N-(hydroxyalkyl (hetero)ARYL) tetrahydrofuran carboxamides as modulators of sodium channels

Abstract

Compounds, and pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels are provided. Also provided are pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts and methods of using the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions in the treatment of various disorders, including pain.

Description

(19) *EP004699607A2* (11) EP 4 699 607 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: 25.02.2026 Bulletin 2026 / 09 (21) Application number: 25210969.9 (22) Date of filing: 03.06.2022 (51) International Patent Classification (IPC): A61K 31 / 443 (2006.01) (52) Cooperative Patent Classification (CPC): A61P 29 / 00; C07D 405 / 12 (84) Designated Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR Designated Extension States: BA ME Designated Validation States: KH MA MD TN (30) Priority: 04.06.2021 US 202163196946 P (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: 22740607.1 / 4 347 031 (71) Applicant: Vertex Pharmaceuticals Incorporated Boston, MA 02210 (US) (72) Inventors: • BECK, Elizabeth Mary Boston, 02210 (US) • PULLIN, Robert Boston, 02210 (US) • ETXEBARRIA JARDI, Gorka Boston, 02210 (US) • STAMOS, Dean Boston, 02210 (US) • SCHMIDT, Yvonne Boston, 02210 (US) • PONTILLO, Joseph Boston, 02210 (US) • THOMSON, Stephen Andrew Boston, 02210 (US) • SHAW, David Matthew Boston, 02210 (US) • AHMAD, Nadia M. Boston, 02210 (US) • CARVALHO MEIRELES, Lidio Marx Boston, 02210 (US) • SKERRATT, Sarah Boston, 02210 (US) • HADIDA RUAH, Sara S. Boston, 02210 (US) • NEUBERT, Timothy Donald Boston, 02210 (US) • HURLEY, Dennis James Boston, 02210 (US) • ZHOU, Jinglan Boston, 02210 (US) • DURRANT, Steven John Boston, 02210 (US) • WRAY, Christopher Boston, 02210 (US) • VIRANI, Anisa Nizarali Boston, 02210 (US) • NORTH, Kiri Boston, 02210 (US) • DODD, James Boston, 02210 (US) • O’DONNELL, Michael Edward Boston, 02210 (US) • GALAN, Bhairavi Boston, 02210 (US) • KNEGTEL, Ronald Marcellus Boston, 02210 (US) • CHUDYK, Ewa Iwona Boston, 02210 (US) • PINDER, Joanne Louise Boston, 02210 (US) (74) Representative: Carpmaels & Ransford LLP One Southampton Row London WC1B 5HA (GB) Remarks: •This application was filed on 24‑10‑2025 as a divisional application to the application mentioned under INID code 62. •Claims filed after the date of filing of the application / after the date of receipt of the divisional application (Rule 68(4) EPC). (54) N‑(HYDROXYALKYL (HETERO)ARYL) TETRAHYDROFURAN CARBOXAMIDES AS MODULATORS OF SODIUM CHANNELS (57) Compounds, and pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels are provided. Also provided are pharmaceutical composi- tions comprising the compounds or pharmaceutically acceptable salts and methods of using the compounds, pharmaceutically acceptable salts, and pharmaceuticalEP 4 69 9 60 7 A 2 Processed by Luminess, 75001 PARIS (FR) (Cont. next page) compositions in the treatment of various disorders, includ- ing pain. 2 EP 4 699 607 A2 Description CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 196,946, filed June 4, 2021, which is incorporated by reference herein in its entirety. BACKGROUND

[0002] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and to prevent further damage to injured tissue. Nonetheless there are many conditions where pain persists beyond its usefulness, or where patients would benefit from inhibition of pain. Neuropathic pain is a form of chronic pain caused by an injury to the sensory nerves (Dieleman, J.P., et al., Incidence ratesand treatment of neuropathic pain conditions in thegeneral 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-inducedneuropathy.Discrete nerve injury indications include post-amputation pain, post-surgical nerve injury pain, and nerve entrapment injuries like neuropathic back pain.

[0003] Voltage-gated sodium channels (NaVs) are involved in pain signaling. NaVs are biologicalmediators 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). 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 NaVs in pain sensation (Rush, A.M. and T.R. Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets NaV1.8 Sodium Channels.Mol. Interv., 2007. 7(4): p. 192‑5);England,S.,Voltage-gated sodiumchannels: thesearch for subtypeselective analgesics.ExpertOpin. Investig.Drugs17 (12), p. 1849‑64 (2008);Krafte,D.S.andBannon,A.W.,Sodiumchannelsand nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8 (1), p. 50‑56 (2008)). NaVsmediate the rapid upstroke of the action potential ofmany excitable cell types (e.g. neurons, skeletalmyocytes, cardiacmyocytes), and thus are involved in the initiation of signaling in those cells (Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). Because of the role NaVs play in the initiation and propagation of neuronal signals, antagonists that reduce NaV currents can prevent or reduce neural signaling and NaV channels have beenconsidered likely targets to reducepain in conditionswherehyper-excitability is observed (Chahine,M.,Chatelier,A., Babich, O., and Krupp, J. J., Voltage-gated sodium channels in neurological disorders. CNSNeurol. Disord. Drug Targets 7 (2), p. 144‑58 (2008)). Several clinically useful analgesics have been identified as inhibitors of NaV channels. The local anesthetic drugs such as lidocaine block pain by inhibitingNaV channels, and other compounds, such as carbamazepine, lamotrigine, and tricyclic antidepressants that have proven effective at reducing pain have also been suggested to act by sodiumchannel inhibition (Soderpalm, B., Anticonvulsants: aspects of theirmechanisms of action. Eur. J. Pain 6Suppl. A, p. 3‑9 (2002);Wang, G. K., Mitchell, J., andWang, S. Y., Block of persistent late Na+ currents by antidepressant sertraline and paroxetine. J. Membr. Biol. 222 (2), p. 79‑90 (2008)).

[0004] TheNaVs form a subfamily of the voltage-gated ion channel super-family and comprises 9 isoforms, designated NaV1.1 - NaV1.9. The tissue localizations of the nine isoforms vary. NaV1.4 is the primary sodium channel of skeletal muscle, and NaV1.5 is primary sodium channel of cardiac myocytes. NaVs 1.7, 1.8 and 1.9 are primarily localized to the peripheral nervous system,whileNaVs1.1, 1.2, 1.3, and1.6areneuronal channels found inboth thecentral andperipheral 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. A., Goldin, A. L., andWaxman, S. G., International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57 (4), p. 397 (2005)).

[0005] Upon their discovery, NaV1.8 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). Since then, NaV1.8 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. andB.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., 2002. 22(23): p. 10277‑90). NaV1.8 is involved in spontaneous firing in damaged neurons, like those that drive neuropathic pain (Roza, C., et al., The tetrodotoxin-resistant Na+ channel NaV1.8 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 NaV1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc. Natl. Acad. Sci. U S A, 2007. 104(20): p. 8520‑5; Joshi, S.K., et al., Involvement of the TTX-resistant sodium channelNaV1.8 in inflammatory andneuropathic, but not post-operative, pain states. Pain, 2006. 123(1‑2): pp. 75‑82; Lai, J., et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8. 3 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 Pain, 2002. 95(1‑2): p. 143‑52; Dong, X.W., et al., Small interfering RNA-mediated selective knockdown of NaV1.8 tetrodotoxin-resistant sodium channel reversesmechanical allodynia in neuropathic rats. Neuroscience, 2007. 146(2): p. 812‑21; Huang, H.L., et al., Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves. Mol. Pain, 2008. 4: p. 33; Black, J.A., et al., Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann. Neurol., 2008. 64(6): p. 644‑53; Coward, K., et al., Immunolocalization of SNS / PN3 and NaN / SNS2 sodium channels in human pain states. Pain, 2000. 85(1‑2): p. 41‑50; Yiangou, Y., et al., SNS / PN3 and SNS2 / NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. FEBS Lett., 2000. 467(2‑3): p. 249‑52; Ruangsri, S., et al., Relationship of axonal voltage-gated sodiumchannel 1.8 (NaV1.8)mRNAaccumulation to sciatic nerve injury-inducedpainful neuropathy in rats. J.Biol.Chem. 286(46): p. 39836‑47). The small DRG neurons where NaV1.8 is expressed include the nociceptors involved in pain signaling.NaV1.8mediates largeamplitudeactionpotentials in small neuronsof thedorsal rootganglia (Blair,N.T. andB.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., 2002. 22(23): p. 10277‑90). NaV1.8 is necessary for rapid repetitive action potentials in nociceptors, and for spontaneous activity of damaged neurons. (Choi, J.S. and S.G. Waxman, Physiological interactions between NaV1.7 and NaV1.8 sodium channels: a computer simulation study. J. Neurophysiol. 106(6): p. 3173‑84; Renganathan,M., T.R. Cummins, andS.G.Waxman,Contribution of Na(V) 1.8 sodium channels to action potential electrogenesis inDRGneurons. J. Neurophysiol., 2001. 86(2): p. 629‑40;Roza, C., et al., The tetrodotoxin-resistant Na+ channel NaV1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550(Pt 3): p. 921‑6). In depolarized or damaged DRG neurons, NaV1.8 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). In some animal pain models, NaV1.8 mRNAexpression levels have been shown to increase in theDRG (Sun,W., et al., Reduced conduction failure of themain axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats. Brain, 135(Pt 2): p. 359‑75; Strickland, I.T., et al., Changes in the expression of NaV1.7, NaV1.8 and NaV1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in amodel of chronic inflammatory joint pain. Eur. J. Pain, 2008. 12(5): p. 564‑72;Qiu, F., et al., Increased expression of tetrodotoxin-resistant sodiumchannelsNaV1.8 andNaV1.9within dorsal root ganglia in a rat model of bone cancer pain. Neurosci. Lett., 512(2): p. 61‑6).

[0006] The inventors have discovered that some voltage-gated sodium channel inhibitors have limitations as ther- apeutic agents due to, for example, a poor therapeutic window (e.g., due to a lack of NaV isoform selectivity, low potency, and / or other reasons). Accordingly, there remains a need to develop selective voltage-gated sodium channel inhibitors, such as selective NaV1.8 inhibitors. SUMMARY

[0007] In one aspect, the invention relates to a compound described herein, or a pharmaceutically acceptable salt thereof.

[0008] In another aspect, 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.

[0009] In still another aspect, the invention relates to amethod of inhibiting a voltage gated sodium channel in a subject by administering the compound, pharmaceutically acceptable salt, or pharmaceutical composition to the subject.

[0010] In yet another aspect, the invention relates toamethodof treatingor lessening the severity ina subject of avariety of diseases, disorders, or conditions, including, but not limited to, chronicpain, gut pain, neuropathic pain,musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomy pain, hernior- rhaphy 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] 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. 4 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 DETAILED DESCRIPTION

[0012] In one aspect, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: X2a is N, N+‑O-, or C-R2a; X3a is N or N+‑O-; X5a is N, N+‑O-, or C-R5a; X6a is N, N+‑O-, or C-R6a; Rd is (CH2)m(CHRe)n(CH2)pH; m, n, and p are each independently 0 or 1; Re is H, OH, halo, C1‑C6 alkoxy, or C1‑C6 haloalkoxy; R2a and R6a are each independently H, halo, C1‑C6 alkyl, or C1‑C6 haloalkyl; R5a is H, halo, CH2OH, C1‑C6 alkyl, or C1‑C6 haloalkyl; R4b1 and R4b2 are each independently H, C1‑C6 alkyl, C3‑C6 cycloalkyl, or C1‑C6 haloalkyl; R5b1 and R5b2 are each independently H, C1‑C6 alkyl, C3‑C6 cycloalkyl, or C1‑C6 haloalkyl; X3c is N or C-R3c; X4c is N or C-R4c; X5c is N or C-R5c; X6c is N or C-R6c; R2c is H, OH, halo, C1‑C6 alkyl, C2‑C6 alkenyl, C1‑C6 haloalkyl, C1‑C6 alkoxy, C1‑C6 haloalkoxy, or ‑L1‑L2‑(C3‑C6 cycloalkyl), wherein said cycloalkyl is optionally substituted with 1‑2 halo; L1 is a bond or O; L2 is a bond or C1‑C6 alkylene; R3c isH,halo,C1‑C6alkyl, orC1‑C6haloalkyl; orX3c isC-R3c, andR2candR3c, togetherwith thecarbonatoms towhich they are attached, form a ring of formula: Z1 and Z2 are each independently O or CH2; each R is independently H or halo; R4c is H, halo, C1‑C6 alkyl, C1‑C6 haloalkyl, C1‑C6 alkoxy, or C1‑C6 haloalkoxy; R5c is H, halo, C1‑C6 alkyl, or C1‑C6 haloalkyl; and R6c is H, halo, C1‑C6 alkyl, or C1‑C6 haloalkyl; provided that no more than two of X2a, X3a, X5a, and X6a are N or N+‑O-; and provided that no more than one of X3c, X4c, X5c, and X6c is N.

[0013] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistryaredescribed in "OrganicChemistry," ThomasSorrell,UniversityScienceBooks,Sausalito: 1999,and "March’s Advanced Organic Chemistry," 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire 5 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 contents of which are hereby incorporated by reference.

[0014] As used herein, 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.

[0015] As described herein, the compounds of the invention comprisemultiple variable groups (e.g., R1, X3a, R5b, etc.). Asoneofordinaryskill in theartwill recognize, combinationsofgroupsenvisionedby this inventionare thosecombinations that result in the formation of stable or chemically feasible compounds. The term "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 ormore of the purposes disclosed herein. In some embodiments, 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.

[0016] The chemical structures depicted herein are intended to be understood as they would be understood by one of ordinary skill in the art. For example, with respect to formulas (I), (I-A), (I-B), and (I-C), X2a and X3a are connected by a singlebond,X5aandX6aareconnectedbyadoublebond,andX4candX5careconnectedbyasinglebond,even though the bonds between these groupsmay be obscured by the atom labels in the chemical structures. Using a different ChemDraw style, formula (I) could be drawn as follows to show the bonds in question: Moreover, a substituent depicted as "CF3" or "F3C" in a chemical structure refers to a trifluoromethyl substituent, regardless of which depiction appears in the chemical structure.

[0017] As used herein, the term "halo" means F, Cl, Br or I.

[0018] Asusedherein, the term "alkyl" refers to a straight or branchedhydrocarbon 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 themolecule by a single bond. For example, a "C1‑C6 alkyl" group is an alkyl group having between one and six carbon atoms.

[0019] As used herein, the term "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. For example, a "C2‑C6 alkenyl" group is an alkenyl group having between two and six carbon atoms.

[0020] As used herein, the term "cycloalkyl" refers to a stable, non-aromatic, mono‑ or bicyclic (fused, bridged, or spiro) saturatedhydrocarbon radical consistingsolelyof carbonandhydrogenatoms, having thespecifiednumberof carbon ring atoms, and which is attached to the rest of the molecule by a single bond. For example, a "C3‑C8 cycloalkyl" group is a cycloalkyl group having between three and eight carbon atoms.

[0021] As used herein, the term "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. For example, a "C1‑C6 haloalkyl" group isanalkyl grouphavingbetweenoneandsix carbonatoms,wherein oneormoreof thehydrogenatomsof the alkyl group are replaced by halo groups.

[0022] As used herein, the term "alkoxy" refers to a radical of the formula ‑ORa where Ra is an alkyl group having the specifiednumberof carbonatoms.Forexample, a "C1‑C6alkoxy"group isa radical of the formula ‑ORawhereRa isanalkyl group having the between one and six carbon atoms.

[0023] As used herein, 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.

[0024] As used herein, 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 6 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 atoms, which is attached to the rest of the molecule by two single bonds. For example, a "C1‑C6 alkylene" group is an alkylene group having between one and six carbon atoms.

[0025] As used herein, the term "optionally substituted" refers to a group that is either unsubstituted or substituted with the subsequently identified substituents. For example, a group that is "optionally substituted with 1‑2 halo" is either unsubstituted, substituted with 1 halo group, or substituted with 2 halo groups.

[0026] As used herein, "*2" and "*3" in the following structure designate the carbon atoms to which the R2c and R3c groups, respectively, are attached.

[0027] Unless otherwise specified, the compounds of the invention, whether identified by chemical name or chemical structure, 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. In addition, 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.

[0028] As used herein, in any chemical structure or formula, 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 compoundmay have any configuration, or amixture of configurations, at the stereocenter.

[0029] Asusedherein, in any chemical structure or formula, a bold or hashed straight bondattached 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.

[0030] Asusedherein, inanychemical structureor formula, aboldorhashedwedgebondattached toastereocenterof 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.

[0031] As used herein, the prefix "rac-,"when used in connection with a chiral compound, refers to a racemicmixture of 7 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 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.

[0032] Asusedherein, the prefix "rel-,"whenused in connectionwith a chiral compound, refers to a single enantiomer of unknown absolute configuration. In a compound bearing the "rel‑" prefix, 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. In these instances, 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 thosestereocenterswith respect toother stereocenters of unknownabsolute configuration, but do not necessarily reflect the relative stereochemistry with respect to the stereocenters of known absolute configuration.

[0033] As used herein, the term "compound," when referring to the compounds of the invention, refers to a collection of moleculeshaving identical chemical structures, except that theremaybe isotopic variationamong theconstituent atomsof themolecules. The term "compound" includes such a collection ofmoleculeswithout regard to the purity of a given sample containing thecollectionofmolecules.Thus, the term"compound" includessuchacollectionofmolecules inpure form, ina 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.

[0034] As used herein, the term "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. For example, 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. See US 2004 / 0006237 for a comparison of XRPDs of an amorphous material and crystallinematerial. In someembodiments, a solidmaterialmay comprise an amorphous compound, and the materialmay, for example, be characterized by a lack of sharp characteristic crystalline peak(s) in its XRPDspectrum (i.e., thematerial isnot crystalline,but isamorphous,asdeterminedbyXRPD). Instead,oneor several broadpeaks (e.g., halos) may appear in the XRPD pattern of the material. See US 2004 / 0006237 for a representative comparison of XRPDs of an amorphousmaterial andcrystallinematerial. Asolidmaterial, comprisinganamorphouscompound,maybecharacterized by, forexample, awider temperature range for themeltingof thesolidmaterial, ascompared to the range for themeltingofa purecrystalline solid.Other techniques, suchas, for example, solid stateNMRmayalsobeused to characterize crystalline or amorphous forms.

[0035] As used herein, the term "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., 13C, 19F, 15N, and 31P SSNMR).

[0036] In the specification and claims, unless otherwise specified, any atom not specifically designated as a particular isotope in any compound of the invention is meant to represent any stable isotope of the specified element. In the Examples, where an atom is not specifically designated as a particular isotope in any compound of the invention, no effort wasmade toenrich that atom inaparticular isotope, and thereforeapersonof ordinary skill in theartwouldunderstand that such atom likely was present at approximately the natural abundance isotopic composition of the specified element.

[0037] As used herein, 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 inV.S.Shirley&C.M. Lederer, IsotopesProject,NuclearScienceDivision, LawrenceBerkeley Laboratory, Table of Nuclides (January 1980).

[0038] As used herein in the specification and claims, "H" refers to hydrogen and includes any stable isotope of hydrogen,namely 1HandD. In theExamples,whereanatom isdesignatedas "H,"noeffortwasmade toenrich thatatom in a particular isotope of hydrogen, and therefore a person of ordinary skill in the art would understand that such hydrogen atom likely was present at approximately the natural abundance isotopic composition of hydrogen.

[0039] As used herein, "1H" 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.

[0040] As used herein, "D," "d," and "2H" refer to deuterium.

[0041] In some embodiments, the compounds of the invention, and pharmaceutically acceptable salts thereof, include 8 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 each constituent atom at approximately the natural abundance isotopic composition of the specified element.

[0042] In some embodiments, the compounds of the invention, and pharmaceutically acceptable salts thereof, include oneormoreatomshavinganatomicmassormassnumberwhichdiffers from theatomicmassormassnumberof themost abundant isotope of the specified element ("isotope-labeled" compounds and salts). Examples of stable isotopes which are commercially available and suitable for the invention includewithout limitation isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, for example 2H, 13C, 15N, 13O, 17O, and 31P, respectively.

[0043] The isotope-labeled compounds and salts can be used in a number of beneficial ways, including as medica- ments. In some embodiments, the isotope-labeled compounds and salts are deuterium (2H)‑labeled. Deuterium (2H)‑la- beled compounds and salts are therapeutically useful with potential therapeutic advantages over the non‑2H-labeled compounds. In general, deuterium (2H)‑labeled compounds and salts can have highermetabolic stability as compared to those that are not isotope-labeled owing to the kinetic isotope effect described below. Highermetabolic 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.

[0044] The deuterium (2H)‑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. For example, if deuterium is bonded to a carbon atom at a non-exchange- able position, rate differences of kH / kD = 2‑7 are typical. For a further discussion, see S. L. Harbeson and R. D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403‑417, incorporated in its entirety herein by reference.

[0045] 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. The term "isotopic enrichment factor," as used herein, 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.

[0046] Where an atom in a compound of the invention, or a pharmaceutically acceptable salt thereof, is designated as deuterium, such compound (or salt) has an isotopic enrichment factor for such atom of at least 3000 (~45% deuterium incorporation). In someembodiments, 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).

[0047] In some embodiments, the invention relates to a compound of formula (I-A) or apharmaceutically acceptable salt thereof,whereinX2a, X3a, X5a, X6a,Rd,R4b1,R4b2,R5b1,R5b2, X3c, X4c, X5c, X6c, and R2c are defined as set forth above in connection with formula (I).

[0048] In some embodiments, the invention relates to a compound of formula (I-A‑1) 9 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 or apharmaceutically acceptable salt thereof,whereinRd,R4b1,R4b2,R5b1,R5b2,R2c,R3c, andR4c aredefinedas set forth above in connection with formula (I).

[0049] In some embodiments, the invention relates to a compound of formula (I-A‑2) or apharmaceutically acceptable salt thereof,whereinRd,R4b1,R4b2,R5b1,R5b2,R2c,R3c, andR4c aredefinedas set forth above in connection with formula (I).

[0050] In some embodiments, the invention relates to a compound of formula (I-A‑3) or a pharmaceutically acceptable salt thereof, wherein Rd, R4b2, R2c, R3c, and R4c are defined as set forth above in connection with formula (I).

[0051] In some embodiments, the invention relates to a compound of formula (I-B) 10 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 or apharmaceutically acceptable salt thereof,whereinX2a, X3a, X5a, X6a,Rd,R4b1,R4b2,R5b1,R5b2, X3c, X4c, X5c, X6c, and R2c are defined as set forth above in connection with formula (I).

[0052] In some embodiments, the invention relates to a compound of formula (I-B‑1) or apharmaceutically acceptable salt thereof,whereinRd,R4b1,R4b2,R5b1,R5b2,R2c,R3c, andR4c aredefinedas set forth above in connection with formula (I).

[0053] In some embodiments, the invention relates to a compound of formula (I-B‑2) or apharmaceutically acceptable salt thereof,whereinRd,R4b1,R4b2,R5b1,R5b2,R2c,R3c, andR4c aredefinedas set forth above in connection with formula (I).

[0054] In some embodiments, the invention relates to a compound of formula (I-B‑3) 11 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof, wherein Rd, R4b2, R2c, R3c, and R4c are defined as set forth above in connection with formula (I).

[0055] In some embodiments, the invention relates to a compound of formula (I-C) or apharmaceutically acceptable salt thereof,whereinX2a, X3a, X5a, X6a,Rd,R4b1,R4b2,R5b1,R5b2, X3c, X4c, X5c, X6c, and R2c are defined as set forth above in connection with formula (I).

[0056] In some embodiments, the invention relates to a compound of formula (I-C‑1) or apharmaceutically acceptable salt thereof,whereinRd,R4b1,R4b2,R5b1,R5b2,R2c,R3c, andR4c aredefinedas set forth above in connection with formula (I).

[0057] In some embodiments, the invention relates to a compound of formula (I-C‑2) 12 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 or apharmaceutically acceptable salt thereof,whereinRd,R4b1,R4b2,R5b1,R5b2,R2c,R3c, andR4c aredefinedas set forth above in connection with formula (I).

[0058] In some embodiments, the invention relates to a compound of formula (I-C‑3) or a pharmaceutically acceptable salt thereof, wherein Rd, R4b2, R2c, R3c, and R4c are defined as set forth above in connection with formula (I).

[0059] 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 X2a is C-R2a. In other embodiments, X2a is C-R2a; and R2a is H.

[0060] 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 X3a is N. In other embodiments, X3a is N+‑O-.

