was added dropwise.
  • Step 4 [00365] Trifluoromethanesulfonic anhydride (6.0 mL, 35.7 mmol) was added dropwise to a solution of ethyl 5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (6.5 g, 27.1 mmol) and DIPEA (14 mL, 80.4 mmol) in DCM (150 mL) at -78 °C. The reaction mixture was stirred for 2.5 h before saturated aqueous NH 4 Cl (75 mL) was added. The mixture was warmed up to ambient temperature. The aqueous layer was extracted with DCM (2 x 30 mL).
  • Step 5 [00367] K 3 PO 4 (13 mL of 2 M aq., 26.0 mmol) was added to a stirred solution of (3,4-difluoro-2- methoxyphenyl)boronic acid (2.0 g, 10.6 mmol) and ethyl 5-methyl-5-(trifluoromethyl)-3- (((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (3 g, 7.90 mmol) in toluene (80 mL). The mixture was degassed by bubbling nitrogen through the solution for 20 min.
  • Step 6 [00369] EtOH (200 mL) was added to a mixture of ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5- methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (5.51 g, 15.0 mmol) and Pd/C (10 wt. % loading, 2.2 g, 2.067 mmol). The mixture was degassed and stirred under a balloon of H 2 for 96 h. The catalyst was removed by filtration and the solids washed with EtOH (50 mL). The filtrates were concentrated in vacuo. A further portion of Pd/C (10 wt.
  • Step 7 [00371] Ethyl rac-(2S,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylate (5.19 g, 14.09 mmol) was dissolved in ethanol (100 mL). Cs 2 CO 3 (7.1 g, 21.79 mmol) was added and the suspension stirred at 50 °C for 2 h. The reaction mixture was concentrated in vacuo and the residue partitioned between 1M HCl and MTBE. The aqueous layer was extracted twice with MTBE.
  • Step 8 [00373] Oxalyl chloride (70 ⁇ L, 0.8024 mmol) was carefully added to an ice cooled solution of rac-(2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxylic acid (150 mg, 0.3968 mmol) and DMF (2-methyl-THF solution, 50 ⁇ L of 0.86 M, 0.04300 mmol) in 2-methyltetrahydrofuran (5 mL).
  • Step 10 [00379] TFA (225 ⁇ L, 2.920 mmol) was added to a solution of rel-(2R,3S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-N-(6-((R*)-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-5-methyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (42 mg, 0.081 mmol) (First Eluting Isomer from SFC separation) in DCM (5 mL) and the mixture stirred for 18 h at ambient temperature.
  • step 9 purification was performed by chiral SFC using a Chiralpak IA column, 5 ⁇ ⁇ m particle size, 25 cm x 20 mm from Daicel Corporation on a Prep-100 SFC instrument from Waters: C C C/ S ( if i ) [00382]
  • the following compounds were made using the method described in Example 3, except that rac-2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrimidin-5-amine was used in place of (R)-6-(2,2-dimethyl- 1,3-dioxolan-4-yl)pyridin-3-amine in the amide coupling step 8.
  • step 9 a mixture of four stereoisomers of rel-(2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(1,2-dihydroxyethyl)pyrimidin- 5-yl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, which had known relative stereochemistry about the THF ring (i.e., (2R,3S,5R)), but unknown relative stereochemistry between the THF ring and the dihydroxyethyl substituent, was performed by chiral SFC using a Chiralcel OJ column, 5 ⁇ ⁇ m particle size, 25 cm x 21.2 mm from Daicel Corporation (40 °C; Mobile Phase: 6 % MeOH (20mM NH3), 94 % CO2; Flow: 70 mL/min.) on a Prep-100 SFC instrument from Waters: [00383] The following compounds were made using the method described in Example 3, except
  • step 9 purification was performed by chiral SFC using a (R,R)-Whelk-O1 column, 5 um particle size, 25 cm x 21.1 mm from Daicel (Mobile phase: 30 % MeOH (containing 20 mM Ammonia), 70 % CO 2 . Flow: 100 mL/min.) on a Minigram SFC instrument from Berger Instruments.
  • the deprotection step 10 was carried out at ambient temperature over 1.5 h using 12 M HCl in THF as the solvent: [00384] Compound 35 was analyzed by X-ray powder diffraction analysis Method B and determined to be amorphous (see Fig.6).
  • Step 2 [00388] K 2 CO 3 (18 mg, 0.1302 mmol) was added to a mixture of 1-fluoro-2-iodoethane (10 ⁇ L, 0.1230 mmol) and (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-N-(6-((R)-1,2- dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (36, 40 mg, 0.08396 mmol) in DMF (2 mL).
  • Step 2 [00394] To a 1 L three necked flask, fitted with a thermometer, was added ethyl rac-(4S,5R)-3-(4- fluoro-2-methoxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (27.35 g, 72.67 mmol) followed by DCM (200 mL). The reaction mixture was cooled to 5 °C with an ice bath. Boron tribromide (112 mL, 1 M solution in DCM, 112.0 mmol) was added via cannula over 30 min, keeping the internal temperature around 5 °C.
  • the reaction mixture was stirred for 1 h.
  • the mixture was quenched by slow addition of water (100 mL) causing effervescence and of a saturated sodium bicarbonate solution (100 mL).
  • the mixture was stirred for 30 min.
  • the aqueous phase was collected and washed with DCM (3 x 50 mL).
  • the combined organic extracts were washed with a saturated sodium bicarbonate solution (5 x 100 mL), dried (MgSO 4 ), filtered and concentrated in vacuo to give a yellow waxy solid.
  • the waxy solid was re-dissolved in EtOAc (100 mL). Charcoal (15 g) was added and the mixture was stirred at ambient temperature overnight. The mixture was filtered through a pad of celite.
  • Step 3 [00397] rac-(1S,2R)-7-fluoro-1,2,6-trimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3- c]chromen-4-one (1.5 g, 3.273 mmol) was dissolved in EtOAc (20 mL) and stirred with activated charcoal (300 mg, 24.98 mmol) for 18 h. The mixture was filtered through a pad of celite. The liquors were concentrated in vacuo to give a yellow solid.
  • the solid was dissolved in methanol (20 mL) and added to a 100 mL flask containing dihydroxypalladium (460 mg of 20 %w/w, 0.6551 mmol). The resulting mixture was stirred under an atmospheric pressure of hydrogen for 120 h. The mixture was filtered through a celite cartridge washing with MeOH. The filtrates were concentrated in vacuo to an approximate volume of 20 mL and added to a flask containing dihydroxypalladium (230 mg of 20 %w/w, 0.3276 mmol). The resulting mixture was stirred under a ballon atmosphere of hydrogen for 12 h. The reaction mixture was filtered through a celite cartridge, washing with MeOH.
  • Step 4 [00399] Potassium tert-butoxide (11.40 g, 101.6 mmol) was added to a stirred solution of a mixture of isomers of methyl 3-(4-fluoro-2-hydroxy-3-methylphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylate (8.896 g, 25.39 mmol), of which methyl rac- (2S,3S,4S,5R)-3-(4-fluoro-2-hydroxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-carboxylate was the major isomer, in tetrahydrofuran (125 mL) at 0 °C.
  • Step 5 [00401] K 2 CO 3 (1.65 g, 11.94 mmol) and iodoethane (1 mL, 12.50 mmol) were added to a solution of a mixture of rac-(2R,3S,4S,5R)-3-(4-fluoro-2-hydroxy-3-methylphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid and rac-(2S,3S,4S,5R)-3-(4-fluoro-2-hydroxy-3- methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1 g, 2.974 mmol) in acetonitrile (10 mL) in a sealed vial.
  • Step 6 [00403] LiOH (3.3 mL of 2 M, 6.600 mmol) was added to a stirred solution of a mixture of ethyl rac-(2R,3S,4S,5R)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylate and rac-(2S,3S,4S,5R)-3-(2-ethoxy-4-fluoro-3- methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1 g, 2.549 mmol) in methanol (15 mL) and water (4 mL).
  • Step 7 [00405] DMF (2.5 ⁇ L, 0.0323 mmol) and oxalyl chloride (27.5 ⁇ L, 0.315 mmol) were added to a solution of a mixture of rac-(2R,3S,4S,5R)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid and rac-(2S,3S,4S,5R)-3-(2-ethoxy-4-fluoro-3- methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (76 mg, 0.209 mmol) in DCM (2 mL) cooled to 0 °C.
  • Step 8 [00409] The mixture of rel-(2R,3S,4S,5R)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3- yl)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide and rel-(2S,3R,4R,5S)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-3-(2-ethoxy- 4-fluoro-3-methylphenyl)-4,5-
  • Step 9 [00413] TFA (10 ⁇ L, 0.130 mmol) was added to a solution of rel-(2R,3S,4S,5R)-N-(6-((R*)-2,2- dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (10 mg, 0.0185 mmol) (First Eluting Isomer from SFC separation) in THF (800 ⁇ L) and water (200 ⁇ L).
  • step 8 purification was performed by chiral SFC using a Lux i-Cellulose-5 column, 5 mm particle size, 25 cm x 20 mm from Daicel Corporation (Mobile phase: 15 % MeOH (containing 20 mM Ammonia), 85 % CO 2 . Flow: 100 mL/min.) on a Prep-100 SFC instrument from Waters:
  • step 5 methyl iodide was used in place of ethyl iodide as the alkylating agent.
  • step 7 in the case of compounds 44 and 45, (S)-6-(2,2- dimethyl-1,3-dioxolan-4-yl)pyridine-3-amine was used in place of (R)-6-(2,2-dimethyl-1,3-dioxolan-4- yl)pyridine-3-amine.
  • step 8 purification was performed by chiral SFC using a (R,R)-Whelk-O1 column, 5 um particle size, 25 cm x 21.1 mm from Daicel (Mobile phase: 5 to 25 % MeOH (containing 20 mM Ammonia), 95 to 75 % CO 2 . Flow: 100 mL/min.) on a Minigram SFC instrument from Berger Instruments.
  • step 9 DCM was used as the solvent rather than a mixture of THF and water: 138
  • Step 2 [00420] A solution of ethyl rac-(4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (3.5 g, 8.488 mmol) in MeOH (100 mL) was added to a two necked flask containing magnesium (2.07 g, 85.17 mmol). The reaction mixture was heated at 70 °C for 3 h.
  • Step 3 Potassium tert-butoxide (1.66 g, 14.79 mmol) was added to a solution of a mixture of methyl rac-(2S,3S,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylate and methyl rac-(2R,3R,4S,5R)-3-(3-(difluoromethyl)-4- fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (2.87 g, 7.169 mmol) in 2-MeTHF (35 mL) in a water bath at ambient temperature.
  • Step 4 [00424] T3P (310 ⁇ L of 50 %w/w, 0.5208 mmol) was added to a solution of a mixture of rac- (2R,3S,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid and rac-(2S,3R,4S,5R)-3-(3-(difluoromethyl)-4-fluoro- 2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (100 mg, 0.2589 mmol), (S)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine (78 mg, 0.4016 mmol) and triethylamine (110
  • reaction mixture was stirred at 50 °C for 30 min and then at ambient temperature overnight.
  • the reaction mixture was partitioned between EtOAc and water and passed through a Whatmann phase separation filter paper.
  • the organic phase was concentrated concentrated in vacuo and loaded onto to silica.
  • step 5 purification was performed by chiral SFC using a (R,R)-Whelk-O1 column, 5 um particle size, 25 cm x 21.1 mm from Daicel (Mobile phase: 5 to 55 % MeOH, 95 to 45 % CO 2 . Flow: 100 mL/min.) on a Minigram SFC instrument from Berger Instruments.
  • the conditions used in step 6 were similar to those described in Example 1 step 16: 144 [00433]
  • the following compounds were made using the method described in Example 6, except that the product of step 1 was prepared in 3 steps using the conditions described in Example 11 steps 1, 2 and 3 and the coupling partner was 1-bromo-3-(difluoromethyl)-4-fluoro-2-methoxybenzene.
  • amide coupling step 4 methyl 5-aminopicolinate was used as the amine coupling partner.
  • the ester formed in step 4 was reduced overnight at 50 °C using an excess of NaBH 4 in MeOH as the solvent, conditions well known in the art.
  • the deprotection step 6 was not required: [00434] The following compounds were made using the method described in Example 6, except that the product of step 1 was prepared in 3 steps using the conditions described in Example 11 steps 1, 2 and 3 and the coupling partner was 1-bromo-3-(difluoromethyl)-4-fluoro-2-methoxybenzene.
  • amide coupling step 4 (5-aminopyrimidin-2-yl)methyl benzoate was used as the amine coupling partner.
  • the chiral SFC separation step 5 was carried out using a Chiralpak IG column, 5 ⁇ m particle size, 25 cm x 20 mm from Daicel (Mobile phase: 17 % MeOH (containing 20 mM Ammonia), 83 % CO 2 . Flow: 100 mL/min.) on a Prep-100 SFC instrument from Waters.
  • the deprotection step 6 was carried out at 30 °C over 16 h using a 2M LiOH solution in excess in MeOH as the solvent, conditions well known in the art: [00435] The following compounds were made using the method described in Example 6, except that the product of step 1 was prepared in 3 steps using the conditions described in Example 11 steps 1, 2 and 3 and the coupling partner was 1-bromo-3-(difluoromethyl)-4-fluoro-2-methoxybenzene. In the amide coupling step 4, 1-(5-aminopyridin-2-yl)ethan-1-one was used as the amine coupling partner.
  • the chiral SFC separation step 5 was carried out using a Chiralpak IG column, 5 ⁇ m particle size, 25 cm x 10 mm from Daicel (Mobile phase: 25 % IPA (containing 20 mM Ammonia), 75 % CO 2 . Flow: 10 mL/min.) on a Minigram SFC instrument from from Berger Instruments.
  • the deprotection step 6 was replaced by a ketone reduction step taking place at ambient temperature over 30 min and using 3 eq of NaBH 4 in MeOH as the solvent, conditions well known in the art.
  • the first eluting isomers in the SFC separation (step 5) was a mixture of epimers at the hydroxyethyl position, which was not further separated and is referred to herein as compound 56.
  • the second eluting isomers in the SFC separation was a mixture of epimers at the hydroxyethyl position, compounds 57 and 58, which were further separated by chiral SFC using a Chiralpak IG column, 5 ⁇ m particle size, 25 cm x 10 mm from Daicel (Mobile phase: 25 % IPA (containing 20 mM Ammonia), 75 % CO 2 .
  • Step 2 [00439] TFA (25 ⁇ L, 0.3245 mmol) was added to a stirred solution of rel-2-((S*)-2,2-dimethyl- 1,3-dioxolan-4-yl)-5-((2R,3S,4S,5R)-3-(4-fluoro-2-methoxy-3-methylphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridine 1-oxide (15.4 mg, 0.02441 mmol) in DCM (500 ⁇ L). The reaction mixture was stirred at ambient temperature for 24 h.
  • Step 2 [00444] A pressure tube was loaded with magnesium powder (2.35 g, 96.69 mmol) and purged with nitrogen. To the reaction vessel was added MeOH (20 mL) followed by a solution of ethyl 3-(2- chloro-4-(trifluoromethoxy)phenyl)-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (2 g, 4.777 mmol) in MeOH (20 mL). The reaction mixture was degassed with nitrogen before adding a few drops of 1,2-dibromoethane (80 mg, 0.4258 mmol). The reaction mixture was stirred vigorously and heated at 50 °C for 5 h.
  • the mixture was cooled down to ambient temperature and quenched by pouring it slowly onto cooled 1M solution of HCl. The mixture was stirred for 30 min until a clear solution was obtained. The mixture was partitioned with TBME. The separated aqueous layer was washed with TBME (x 3). The combined organic phases were passed through a phase separator cartridge.
  • Step 3 [00446] Sodium methoxide (310 ⁇ L of 25 %w/v in MeOH, 1.435 mmol) was added to a stirred solution containing a mixture of methyl rac-(2S,3S,5R)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-5- methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate and methyl rac-(2R,3R,5R)-3-(2-chloro-4- (trifluoromethoxy)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (3.8 g, 9.343 mmol) in THF (40 mL) at ambient temperature under nitrogen.
  • Step 4 [00448] Dimethylformamide (0.3 ⁇ L, 0.003874 mmol) and oxalyl chloride (78 ⁇ L, 0.8941 mmol) were added to an ice cold stirring solution of a mixture of diastereoisomers containing rac-(2R,3S,5R)-3- (2-chloro-4-(trifluoromethoxy)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid and rac-(2S,3R,5R)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxylic acid (167 mg, 0.4253 mmol) in
  • reaction mixture was stirred and warmed up to ambient temperature over 1.5 h.
  • the reaction mixture was concentrated in vacuo.
  • the residue was taken up in 2-methyltetrahydrofuran (2 mL) and added to an ice cooled solution of (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine (90 mg, 0.4634 mmol) and TEA (178 ⁇ L, 1.277 mmol) in a mixture of 2-methyltetrahydrofuran (2 mL) and NMP (0.1 mL).
  • the resulting mixture was stirred and warmed up to ambient temperature over 18 h.
  • the reaction mixture was quenched with water (5 mL) and the layers separated.
  • Step 5 [00452] The mixture of rel-(2R,3S,5R)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-N-(6-((R*)-2,2- dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide and rel-(2S,3R,5S)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4- yl)pyridin-3-yl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (95 mg, 0.120 mmol) (First Eluting Isomers from Step 4) were separated by chiral SFC using a (R,R)-Whelk-
  • the stirred mixture is degassed and flushed with nitrogen.
  • KOAc 32 g, 326.1 mmol
  • bis(pinacolato)diboron 32 g, 126.0 mmol
  • the reaction mixture was evacuated and back filled with nitrogen (x3).
  • Pd(dppf)Cl 2 (4 g, 5.467 mmol) was added and the mixture was heated to 80 °C for 20 h.
  • the reaction mixture was cooled down to ambient temperature and partitioned between ethyl acetate (300 mL) and water (100 mL).
  • the mixture was filtered through a pad of celite, washing with ethyl acetate (5 x 100 ml) until no more product came off.
  • the filtrate phases were separated.
  • Step 2 An aqueous solution of K 3 PO 4 (8 mL of 2 M, 16.00 mmol) was added to a solution of rac-(4S,5R)-4,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-4,5- dihydrofuran-2-carboxylate (3 g, 7.414 mmol), 1-bromo-3,4-difluoro-2-methylbenzene (1.4 g, 6.763 mmol) and Pd(dppf)Cl 2 .CH 2 Cl 2 (350 mg, 0.4286 mmol) in 1,4-dioxane (60 mL).
  • the mixture was degassed and placed under a nitrogen atmosphere. The reaction was stirred at 100 °C for 2 h. The mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted 3 times with ethyl acetate. The organic phases were combined and passed through a Whatmann phase separation filter paper. The filtrates were concentrated in vacuo to give a brown oil.
  • Step 3 [00464] A pressure tube was loaded with magnesium powder (200 mg, 8.229 mmol) and purged with nitrogen. To the reaction vessel was added a solution of ethyl rac-(4S,5R)-3-(3,4-difluoro-2- methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (2.02 g, 5.545 mmol) in MeOH (30 mL). The mixture was degassed and placed under a nitrogen atmosphere. A few drops of 1,2- dibromoethane (5 ⁇ L, 0.058 mmol) were added.