[0061] 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 X5a is N or C-R5a; andR5a is H, halo, or CH2OH. In other embodiments, X5a is N. In other embodiments, X5a is C-R5a. In other embodiments, X5a is C-R5a; and R5a is H, halo, or CH2OH. In other embodiments, X5a is C-R5a; and R5a is H, F, or CH2OH. In other embodiments, X5a is C-R5a; and R5a is H. In other embodiments, X5a isC-R5a; andR5a is halo. In other embodiments,X5a isC-R5a; andR5a isF. In other embodiments, X5a is C-R5a; and R5a is CH2OH.

[0062] 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 X6a is N or C-R6a; andR6a is H. In other embodiments, X6a is N. In other embodiments, X6a is C-R6a. In other embodiments, X6a is C-R6a; and R6a is H.

[0063] In some embodiments, 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, whereinR4b1 isHorC1‑C6alkyl. In other embodiments, R4b1 is H. In other embodiments, R4b1 is C1‑C6 alkyl. In other embodiments, R4b1 is H orCH3. In other embodiments, R4b1 is CH3.

[0064] 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 R4b2 isHorC1‑C6alkyl. In otherembodiments,R4b2 isH. Inother embodiments,R4b2 isC1‑C6alkyl. In otherembodiments, R4b2 is H or CH3. In other embodiments, R4b2 is CH3.

[0065] In some embodiments, 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 R5b1 is C1‑C6 alkyl or C1‑C6 haloalkyl. In other embodiments, R5b1 is C1‑C6 alkyl. In other embodiments, R5b1 is C1‑C6 haloalkyl. In other embodiments, R5b1 is CH3 or CF3. In other embodiments, R5b1 is CH3. In other embodiments, R5b1 is CF3.

[0066] In some embodiments, 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 R5b2 is C1‑C6 alkyl or 13 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 C1‑C6 haloalkyl. In other embodiments, R5b2 is C1‑C6 alkyl. In other embodiments, R5b2 is C1‑C6 haloalkyl. In other embodiments, R5b2 is CH3 or CF3. In other embodiments, R5b2 is CH3. In other embodiments, R5b2 is CF3.

[0067] 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 R2c is OH, halo, C1‑C6 alkyl, C1‑C6 alkoxy, or C1‑C6 haloalkoxy. In other embodiments, R2c is OH. In other embodiments, R2c is halo. In other embodiments, R2c is C1‑C6 alkyl. In other embodiments, R2c is C1‑C6 alkoxy. In other embodiments, R2c is C1‑C6 haloalkoxy. In other embodiments, R2c isOH,Cl, CH3,OCH3,OCD3,OCH2CH3,OCH(CH3)2,OCH2CH2F, or OCH2CHF2. In other embodiments, R2c is Cl. In other embodiments, R2c is CH3. In other embodiments, R2c is OCH3. In other embodiments, R2c is OCD3. In other embodiments, R2c is OCH2CH3. In other embodiments, R2c is OCH(CH3)2. In other embodiments, R2c is OCH2CH2F. In other embodiments, R2c is OCH2CHF2.

[0068] 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 X3c is N or C-R3c; and R3c is H, halo, C1‑C6 alkyl, or C1‑C6 haloalkyl. In otherembodiments,X3c isN. Inotherembodiments,X3c isC-R3c. Inotherembodiments,X3c isC-R3c; andR3c isH. Inother embodiments, X3c is C-R3c; and R3c is halo. In other embodiments, X3c is C-R3c; and R3c is C1‑C6 alkyl. In other embodiments, X3c is C-R3c; andR3c is C1‑C6 haloalkyl. In other embodiments, X3c is C-R3c; andR3c is H, F, CH3, CHF2, or CF3. In other embodiments, X3c is C-R3c; and R3c is F. In other embodiments, X3c is C-R3c; and R3c is CH3. In other embodiments, X3c is C-R3c; and R3c is CHF2. In other embodiments, X3c is C-R3c; and R3c is CF3.

[0069] In someembodiments, the invention relates to a compoundof any oneof 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 R3c is H, halo, C1‑C6 alkyl, or C1‑C6 haloalkyl. In other embodiments, R3c is H. In other embodiments, R3c is halo. In other embodiments, R3c is C1‑C6 alkyl. In other embodiments, R3c is C1‑C6 haloalkyl. In other embodiments, R3c is H, F, CH3, CHF2, or CF3. In other embodiments, R3c is F. In other embodiments, R3c is CH3. In other embodiments, R3c is CHF2. In other embodiments, R3c is CF3.

[0070] 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 X3c is C-R3c; and R2c and R3c, together with the carbon atoms to which they are attached, form a ring of formula: In other embodiments, the ring is of formula:

[0071] In someembodiments, the invention relates to a compoundof any oneof 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 R2c and R3c, together with the carbon atoms to which they are attached, form a ring of formula: In other embodiments, the ring is of formula:

[0072] 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, whereinX4c isC-R4c; andR4c isH, halo,C1‑C6haloalkyl, C1‑C6alkoxy, or C1‑C6 14 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 haloalkoxy. In other embodiments, X4c is C-R4c. In other embodiments, X4c is C-R4c; and R4c is H. In other embodiments, X4c is C-R4c; andR4c is halo. In other embodiments, X4c is C-R4c; andR4c is C1‑C6 haloalkyl. In other embodiments, X4c is C-R4c; and R4c is C1‑C6 alkoxy. In other embodiments, X4c is C-R4c; and R4c is C1‑C6 haloalkoxy. In other embodiments, X4c is C-R4c; and R4c is H, F, CHF2, OCH2CH3, OCHF2, OCF3. In other embodiments, X4c is C-R4c; and R4c is F. In other embodiments, X4c is C-R4c; and R4c is CHF2. In other embodiments, X4c is C-R4c; and R4c is OCH2CH3. In other embodiments, X4c is C-R4c; and R4c is OCHF2. In other embodiments, X4c is C-R4c; and R4c is OCF3.

[0073] In someembodiments, the invention relates to a compoundof any oneof 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 R4c is H, halo, C1‑C6 haloalkyl, C1‑C6 alkoxy, or C1‑C6 haloalkoxy. In other embodiments, R4c is H. In other embodiments, R4c is halo. In other embodiments, R4c is C1‑C6 haloalkyl. In other embodiments, R4c is C1‑C6 alkoxy. In other embodiments, R4c is C1‑C6 haloalkoxy. In other embodiments, R4c is H, F, CHF2, OCH2CH3, OCHF2, OCF3. In other embodiments, R4c is F. In other embodiments, R4c is CHF2. In other embodiments, R4c is OCH2CH3. In other embodiments, R4c is OCHF2. In other embodiments, R4c is OCF3.

[0074] 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 X5c is C-R5c; and R5c is H.

[0075] 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 X6c is C-R6c; and R6c is H.

[0076] 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 Rd is (CH2)pH. Inotherembodiments,Rd isHorCH3. Inotherembodiments,Rd is (CHRe)n(CH2)pH. Inotherembodiments, Rd is CH2F, CH2OH, or CH(OH)CH3. In other embodiments, Rd is (CH2)m(CHRe)nH. In other embodiments, Rd is CH2OCH3 or CH2CH2OCH3.

[0077] 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 any embodiment thereof, i.e., the compound in non- salt form.

[0078] In some embodiments, 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. Table A. Compound Structures and Names. (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(6‑((S)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(6‑((1R,2R)‑1,2-dihydroxypropyl)pyridin‑3- yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2- carboxamide (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(6‑((1S,2S)‑1,2-dihydroxypropyl)pyridin‑3-yl)‑4,5- dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide 15 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(6‑((R)‑1-hydroxy‑2-methoxyethyl)pyridin‑3- yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2- carboxamide (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(6‑((S)‑1-hydroxy‑2-methoxyethyl)pyridin‑3- yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2- carboxamide (2S,3R,4R,5S)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(6‑((S)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑5- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,5S)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑5- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(6‑((S)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑5- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,5S)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(6‑((S)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑5- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-hydroxyphe- nyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide 16 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2‑(2-fluoroethoxy)phe- nyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(2‑(2,2-difluoroethoxy)‑3,4-difluoro- phenyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5- dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑N‑(6‑((S)‑1,2-dihydroxyethyl)pyridin‑3- yl)‑3‑(2-ethoxy‑3,4-difluorophenyl)‑4,5-dimethyl‑5‑(tri- fluoromethyl)tetrahydrofuran‑2-carboxamide (2R,3S,4S,5R)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3- yl)‑3‑(2-ethoxy‑3,4-difluorophenyl)‑4,5-dimethyl‑5‑(tri- fluoromethyl)tetrahydrofuran‑2-carboxamide (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2‑(methoxy‑d3)phe- nyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,5S)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(2‑((S)‑1,2-dihydroxyethyl)pyrimidin‑5-yl)‑5- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(2‑((S)‑1,2-dihydroxyethyl)pyrimidin‑5-yl)‑5- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,5S)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(2‑((R)‑1,2-dihydroxyethyl)pyrimidin‑5-yl)‑5- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide 17 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) (2R,3S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(2‑((R)‑1,2-dihydroxyethyl)pyrimidin‑5-yl)‑5- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3- yl)‑3‑(2-ethoxy‑4-fluoro‑3-methylphenyl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,4R,5S)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3- yl)‑3‑(2-ethoxy‑4-fluoro‑3-methylphenyl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑N‑(6‑((S)‑1,2-dihydroxyethyl)pyridin‑3- yl)‑3‑(2-ethoxy‑4-fluoro‑3-methylphenyl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,4R,5S)‑N‑(6‑((S)‑1,2-dihydroxyethyl)pyridin‑3- yl)‑3‑(2-ethoxy‑4-fluoro‑3-methylphenyl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,4R,5S)‑N‑(6‑((S)‑1,2-dihydroxyethyl)pyridin‑3- yl)‑3‑(4-fluoro‑2-methoxy‑3-methylphenyl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑N‑(6‑((S)‑1,2-dihydroxyethyl)pyridin‑3- yl)‑3‑(4-fluoro‑2-methoxy‑3-methylphenyl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,4R,5S)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3- yl)‑3‑(4-fluoro‑2-methoxy‑3-methylphenyl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide 18 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) (2R,3S,4S,5R)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3- yl)‑3‑(4-fluoro‑2-methoxy‑3-methylphenyl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,4R,5S)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methox- yphenyl)‑N‑(6‑((S)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5- dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methox- yphenyl)‑N‑(6‑((S)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5- dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,4R,5S)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methox- yphenyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5- dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methox- yphenyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5- dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-isopropoxyphe- nyl)‑N‑(2‑((R)‑1,2-dihydroxyethyl)pyrimidin‑5-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-isopropoxyphe- nyl)‑N‑(2‑((S)‑1,2-dihydroxyethyl)pyrimidin‑5-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(2‑((R)‑1,2-dihydroxyethyl)pyrimidin‑5-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide 19 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(2‑((S)‑1,2-dihydroxyethyl)pyrimidin‑5-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,5S)‑N‑(6‑((S)‑1,2-dihydroxyethyl)pyridin‑3- yl)‑3‑(2-ethoxy‑3,4-difluorophenyl)‑5-methyl‑5‑(trifluoro- methyl)tetrahydrofuran‑2-carboxamide (2R,3S,5R)‑N‑(6‑((S)‑1,2-dihydroxyethyl)pyridin‑3- yl)‑3‑(2-ethoxy‑3,4-difluorophenyl)‑5-methyl‑5‑(trifluoro- methyl)tetrahydrofuran‑2-carboxamide (2S,3R,5S)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3- yl)‑3‑(2-ethoxy‑3,4-difluorophenyl)‑5-methyl‑5‑(trifluoro- methyl)tetrahydrofuran‑2-carboxamide (2R,3S,5R)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3- yl)‑3‑(2-ethoxy‑3,4-difluorophenyl)‑5-methyl‑5‑(trifluoro- methyl)tetrahydrofuran‑2-carboxamide 2‑((S)‑1,2-dihydroxyethyl)‑5‑((2R,3S,4S,5R)‑3‑(4- fluoro‑2-methoxy‑3-methylphenyl)‑4,5-dimethyl‑5‑(tri- fluoromethyl)tetrahydrofuran‑2-carboxamido)pyridine 1- oxide 5‑((2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2- carboxamido)‑2‑((R)‑1,2-dihydroxyethyl)pyridine 1- oxide (2S,3R,5S)‑3‑(2-chloro‑4‑(trifluoromethoxy)phe- nyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑5- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide 20 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) (2R,3S,5R)‑3‑(2-chloro‑4‑(trifluoromethoxy)phe- nyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑5- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,5S)‑3‑(2-chloro‑4‑(trifluoromethoxy)phe- nyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑5- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,5R)‑3‑(2-chloro‑4‑(trifluoromethoxy)phe- nyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑5- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,4S,5R)‑3‑(3,4-difluoro‑2-methylphe- nyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methylphe- nyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4R,5S)‑3‑(3,4-difluoro‑2-methylphe- nyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,4R,5S)‑3‑(3,4-difluoro‑2-methylphe- nyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,4R,5S)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3- yl)‑3‑(2-methoxy‑3‑(trifluoromethyl)phenyl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide 21 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) (2R,3S,4S,5R)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3- yl)‑3‑(2-methoxy‑3‑(trifluoromethyl)phenyl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑N‑(2‑((S)‑1,2-dihydroxyethyl)pyrimi- din‑5-yl)‑3‑(2-methoxy‑3‑(trifluoromethyl)phenyl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,4R,5S)‑N‑(2‑((R)‑1,2-dihydroxyethyl)pyrimi- din‑5-yl)‑3‑(2-methoxy‑3‑(trifluoromethyl)phenyl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑N‑(2‑((R)‑1,2-dihydroxyethyl)pyrimi- din‑5-yl)‑3‑(2-methoxy‑3‑(trifluoromethyl)phenyl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,4R,5S)‑N‑(2‑((S)‑1,2-dihydroxyethyl)pyrimi- din‑5-yl)‑3‑(2-methoxy‑3‑(trifluoromethyl)phenyl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3- yl)‑3‑(7-ethoxy‑2,2-difluorobenzo[d][1,3]dioxol‑4-yl)‑4,5- dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,4R,5S)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3- yl)‑3‑(7-ethoxy‑2,2-difluorobenzo[d][1,3]dioxol‑4-yl)‑4,5- dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(6‑(hydroxymethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide 22 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(2‑(hydroxymethyl)pyrimidin‑5-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(6‑((R)‑2-fluoro‑1-hydroxyethyl)pyridin‑3-yl)‑4,5- dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(6‑((S)‑2-fluoro‑1-hydroxyethyl)pyridin‑3-yl)‑4,5- dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(6‑((S)‑1-hydroxy‑3-methoxypropyl)pyridin‑3- yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2- carboxamide (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(6‑((R)‑1-hydroxy‑3-methoxypropyl)pyridin‑3- yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2- carboxamide (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-hydroxyphe- nyl)‑N‑(2‑(hydroxymethyl)pyrimidin‑5-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4R,5S)‑3‑(3,4-difluoro‑2-methylphe- nyl)‑N‑(6‑(hydroxymethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,4R,5S)‑3‑(3,4-difluoro‑2-methylphe- nyl)‑N‑(6‑(hydroxymethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide 23 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) (2S,3R,4S,5R)‑3‑(3,4-difluoro‑2-methylphe- nyl)‑N‑(6‑(hydroxymethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methylphe- nyl)‑N‑(6‑(hydroxymethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,4R,5S)‑N‑(6‑(hydroxymethyl)pyridin‑3-yl)‑3‑(2- methoxy‑3‑(trifluoromethyl)phenyl)‑4,5-dimethyl‑5‑(tri- fluoromethyl)tetrahydrofuran‑2-carboxamide (2R,3S,4S,5R)‑N‑(6‑(hydroxymethyl)pyridin‑3-yl)‑3‑(2- methoxy‑3‑(trifluoromethyl)phenyl)‑4,5-dimethyl‑5‑(tri- fluoromethyl)tetrahydrofuran‑2-carboxamide (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑N‑(5- fluoro‑6‑(hydroxymethyl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(tri- fluoromethyl)tetrahydrofuran‑2-carboxamide (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(6‑((R)‑1-hydroxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(6‑((S)‑1-hydroxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(5‑(hydroxymethyl)pyrazin‑2-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide 24 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) (2R,3S,4S,5R)‑N‑(5,6-bis(hydroxymethyl)pyridin‑3- yl)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑4,5-dimethyl‑5‑(tri- fluoromethyl)tetrahydrofuran‑2-carboxamide (2R,3S,4S,5R)‑3‑(6‑(difluoromethyl)‑2-methoxypyri- din‑3-yl)-N‑(6‑(hydroxymethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,4R,5S)‑3‑(6‑(difluoromethyl)‑2-methoxypyri- din‑3-yl)‑N‑(6‑(hydroxymethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,4R,5S)‑3‑(4‑(difluoromethyl)‑3-fluoro‑2-methox- yphenyl)‑N‑(6‑(hydroxymethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethytetrahydrofuran‑2-carboxamide (2R,3S,4S,5R)‑3‑(4‑(difluoromethyl)‑3-fluoro‑2-methox- yphenyl)‑N‑(6‑(hydroxymethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,4R,5S)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methox- yphenyl)‑N‑(6‑(hydroxymethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methox- yphenyl)‑N‑(6‑(hydroxymethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methox- yphenyl)‑N‑(2‑(hydroxymethyl)pyrimidin‑5-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide 25 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) (2S,3R,4R,5S)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methox- yphenyl)‑N‑(2‑(hydroxymethyl)pyrimidin‑5-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methox- yphenyl)‑N‑(6‑(1-hydroxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,4R,5S)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methox- yphenyl)‑N‑(6‑((R)‑1-hydroxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2S,3R,4R,5S)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methox- yphenyl)‑N‑(6‑((S)‑1-hydroxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(4‑(difluoromethoxy)‑3-fluoro‑2-meth- oxyphenyl)‑N‑(6‑(hydroxymethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(4‑(difluoromethoxy)‑3-fluoro‑2-meth- oxyphenyl)‑N‑(2‑(hydroxymethyl)pyrimidin‑5-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3- yl)‑3‑(3-fluoro‑2-methoxyphenyl)‑4,5-dimethyl‑5‑(tri- fluoromethyl)tetrahydrofuran‑2-carboxamide 2‑((S)‑1,2-dihydroxyethyl)‑5‑((2S,3R,4R,5S)‑3‑(4- fluoro‑2-methoxy‑3-methylphenyl)‑4,5-dimethyl‑5‑(tri- fluoromethyl)tetrahydrofuran‑2-carboxamido)pyridine 1- oxide 26 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) (2R,3S,4S,5R)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methox- yphenyl)‑N‑(6‑((S)‑1-hydroxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (2R,3S,4S,5R)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methox- yphenyl)‑N‑(6‑((R)‑1-hydroxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide

[0079] 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.

[0080] 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.

[0081] In some embodiments, the invention relates to a compound of formula 27 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 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-methoxy- phenyl)‑N-(6‑(2,2-dimethyl‑1,3-dioxolan‑4-yl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide are separated by SFC as described in Example 1, Step 15. 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.

[0082] In some embodiments, 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-methox- yphenyl)‑N-(6‑(2,2-dimethyl‑1,3-dioxolan‑4-yl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide are separated by SFC as described in Example 1, Step 15. 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.

[0083] 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.

[0084] 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.

[0085] In some embodiments, the invention relates to a compound of formula 28 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 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)pyr- idin‑3-yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide is separatedbySFCasdescribed inExample6. 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, 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 Exam- ple 6. 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.

[0087] 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.

[0088] In some embodiments, the invention relates to a compound of formula 29 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 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.

[0089] 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.

[0090] In some embodiments, 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 benzo- ate are separated by SFC as described in Example 6. In other embodiments, the invention relates to the foregoing compound innon-salt form.Suchcompound is considered tobea "compoundof the invention," as that term is usedherein.

[0091] In some embodiments, the invention relates to a compound of formula or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute and relative stereochemistry 30 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 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 benzo- ate are separated by SFC as described in Example 6. In other embodiments, the invention relates to the foregoing compound innon-salt form.Suchcompound is considered tobea "compoundof the invention," as that term is usedherein.

[0092] 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.

[0093] 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.

[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. In other embodiments, the invention relates to the foregoing compound in 31 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 non-salt form. Such compound is considered to be a "compound of the invention," as that term is used herein.

[0096] In some embodiments, 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 to the first eluting isomer when the two diastereoisomers rel-(2S,3R,4R,5S)‑N-(6‑((R*)- 2,2-di- methyl‑1,3-dioxolan‑4-yl)pyridin‑3-yl)‑3‑(4-fluoro‑2-methoxy‑3-methylphenyl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahy- drofuran‑2-carboxamide and rel‑(2R,3S,4S,5R)‑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 are separated by SFC as de- scribed in Example 5. 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.

[0097] 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-fluoro‑2-methoxy‑3-methylphenyl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide and rel-(2R,3S,4S,5R)‑N‑(6‑((R*)‑ 2,2-dimethyl‑1,3-dioxolan‑4-yl)pyridin‑3-yl)‑3‑(4-fluoro‑2-methoxy‑3-methylphe- nyl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide are separated by SFC as described in Example 5. 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.

[0098] 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.

[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.

[0100] 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 32 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 non-salt form. Such compound is considered to be a "compound of the invention," as that term is used herein.

[0101] In some embodiments, 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-carboxa- mide are separated by SFC as described in Example 9. In other embodiments, the invention relates to the foregoing compound innon-salt form.Suchcompound is considered tobea "compoundof the invention," as that term is usedherein.

[0102] In some embodiments, 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-butyldimethyl- silyl)oxy)methyl)pyridin‑3-yl)‑3‑(3,4-difluoro‑2-methylphenyl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carbox- amide are separated by SFC as described in Example 9. In other embodiments, the invention relates to the foregoing compound innon-salt form.Suchcompound is considered tobea "compoundof the invention," as that term is usedherein.

[0103] 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.

[0104] In some embodiments, the invention relates to a compound of formula 33 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 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.

[0105] In some embodiments, 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-butyldimethylsi- lyl)oxy)‑2-methoxyethyl)pyridin‑3-yl)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofur- an‑2-carboxamideareseparatedbySFCasdescribed inExample2,Step2. Inotherembodiments, 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.

[0106] In some embodiments, 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-butyldi- methylsilyl)oxy)‑2-methoxyethyl)pyridin‑3-yl)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahy- drofuran‑2-carboxamide are separated by SFC as described in Example 2, Step 2. 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.

[0107] In some embodiments, the invention relates to a compound of formula 34 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 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.

[0108] 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.

[0109] In some embodiments, the invention relates to a compound rel‑(2R*,3S*,4S*,5R*)‑3‑(3,4-difluoro‑2-methox- yphenyl)‑N‑(6‑((1R,2R)‑1,2-dihydroxypropyl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide, 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-methox- yphenyl)‑4,5-dimethyl‑5‑(trifluoromethyl)‑N‑(6‑((4R,5R)‑2,2,5-trimethyl‑1,3-dioxolan‑4-yl)pyridin‑3-yl)tetrahydrofur- an‑2-carboxamide and rel‑(2R*,3S*,4S*,5R*)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑4,5-dimethyl‑5‑(trifluoro- methyl)‑N‑(6‑((4S,5S)‑2,2,5-trimethyl‑1,3-dioxolan‑4-yl)pyridin‑3-yl)tetrahydrofuran‑2-carboxamide are separated by SFC as described in Example 1. 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.

[0110] In some embodiments, the invention relates to a compound rel‑(2R*,3S*,4S*,5R*)‑3‑(3,4-difluoro‑2-methox- yphenyl)‑N‑(6‑((1S,2S)‑1,2-dihydroxypropyl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide, 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‑(trifluoromethyl)‑N‑(6‑((4R,SR)‑2,2,5-trimethyl‑1,3-dioxolan‑4-yl)pyridin‑3-yl)tetrahy- drofuran‑2-carboxamide and rel‑(2R*,3S*,4S*,5R*)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑4,5-dimethyl‑5‑(trifluoro- methyl)‑N‑(6‑((4S,5S)‑2,2,5-trimethyl‑1,3-dioxolan‑4-yl)pyridin‑3-yl)tetrahydrofuran‑2-carboxamide are separated by SFC as described in Example 1. 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.

[0111] 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 35 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 non-salt form. Such compound is considered to be a "compound of the invention," as that term is used herein.

[0112] 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.

[0113] In some embodiments, 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 corre- sponding to the first eluting isomer when the two diastereomers rel‑(2R,3S,5R)‑3‑(2-chloro‑4‑(trifluoromethoxy)phe- nyl)‑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 are separated by SFC as described in Example 8. 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.

[0114] 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 corre- sponding 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)pyridin‑3-yl)‑5-methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide 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 are separated by SFC as described in Example 8. 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. Salts, Compositions, Uses, Formulation, Administration and Additional Agents Pharmaceutically acceptable salts and compositions

[0115] Asdiscussed herein, 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. Accordingly, in another aspect of the invention, pharmaceutical compositions are provided, wherein these compositions comprise a compound as described herein, or a pharmaceutically acceptable salt thereof, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0116] As used herein, the term "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 activemetabolite or residue thereof. Thesaltmaybe inpure form, inamixture (e.g., solution, suspension, or colloid)withoneormoreother substances, or in the form of a hydrate, solvate, or co-crystal. As used herein, the term "inhibitorily activemetabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of a voltage-gated sodium channel.

[0117] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1‑19, incorporated herein by 36 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 reference. Pharmaceutically acceptable salts of the compound of this invention include those derived from suitable inorganic and organic acids and bases. Examples of 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. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethane sulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesul- fonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfo- nate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, vale- rate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1‑4 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.

[0118] As described herein, the pharmaceutically acceptable compositions of the invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as usedherein, includes any andall 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 techniques for the preparation thereof. Except insofar as 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 deleteriousmanner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serumproteins, suchashumanserumalbumin, buffer substancessuch 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, polyethy- lene-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; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0119] In another aspect, the invention features a pharmaceutical composition comprising a compoundof the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0120] In another aspect, 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

[0121] In another aspect, the invention 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. In another aspect, the voltage-gated sodium channel is NaV1.8.

[0122] In yet another aspect, the invention features amethod 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.

[0123] In yet another aspect, the invention features amethod 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, 37 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 postsurgical pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incon- tinence, or cardiac arrhythmia comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0124] In yet another aspect, the invention features amethodof treating or lessening the severity in a subject of gut pain, wherein gut pain comprises inflammatory bowel diseasepain,Crohn’sdiseasepain or interstitial cystitis painwherein said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0125] In yet another aspect, 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. In some aspects, the neuropathic pain comprises post- herpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small-fiber neuropathy. In some aspects, the neuropathic pain comprises diabetic neuropathy (e.g., diabetic peripheral neuropathy). As used herein, the phrase "idiopathic small-fiber neuropathy" shall be understood to include any small fiber neuropathy.

[0126] In yet another aspect, the invention features a method of treating or lessening the severity in a subject of neuropathic pain,wherein neuropathic pain comprisespost-herpetic neuralgia, diabetic neuralgia, painfulHIV-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 inducedneuralgia, cancer chemotherapy inducedneuralgia, anti-retroviral therapy inducedneuralgia; post spinal cord injury pain, small fiber neuropathy, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgiawherein saidmethod comprisesadministering aneffective amount of a compoundof the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0127] In yet another aspect, 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. In some aspects, the musculoskeletal pain comprises osteoarthritis pain.

[0128] In yet another aspect, 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.

[0129] In yet another aspect, 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 comprisesadministeringaneffectiveamountof acompoundof the invention, apharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0130] In yet another aspect, 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.

[0131] In yet another aspect, 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.

[0132] In yet another aspect, 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.

[0133] In yet another aspect, 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. In some aspects, the acute pain comprises acute post-operative pain.

[0134] In yet another aspect, 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.

[0135] In yet another aspect, 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.

[0136] In yet another aspect, 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. 38 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55

[0137] In yet another aspect, 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.

[0138] In yet another aspect, the invention features amethod 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. In some aspects, the visceral pain comprises visceral pain from abdominoplasty.

[0139] In yet another aspect, 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 pharma- ceutically acceptable salt thereof or a pharmaceutical composition thereof. In some aspects, the neurodegenerative disease comprisesmultiple sclerosis. In someaspects, theneurodegenerativedisease comprisesPitt HopkinsSyndrome (PTHS).

[0140] In yet another aspect, the invention features amethod 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. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0141] In another aspect, 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. In another aspect, the voltage-gated sodium channel is NaV1.8.

[0142] In another aspect, the invention features amethod 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, neurode- generative 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 tissue surgery pain, hernior- rhaphy pain, bunionectomy pain or abdominoplasty pain), cancer pain including chronic cancer pain and breakthrough cancer pain, stroke (e.g., post stroke central neuropathic pain), whiplash associated disorders, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud’s Disease, scleroderma, systemic lupus erythematosus, Epider- molysis bullosa, gout, juvenile idiopathic arthritis, melorheostosis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperostosis, disc degeneration / herniation pain, radiculopathy, facet joint syndrome, failedbacksurgery syndrome,burns, carpal tunnel syndrome,Paget’s diseasepain, spinal canal stenosis, spondylodiscitis, transversemyelitis, Ehlers-Danlos syndrome, Fabry’s disease,mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy induced oral mucositis, Charcot neuro- pathic osteoarthropathy, temporo-mandibular joint disorder, painful joint arthroplasties, non-cardiac chest pain, pudendal, renal colic, biliary tract diseases, vascular leg ulcers, pain in Parkinson’s disease, pain in Alzheimer’s disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, palpita- tions, hypertension, or abnormal gastro-intestinalmotility, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0143] In another aspect, 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 neuro- pathic pain; persistent / chronic post-surgical pain (e.g., post amputation, post-thoracotomy, post-cardiac surgery), post- mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; phantom pain (e.g., following removal of lower extremity, upper extremity, breast); intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury pain; exercise pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, burn pain, trauma pain; acute intermittent pain, endometriosis; acuteherpeszoster pain; sickle cell anemia; acutepancreatitis; breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet’s disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry’s disease pain; bladder and urogenital disease; urinary incontinence, pathological cough; 39 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 hyperactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS), type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal extreme pain, pruritus, tinnitus, or angina-induced pain, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. Compounds, Pharmaceutically Acceptable Salts, and Compositions for Use

[0144] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use as a medicament.

[0145] In another aspect, 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. In another aspect, the voltage-gated sodium channel is NaV1.8.

[0146] In another aspect, 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.

[0147] In another aspect, 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, herniorrhaphypain, bunionectomypain,multiple sclerosis,Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia.

[0148] In another aspect, 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.

[0149] In another aspect, 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. In some aspects, the neuropathic pain comprises post-herpetic neuralgia, small fiber neuropathy, diabetic neuro- pathy, or idiopathic small-fiber neuropathy. In some aspects, the neuropathic pain comprises diabetic neuropathy (e.g., diabetic peripheral neuropathy). As used herein, the phrase "idiopathic small-fiber neuropathy" shall be understood to include any small fiber neuropathy.

[0150] In another aspect, 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; nerveavulsion injury, brachial plexusavulsion 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 cepha- lalgia.

[0151] In another aspect, 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 muscu- loskeletal pain. In some aspects, the musculoskeletal pain comprises osteoarthritis pain.

[0152] In another aspect, 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 muscu- loskeletal pain, whereinmusculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain.

[0153] In another aspect, 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.

[0154] In another aspect, 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.

[0155] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in amethod of treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.

[0156] In another aspect, 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. 40 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55

[0157] In another aspect, 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. In some aspects, the acute pain comprises acute post-operative pain.

[0158] In another aspect, 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).

[0159] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in amethod of treating or lessening the severity in a subject of bunionectomy pain.

[0160] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in amethod of treating or lessening the severity in a subject of herniorrhaphy pain.

[0161] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use inamethodof treatingor lessening theseverity inasubjectof abdominoplasty pain.

[0162] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in amethodof treatingor lessening the severity in a subject of visceral pain. In some aspects, the visceral pain comprises visceral pain from abdominoplasty.

[0163] In another aspect, 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. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt Hopkins Syndrome (PTHS).

[0164] In another aspect, 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. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0165] In another aspect, 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. In another aspect, the voltage-gated sodium channel is NaV1.8.

[0166] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use inamethodof treatingor lessening theseverity ina subject of acutepain, 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, neurodegenera- tive disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain of multiple sclerosis and irritable bowel syndrome, incon- tinence, 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 tissue surgery pain, hernior- rhaphy pain, bunionectomy pain or abdominoplasty pain), cancer pain including chronic cancer pain and breakthrough cancer pain, stroke (e.g., post stroke central neuropathic pain), whiplash associated disorders, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud’s Disease, scleroderma, systemic lupus erythematosus, Epider- molysis bullosa, gout, juvenile idiopathic arthritis, melorheostosis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperostosis, disc degeneration / herniation pain, radiculopathy, facet joint syndrome, failedbacksurgery syndrome,burns, carpal tunnel syndrome,Paget’s diseasepain, spinal canal stenosis, spondylodiscitis, transversemyelitis, Ehlers-Danlos syndrome, Fabry’s disease,mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy induced oral mucositis, Charcot neuro- pathic osteoarthropathy, temporo-mandibular joint disorder, painful joint arthroplasties, non-cardiac chest pain, pudendal, renal colic, biliary tract diseases, vascular leg ulcers, pain in Parkinson’s disease, pain in Alzheimer’s disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, palpita- tions, hypertension, or abnormal gastro-intestinal motility.

[0167] In another aspect, 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 41 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 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; Char- cot-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-thoracotomy, post-cardiac surgery), post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; phantom pain (e.g., following removal of lower extremity, upper extremity, breast); intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury pain; exercise pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, burn pain, trauma pain; acute intermittent pain, endometriosis; acuteherpes zoster pain; sickle cell anemia; acutepancreatitis; breakthroughpain; orofacial pain; sinusitis pain; dental pain;multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet’s disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry’s disease pain; bladder and urogenital disease; urinary incontinence, pathological cough; hyperactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS), type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal extreme pain, pruritus, tinnitus, or angina-induced pain.

[0168] In another aspect, 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 treatedwith botox, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbrosacral radiculopathy, iliolin- gual neuralgia, pudendal neuralgia, femoral neuropathy, meralgia paresthetica, saphenous neuropathy, sciatic neuro- pathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain or postamputation pain. Manufacture of Medicaments

[0169] In another aspect, 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.

[0170] In another aspect, 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. In another aspect, the voltage-gated sodium channel is NaV1.8.

[0171] In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for themanufacture of amedicament for use in treatingor 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.

[0172] In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for themanufacture of amedicament for use in treatingor 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.

[0173] In yet another aspect, 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.

[0174] In yet another aspect, the invention provides a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for themanufacture of a medicament for use in treating or lessening the severity in a subject of neuropathic pain. In some aspects, the neuropathic pain comprises post-herpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small-fiber neuropathy. In some aspects, the neuropathic pain comprises diabetic neuropathy (e.g., diabetic peripheral neuropathy).

[0175] In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for themanufacture of amedicament 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 inducedneuralgia, cancer chemotherapy inducedneuralgia, anti-retroviral 42 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 therapy inducedneuralgia; post spinal cord injurypain, small fiberneuropathy, idiopathic small-fiberneuropathy, idiopathic sensory neuropathy or trigeminal autonomic neuropathy.

[0176] In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for themanufacture of amedicament for use in treatingor lessening the severity in a subject of musculoskeletal pain. In some aspects the musculoskeletal pain comprises osteoarthritis pain.

[0177] In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for themanufacture of amedicament for use in treatingor lessening the severity in a subject of musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain.

[0178] In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for themanufacture of amedicament for use in treatingor lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain or vulvodynia.

[0179] In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for themanufacture of amedicament for use in treatingor lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain.

[0180] In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for themanufacture of amedicament for use in treatingor lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.

[0181] In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for themanufacture of amedicament for use in treatingor lessening the severity in a subject of pathological cough.

[0182] In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for themanufacture of amedicament for use in treatingor lessening the severity in a subject of acute pain. In some aspects, the acute pain comprises acute post-operative pain.

[0183] In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for themanufacture of amedicament for use in treatingor lessening the severity in a subject of postsurgical pain (e.g., joint replacement pain, soft tissuesurgery pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain).

[0184] In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for themanufacture of amedicament for use in treatingor lessening the severity in a subject of herniorrhaphy pain.

[0185] In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for themanufacture of amedicament for use in treatingor lessening the severity in a subject of bunionectomy pain.

[0186] In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for themanufacture of amedicament for use in treatingor lessening the severity in a subject of abdominoplasty pain.

[0187] In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for themanufacture of amedicament for use in treatingor lessening the severity in a subject of visceral pain. In some aspects, the visceral pain comprises visceral pain from abdominoplasty.

[0188] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for themanufacture of amedicament for use in treating or lessening the severity in a subject of a neurodegenerative disease. In someaspects, theneurodegenerativedisease comprisesmultiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt Hopkins Syndrome (PTHS).

[0189] In yet another aspect, 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. In someembodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0190] In another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for themanufacture of amedicament 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 43 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, backpain, unspecific chronic backpain, headpain, neckpain,moderatepain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain), cancer pain including chronic cancer pain and breakthrough cancer pain, stroke (e.g., post stroke central neuropathic pain), whiplash associated disorders, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud’s Disease, scleroderma, systemic lupus erythematosus, Epidermolysis bullosa, gout, juvenile idiopathic arthritis, melorheostosis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperostosis, disc degener- ation / herniation pain, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget’s disease pain, spinal canal stenosis, spondylodiscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry’s disease, mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, che- motherapy inducedoralmucositis, Charcot neuropathic osteoarthropathy, temporo-mandibular joint disorder, painful joint arthroplasties, non-cardiac chest pain, pudendal, renal colic, biliary tract diseases, vascular leg ulcers, pain inParkinson’s disease, pain in Alzheimer’s disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastro-intestinal motility.

[0191] In another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for themanufacture of amedicament 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 neuro- pathy; 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-thoracotomy, post-cardiac surgery), post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; phantom pain (e.g., following removal of lower extremity, upper extremity, breast); intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury pain; exercise pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, burn pain, trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthroughpain; orofacial pain; sinusitis pain; dental pain;multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet’s disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry’s disease pain; bladder and urogenital disease; urinary incontinence, pathological cough; hyperactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS), type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal extreme pain, pruritus, tinnitus, or angina-induced pain.

[0192] In another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for themanufacture of amedicament 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, sa- phenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain or postamputation pain. Administration of Compounds, Pharmaceutically Acceptable Salts, and Compositions

[0193] In certain embodimentsof the inventionan "effective amount" of a compoundof 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.

[0194] 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 oneormore 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. The expression "dosage unit form" as used herein 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 44 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 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, bodyweight, general health, sex anddiet of the subject; the timeof 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. The term "subject" or "patient," as used herein, means an animal, preferably a mammal, and most preferably a human.

[0195] The pharmaceutically acceptable 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. In certain embodiments, 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.

[0196] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound or salt, 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, andsesameoils), glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycolsand fattyacidestersof sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0197] 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 preparationmay also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, asasolution in1,3-butanediol.Among theacceptable vehiclesandsolvents thatmaybeemployed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0198] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the formof sterile solid compositionswhich canbedissolvedor dispersed in sterilewater or other sterile injectable medium prior to use.

[0199] In order to prolong the effect of the compounds of the invention, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. Thismay be accomplished by the use of a liquid suspension of crystalline or amorphousmaterial with poorwater solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectabledepot formsaremadeby formingmicroencapsulematricesof thecompound inbiodegradablepolymerssuchas polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0200] 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 suppositorywaxwhich are solid at ambient temperature but liquid at body temperature and thereforemelt in the rectum or vaginal cavity and release the active compound.

[0201] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, theactive compoundor salt ismixedwith 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, polyvinylpyrroli- dinone, 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 sodiumcarbonate, e) solution retarding agents such asparaffin, f) absorption accelerators suchasquaternary ammoniumcompounds, g)wetting agents suchas, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0202] Solid compositions of a similar typemay 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 45 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 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. Examples of embedding compositions that can be used 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 ormilk sugar aswell as highmolecular weight polyethylene glycols and the like.

[0203] The active compound or salt can also be inmicroencapsulated formwith one ormore excipients as noted above. The solid dosage formsof tablets, dragees, capsules, pills, and granules canbe preparedwith coatings and shells suchas enteric coatings, release controlling coatings and other coatingswell known in the pharmaceutical formulating art. In such solid dosage forms the active compound or salt may be admixedwith at least one inert diluent such as sucrose, lactose or starch. Such dosage formsmay 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. In the case of capsules, tablets and pills, the dosage formsmay also comprise buffering agents. Theymay 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. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0204] 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 conditionswith a pharmaceutically acceptable carrier and any needed preservatives or buffers asmay be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the invention contemplates the use of transdermal patches, which have the added advantage of providing controlleddelivery of a compound to thebody.Suchdosage formsarepreparedbydissolving 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 ratecanbecontrolledbyeitherprovidinga ratecontrollingmembraneorbydispersing thecompound inapolymermatrix or gel.

[0205] As described generally above, the compounds of the invention are useful as inhibitors of voltage-gated sodium channels. In one embodiment, the compounds are inhibitors of NaV1.8 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 NaV1.8 is implicated in the disease, condition, or disorder. When activation or hyperactivity of NaV1.8 is implicated in a particular disease, condition, or disorder, the disease, condition, or disordermayalsobe referred to as a "NaV1.8-mediated disease, conditionor disorder." Accordingly, in another aspect, the invention provides amethod for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of NaV1.8 is implicated in the disease state.

[0206] The activity of a compound utilized in this invention as an inhibitor of NaV1.8 may be assayed according to methods described generally in International Publication No. WO 2014 / 120808 A9 and U.S. Publication No. 2014 / 0213616 A1, both of which are incorporated by reference in their entirety, methods described herein, and other methods known and available to one of ordinary skill in the art. Additional Therapeutic Agents

[0207] It will also be appreciated that the compounds, salts, and pharmaceutically acceptable 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 ormore other desired therapeutics or medical 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. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (forexample, an inventivecompoundmaybeadministeredconcurrentlywithanotheragentused to treat thesame disorder), or theymayachieve different effects (e.g., control of anyadverseeffects). Asusedherein, 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." For example, exemplary 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 asFenoprofen, Flurbiprofen, Ibuprofen,Ketoprofen,Naproxen,Naproxensodium,Oxaprozin; salicylates suchasAspirin, Choline magnesium trisalicylate, Diflunisal; fenamates such as meclofenamic acid, Mefenamic acid; and pyrazoles such as Phenylbutazone); or opioid (narcotic) agonists (such as Codeine, Fentanyl, Hydromorphone, Levorphanol, Meper- idine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol, Dezocine, Nal- buphine, andPentazocine).Additionally, nondruganalgesic approachesmaybeutilized in conjunctionwithadministration of one or more compounds of the invention. For example, anesthesiologic (intraspinal infusion, neural blockade), neurosurgical (neurolysis of CNS pathways), neurostimulatory (transcutaneous electrical nerve stimulation, dorsal 46 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 column stimulation), physiatric (physical therapy, orthotic devices, diathermy), or psychologic (cognitive methods- hypnosis, biofeedback, or behavioral methods) approaches may also be utilized. Additional appropriate therapeutic agents or approachesaredescribedgenerally inTheMerckManual,NineteenthEdition,Ed.Robert S.Porter and Justin L. Kaplan, Merck Sharp &Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and the Food and Drug Administration website, www.fda.gov, the entire contents of which are hereby incorporated by reference.