  • the reaction mixture was stirred vigorously and heated at 70 °C for 6 h. A further 3 consecutive portions of magnesium powder (200 mg, 8.229 mmol) were added followed by a drop of 1,2-dibromoethane (5 ⁇ L, 0.058 mmol). The mixture was stirred overnight at 70 °C for 88 h. The reaction mixture was cooled down to 0 °C prior to opening the pressure vessel. The cooled mixture was added dropwise to an ice cold 1M solution of HCl. The reaction was stirred at 0 °C for 30 min until all Mg solids dissolved. The mixture was concentrated in vacuo to remove the MeOH. The resulting aqueous solution was extracted with ethyl acetate (x 3).
  • Step 4 [00466] To a cooled solution of a mixture of methyl rac-(2R,3R,4S,5R)-3-(3,4-difluoro-2- methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate and methyl rac- (2S,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxylate (1.487 g, 4.221 mmol) in 2-MeTHF (20 mL) was added potassium tert-butoxide (1.4 g, 12.48 mmol), causing a ⁇ 5 °C increase in temperature.
  • the reaction mixture turned yellow on addition of potassium t-butoxide.
  • the reaction was stirred for 1 h at ambient temperature.
  • the reaction was diluted with ethyl acetate and 1N NaOH.
  • the aqueous layer was separated.
  • the organic layer was washed further with 1M NaOH (x 2).
  • the combined organic layers were passed through a Whatmann phase separation filter paper.
  • Step 5 [00468] DMF (2 ⁇ L, 0.026 mmol) and oxalyl chloride (154.2 mg, 106.0 ⁇ L, 1.215 mmol) were carefully added to an ice cold stirring solution of a mixture of rac-(2S,3R,4S,5R)-3-(3,4-difluoro-2- methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid and rac-(2R,3S,4S,5R)- 3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (200 mg, 0.591 mmol) in 2-MeTHF (5 mL).
  • Step 6 [00470] T mixture of diastereoisomers obtained in Step 5 was separated by chiral SFC using a (R,R)-Whelk-O1 column, 5 um particle size, 25 cm x 21 mm Mobile phase: 5 to 45 % MeOH (containing 20 mM Ammonia), 95 to 55 % CO 2 .
  • Step 7 [00476] TFA (100 ⁇ L, 1.298 mmol) was added to a stirred solution of rel-(2S,3R,4S,5R)-3-(3,4- difluoro-2-methylphenyl)-N-(6-((R*)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (16 mg, 0.025 mmol) (First Eluting Isomer from SFC separation) in DCM (5 mL).
  • the reaction mixture was stirred overnight at ambient temperature. The mixture was concentrated in vacuo. The residue was azeotroped twice with DCM, quenched with a 1M NaOH solution and partitioned with DCM. The aqueous layer was extracted with DCM (x 3). The combined organic phases were passed through a phase separator cartridge and concentrated in vacuo.
  • step 6 purification was performed by chiral SFC using a (R,R)-Whelk-O1 column, 5 um particle size, 25 cm x 21.1 mm from Daicel (Mobile phase: 5 to 20 % MeOH (containing 20 mM Ammonia), 95 to 80 % CO 2 .
  • step 2 Flow: 100 mL/min.) on a Minigram SFC instrument from Berger Instruments: [00481]
  • the following compounds were made using the method described in Example 9, except that the product of step 2 was prepared by reaction of ethyl rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)- 3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate and (2-methoxy-3- (trifluoromethyl)phenyl)boronic acid using the Suzuki condition of step 2 with K 2 CO 3 as the base.
  • step 5 2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrimidin-5-amine was used as the coupling partner.
  • step 6 purification was performed by chiral SFC using a Chiralcel OJ column, 5 um particle size, 25 cm x 20 mm from Daicel (Mobile phase: 2 to 7 % MeOH (containing 20 mM Ammonia), 98 to 93 % CO 2 . Flow: 75 mL/min.) on a Prep-100 SFC instrument from Waters:
  • step 6 purification was performed by chiral SFC using a (R,R)-Whelk-O1 column, 5 ⁇ m particle size, 25 cm x 21.1 mm from Daicel (Mobile phase: 5 to 15 % IPA (containing 20 mM Ammonia), 95 to 85 % CO 2 . Flow: 100 mL/min.) on a Minigram SFC instrument from Berger Instruments:
  • step 2 The following compounds were made using the method described in Example 9, except that the product of step 2 was prepared by reaction of ethyl rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)- 3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate and (2-methoxy-3- (trifluoromethyl)phenyl)boronic acid using the Suzuki conditions of step 2 with K 2 CO 3 as the base.
  • the amine used in the amide coupling step 5 was 6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-amine.
  • step 6 purification was performed by chiral SFC using a (R,R)-Whelk-O1 column, 5 ⁇ m particle size, 25 cm x 21.1 mm from Daicel (Mobile phase: 40 % MeOH (containing 20 mM Ammonia), 60 % CO 2 .
  • reaction mixture warmed to room temperature and stirred for 90 min.
  • the reaction mixture was concentrated in vacuo and the residue dissolved in 2- methyltetrahydrofuran (10 mL).
  • This solution was added to an ice cooled solution of ammonium hydroxide (10 mL of 28 % w/v, 79.90 mmol) in 2-methyltetrahydrofuran (10 mL).
  • the resulting mixture was stirred at room temperature for 1.5 h.
  • the reaction mixture was quenched with water (15 mL) and partitioned with ethyl acetate (15 mL).
  • Step 2 [00488] (5-bromo-3-fluoropyridin-2-yl)methanol (42.8 mg, 0.2078 mmol), Pd(OAc) 2 (4.92 mg, 0.02191 mmol), Xantphos (21.2 mg, 0.03664 mmol) and cesium carbonate (117.6 mg, 0.3609 mmol) were added to a solution of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (64 mg, 0.1812 mmol) in 1,4-dioxane (2 mL).
  • reaction mixture was degassed (N 2 /vac cycles x 5) and heated at 90 °C for 2h. The mixture was concentrated in vacuo. Purification by reversed phase HPLC-MS using a X-bridge C18 OBD column (150 ⁇ 19 mm, 5 ⁇ m particle size) from Waters gave (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N- (5-fluoro-6-(hydroxymethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (83, 41.3 mg, 46%).
  • Step 2 [00493] Ethyl rac-(4S,5R)-4,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (47 g) was dissolved in a mixture of water (50 mL) and THF (100 mL). Sodium periodate (50 g, 233.8 mmol) was added and the reaction was stirred for 1 h at ambient temperature. The reaction mixture was cooled with an ice bath.1M HCl (60 mL) was added and reaction mixture was stirred for 1 h.
  • the mixture was diluted with water (50 mL) and ethyl acetate (100 mL). A white solid was filtered and washed with ethyl acetate. The filtrate was washed with sodium thiosulphate (shaken vigorously at every wash to remove traces of iodine) (3 x 50 ml) followed by a brine solution.
  • Step 3 [00495] Pd(PPh 3 ) 4 (82 mg, 0.07096 mmol) and an aqueous solution of K 2 CO 3 (3.5 mL of 2 M, 7.000 mmol) were successively added to a solution of rac-((4S,5R)-2-(ethoxycarbonyl)-4,5-dimethyl-5- (trifluoromethyl)-4,5-dihydrofuran-3-yl)boronic acid (1 g, 3.546 mmol) and 3-bromo-6-(difluoromethyl)- 2-methoxypyridine (902 mg, 3.789 mmol) in 1,4-dioxane (20 mL).
  • reaction was heated with stirring at 100 °C for 5 h. A further 30 mg of Pd(PPh 3 ) 4 was added and the mixture was stirred at reflux for 30 min.
  • the reaction mixture was partitioned between water and ethyl acetate. Aqueous brine was added to help separate the layers. The aqueous phase was separated and extracted twice with EtOAc. The combined organic layers were washed with a brine, dried (MgSO 4 ) and concentrated in vacuo.
  • Step 4 [00497] A solution of ethyl rac-(4S,5R)-3-(6-(difluoromethyl)-2-methoxypyridin-3-yl)-4,5- dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (670 mg, 1.695 mmol) in MeOH (50 mL) was stirred with activated charcoal for 3h. The mixture was filtered and added to Pd(OH) 2 (505 mg of 20 % w/w, 0.7192 mmol) under nitrogen in a Parr bottle. The bottle was connected to the Parr shaker and agitated under hydrogen (60 psi, 4 bar) at ambient temperature over the weekend.
  • reaction mixture was filtered through a pad of celite and concentrated in vacuo to give a mixture of ethyl rac- (2S,3S,4S,5R)-3-(6-(difluoromethyl)-2-methoxypyridin-3-yl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylate and ethyl rac-(2R,3R,4S,5R)-3-(6-(difluoromethyl)-2- methoxypyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (670 mg, 99%) as the 2 major diastereoisomers in a ⁇ 1:0.7 ratio.
  • Step 6 [00501] Triethylamine (225 ⁇ L, 1.614 mmol) and T3P (450 ⁇ L of 50 % w/w, 0.7559 mmol) were successively added to a solution of methyl 5-aminopicolinate (102.5 mg, 0.6737 mmol) and a mixture of rac-(2R,3S,4S,5R)-3-(6-(difluoromethyl)-2-methoxypyridin-3-yl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid and rac-(2S,3R,4S,5R)-3-(6-(difluoromethyl)-2- methoxypyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)t
  • reaction mixture was stirred at 40 °C overnight.
  • the mixture was partitioned between water and EtOAc.
  • the aqueous layer was extracted with EtOAc.
  • the combined organic phases were washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo.
  • Step 7 [00503] LiBH 4 (75 ⁇ L, 2 M in THF solution, 0.1500 mmol) was added to a solution of methyl rac-5-((2R,3S,4S,5R)-3-(6-(difluoromethyl)-2-methoxypyridin-3-yl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinate (40 mg, 0.07946 mmol) in THF (2 mL).
  • Step 8 [00505] The enantiomers of rac-(2R,3S,4S,5R)-3-(6-(difluoromethyl)-2-methoxypyridin-3-yl)-N- (6-(hydroxymethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (15 mg, 0.032 mmol) were separated by chiral SFC using a Chiralcel OD-H column, 5 ⁇ m particle size, 25 cm x 10 mm from Daicel (Mobile phase: 25 % IPA:MeCN 1:1 (containing 0.2% DMIPA), 75 % CO 2 .
  • the conditions for the amide coupling step 6 were those described in Example 9 step 5 using 6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-amine as the coupling partner.
  • the LiBH 4 reduction step 7 was not required.
  • the separation step 8 was carried by chiral SFC using a (R,R)-Whelk-O1 column, 21 x 250 mm (Mobile phase: 10 to 25 % IPA (containing 20 mM Ammonia), 90 to 75 % CO 2 . Flow: 100 mL/min.).
  • a TBS deprotection step was carried out overnight at ambient temperature as a last step in the sequence, using TFA in excess and DCM as the solvent:
  • Step 2 [00512] Nickel dichloride hexahydrate (1.8 g, 7.573 mmol) was added to a solution of (R)-3-(4- (benzyloxy)-3-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one (3 g, 7.311 mmol) in MeOH (300 mL) and THF (60 mL) at -40 oC under nitrogen.
  • Step 3 [00514] To a stirred solution of (3S,4S,5R)-3-(3-fluoro-4-hydroxy-2-methoxyphenyl)-4,5-dimethyl- 5-(trifluoromethyl)dihydrofuran-2(3H)-one (2.3 g, 7.137 mmol) in DCM (40 mL) at -78 oC under a nitrogen atmosphere was added DIBAL (15 mL of 1 M in DCM, 15 mmol) dropwise. The reaction mixture was stirred at -78 °C.
  • Step 4 To a solution of (3S,4S,5R)-3-(3-fluoro-4-hydroxy-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-ol (380 mg, 1.172 mmol) in DCM (4 mL) was added DMAP (210 mg, 1.719 mmol) and acetic anhydride (700 ⁇ L, 7.419 mmol). The reaction mixture was stirred at ambient temperature. Upon reaction completion, the mixture was quenched by addition of NaHCO 3 (30 mL of saturated aqueous solution). The mixture was diluted with DCM (20 mL) and extracted with DCM (10 mL).
  • Step 5 [00518] TMSCN (400 ⁇ L, 3.000 mmol) and BF 3 .OEt 2 (1000 ⁇ L, 8.103 mmol) were added successively to a solution of (3S,4S,5R)-3-(4-acetoxy-3-fluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl acetate (470 mg, 1.151 mmol) in DCM (15 mL) at -78 oC. The reaction mixture was stirred at -78 oC for 30 min and then allowed to warm to ambient temperature.
  • Step 6 [00520] Sodium 2-chloro-2,2-difluoroacetate (1.1 g, 7.168 mmol) was added to a mixture of methyl (2R,3S,4S,5R)-3-(3-fluoro-4-hydroxy-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylate (1.01 g, 2.757 mmol) and Cs 2 CO 3 (2.7 g, 8.287 mmol) in DMF (10 mL). The reaction mixture was heated to 90 oC. Upon reaction completion, the mixture was partitioned between DCM (20 mL) and water (50 mL).
  • Step 7 [00522] To a solution of methyl (2R,3S,4S,5R)-3-(4-(difluoromethoxy)-3-fluoro-2-methoxyphenyl)- 4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (180 mg, 0.4324 mmol) in THF (3 mL) at ambient temperature was added KO-t-Bu (200 mg, 1.782 mmol). The reaction mixture was stirred at ambient temperature for 5 min. The reaction mixture was quenched by addition of NH 4 Cl (3 mL of saturated aqueous solution) and diluted with DCM (3 mL).
  • Step 8 Oxalyl chloride (25 ⁇ L, 0.287 mmol) was added to a solution of (2R,3S,4S,5R)-3-(4- (difluoromethoxy)-3-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxylic acid (50 mg, 0.124 mmol) and DMF (2 ⁇ L, 0.026 mmol) in DCM (500 ⁇ L). The reaction mixture was stirred at ambient temperature for 30 min.
  • reaction mixture was concentrated in vacuo then dissolved in DCM (1 mL) and treated with Et 3 N (25 ⁇ L, 0.179 mmol) and (5-aminopyrimidin-2- yl)methyl benzoate. The mixture was stirred at ambient temperature for 1 h and then quenched by the addition of MeOH (100 ⁇ L). The mixture was concentrated in vacuo.
  • Step 9 [00526] A solution of [5-[[(2R,3S,4S,5R)-3-[4-(difluoromethoxy)-3-fluoro-2-methoxy-phenyl]-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidin-2-yl]methyl benzoate (23 mg) in MeOH (0.5 mL)/NaOMe (60 ⁇ L of 25 %w/w, 0.2624 mmol) was stirred at ambient temperature. After complete reaction, the mixture was concentrated in vacuo.
  • Step 1 [00529] Cs 2 CO 3 (100 g, 306.92 mmol) was added to a stirred solution of 2-chloro-5-nitro-pyridine (25 g, 157.69 mmol) and potassium vinyltrifluoroborate (25 g, 186.64 mmol ) in 2-MeTHF (250 mL) and water (25 mL). The mixture was degassed for 5 min with argon.
  • Step 2 [00531] NMO (104 mL of 50 %w/v aqueous solution, 443.89 mmol) and OsO 4 (19 mL of 4 %w/v aqueous solution, 2.989 mmol) were added to a stirred solution of 5-nitro-2-vinylpyridine (22 g, 146.53 mmol) in acetone (250 mL). The reaction mixture was stirred for 3h at ambient temperature. The acetone was removed in vacuo and the mixture was partitioned with ethyl acetate (150 mL). The organic layer was separated, dried (MgSO 4 ), filtered and concentrated in vacuo.
  • Step 3 [00533] p-TsOH (30 mg, 0.028 mL, 0.174 mmol) and 2,2-dimethoxypropane (338.80 mg, 0.4 mL, 3.253 mmol) were added to a stirred solution of rac-1-(5-nitropyridin-2-yl)ethane-1,2-diol (295 mg, 1.602 mmol) in 2-MeTHF (5 mL) and acetone (5 mL). The reaction mixture was stirred at ambient temperature for 16h. The reaction mixture was quenched with a solution of NaHCO 3 (7 mL). The mixture was concentrated in vacuo and ethyl acetate (50 mL) was added.
  • Step 4 [00535] Pd/C (10 wt % loading, wet, Degussa, 285 mg, 0.268 mmol) was added to a solution of rac-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-5-nitropyridine (2 g, 8.920 mmol) in ethyl acetate (60 mL). The reaction mixture was degassed for 5 min with argon and stirred under a balloon atmosphere of hydrogen for 6h. The reaction mixture was filtered through a pad of celite.
  • Step 2 [00540] Imidazole (3 g, 44.068 mmol) and DMAP (360 mg, 2.9468 mmol) were added at ambient temperature to a stirred solution of rac-2-methoxy-1-(5-nitropyridin-2-yl)ethan-1-ol (2.86 g, 11.690 mmol) in DMF (30 mL). TBSCl (3.3 g, 21.895 mmol) was added portionwise at ambient temperature. The reaction mixture was stirred for 32 h at 60 °C. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (120 mL).
  • Step 3 [00542] Pd/C (640 mg, 10 wt % loading, 0.601 mmol) was added to a solution of rac-2-(1-((tert- butyldimethylsilyl)oxy)-2-methoxyethyl)-5-nitropyridine (3.28 g, 10.498 mmol) in ethyl acetate (3 mL). The reaction mixture was degassed with nitrogen gas for 10 min and stirred overnight under a balloon atmosphere of hydrogen. The reaction mixture was filtered through a pad of celite, washing with ethyl acetate (50 mL). The filtrates were concentrated in vacuo.
  • Step 1 (S)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine and (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine
  • Step 1 [00544] rac-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine (9g, 46.34 mmol) was separated by using a Chiralpak IB column, 5 ⁇ ⁇ m particle size, 25 cm x 20 mm from Daicel (Mobile phase: 7 % MeOH (containing 20 mM Ammonia), 93 % CO 2 .
  • Step 2 [00550] Benzyl (2-chloropyrimidin-5-yl)carbamate (25 g, 94.81 mmol), potassium vinyltrifluoroborate (40 g, 298.62 mmol) and Cs 2 CO 3 (92.5 g, 283.90 mmol) were added to an oven dried 2-neck round bottom flask containing 1,4-dioxane (150 mL) and water (150 mL). The flask was flanked with a reflux condenser and the apparatus was degassed and purged with nitrogen gas for 15 min. PdCl 2 (PPh 3 ) 2 (6.25 g, 8.90 mmol) was added.
  • Step 3 To a solution of benzyl (2-vinylpyrimidin-5-yl)carbamate (6 g, 23.504 mmol) in acetone (380 mL) and water (60 mL), was successively added NMO (3 g, 25.609 mmol) and osmium tetroxide in tert-butanol (5 mL of 2.5 %w/w, 0.4917 mmol). The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated in vacuo. The residue was poured on saturated aqueous NH 4 Cl (100 mL) and extracted with EtOAc (3 x 100 mL).
  • Step 4 [00554] PPTS (2.42 g, 9.6298 mmol) was added to a solution of benzyl rac-(2-(1,2- dihydroxyethyl)pyrimidin-5-yl)carbamate (13.80 g, 45.318 mmol) in 2,2-dimethoxypropane (100 mL). The reaction mixture was stirred at 60 °C overnight. The mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated in vacuo.
  • Step 5 A solution of benzyl rac-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrimidin-5-yl)carbamate (15.6 g, 44.998 mmol) in ethanol (600 mL) was extensively degassed and purged with nitrogen. The reaction was placed under a hydrogen atmosphere (balloon) and stirred for 5 h. The mixture was filtered over a bed of celite. The filtrates were concentrated in vacuo.
  • Step 1 Isopropylamine (23.460 g, 34.5 mL, 396.89 mmol) was slowly added to a stirred solution of 3-fluoro-2-methyl-phenol (50 g, 396.42 mmol) in DCM (2.5 L). The reaction mixture was cooled to - 78°C. NBS (70 g, 393.29 mmol) was added portion wise over 2 h 10 min and the mixture was stirred for a further 30 min.
  • Step 2 [00560] To a stirred solution of 6-bromo-3-fluoro-2-methylphenol (40 g, 195.10 mmol) in acetone (400 mL) at ambient temperature was added potassium carbonate (135 g, 976.80 mmol). The reaction mixture was stirred for 10 min at 25 °C.
  • Methyl iodide (39 g, 17.105 mL, 274.77 mmol) was added dropwise over 10 min and the mixture was stirred for 16 h at 25 °C.
  • the reaction mixture was filtered and the solid residues washed with acetone (50 ml).
  • the mother liquors were concentrated at 15 °C under reduced pressure.
  • Hexane 200 ml was added and the mixture was stirred for 15 min.
  • the solid was collected and washed with hexane (8 ml).
  • the mother liquors were concentrated under reduced pressure at 15 °C.
  • Step 1 2-(3-(Difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [00563]
  • Step 1 To a solution of 1-bromo-3-(difluoromethyl)-4-fluoro-2-methoxybenzene (1.60 g, 6.274 mmol) and Pd(PPh 3 ) 2 Cl 2 (200 mg, 0.2849 mmol) in 1,4-dioxane (25 mL) was added 4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (1.6 mL, 11.03 mmol) and TEA (2.5 mL, 17.94 mmol).
  • Step 1 2-(2-ethoxy-3,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [00565]
  • Step 1 An oven dried 250 ml three necked flask was flanked with an air condenser, an additional funnel and a thermometer. Magnesium (1.8 g, 74.06 mmol) turnings were added. The flask was evacuated three times with vac/N 2 and then left under vacuum for 10 min while the flask was heated to 65 °C. Using a nitrogen flushed needle, THF (35 mL) was added to the flask and the mixture was flushed once again with nitrogen.
  • Step 1 4-bromo-2,2,7-trifluorobenzo[d][1,3]dioxole [00567]
  • Step 1 Triethylamine (23.232 g, 32 mL, 229.59 mmol) was added to a mixture of paraformaldehyde (20 g, 322.23 mmol) and MgCl 2 (20 g, 210.06 mmol) in THF (500 mL) under argon. The reaction mixture was stirred at room temperature for 10 min before adding 2-bromo-5-fluorophenol (20 g, 104.71 mmol). The reaction was heated to reflux for 2 h then allowed to cool to ambient temperature.
  • Step 2 [00570] H 2 O 2 (25.530 g, 23 mL of 30 %w/v, 750.56 mmol) was added to a solution of 3-bromo-6- fluoro-2-hydroxybenzaldehyde (22 g, 100.45 mmol) in NaOH (120 mL of 1 M, 120.00 mmol) while applying external cooling to keep the temperature below 50 °C. The reaction mixture was stirred for 2 hr. The reaction was quenched by pouring the mixture in a NaHSO 3 solution (120 ml). The resulting mixture was extracted with ethyl acetate (500 ml).
  • Step 3 A mixture of 3-bromo-6-fluorobenzene-1,2-diol (2.3 g, 11.111 mmol) and thiophosgene (1.5 g, 1 mL, 13.046 mmol) in chloroform (15 mL) was cooled down to 10 °C. NaOH (10 mL of 10 %w/v, 25.002 mmol) was added dropwise over 30 min under vigorous stirring. The reaction mixture was stirred for 2 hr at ambient temperature. The mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL).
  • Step 4 [00574] Pyridine hydrofluoride (9 mL of 70 %w/v, 63.568 mmol) was added to a solution of 4- bromo-7-fluorobenzo[d][1,3]dioxole-2-thione (3.3 g, 13.250 mmol) in DCM (35 mL) cooled down to -30 °C.1,3-Dibromo-5,5-dimethylimidazolidine-2,4-dione (4.6 g, 16.088 mmol) was added portionwise over 30 min. The mixture was stirred for 2 hr between -20 to -30 °C.
  • Step 1 [00576] Lithium aluminium hydride (120 mL of 2 M, 240.00 mmol) was added at 0 °C under argon to a stirred suspension of methyl 5-aminopicolinate (21.05 g, 138.35 mmol) in dry THF (400 mL). The suspension was stirred at ambient temperature overnight then heated at 90 °C for 6 h. The reaction was left standing at room temperature for 30 h, after which time it was cooled back down to 0 °C.
  • Step 2 [00578] Imidazole (1.97 g, 28.938 mmol) was added to a mixture of (5-aminopyridin-2- yl)methanol (3.65 g, 18.641 mmol) and tert-butylchlorodimethylsilane (3.41 g, 22.624 mmol) in THF (60 mL). The mixture was stirred at room temperature for 17 h. The THF layer was decanted off and the oily lower phase was dissolved in water (20 mL) and extracted with ethyl acetate (2 x 20 mL).
  • Step 1 [00580] Benzoyl chloride (4.62 mL, 39.80 mmol) was added dropwise to a mixture of (5- bromopyrimidin-2-yl)methanol (7.2 g, 38.09 mmol) and triethylamine (7 mL, 50.22 mmol) in DCM (40 mL). The mixture was stirred under nitrogen at ambient temperature until reaction completion. The reaction mixture was washed with NaOH 0.5 M. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to give (5-bromopyrimidin-2-yl)methyl benzoate (11.05 g, 99%).
  • Step 2 [00582] Diphenylmethanimine (8.6 g, 47.45 mmol), rac-BINAP (2.41 g, 3.870 mmol) and Cs 2 CO 3 (15.8 g, 48.49 mmol) were added to the stirred solution of (5-bromopyrimidin-2-yl)methyl benzoate (11.60 g, 39.57 mmol) in toluene (100 mL). The reaction mixture was purged with nitrogen gas for 5 min.
  • Step 3 [00584] (5-((diphenylmethylene)amino)pyrimidin-2-yl)methyl benzoate was dissolved in MeOH (100 mL) and treated with sodium acetate (14.31 g, 174.4 mmol) and hydroxylamine hydrochloride (8.471 g, 121.9 mmol). The mixture was stirred at ambient temperature for 7 h. The reaction was concentrated in vacuo. The residue was dissolved in DCM, washed with water, dried (MgSO 4 ), filtered and concentrated in vacuo.
  • Step 1 [00586] TBSOTf (10.005 g, 8.7 mL, 37.849 mmol) was added to a stirred solution of 1-(5- bromopyridin-2-yl)ethan-1-one (5 g, 24.996 mmol) and Et 3 N (5.372 g, 7.4 mL, 53.092 mmol) in toluene (80 mL) under nitrogen. The reaction was heated to 80 °C for 2 h. The upper toluene phase was separated and concentrated under reduced pressure to give a yellow oil.
  • Step 2 [00588] Sodium borohydride (2.3 g, 60.794 mmol) was added portionwise to a stirred solution of 1-(5-bromopyridin-2-yl)-2-fluoroethan-1-one (6.5 g, 29.813 mmol) in MeOH (80 mL) at 0 °C under nitrogen.
  • Step 3 [00590] Imidazole (4.2 g, 61.695 mmol) and TBSCl (5.45 g, 36.159 mmol) were successively added under nitrogen to a stirred solution of 1-(5-bromopyridin-2-yl)-2-fluoroethan-1-ol (4.2 g, 19.088 mmol) in DMF (25 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned with ethyl acetate and ice cold water. The aqueous layer was extracted with EtOAc (2 x 150 mL).
  • Step 4 A solution of 5-bromo-2-(1-((tert-butyldimethylsilyl)oxy)-2-fluoroethyl)pyridine (200 mg, 0.598 mmol) in 1,4-dioxane (7 mL) was degassed by bubbling nitrogen through for 15 min. Cesium carbonate (403 mg, 1.237 mmol), benzyl carbamate (140 mg, 0.926 mmol), Xphos (45 mg, 0.094 mmol) and Pd 2 (dba) 3 (40 mg, 0.044 mmol) were successively added under nitrogen. The reaction mixture was heated in a preheated oil bath to 100 °C.
  • Step 5 A stirred solution of benzyl (6-(1-((tert-butyldimethylsilyl)oxy)-2-fluoroethyl)pyridin-3- yl)carbamate (2 g, 4.944 mmol) in MeOH (15 mL) degassed by bubbling argon through for 10 min. Pd/C (120 mg, 0.988 mmol) was added and the reaction mixture was stirred for 3 h under a hydrogen atmosphere. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated in vacuo.
  • Step 1 [00596] DIPEA (96.460 g, 130 mL, 746.35 mmol), EDC.HCl (85 g, 443.40 mmol), HOBt (50 g, 370.03 mmol) and N-methoxymethanamine hydrochloride (35 g, 358.81 mmol) were successively added to a stirred solution of 3-methoxypropanoic acid (30 g, 288.17 mmol) in DCM (800 mL). The reaction mixture was stirred at ambient temperature for 16 h.
  • Step 2 [00598] nBuLi (25 mL of 2 M, 50.000 mmol) was added to a stirred solution of 2,5- dibromopyridine (10 g, 42.213 mmol) in toluene (300 mL) at -78 °C. The reaction mixture was stirred for 45 min at -78 °C. A solution of N,3-dimethoxy-N-methylpropanamide (7.5 g, 50.961 mmol) in toluene (100 mL) was added to the mixture and the stirring was continued for a further 30 min at -78 °C. The reaction mixture was quenched with an aqueous saturated ammonium chloride (200 mL) solution.
  • Step 3 [00600] Sodium borohydride (1.6 g, 42.292 mmol) was added to a stirred solution of 1-(5- bromopyridin-2-yl)-3-methoxypropan-1-one (10 g, 43.467 mmol) in MeOH (100 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The mixture was quenched by addition of water (30 mL). The mixture was concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with ethyl acetate (2 x 200 mL).
  • Step 4 [00602] Imidazole (8.299 g, 121.90 mmol) and DMAP (1.142 g, 9.346 mmol) were successively added to a stirred solution of 1-(5-bromopyridin-2-yl)-3-methoxypropan-1-ol (10 g, 40.634 mmol) in DMF (100 mL). TBSCl (9.187 g, 60.951 mmol) was added portionwise and the mixture was stirred at 60 °C for 3 h.
  • reaction mixture was quenched by addition of an aqueous ammonium chloride (500 mL) solution.
  • the aqueous phase was extracted with ethyl acetate (200 mL).
  • the organic layer was dried (MgSO 4 ), filtered and concentrated in vacuo.
  • Purification by flash chromatography (SiO 2 , 5 to 10% ethyl acetate in hexanes) gave 5-bromo-2-(1-((tert-butyldimethylsilyl)oxy)-3- methoxypropyl)pyridine (12 g, 78%) as a pale yellow oil.
  • Step 5 A 1,4-dioxane (100 mL) suspension of 5-bromo-2-(1-((tert-butyldimethylsilyl)oxy)-3- methoxypropyl)pyridine (10 g, 27.750 mmol), benzyl carbamate (6.3 g, 41.677 mmol) and cesium carbonate (18 g, 55.246 mmol) was degassed by bubbling nitrogen through for 30 min. Pd 2 (dba) 3 (1.8 g, 1.966 mmol) and X-phos (1.9 g, 3.9856 mmol) were successively added under nitrogen at ambient temperature.
  • Step 6 [00606] A solution of benzyl (6-(1-((tert-butyldimethylsilyl)oxy)-3-methoxypropyl)pyridin-3- yl)carbamate (8 g, 18.578 mmol) in ethyl acetate (150 mL) was degassed by bubbling nitrogen through for 10 min. Pd/C (3 g, 10 % w/w, 2.819 mmol) was added and the mixture was stirred for 18 h under an atmospheric pressure of hydrogen (balloon) at ambient temperature.
  • Step 1 [00608] Sodium methoxide (20 mL of 25 % w/v solution in MeOH, 92.552 mmol) was added at 0 °C to a stirred solution of 3-bromo-2-chloro-6-methylpyridine (8 g, 38.747 mmol) in MeOH (50 mL) in a sealed tube. The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL).
  • Step 2 [00610] KMnO 4 (13 g, 82.261 mmol) was added at ambient temperature to a stirred solution of 3- bromo-2-methoxy-6-methylpyridine (5.5 g, 27.221 mmol) in tert-butanol (150 mL) and water (300 mL). The reaction mixture was heated at 70 °C for 16 h. The reaction mixture was quenched by addition of a 1M aqueous solution of HCl (80 mL). The resulting mixture was stirred for 30 min, filtered and washed with EtOAc (2 x 100 mL). The mother liquors were extracted with EtOAc (2 x 50 mL).
  • Step 4 [00614] Diisobutylaluminum hydride (14 mL of 25 % w/v solution in toluene, 24.610 mmol) was added at -78 °C to a stirred solution of methyl 5-bromo-6-methoxypyridine-2-carboxylate (2 g, 8.128 mmol) in DCM (80 mL). The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was quenched by addition of a saturated aqueous solution of sodium tartrate (50 mL). The mixture was stirred for 30 min then extracted with DCM (3 x 100 mL).
  • Step 5 [00616] MnO 2 (8 g, 92.021 mmol) was added to a stirred solution of (5-bromo-6-methoxy-2- pyridyl)methanol (1.6 g, 7.3378 mmol) in DCM (80 mL). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was filtered and concentrated in vacuo to give 5-bromo-6- methoxypyridine-2-carbaldehyde (1.22 g, 77%) as off-white solid.
  • Step 6 [00618] DAST (1.9740 g, 1.5 mL, 12.246 mmol) was slowly added at -20 °C to a stirred solution of 5-bromo-6-methoxypyridine-2-carbaldehyde (1.2 g, 5.5547 mmol) in DCM (30.000 mL). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched by addition of ice-water.
  • Step 1 A 1,4-dioxane (4 mL) suspension of 1-(5-chloropyridin-2-yl)ethan-1-one (114 mg, 0.733 mmol), benzyl carbamate (170 mg, 1.125 mmol) and K 3 PO 4 (310 mg, 1.460 mmol) was degassed and put under a nitrogen atmosphere.
  • Josiphos Palladacycle Gen 3 (36 mg, 0.039 mmol) was added under nitrogen at ambient temperature. The suspension was degassed by bubbling nitrogen through and heated overnight at 110 °C. The reaction mixture was cooled down to ambient temperature and partitioned between water and EtOAc. The aqueous layer was extracted further with EtOAc. The combined organic phases were dried (MgSO 4 ), filtered and concentrated in vacuo. Purification by flash chromatography (SiO 2 , 0 to 100% EtOAc in heptane) gave benzyl (6-acetylpyridin-3-yl)carbamate (130 mg, 66%).
  • Step 2 A solution of benzyl (6-acetylpyridin-3-yl)carbamate (1.37 g, 5.069 mmol) in EtOH (50 mL) was added under nitrogen to a flask containing Pd/C (190 mg of 10 % w/w, 0.1785 mmol). The reaction mixture was degassed and stirred overnight under an atmospheric pressure of hydrogen. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated in vacuo.
  • Step 2 To a stirred suspension of sodium hydride (1.05 g, 60 % w/w, 26.253 mmol) in DMF (40 mL) at room temperature was added a solution of benzyl alcohol (2.9 g, 26.818 mmol) in DMF (10 mL) and the mixture was stirred for 5 min.1-(3,4-difluoro-2-methoxyphenyl)ethan-1-one (5 g, 26.859 mmol) was added and the reaction mixture was stirred at room temperature for 30 min.
  • Step 3 A solution of 1-(4-(benzyloxy)-3-fluoro-2-methoxyphenyl)ethan-1-one (14.8 g, 53.958 mmol) in MeOH (50 mL) was added dropwise to a stirred solution of Tl(NO 3 ) 3 .3H 2 O (24 g, 54.0 mmol) and perchloric acid (50 mL of 60 % w/v in water, 298.63 mmol) in MeOH (200 mL). The reaction mixture was stirred at room temperature for 4.5 h. The reaction mixture was filtered, washing through with MeOH (2 x 50 mL).
  • Step 4 [00629] Methyl 2-(4-benzyloxy-3-fluoro-2-methoxy-phenyl)acetate (15.2 g, 49.949 mmol) was added to a solution of sodium hydroxide (6 g, 150.01 mmol) in MeOH (30 mL) and water (10 mL). The solution was stood at room temperature for 14 h giving an orange solid. The crude product was diluted with 2 N sodium hydroxide solution (200 mL) and washed with dichloromethane (2 x 30 mL).
  • the aqueous layer was acidified with 6 M hydrochloric acid (100 mL) and extracted with dichloromethane- isopropanol (9:1, 2 x 150 mL). The combined organic extracts were dried (Na 2 SO4), filtered and concentrated in vacuo to give 2-(4-(benzyloxy)-3-fluoro-2-methoxyphenyl)acetic acid (13.15 g, 85%) as an orange solid.
  • Step 1 [00631] A jacketed glass reactor, dried and placed under nitrogen atmosphere, was charged with (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.0 kg, 6.3261 mol) and diethyl ether (10 L). Methyllithium lithium bromide complex (3.4 L of 1.5 M in Et 2 O, 5.1000 mol) was added slowly with evolution of gas and heat formation. The reactor was cooled to maintain a temperature of approximately 16 °C. Then methyllithium with lithium bromide (6.1 L of 2.2 M in Et 2 O, 13.420 mol) was added slowly.
  • the distillation residue was further concentrated in a distillation setup with vigreux (30 cm height) at normal pressure.
  • the distillation was continued at reduced pressure (770 mbar) and the pressure was gradually lowered (until 200 mbar) with the collection flask cooled in ice and a cold trap between pump and setup.
  • Mixed fractions were collected until the distillation temperature reached 71°C.
  • the major fraction (590 g) was then collected until the distillation temperature dropped below 70°C.
  • the combined mixed fractions were poured in brine and extracted with diethyl ether (3 x 75 mL).
  • the combined organic layers were dried (Na 2 SO4), filtered and concentrated in a distillation setup at normal pressure.
  • the instrument comprises a microtiter plate handler, an optical system for exciting the coumarin dye while simultaneously recording the coumarin and oxonol emissions, a waveform generator, a current- or voltage-controlled amplifier, and parallel electrode pairs that are inserted into assay plate wells. Under integrated computer control, this instrument passes user- programmed electrical stimulus protocols to cells within the wells of the microtiter plate.
  • HEK cells expressing a truncated form of human Na V 1.8 with full channel activity were seeded into microtiter 384-well plates, pre-coated with matrigel, at a density of 25,000 cells per well.2.5-5% KIR2.1 Bacmam virus was added to the final cell suspension before seeding into cell plates.
  • HEK cells were grown in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% FBS (Fetal Bovine Serum, qualified; Sigma #F4135), 1% NEAA (Non-Essential Amino Acids, Gibco #11140), 1% HEPES (Gibco #15630), 1% Pen-Strep (Penicillin-Streptomycin; Gibco #15140) and 5 ⁇ g/ml Blasticidin (Gibco #R210-01). Cells were expanded in vented cap cell culture flasks, with 90-95% humidity and 5% CO 2 .
  • DMEM Dulbecco's Modified Eagle's Medium
  • the concentration used can be dependent on viral titer of each batch.