[0208] In another embodiment, additional appropriate therapeutic agents are selected from the following: (1) an opioid analgesic, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, metha- done,meperidine, fentanyl, cocaine, codeine, dihydrocodeine,oxycodone, hydrocodone,propoxyphene,nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, pentazocine, or difelikefalin; (2) a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen (including without limitation intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketorolac (including without limitation ketorolac tromethamine (e.g., Toradol®)), meclofenamic acid, mefenamic acid, meloxicam, IV meloxicam (e.g., Anjeso®), nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac; (3) a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal or thiopental; (4) a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, loraze- pam, oxazepam, temazepam or triazolam; (5) a histamine (H1) antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlor- pheniramine or chlorcyclizine; (6) a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone; (7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine; (8) 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‑(phospho- nomethyl)‑2‑piperidinecarboxylic acid, budipine,EN‑3231 (MorphiDex®), a combination formulationofmorphineand dextromethorphan), topiramate, neramexane or perzinfotel including anNR2B antagonist, e.g. ifenprodil, traxoprodil or (‑)‑(R)‑6‑{2‑[4‑(3-fluorophenyl)‑4-hydroxy-l‑ piperidinyl]‑l-hydroxyethyl‑3,4-dihydro‑2(lH)‑quinolinone; (9) an alpha-adrenergic, 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; (10) a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline; (11) an anticonvulsant, e.g. carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®) or valproate; (12) a tachykinin (NK) antagonist, particularly an NK‑3, NK‑2 or NK‑1 antagonist, e.g. (alphaR,9R)‑7‑[3,5-bis(tri- fluoromethyl)benzyl]‑8,9,10,11 -tetrahydro‑9-methyl‑5‑(4‑ methylphenyl)‑7H‑[l,4]diazocino[2,l-g][l,7]‑naphthyri- dine‑6‑13-dione (TAK‑637), 5‑ [[(2R,3S)‑2‑[(lR)‑l‑[3,5-bis(trifluoromethyl)phenyl]ethoxy‑3‑(4-fluorophenyl)‑4-mor- pholinyl]‑methyl]‑l,2-dihydro‑3H-l,2,4-triazol‑3-one (MK‑869), aprepitant, lanepitant, dapitant or 3‑[[2-methoxy‑5‑(tri- fluoromethoxy)phenyl]‑methylamino]‑2-phenylpiperidine (2S,3S); (13) a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium; (14) a COX‑2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumira- coxib; (15) a coal-tar analgesic, in particular paracetamol; (16) a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan; (17) a vanilloid receptor agonist (e.g. resinferatoxin or civamide) or antagonist (e.g. capsazepine, GRC‑15300); (18) a beta-adrenergic such as propranolol; (19) a local anesthetic such as mexiletine; (20) a corticosteroid such as dexamethasone; (21) a 5-HT receptor agonist or antagonist, particularly a 5-HT1B / 1D agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan; (22) a 5-HT2A receptor antagonist such as R(+)‑alpha‑(2,3-dimethoxy-phenyl)‑l‑[2‑(4-fluorophenylethyl)]‑4-piper- idinemethanol (MDL‑100907); (23) a cholinergic (nicotinic) analgesic, such as ispronicline (TC‑1734), (E)‑N-methyl‑4‑(3-pyridinyl)‑3-buten-l-amine (RJR‑2403), (R)‑5‑(2-azetidinylmethoxy)‑2-chloropyridine (ABT‑594) or nicotine; (24) Tramadol®, Tramadol ER (Ultram ER®), IV Tramadol, Tapentadol ER (Nucynta®); 47 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 (25) a PDE5 inhibitor, such as 5‑[2-ethoxy‑5‑(4-methyl-l-piperazinyl-sulphonyl)phenyl]‑l-methyl‑3-n-propyl-l,6-dihy- dro‑7H-pyrazolo[4,3-d]pyrimidin‑7-one (sildenafil), (6R,12aR)‑2,3,6,7,12,12a-hexahydro‑2-methyl‑6‑(3,4-methyle- nedioxyphenyl)‑pyrazino[2’,l’:6,l]‑pyrido[3,4-b]indole-l,4-dione (IC‑351 or tadalafil), 2‑[2-ethoxy‑5‑(4-ethyl-pipera- zin-l-yl-l-sulphonyl)‑phenyl]‑5-methyl‑7-propyl‑3H-imidazo[5,l-f][l,2,4]triazin‑4-one (vardenafil), 5‑(5-acetyl‑2-bu- toxy‑3-pyridinyl)‑3-ethyl‑2‑(l-ethyl‑3-azetidinyl)‑2,6-dihydro‑7H‑ pyrazolo[4,3‑d]pyrimidin‑7-one, 5‑(5-acetyl‑2-pro- poxy‑3-pyridinyl)‑3-ethyl‑2‑(l-isopropyl‑3-azetidinyl)‑2,6-dihydro‑7H-pyrazolo[4,3‑d]pyrimidin‑7-one, 5‑[2- ethoxy‑5‑(4-ethylpiperazin-l-ylsulphonyl)pyridin‑3-yl]‑3-ethyl‑2‑[2-methoxyethyl]‑2,6-dihydro‑7H‑ pyrazolo[4,3-d] pyrimidin‑7-one, 4‑[(3-chloro‑4-methoxybenzyl)amino]‑2‑[(2S)‑2‑(hydroxymethyl)pyrrolidin-l-yl]‑N‑(pyrimidin‑2-yl- methyl)pyrimidine‑5-carboxamide, 3‑(l‑ methyl‑7-oxo‑3-propyl‑6,7-dihydro-lH-pyrazolo[4,3-d]pyrimidin‑5- yl)‑N‑[2‑(l-methylpyrrolidin‑2-yl)ethyl]‑4-propoxybenzenesulfonamide; (26) an alpha‑2-delta ligand such as gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methyl gabapentin, (l[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0] hept‑3-yl)‑acetic acid, (3S,5R)‑3-aminomethyl‑5-methyl-heptanoic acid, (3S,5R)‑3-amino‑5-methyl-heptanoic acid, (3S,5R)‑3-amino‑5-methyl-octanoic acid, (2S,4S)‑4‑(3-chlorophenoxy)proline, (2S,4S)‑4‑(3-fluorobenzyl)‑proline, [(lR,5R,6S)‑6‑(aminomethyl)bicyclo[3.2.0]hept‑6-yl]acetic acid, 3‑(l-aminomethyl-cyclohexylmethyl)‑4H‑[1,2,4]oxa- diazol‑5-one, C‑[1‑(1H-tetrazol‑5-ylmethyl)‑cycloheptyl]‑methylamine, (3S,4S)‑(l-aminomethyl‑3,4-dimethyl-cyclo- pentyl)‑acetic acid, (3S,5R)‑3-aminomethyl‑5-methyl-octanoic acid, (3S,5R)‑3-amino‑5-methyl-nonanoic acid, (3S,5R)‑3-amino‑5-methyl-octanoic acid, (3R,4R,5R)‑3-amino‑4,5-dimethyl-heptanoic acid and (3R,4R,5R)‑3-ami- no‑4,5-dimethyl-octanoic acid; (27) a cannabinoid such as KHK‑6188; (28) metabotropic glutamate subtype 1 receptor (mGluRl) antagonist; (29) a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluox- etine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcita- lopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone; (30) a noradrenaline (norepinephrine) reuptake inhibitor, such asmaprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, bupropionmetabolite hydroxybupropion, nomifensine and viloxazine (Vivalan®), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)‑reboxetine; (31) a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine metabolite O-desmethyl- venlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran and imipramine; (32) an inducible nitric oxide synthase (iNOS) inhibitor such as S‑[2‑[(l-iminoethyl)amino]ethyl]‑L-homocysteine, S‑[2‑[(l-iminoethyl)‑amino]ethyl]‑4,4-dioxo-L-cysteine, S‑[2‑[(l-iminoethyl)amino]ethyl]‑2-methyl-L-cysteine, (2S,SZ)‑2-amino‑2-methyl‑7‑[(l-iminoethyl)amino]‑5-heptenoic acid, 2‑[[(lR,3S)‑3-amino‑4-hydroxy-l‑(5-thiazo- lyl)‑butyl]thio]‑S-chloro-S-pyridinecarbonitrile; 2‑[[(lR,3S)‑3-amino‑4-hydroxy-l‑(5‑ thiazolyl)butyl]thio]‑4-chloroben- zonitrile, (2S,4R)‑2-amino‑4‑[[2-chloro‑5‑ (trifluoromethyl)phenyl]thio]‑5-thiazolebutanol, 2‑[[(lR,3S)‑3-amino‑4-hy- droxy-l‑(5-thiazolyl) butyl]thio]‑6‑(trifluoromethyl)‑3-pyridinecarbonitrile, 2‑[[(lR,3S)‑3-amino‑4-hydroxy‑1‑(5-thiazo- lyl)butyl]thio]‑5-chlorobenzonitrile, N‑[4‑[2‑(3-chlorobenzylamino)ethyl]phenyl]thiophene‑2-carboxamidine, NXN‑462, or guanidinoethyldisulfide; (33) an acetylcholinesterase inhibitor such as donepezil; (34) a prostaglandinE2 subtype 4 (EP4) antagonist such asN‑[({2‑[4‑(2-ethyl‑4,6‑ dimethyl-lH-imidazo[4,5-c]pyridin- l-yl)phenyl]ethyl}amino)‑carbonyl]‑4‑ methylbenzenesulfonamide or 4‑[(15)‑l‑({[5-chloro‑2‑(3-fluorophenoxy)pyri- din‑3‑ yl]carbonyl}amino)ethyl]benzoic acid; (35) a leukotriene B4 antagonist; such as l‑(3-biphenyl‑4-ylmethyl‑4-hydroxy-chroman‑7-yl)‑cyclopentanecarboxylic acid (CP‑ 105696), 5‑[2‑(2-Carboxyethyl)‑3‑[6‑(4-methoxyphenyl)‑5E-hexenyl]oxyphenoxy]‑valeric acid (ONO‑4057) or DPC‑11870; (36) a 5-lipoxygenase inhibitor, such as zileuton, 6‑[(3-fluoro‑5‑[4-methoxy‑3,4,5,6-tetrahydro‑2H-pyran‑4-yl])phe- noxy-methyl]‑l-methyl‑2-quinolone (ZD‑2138), or 2,3,5‑ trimethyl‑6‑(3-pyridylmethyl)‑l,4-benzoquinone (CV‑6504); (37) a sodium channel blocker, such as lidocaine, lidocaine plus tetracaine cream (ZRS‑201) or eslicarbazepine acetate; (38) a NaV1.7 blocker, such as XEN‑402, XEN403, TV‑45070, PF‑05089771, CNV1014802, GDC‑0276, RG7893 BIIB‑074 (Vixotrigine), BIIB‑095, ASP‑1807, DSP‑3905, OLP‑1002, RQ‑00432979, FX‑301, DWP‑1706, DWP‑17061, IMB‑110, IMB‑111, IMB‑112 and such as those disclosed in WO2011 / 140425 (US2011 / 306607); WO2012 / 106499 (US2012196869); WO2012 / 112743 (US2012245136); WO2012 / 125613 (US2012264749), WO2012 / 116440 (US2014187533), WO2011026240 (US2012220605), US8883840, US8466188, WO2013 / 109521 (US2015005304), WO2020 / 117626, and CN111217776, the entire contents of each application hereby incorporated by reference; (38a) a NaV1.7 blocker such as (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine‑1,4’-piperidine]‑1’-yl)‑(4-isopro- 48 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 poxy‑3-methyl-phenyl)methanone, 2,2,2-trifluoro‑1‑[1’‑[3-methoxy‑4‑[2‑(trifluoromethoxy)ethoxy]benzoyl]‑2,4-di- methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine‑1,4’-piperidine]‑6-yl]ethanone, [8-fluoro‑2-methyl‑6‑(trifluoro- methyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine‑1,4’-piperidine]‑1’-yl]‑(4-isobutoxy‑3-methoxy-phenyl)methanone, 1‑(4-benzhydrylpiperazin‑1-yl)‑3‑[2‑(3,4-dimethylphenoxy)ethoxy]propan‑2-ol, (4-butoxy‑3-methoxy-phenyl)‑[2- methyl‑6‑(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine‑1,4’-piperidine]‑1’-yl]methanone, [8-fluoro‑2- methyl‑6‑(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine‑1,4’-piperidine]‑1’-yl]‑(5-isopropoxy‑6-methyl‑2- pyridyl)methanone, (4-isopropoxy‑3-methyl-phenyl)‑[2-methyl‑6‑(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyr- rolo[1,2-a]pyrazine‑1,4’-piperidine]‑1’-yl]methanone, 5‑[2-methyl‑4‑[2-methyl‑6‑(2,2,2-trifluoroacetyl)spiro[3,4-di- hydropyrrolo[1,2-a]pyrazine‑1,4’-piperidine]‑1’-carbonyl]phenyl]pyridine‑2-carbonitrile, (4-isopropoxy‑3-methyl- phenyl)‑[6‑(trifluoromethyl)spiro[3,4-dihydro‑2H-pyrrolo[1,2-a]pyrazine‑1,4’-piperidine]‑1’-yl]methanone, 2,2,2-tri- fluoro‑1‑[1’‑[3-methoxy‑4‑[2‑(trifluoromethoxy)ethoxy]benzoyl]‑2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyra- zine‑1,4’-piperidine]‑6-yl]ethanone, 2,2,2-trifluoro‑1‑[1’‑(5-isopropoxy‑6-methyl-pyridine‑2-carbonyl)‑3,3-dimethyl- spiro[2,4-dihydropyrrolo[1,2-a]pyrazine‑1,4’-piperidine]‑6-yl]ethanone, 2,2,2-trifluoro‑1‑[1’‑(5-isopentyloxypyri- dine‑2-carbonyl)‑2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine‑1,4’-piperidine]‑6-yl]ethanone, (4-isopropoxy‑3- methoxy-phenyl)‑[2-methyl‑6‑(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine‑1,4’-piperidine]‑1’-yl]metha- none, 2,2,2-trifluoro‑1‑[1’‑(5-isopentyloxypyridine‑2-carbonyl)‑2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyra- zine‑1,4’-piperidine]‑6-yl]ethanone, 1‑[(3S)‑2,3-dimethyl‑1’‑[4‑(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4-di- hydropyrrolo[1,2-a]pyrazine‑1,4’-piperidine]‑6-yl]‑2,2,2-trifluoro-ethanone, [8-fluoro‑2-methyl‑6‑(trifluoromethyl) spiro|3,4-dihydropyrrolo[1,2-a]pyrazine‑1,4’-piperidine]‑1’-yl]‑[3-methoxy‑4‑[(1R)‑1-methylpropoxy]phenyl]metha- none, 2,2,2-trifluoro‑1‑[1’‑(5-isopropoxy‑6-methyl-pyridine‑2-carbonyl)‑2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a] pyrazine‑1,4’-piperidine]‑6-yl]ethanone, 1‑[1’‑[4-methoxy‑3‑(trifluoromethyl)benzoyl]‑2-methyl-spiro[3,4-dihydro- pyrrolo[1,2-a]pyrazine‑1,4’-piperidine]‑6-yl]‑2,2-dimethyl-propan‑1-one, (4-isopropoxy‑3-methyl-phenyl)‑[2- methyl‑6‑(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine‑1,4’-piperidine]‑1’-yl]methanone, [2-methyl‑6‑(1- methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine‑1,4’-piperidine]‑1’-yl]‑[4‑(3,3,3-trifluoropro- poxymethyl)phenyl]methanone, 4-bromo-N‑(4-bromophenyl)‑3‑[(1-methyl‑2-oxo‑4-piperidyl)sulfamoyl]benzamide or (3-chloro‑4-isopropoxy-phenyl)‑[2-methyl‑6‑(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyra- zine‑1,4’-piperidine]‑1’-yl]methanone. (39) a NaV1.8 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 / 261114, WO2020 / 140959, WO2020 / 151728, WO2021 / 032074, CN112390745, CN111808019, CN112225695, CN112457294, CN112300051, CN112300069, CN112441969, and CN112479996 (WO2021 / 047622), the entire contents of each application hereby incorporated by reference; (39a) a NaV1.8 blocker such as 4,5-dichloro‑2‑(4-fluoro‑2-methoxyphenoxy)‑N‑(2-oxo‑1,2-dihydropyridin‑4-yl)ben- zamide, 2‑(4-fluoro‑2-methoxyphenoxy)‑N‑(2-oxo‑1,2-dihydropyridin‑4-yl)‑4‑(perfluoroethyl)benzamide, 4,5-di- chloro‑2‑(4-fluorophenoxy)‑N‑(2-oxo‑1,2-dihydropyridin‑4-yl)benzamide, 4,5-dichloro‑2‑(3-fluoro‑4-methoxyphe- noxy)‑N‑(2-oxo‑1,2-dihydropyridin‑4-yl)benzamide, 2‑(4-fluoro‑2-methoxyphenoxy)‑N‑(2-oxo‑1,2-dihydropyri- din‑4-yl)‑5‑(trifluoromethyl)benzamide, N‑(2-oxo‑1,2-dihydropyridin‑4-yl)‑2‑(4‑(trifluoromethoxy)phenoxy)‑4‑(tri- fluoromethyl)benzamide, 2‑(4-fluorophenoxy)‑N‑(2-oxo‑1,2-dihydropyridin‑4-yl)‑4‑(perfluoroethyl)benzamide, 5- chloro‑2‑(4-fluoro‑2-methoxyphenoxy)‑N‑(2-oxo‑1,2-dihydropyridin‑4-yl)benzamide, N‑(2-oxo‑1,2-dihydropyri- din‑4-yl)‑2‑(4‑(trifluoromethoxy)phenoxy)‑5‑(trifluoromethyl)benzamide, 2‑(4-fluoro‑2-methylphenoxy)‑N‑(2- oxo‑1,2-dihydropyridin‑4-yl)‑5‑(trifluoromethyl)benzamide, 2‑(2-chloro‑4-fluorophenoxy)‑N‑(2-oxo‑1,2-dihydropyri- din‑4-yl)‑5‑(trifluoromethyl)benzamide, 5-chloro‑2‑(4-fluoro‑2-methylphenoxy)‑N‑(2-oxo‑1,2-dihydropyridin‑4-yl) benzamide, 4-chloro‑2‑(4-fluoro‑2-methylphenoxy)‑N‑(2-oxo‑1,2-dihydropyridin‑4-yl)benzamide, 5-chloro‑2‑(2- chloro‑4-fluorophenoxy)‑N‑(2-oxo‑1,2-dihydropyridin‑4-yl)benzamide, 2‑((5-fluoro‑2-hydroxybenzyl)oxy)‑N‑(2- oxo‑1,2-dihydropyridin‑4-yl)‑4‑(trifluoromethyl)benzamide, N‑(2-oxo‑1,2-dihydropyridin‑4-yl)‑2‑(o-tolyloxy)‑5‑(tri- fluoromethyl)benzamide, 2‑(2,4-difluorophenoxy)‑N‑(2-oxo‑1,2-dihydropyridin‑4-yl)‑4‑(trifluoromethyl)benzamide, N‑(2-oxo‑1,2-dihydropyridin‑4-yl)‑2‑(2‑(trifluoromethoxy)phenoxy)‑5‑(trifluoromethyl)benzamide, 2‑(4-fluorophe- noxy)‑N‑(2-oxo‑1,2-dihydropyridin‑4-yl)‑5‑(trifluoromethyl)benzamide, 2‑(4-fluoro‑2-methyl-phenoxy)‑N‑(2- oxo‑1H-pyridin‑4-yl)‑4‑(trifluoromethyl)benzamide, [4‑[[2‑(4-fluoro‑2-methyl-phenoxy)‑4‑(trifluoromethyl)benzoyl] amino]‑2-oxo‑1-pyridyl]methyl dihydrogen phosphate, 2‑(4-fluoro‑2‑(methyl-d3)phenoxy)‑N‑(2-oxo‑1,2-dihydropyr- idin‑4-yl)‑4‑(trifluoromethyl)benzamide, (4‑(2‑(4-fluoro‑2‑(methyl-d3)phenoxy)‑4‑(trifluoromethyl)benzamido)‑2-ox- opyridin‑1(2H)‑yl)methyl dihydrogen phosphate, 3‑(4-fluoro‑2-methoxyphenoxy)‑N‑(3‑(methylsulfonyl)phenyl)qui- noxaline‑2-carboxamide, 3‑(2-chloro‑4-fluorophenoxy)‑N‑(3-sulfamoylphenyl)quinoxaline‑2-carboxamide, 3‑(2- chloro‑4-methoxyphenoxy)‑N‑(3-sulfamoylphenyl)quinoxaline‑2-carboxamide, 3‑(4-chloro‑2-methoxyphenox- 49 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 y)‑N‑(3-sulfamoylphenyl)quinoxaline‑2-carboxamide, 4‑(3‑(4‑(trifluoromethoxy)phenoxy)quinoxaline‑2-carboxami- do)picolinic acid, 2‑(2,4-difluorophenoxy)‑N‑(3-sulfamoylphenyl)quinoline‑3-carboxamide, 2‑(4-fluoro‑2-methoxy- phenoxy)‑N‑(3-sulfamoylphenyl)quinoline‑3-carboxamide, 3‑(2,4-difluorophenoxy)‑N‑(3-sulfamoylphenyl)quinoxa- line‑2-carboxamide, N‑(3-sulfamoylphenyl)‑2‑(4‑(trifluoromethoxy)phenoxy)quinoline‑3-carboxamide, N‑(3-sulfa- moylphenyl)‑3‑(4‑(trifluoromethoxy)phenoxy)quinoxaline‑2-carboxamide, 3‑(4-chloro‑2-methylphenoxy)‑N‑(3-sul- famoylphenyl)quinoxaline‑2-carboxamide, 5‑(3‑(4‑(trifluoromethoxy)phenoxy)quinoxaline‑2-carboxamido)picolinic acid, 3‑(4-fluoro‑2-methoxyphenoxy)‑N‑(2-oxo‑2,3-dihydro‑1H-benzo[d]imidazol‑5-yl)quinoxaline‑2-carboxamide, 3‑(4-fluoro‑2-methoxyphenoxy)‑N‑(pyridin‑4-yl)quinoxaline‑2-carboxamide, 3‑(4-fluorophenoxy)‑N‑(3-sulfamoyl- phenyl)quinoxaline‑2-carboxamide, N‑(3-cyanophenyl)‑3‑(4-fluoro‑2-methoxyphenoxy)quinoxaline‑2-carboxa- mide, N‑(4-carbamoylphenyl)‑3‑(4-fluoro‑2-methoxyphenoxy)quinoxaline‑2-carboxamide, 4‑(3‑(4‑(trifluoro- methoxy)phenoxy)quinoxaline‑2-carboxamido)benzoic acid, N‑(4-cyanophenyl)‑3‑(4-fluoro‑2-methoxyphenoxy) quinoxaline‑2-carboxamide, 5‑(4,5-dichloro‑2‑(4-fluoro‑2-methoxyphenoxy)benzamido)picolinic acid, 5‑(2‑(2,4-di- methoxyphenoxy)‑4,6-bis(trifluoromethyl)benzamido)picolinic acid, 4‑(4,5-dichloro‑2‑(4-fluoro‑2-methoxyphenoxy) benzamido)benzoic acid, 5‑(2‑(4-fluoro‑2-methoxyphenoxy)‑4,6-bis(trifluoromethyl)benzamido)picolinic acid, 4‑(2‑(4-fluoro‑2-methoxyphenoxy)‑4‑(perfluoroethyl)benzamido)benzoic acid, 5‑(2‑(4-fluoro‑2-methoxyphenox- y)‑4‑(perfluoroethyl)benzamido)picolinic acid, 4‑(2‑(4-fluoro‑2-methylphenoxy)‑4‑(trifluoromethyl)benzamido)ben- zoic acid, 5‑(4,5-dichloro‑2‑(4-fluoro‑2-methoxyphenoxy)benzamido)picolinic acid, 4‑(2‑(2-chloro‑4-fluorophenox- y)‑4‑(perfluoroethyl)benzamido)benzoic acid, 4‑(2‑(4-fluoro‑2-methylphenoxy)‑4‑(perfluoroethyl)benzamido)ben- zoic acid, 4‑(4,5-dichloro‑2‑(4‑(trifluoromethoxy)phenoxy)benzamido)benzoic acid, 4‑(4,5-dichloro‑2‑(4-chloro‑2- methylphenoxy)benzamido)benzoic acid, 5‑(4‑(tert-butyl)‑2‑(4-fluoro‑2-methoxyphenoxy)benzamido)picolinic acid, 5‑(4,5-dichloro‑2‑(4‑(trifluoromethoxy)phenoxy)benzamido)picolinic acid, 4‑(4,5-dichloro‑2‑(4-fluoro‑2-methylphe- noxy)benzamido)benzoic acid, 5‑(4,5-dichloro‑2‑(2,4-dimethoxyphenoxy)benzamido)picolinic acid, 5‑(4,5-di- chloro‑2‑(2-chloro‑4-fluorophenoxy)benzamido)picolinic acid, 5‑(4,5-dichloro‑2‑(4-fluoro‑2-methylphenoxy)benza- mido)picolinic acid, 4‑(4,5-dichloro‑2‑(4-chloro‑2-methoxyphenoxy)benzamido)benzoic acid, 5‑(4,5-dichloro‑2‑(2,4- difluorophenoxy)benzamido)picolinic acid, 2‑(4-fluorophenoxy)‑N‑(3-sulfamoylphenyl)‑5‑(trifluoromethyl)benza- mide, 2‑(4-fluorophenoxy)‑N‑(3-sulfamoylphenyl)‑4‑(trifluoromethyl)benzamide, 2‑(2-chloro‑4-fluorophenox- y)‑N‑(3-sulfamoylphenyl)‑5‑(trifluoromethyl)benzamide, 2‑(4-fluorophenoxy)‑N‑(3-sulfamoylphenyl)‑4‑(trifluoro- methyl)benzamide, 2‑(2-chloro‑4-fluorophenoxy)‑N‑(3-sulfamoylphenyl)‑6‑(trifluoromethyl)benzamide, 2‑(2- chloro‑4-fluorophenoxy)‑5‑(difluoromethyl)‑N‑(3-sulfamoylphenyl)benzamide, 2‑(4-fluorophenoxy)‑4‑(perfluor- oethyl)‑N‑(3-sulfamoylphenyl)benzamide, 2‑(4-chloro‑2-methoxyphenoxy)‑4‑(perfluoroethyl)‑N‑(3-sulfamoylphe- nyl)benzamide, 2‑(4-fluoro‑2-methoxyphenoxy)‑N‑(3-sulfamoylphenyl)‑5‑(trifluoromethyl)benzamide, 5- chloro‑2‑(4-fluoro‑2-methylphenoxy)‑N‑(3-sulfamoylphenyl)benzamide, 4,5-dichloro‑2‑(4-fluoro‑2-methoxyphe- noxy)‑N‑(3-sulfamoylphenyl)benzamide, 2,4-dichloro‑6‑(4-chloro‑2-methoxyphenoxy)‑N‑(3-sulfamoylphenyl)ben- zamide, 2,4-dichloro‑6‑(4-fluoro‑2-methylphenoxy)‑N‑(3-sulfamoylphenyl)benzamide, 2‑(4-fluoro‑2-methoxyphe- noxy)‑N‑(3-sulfamoylphenyl)‑4,6-bis(trifluoromethyl)benzamide, 2‑(4-fluoro‑2-methylphenoxy)‑N‑(3-sulfamoylphe- nyl)‑4,6-bis(trifluoromethyl)benzamide, 5-chloro‑2‑(2-chloro‑4-fluorophenoxy)‑N‑(3-sulfamoylphenyl)benzamide, 2‑(4-fluoro‑2-methoxyphenoxy)‑N‑(3-sulfamoylphenyl)‑4‑(trifluoromethoxy)benzamide, 2‑(4-fluoro‑2-methoxyphe- noxy)‑N‑(3-sulfamoylphenyl)‑4‑(trifluoromethyl)benzamide, 4,5-dichloro‑2‑(4-fluorophenoxy)‑N‑(3-sulfamoylphe- nyl)benzamide, 2‑(4-fluoro‑2-methoxyphenoxy)‑4‑(perfluoroethyl)‑N‑(3-sulfamoylphenyl)benzamide, 5- fluoro‑2‑(4-fluoro‑2-methylphenoxy)‑N‑(3-sulfamoylphenyl)benzamide, 2‑(2-chloro‑4-fluorophenoxy)‑4-cyano- N‑(3-sulfamoylphenyl)benzamide, N‑(3-sulfamoylphenyl)‑2‑(4‑(trifluoromethoxy)phenoxy)‑4‑(trifluoromethyl)ben- zamide, N‑(3-carbamoyl‑4-fluoro-phenyl)‑2-fluoro‑6‑[2‑(trideuteriomethoxy)‑4‑(trifluoromethoxy)phenoxy]‑3‑(tri- fluoromethyl)benzamide, N‑(3-carbamoyl‑4-fluoro-phenyl)‑2-fluoro‑6‑[2-methoxy‑4‑(trifluoromethoxy)phenox- y]‑3‑(trifluoromethyl)benzamide, N‑(3-carbamoyl‑4-fluorophenyl)‑2-fluoro‑6‑[2‑(trideuteriomethoxy)‑4‑(trifluoro- methoxy)phenoxy]‑3‑(trifluoromethoxy)benzamide, 4‑[[2-fluoro‑6‑[2-methoxy‑4‑(trifluoromethoxy)phenoxy]‑3‑(tri- fluoromethyl)benzoyl]amino]pyridine‑2-carboxamide, 4‑[[3-chloro‑2-fluoro‑6‑[2-methoxy‑4‑(trifluoromethoxy)phe- noxy]benzoyl]amino]pyridine‑2-carboxamide, 4‑[[2-fluoro‑6‑[2‑(trideuteriomethoxy)‑4‑(trifluoromethoxy)phenox- y]‑3‑(trifluoromethyl)benzoyl]amino]pyridine‑2-carboxamide, N‑(3-carbamoyl‑4-fluoro-phenyl)‑3‑(difluoro- methyl)‑2-fluoro‑6‑[2-methoxy‑4‑(trifluoromethoxy)phenoxy]benzamide, 4‑[[2-fluoro‑6‑[2‑(trideuteriomethox- y)‑4‑(trifluoromethoxy)phenoxy]‑3‑(trifluoromethoxy)benzoyl]amino]pyridine‑2-carboxamide, N‑(3-carbamoyl‑4- fluoro-phenyl)‑6‑[2-chloro‑4‑(trifluoromethoxy)phenoxy]‑2-fluoro‑3‑(trifluoromethyl)benzamide, N‑(3-carbamoyl‑4- fluoro-phenyl)‑2-fluoro‑6‑[2-methyl‑4‑(trifluoromethoxy)phenoxy]‑3‑(trifluoromethyl)benzamide, N‑(3-carbamoyl‑4- fluoro-phenyl)‑2,3,4-trifluoro‑6‑[2-methoxy‑4‑(trifluoromethoxy)phenoxy]benzamide, N‑(2-carbamoyl‑4-pyridyl)‑3- fluoro‑5‑[2-methoxy‑4‑(trifluoromethoxy)phenoxy]‑2‑(trifluoromethyl)pyridine‑4-carboxamide, 4‑[[6‑[2‑(difluoro- methoxy)‑4‑(trifluoromethoxy)phenoxy]‑2-fluoro‑3‑(trifluoromethyl)benzoyl]amino]pyridine‑2-carboxamide, N‑(3- carbamoyl‑4-fluoro-phenyl)‑6‑[3-chloro‑4‑(trifluoromethoxy)phenoxy]‑2-fluoro‑3‑(trifluoromethyl)benzamide, N‑(3- carbamoyl‑4-fluoro-phenyl)‑2-fluoro‑6‑[4‑(trifluoromethoxy)phenoxy]‑3‑(trifluoromethyl)benzamide, N‑(4-carba- moyl‑3-fluoro-phenyl)‑2-fluoro‑6‑[2-methoxy‑4‑(trifluoromethoxy)phenoxy]‑3‑(trifluoromethyl)benzamide, 4‑[[2- 50 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 fluoro‑6‑[2‑(trideuteriomethoxy)‑4‑(trifluoromethoxy)phenoxy]‑4‑(trifluoromethyl)benzoyl]amino]pyridine‑2-carbox- amide, N‑(3-carbamoyl‑4-fluoro-phenyl)‑2-fluoro‑6‑[3-fluoro‑4‑(trifluoromethoxy)phenoxy]‑3‑(trifluoromethyl)ben- zamide, N‑(3-carbamoyl‑4-fluoro-phenyl)‑2‑[2-methoxy‑4‑(trifluoromethoxy)phenoxy]‑5‑(1,1,2,2,2-pentafluor- oethyl)benzamide, 4‑[[4‑(difluoromethoxy)‑2-fluoro‑6‑[2-methoxy‑4‑(trifluoromethoxy)phenoxy]benzoyl]amino]pyri- dine‑2-carboxamide, N‑(3-carbamoyl‑4-fluoro-phenyl)‑2-fluoro‑6‑[2-fluoro‑4‑(trifluoromethoxy)phenoxy]‑3‑(trifluor- omethyl)benzamide, 4‑[[4-cyclopropyl‑2-fluoro‑6‑[2-methoxy‑4‑(trifluoromethoxy)phenoxy]benzoyl]amino]pyri- dine‑2-carboxamide, N‑(3-carbamoyl‑4-fluoro-phenyl)‑5-fluoro‑2‑[2-methoxy‑4‑(trifluoromethoxy)phenoxy]‑4‑(tri- fluoromethyl)benzamide, 5‑[[2-fluoro‑6‑[2‑(trideuteriomethoxy)‑4‑(trifluoromethoxy)phenoxy]‑3‑(trifluoromethyl) benzoyl]amino]pyridine‑2-carboxamide, N‑(3-carbamoyl‑4-fluoro-phenyl)‑2-fluoro‑6‑(4-fluorophenoxy)‑3‑(trifluoro- methyl)benzamide, 4‑(2-fluoro‑6‑(2-methoxy‑4‑(trifluoromethoxy)phenoxy)‑3‑(trifluoromethyl)benzamido)picolina- mide, or 4‑[[2-fluoro‑6‑[3-fluoro‑2-methoxy‑4‑(trifluoromethoxy)phenoxy]‑3‑(trifluoromethyl)benzoyl]amino]pyri- dine‑2-carboxamide; (40) a combined NaV1.7 and NaV1.8 blocker, such as DSP‑2230, Lohocla201 or BL‑1021; (41) a 5-HT3 antagonist, such as ondansetron; (42) a TPRV 1 receptor agonist, such as capsaicin (NeurogesX®, Qutenza®); and the pharmaceutically acceptable salts and solvates thereof; (43) a nicotinic receptor antagonist, such as varenicline; (44) an N-type calcium channel antagonist, such as Z‑160; (45) a nerve growth factor antagonist, such as tanezumab; (46) an endopeptidase stimulant, such as senrebotase; (47) an angiotensin II antagonist, such as EMA‑401; (48) acetaminophen (including without limitation intravenous acetaminophen (e.g., Ofirmev®)); (49) bupivacaine (including without limitation bupivacaine liposome injectable suspension (e.g., Exparel®) bupiva- caine ER (Posimir), bupivacaine collagen (Xaracoll) and transdermal bupivacaine (Eladur®)); and (50) bupivacaine and meloxicam combination (e.g., HTX‑011).