  • DiSBAC 6 (3) The preparation of DiSBAC 6 (3) is analogous to that of DiSBAC 4 (3) as described in Voltage Sensing by Fluorescence Resonance Energy Transfer in Single Cells, Gonzalez, J.E. and Tsien, R.Y. (1995) Biophys. J.69, 1272–1280.
  • CC2-DMPE a commercially available membrane-bound coumarin phospholipid FRET donor (ThermoFisher Scientific catalog number K1017, CAS number 393782-57-5; tetradecanoic acid, 1,1'-[(1R)-1-[8-(6-chloro-7-hydroxy-2-oxo-2H-1-benzopyran-3-yl)-3-hydroxy-3-oxido-8-oxo-2,4- dioxa-7-aza-3-phosphaoct-1-yl]-1,2-ethanediyl] ester) was prepared in dry DMSO. See also, Improved indicators of cell membrane potential that use fluorescence resonance energy transfer, Gonzalez, J.E.
  • Voltage Assay Background Suppression Compound (VABSC-1) is prepared in H 2 O (89-363 mM, range used to maintain solubility)
  • Human Serum (HS, Millipore #S1P1-01KL, or Sigma SLBR5469V and SLBR5470V as a 50%/50% mixture, for 25% assay final concentration)
  • Bath 1 Buffer Sodium Chloride 160 mM (9.35 g/L), Potassium Chloride, 4.5 mM (0.335 g/L), Glucose 10 mM (1.8 g/L), Magnesium Chloride (Anhydrous) 1 mM (0.095 g/L), Calcium Chloride 2 mM (0.222 g/L), HEPES 10 mM (2.38 g/L) in water.
  • Na/TMA Cl Bath 1 Buffer Sodium Chloride 96 mM (5.61 g/L), Potassium Chloride 4.5 mM (0.335 g/L), Tetramethylammonium (TMA)-Cl 64 mM (7.01 g/ L), Glucose 10 mM (1.8 g/L), Magnesium Chloride (Anhydrous) 1 mM (0.095 g/L), Calcium Chloride 2 mM (0.222 g/L) HEPES 10 mM (2.38 g/L) in water.
  • Hexyl Dye Solution (2X concentration) Bath 1 Buffer containing 0.5% ⁇ -cyclodextrin (made fresh prior to each use, Sigma #C4767), 8 ⁇ M CC2-DMPE and 2 ⁇ M DiSBAC 6 (3). The solution was made by adding 10% Pluronic F127 stock equal to combined volumes of CC2-DMPE and DiSBAC 6 (3). The order of preparation was first mix Pluronic and CC2-DMPE, then add DiSBAC 6 (3), then while vortexing add Bath 1/ ⁇ -Cyclodextrin.
  • Compound Loading Buffer (2X concentration) Na/TMA Cl Bath1 Buffer containing HS (omitted in experiments run in the absence of human serum (HS))50%, VABSC-11 mM, BSA 0.2 mg/ml (in Bath-1), KCl 9 mM, DMSO 0.625%.
  • the compound plate was backfilled with 45 ⁇ L per well of Compound Loading Buffer resulting in a 240-fold dilution of compound following a 1:1 transfer of compound into the cell plate (see Step 6).
  • Final DMSO concentration for all wells in the assay was 0.625% (0.75% DMSO was supplemented to the Compound Loading Buffer for a final DMSO concentration of 0.625%).
  • This assay dilution protocol was adjusted to enable a higher dose range to be tested in the presence of HS or if the final assay volume was altered.
  • 2) Hexyl Dye Solution was prepared.
  • the media was aspirated, and the cells were washed three times with 80 ⁇ L of Bath-1 buffer, maintaining 25 ⁇ L residual volume in each well.
  • 25 ⁇ L per well of Hexyl Dye Solution was dispensed into the cell plates. The cells were incubated for 20 minutes at room temperature or ambient conditions in darkness.
  • 45 ⁇ L per well of Compound Loading Buffer was dispensed into compound plates.
  • the cell plates were washed three times with 80 ⁇ L per well of Bath-1 Buffer, leaving 25 ⁇ L of residual volume. Then 25 ⁇ L per well from compound plate was transferred to each cell plate.
  • the mixture was incubated for 30 minutes at room temperature/ambient conditions.
  • 7) The cell plate containing compound was read on E-VIPR using the current-controlled amplifier to deliver stimulation wave pulses using a symmetrical biphasic waveform.
  • the user- programmed electrical stimulus protocols were 1.25-4 Amps and 4 millisecond pulse width (dependent on electrode composition) were delivered at 10 Hz for 10 seconds.
  • a pre-stimulus recording was performed for each well for 0.5 seconds to obtain the un-stimulated intensities baseline.
  • the stimulatory waveform was followed by 0.5 seconds of post-stimulation recording to examine the relaxation to the resting state. All E-VIPR responses were measured at 200 Hz acquisition rate.
  • Control responses were obtained by performing assays in the presence of the positive control, and in the absence of pharmacological agents (DMSO vehicle negative control). Responses to the negative (N) and positive (P) controls were calculated as above.
  • the compound antagonist % activity A was then defined as: where X is the ratio response of the test compound (i.e. the maximum amplitude of the ratio response or number of action potential peaks, at the beginning of the pulse train in the presence of the test compound). Using this analysis protocol, dose response curves were plotted and IC 50 values were generated for various compounds of the present invention.
  • Compounds having a measured IC 50 value less than 0.01 ⁇ M in the E-VIPR assay described above include: 1, 2, 3, 4, 6, 7, 8, 11, 14, 15, 16, 37, 38, 40, 42, 47, 49, 51, 53, 54, 60, 70, 80, 82, 83, and 84.
  • Compounds having a measured IC 50 value less than 0.1 ⁇ M and greater than or equal to 0.01 ⁇ M in the E-VIPR assay described above include: 9, 10, 12, 17, 18, 19, 20, 21, 22, 35, 45, 56, 59, 66, 73, 85, 86, and 91.
  • Compounds having a measured IC 50 value less than 1 ⁇ M and greater than or equal to 0.1 ⁇ M in the E-VIPR assay described above include: 23, 24, 26, 29, 31, 33, 36, 55, 62, 71, 87, and 88.
  • Compounds having a measured IC 50 value greater than or equal to 1 ⁇ M in the E-VIPR assay described above include: 25, 27, 28, 30, 32, 34, 39, 41, 43, 44, 46, 48, 50, 52, 57, 58, 61, 63, 64, 65, 67, 68, 69, 72, 74, 75, 77, 78, 79, 81, 89, and 90.

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MX2023014378A MX2023014378A (es) 2021-06-04 2022-06-03 N-(hidroxialquil(hetero)aril)tetrahidrofurano carboxamidas como moduladores de canales de sodio.
HRP20251504TT HRP20251504T1 (hr) 2021-06-04 2022-06-03 N-(hidroksialkil (hetero)aril) tetrahidrofuran karboksamidi kao modulatori natrijevih kanala
MA64853A MA64853B1 (fr) 2021-06-04 2022-06-03 N-(hydroxyalkyl (hétéro)aryl) tétrahydrofuran carboxamides utilisés en tant que modulateurs de canaux sodiques
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SI202230218T SI4347031T1 (sl) 2021-06-04 2022-06-03 N-(hidroksialkil (hetero)aril) tetrahidrofuran karboksamidi kot modulatorji natrijevih kanalčkov
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PE2023003208A PE20241335A1 (es) 2021-06-04 2022-06-03 N-(hidroxialquil (hetero)aril) tetrahidrofurano carboxamidas como moduladores de canales de sodio
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JP2023574395A JP2024522292A (ja) 2021-06-04 2022-06-03 ナトリウムチャネルのモジュレーターとしてのｎ－（ヒドロキシアルキル（ヘテロ）アリール）テトラヒドロフランカルボキサミド
CR20230586A CR20230586A (es) 2021-06-04 2022-06-03 N-(hydroxyalquil (hetero)aril) tetrahidrofurano carboxamidas como moduladores de canales de sodio
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024041613A1 (zh) 2022-08-24 2024-02-29 江苏恒瑞医药股份有限公司 杂环类化合物、其制备方法及其在医药上的应用
WO2024046253A1 (zh) * 2022-08-28 2024-03-07 上海汇伦医药股份有限公司 一种钠通道调节剂及其应用
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WO2025162194A1 (zh) * 2024-01-31 2025-08-07 上海汇伦医药股份有限公司 钠通道调节剂新化合物及其应用
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WO2026030525A1 (en) 2024-07-31 2026-02-05 Vertex Pharmaceuticals Incorporated Zilvetrigine dosage forms and dosing regimens for treating pain
US12612383B2 (en) 2023-07-26 2026-04-28 Shanghai Wennai Therapeutics Co., Ltd. Polysubstituted pyrrolidine derivative, preparation method therefor and use thereof

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WO2025252109A1 (zh) * 2024-06-04 2025-12-11 成都苑东生物制药股份有限公司 一种取代四氢呋喃类衍生物、其制备方法及用途
CN119285621B (zh) * 2024-12-13 2025-07-18 嘉兴安帝康生物科技有限公司 作为钠通道调节剂的四氢呋喃甲酰胺类化合物及其在医药上的应用

Citations (67)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5304121A (en) 1990-12-28 1994-04-19 Boston Scientific Corporation Drug delivery system making use of a hydrogel polymer coating
US5886026A (en) 1993-07-19 1999-03-23 Angiotech Pharmaceuticals Inc. Anti-angiogenic compositions and methods of use
US6099562A (en) 1996-06-13 2000-08-08 Schneider (Usa) Inc. Drug coating with topcoat
WO2002008748A2 (en) 2000-07-10 2002-01-31 Aurora Biosciences Corporation Ion channel assay methods
US20040006237A1 (en) 2001-11-14 2004-01-08 Teva Pharmaceutical Industries Ltd. Amorphous and crystalline forms of losartan potassium and process for their preparation
WO2006011050A2 (en) 2004-07-23 2006-02-02 Pfizer Limited Pyridine derivatives
WO2008135826A2 (en) 2007-05-03 2008-11-13 Pfizer Limited 2 -pyridine carboxamide derivatives as sodium channel modulators
WO2010129864A2 (en) 2009-05-07 2010-11-11 The Board Of Trustees Of The Leland Stanford Junior University Methods and compositions for studying, imaging, and treating pain
WO2011026240A1 (en) 2009-09-04 2011-03-10 Zalicus Pharmaceuticals Ltd. Oxopiperazine derivatives for the treatment of pain and epilepsy
WO2011140425A1 (en) 2010-05-06 2011-11-10 Vertex Pharmaceuticals Incorporated Heterocyclic chromene-spirocyclic piperidine amides as modulators of ion channels
US20120196869A1 (en) 2011-02-02 2012-08-02 Sara Sabina Hadida Ruah Pyrrolopyrazine-spirocyclic piperidine amides as modulators of ion channels
WO2012112743A1 (en) 2011-02-18 2012-08-23 Vertex Pharmaceuticals Incorporated Chroman - spirocyclic piperidine amides as modulators of ion channels
WO2012116440A1 (en) 2011-03-03 2012-09-07 Zalicus Pharmaceuticals Ltd. Benzimidazole inhibitors of the sodium channel
WO2012125613A1 (en) 2011-03-14 2012-09-20 Vertex Pharmaceuticals Incorporated Morpholine-spirocyclic piperidine amides as modulators of ion channels
WO2013061205A2 (en) 2011-10-26 2013-05-02 Pfizer Limited Chemical compounds
WO2013086229A1 (en) 2011-12-07 2013-06-13 Amgen Inc. Bicyclic aryl and heteroaryl sodium channel inhibitors
US8466188B2 (en) 2006-10-12 2013-06-18 Xenon Pharmaceuticals Inc. Use of spiro-oxindole compounds as therapeutic agents
WO2013109521A1 (en) 2012-01-16 2013-07-25 Vertex Pharmaceuticals Incorporated Pyran-spirocyclic piperidine amides as modulators of ion channels
WO2013114250A1 (en) 2012-02-03 2013-08-08 Pfizer Inc. Benziimidazole and imidazopyridine derivatives as sodium channel modulators
WO2013131018A1 (en) 2012-03-02 2013-09-06 Zalicus Pharmaceuticals Ltd. Biaryl inhibitors of the sodium channel
WO2013134518A1 (en) 2012-03-09 2013-09-12 Amgen Inc. Sulfamide sodium channel inhibitors
US20130303535A1 (en) 2008-12-26 2013-11-14 Dainippon Sumitomo Pharma Co., Ltd. Novel bicyclic heterocyclic compound
US20140213616A1 (en) 2013-01-31 2014-07-31 Vertex Pharmaceuticals Incorporated Pyridone amides as modulators of sodium channels
WO2014120820A1 (en) 2013-01-31 2014-08-07 Vertex Pharmaceuticals Incorporated Amides as modulators of sodium channels
WO2014120815A1 (en) 2013-01-31 2014-08-07 Vertex Pharmaceuticals Incorporated Quinoline and quinazoline amides as modulators of sodium channels
US8883840B2 (en) 2009-06-29 2014-11-11 Xenon Pharmaceuticals Inc. Enantiomers of spiro-oxindole compounds and their uses as therapeutic agents
WO2014201206A1 (en) 2013-06-12 2014-12-18 Amgen Inc. Bicyclic sulfonamide compounds as sodium channel inhibitors
WO2015010065A1 (en) 2013-07-19 2015-01-22 Vertex Pharmaceuticals Incorporated Sulfonamides as modulators of sodium channels
WO2015089361A1 (en) 2013-12-13 2015-06-18 Vertex Pharmaceuticals Incorporated Prodrugs of pyridone amides useful as modulators of sodium channels
WO2015157559A2 (en) 2014-04-09 2015-10-15 Siteone Therapeutics, Inc. 10',11'-modified saxitoxins for the treatment of pain
WO2016141035A1 (en) 2015-03-02 2016-09-09 Amgen Inc. Bicyclic ketone sulfonamide compounds
WO2017059385A1 (en) 2015-09-30 2017-04-06 Siteone Therapeutics, Inc. 11,13-modified saxitoxins for the treatment of pain
WO2018183781A1 (en) 2017-03-29 2018-10-04 Siteone Therapeutics, Inc. 11,13-modified saxitoxins for the treatment of pain
WO2018183782A1 (en) 2017-03-29 2018-10-04 Siteone Therapeutics, Inc. 11,13-modified saxitoxins for the treatment of pain
WO2018213426A1 (en) 2017-05-16 2018-11-22 Vertex Pharmaceuticals Incorporated Deuterated pyridone amides and prodrugs thereof as modulators of sodium channels
US20190016671A1 (en) 2017-07-11 2019-01-17 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
WO2020014243A1 (en) 2018-07-09 2020-01-16 Lieber Institute, Inc. PYRIDAZINE COMPOUNDS FOR INHIBITING Nav1.8
WO2020014246A1 (en) 2018-07-09 2020-01-16 Lieber Institute, Inc. Pyridine carboxamide compounds for inhibiting nav1.8
WO2020072835A1 (en) 2018-10-03 2020-04-09 Siteone Therapeutics, Inc. 11,13-modified saxitoxins for the treatment of pain
WO2020092187A1 (en) 2018-11-02 2020-05-07 Merck Sharp & Dohme Corp. 2-amino-n-phenyl-nicotinamides as nav1.8 inhibitors
WO2020092667A1 (en) 2018-11-02 2020-05-07 Merck Sharp & Dohme Corp. 2-amino-n-heteroaryl-nicotinamides as nav1.8 inhibitors
CN111217776A (zh) 2020-01-19 2020-06-02 中国人民解放军军事科学院军事医学研究院 含苯并杂环结构的酰胺衍生物、组合物和应用
WO2020117626A1 (en) 2018-12-05 2020-06-11 Merck Sharp & Dohme Corp. 4-amino or 4-alkoxy-substituted aryl sulfonamide compounds with selective activity in voltage-gated sodium channels
WO2020140959A1 (zh) 2019-01-04 2020-07-09 江苏恒瑞医药股份有限公司 6-氧代-1,6-二氢哒嗪类衍生物、其制备方法及其在医药上的应用
WO2020146682A1 (en) 2019-01-10 2020-07-16 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
WO2020146612A1 (en) 2019-01-10 2020-07-16 Vertex Pharmaceuticals Incorporated Esters and carbamates as modulators of sodium channels
WO2020151728A1 (zh) 2019-01-25 2020-07-30 江苏恒瑞医药股份有限公司 2-氧代-1,2-二氢吡啶类衍生物、其制备方法及其在医药上的应用
CN111808019A (zh) 2020-09-08 2020-10-23 上海济煜医药科技有限公司 一种并环化合物及其应用
WO2020261114A1 (en) 2019-06-27 2020-12-30 Glaxosmithkline Intellectual Property Development Limited 2,3-dihydroquinazolin compounds as nav1.8 inhibitors
CN112225695A (zh) 2020-12-15 2021-01-15 上海济煜医药科技有限公司 一种氮氧化合物及其制备方法和用途
CN112300069A (zh) 2019-07-31 2021-02-02 明慧医药（上海）有限公司 一种选择性钠通道调节剂及其制备和应用
CN112300051A (zh) 2019-07-31 2021-02-02 明慧医药（上海）有限公司 一种选择性钠通道调节剂及其制备和应用
CN112390745A (zh) 2019-08-19 2021-02-23 江苏恒瑞医药股份有限公司 吡啶烟酰胺类衍生物、其制备方法及其在医药上的应用
WO2021032074A1 (zh) 2019-08-19 2021-02-25 江苏恒瑞医药股份有限公司 苯甲酰胺稠芳环类衍生物、其制备方法及其在医药上的应用
CN112441969A (zh) 2019-08-30 2021-03-05 明慧医药（上海）有限公司 一种选择性钠通道调节剂及其制备和应用
CN112457294A (zh) 2021-01-27 2021-03-09 上海济煜医药科技有限公司 一种作为NaV1.8阻滞剂的化合物及其制备方法和用途
CN112479996A (zh) 2019-09-12 2021-03-12 上海济煜医药科技有限公司 吡啶氮氧化合物及其制备方法和用途
WO2021113627A1 (en) 2019-12-06 2021-06-10 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
WO2021252822A1 (en) 2020-06-10 2021-12-16 Amgen Inc. Heteroalkyl dihydroquinoline sulfonamide compounds
WO2021252818A1 (en) 2020-06-10 2021-12-16 Amgen Inc. Cyclopropyl dihydroquinoline sulfonamide compounds
WO2021252820A1 (en) 2020-06-10 2021-12-16 Amgen Inc. Cyclobutyl dihydroquinoline sulfonamide compounds
WO2021257490A1 (en) 2020-06-17 2021-12-23 Merck Sharp & Dohme Corp. 2-oxoimidazolidine-4-carboxamides as nav1.8 inhibitors
WO2021257420A1 (en) 2020-06-17 2021-12-23 Merck Sharp & Dohme Corp. 5-oxopyrrolidine-3-carboxamides as nav1.8 inhibitors
WO2021257418A1 (en) 2020-06-17 2021-12-23 Merck Sharp & Dohme Corp. 2-oxo-oxazolidine-5-carboxamides as nav1.8 inhibitors
WO2022036297A1 (en) 2020-08-14 2022-02-17 Siteone Therapeutics, Inc. Non-hydrated ketone inhibitors of nav1.7 for the treatment of pain
WO2022037641A1 (zh) 2020-08-19 2022-02-24 江苏恒瑞医药股份有限公司 一种选择性NaV抑制剂的前药及其晶型
WO2022037647A1 (zh) 2020-08-19 2022-02-24 江苏恒瑞医药股份有限公司 一种选择性Nav抑制剂的结晶形式及其制备方法

Family Cites Families (366)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4844732A (en) 1985-10-24 1989-07-04 Daicel Chemical Industries Ltd. Pyridine-3-carboxamide derivatives
JPH075554B2 (ja) 1986-02-25 1995-01-25 ダイセル化学工業株式会社 ５−ブロモピリドン−３−カルボキサミド化合物の製法
JPH075555B2 (ja) 1986-02-25 1995-01-25 ダイセル化学工業株式会社 ピリドン−３−カルボキサミドの製法
IE902465A1 (en) 1989-07-07 1991-02-13 Schering Corp Pharmaceutically active compounds
MY106399A (en) 1990-07-24 1995-05-30 Pfizer Cephalosporins and homologeus, preparation and pharmaceutical composition
FR2665440B1 (fr) 1990-07-31 1994-02-04 Lipha Nouveaux cycloalkylsulfonamides substitues, procedes de preparation et medicaments les contenant.
JPH05107574A (ja) 1991-03-12 1993-04-30 Mitsui Petrochem Ind Ltd 有機非線形光学材料
WO1993000313A2 (en) 1991-06-27 1993-01-07 Virginia Commonwealth University Sigma receptor ligands and the use thereof
US5356897A (en) 1991-09-09 1994-10-18 Fujisawa Pharmaceutical Co., Ltd. 3-(heteroaryl)-pyrazololi[1,5-a]pyrimidines
IT1254134B (it) 1992-01-16 1995-09-08 Angeletti P Ist Richerche Bio Oligonucleotidi antisenso chimicamente modificati.
SG65570A1 (en) 1992-02-25 1999-06-22 Recordati Chem Pharm Heterobicyclic compounds
IT1254469B (it) 1992-02-25 1995-09-25 Recordati Chem Pharm Derivati benzopiranici e benzotiopiranici
US5559127A (en) 1992-10-14 1996-09-24 Merck & Co., Inc. Fibrinogen receptor antagonists
GB2300856A (en) 1995-05-16 1996-11-20 Pfizer Ltd Beta-lactam preparation
JP3964478B2 (ja) 1995-06-30 2007-08-22 エーザイ・アール・アンド・ディー・マネジメント株式会社 ヘテロ環含有カルボン酸誘導体及びそれを含有する医薬
AU4153496A (en) 1995-10-20 1997-05-07 Flora Inc. Transdermal delivery of alpha adrenoceptor blocking agents
US5968965A (en) 1996-01-30 1999-10-19 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
JP2000504014A (ja) 1996-01-30 2000-04-04 メルク エンド カンパニー インコーポレーテッド ファルネシル―タンパク質転移酵素の阻害剤
FR2746309B1 (fr) 1996-03-22 1998-04-17 Oreal Composition de teinture des fibres keratiniques contenant des pyrazolopyrimidineoxo ; leur utilisation pour la teinture comme coupleurs, procedes de teinture
IL129126A0 (en) 1996-10-16 2000-02-17 Icn Pharmaceuticals Monocyclic l-nucleosides analogs and uses thereof
US5955462A (en) 1996-10-31 1999-09-21 Harbor Branch Oceanographic Institution, Inc. Anti-neurogenic inflammatory compounds and compositions and methods of use thereof
JPH10213820A (ja) 1997-01-31 1998-08-11 Canon Inc 液晶素子及び液晶装置
US5942508A (en) 1997-02-04 1999-08-24 Senju Pharmaceutical Co., Ltd. Method for solubilizing pyridonecarboxylic acid solubilizer thereof and aqueous solution containing solubilized pyridonecarboxylic acid
CA2307613A1 (en) 1997-10-22 1999-04-29 Eisai Co., Ltd. Retinoic acid agonist as a prophylactic and therapeutic agent for nephritis
US6150379A (en) 1997-11-26 2000-11-21 Axys Pharmaceuticals, Inc. Compounds and compositions as anticoagulants
AU6060099A (en) 1998-09-30 2000-04-17 Procter & Gamble Company, The 2-substituted ketoamides
WO2000025789A1 (en) 1998-10-29 2000-05-11 Merck & Co., Inc. A method of treating endometriosis
EP1177176B1 (en) 1999-04-28 2006-04-19 Aventis Pharma Deutschland GmbH Tri-aryl acid derivatives as ppar receptor ligands
WO2001012183A1 (en) 1999-08-16 2001-02-22 Merck & Co., Inc. Heterocycle amides as cell adhesion inhibitors
DE60040676D1 (de) 1999-09-17 2008-12-11 Millennium Pharm Inc BENZAMIDE UND ÄHNLICHE INHIBITOREN VON FAKTOR Xa
JP2003509412A (ja) 1999-09-17 2003-03-11 シーオーアール セラピューティクス インコーポレイテッド Ｘａ因子阻害剤
EE200200228A (et) 1999-10-29 2003-06-16 Pfizer Products Inc. Hügromütsiini derivaadid
DE60026348T2 (de) 1999-11-05 2006-10-19 Societe De Conseils De Recherches Et D`Applications Scientifiques (S.C.R.A.S.) Heterocyclische verbindungen und ihre verwendung als medikamente
TWI284639B (en) 2000-01-24 2007-08-01 Shionogi & Co A compound having thrombopoietin receptor agonistic effect
AU2001250783A1 (en) 2000-02-29 2001-09-12 Cor Therapeutics, Inc. Benzamides and related inhibitors of factor xa
KR20020081424A (ko) 2000-03-09 2002-10-26 아벤티스 파마 도이칠란트 게엠베하 Ｐｐａｒ 매개인자의 치료학적 용도
BR0113697A (pt) 2000-09-06 2003-07-22 Neurogen Corp Composto ou um sal farmaceuticamente aceitável do mesmo, composição farmacêutica, uso de um composto ou sal, embalagem e métodos para, para alterar a atividade transdutora de sinal dos receptores de gabaa, para tratar ansiedade, depressão, um distúrbio do sono, ou demência de alzheimer, para demonstrar a presença dos receptores de gabaa em células ou amostras de tecido e para preparar um composto
AU2002255473A1 (en) 2000-10-24 2002-09-04 Glaxo Group Limited Process for preparing intermediates of hiv protease inhibitors
EP1330432A2 (en) 2000-11-04 2003-07-30 Aventis Pharma Limited Substituted alkanoic acids
EP1217000A1 (en) 2000-12-23 2002-06-26 Aventis Pharma Deutschland GmbH Inhibitors of factor Xa and factor VIIa
NZ535574A (en) 2001-01-16 2006-07-28 Astrazeneca Ab Therapeutic heterocyclic compounds
PL364660A1 (en) 2001-03-05 2004-12-13 E.I.Du Pont De Nemours And Company Heterocyclic diamide invertebrate pest control agents
MXPA03009000A (es) 2001-04-13 2004-02-12 Boehringer Ingelheim Pharma Compuestos benzo-fusionados 1,4-disustituidos.
JP2003034671A (ja) 2001-05-17 2003-02-07 Nippon Nohyaku Co Ltd ベンズアミド誘導体及び農園芸用薬剤並びにその使用方法
US20030175950A1 (en) 2001-05-29 2003-09-18 Mcswiggen James A. RNA interference mediated inhibition of HIV gene expression using short interfering RNA
WO2003070912A2 (en) 2001-06-06 2003-08-28 Sirna Therapeutics, Inc. RNA INTERFERENCE MEDIATED INHIBITION OF EPIDERMAL GROWTH FACTOR RECEPTOR GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
WO2003000245A1 (en) 2001-06-22 2003-01-03 Poseidon Pharmaceuticals A/S Compounds for use in disorders associated with mast cell or basophil activity
CA2461202C (en) 2001-09-21 2011-07-12 Donald Pinto Lactam-containing compounds and derivatives thereof as factor xa inhibitors
FR2831536A1 (fr) 2001-10-26 2003-05-02 Aventis Pharma Sa Nouveaux derives de benzimidazoles, leur procede de preparation, leur application a titre de medicament, compositions pharmaceutiques et nouvelle utilisation notamment comme inhibiteurs de kdr
SE0103648D0 (sv) 2001-11-01 2001-11-01 Astrazeneca Ab Therapeutic quinolone compounds
JP2005510564A (ja) 2001-11-28 2005-04-21 藤沢薬品工業株式会社 アポリポタンパク質ｂ阻害剤としての複素環式アミド化合物
AU2002350217A1 (en) 2001-12-04 2003-06-17 Bristol-Myers Squibb Company Glycinamides as factor xa inhibitors
JP2005516037A (ja) 2002-01-22 2005-06-02 イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー ジアミド無脊椎有害生物防除剤
EP1336602A1 (en) 2002-02-13 2003-08-20 Giovanni Scaramuzzino Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases
RS52392B (sr) 2002-02-14 2013-02-28 Pharmacia Corporation Supstituisani piridinoni kao modulatori p38 map kinaze
ATE375350T1 (de) 2002-02-21 2007-10-15 Lilly Co Eli Modulatoren von peroxisome proliferator- aktivierten rezeptoren
RU2004128943A (ru) 2002-02-28 2005-04-20 Байота, Инк. (Us) Средства, имитирующие нуклеотиды, и их пролекарственные формы
EP1581217A4 (en) 2002-11-01 2007-07-11 Merck & Co Inc CARBONYLAMINO-BENZIMIDAZOLE DERIVATIVES AS MODULATORS OF ANDROGENIC RECEPTORS
US7189716B2 (en) 2003-01-03 2007-03-13 Bristol-Myers Squibb Company Tyrosine kinase inhibitors
CA2851462A1 (en) 2003-01-08 2004-07-29 University Of Washington Antibacterial agents
US7122557B2 (en) 2003-03-18 2006-10-17 Bristol-Myers Squibb Company Sulfonyl-amidino-containing and tetrahydropyrimidino-containing compounds as factor Xa inhibitors
EP1616034A4 (en) 2003-04-01 2008-12-03 Activx Biosciences Inc ACYL PHOSPHATE AND PHOSPHONATE EASTS AND PROCESSES FOR THEIR SYNTHESIS AND USE IN PROTEAM ANALYSIS
WO2004091499A2 (en) 2003-04-09 2004-10-28 Neose Technologies, Inc. Intracellular formation of peptide conjugates
US20040229839A1 (en) 2003-05-14 2004-11-18 Biocryst Pharmaceuticals, Inc. Substituted nucleosides, preparation thereof and use as inhibitors of RNA viral polymerases
US7652044B2 (en) 2003-06-03 2010-01-26 Novartis A.G. P-38 inhibitors
WO2005000309A2 (en) 2003-06-27 2005-01-06 Ionix Pharmaceuticals Limited Chemical compounds
GB0315111D0 (en) 2003-06-27 2003-07-30 Cancer Rec Tech Ltd Substituted 5-membered ring compounds and their use
US8202861B2 (en) 2003-08-08 2012-06-19 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of voltage-gated sodium channels
BRPI0413684A (pt) 2003-08-21 2006-10-24 Univ Griffith compostos, composição farmacêutica e respectivos métodos de preparação, de tratamento de infecção microbiana e de extermìnio de microrganismo e usos
JP2007502778A (ja) 2003-08-21 2007-02-15 グリフィス ユニバーシティ 新規スルフェンアミドオキシド
CN1863813B (zh) 2003-08-27 2011-03-30 生物区科学管理控股有限公司 作为治疗剂的三环核苷或核苷酸
WO2005033079A1 (ja) 2003-09-30 2005-04-14 Eisai Co., Ltd. ヘテロ環化合物を含有する新規な抗真菌剤
GB0325956D0 (en) 2003-11-06 2003-12-10 Addex Pharmaceuticals Sa Novel compounds
JP4526801B2 (ja) 2003-11-13 2010-08-18 新日鐵化学株式会社 複素環化合物の製造方法
EP1532980A1 (en) 2003-11-24 2005-05-25 Novo Nordisk A/S N-heteroaryl indole carboxamides and analogues thereof, for use as glucokinase activators in the treatment of diabetes
JP2007512316A (ja) 2003-11-25 2007-05-17 ファイザー・プロダクツ・インク アテローム性動脈硬化症の治療方法
AU2005274681A1 (en) 2004-08-16 2006-02-23 Verva Pharmaceuticals Pty Ltd Metabolism-modulating agents and uses therefor
BRPI0514893A (pt) 2004-09-02 2007-11-27 Vertex Pharma quinazolinas úteis como moduladores de canais de ìon
EP1858889A1 (en) 2005-03-08 2007-11-28 Biota Scientific Management Pty. Ltd. Bicyclic nucleosides and nucleotides as therapeutic agents
US8461128B2 (en) 2005-04-15 2013-06-11 Sloan-Kettering Institute For Cancer Research Anti-microbial agents and uses thereof
AU2006244173A1 (en) 2005-05-09 2006-11-16 Vertex Pharmaceuticals Incorporated Processes for preparing biaryl ureas and analogs thereof
WO2006124780A2 (en) 2005-05-12 2006-11-23 Kalypsys, Inc. Ih-benzo [d] imidazole compounds as inhibitors of b-raf kinase
GB0510141D0 (en) 2005-05-18 2005-06-22 Addex Pharmaceuticals Sa Novel compounds B3
WO2006127329A1 (en) 2005-05-20 2006-11-30 Vertex Pharmaceuticals Incorporated Quinoline derivatives useful as modulators of ion channels
WO2006130493A2 (en) 2005-05-31 2006-12-07 Vertex Pharmaceuticals Incorporated Heterocycles useful as modulators of ion channels
JP2007056213A (ja) 2005-08-26 2007-03-08 Fujifilm Corp 焼結含油軸受油用組成物、並びにそれを用いた軸受け装置及び摺動部材
KR20080064173A (ko) 2005-10-21 2008-07-08 글락소 그룹 리미티드 항균제로서 유용한 페리 축합 트리시클릭 화합물
WO2007052843A1 (ja) 2005-11-04 2007-05-10 Takeda Pharmaceutical Company Limited 複素環アミド化合物およびその用途
WO2007081966A2 (en) 2006-01-09 2007-07-19 University Of Southern California Small molecules for treating cancer and abnormal cell proliferation disorders
PE20071025A1 (es) 2006-01-31 2007-10-17 Mitsubishi Tanabe Pharma Corp Compuesto amina trisustituido
CA2642754A1 (en) 2006-02-13 2007-08-23 Trustees Of Boston University Compositions and methods for antibiotic potentiation and drug discovery
AR059826A1 (es) 2006-03-13 2008-04-30 Univ California Inhibidores de urea conformacionalmente restringidos de epoxido hidrolasa soluble
US7480400B2 (en) 2006-03-16 2009-01-20 Siemens Medical Solutions Usa, Inc. Detection of fiber pathways
CA2648202A1 (en) 2006-04-11 2007-10-25 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of voltage-gated sodium channels
CA2691214A1 (en) 2006-06-09 2007-12-21 Kemia, Inc. Therapy using cytokine inhibitors
EP2035395A2 (en) 2006-06-27 2009-03-18 Glenmark Pharmaceuticals S.A. Novel processes for the preparation of dpp iv inhibitors
WO2008005542A2 (en) 2006-07-07 2008-01-10 Gilead Sciences, Inc., Antiviral phosphinate compounds
PE20080948A1 (es) 2006-07-25 2008-09-10 Irm Llc Derivados de imidazol como moduladores de la senda de hedgehog
EP1882475A1 (en) 2006-07-26 2008-01-30 Novartis AG Method of treating disorders mediated by the fibroblast growth factor receptor
ZA200900670B (en) 2006-08-08 2010-04-28 Millennium Pharm Inc Heteroaryl compounds useful as inhititors of E1 activating enzymes
WO2008018129A1 (fr) 2006-08-09 2008-02-14 Shinichiro Isobe Procédé de détection de protéine et colorant fluorescent utilisé à cet effet
CA2663147A1 (en) 2006-09-11 2008-03-20 Curis, Inc. Substituted 2-indolinone as ptk inhibitors containing a zinc binding moiety
AU2007296743B2 (en) 2006-09-11 2012-02-16 Curis, Inc. Tyrosine kinase inhibitors containing a zinc binding moiety
EP2097386A2 (en) 2006-11-27 2009-09-09 Novartis AG Substituted dihydroimidazoles and their use in the treatment of tumors
CN105193799A (zh) 2006-12-08 2015-12-30 米伦纽姆医药公司 使用经口因子xa抑制剂治疗血栓形成的单位剂量调配物和方法
US8236950B2 (en) 2006-12-20 2012-08-07 Abbott Laboratories Anti-viral compounds
FR2911140B1 (fr) 2007-01-05 2009-02-20 Sanofi Aventis Sa Nouveaux derives de 2-anilino 4-heteroaryle pyrimides, leur preparation a titre de medicaments, compositions pharmaceutiques et notamment comme inhibiteurs de ikk
FR2911138B1 (fr) 2007-01-05 2009-02-20 Sanofi Aventis Sa Nouveaux derives de n, n'-2,4-dianilinopyrimidines, leur preparation a titre de medicaments, compositions pharmaceutiques et notamment comme inhibiteurs de ikk
FR2911139A1 (fr) 2007-01-05 2008-07-11 Sanofi Aventis Sa Nouveaux derives de phenyl-(4-phenyl-pyrimidin-2-yl)amines, leur preparation a titre de medicaments, compositions pharmaceutiques et notamment comme inhibiteurs de ikk
WO2008094507A2 (en) 2007-01-26 2008-08-07 Cellicon Biotechnologies, Inc. Novel fusion compounds
EP2136809A4 (en) 2007-03-20 2012-01-04 Curis Inc INHIBITORS OF RAF KINASE CONTAINING A ZINC BINDING FRAGMENT
US20080234297A1 (en) 2007-03-20 2008-09-25 Changgeng Qian HSP90 Inhibitors Containing a Zinc Binding Moiety
US8088385B2 (en) 2007-06-18 2012-01-03 University Of Louisville Research Foundation Inc. PFKB3 inhibitor for the treatment of a proliferative cancer
WO2009000413A1 (en) 2007-06-26 2008-12-31 Sanofi-Aventis A regioselective copper catalyzed synthesis of benzimidazoles and azabenzimidazoles
RS54303B1 (sr) 2007-07-19 2016-02-29 Lundbeck, H., A/S 5-člani heterociklični amidi i srodna jedinjenja
JP4834699B2 (ja) 2007-07-30 2011-12-14 田辺三菱製薬株式会社 医薬組成物
JP4846769B2 (ja) 2007-07-30 2011-12-28 田辺三菱製薬株式会社 医薬組成物
FR2919869B1 (fr) 2007-08-09 2009-09-25 Sanofi Aventis Sa Nouveaux derives de n, n'-2,4-dianilinopyrimidines, leur preparation a titre de medicaments, compositions pharmaceutiques et notamment comme inhibiteurs de ikk
WO2009036066A1 (en) 2007-09-10 2009-03-19 Curis, Inc. Vegfr inhibitors containing a zinc binding moiety
WO2009036051A1 (en) 2007-09-10 2009-03-19 Curis, Inc. Bcl-2 inhibitors containing a zinc binding moiety
TW200920357A (en) 2007-09-10 2009-05-16 Curis Inc HSP90 inhibitors containing a zinc binding moiety
JP5564947B2 (ja) 2007-09-26 2014-08-06 アステラス製薬株式会社 キノロン誘導体
US8501955B2 (en) 2007-10-08 2013-08-06 Advinus Therapeutics Private Limited Acetamide derivatives as glucokinase activators, their process and medicinal application
CN101883760A (zh) 2007-10-11 2010-11-10 沃泰克斯药物股份有限公司 用作电压-门控钠通道抑制剂的杂芳基酰胺类
CA2702101A1 (en) 2007-10-11 2009-04-16 Vertex Pharmaceuticals Incorporated Aryl amides useful as inhibitors of voltage-gated sodium channels
AU2008310661A1 (en) 2007-10-11 2009-04-16 Vertex Pharmaceuticals Incorporated Amides useful as inhibitors of voltage-gated sodium channels
WO2009069132A2 (en) 2007-11-29 2009-06-04 Ramot At Tel Aviv University Ltd. Novel reverse transcriptase inhibitors
JP5637859B2 (ja) 2007-12-13 2014-12-10 バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ 嚢胞性線維症膜コンダクタンスレギュレーターのモジュレーター
CA2709784A1 (en) 2007-12-21 2009-07-09 University Of Rochester Method for altering the lifespan of eukaryotic organisms
WO2009091941A1 (en) 2008-01-17 2009-07-23 Purdue Research Foundation Small molecule inhibitors of hiv proteases
US20120108630A1 (en) 2008-02-12 2012-05-03 The Board Of Trustees Of The Leland Stanford Junior University Hedgehog Pathway Antagonists and Methods of Use
WO2009114470A2 (en) 2008-03-10 2009-09-17 Curis, Inc. Tetrahydroindole and tetrahdyroindazole as hsp90 inhibitors containing a zinc binding moiety
JP5219583B2 (ja) 2008-03-31 2013-06-26 住友化学株式会社 組成物、光学フィルムとその製造方法、光学部材及び表示装置
TW201000107A (en) 2008-04-09 2010-01-01 Infinity Pharmaceuticals Inc Inhibitors of fatty acid amide hydrolase
AU2009330686B2 (en) 2008-06-16 2014-07-03 The Ohio State University Research Foundation Compounds for the treatment of cancer
US9029408B2 (en) 2008-06-16 2015-05-12 Gtx, Inc. Compounds for treatment of cancer
AU2009266889B2 (en) 2008-07-03 2013-05-02 Glaxosmithkline Llc Benzimidazoles and related analogs as sirtuin modulators
JP5443720B2 (ja) 2008-09-05 2014-03-19 住友化学株式会社 組成物、光学フィルム及びその製造方法、光学部材ならびに表示装置
EP2326656B1 (en) 2008-09-06 2017-01-25 Chemgenes Corporation Rna synthesis - phosphoramidites for synthetic rna in the reverse direction, and application in convenient introduction of ligands, chromophores and modifications of synthetic rna at the 3' - end
US8541569B2 (en) 2008-09-06 2013-09-24 Chemgenes Corporation Phosphoramidites for synthetic RNA in the reverse direction, efficient RNA synthesis and convenient introduction of 3'-end ligands, chromophores and modifications of synthetic RNA
AU2009294673B2 (en) 2008-09-18 2014-08-14 F. Hoffmann-La Roche Ag Substituted pyrrolidine-2-carboxamides
US8354444B2 (en) 2008-09-18 2013-01-15 Hoffmann-La Roche Inc. Substituted pyrrolidine-2-carboxamides
US9326986B2 (en) 2008-09-29 2016-05-03 Glaxosmithkline Llc Quinazolinone, quinolone and related analogs as sirtuin modulators
WO2010048149A2 (en) 2008-10-20 2010-04-29 Kalypsys, Inc. Heterocyclic modulators of gpr119 for treatment of disease
EP2184273A1 (de) 2008-11-05 2010-05-12 Bayer CropScience AG Halogen-substituierte Verbindungen als Pestizide
AR074231A1 (es) 2008-11-27 2010-12-29 Boehringer Ingelheim Int Derivados de 6, 7, 8, 9-tetrahidro-5h-1, 4, 7, 10a-tetraaza-ciclohept[f]indeno, composiciones farmacéuticas que contienen estos compuestos, su uso en el agonismo del receptor 5-ht2c y procesos para prepararlos.