[0209] In one embodiment, the additional appropriate therapeutic agents are selected from V‑116517, Pregabalin, controlled release Pregabalin, Ezogabine (Potiga®). Ketamine / amitripty line topical cream (Amiket®), AVP‑923, Per- ampanel (E‑2007), Ralfinamide, transdermal bupivacaine (Eladur®), CNV1014802, JNJ‑10234094 (Carisbamate), BMS‑954561 or ARC‑4558.

[0210] In another embodiment, 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.

[0211] In another embodiment, 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.

[0212] In another embodiment, the additional therapeutic agent is oliceridine or ropivacaine (TLC590).

[0213] In another embodiment, the additional therapeutic agent is a NaV1.7 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. In some embodiments, the additional therapeutic agent is a NaV1.7 blocker disclosed in WO2020072835. In some embodiments, the additional therapeutic agent is a NaV1.7 blocker disclosed in WO2022036297.

[0214] In another embodiment, 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™), 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.

[0215] In another embodiment, 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.

[0216] In another embodiment, 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. 51 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55

[0217] In some embodiments, 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 ther- apeutic agent is a compound disclosed in WO2014201206. In some embodiments, the additional therapeutic agent is a compounddisclosed inWO2016141035. Insomeembodiments, theadditional therapeuticagent isacompounddisclosed inWO2021252818. In someembodiments, the additional therapeutic agent is a compound disclosed inWO2021252822. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2021252820. In some embodi- ments, theadditional therapeutic agent isacompounddisclosed inWO2020072835. Insomeembodiments, theadditional therapeutic agent is a compound disclosed in WO2022036297.

[0218] In another embodiment, the additional therapeutic agent is a sodium channel inhibitor (also known as a sodium channel blocker), such as the NaV1.7 and NaV1.8 blockers identified above.

[0219] Theamount of additional therapeutic agent present in the compositions of this inventionmaybenomore than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Theamount of additional therapeutic agent in the presently disclosed compositionsmay range fromabout 10% to 100%of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0220] The compounds and salts of this invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, 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. In still another aspect, 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, polymethyldisilox- ane, polycaprolactone,polyethyleneglycol, polylactic acid, ethylenevinyl acetate, andmixtures thereof. Thecoatingsmay optionallybe further coveredbyasuitable topcoat of fluorosilicone,polysaccharides, polyethyleneglycol, phospholipidsor combinations thereof to impart controlled release characteristics in the composition.

[0221] Another aspect of the invention relates to inhibiting NaV1.8 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. The term "biological sample," as used herein, includes, without limitation, cell cultures or extracts thereof; biopsiedmaterial obtained fromamammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0222] InhibitionofNaV1.8activity in abiological sample is useful for a variety of purposes that are known tooneof skill in the art. Examples of such purposes include, but are not limited to, the study of sodium channels in biological and pathological phenomena; and the comparative evaluation of new sodium channel inhibitors. Synthesis of the Compounds of the Invention

[0223] 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. As one skilled in the art would appreciate, 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

[0224] In another aspect, the invention relates to radiolabeled analogs of the compounds of the invention. As used herein, 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.

[0225] As used herein, the term "radioisotope" refers to an isotope of an element that is known to undergo spontaneous radioactive decay. Examples of radioisotopes include 3H, 14C, 32P, 35S, 18F, 36Cl, 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).

[0226] The radiolabeled analogs can be used in a number of beneficial ways, including in various types of assays, such as substrate tissue distribution assays. For example, tritium (3H)‑ and / or carbon‑14 (14C)‑labeled compounds may be useful for various types of assays, such as substrate tissue distribution assays, due to relatively simple preparation and 52 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 excellent detectability.

[0227] In another aspect, 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.

[0228] In another aspect, 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.

[0229] In another aspect, the invention relates to methods of inhibiting voltage-gated sodium channels andmethods 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.

[0230] In another aspect, the invention relates to radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use, in accordancewith any of the embodiments described herein in connection with the compounds of the invention.

[0231] In another aspect, 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.

[0232] In another aspect, 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

[0233] 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: X2a is N, N+‑O-, or C-R2a; X3a is N or N+‑O-; X5a is N, N+‑O-, or C-R5a; X6a is N, N+‑O-, or C-R6a; Rd is (CH2)m(CHRe)n(CH2)pH; m, n, and p are each independently 0 or 1; Re is H, OH, halo, C1‑C6 alkoxy, or C1‑C6 haloalkoxy; R2a and R6a are each independently H, halo, C1‑C6 alkyl, or C1‑C6 haloalkyl; R5a is H, halo, CH2OH, C1‑C6 alkyl, or C1‑C6 haloalkyl; R4b1 and R4b2 are each independently H, C1‑C6 alkyl, C3‑C6 cycloalkyl, or C1‑C6 haloalkyl; R5b1 and R5b2 are each independently H, C1‑C6 alkyl, C3‑C6 cycloalkyl, or C1‑C6 haloalkyl; X3c is N or C-R3c; X4c is N or C-R4c; X5c is N or C-R5c; X6c is N or C-R6c; R2c is H, OH, halo, C1‑C6 alkyl, C2‑C6 alkenyl, C1‑C6 haloalkyl, C1‑C6 alkoxy, C1‑C6 haloalkoxy, or ‑L1‑L2‑(C3‑C6 cycloalkyl), wherein said cycloalkyl is optionally substituted with 1‑2 halo; 53 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 L1 is a bond or O; L2 is a bond or C1‑C6 alkylene; R3c is H, halo, C1‑C6 alkyl, or C1‑C6 haloalkyl; or X3c is C-R3c, andR2c andR3c, together with the carbon atoms to which they are attached, form a ring of formula: Z1 and Z2 are each independently O or CH2; each R is independently H or halo; R4c is H, halo, C1‑C6 alkyl, C1‑C6 haloalkyl, C1‑C6 alkoxy, or C1‑C6 haloalkoxy; R5c is H, halo, C1‑C6 alkyl, or C1‑C6 haloalkyl; and R6c is H, halo, C1‑C6 alkyl, or C1‑C6 haloalkyl; provided that no more than two of X2a, X3a, X5a, and X6a are N or N+‑O-; and provided that no more than one of X3c, X4c, X5c, and X6c is N. 2. The compound of clause 1, wherein the compound has formula (I-A) or a pharmaceutically acceptable salt thereof. 3. The compound of clause 1, wherein the compound has formula (I-A‑1) or a pharmaceutically acceptable salt thereof. 4. The compound of clause 1, wherein the compound has formula (I-B) 54 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof. 5. The compound of clause 1, wherein the compound has formula (I-B‑1) or a pharmaceutically acceptable salt thereof. 6. The compound of any one of clauses 1, 2, and 4, or a pharmaceutically acceptable salt thereof, wherein X2a is C- R2a; and R2a is H. 7. The compound of any one of clauses 1, 2, 4, and 6, or a pharmaceutically acceptable salt thereof, wherein X3a is N. 8. The compound of any one of clauses 1, 2, 4, and 6, or a pharmaceutically acceptable salt thereof, wherein X3a is N+‑O-. 9. Thecompoundof anyoneof clauses1, 2, 4, and6‑8, or apharmaceutically acceptable salt thereof,whereinX5a isN or C-R5a; and R5a is H, halo, or CH2OH. 10. The compound of clause 9, or a pharmaceutically acceptable salt thereof, wherein X5a is N. 11. The compound of clause 9, or a pharmaceutically acceptable salt thereof, wherein X5a is C-R5a; andR5a is H, F, or CH2OH. 12.Thecompoundofanyoneof clauses1, 2, 4, and6‑11,or apharmaceutically acceptable salt thereof,whereinX6a is N or C-R6a; and R6a is H. 13. The compound of clause 12, or a pharmaceutically acceptable salt thereof, wherein X6a is C-R6a; and R6a is H. 14. The compound of any one of clauses 1‑13, or a pharmaceutically acceptable salt thereof, wherein R4b1 is H or C1‑C6 alkyl. 15. The compound of clause 14, or a pharmaceutically acceptable salt thereof, wherein R4b1 is H or CH3. 16. The compound of any one of clauses 1‑15, or a pharmaceutically acceptable salt thereof, wherein R4b2 is H or 55 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 C1‑C6 alkyl. 17. The compound of clause 16, or a pharmaceutically acceptable salt thereof, wherein R4b2 is H or CH3. 18. The compound of any one of clauses 1‑17, or a pharmaceutically acceptable salt thereof, wherein R5b1 is C1‑C6 alkyl or C1‑C6 haloalkyl. 19. The compound of clause 18, or a pharmaceutically acceptable salt thereof, wherein R5b1 is CH3 or CF3. 20. The compound of any one of clauses 1‑19, or a pharmaceutically acceptable salt thereof, wherein R5b2 is C1‑C6 alkyl or C1‑C6 haloalkyl. 21. The compound of clause 20, or a pharmaceutically acceptable salt thereof, wherein R5b2 is CH3 or CF3. 22. The compound of any one of clauses 1‑21, or a pharmaceutically acceptable salt thereof, whereinR2c isOH, halo, C1‑C6 alkyl, C1‑C6 alkoxy, or C1‑C6 haloalkoxy. 23. The compound of clause 22, or a pharmaceutically acceptable salt thereof, wherein R2c is OH, Cl, CH3, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCH2CH2F, or OCH2CHF2. 24. The compound of any one of clauses 1‑23, or a pharmaceutically acceptable salt thereof, wherein X3c is N or C- R3c; and R3c is H, halo, C1‑C6 alkyl, or C1‑C6 haloalkyl. 25. The compound of clause 24, or a pharmaceutically acceptable salt thereof, wherein X3c is N. 26. The compound of clause 24, or a pharmaceutically acceptable salt thereof, wherein X3c is C-R3c; and R3c is H, F, CH3, CHF2, or CF3. 27.Thecompoundofanyoneof clauses1‑23,orapharmaceuticallyacceptable salt thereof,whereinX3c isC-R3c;and R2c and R3c, together with the carbon atoms to which they are attached, form a ring of formula: 28. The compound of clause 27, or a pharmaceutically acceptable salt thereof, wherein the ring is of formula: 29.Thecompoundofanyoneof clauses1‑28,orapharmaceuticallyacceptable salt thereof,whereinX4c isC-R4c;and R4c is H, halo, C1‑C6 haloalkyl, C1‑C6 alkoxy, or C1‑C6 haloalkoxy. 30. The compound of clause 29, or a pharmaceutically acceptable salt thereof, wherein X4c is C-R4c; and R4c is H, F, CHF2, OCH2CH3, OCHF2, OCF3. 31.Thecompoundofanyoneof clauses1‑30,orapharmaceuticallyacceptable salt thereof,whereinX5c isC-R5c;and R5c is H. 32.Thecompoundofanyoneof clauses1‑31,orapharmaceuticallyacceptable salt thereof,whereinX6c isC-R6c;and R6c is H. 33. The compound of any one of clauses 1‑32, or a pharmaceutically acceptable salt thereof, wherein Rd is (CH2)pH. 56 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 34. The compound of clause 33, or a pharmaceutically acceptable salt thereof, wherein Rd is H or CH3. 35. The compound of any one of clauses 1‑32, or a pharmaceutically acceptable salt thereof, wherein Rd is (CHRe)n (CH2)pH. 36. The compound of clause 35, or a pharmaceutically acceptable salt thereof, wherein Rd is CH2F, CH2OH, or CH(OH)CH3. 37. The compound of any one of clauses 1‑32, or a pharmaceutically acceptable salt thereof, wherein Rd is (CH2)m (CHRe)nH. 38. The compound of clause 37, or a pharmaceutically acceptable salt thereof, wherein Rd is CH2OCH3 or CH2CH2OCH3. 39. A compound selected from Table A, or a pharmaceutically acceptable salt thereof. 40. The compound of any one of clauses 1‑39 in non-salt form. 41. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of clauses 1‑39, or a pharmaceutically acceptable salt thereof, or the compound of clause 40 and one or more pharmaceutically acceptable carriers or vehicles. 42. A pharmaceutical composition comprising the compound of any one of clauses 1‑39, or a pharmaceutically acceptable salt thereof, or the compound of clause 40 and one or more pharmaceutically acceptable carriers or vehicles. 43. 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 NaV1.8. 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 compris- ingadministering to thesubject aneffectiveamount of thecompoundof anyoneof clauses1‑39, orapharmaceutically acceptable salt thereof, the compound of clause 40, or the pharmaceutical composition of clause 41 or 42. 46. The method of clause 45, where the method comprises treating or lessening the severity in the subject of neuropathic pain. 47. The method of clause 46, wherein the neuropathic pain comprises post-herpetic neuralgia. 48. The method of clause 46, wherein the 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. Themethod of clause 45, wherein themethod comprises treating or lessening the severity in the subject of acute pain. 57 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 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. 57. The method of clause 56, wherein the postsurgical pain comprises bunionectomy pain. 58. The method of clause 56, wherein the postsurgical pain comprises abdominoplasty pain. 59. The method of clause 56, wherein the postsurgical pain comprises herniorrhaphy pain. 60. Themethodof clause45,wherein themethodcomprises treatingor lessening the severity in thesubject of visceral pain. 61. The method of any one of clauses 43‑60, wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound, pharmaceutically acceptable salt, or pharmaceutical composition. 62. Use 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, as a medicament. EXAMPLES

[0234] General methods. 1H NMR spectra were obtained as solutions in an appropriate deuterated solvent such as dimethyl sulfoxide-d6 (DMSO-d6).

[0235] Compound purity, retention time, and electrospray mass spectrometry (ESI-MS) data were determined by LC / MS analysis.

[0236] LC / MSMethod: LC / MS analysis was conducted using an Acquity UPLC BEHC8 column (50× 2.1 mm, 1.7 µm particle)made byWaters (pn: 186002877)with a (2.1× 5mm, 1.7µmparticle) guard column (pn: 186003978), and a dual gradient run from2‑98%mobilephaseBover 4.45minutes.MobilephaseA=H2O(10mMammonium formatewith0.05% ammonium hydroxide). Mobile phase B = acetonitrile. Flow rate = 0.6 mL / min, injection volume = 2 µL, and column temperature = 45 °C.

[0237] X-ray powder diffraction analysis Method A: X-ray powder diffraction (XRPD) analysis was performed at room temperature in transmissionmodeusingaPANalyticalEmpyreansystemequippedwithasealed tubesourceandaPIXcel 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 Å). The powder sample was placed on a 96 well sample holderwithmylar filmand loaded into the instrument. The samplewas scanned over the range of about 5° to about 40°20 with a step size of 0.0131303° and 8.67s x 5 (wobbled omega = 0, ±1, ±2) per step.

[0238] X-ray powder diffraction analysis Method B: X-ray powder diffraction (XRPD) analysis was performed at room temperature in transmissionmodeusingaPANalyticalEmpyreansystemequippedwithasealed tubesourceandaPIXcel 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 Å). The powder sample was placed on a 96 well sample holderwithmylar filmand loaded into the instrument. The samplewas scanned over the range of about 3° to about 40°20 with a step size of 0.0131303° and 49s per step. Abbreviations

[0239] Unlessotherwise noted, orwhere the context dictates otherwise, the followingabbreviations shall be understood to have the following meanings: Abbreviation Meaning NMR Nuclear magnetic resonance ESI-MS Electrospray mass spectrometry LC / MS Liquid chromatography-mass spectrometry UPLC Ultra performance liquid chromatography HPLC / MS / MS High performance liquid chromatography / tandem mass spectrometry IS Internal standard 58 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Abbreviation Meaning HPLC High performance liquid chromatography SFC Supercritical fluid chromatography ESI Electrospray ionization g Grams mg Milligrams kg Kilograms L Liter(s) mL Milliliters µL Microliters nL Nanoliters mol Moles mmol Millimoles hr, h Hours min Minutes ms Millisecond mm Millimeters µm Micrometers nm Nanometer MHz Megahertz Hz Hertz N Normal (concentration) M Molar (concentration) mM Millimolar (concentration) µM Micromolar (concentration) ppm Parts per million % w / v Weight-volume concentration % w / w Weight-weight concentration t-BuOH Tert-butyl alcohol CDI 1,1’-Carbonyl diimidazole DAST Diethylaminosulfur trifluoride DCM Dichloromethane DCE Dichloroethane DIEA, DIPEA N, N-Diisopropyl ethyl amine DMA N,N-Dimethylacetamide DMAP N,N-Dimethylaminopyridine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DRG Dorsal root ganglia EDC.HCl Ethyl carbodiimide hydrochloride EtOH Ethanol EtOAc Ethyl acetate HATU 1‑[Bis(dimethylamino)methylene]‑1H‑1,2,3-triazolo[4,5-b]pyridinium 3-Oxide hexafluorophosphate HOBt Hydroxybenzotriazole EDCI 1-Ethyl‑3‑(3-dimethylaminopropyl)carbodiimide T3P Propylphosphonic anhydride, i.e., 2,4,6-tripropyl‑1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide KOAc Potassium acetate m‑CPBA Meta-chloroperoxybenzoic acid MeOH Methanol MTBE Methyl tert-butyl ether NaOH Sodium hydroxide 59 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Abbreviation Meaning NBS N-Bromosuccinimide NMP N-Methylpyrrolidone NMO N-Methylmorpholine N-oxide PPTS Pyridinium para-toluene sulfonate TBAB Tetra-n-butylammonium bromide TBAF Tetra-n-butylammonium fluoride TBSCl Tert-butyldimethylsilyl chloride TBSOTf Tert-butyldimethylsilyl trifluoromethanesulfonate THF Tetrahydrofuran TEA Triethylamine TFA Trifluoroacetic acid RB Round bottom (flask) RT Room temperature ca. Circa (approximately) E-VIPR Electrical stimulation voltage ion probe reader HEK Human embryonic kidney KIR2.1 Inward-rectifier potassium ion channel 2.1 DMEM Dulbecco’s Modified Eagle’s Medium FBS Fetal bovine serum NEAA Non-essential amino acids HEPES 2‑[4‑(2-Hydroxyethyl)piperazin‑1-yl]ethanesulfonic acid DiSBAC6(3) Bis‑(1,3-dihexyl-thiobarbituric acid) trimethine oxonol CC2-DMPE Chlorocoumarin‑2-dimyristoyl phosphatidylethanolamine VABSC‑1 Voltage Assay Background Suppression Compound HS Human serum BSA Bovine Serum Albumin Example 1 (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoro- methyl)tetrahydrofuran‑2-carboxamide (1), (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑N‑(6‑((S)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoro- methyl)tetrahydrofuran‑2-carboxamide (2)

[0240] 60 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 Step 1:

[0241] NEt3 (7.7mL, 55.2mmol) was added to a solution of ethyl 2-diazo‑3-oxo-pentanoate (6.69 g, 39.3mmol) inDCM (80 mL) with stirring at 0 °C under nitrogen. Trimethylsilyl trifluoromethanesulfonate (8.5 mL, 47.0 mmol) was added dropwise over 5min and themixture was stirred for a further 30min at 0 °C. The reactionmixture was dilutedwith pentane (100mL), the layers separatedand theorganic phasewashedwith dilute aqueous sodiumbicarbonate (100mL) andbrine (100 mL). The organic layer was dried (MgSO4), and concentrated in vacuo to give ethyl (Z)‑2-diazo‑3-trimethylsilyloxy- pent‑3-enoate (9.4 g, 99%)asa redoil. 1HNMR(500MHz,Chloroform-d) δ5.33 (q, J =7.0Hz, 1H), 4.25 (q, J =7.1Hz, 2H), 1.67 (d, J = 7.0 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 0.22 (s, 9H) ppm. Step 2:

[0242] To a stirred solution of 1,1,1-trifluoropropan‑2-one (8mL, 89.4mmol) in DCM (80mL) at ‑78 °C was added TiCl4 (70mLof 1M inDCM,70.00mmol) via cannula. To the resulting solution, a solution of ethyl (Z)‑2-diazo‑3-trimethylsilyloxy- pent‑3-enoate (36.1 g of 31.3 %w / w, 46.6 mmol) in DCM (40 mL) was added dropwise over 15 min. After stirring for 100 61 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 min, the reactionwas carefully quenchedwithwater, allowing the temperature to rise slowly, and then extractedwithDCM. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography (330 g SiO2, 0 to 20% EtOAc in heptane) gave ethyl rac‑(4R,5R)‑2-diazo‑6,6,6-trifluoro‑5-hydro- xy‑4,5-dimethyl‑3-oxohexanoate (8.82 g, 67%) as the main diastereoisomer, which was stored as a solution in toluene. 1HNMR (500MHz, Chloroform-d) δ 4.33 (q, J = 7.1 Hz, 2H), 4.14 (q, J = 7.0 Hz, 1H), 3.98 (s, 1H), 1.43 (q, J = 1.2 Hz, 3H), 1.35 (t, J = 7.1Hz, 3H), 1.31 (dq, J = 7.0, 1.4Hz, 3H) ppm. ESI-MSm / z calc. 282.08273, found 283.1 (M+1)+; 281.0 (M‑1)-. Step 3:

[0243] Asolutionof rhodium tetraacetate (245mg, 0.55mmol) in benzene (32mL)washeatedat reflux for 10min 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. The mixture was concentrated in vacuo to give ethyl rac-(4R,5R)‑4,5-dimethyl‑3-oxo‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxylate (9.0 g, 100%) as a green coloured residue containing residual catalyst, and as a mixture of epimers at the position next to the ester. This material was usedwithout further purification in thenext step. 1HNMR (500MHz,Chloroform-d) δ4.83 - 4.57 (m, 1H), 4.38 - 4.16 (m, 2H), 2.60 (dddd, J = 9.3, 8.2, 5.6, 1.4 Hz, 1H), 1.73 - 1.63 (m, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.24 (ddq, J = 6.4, 4.1, 1.9 Hz, 3H) ppm. Step 4:

[0244] 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. The reaction mixture was stirred for 30 min at 0 °C before being quenched with 100 mL saturated aqueous NaHCO3 solution. The organic layer was separated and aqueous layer extracted with DCM (160 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give ethyl rac‑(4R,5R)‑2,3-dimethyl‑2‑(trifluoromethyl)‑4‑(trifluoromethylsulfonyloxy)‑3H-furan‑5-carboxylate (71 g, 97%). 1HNMR (400 MHz, Chloroform-d) δ 4.38 - 4.32 (m, 2H), 3.29 - 3.23 (m, 1H), 1.64 (s, 3H), 1.37 - 1.33 (m, 6H) ppm. Step 5:

[0245] To stirred a solution of ethyl rac‑(4R,5R)‑2,3-dimethyl‑2‑(trifluoromethyl)‑4‑(trifluoromethylsulfonyloxy)‑3H-fur- an‑5-carboxylate (26 g, 67.311mmol) in toluene (130.00mL)was added (3,4-difluoro‑2-methoxy-phenyl)boronic acid (14 g, 74.5mmol) followed by K3PO4 (100mL of 2M, 200.00mmol) 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 100mL). The combined organic layers were concentrated in vacuo. Purification by silica gel chromatography (SiO2, 0 to 10%EtOAc in heptane) gave ethyl 4‑(3,4-difluoro‑2-methoxyphenyl)‑2,3-dimethyl‑2‑(trifluoromethyl)‑3H-furan‑5-carboxylate (24.4 g, 93%) as a 6:1 diastereomeric mixture, with the major isomer believed to be ethyl rac‑(4S,5R)‑4‑(3,4-difluoro‑2-methox- yphenyl)‑2,3-dimethyl‑2‑(trifluoromethyl)‑3H-furan‑5-carboxylate. Major isomer: 1H NMR (400 MHz, Chloroform-d) δ 6.88 - 6.79 (m, 2H), 4.17 - 4.09 (m, 2H), 3.90 (s, 3H), 3.46 (q, J =7.4Hz, 1H), 1.67 (s, 3H), 1.12 (t, J = 7.4Hz, 3H), 1.06 (dd, J = 5.4, 2.7 Hz, 3H) ppm.Minor isomer: 1HNMR (400MHz, Chloroform-d) δ 6.88 - 6.79 (m, 2H), 4.17 - 4.09 (m, 2H), 3.88 (s, 3H), 3.76 - 3.71 (m,1H), 1.51 (s, 3H), 1.12 (t, J =7.4Hz, 3H), 0.99 (dd, J=5.4, 2.7Hz, 3H)ppm.ESI-MSm / z calc. 380.1047, found 381.02 (M+1)+. Step 6:

[0246] To an ice-cooled solution of ethyl rac‑(4S,5R)‑4‑(3,4-difluoro‑2-methoxyphenyl)‑2,3-dimethyl‑2‑(trifluoro- methyl)‑3H-furan‑5-carboxylate (110 g, 243.0 mmol) in DCM (360 mL) was added BBr3 (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 (MgSO4), filtered and concentrated in vacuo.The residuewasdissolved inDCM(430mL) at ambient temperature andTFA (40mL, 519.2mmol) was added. The reaction was heated to 45 °C. Upon reaction completion, the mixture was quenched by addition of aqueous sodium bicarbonate solution and the aqueous layer extracted with DCM, dried (MgSO4), filtered and concen- trated in vacuo to give the desired product in a 5:1 mixture of diastereomers. Recrystallization was carried out by solubilizing the crudematerial in the smallest possible amount of DCMandadding a layer of heptane on top of this solution (liquid-liquid diffusion). After approximately 1 h, 56.5 g (d.r. 97:3 syn:anti) from the first and second crystallization was obtained, and a further 4.6 g (d.r. 96:4 syn:anti) from the third crystallization was obtained. The first to third batches were 62 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 combined to give 6,7-difluoro‑1,2-dimethyl‑2‑(trifluoromethyl)‑1H-furo[2,3-c]chromen‑4-one (61 g, 78%), with the major isomer believed to be rac‑(1S,2R)‑6,7-difluoro‑1,2-dimethyl‑2‑(trifluoromethyl)‑1,2-dihydro‑4H-furo[2,3‑c]chromen‑4- one. ESI-MS m / z calc. 320.04718, found 321.5 (M+1)+; 319.6 (M‑1)-. Step 7:

[0247] rac‑(1S,2R)‑6,7-difluoro‑1,2-dimethyl‑2‑(trifluoromethyl)‑1,2-dihydro‑4H-furo[2,3-c]chromen‑4-one (1348 g, 4.366 mol) was separated by chiral SFC using a (R,R)‑Whelk-O1 column, 5 µm particle size, 15 cm x 3 cm from Regis Technologies on a MultiGram III SFC instrument from Berger Instruments using a mobile phase made up of MeOH (containing 5 mM ammonia) and CO2 to give: First Eluting Isomers (rt = 1.85 min): (1R,2S)‑6,7-difluoro‑1,2-dimethyl‑2‑(trifluoromethyl)‑1,2-dihydro‑4H-furo[2,3‑c] chromen‑4-one (only an analytical sample was collected). 1HNMR (400MHz, DMSO-d6) δ 7.57 (ddd, J = 9.0, 5.5, 2.0 Hz, 1H),7.51 (ddd, J=10.3, 9.0, 7.0Hz,1H),4.03 (q, J=7.2Hz,1H), 1.65 (s, 3H), 1.45 (dt, J=6.9,2.2Hz,3H)ppm.ESI-MSm / z calc. 320.04718, found 321.3 (M+1)+; 319.4 (M‑1)-.

[0248] Second Eluting Isomer (rt = 2.38 min): (1S,2R)‑6,7-Difluoro‑1,2-dimethyl‑2‑(trifluoromethyl)‑1,2-dihydro‑4H- furo[2,3‑c]chromen‑4-one (366.99 g, 26%). 1HNMR (400MHz,DMSO-d6) δ 7.57 (ddd, J = 9.0, 5.5, 2.0Hz, 1H), 7.50 (ddd, J = 10.3, 9.0, 7.0 Hz, 1H), 4.03 (q, J = 7.2 Hz, 1H), 1.65 (s, 3H), 1.45 (dt, J = 6.9, 2.2 Hz, 3H) ppm. ESI-MS m / z calc. 320.04518, found 321.4 (M+1)+; 319.4 (M‑1)-. Step 8:

[0249] 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. The hydrogenation was continued for a total of 48 h. The mixture was filtered through celite, washing with MeOH (20 L) and the filtrates were concentrated in vacuo. The residue was dissolved in toluene (4L)andconcentrated in vacuo,and thisprocess repeated.The residuewasdriedundervacuumat40 °C overnight to give methyl (2S,3S,4S,5R)‑3‑(3,4-difluoro‑2-hydroxyphenyl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydro- furan‑2-carboxylate (1.0 kgat 91%purity, 100%)asabeigesolid. 1HNMR(400MHz,DMSO-d6) 10.20 (br s, 1H), 6.94 (br t, J = 7.4Hz, 1H), 6.79‑6.69 (m, 1H), 5.10 (d, J =6.0Hz, 1H), 4.20 (dd, J =6.1, 8.2Hz, 1H), 3.43 (s, 3H), 2.94 (quin, J = 7.7Hz, 1H), 1.46 (s, 3H), 0.77 (br d, J = 6.8 Hz, 3H) ppm. Step 9:

[0250] 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, 2.82mol) in acetonitrile (10 L) under nitrogen stirring at ambient temperature. After stirring overnight, additional iodomethane (120mL, 2mmol) wasadded. After stirring overnight, additional iodomethane (60mL, 0.85mmol) wasadded and themixturewas stirred for a further 3 days. The reactionmixturewasdilutedwithMTBE (30L), treatedwith celite (1 kg) and filtered through a bed of celite (1 kg) washing with MTBE (10 L). The filtrate was filtered a second time through celite (1 kg) washing withMTBE (4 L) and the filtrate concentrated in vacuo. The residuewas dissolved in toluene (4L) andconcentrated in vacuo,and this process repeated. The residuewasdriedunder vacuumat40 °Covernight togive methyl (2S,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxylate (0.99 kg at 90% purity, 95%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) 7.14‑7.00 (m, 2H), 5.14 (d, J = 6.0 Hz, 1H), 4.15 (dd, J=6.2, 8.4Hz, 1H), 3.88 (d, J =1.7Hz, 3H), 2.97 (quin, J =7.8Hz, 1H), 1.48 (s, 3H), 0.72 (br d, J =6.6Hz, 3H) ppm. Steps 10 and 11:

[0251] Sodiummethoxide (25% inmethanol, 65mL, 0.28mol) was added to a solution ofmethyl (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. The reaction mixture was poured into 1MHCl (4.4 L, 4.4mol) then extractedwithMTBE (20L). Theaqueous layerwas further extractedwithMTBE (2 x 5 L), and the combined organic layerswerewashedwith brine (2 L), dried (Na2SO4), filtered, and then treatedwith activated carbon (50 g, 5%w / w)with stirring for 1 h. Themixturewas filtered through celite, washingwithMTBE (2 x 4 L), and the filtratewas concentrated in vacuo.The residuewasdissolved in toluene (4L) andconcentrated in vacuo, thendissolved inMTBE (4L) and concentrated in vacuo again to give (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑4,5-dimethyl‑5‑(trifluoro- 63 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 methyl)tetrahydrofuran‑2-carboxylic acid (1.06 kg at 77.7% purity) as an amber oil, which was used without further purification. Step 12:

[0252] Crude (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-car- boxylic acid (2.09 kg at 77%purity, 4.54mol) was dissolved inMTBE (25 L) in a 100 LChemglass 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, followedbyadditionalMTBE togivea total volumeof 30L in the reactor.After 2h, additionalMTBE (2L)wasadded to the reaction.After a total of 3.5h, themixturewasfiltered,washingwithMTBE (2L).The reactorwas rinsedwithMTBE(4 L), which was used to rinse the solids, which were then compressed and dried on the Büchner funnel for 2 h. The solid product cakewas loosened then dried under a streamof nitrogenandunder vacuumovernight on theBüchner funnel. The isolated solids were dried in a convection oven at 40 °C for 24 h to give (2R,3S,4S,5R)‑3‑(3,4-Difluoro‑2-methoxyphe- nyl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxylic acid (R)‑1-phenylethan‑1-amine salt (1.86 kg at 95.7% purity, 74%over 3 steps) as an off-white solid. 1HNMR, 400MHz, DMSO-d6) 8.34 (br s, 2H), 7.46‑7.41 (m, 2H), 7.36‑7.27 (m, 3H), 7.16‑7.11 (m, 1H), 7.10‑7.03 (m, 1H), 4.58 (d, J=9.9Hz, 1H), 4.23 (q, J=6.7Hz, 1H), 3.99 (dd, J=7.8, 9.8Hz, 1H), 3.90 (d, J = 2.0 Hz, 3H), 2.60 (quin, J = 7.5 Hz, 1H), 1.50 (s, 3H), 1.40 (d, J = 6.7 Hz, 3H), 0.71‑0.59 (m, 3H) ppm. Step 13:

[0253] To a suspension of (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxy-phenyl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahy- drofuran‑2-carboxylic acid (1R)‑1-phenylethanamine salt (10.6 g, 22.29mmol) inMTBE (250mL)wasaddedHCl (200mL of 2 M, 400.0 mmol). The layers were separated, and the organic layer was washed with water (200 mL), dried (MgSO4), filtered, and concentrated in vacuo to give (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxy-phenyl)‑4,5-dimethyl‑5‑(trifluoro- methyl)tetrahydrofuran‑2-carboxylic acid (8.4 g, 99%)asanoil. 1HNMR (400MHz,Chloroform-d) δ6.96 (ddd, J =7.9, 5.6, 2.0 Hz, 1H), 6.88 (td, J = 9.2, 7.3 Hz, 1H), 4.96 (d, J = 10.5 Hz, 1H), 4.15 (dd, J = 10.5, 8.0 Hz, 1H), 4.02 (d, J = 2.8 Hz, 3H), 2.74 (p, J = 7.6 Hz, 1H), 1.64 (t, J = 1.2 Hz, 3H), 0.79 (dq, J = 7.4, 2.3 Hz, 3H) ppm. Steps 14 and 15:

[0254] Oxalyl chloride (738 µL, 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, 4.234mmol) and DMF (31µL, 0.4004mmol) in dichloromethane (10mL). After stirring for 30min at ambient temperature, the solutionwas concentrated in vacuo.The residuewas re-dissolved in dichloromethane (10mL), and amixture of rac‑6‑(2,2-Dimethyl‑1,3-dioxolan‑4- yl)pyridin‑3-amine (904mg, 4.654mmol) and triethylamine (706µL, 5.065mmol) was. Themixturewas stirred at ambient temperature for 1h. The reactionmixture was partitioned between ethyl acetate (30mL) and water (30mL). The aqueous layer was further extracted with EtOAc (50mL). The combined organic extracts were washed with brine (1 x 20mL), dried (MgSO4), filtered, and concentrated in vacuo. Purification by reverse phase preparative HPLC (Waters Sunfire C18, 10 µM, 100 Å column, 0% to 100% MeCN in water containing 0.1% ammonia) gave after freeze-drying a mixture of the 2 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.

[0255] The mixture of the 2 diastereoisomers of (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑N‑(6‑(2,2-di- methyl‑1,3-dioxolan‑4-yl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide was separated by chiral SFC using a Chiralcel OJ-H column, 5 µm particle size, 25 cm x 10 mm from Daicel (Mobile phase: 12 % MeOH (containing 20 mM Ammonia), 88 % CO2. Flow: 10 mL / min.) on a Minigram SFC instrument from Berger Instruments: First Eluting Isomer (rt = 2.99 min): (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑N‑(6‑((R)‑2,2-dimethyl‑1,3-di- oxolan‑4-yl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (700 mg, 60%). ESI-MS m / z calc. 530.184, found 531.2 (M+1)+; Retention time: 3.56 minutes.

[0256] Second Eluting Isomer (rt = 3.63 min): (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑N‑(6‑((S)‑2,2-di- methyl‑1,3-dioxolan‑4-yl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (700 mg, 60%). ESI-MS m / z calc. 530.184, found 531.2 (M+1)+; Retention time: 3.56 minutes. Step 16:

[0257] TFA (1.743 mL, 22.62 mmol) was added to a solution of (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(6‑((R)‑2,2-dimethyl‑1,3-dioxolan‑4-yl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (600 mg, 1.112 mmol) (First Eluting Isomer from SFC separation) in DCM (20 mL) and the mixture stirred for 2 h at 64 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 ambient temperature. Themixturewasconcentrated in vacuoand freeze-dried fromMeCNandwater to give awhite solid. Purification by reverse phase preparative HPLC (Waters Sunfire C18, 10 µM, 100 Å column, 0% to 100%MeCN in water containing 0.1% ammonia) gave after freeze-drying (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑N‑(6‑((R)‑1,2-di- hydroxyethyl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (1, 304 mg, 55%). 1H NMR (500 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.73 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.23 - 7.13 (m, 2H), 5.11 (d, J =10.3Hz, 1H), 4.61 (s, 1H), 4.25 (dd, J =10.3, 7.6Hz, 1H), 3.95 (d, J = 2.1Hz, 3H), 3.63 (dd, J= 11.0, 4.4Hz, 2H), 3.48 (dd, J = 11.0, 6.5 Hz, 2H), 2.77 (p, J = 7.6 Hz, 1H), 1.61 (s, 3H), 0.79 - 0.69 (m, 3H) ppm. ESI-MS m / z calc. 490.1527, found 491.6 (M+1)+; Retention time: 2.98 minutes.

[0258] (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑N‑(6‑((,S)‑2,2-dimethyl‑1,3-dioxolan‑4-yl)pyridin‑3-yl)‑4,5- dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (600 mg, 1.106 mmol) (Second Eluting Isomer from SFC separation) was treated in the same way to give after freeze-drying (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(6‑((S)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (2, 340 mg, 61%). 1H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.67 (dd, J = 2.5, 0.7 Hz, 1H), 7.98 (dd, J = 8.5, 2.6 Hz, 1H), 7.43 (d, J = 8.5Hz, 1H), 7.17 (dd, J = 9.4, 6.3 Hz, 2H), 5.32 (d, J = 4.9 Hz, 1H), 5.09 (d, J = 10.3 Hz, 1H), 4.63 (t, J = 5.9 Hz, 1H), 4.54 (dt, J=6.7, 4.4Hz, 1H), 4.24 (dd, J=10.3, 7.7Hz, 1H), 3.95 (d, J =2.1Hz, 3H), 3.63 (ddd, J=11.0, 6.0, 4.1Hz, 1H), 3.45 (ddd, J = 11.0, 6.9, 5.8 Hz, 1H), 2.77 (p, J = 7.5 Hz, 1H), 1.61 (s, 3H), 0.82 - 0.65 (m, 3H) ppm. ESI-MSm / z calc. 490.1527, found 491.6 (M+1)+; Retention time: 2.99 minutes.

[0259] The absolute stereochemistry of 1 and 2 was determined by single-crystal X-ray crystallography analysis of 1.

[0260] Compound1wasanalyzedbyX-raypowder diffraction analysisMethodAanddetermined tobeamorphous (see Fig. 1).

[0261] 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-dioxo- lan‑4-yl)pyridin‑3-amine in the amide coupling step 14. In step 15, purification was performed by chiral SFC using a ChiralcelOD-Hcolumn,5µmparticle size, 25cmx10mmfromDaicelCorporation (Mobile phase:12%MeOH(containing 20 mM Ammonia), 88 % CO2. Flow: 10 mL / min.) on a Minigram SFC instrument from Berger Instruments: Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 3 rel‑(2R*,3S*,4S*,5R*)‑3‑(3,4-di- fluoro‑2-methoxyphe- nyl)‑N‑(6‑((1R,2R)‑1,2-dihydroxypro- pyl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(tri- fluoromethyl)tetrahydrofura n‑2-car- boxamide ESI-MS m / z calc. 1H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.68 (d, J = 2.2 Hz, 1H), 7.97 (dd, J = 8.5, 2.5 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.20 - 7.13 (m, 2H), 5.20 (d, J = 5.3 Hz, 1H), 5.09 (d, J = 10.3 Hz, 1H), 4.46 (d, J = 5.5 Hz, 1H), 4.30 (t, J = 5.2 Hz, 1H), 4.25 (dd, J = 10.1, 7.8 Hz, 1H), 3.95 (d, J = 2.1 Hz, 3H), 3.81 - 3.75 (m, 1H), 2.77 (p, J = 7.2 Hz, 1H), 1.61 (s, 3H), 0.94 (d, J = 6.4 Hz, 3H), 0.74 (d, J = 7.3 Hz, 3H) ppm. 504.16837, found 505.0 (M+1)+; 503.1 (M‑1)-; Retention time: 3.08 minutes (Precursor was the first eluting peak by SFC on Chiralcel OD-H column, rt = 4.36 min) 4 rel‑(2R*,3S*,4S*,5R*)‑3‑(3,4-di- fluoro‑2-methoxyphe- nyl)‑N‑(6‑((1S,2S)‑1,2-dihydroxypro- pyl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(tri- fluoromethyl)tetrahydrofura n‑2-car- boxamide ESI-MS m / z calc. 1H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.65 (d, J = 2.5 Hz, 1H), 7.99 (dd, J = 8.6, 2.5 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.20 - 7.13 (m, 2H), 5.20 (d, J = 5.3 Hz, 1H), 5.09 (d, J = 10.3 Hz, 1H), 4.45 (d, J = 5.5 Hz, 1H), 4.30 (t, J = 5.2 Hz, 1H), 4.25 (dd, J = 10.4, 7.6 Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 3.81 - 3.75 (m, 1H), 2.80 - 2.73 (m, 1H), 1.61 (s, 3H), 0.94 (d, J = 6.4 Hz, 3H), 0.73 (d, J = 6.5 Hz, 3H) ppm. 504.16837, found 505.0 (M+1)+; 503.1 (M‑1)-; Retention time: 3.08 minutes (Precursor was the second eluting peak by SFC on Chiralcel OD-H col- umn, rt = 5.28 min)

[0262] The following compound was made using the method described in Example 1, except that (1R,2S)‑6,7- difluoro‑1,2-dimethyl‑2‑(trifluoromethyl)‑1,2-dihydro‑4H-furo[2,3‑c]chromen‑4-one was used in place of (1S,2R)‑6,7- Difluoro‑1,2-dimethyl‑2‑(trifluoromethyl)‑1,2-dihydro‑4H-furo[2,3-c]chromen‑4-one in the hydrogenation step 8 and (S)‑6‑(2,2-dimethyl‑1,3-dioxolan‑4-yl)pyridin‑3-amine was used as the coupling partner in step 14. The SFC separation 65 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 step 15 was not required: Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 5 (2S,3R,4R,5S)‑3‑(3,4-difluoro‑2- methoxyphenyl)‑N‑(6‑((S)‑1,2-di- hydroxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahy- drofura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.65 (dd, J = 2.5, 0.7 Hz, 1H), 8.00 (dd, J = 8.6, 2.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.17 (dd, J = 8.6, 5.2 Hz, 2H), 5.33 (d, J = 4.9 Hz, 1H), 5.10 (d, J = 10.3 Hz, 1H), 4.63 (t, J = 5.9 Hz, 1H), 4.54 (dt, J = 6.9, 4.5 Hz, 1H), 4.24 (dd, J = 10.3, 7.6 Hz, 1H), 3.95 (d, J = 2.2 Hz, 3H), 3.63 (ddd, J = 10.9, 6.0, 4.1 Hz, 1H), 3.44 (ddd, J = 10.9, 6.8, 5.8 Hz, 1H), 2.77 (t, J = 7.5 Hz, 1H), 1.61 (s, 3H), 0.80 - 0.68 (m, 3H) ppm. 490.1527, found 491.2 (M+1)+; 489.2 (M‑1)-; Retention time: 2.97 minutes

[0263] The following compounds were made using the method described in Example 1, except that ethyl iodide was used in place ofmethyl iodide in the alkylation step 9. The conditions used for the epimerization / hydrolysis steps 10 and11 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 part- ner for compounds 6 and 7. The SFC separation step 15 was not required: Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 6 (2R,3S,4S,5R)‑N‑(6‑((S)‑1,2-dihy- droxyethyl)pyridin‑3-yl)‑3‑(2- ethoxy‑3,4-difluorophenyl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahy- drofura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.65 (s, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.16 (dd, J = 8.5, 4.6 Hz, 2H), 5.31 (s, 1H), 5.08 (d, J = 10.6 Hz, 1H), 4.62 (t, J = 5.7 Hz, 1H), 4.53 (s, 1H), 4.27 (dd, J = 10.5, 7.5 Hz, 1H), 4.24 - 4.09 (m, 2H), 3.62 (s, 1H), 3.44 (d, J = 9.8 Hz, 1H), 2.74 (p, J = 7.4 Hz, 1H), 1.60 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H), 0.73 (d, J = 7.3 Hz, 3H) ppm. 504.16837, found 505.4 (M+1)+; 503.5 (M‑1)-; Retention time: 3.12 minutes 7 (2R,3S,4S,5R)‑N‑(6‑((R)‑1,2-dihy- droxyethyl)pyridin‑3-yl)‑3‑(2- ethoxy‑3,4-difluorophenyl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahy- drofura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.63 (dd, J = 2.5, 0.8 Hz, 1H), 7.99 (dd, J = 8.5, 2.6 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.21 - 7.08 (m, 2H), 5.31 (d, J = 4.9 Hz, 1H), 5.08 (d, J = 10.5 Hz, 1H), 4.62 (t, J = 5.9 Hz, 1H), 4.53 (dt, J = 6.8, 4.5 Hz, 1H), 4.27 (dd, J = 10.5, 7.5 Hz, 1H), 4.24 - 4.08 (m, 2H), 3.62 (ddd, J = 10.9, 6.0, 4.1 Hz, 1H), 3.44 (ddd, J = 11.0, 6.8, 5.8 Hz, 1H), 2.74 (p, J = 7.5 Hz, 1H), 1.60 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H), 0.77 - 0.67 (m, 3H) ppm. 504.16837, found 505.4 (M+1)+; 503.5 (M‑1)-; Retention time: 3.11 minutes

[0264] Compound7wasanalyzedbyX-raypowder diffraction analysisMethodBanddetermined tobeamorphous (see Fig. 2).