GB0821913D0 (en) 2008-12-02 2009-01-07 Price & Co Antibacterial compounds
US20110237622A1 (en) 2008-12-10 2011-09-29 Merck Frosst Canada Ltd. Renin inhibitors
US20120040916A1 (en) 2008-12-22 2012-02-16 Massachusetts Institute Of Technology Molecular inhibitors of the wnt/beta-catenin pathway
CN102264722B (zh) 2008-12-23 2014-04-02 霍夫曼-拉罗奇有限公司 作为p2x7调节剂的二氢吡啶酮酰胺
KR20100087540A (ko) 2009-01-28 2010-08-05 삼성전자주식회사 잉크젯 기록용 잉크 조성물
WO2010107739A2 (en) 2009-03-18 2010-09-23 The Board Of Trustees Of The Leland Stanford Junior University Methods and compositions of treating a flaviviridae family viral infection
WO2010115736A2 (en) 2009-04-02 2010-10-14 Merck Serono S.A. Dihydroorotate dehydrogenase inhibitors
TWI687408B (zh) 2009-04-28 2020-03-11 美商環球展覽公司 具有甲基-ｄ３取代之銥錯合物
US8536180B2 (en) 2009-05-27 2013-09-17 Abbvie Inc. Pyrimidine inhibitors of kinase activity
CN102459264A (zh) 2009-05-27 2012-05-16 雅培制药有限公司 激酶活性的嘧啶抑制剂
EP2435407B1 (en) 2009-05-29 2019-12-25 RaQualia Pharma Inc. Aryl substituted carboxamide derivatives as calcium or sodium channel blockers
AR077033A1 (es) 2009-06-11 2011-07-27 Hoffmann La Roche Compuestos inhibidores de las quinasas de janus y su uso en el tratamiento de enfermedades inmunologicas
US8927513B2 (en) 2009-07-07 2015-01-06 Alnylam Pharmaceuticals, Inc. 5′ phosphate mimics
CA2773561A1 (en) 2009-09-14 2011-03-17 Phusis Therapeutics Inc. Pharmaceutical compositions and formulations including inhibitors of the pleckstrin homology domain and methods for using same
US20110124597A1 (en) 2009-09-25 2011-05-26 Anacor Pharmaceuticals, Inc. Boron containing small molecules
MX2012004341A (es) 2009-10-16 2012-10-05 Rib X Pharmaceuticals Inc Compuestos antimicrobianos y metodos para fabricar y utilizar los mismos.
MX2012010115A (es) 2010-03-01 2013-02-26 Gtx Inc Compuestos para el tratamiento de cancer.
US11084811B2 (en) 2010-03-01 2021-08-10 Oncternal Therapeutics, Inc. Compounds for treatment of cancer
JP2013526514A (ja) 2010-05-10 2013-06-24 ラディカル・セラピューティックス・インコーポレイテッド リポ酸およびニトロキシド誘導体およびその使用
WO2011151619A1 (en) 2010-06-01 2011-12-08 Summit Corporation Plc Compounds for the treatment of clostridium difficile associated disease
US20120010235A1 (en) 2010-07-12 2012-01-12 Xin-Jie Chu N-substituted pyrrolidines
WO2012016133A2 (en) 2010-07-29 2012-02-02 President And Fellows Of Harvard College Ros1 kinase inhibitors for the treatment of glioblastoma and other p53-deficient cancers
US9290485B2 (en) 2010-08-04 2016-03-22 Novartis Ag N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides
WO2012020725A1 (ja) 2010-08-10 2012-02-16 塩野義製薬株式会社 Ｎｐｙ ｙ５受容体拮抗作用を有するヘテロ環誘導体
RU2013120966A (ru) 2010-10-08 2014-11-20 Эббви Инк. ФУРО[3,2-d]ПИРИМИДИНОВЫЕ СОЕДИНЕНИЯ
GB201017315D0 (en) 2010-10-13 2010-11-24 Antoxis Ltd Compound
US9394290B2 (en) 2010-10-21 2016-07-19 Universitaet Des Saarlandes Campus Saarbruecken Selective CYP11B1 inhibitors for the treatment of cortisol dependent diseases
FI20106119A0 (fi) 2010-10-27 2010-10-27 Sirtuin Valley Oy Energia-aineenvaihduntaan vaikuttava koostumus
GB201020076D0 (en) 2010-11-26 2011-01-12 Liverpool School Tropical Medicine Antimalarial compounds
AU2011336209B2 (en) 2010-11-29 2015-03-19 Pfizer Inc. Monobactams
EP2651405A2 (en) 2010-12-14 2013-10-23 Electrophoretics Limited Casein kinase 1 (ck1 ) inhibitors
TWI574687B (zh) 2011-01-03 2017-03-21 古利斯股份有限公司 具有鋅結合部份之刺蝟拮抗劑
WO2012097330A2 (en) 2011-01-14 2012-07-19 University Of Washington Compositions and methods for treating degenerative muscle conditions
WO2012106534A2 (en) 2011-02-02 2012-08-09 The Regents Of The University Of California Hiv integrase inhibitors
JP5881744B2 (ja) 2011-02-02 2016-03-09 バイオ−ラッド ラボラトリーズ インコーポレーティッド アルカリ溶液でのアパタイトの表面中和方法
JP2012167027A (ja) 2011-02-10 2012-09-06 Shionogi & Co Ltd Ｎｐｙｙ５受容体拮抗作用を有する縮合ヘテロ環誘導体
PE20141211A1 (es) 2011-03-15 2014-10-15 Abbvie Inc Moduladores receptores de hormonas nucleares
WO2012129562A2 (en) 2011-03-24 2012-09-27 The Scripps Research Institute Compounds and methods for inducing chondrogenesis
JP5866100B2 (ja) 2011-04-13 2016-02-17 住友化学株式会社 レジスト組成物及びレジストパターンの製造方法
US8629141B2 (en) 2011-05-11 2014-01-14 The Regents Of The University Of Michigan Spiro-oxindole MDM2 antagonists
JP6007417B2 (ja) 2011-05-31 2016-10-12 レセプトス エルエルシー 新規ｇｌｐ−１受容体安定剤および調節剤
US20140094465A1 (en) 2011-06-10 2014-04-03 N30 Pharmaceuticals, Inc. Compounds as S-Nitrosoglutathione Reductase Inhibitors
EP2723745A1 (en) 2011-06-22 2014-04-30 Vertex Pharmaceuticals Inc. Compounds useful as inhibitors of atr kinase
WO2013005057A1 (en) 2011-07-07 2013-01-10 Centro Nacional De Investigaciones Oncológicas (Cnio) New compounds
GB201111705D0 (en) 2011-07-07 2011-08-24 Takeda Pharmaceutical Compounds and their use
WO2013022740A2 (en) 2011-08-05 2013-02-14 Corning Incorporated Gpr35 ligands and the uses thereof
MX346095B (es) 2011-09-12 2017-03-07 Merck Patent Gmbh Nuevas imidazol-aminas como moduladores de la actividad de cinasas.
US20140241990A1 (en) 2011-09-30 2014-08-28 Tufts University Methods of using adenosine a1 receptor activation for treating depression
CN103159738B (zh) 2011-12-19 2016-09-07 上海泓博智源医药股份有限公司 炔基桥连的杂芳香化合物及其应用
FR2985916B1 (fr) 2012-01-25 2015-12-04 Univ Bordeaux Segalen Decontamination par hydrogels d'echantillons aqueux contenant des nanoparticules
CN104395335A (zh) 2012-02-08 2015-03-04 努艾利克斯德国股份有限公司 用于抗体和Fc-融合蛋白亲和色谱IV纯化的配体
KR102251706B1 (ko) 2012-02-22 2021-05-14 메르크 파텐트 게엠베하 액정 매질
HUE034118T2 (en) 2012-03-06 2018-01-29 Pfizer Macrocyclic derivatives for the treatment of proliferative diseases
JP5798066B2 (ja) 2012-03-08 2015-10-21 富士フイルム株式会社 化合物、液晶組成物、高分子材料およびフィルム
JP5804991B2 (ja) 2012-03-19 2015-11-04 富士フイルム株式会社 光反射フィルム、自動車用フロントガラス、建材用ガラス
WO2013151975A1 (en) 2012-04-02 2013-10-10 Northeastern University Compositions and methods for the inhibition of methyltransferases
NZ631477A (en) 2012-05-30 2016-12-23 Hoffmann La Roche Substituted pyrrolidine-2-carboxamides
JP5867298B2 (ja) 2012-06-06 2016-02-24 Jsr株式会社 フォトレジスト組成物及びレジストパターン形成方法
WO2013188881A1 (en) 2012-06-15 2013-12-19 President And Fellows Of Harvard College Compounds, compositions and methods for treating or preventing neurodegenerative disorders
US20140005181A1 (en) 2012-06-21 2014-01-02 Sanford-Burnham Medical Research Institute Small molecule antagonists of the apelin receptor for the treatment of disease
WO2014003153A1 (ja) 2012-06-28 2014-01-03 協和発酵キリン株式会社 置換アミド化合物
WO2014005125A2 (en) 2012-06-29 2014-01-03 Biotium, Inc. Fluorescent compounds and uses thereof
US9040498B2 (en) 2012-07-06 2015-05-26 Research Foundation Of The City University Of New York 1,2,3-Triazolyl purine derivatives
US9403830B2 (en) 2012-07-17 2016-08-02 Boehringer Ingelheim International Gmbh Inhibitors of leukotriene production
US9758480B2 (en) 2012-07-19 2017-09-12 Sumitomo Dainippon Pharma Co., Ltd. 1-(cycloalkyl-carbonyl)proline derivative
WO2014015523A1 (en) 2012-07-27 2014-01-30 Hutchison Medipharma Limited Novel heteroaryl and heterocycle compounds, compositions and methods
EA027809B1 (ru) 2012-07-27 2017-09-29 Биоген Айдек Ма Инк. Соединения, которые являются s1p-модулирующими агентами и/или atx-модулирующими агентами
WO2014020152A1 (en) 2012-08-02 2014-02-06 Graffinity Pharmaceuticals Gmbh Ligands for apheresis and immunoabsorption
ES2666353T3 (es) 2012-09-06 2018-05-04 Bristol-Myers Squibb Company Inhibidores de JAK3 de imidazopiridazina y su uso para el tratamiento de enfermedades inflamatorias y autoinmunitarias
AU2013318206B2 (en) 2012-09-20 2018-07-26 Temple University - Of The Commonwealth System Of Higher Education Substituted alkyl diaryl derivatives, methods of preparation and uses
UA110688C2 (uk) 2012-09-21 2016-01-25 Пфайзер Інк. Біциклічні піридинони
FR2997851B1 (fr) 2012-11-09 2014-11-28 Oreal Composition comprenant un derive dicarbonyle et procede de lissage des cheveux a partir de cette composition
US9757379B2 (en) 2012-11-14 2017-09-12 The Board Of Regents Of The University Of Texas System Inhibition of HIF-2α heterodimerization with HIF1β (ARNT)
JP6322200B2 (ja) 2012-11-16 2018-05-09 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． ヒトホスファチジルイノシトール３−キナーゼデルタのプリン阻害剤
EP2928877B1 (en) 2012-12-06 2020-01-22 Merck Sharp & Dohme Corp. Disulfide masked prodrug compositions and methods
RU2015125570A (ru) 2013-01-08 2017-02-10 Савира Фармасьютикалз Гмбх Пиридоновые производные и их применение в лечении, уменьшении интенсивности симптомов или предотвращении вирусного заболевания
US20140200215A1 (en) 2013-01-15 2014-07-17 Intermune, Inc. Lysophosphatidic acid receptor antagonists
PT2951172T (pt) 2013-01-29 2017-07-12 Redx Pharma Plc Derivados de piridina como inibidores de rock leves
TWI606048B (zh) 2013-01-31 2017-11-21 帝人製藥股份有限公司 唑苯衍生物
WO2014130856A2 (en) 2013-02-21 2014-08-28 Wayne Rothbaum Treatment of skeletal-related disorders
WO2014134127A1 (en) 2013-02-26 2014-09-04 Northeastern University Cannabinergic nitrate esters and related analogs
EP2970340B1 (en) 2013-03-14 2020-02-12 Venatorx Pharmaceuticals, Inc. Beta-lactamase inhibitors
WO2014179785A1 (en) 2013-05-03 2014-11-06 Inscent, Inc. Improved honeybee repellents and uses thereof
JP2014232188A (ja) 2013-05-29 2014-12-11 コニカミノルタ株式会社 セルロースアシレートフィルム、円偏光板及び画像表示装置
TWI637949B (zh) 2013-06-14 2018-10-11 塩野義製藥股份有限公司 胺基三衍生物及含有其等之醫藥組合物
TW201534597A (zh) 2013-06-20 2015-09-16 Ab Science 作為選擇性蛋白質激酶抑制劑之苯并咪唑衍生物
WO2015003991A1 (en) 2013-07-12 2015-01-15 Syngenta Participations Ag Novel microbiocides
JP6730183B2 (ja) 2013-07-12 2020-07-29 ヘルムホルツ−ツェントルム フュア インフェクツィオンスフォルシュンク ゲーエムベーハー シストバクトアミド（Ｃｙｓｔｏｂａｃｔａｍｉｄｅｓ）
WO2015003723A1 (en) 2013-07-12 2015-01-15 Københavns Universitet Substituted 4-proline derivatives as iglur antagonists
AU2014295000A1 (en) 2013-07-25 2016-02-18 Fondazione Telethon Inhibitors of FAPP2 and uses thereof
US9789096B2 (en) 2013-09-04 2017-10-17 Board Of Regents Of The University Of Texas System Methods and compositions for selective and targeted cancer therapy
SI3043803T1 (sl) 2013-09-11 2022-09-30 Emory University Nukleotidne in nukleozidne sestave in njihova uporaba
KR101628288B1 (ko) 2013-09-30 2016-06-08 주식회사 엘지화학 음성 광학 분산도를 갖는 광학 소자 제조용 조성물 및 이로부터 제조된 광학 이방체
WO2015049651A1 (en) 2013-10-01 2015-04-09 Glaxosmithkline Intellectual Property Development Limited Compounds for affinity chromatography and for extending the half-life of a therapeutic agent
EP3052479A4 (en) 2013-10-02 2017-10-25 Moderna Therapeutics, Inc. Polynucleotide molecules and uses thereof
WO2015054337A1 (en) 2013-10-09 2015-04-16 Emory University Heterocyclic coupling catalysts and methods related thereto
CA2931961C (en) 2013-12-03 2023-10-31 Andrew Duncan Satterfield Pyrrolidinones as herbicides
WO2015085238A1 (en) 2013-12-05 2015-06-11 The Regents Of The University Of California, A California Corporation Inhibitors of lpxc
US20150167017A1 (en) 2013-12-13 2015-06-18 Moderna Therapeutics, Inc. Alternative nucleic acid molecules and uses thereof
US10131841B2 (en) 2013-12-16 2018-11-20 Merck Patent Gmbh Liquid-crystalline medium
BR112016015449A8 (pt) 2013-12-30 2020-06-09 Lifesci Pharmaceuticals Inc compostos inibidores terapêuticos, composição farmacêutica os compreendendo e uso dos mesmos
US9611252B2 (en) 2013-12-30 2017-04-04 Lifesci Pharmaceuticals, Inc. Therapeutic inhibitory compounds
WO2015162244A1 (en) 2014-04-25 2015-10-29 Basf Se N-acylamidine compounds
JP6295992B2 (ja) 2014-05-09 2018-03-20 信越化学工業株式会社 単量体の製造方法
US9701627B2 (en) 2014-06-16 2017-07-11 University Of Maryland, Baltimore LRRK2 GTP binding inhibitors for treatment of Parkinson's disease and neuroinflammatory disorders
WO2015196130A2 (en) 2014-06-19 2015-12-23 Moderna Therapeutics, Inc. Alternative nucleic acid molecules and uses thereof
WO2015196128A2 (en) 2014-06-19 2015-12-23 Moderna Therapeutics, Inc. Alternative nucleic acid molecules and uses thereof
US20170136132A1 (en) 2014-06-19 2017-05-18 Moderna Therapeutics, Inc. Alternative nucleic acid molecules and uses thereof
WO2016003929A1 (en) 2014-07-01 2016-01-07 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
WO2016007837A1 (en) 2014-07-11 2016-01-14 Spero Therapeutics, Inc. Carbonyl linked bicyclic heteroaryl antibiotic tolerance inhibitors
MX381342B (es) 2014-07-16 2025-03-12 Lifesci Pharmaceuticals Inc Compuestos terapeuticos inhibidores.
EP2977374A1 (en) 2014-07-21 2016-01-27 Université de Strasbourg Molecules presenting dual emission properties
EP2985334B1 (en) 2014-08-15 2018-06-20 Merck Patent GmbH Liquid-crystalline medium
WO2016029146A1 (en) 2014-08-22 2016-02-25 University Of Washington Specific inhibitors of methionyl-trna synthetase
WO2016040449A1 (en) 2014-09-10 2016-03-17 Raze Therapeutics, Inc. 3-phosphoglycerate dehydrogenase inhibitors and uses thereof
WO2016040505A1 (en) 2014-09-10 2016-03-17 Epizyme, Inc. Smyd inhibitors
JP2016079098A (ja) 2014-10-10 2016-05-16 塩野義製薬株式会社 セフェム化合物
WO2016073633A1 (en) 2014-11-05 2016-05-12 University Of Kansas SMALL MOLECULE INHIBITORS OF THE MITOCHONDRIAL PERMEABILITY TRANSITION PORE (mtPTP)
MX387871B (es) 2014-12-10 2025-03-19 Mars Inc Metodos para modular los receptores del gusto.
FR3030242B1 (fr) 2014-12-18 2018-01-26 L'oreal Emulsion contenant un tensioactif gemine ayant deux groupements amide gras et un filtre uv organique hydrosoluble
CN105985330A (zh) 2015-02-04 2016-10-05 苏州旺山旺水生物医药有限公司 一类杂环化合物、其制备方法和用途
JP6394430B2 (ja) 2015-02-13 2018-09-26 信越化学工業株式会社 化合物、高分子化合物、レジスト材料及びパターン形成方法
WO2016145142A1 (en) 2015-03-10 2016-09-15 Emory University Nucleotide and nucleoside therapeutics compositions and uses related thereto
EP3085360A1 (en) 2015-04-20 2016-10-26 Universite De Bordeaux Lipid based nanocarrier compositions loaded with metal nanoparticles and therapeutic agent
WO2016172631A2 (en) 2015-04-24 2016-10-27 President And Fellows Of Harvard College Substrate selective inhibitors of insulin-degrading enzyme (ide) and uses thereof
BR112017024331A2 (pt) 2015-05-15 2018-07-24 Gilead Sciences, Inc. composto, composição farmacêutica, método de tratamento de um humano, métodos para inibir a atividade de uma proteína ido1, o crescimento ou a proliferação de células cancerosas, e a imunossupressão em um paciente, e de tratamento de uma doença, e, uso de um composto
CN107709310B (zh) 2015-06-02 2021-09-24 Fmc公司 取代的环酰胺及其作为除草剂的用途
WO2016198908A1 (en) 2015-06-09 2016-12-15 Abbvie Inc. Ror nuclear receptor modulators
JP2018521066A (ja) 2015-07-06 2018-08-02 バイエル・クロップサイエンス・アクチェンゲゼルシャフト 有害生物防除剤としての含窒素複素環
WO2017011371A1 (en) 2015-07-10 2017-01-19 Arvinas, Inc Mdm2-based modulators of proteolysis and associated methods of use
CN106518767A (zh) 2015-09-11 2017-03-22 中国人民解放军军事医学科学院毒物药物研究所 取代苯并吡唑二芳基脲类化合物,其制备方法及其医药用途
CN106518766A (zh) 2015-09-11 2017-03-22 中国人民解放军军事医学科学院毒物药物研究所 新型二芳基脲类化合物,其制备方法及其医药用途
WO2017051319A1 (en) 2015-09-21 2017-03-30 Glenmark Pharmaceuticals S.A. Aryl and heteroaryl ether compounds as ror gamma modulators
WO2017059446A1 (en) 2015-10-01 2017-04-06 Memorial Sloan-Kettering Cancer Center Anthranilyl-adenosinemonosulfamate analogs and uses thereof
WO2017062751A1 (en) 2015-10-08 2017-04-13 The Regents Of The University Of California Compounds and methods for promoting stress resistance
WO2017066705A1 (en) 2015-10-14 2017-04-20 Aquinnah Pharmaceuticals, Inc. Compounds, compositions and methods of use against stress granules
WO2017066781A1 (en) 2015-10-16 2017-04-20 Modernatx, Inc. Mrna cap analogs with modified phosphate linkage
WO2017066782A1 (en) 2015-10-16 2017-04-20 Modernatx, Inc. Hydrophobic mrna cap analogs
WO2017066791A1 (en) 2015-10-16 2017-04-20 Modernatx, Inc. Sugar substituted mrna cap analogs
US10487072B2 (en) 2015-11-27 2019-11-26 Mitsubishi Tanabe Pharma Corporation Substituted imidazoles as melanocortin receptor agonists
GB201522232D0 (en) 2015-12-16 2016-01-27 Liverpool School Tropical Medicine Combination product
KR102606339B1 (ko) 2016-03-02 2023-11-24 삼성전자주식회사 유기금속 화합물 및 이를 포함한 유기 발광 소자
CN109152784B (zh) 2016-03-16 2021-12-28 库拉肿瘤学公司 经取代的menin-mll抑制剂及使用方法
GB201604638D0 (en) 2016-03-18 2016-05-04 Mission Therapeutics Ltd Novel compounds
CA3019380A1 (en) 2016-03-31 2017-10-05 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
CN105906591A (zh) 2016-04-22 2016-08-31 中国药科大学 2-氨基-γ-丁内酯类盐酸盐的合成
WO2017223260A1 (en) 2016-06-23 2017-12-28 Albert Einstein College Of Medicine, Inc. Pu.1 inhibitors
CN106220667B (zh) 2016-07-21 2018-10-30 北京航空航天大学 螺环有机硅化合物及其应用
WO2018045106A1 (en) 2016-08-30 2018-03-08 Ohio State Innovation Foundation Anti-fungal treatment
WO2018055235A1 (en) 2016-09-21 2018-03-29 University Of Helsinki Isoxazole-amides for treating cardiac diseases
WO2018060110A1 (en) 2016-09-28 2018-04-05 Merck Patent Gmbh Polymerisable liquid crystal material and polymerised liquid crystal film
BR112019006110A2 (pt) 2016-09-28 2019-09-10 Blade Therapeutics Inc moduladores de calpaína e usos terapêuticos dos mesmos
US11179708B2 (en) 2016-10-04 2021-11-23 Massachusetts Institute Of Technology Compositions and methods for selective carbonylation of heterocyclic compounds
US11142535B2 (en) 2016-12-12 2021-10-12 Hangzhou Innogate Pharma Co., Ltd. Heterocyclic compound as Syk inhibitor and/or Syk-HDAC dual inhibitor
US20190388426A1 (en) 2017-01-30 2019-12-26 Université de Liège Perk and ire-1a inhibitors against neurodevelopmental disorders
WO2018161033A1 (en) 2017-03-02 2018-09-07 Wright, Adrian Small molecule ire1-alpha inhibitors
CN108658972A (zh) 2017-03-28 2018-10-16 中国海洋大学 一种取代内酰胺类化合物及其制备方法和用途
CN108658974A (zh) 2017-03-28 2018-10-16 中国海洋大学 一种内酰胺类化合物及其制备方法和用途
EP3600318A4 (en) 2017-03-31 2021-06-09 Epizyme, Inc. METHOD OF USING EHMT2 INHIBITORS
JP2020100564A (ja) 2017-04-03 2020-07-02 京都薬品工業株式会社 リードスルー誘導剤およびその医薬用途
WO2018191146A1 (en) 2017-04-10 2018-10-18 Navitor Pharmaceuticals, Inc. Heteroaryl rheb inhibitors and uses thereof
CN108689942B (zh) 2017-04-11 2023-06-09 广东东阳光药业有限公司 含氮双环化合物及其制备方法和用途
BR112019021899A2 (pt) 2017-04-20 2020-08-18 The Regents Of The University Of California moduladores de k-ras
CN110621316B (zh) 2017-04-21 2024-01-26 Epizyme股份有限公司 用ehmt2抑制剂进行的组合疗法
CN107033149B (zh) 2017-06-12 2020-01-03 上海交通大学 一种dpp-4酶抑制剂及其制备和应用
US11718638B2 (en) 2017-06-21 2023-08-08 Wave Life Sciences Ltd. Compounds, compositions and methods for synthesis
CN109320509B (zh) 2017-07-31 2022-02-08 轩竹生物科技股份有限公司 Fxr受体激动剂
CN109384712B (zh) 2017-08-14 2021-05-07 北京宽厚医药科技有限公司 靶向nk1受体拮抗剂及其在化疗所致恶心、呕吐治疗中的应用
WO2019036657A1 (en) 2017-08-17 2019-02-21 Kyn Therapeutics AHR INHIBITORS AND USES THEREOF
US11795162B2 (en) 2017-08-18 2023-10-24 Saint Louis University Modulators of the estrogen-related receptor
CN109553608B (zh) 2017-09-26 2020-12-08 北京大学 一类五元六元杂环化合物及其制备方法和治疗肿瘤的用途
IL273824B2 (en) 2017-10-18 2024-07-01 Epizyme Inc Methods for using EHMT2 inhibitors in the treatment or prevention of blood disorders
EP3697420A4 (en) 2017-10-18 2021-11-24 Epizyme, Inc. METHOD OF USING EHMT2 INHIBITORS IN IMMUNOTHERAPY
US12171755B2 (en) 2017-10-25 2024-12-24 Children's Medical Center Corporation PAPD5 inhibitors and methods of use thereof
EP3479843A1 (en) 2017-11-01 2019-05-08 GenKyoTex Suisse SA Use of nox inhibitors for treatment of cancer
TW201922690A (zh) 2017-11-10 2019-06-16 中央研究院 環－amp反應元素結合蛋白的抑制劑
KR20200089291A (ko) 2017-11-15 2020-07-24 메타보메드 리미티드 Acss2 저해제 및 이의 사용 방법
KR20190076339A (ko) 2017-12-22 2019-07-02 한미약품 주식회사 신규한 2,6-나프티리딘 2-옥시드 유도체 화합물 및 이의 용도
EP3502684A1 (en) 2017-12-22 2019-06-26 Universite De Bordeaux Method for metal ion detection in aqueous solutions using nucleolipid compounds
CN111315744B (zh) 2018-01-09 2023-07-14 四川科伦博泰生物医药股份有限公司 杂芳基并四氢吡啶类化合物、其制备方法、药物组合物及应用
BR112020015743A2 (pt) 2018-02-08 2020-12-15 Enyo Pharma Derivados de tiofeno não fundido e seus usos
WO2019157505A1 (en) 2018-02-12 2019-08-15 Vertex Pharmaceuticals Incorporated A method of treating pain
WO2019195439A1 (en) 2018-04-05 2019-10-10 St. Jude Medical, Cardiology Division, Inc. High density electrode mapping catheter
WO2019207081A1 (en) 2018-04-27 2019-10-31 Merck Patent Gmbh Polymerisable liquid crystal material and polymerised liquid crystal film
KR102785469B1 (ko) 2018-04-27 2025-03-26 메르크 파텐트 게엠베하 중합성 액정 물질 및 중합된 액정 필름
TWI902662B (zh) 2018-05-16 2025-11-01 仁新醫藥股份有限公司 脂肪酸類似物及使用方法
TWI812739B (zh) 2018-06-21 2023-08-21 景凱生物科技股份有限公司 Nadph氧化酶抑制劑、含其的醫藥組合物、及其應用
US20210347785A1 (en) 2018-08-01 2021-11-11 Shanghai Ennovabio Pharmaceuticals Co., Ltd. Preparation and application of aromatic compound having immunoregulatory function
US11945803B2 (en) 2018-08-07 2024-04-02 Tosk, Inc. Modulators of RAS GTPase
WO2020034058A1 (en) 2018-08-13 2020-02-20 Rhodia Operations PROCESS FOR REDUCTIVE AMINATION OF α,β-UNSATURATED CARBONYL COMPOUND
WO2020034062A1 (en) 2018-08-13 2020-02-20 Rhodia Operations Process for the reductive amination of a carbonyl compound
EP3847159A2 (en) 2018-09-04 2021-07-14 Magenta Therapeutics, Inc. Aryl hydrocarbon receptor antagonists and methods of use
CN113164454A (zh) 2018-09-28 2021-07-23 奥克塞拉有限公司 Vap-1的抑制剂
KR102092838B1 (ko) 2018-10-02 2020-03-24 성균관대학교산학협력단 신규 퓨란계 폴리카보네이트 및 이의 제조 방법
TW202028183A (zh) 2018-10-10 2020-08-01 大陸商江蘇豪森藥業集團有限公司 含氮雜芳類衍生物調節劑、其製備方法和應用
WO2020081572A1 (en) 2018-10-15 2020-04-23 Dana-Farber Cancer Institute, Inc. Transcriptional enhanced associate domain (tead) transcription factor inhibitors and uses thereof
KR102151855B1 (ko) 2018-11-30 2020-09-03 롯데케미칼 주식회사 공액 디엔계 및 방향족 비닐계 공중합체의 제조 방법 및 이로부터 제조된 공액 디엔계 및 방향족 비닐계의 공중합체를 포함하는 타이어
WO2020118036A1 (en) 2018-12-06 2020-06-11 The Children's Medical Center Corporation Antibacterial compounds and uses thereof
US12098117B2 (en) 2018-12-11 2024-09-24 Duke University Compositions and methods for the treatment of cancer
CN111434655A (zh) 2019-01-15 2020-07-21 武汉朗来科技发展有限公司 溶血磷脂酸受体拮抗剂及其制备方法
US11718790B2 (en) 2019-01-22 2023-08-08 Merck Patent Gmbh Method for the preparation of a liquid crystal polymer film
EP3917508A4 (en) 2019-01-28 2022-12-21 Mitochondria Emotion, Inc. EAAT2 ACTIVATORS AND METHODS OF USE THEREOF
WO2020160225A1 (en) 2019-01-30 2020-08-06 Ohio State Innovation Foundation ESTROGEN RECEPTOR BETA (ERβ) AGONISTS FOR THE TREATMENT OF FIBROTIC CONDITIONS
WO2020191227A1 (en) 2019-03-20 2020-09-24 Cornell University Methods for controlling prostaglandin-mediated biological processes
WO2020191501A1 (en) 2019-03-27 2020-10-01 Algernon Pharmaceuticals Inc. Methods and uses of bemithyl and derivatives for treating lung disease, fatty liver disease, and kidney disorders
CN113785032A (zh) 2019-04-30 2021-12-10 默克专利股份有限公司 反应性介晶
CN113811536A (zh) 2019-05-10 2021-12-17 瓦克化学股份公司 阳离子锗(ii)化合物、用于制备其的方法、以及其在氢化硅烷化中作为催化剂的用途
US12441689B2 (en) 2019-05-14 2025-10-14 Epivario, Inc. ACSS2 inhibitors and methods of use thereof
US20220324880A1 (en) 2019-06-10 2022-10-13 Kymara Therapeutics, Inc. Smarca inhibitors and uses thereof
BR112021025317A2 (pt) 2019-06-21 2022-03-15 Bayer Ag Tienilhidroxiisoxazolinas e derivados das mesmas
WO2021001739A1 (en) 2019-07-02 2021-01-07 Effector Therapeutics, Inc. Translational enhancers and related methods
CN112409331B (zh) 2019-08-21 2024-02-20 上海翰森生物医药科技有限公司 杂环类衍生物抑制剂、其制备方法和应用
CN114555577A (zh) 2019-10-17 2022-05-27 埃尼奥制药公司 用于治疗门静脉炎症和纤维化的噻吩衍生物
KR102512868B1 (ko) 2019-12-20 2023-03-22 주식회사 삼양홀딩스 올라파립의 용해도 및 생체이용율이 개선된 조성물
EP4157888A4 (en) 2020-05-28 2024-07-10 Cullgen (Shanghai), Inc. MODIFIED PROTEINS AND PROTEIN DEGRADATION AGENTS
GB202011996D0 (en) 2020-07-31 2020-09-16 Adorx Therapeutics Ltd Antagonist compounds
EP4217442B1 (en) 2020-09-24 2025-06-18 Merck Patent GmbH Polymerizable liquid crystal material and polymerized liquid crystal film
WO2022070048A1 (en) 2020-09-29 2022-04-07 Cadila Healthcare Limited Novel amide derivatives
WO2022086986A1 (en) 2020-10-21 2022-04-28 Kura Oncology, Inc. Treatment of hematological malignancies with inhibitors of menin
SI4347031T1 (sl) 2021-06-04 2026-01-30 Vertex Pharmaceuticals Incorporated N-(hidroksialkil (hetero)aril) tetrahidrofuran karboksamidi kot modulatorji natrijevih kanalčkov

Patent Citations (87)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5304121A (en) 1990-12-28 1994-04-19 Boston Scientific Corporation Drug delivery system making use of a hydrogel polymer coating
US5886026A (en) 1993-07-19 1999-03-23 Angiotech Pharmaceuticals Inc. Anti-angiogenic compositions and methods of use
US6099562A (en) 1996-06-13 2000-08-08 Schneider (Usa) Inc. Drug coating with topcoat
WO2002008748A2 (en) 2000-07-10 2002-01-31 Aurora Biosciences Corporation Ion channel assay methods
US20040006237A1 (en) 2001-11-14 2004-01-08 Teva Pharmaceutical Industries Ltd. Amorphous and crystalline forms of losartan potassium and process for their preparation
WO2006011050A2 (en) 2004-07-23 2006-02-02 Pfizer Limited Pyridine derivatives
US20080312235A1 (en) 2004-07-23 2008-12-18 Charlotte Alice Louise Lane Pyridine Derivatives
US8466188B2 (en) 2006-10-12 2013-06-18 Xenon Pharmaceuticals Inc. Use of spiro-oxindole compounds as therapeutic agents
WO2008135826A2 (en) 2007-05-03 2008-11-13 Pfizer Limited 2 -pyridine carboxamide derivatives as sodium channel modulators
US20090048306A1 (en) 2007-05-03 2009-02-19 Pfizer, Inc. Pyridine derivatives
US20130303535A1 (en) 2008-12-26 2013-11-14 Dainippon Sumitomo Pharma Co., Ltd. Novel bicyclic heterocyclic compound
WO2010129864A2 (en) 2009-05-07 2010-11-11 The Board Of Trustees Of The Leland Stanford Junior University Methods and compositions for studying, imaging, and treating pain
US8883840B2 (en) 2009-06-29 2014-11-11 Xenon Pharmaceuticals Inc. Enantiomers of spiro-oxindole compounds and their uses as therapeutic agents
WO2011026240A1 (en) 2009-09-04 2011-03-10 Zalicus Pharmaceuticals Ltd. Oxopiperazine derivatives for the treatment of pain and epilepsy
US20120220605A1 (en) 2009-09-04 2012-08-30 Zalicus Pharmaceuticals Ltd. Oxopiperazine derivatives for the treatment of pain and epilepsy
US20110306607A1 (en) 2010-05-06 2011-12-15 Vertex Pharmaceuticals Incorporated Heterocyclic chromene-spirocyclic piperidine amides as modulators of ion channels
WO2011140425A1 (en) 2010-05-06 2011-11-10 Vertex Pharmaceuticals Incorporated Heterocyclic chromene-spirocyclic piperidine amides as modulators of ion channels
WO2012106499A1 (en) 2011-02-02 2012-08-09 Vertex Pharmaceuticals Incorporated Pyrrolopyrazine-spirocyclic piperidine amides as modulators of ion channels
US20120196869A1 (en) 2011-02-02 2012-08-02 Sara Sabina Hadida Ruah Pyrrolopyrazine-spirocyclic piperidine amides as modulators of ion channels