[0265] The following compound was made using a method similar to that described in Example 1 except that iodomethane-d3 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: 66 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 8 (2R,3S,4S,5R)‑3‑(3,4-difluor- o‑2‑(methoxy-d3)phenyl)‑N‑(6‑((R)‑1,2- dihydroxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.65 (dd, J = 2.6, 0.7 Hz, 1H), 8.00 (dd, J = 8.5, 2.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.18 - 7.13 (m, 2H), 5.32 (d, J = 4.9 Hz, 1H), 5.09 (d, J = 10.3 Hz, 1H), 4.62 (t, J = 5.9 Hz, 1H), 4.54 (dt, J = 6.8, 4.5 Hz, 1H), 4.24 (dd, J = 10.3, 7.6 Hz, 1H), 3.63 (ddd, J = 11.0, 6.1, 4.2 Hz, 1H), 3.48 - 3.42 (m, 1H), 2.77 (t, J = 7.5 Hz, 1H), 1.61 (s, 3H), 0.76 - 0.71 (m, 3H) ppm. 493.17154, found 494.3 (M+1)+; 492.3 (M‑1)-; Retention time: 2.99 minutes

[0266] Compound8wasanalyzedbyX-raypowder diffraction analysisMethodBanddetermined tobeamorphous (see Fig. 3).

[0267] The following compoundsweremade using themethod described in Example 1, except that 2-iodopropanewas used inplaceofmethyl iodide instep9and the reactionwascarriedoutat 75 °C.Theepimerization / hydrolysis steps10and 11werecarriedout inonestep following theconditionsdescribed inExample6step3.Steps12and13wereomittedand, in theamidecoupling step14, 2‑(2,2-dimethyl‑1,3-dioxolan‑4-yl)pyrimidin‑5-aminewasusedas thecouplingpartner. In 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 20mMAmmonia), 80%CO2. Flow: 100mL / min.) on aMinigramSFC instrument from Berger Instruments: Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 9 rel‑(2R*,3S*,4S*,5R*)‑3‑(3,4-di- fluoro‑2-isopropoxyphenyl)‑N‑(2‑(1,2- dihydroxyethyl)pyrimidin‑5-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydro- fura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (400 MHz, Methanol-d4) δ 9.02 (s, 2H), 7.14 (ddd, J = 8.4, 5.6, 2.1 Hz, 1H), 6.97 (ddd, J = 9.9, 8.9, 7.5 Hz, 1H), 5.08 (d, J = 10.7 Hz, 1H), 4.78 (dd, J = 6.0, 4.6 Hz, 1H), 4.66 (pd, J = 6.1, 1.2 Hz, 1H), 4.37 (dd, J = 10.7, 7.9 Hz, 1H), 3.94 - 3.78 (m, 2H), 2.78 (p, J = 7.6 Hz, 1H), 1.67 (d, J = 1.2 Hz, 3H), 1.40 (dd, J = 6.2, 1.0 Hz, 3H), 1.25 (d, J = 6.1Hz, 3H), 0.79 (dt, J = 7.4, 2.3 Hz, 3H) ppm; alcohols OH and amide NH not observed. 519.17926, found 520.3 (M+1)+; 518.2 (M‑1)-; Retention time: 3.2 minutes (Precursor was the first eluting peak by SFC on Chiralpak IB column, rt = 0.80 min) 10 rel-(2R*,3S*,4S*,5R*)‑3‑(3,4-di- fluoro‑2-isopropoxyphenyl)‑N‑(2‑(1,2- dihydroxyethyl)pyrimidin‑5-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydro- fura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (400 MHz, Methanol-d4) δ 9.02 (s, 2H), 7.14 (ddd, J = 8.3, 5.6, 2.1 Hz, 1H), 6.97 (ddd, J = 9.9, 8.9, 7.6 Hz, 1H), 5.08 (d, J = 10.7 Hz, 1H), 4.78 (dd, J = 6.0, 4.6 Hz, 1H), 4.66 (pd, J = 6.2, 1.3 Hz, 1H), 4.37 (dd, J = 10.7, 7.9 Hz, 1H), 3.94 - 3.77 (m, 2H), 2.78 (p, J = 7.6 Hz, 1H), 1.67 (d, J = 1.1 Hz, 3H), 1.40 (dd, J = 6.1, 0.9 Hz, 3H), 1.25 (d, J = 6.1Hz, 3H), 0.80 (dt, J = 7.6, 2.3 Hz, 3H) ppm; alcohols OH and amide NH not observed. 519.17926, found 520.3 (M+1)+; 518.2 (M‑1)-; Retention time: 3.19 minutes (Precursor was the second eluting peak by SFC on Chiralpak IB column, rt = 0.95 min)

[0268] 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 couplingpartner. In step15, purificationwasperformedbychiralSFCusingaChiralcelOD-Hcolumn, 5umparticle size, 25 67 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 cm x 10 mm from Daicel Corporation (Mobile phase: 22 % MeOH (containing 20 mM Ammonia), 78 % CO2. Flow: 10 mL / min.) on a Minigram SFC instrument from Berger Instruments: Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 11 rel‑(2R*,3S*,4S*,5R*)‑3‑(3,4-difluoro‑2- methoxyphenyl)‑N‑(2‑(1,2-dihydrox- yethyl)pyrimidin‑5-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (500 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.99 (s, 2H), 7.19 - 7.16 (m, 2H), 5.17 (d, J = 6.0 Hz, 1H), 5.14 (d, J = 10.4 Hz, 1H), 4.59 (dt, J = 12.6, 6.0 Hz, 2H), 4.25 (dd, J = 10.3, 7.7 Hz, 1H), 3.95 (d, J = 2.1 Hz, 3H), 3.71 (dt, J = 11.5, 6.0 Hz, 1H), 3.65 - 3.61 (m, 1H), 2.80 - 2.75 (m, 1H), 1.62 (s, 3H), 0.74 (d, J = 7.4 Hz, 3H) ppm. 491.14795, found 492.0 (M+1)+; 490.1 (M‑1)-; Retention time: 2.94 minutes (Precursor was the first eluting peak by SFC on Chiralcel OD-H column, rt = 2.91 min) 12 rel‑(2R*,3S*,4S*,5R*)‑3‑(3,4-difluoro‑2- methoxyphenyl)‑N‑(2‑(1,2-dihydrox- yethyl)pyrimidin‑5-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (500 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.99 (s, 2H), 7.19 - 7.14 (m, 2H), 5.17 (br s, 1H), 5.15 (d, J = 10.2 Hz, 1H), 4.61 - 4.58 (m, 2H), 4.25 (dd, J = 10.3, 7.6 Hz, 1H), 3.95 (d, J = 2.0Hz, 3H), 3.73 - 3.70 (m, 1H), 3.65 - 3.61 (m, 1H), 2.80 - 2.74 (m, 1H), 1.62 (s, 3H), 0.74 (d, J = 7.4 Hz, 3H) ppm. 491.14795, found 492.0 (M+1)+; 490.1 (M‑1)-; Retention time: 2.94 minutes (Precursor was the second eluting peak by SFC on Chiralcel OD-H column, rt = 3.79 min)

[0269] The following compound was made using the method described in Example 1, except that (3-fluoro‑2-methox- yphenyl)boronic acid was used in place of (3,4-difluoro‑2-methoxyphenyl)boronic acid in the Suzuki step 5. In the amide coupling step 14, (R)‑6‑(2,2-dimethyl‑1,3-dioxolan‑4-yl)pyridin‑3-amine was used in place of 6‑(2,2-dimethyl‑1,3-dioxo- lan‑4-yl)pyridin‑3-amine and the coupling conditions were those used in Example 2 step 1. The compound did not require the chiral SFC separation step 15: Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 13 (2R,3S,4S,5R)‑N‑(6‑((R)‑1,2- dihydroxyethyl)pyridin‑3- yl)‑3‑(3-fluoro‑2-methoxyphe- nyl)‑4,5-dimethyl‑5‑(trifluoro- methyl)tetrahydrofura n‑2-car- boxamide 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.63 (d, J = 2.0 Hz, 1H), 7.99 (dd, J = 2.0, 6.8 Hz, 1H), 7.42 (d, J = 6.8 Hz, 1H), 7.24‑7.06 (m, 3H), 5.31 (d, J = 4.0 Hz, 1H), 5.08 (d, J = 8.4 Hz, 1H), 4.61 (t, J = 4.8 Hz, 1H), 4.52 (m, 1H), 4.29 (dd, J = 4.8, 8.4 Hz, 1H), 3.86 (s, 3H), 3.60 (m, 1H), 3.43 (m, 1H), 2.76 (qint, J = 6.0 Hz, 1H), 1.59 (s, 3H), 0.71 (d, J = 5.2 Hz, 3H) ppm.

[0270] The following compound was made using the method described in Example 1, except that 6‑(((tert-butyldi- methylsilyl)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: 68 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 14 (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxy- phenyl)‑N‑(6‑(hydroxymethyl)pyridin‑3- yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahy- drofura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.68 (d, J = 2.5 Hz, 1H), 8.03 (dd, J = 8.5, 2.5 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.18 (dd, J = 9.9, 6.5 Hz, 2H), 5.36 (t, J = 5.8 Hz, 1H), 5.10 (d, J = 10.3 Hz, 1H), 4.52 (d, J = 5.8 Hz, 2H), 4.26 (dd, J = 10.3, 7.7 Hz, 1H), 3.97 (d, J = 2.0 Hz, 3H), 2.78 (t, J = 7.5 Hz, 1H), 1.62 (s, 3H), 0.77 - 0.73 (m, 3H) ppm. 460.14215, found 461.7 (M+1)+; 459.6 (M‑1)-; Retention time: 3.11 minutes

[0271] The following compoundwasmade using themethod 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: Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 15 (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxy- phenyl)‑N‑(2‑(hydroxymethyl)pyrimidin‑5- yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahy- drofura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (500 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.98 (s, 2H), 7.20 - 7.13 (m, 2H), 5.25 (t, J = 6.3 Hz, 1H), 5.14 (d, J = 10.3 Hz, 1H), 4.55 (d, J = 6.1 Hz, 2H), 4.25 (dd, J = 10.3, 7.5 Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.77 (dq, J = 7.5, 7.5 Hz, 1H), 1.62 (s, 3H), 0.73 (d, J = 6.2 Hz, 3H) ppm. 461.1374, found 462.6 (M+1)+; 460.5 (M‑1)-; Retention time: 3.09 minutes

[0272] 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 µm particle size, 25 cm x 20 mm from Daicel (Mobilephase:5%IPA(containing20mMAmmonia), 95%CO2.Flow:100mL / min.)onaPrep‑100SFC instrument fromWaters. The conditions used for the deprotection step 16 were those described in Example 2 step 3 utilizing THF as the solvent rather than 2-MeTHF:

[0273] Compound16wasanalyzedbyX-raypowder diffraction analysisMethodBanddetermined to becrystalline (see Fig. 4). Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 16 rel‑(2R*,3S*,4S*,5R*)‑3‑(3,4-di- fluoro‑2-methoxyphenyl)‑N-(6‑(2- fluoro‑1-hydroxyethyl)pyridin‑3- yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tet- rahydrofura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.70 (d, J = 2.4 Hz, 1H), 8.06 (dd, J = 8.6, 2.5 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.23 - 7.07 (m, 2H), 5.86 (d, J = 5.2 Hz, 1H), 5.10 (d, J = 10.2 Hz, 1H), 4.81 (dtd, J = 20.5, 5.8, 3.3 Hz, 1H), 4.73 - 4.55 (m, 1H), 4.55 - 4.36 (m, 1H), 4.25 (dd, J = 10.3, 7.7 Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.77 (p, J = 7.5 Hz, 1H), 1.61 (s, 3H), 0.74 (dd, J = 7.4, 2.5 Hz, 3H) ppm. 492.1484, found 493.3 (M+1)+; 491.3 (M‑1)-; Retention time: 3.28 minutes (Precursor was the first eluting peak by SFC on Chiralpak IB column, rt = 0.46 min) 69 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 17 rel‑(2R*,3S*,4S*,5R*)‑3‑(3,4-di- fluoro‑2-methoxyphenyl)‑N-(6‑(2- fluoro‑1-hydroxyethyl)pyridin‑3- yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tet- rahydrofura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.67 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 8.5, 2.5 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.19 - 7.05 (m, 2H), 5.82 (s, 1H), 5.05 (d, J = 10.3 Hz, 1H), 4.76 (ddd, J = 20.5, 6.3, 3.2 Hz, 1H), 4.59 (ddd, J = 47.6, 9.4, 3.3 Hz, 1H), 4.45 (ddd, J = 47.9, 9.3, 6.3 Hz, 1H), 4.20 (dd, J = 10.3, 7.6 Hz, 1H), 3.91 (d, J = 2.0 Hz, 3H), 2.73 (q, J = 7.5 Hz, 1H), 1.56 (s, 3H), 0.69 (dd, J = 7.3, 2.5 Hz, 3H) ppm. 492.1484, found 493.3 (M+1)+; 491.3 (M‑1)-; Retention time: 3.28 minutes (Precursor was the second eluting peak by SFC on Chiralpak IB column, rt = 0.75 min) Example 2 rel‑(2R*,3S*,4S*,5R*)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑N‑(6‑(1-hydroxy‑2-methoxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (20) and rel‑(2R*,3S*,4S*,5R*)‑3‑(3,4-difluoro‑2-methoxyphenyl)-N‑(6‑(1-hydroxy‑2-methoxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (21)

[0274] Step 1:

[0275] T3P (1000 µL of 50 %w / v, 1.571 mmol) was added to a mixture of (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methox- yphenyl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxylic acid (130 mg, 0.3486 mmol), rac‑6‑(1‑((tert-butyl- dimethylsilyl)oxy)‑2-methoxyethyl)pyridin‑3-amine (108mg,0.3824mmol) andEt3N (100µL,0.7175mmol) inEtOAc (1.5 mL). The clear mixture was stirred at ambient temperature for 2 h. Themixture was partitioned between EtOAc and water and passed through a phase separation cartridge. The organic filtrates were concentrated in vacuo to give a clear oil. Purification by silica gel chromatography (12gSiO2, 0 to 30%EtOAc in hexanes) gave amixture of the 2 diastereoisomers of (2R,3S,4S,5R)‑N-(6‑(1‑((tert-butyldimethylsilyl)oxy)‑2-methoxyethyl)pyridin‑3-yl)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (211 mg, 92%) as a clear oil. ESI-MS m / z calc. 618.2548, found 619.0 (M+1)+; 617.0 (M‑1)-; Retention time: 4.3 minutes.

[0276] Step 2: The 2 diastereoisomers of (2R,3S,4S,5R)‑N‑(6‑(1‑((tert-butyldimethylsilyl)oxy)‑2-methoxyethyl)pyridin‑3-yl)‑3‑(3,4-di- fluoro‑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 µm particle size, 25 cm x 10 mm from Daicel (Mobile phase: 15 % MeOH (containing 20 mM Ammonia), 85 % CO2. Flow: 10 mL / min.) on a Minigram SFC instrument from Berger In- struments:

[0277] First Eluting Isomer (rt = 2.24 min): rel‑(2R*,3S*,4S*,5R*)‑N‑(6‑(1‑((tert-butyldimethylsilyl)oxy)‑2-methox- yethyl)pyridin‑3-yl)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide 70 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 (83 mg, 84%). ESI-MS m / z calc. 618.2548, found 619.0 (M+1)+; 617.0 (M‑1)-; Retention time: 4.3 minutes.

[0278] SecondEluting Isomer (rt = 3.01min): rel‑(2R*,3S*,4S*,5R*)‑N‑(6‑(1‑((tert-butyldimethylsilyl)oxy)‑2-methox- yethyl)pyridin‑3-yl)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (82 mg, 83%). ESI-MS m / z calc. 618.2548, found 619.0 (M+1)+; 617.0 (M‑1)-; Retention time: 4.3 minutes. Step 3:

[0279] A THF solution of TBAF (650 µL of 1 M, 0.6500 mmol) was added to a stirred solution of re- l‑(2R*,3S*,4S*,5R*)‑N‑(6‑(1‑((tert-butyldimethylsilyl)oxy)‑2-methoxyethyl)pyridin‑3-yl)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (80mg, 0.1293mmol) (FirstEluting Isomer fromSFC separation) in 2-MeTHF (4mL) at 0 °C. The reactionwas stirred at ambient temperature over theweekend (convenience). The reaction mixture was quenched with saturated aqueous NaHCO3 (10mL), stirred for 10min and extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by reverse phase preparative HPLC (Waters Sunfire C18, 10 µM, 100 Å column, 0% to 100%MeCN in water containing 0.1% ammonia) gave after freeze-drying rel‑(2R*,3S*,4S*,5R*)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑N‑(6‑(1-hydroxy‑2- methoxyethyl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (20, 52 mg, 79%). 1H NMR (400MHz, DMSO-d6) δ 10.38 (s, 1H), 8.66 (dd, J = 2.5, 0.7 Hz, 1H), 8.01 (dd, J = 8.5, 2.5 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.21 - 7.13 (m, 2H), 5.47 (d, J =5.0Hz, 1H), 5.09 (d, J =10.3Hz, 1H), 4.73 - 4.64 (m, 1H), 4.29 - 4.19 (m, 1H), 3.95 (d, J =2.2 Hz, 3H), 3.57 (dd, J = 10.0, 3.9 Hz, 1H), 3.44 (dd, J = 10.1, 7.0 Hz, 1H), 3.24 (s, 3H), 2.78 (q, J = 7.5 Hz, 1H), 1.61 (s, 3H), 0.74 (d, J=6.7Hz, 3H)ppm.ESI-MSm / zcalc. 504.16837, found505.0 (M+1)+; 503.0 (M‑1)-;Retention time: 3.16minutes.

[0280] 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) (Second Eluting Isomer from SFC separation) was treated in the same way to give after freeze-drying rel‑(2R*,3S*,4S*,5R*)‑3‑(3,4- difluoro‑2-methoxyphenyl)‑N‑(6‑(1-hydroxy‑2-methoxyethyl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofur- an‑2-carboxamide (21, 54mg, 82%). 1HNMR(400MHz,DMSO-d6) δ10.38 (s, 1H), 8.68 (dd, J=2.5, 0.7Hz, 1H), 7.99 (dd, J=8.5, 2.5Hz, 1H), 7.44 (d, J=8.5Hz, 1H), 7.21 -7.13 (m,2H), 5.47 (d, J=4.4Hz,1H), 5.09 (d, J=10.3Hz, 1H), 4.69 (d, J= 6.2Hz, 1H), 4.24 (dd, J=10.3, 7.7Hz, 1H), 3.95 (d, J=2.2Hz, 3H), 3.57 (dd, J=10.0, 3.9Hz, 1H), 3.44 (dd, J=10.0, 6.9Hz, 1H), 3.24 (s, 3H), 2.77 (p, J = 7.6 Hz, 1H), 1.61 (s, 3H), 0.74 (d, J = 7.0 Hz, 3H) ppm. ESI-MS m / z calc. 504.16837, found 505.0 (M+1)+;503.0 (M‑1)-; Retention time: 3.16 minutes.

[0281] Compound 21 was analyzed by X-ray powder diffraction analysis Method B and determined to be amorphous (see Fig. 5).