WO2012112743A1 (en) 2011-02-18 2012-08-23 Vertex Pharmaceuticals Incorporated Chroman - spirocyclic piperidine amides as modulators of ion channels
US20120245136A1 (en) 2011-02-18 2012-09-27 Sara Sabina Hadida-Ruah Chroman-spirocyclic piperidine amides as modulators of ion channels
US20140187533A1 (en) 2011-03-03 2014-07-03 Zalicus Pharmaceuticals Ltd. Benzimidazole inhibitors of the sodium channel
WO2012116440A1 (en) 2011-03-03 2012-09-07 Zalicus Pharmaceuticals Ltd. Benzimidazole inhibitors of the sodium channel
US20120264749A1 (en) 2011-03-14 2012-10-18 Sara Sabina Hadida-Ruah Morpholine-spirocyclic piperidine amides as modulators of ion channels
WO2012125613A1 (en) 2011-03-14 2012-09-20 Vertex Pharmaceuticals Incorporated Morpholine-spirocyclic piperidine amides as modulators of ion channels
US20140296313A1 (en) 2011-10-26 2014-10-02 Pfizer Limited (4-Phenylimidazol-2-yl) Ethylamine Derivatives Useful As Sodium Channel Modulators
WO2013061205A2 (en) 2011-10-26 2013-05-02 Pfizer Limited Chemical compounds
WO2013086229A1 (en) 2011-12-07 2013-06-13 Amgen Inc. Bicyclic aryl and heteroaryl sodium channel inhibitors
WO2013109521A1 (en) 2012-01-16 2013-07-25 Vertex Pharmaceuticals Incorporated Pyran-spirocyclic piperidine amides as modulators of ion channels
US20150005304A1 (en) 2012-01-16 2015-01-01 Vertex Pharmaceuticals Incorporated Pyran-Spirocyclic Piperidine Amides as Modulators of Ion Channels
WO2013114250A1 (en) 2012-02-03 2013-08-08 Pfizer Inc. Benziimidazole and imidazopyridine derivatives as sodium channel modulators
US20130274243A1 (en) 2012-02-03 2013-10-17 Pfizer Limited Chemical Compounds
WO2013131018A1 (en) 2012-03-02 2013-09-06 Zalicus Pharmaceuticals Ltd. Biaryl inhibitors of the sodium channel
WO2013134518A1 (en) 2012-03-09 2013-09-12 Amgen Inc. Sulfamide sodium channel inhibitors
WO2014120815A1 (en) 2013-01-31 2014-08-07 Vertex Pharmaceuticals Incorporated Quinoline and quinazoline amides as modulators of sodium channels
WO2014120808A1 (en) 2013-01-31 2014-08-07 Vertex Parmaceuticals Incorporated Pyridone amides as modulators of sodium channels
US20140228371A1 (en) 2013-01-31 2014-08-14 Vertex Pharmaceuticals Incorporated Quinoline and quinazoline amides as modulators of sodium channels
US20140221435A1 (en) 2013-01-31 2014-08-07 Vertex Pharmaceuticals Incorporated Amides as modulators of sodium channels
WO2014120820A1 (en) 2013-01-31 2014-08-07 Vertex Pharmaceuticals Incorporated Amides as modulators of sodium channels
US20140213616A1 (en) 2013-01-31 2014-07-31 Vertex Pharmaceuticals Incorporated Pyridone amides as modulators of sodium channels
WO2014120808A9 (en) 2013-01-31 2015-05-14 Vertex Parmaceuticals Incorporated Pyridone amides as modulators of sodium channels
WO2014201206A1 (en) 2013-06-12 2014-12-18 Amgen Inc. Bicyclic sulfonamide compounds as sodium channel inhibitors
WO2015010065A1 (en) 2013-07-19 2015-01-22 Vertex Pharmaceuticals Incorporated Sulfonamides as modulators of sodium channels
US20160152561A1 (en) 2013-07-19 2016-06-02 Vertex Pharmaceuticals Incorporated Sulfonamides as modulators of sodium channels
WO2015089361A1 (en) 2013-12-13 2015-06-18 Vertex Pharmaceuticals Incorporated Prodrugs of pyridone amides useful as modulators of sodium channels
US20150166589A1 (en) 2013-12-13 2015-06-18 Vertex Pharmaceuticals Incorporated Prodrugs of pyridone amides useful as modulators of sodium channels
WO2015157559A2 (en) 2014-04-09 2015-10-15 Siteone Therapeutics, Inc. 10',11'-modified saxitoxins for the treatment of pain
WO2016141035A1 (en) 2015-03-02 2016-09-09 Amgen Inc. Bicyclic ketone sulfonamide compounds
WO2017059385A1 (en) 2015-09-30 2017-04-06 Siteone Therapeutics, Inc. 11,13-modified saxitoxins for the treatment of pain
WO2018183781A1 (en) 2017-03-29 2018-10-04 Siteone Therapeutics, Inc. 11,13-modified saxitoxins for the treatment of pain
WO2018183782A1 (en) 2017-03-29 2018-10-04 Siteone Therapeutics, Inc. 11,13-modified saxitoxins for the treatment of pain
WO2018213426A1 (en) 2017-05-16 2018-11-22 Vertex Pharmaceuticals Incorporated Deuterated pyridone amides and prodrugs thereof as modulators of sodium channels
WO2019014352A1 (en) 2017-07-11 2019-01-17 Vertex Pharmaceuticals Incorporated CARBOXAMIDES AS INHIBITORS OF SODIUM CHANNELS
US20190016671A1 (en) 2017-07-11 2019-01-17 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
WO2020014243A1 (en) 2018-07-09 2020-01-16 Lieber Institute, Inc. PYRIDAZINE COMPOUNDS FOR INHIBITING Nav1.8
WO2020014246A1 (en) 2018-07-09 2020-01-16 Lieber Institute, Inc. Pyridine carboxamide compounds for inhibiting nav1.8
WO2020072835A1 (en) 2018-10-03 2020-04-09 Siteone Therapeutics, Inc. 11,13-modified saxitoxins for the treatment of pain
WO2020092187A1 (en) 2018-11-02 2020-05-07 Merck Sharp & Dohme Corp. 2-amino-n-phenyl-nicotinamides as nav1.8 inhibitors
WO2020092667A1 (en) 2018-11-02 2020-05-07 Merck Sharp & Dohme Corp. 2-amino-n-heteroaryl-nicotinamides as nav1.8 inhibitors
US20200140411A1 (en) 2018-11-02 2020-05-07 Merck Sharp & Dohme Corp. 2-amino-n-heteroaryl-nicotinamides as nav1.8 inhibitors
WO2020117626A1 (en) 2018-12-05 2020-06-11 Merck Sharp & Dohme Corp. 4-amino or 4-alkoxy-substituted aryl sulfonamide compounds with selective activity in voltage-gated sodium channels
WO2020140959A1 (zh) 2019-01-04 2020-07-09 江苏恒瑞医药股份有限公司 6-氧代-1,6-二氢哒嗪类衍生物、其制备方法及其在医药上的应用
WO2020146612A1 (en) 2019-01-10 2020-07-16 Vertex Pharmaceuticals Incorporated Esters and carbamates as modulators of sodium channels
WO2020146682A1 (en) 2019-01-10 2020-07-16 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
WO2020151728A1 (zh) 2019-01-25 2020-07-30 江苏恒瑞医药股份有限公司 2-氧代-1,2-二氢吡啶类衍生物、其制备方法及其在医药上的应用
WO2020261114A1 (en) 2019-06-27 2020-12-30 Glaxosmithkline Intellectual Property Development Limited 2,3-dihydroquinazolin compounds as nav1.8 inhibitors
CN112300069A (zh) 2019-07-31 2021-02-02 明慧医药（上海）有限公司 一种选择性钠通道调节剂及其制备和应用
CN112300051A (zh) 2019-07-31 2021-02-02 明慧医药（上海）有限公司 一种选择性钠通道调节剂及其制备和应用
CN112390745A (zh) 2019-08-19 2021-02-23 江苏恒瑞医药股份有限公司 吡啶烟酰胺类衍生物、其制备方法及其在医药上的应用
WO2021032074A1 (zh) 2019-08-19 2021-02-25 江苏恒瑞医药股份有限公司 苯甲酰胺稠芳环类衍生物、其制备方法及其在医药上的应用
CN112441969A (zh) 2019-08-30 2021-03-05 明慧医药（上海）有限公司 一种选择性钠通道调节剂及其制备和应用
CN112479996A (zh) 2019-09-12 2021-03-12 上海济煜医药科技有限公司 吡啶氮氧化合物及其制备方法和用途
WO2021047622A1 (zh) 2019-09-12 2021-03-18 上海济煜医药科技有限公司 吡啶氮氧化合物及其制备方法和用途
WO2021113627A1 (en) 2019-12-06 2021-06-10 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
CN111217776A (zh) 2020-01-19 2020-06-02 中国人民解放军军事科学院军事医学研究院 含苯并杂环结构的酰胺衍生物、组合物和应用
WO2021252822A1 (en) 2020-06-10 2021-12-16 Amgen Inc. Heteroalkyl dihydroquinoline sulfonamide compounds
WO2021252818A1 (en) 2020-06-10 2021-12-16 Amgen Inc. Cyclopropyl dihydroquinoline sulfonamide compounds
WO2021252820A1 (en) 2020-06-10 2021-12-16 Amgen Inc. Cyclobutyl dihydroquinoline sulfonamide compounds
WO2021257490A1 (en) 2020-06-17 2021-12-23 Merck Sharp & Dohme Corp. 2-oxoimidazolidine-4-carboxamides as nav1.8 inhibitors
WO2021257420A1 (en) 2020-06-17 2021-12-23 Merck Sharp & Dohme Corp. 5-oxopyrrolidine-3-carboxamides as nav1.8 inhibitors
WO2021257418A1 (en) 2020-06-17 2021-12-23 Merck Sharp & Dohme Corp. 2-oxo-oxazolidine-5-carboxamides as nav1.8 inhibitors
WO2022036297A1 (en) 2020-08-14 2022-02-17 Siteone Therapeutics, Inc. Non-hydrated ketone inhibitors of nav1.7 for the treatment of pain
WO2022037641A1 (zh) 2020-08-19 2022-02-24 江苏恒瑞医药股份有限公司 一种选择性NaV抑制剂的前药及其晶型
WO2022037647A1 (zh) 2020-08-19 2022-02-24 江苏恒瑞医药股份有限公司 一种选择性Nav抑制剂的结晶形式及其制备方法
CN111808019A (zh) 2020-09-08 2020-10-23 上海济煜医药科技有限公司 一种并环化合物及其应用
CN112225695A (zh) 2020-12-15 2021-01-15 上海济煜医药科技有限公司 一种氮氧化合物及其制备方法和用途
CN112457294A (zh) 2021-01-27 2021-03-09 上海济煜医药科技有限公司 一种作为NaV1.8阻滞剂的化合物及其制备方法和用途

Non-Patent Citations (40)

* Cited by examiner, † Cited by third party
Title
"Handbook of Chemistry and Physics", article "Periodic Table of the Elements, CAS version"
"March's Advanced Organic Chemistry", 2001, JOHN WILEY & SONS
"Remington's Pharmaceutical Sciences", 1980, MACK PUBLISHING CO.
"The Merck Manual", 2011, MERCK SHARP &DOHME CORP.
AKOPIAN, A.N.L. SIVILOTTIJ.N. WOOD: "A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons", NATURE, vol. 379, no. 6562, 1996, pages 257 - 62, XP000605462, DOI: 10.1038/379257a0
BLACK, J.A. ET AL.: "Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas", ANN. NEUROL., vol. 64, no. 6, 2008, pages 644 - 53, XP009143330, DOI: 10.1002/ana.21527
BLAIR, N.T.B.P. BEAN: "Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons", J. NEUROSCI., vol. 22, no. 23, 2002, pages 10277 - 90
C.-J. HUANG ET AL.: "Characterization of voltage-gated sodium channel blockers by electrical stimulation and fluorescence detection of membrane potential", NATURE BIOTECH, 2006, pages 439 - 46, XP002639729, DOI: 10.1038/NBT1194
CAS , no. 393782-57-5
CATTERALL, W. A.GOLDIN, A. L.WAXMAN, S. G.: "International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels", PHARMACOL. REV., vol. 57, no. 4, 2005, pages 397, XP055213863, DOI: 10.1124/pr.57.4.4
CHAHINE, M.CHATELIER, A.BABICH, O.KRUPP, J. J.: "Voltage-gated sodium channels in neurological disorders", CNS NEUROL. DISORD. DRUG TARGETS, vol. 7, no. 2, 2008, pages 144 - 58
CHOI, J.S.S.G. WAXMAN: "Physiological interactions between Na l.7 and Na l.8 sodium channels: a computer simulation study", J. NEUROPHYSIOL., vol. 106, no. 6, pages 3173 - 84
COWARD, K. ET AL.: "Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states", PAIN, vol. 85, 2000, pages 41 - 50
DIELEMAN, J.P ET AL.: "Incidence rates and treatment of neuropathic pain conditions in the general population", PAIN, vol. 137, no. 3, 2008, pages 681 - 8, XP022853979, DOI: 10.1016/j.pain.2008.03.002
DONG, X.W. ET AL.: "Small interfering RNA-mediated selective knockdown of Na l.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats", NEUROSCIENCE, vol. 146, no. 2, 2007, pages 812 - 21, XP022061734, DOI: 10.1016/j.neuroscience.2007.01.054
ENGLAND, S.: "Voltage-gated sodium channels: the search for subtypeselective analgesics", EXPERT OPIN. INVESTIG. DRUGS, vol. 17, no. 12, 2008, pages 1849 - 64
GONZALEZ, J.E.TSIEN, R.Y.: "Voltage Sensing by Fluorescence Resonance Energy Transfer in Single Cells", BIOPHYS. J., vol. 69, 1995, pages 1272 - 1280, XP000961694
GONZALEZ, J.E.TSIEN, RY.: "Improved indicators of cell membrane potential that use fluorescence resonance energy transfer", CHEM. BIOL., vol. 4, 1997, pages 269 - 277, XP000961796, DOI: 10.1016/S1074-5521(97)90070-3
HUANG, H.L. ET AL.: "Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves", MOL. PAIN, vol. 4, 2008, pages 33, XP021045080, DOI: 10.1186/1744-8069-4-33
J. A. FORNWALD ET AL.: "Gene Expression in Mammalian Cells Using BacMam, a Modified Baculovirus System", METHODS IN MOLECULAR BIOLOGY, 2016, pages 95 - 116
JARVIS, M.F. ET AL.: "A-803467, a potent and selective Na l.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat", PROC. NATL. ACAD. SCI. USA, vol. 104, no. 20, 2007, pages 8520 - 5, XP055030736, DOI: 10.1073/pnas.0611364104
JOSHI, S.K. ET AL.: "Involvement of the TTX-resistant sodium channel Navl.8 in inflammatory and neuropathic, but not post-operative, pain states", PAIN, vol. 123, no. 1-2, 2006, pages 75 - 82
KRAFTE, D. S.BANNON, A. W.: "Sodium channels and nociception: recent concepts and therapeutic opportunities", CURR. OPIN. PHARMACOL., vol. 8, no. 1, 2008, pages 50 - 56, XP002540499, DOI: 10.1016/j.coph.2007.09.007
LAI, J. ET AL.: "Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, Na l.8", PAIN, vol. 95, no. 1-2, 2002, pages 143 - 52, XP002374879, DOI: 10.1016/S0304-3959(01)00391-8
QIU, F. ET AL.: "Increased expression of tetrodotoxin-resistant sodium channels Na l.8 and Na l.9 within dorsal root ganglia in a rat model of bone cancer pain", NEUROSCI. LETT., vol. 512, no. 2, pages 61 - 6, XP028903612, DOI: 10.1016/j.neulet.2012.01.069
ROZA, C. ET AL.: "The tetrodotoxin-resistant Na+ channel Na l.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice", J. PHYSIOL., vol. 550, 2003, pages 921 - 6
RUANGSRI, S. ET AL.: "Relationship of axonal voltage-gated sodium channel 1.8 (Na 1.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats", J. BIOL. CHEM., vol. 286, no. 46, pages 39836 - 47, XP055624203, DOI: 10.1074/jbc.M111.261701
RUSH, A.M. ET AL.: "A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons", PROC. NATL. ACAD. SCI. USA, vol. 103, no. 21, 2006, pages 8245 - 50
RUSH, A.M.T.R. CUMMINS: "Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Navl.8 Sodium Channels", MOL. INTERV., vol. 7, no. 4, 2007, pages 192 - 5, XP009165204, DOI: 10.1124/mi.7.4.4
S. L. HARBESONR. D. TUNG: "Deuterium In Drug Discovery and Development", ANN. REP. MED. CHEM., vol. 46, 2011, pages 403 - 417
S. M. BERGE ET AL., J. PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19
S.G. WAXMAN: "Contribution of Na( )1.8 sodium channels to action potential electrogenesis in DRG neurons", J. NEUROPHYSIOL., vol. 86, no. 2, 2001, pages 629 - 40
SODERPALM, B.: "Anticonvulsants: aspects of their mechanisms of action", EUR. J. PAIN, vol. 6, 2002, pages 3 - 9, XP003009563, DOI: 10.1053/eujp.2001.0315
STRICKLAND, I.T. ET AL.: "Changes in the expression of Na l.7, Na l.8 and Na l.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain", EUR. J. PAIN, vol. 12, no. 5, 2008, pages 564 - 72, XP022632366, DOI: 10.1016/j.ejpain.2007.09.001
SUN, W. ET AL.: "Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats", BRAIN, vol. 135, pages 359 - 75
T.G.M. WUTS ET AL., GREENE'S PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 2006
THOMAS SORRELL: "Organic Chemistry", 1999, UNIVERSITY SCIENCE BOOKS
V.S. SHIRLEYC.M. LEDERER: "Isotopes Project, Nuclear Science Division", TABLE OF NUCLIDES, January 1980 (1980-01-01)
WANG, G. K.MITCHELL, J.WANG, S. Y.: "Block of persistent late Na+ currents by antidepressant sertraline and paroxetine", J. MEMBR. BIOL., vol. 222, no. 2, 2008, pages 79 - 90, XP019622596
YIANGOU, Y. ET AL.: "SNS/PN3 and SNS2/NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves", FEBS LETT., vol. 467, 2000, pages 249 - 52, XP004260962, DOI: 10.1016/S0014-5793(00)01166-2

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