[0282] The following compounds were made using the method described in Example 2, except that 6‑(1‑((tert- butyldimethylsilyl)oxy)‑3-methoxypropyl)pyridin‑3-amine was used as the coupling partner in the amide coupling step 1. In step 2, purificationwas performed by chiral SFC using aChiralpak IB column, 5µmparticle size, 25 cm x 20mm from Daicel (Mobile phase: 5 % MeOH (containing 20 mM Ammonia), 95 % CO2. Flow: 100 mL / min.) on a Prep‑100 SFC instrument from Waters: Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 22 rel‑(2R*,3S*,4S*,5R*)‑3‑(3,4-di- fluoro‑2-methoxyphenyl)‑N-(6‑(1-hy- droxy‑3-methoxypropyl)pyridin‑3- yl)‑4,5-dimethyl‑5‑(trifluoromethyl) tetrahydrofura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.64 (dd, J = 2.6, 0.7 Hz, 1H), 8.01 (dd, J = 8.5, 2.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.17 (dd, J = 9.0, 6.3 Hz, 2H), 5.32 (d, J = 5.2 Hz, 1H), 5.09 (d, J = 10.4 Hz, 1H), 4.61 (dt, J = 9.0, 4.7 Hz, 1H), 4.25 (dd, J = 10.3, 7.6 Hz, 1H), 3.95 (d, J = 2.2 Hz, 3H), 3.46 (ddd, J = 9.4, 7.5, 6.7 Hz, 1H), 3.38 - 3.33 (m, 1H), 3.20 (s, 3H), 2.77 (p, J = 7.5 Hz, 1H), 1.96 (dtd, J = 14.4, 7.4, 4.3 Hz, 1H), 1.73 (dddd, J = 13.6, 8.6, 6.7, 5.1 Hz, 1H), 1.61 (s, 3H), 0.77 - 0.70 (m, 3H) ppm. 518.184, found 519.0 (M+1)+; 517.0 (M‑1)-; Retention time: 3.20 minutes (Precursor was the first eluting peak by SFC on Chiralpak IB column, rt = 0.37 min) 71 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 23 rel‑(2R*,3S*,4S*,5R*)‑3‑(3,4-di- fluoro‑2-methoxyphenyl)‑N-(6‑(1-hy- droxy‑3-methoxypropyl)pyridin‑3- yl)‑4,5-dimethyl‑5‑(trifluoromethyl) tetrahydrofura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.67 (dd, J = 2.6, 0.7 Hz, 1H), 7.99 (dd, J = 8.5, 2.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.22 - 7.13 (m, 2H), 5.32 (d, J = 5.2 Hz, 1H), 5.09 (d, J = 10.3 Hz, 1H), 4.61 (dt, J = 9.0, 4.7 Hz, 1H), 4.25 (dd, J = 10.3, 7.6 Hz, 1H), 3.95 (d, J = 2.2 Hz, 3H), 3.46 (dt, J = 9.4, 7.2 Hz, 1H), 3.39 - 3.32 (m, 1H), 3.21 (s, 3H), 2.77 (p, J = 7.5 Hz, 1H), 1.96 (dtd, J = 14.2, 7.4, 4.2 Hz, 1H), 1.80 - 1.67 (m, 1H), 1.61 (s, 3H), 0.77 - 0.70 (m, 3H) ppm. 518.184, found 519.0 (M+1)+; 517.0 (M‑1)-; Retention time: 3.20 minutes (Precursor was the second eluting peak by SFC on Chiralpak IB col- umn, rt = 0.75 min) Example 3 rel‑(2R,3S,5R)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑N‑(6‑((R*)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑5-methyl‑5‑(trifluoro- methyl)tetrahydrofuran‑2-carboxamide (24) and rel‑(2S,3R,5S)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑N‑(6‑((R*)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑5-methyl‑5‑(trifluoro- methyl)tetrahydrofuran‑2-carboxamide (25)

[0283] Step 1:

[0284] Triethylamine (8.05g,11.2mL,78.8mmol)wasadded toastirredsolutionofethyl 2-diazo‑3-oxobutanoate (5.0g, 31.4 mmol) in DCM (50mL) at 0 °C. TBSOTf (9.24 g, 8.2 mL, 34.3 mmol) was added slowly and the reaction mixture was stirred for 30min at 0 °C. The reactionmixture waswashedwith a 30%NaHCO3 solution (200mL). The organic layer was separated, washed with water (500 mL), dried (MgSO4), filtered and concentrated in vacuo to give ethyl 3‑((tert- butyldimethylsilyl)oxy)‑2-diazobut‑3-enoate (8.22 g, 97%), which was used in the next step without further purification.. 72 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 Step 2:

[0285] 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. TiCl4 (56.8 g, 33mL, 299.2mmol) was added dropwise to the stirred reactionmixture. 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. The reaction was kept at ‑78 °C for 1 h. A saturated solution of NaHCO3 was added and the mixture was diluted with DCM. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. Purificationbysilicagel chromatography (SiO2, 0 to30%EtOAc inhexane)gaveethyl 2-diazo‑6,6,6-trifluoro‑5-hydroxy‑5- methyl‑3-oxohexanoate (39 g, 61%) as a pale yellow liquid. 1H NMR (400 MHz, Chloroform-d) δ 4.92 (s, 1H), 4.32 (q, J = 7.1 Hz, 2H), 3.63 (d, J = 15.5 Hz, 1H), 2.84 (d, J = 15.5 Hz, 1H), 1.41 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H) ppm. Step 3:

[0286] Rhodium (II) acetate (643 mg, 1.45 mmol) was charged into an oven dried two necked flask. Toluene (970 mL) wasaddedand the solutionwasstirredat 100 °C for 10min. Thesolutionwasbriefly liftedout of theoil bathwhilst a solution of ethyl 2-diazo‑6,6,6-trifluoro‑5-hydroxy‑5-methyl‑3-oxohexanoate (39 g, 145.4 mmol) in a toluene (200mL) was added dropwise. The reactionmixturewasheatedat reflux for 1 h. Themixturewas filtered throughfilter paper and the filtratewas concentrated in vacuo to give ethyl 5-methyl‑3-oxo‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxylate (30.89 g, 88%) as a mixture of epimers at the position next to the ester. 1H NMR (400 MHz, Chloroform-d) δ 4.68 (s, 1H), 4.35 - 4.17 (m, 2H), 2.89 (d, J = 18.8, 1H), 2.58 (d, J = 18.8, 1H), 1.70 (s, 3H), 1.30 (t, J = 7.2, Hz, 3H) ppm. Step 4:

[0287] 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, 27.1mmol) andDIPEA (14mL, 80.4mmol) in DCM (150mL) at ‑78 °C. The reactionmixturewas stirred for 2.5 h before saturated aqueousNH4Cl (75mL)was added. Themixturewas warmed up to ambient temperature. The aqueous layer was extracted with DCM (2 x 30 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give ethyl 5-methyl‑5‑(trifluoromethyl)‑3‑(((trifluor- omethyl)sulfonyl)oxy)‑4,5-dihydrofuran‑2-carboxylate (10.1 g), which was used directly in the next reaction. Step 5:

[0288] K3PO4 (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-car- boxylate (3 g, 7.90 mmol) in toluene (80 mL). The mixture was degassed by bubbling nitrogen through the solution for 20 min. Pd(PPh3)4 (466 mg, 0.40 mmol) was added and the reaction was heated to 100 °C for 1 h. The mixture was filtered through a pad of celite. The filtrates were diluted with water (50 mL) and the phases were separated. The aqueous layer was extracted with EtOAc (50 x 2 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by silica gel chromatography (SiO2, 0 to 2% EtOAc in hexane) gave ethyl 3‑(3,4-difluoro‑2-methox- yphenyl)‑5-methyl‑5‑(trifluoromethyl)‑4,5-dihydrofuran‑2-carboxylate (2.5 g, 85%) as a light-yellow liquid. 1H NMR (400 MHz,Chloroform-d) δ6.87 (pd, J=8.8, 6.2Hz, 2H), 4.15 (q, J =7.1Hz, 2H), 3.89 (s, 3H), 3.42 (d, J =17.4Hz, 1H), 2.93 (d, J =17.4Hz,1H), 1.65 (s, 3H), 1.14 (t, J = 7.1Hz, 3H) ppm.ESI-MSm / z calc. 366.08905, found367.4 (M+1)+;Retention time: 1.01 minutes. Step 6:

[0289] EtOH (200 mL) was added to a mixture of ethyl 3‑(3,4-difluoro‑2-methoxyphenyl)‑5-methyl‑5‑(trifluoro- methyl)‑4,5-dihydrofuran‑2-carboxylate (5.51 g, 15.0mmol) and Pd / C (10 wt. % loading, 2.2 g, 2.067mmol). Themixture was degassed and stirred under a balloon of H2 for 96 h. The catalyst was removed by filtration and the solidswashedwith EtOH (50mL). The filtrates were concentrated in vacuo.A further portion of Pd / C (10wt.% loading, 2.2 g, 2.07mmol) was added to the residue followed by EtOH (200 mL). The reaction mixture was stirred under a balloon of H2 at ambient temperature for 24 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 (10wt.% loading, 2.2 g, 2.07mmol) was added to the residue followed by EtOH (200mL) and the reactionmixture stirred under a balloon of H2 at ambient temperature for 4 days. The catalyst was removed by filtration and the solids washed with EtOH (50 mL). The filtrates were concentrated in vacuo to give ethyl rac‑(2S,3S,5R)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑5-methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxylate (5.19 g, 94%) as a white solid, and as a single diastereomer. 1H NMR (500 MHz, Chloroform-d) δ 6.89 - 6.86 (m, 1H), 6.82 - 6.77 (m, 1H), 4.93 (d, J = 8.9Hz, 1H), 4.23 (dt, J = 13.0, 7.6Hz, 1H), 4.08 (d, J = 2.9Hz, 3H), 3.85 - 3.71 (m, 2H), 2.82 (t, J = 73 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 12.5Hz, 1H), 2.04 (dd, J = 12.0, 6.7Hz, 1H), 1.53 (s, 3H), 0.94 (t, J = 7.1Hz, 3H) ppm; 19FNMR (471MHz,Chloroform-d) δ ‑80.15, ‑136.84 (d, J = 19.4 Hz), ‑154.77 (d, J = 19.6 Hz) ppm. Step 7:

[0290] Ethyl rac-(2S,3S,5R)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑5-methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carbox- ylate (5.19 g, 14.09mmol) was dissolved in ethanol (100mL). Cs2CO3 (7.1 g, 21.79mmol)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. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give rac‑(2R,3S,5R)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑5-methyl‑5‑(trifluoromethyl)tetra- hydrofuran‑2-carboxylic acid (5.1063 g, 96%) as a colourless oil. 1H NMR (500MHz, Chloroform-d) δ 6.99 - 6.96 (m, 1H), 6.92 - 6.87 (m, 1H), 4.68 (d, J = 10.5Hz, 1H), 4.00 (d, J = 2.7Hz, 3H), 3.90 (ddd, J = 12.0, 10.6, 8.2Hz, 1H), 2.58 (t, J = 12.5 Hz, 1H), 2.31 (dd, J = 13.0, 8.2 Hz, 1H), 1.60 (s, 3H) ppm; 19FNMR (471MHz,Chloroform-d) δ ‑81.56, ‑136.40 (d, J = 19.6 Hz), ‑153.60 (d, J = 19.5 Hz) ppm. ESI-MS m / z calc. 340.0734, found 339.5 (M‑1)-; Retention time: 0.52 minutes. Step 8:

[0291] Oxalyl chloride (70 µL, 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 µL of 0.86 M, 0.04300 mmol) in 2-methyltetrahydrofuran (5 mL). The reaction mixture wasstirredandwarmed to room temperatureover 45min. The reactionmixturewasconcentrated in vacuoand the residue dissolved in 2-methyltetrahydrofuran (5mL). This solution was 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 (250 µL, 1.794 mmol) in 2-methyltetrahydrofuran (5 mL). The resulting mixture was stirred and warmed to ambient temperature over 1 h. The reaction mixture was quenched with water (2 mL) and the layers separated. The aqueous phase was extracted with EtOAc (2 x 5 mL). The combined organic extractswere dried (MgSO4), filtered and concentrated in vacuo.Purification by silica gel chromatography (24 gSiO2, 0 to 100% EtOAc in heptane, loaded from DCM) gave 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 (120.4 mg, 59%) as a white solid and as a mixture of 2 diastereoisomers. 1H NMR (500 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.70 - 8.69 (m,1H),8.03 (dt, J=8.4,2.6Hz,1H), 7.45 (d, J=8.5Hz,1H), 7.22 -7.15 (m,2H), 5.07 (t, J=6.8Hz,1H), 4.65 (d, J=10.1Hz, 1H), 4.33 (dd, J=8.2, 6.7Hz, 1H), 4.05 (q, J =10.0Hz, 1H), 3.87 (d, J =2.0Hz, 3H), 3.83 (ddd, J=8.0, 6.7, 1.2Hz, 1H), 2.46 (d, J = 10.5 Hz, 2H), 1.57 (s, 3H), 1.43 (s, 3H), 1.40 (s, 3H) ppm; 19F NMR (471MHz, DMSO-d6) δ ‑80.12, ‑138.13 (d, J = 21.1 Hz), ‑154.77 (d, J = 21.2 Hz) ppm. ESI-MS m / z calc. 516.16833, found 517.5 (M+1)+; 515.6 (M‑1)-; Retention time: 0.99 minutes. Step 9:

[0292] The 2 diastereoisomers of rel‑(2R,3S,5R)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑N‑(6‑((R*)‑2,2-dimethyl‑1,3-diox- olan‑4-yl)pyridin‑3-yl)‑5-methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide were separated by chiral SFC using a Chiralpak IA column, 5 µm particle size, 25 cm x 20 mm from Daicel (Mobile phase: 15 % MeOH (containing 20 mM Ammonia), 85 % CO2. Flow: 100 mL / min.) on a Prep‑100 SFC instrument from Waters: First Eluting Isomer (rt = 0.73 min): 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, 60%) as a white solid. ESI-MS m / z calc. 516.16833, found 517.2 (M+1)+; 515.3 (M‑1)-; Retention time: 3.41 minutes.

[0293] Second Eluting Isomer (rt = 0.95 min): rel‑(2S,3R,5S)‑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 (51 mg, 73%) as a white solid. ESI-MS m / z calc. 516.16833, found 517.2 (M+1)+; 515.3 (M‑1)-; Retention time: 3.41 minutes. Step 10:

[0294] TFA (225 µL, 2.920 mmol) was added to a solution of rel‑(2R,3S,5R)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(6‑((R*)‑(2,2-dimethyl‑1,3-dioxolan‑4-yl)pyridin‑3-yl)‑5-methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (42mg, 0.081mmol) (First Eluting Isomer fromSFC separation) in DCM (5mL) and themixture stirred for 18 h at ambient temperature. The mixture was concentrated in vacuo and azeotroped twice with DCM. Purification by reverse phase preparative HPLC (Waters Sunfire C18, 10 µM, 100 Å column, 0% to 100% MeCN in water containing 0.1% ammonia) gave after freeze-drying rel‑(2R,3S,5R)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑N‑(6‑((R*)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑5- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (24, 24.6mg, 62%)asawhite solid. 1HNMR (500MHz,DMSO- d6)δ10.09 (s, 1H), 8.64 (d, J=2.2Hz,1H), 7.97 (dd, J=8.5, 2.5Hz,1H), 7.42 (d, J=8.5Hz, 1H), 7.22 -7.15 (m,2H), 5.32 (d, 74 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 J=4.9Hz, 1H), 4.66 -4.62 (m,2H), 4.54 (dt, J=6.6, 4.5Hz, 1H), 4.05 (q, J=10.1Hz, 1H), 3.88 (d, J=1.9Hz,3H), 3.63 (ddd, J = 10.3, 6.0, 4.2Hz, 1H), 3.48 - 3.43 (m, 1H), 2.47 (s, 1H), 2.45 (s, 1H), 1.56 (s, 3H) ppm; 19FNMR (471MHz,DMSO-d6) δ ‑80.12, ‑138.14 (d, J = 21.0 Hz), ‑154.77 (d, J = 21.0 Hz) ppm. ESI-MS m / z calc. 476.13705, found 474.4 (M+1)+; 475.5 (M‑1)-; Retention time: 2.77 minutes.

[0295] rel‑(2S,3R,5S)‑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 (51 mg, 0.099 mmol) (Second Eluting Isomer from SFC se- paration) was treated in the same way to give after freeze-drying rel-(2S,3R,5S)‑3‑(3,4-difluoro‑2-methoxyphe- nyl)‑N‑(6‑((R*)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑5-methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (25, 32.0 mg, 66%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.65 (d, J = 2.5 Hz, 1H), 7.96 (dd, J = 8.5, 2.5Hz, 1H), 7.42 (d, J =8.5Hz, 1H), 7.22 - 7.15 (m,2H), 5.32 (d, J =4.9Hz, 1H), 4.66 - 4.62 (m, 2H), 4.54 (dt, J =6.7, 4.5Hz, 1H), 4.05 (q, J = 10.0Hz, 1H), 3.88 (d, J = 1.9Hz, 3H), 3.64 (ddd, J = 10.4, 6.0, 4.2 Hz, 1H), 3.45 (ddd, J = 11.0, 6.7, 5.9 Hz, 1H), 2.47 (s, 1H), 2.45 (s, 1H), 1.57 (s, 3H) ppm; 19FNMR (471MHz,DMSO-d6) δ ‑80.12, - 138.14 (d, J = 21.1Hz), ‑154.77 (d, J = 21.1 Hz) ppm. ESI-MS m / z calc. 476.13705, found 477.4 (M+1)+;475.4 (M‑1)-; Retention time: 2.77 minutes.

[0296] The following compounds were made using the method described in Example 3, except that (S)‑6‑(2,2- dimethyl‑1,3-dioxolan‑4-yl)pyridin‑3-amine was used in place of (R)‑6‑(2,2-dimethyl‑1,3-dioxolan‑4-yl)pyridin‑3-amine in the amide coupling step8. In step 9, purificationwasperformedby chiral SFCusing aChiralpak IA column, 5µmparticle size, 25 cm x 20 mm from Daicel Corporation on a Prep‑100 SFC instrument from Waters: Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 26 rel‑(2R,3S,5R)‑3‑(3,4-difluoro‑2-methoxy- phenyl)‑N‑(6‑((S*)‑1,2-dihydroxyethyl) pyridin‑3-yl)‑5-methyl‑5‑(trifluoromethyl) tetrahydrofura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (500 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.65 (d, J = 2.3 Hz, 1H), 7.96 (dd, J = 8.5, 2.5 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.21 - 7.15 (m, 2H), 5.32 (d, J = 4.9 Hz, 1H), 4.66 - 4.62 (m, 2H), 4.54 (dt, J = 6.7, 4.5 Hz, 1H), 4.08 - 4.02 (m, 1H), 3.87 (d, J = 1.8 Hz, 3H), 3.64 (ddd, J = 10.5, 6.0, 4.4 Hz, 1H), 3.48 - 3.43 (m, 1H), 2.47 (s, 1H), 2.45 (s, 1H), 1.57 (s, 3H) ppm. 476.13705, found 477.4 (M+1)+; 475.5 (M‑1)-; Retention time: 2.78 minutes (Precursor was the first eluting peak by SFC on Chiralpak IA column, rt = 0.70 min) 27 rel‑(2S,3R,5S)‑3‑(3,4-difluoro‑2-methoxy- phenyl)‑N‑(6‑((S*)‑1,2-dihydroxyethyl) pyridin‑3-yl)‑5-methyl‑5‑(trifluoromethyl) tetrahydrofura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (500 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.64 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 8.5, 2.5 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.22 - 7.15 (m, 2H), 5.32 (d, J = 4.9 Hz, 1H), 4.66 - 4.62 (m, 2H), 4.54 (dt, J = 6.7, 4.5 Hz, 1H), 4.05 (q, J = 10.1 Hz, 1H), 3.88 (d, J = 1.9 Hz, 3H), 3.63 (ddd, J = 10.4, 6.0, 4.2 Hz, 1H), 3.45 (ddd, J = 11.0, 6.9, 5.8Hz, 1H), 2.47 (s, 1H), 2.45 (s, 1H), 1.57 (s, 3H) ppm. 476.13705, found 477.3 (M+1)+; 475.5 (M‑1)-; Retention time: 2.78 minutes (Precursor was the second eluting peak by SFC on Chiralpak IA column, rt = 0.87 min)

[0297] 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-aminewasused in placeof (R)‑6‑(2,2-dimethyl‑1,3-dioxolan‑4-yl)pyridin‑3-amine in the amide coupling step 8. In the Suzuki coupling step 5, Pd(PPh3)4 was used as the catalyst together with Na2CO3 as thebaseandamixture of toluene,water andmethanol as the solvent and the reactionwas carried out at 80 °Cover 16 h. In 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 µm particle size, 25 cm x 21.2 mm from Daicel Corporation (40 °C;Mobile Phase: 6%MeOH (20mMNH3), 94%CO2; Flow: 70mL / min.) on a Prep‑100SFC instrument from Waters: 75 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 28 rel‑(2S,3R,5S)‑3‑(3,4-difluoro‑2-meth- oxyphenyl)‑N‑(2‑(1,2-dihydroxyethyl) pyrimidin‑5-yl)‑5-methyl‑5‑(trifluoro- methyl)tetrahydrofura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.96 (s, 2H), 7.23 - 7.15 (m, 2H), 5.17 (d, J = 6.0 Hz, 1H), 4.68 (d, J = 10.1 Hz, 1H), 4.60 (dt, J = 10.2, 5.9 Hz, 2H), 4.04 (q, J = 10.3 Hz, 1H), 3.88 (d, J = 2.0 Hz, 3H), 3.72 (dt, J = 11.6, 6.0 Hz, 1H), 3.64 (dt, J = 11.2, 6.0 Hz, 1H), 1.58 (s, 3H) ppm. 2 protons hidden by DMSO signal. 477.13232, found 478.0 (M+1)+; 476.0 (M‑1)-; Retention time: 2.78 minutes (Precursor was the first eluting peak by SFC on Chiralcel OJ column, rt = 4.75 min) 29 rel‑(2R,3S,5R)‑3‑(3,4-difluoro‑2-meth- oxyphenyl)‑N‑(2‑(1,2-dihydroxyethyl) pyrimidin‑5-yl)‑5-methyl‑5‑(trifluoro- methyl)tetrahydrofura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.96 (s, 2H), 7.23 - 7.15 (m, 2H), 5.17 (d, J = 6.0 Hz, 1H), 4.68 (d, J = 10.2 Hz, 1H), 4.60 (dt, J = 11.4, 5.9 Hz, 2H), 4.04 (q, J = 10.1 Hz, 1H), 3.89 (d, J = 2.0 Hz, 3H), 3.72 (dt, J = 11.5, 6.0 Hz, 1H), 3.64 (dt, J = 11.0, 5.9 Hz, 1H), 1.58 (s, 3H) ppm. 2 protons hidden by DMSO signal. 477.13232, found 478.0 (M+1)+; 476.0 (M‑1)-; Retention time: 2.78 minutes (Precursor was the second eluting peak by SFC on Chiralcel OJ column, rt = 5.42 min) 30 rel‑(2S,3R,5S)‑3‑(3,4-difluoro‑2-meth- oxyphenyl)‑N‑(2‑(1,2-dihydroxyethyl) pyrimidin‑5-yl)‑5-methyl‑5‑(trifluoro- methyl)tetrahydrofura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.96 (s, 2H), 7.23‑7.15 (m, 2H), 5.17 (d, J = 6.0 Hz, 1H), 4.68 (d, J = 10.1 Hz, 1H), 4.62‑ 4.57 (m, 2H), 4.04 (q, J = 11.0, 10.5 Hz, 1H), 3.88 (d, J = 1.9 Hz, 3H), 3.72 (dt, J = 11.5, 6.0 Hz, 1H), 3.64 (dt, J = 11.1, 6.0 Hz, 1H), 1.58 (s, 3H) ppm. 2 protons hidden by DMSO signal. 477.13232, found 477.8 (M+1)+; 476.0 (M‑1)-; Retention time: 2.78 minutes (Precursor was the third eluting peak by SFC on Chiralcel OJ column, rt = 10.45 min) 31 rel‑(2R,3S,5R)‑3‑(3,4-difluoro‑2-meth- oxyphenyl)‑N‑(2‑(1,2-dihydroxyethyl) pyrimidin‑5-yl)‑5-methyl‑5‑(trifluoro- methyl)tetrahydrofura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.96 (s, 2H), 7.23 - 7.15 (m, 2H), 5.17 (d, J = 6.0 Hz, 1H), 4.68 (d, J = 10.1 Hz, 1H), 4.62 - 4.57 (m, 2H), 4.04 (q, J = 10.2 Hz, 1H), 3.88 (d, J = 1.9 Hz, 3H), 3.72 (dt, J = 11.5, 5.9 Hz, 1H), 3.64 (dt, J = 11.0, 5.9 Hz, 1H), 1.58 (s, 3H) ppm. 2 protons hidden by DMSO signal. 477.13232, found 478.0 (M+1)+; 476.0 (M‑1)-; Retention time: 2.78 minutes (Precursor was the fourth eluting peak by SFC on Chiralcel OJ column, rt = 12.17 min)

[0298] The following compounds were made using the method described in Example 3, except that 2‑(2-ethoxy‑3,4- difluoro-phenyl)‑4,4,5,5-tetramethyl‑1,3,2-dioxaborolane was used in place of (3,4-difluoro‑2-methoxyphenyl)boronic acid in theSuzuki coupling of step 5. In the caseof compounds 32 and33, (S)‑6‑(2,2-dimethyl‑1,3-dioxolan‑4-yl)pyridin‑3- 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. In the Suzuki coupling step 5, Pd(PPh3)4 was used as the catalyst together with Na2CO3 as the base and a mixture of toluene, water andmethanol as the solvent and the reactionwascarriedout at 80 °Cover 16h. In step9, purificationwasperformed bychiralSFCusinga (R,R)‑Whelk-O1column,5umparticle size, 25cmx21.1mmfromDaicel (Mobilephase: 30%MeOH (containing20mMAmmonia), 70%CO2.Flow: 100mL / min.) onaMinigramSFC instrument fromBerger Instruments. The deprotection step 10 was carried out at ambient temperature over 1.5 h using 12 M HCl in THF as the solvent: 76 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 32 rel‑(2S,3R,5S)‑N‑(6‑((S*)‑1,2-dihydroxyethyl) pyridin‑3-yl)‑3‑(2-ethoxy‑3,4-difluorophe- nyl)‑5-methyl‑5‑(trifluoromethyl)tetrahydrofura n‑2-carboxamide ESI-MS m / z calc. 490.1527, found 491.4 (M+1)+; 489.5 (M‑1)-; Retention time: 2.93 min- utes (Precursor was the first eluting peak by SFC on (R,R)‑Whelk-O1 column, rt = 3.62 min) 33 rel‑(2R,3S,5R)‑N‑(6‑((S*)‑1,2-dihydroxyethyl) pyridin‑3-yl)‑3‑(2-ethoxy‑3,4-difluorophe- nyl)‑5-methyl‑5‑(trifluoromethyl)tetrahydrofura n‑2-carboxamide ESI-MS m / z calc. 490.1527, found 491.4 (M+1)+; 489.5 (M‑1)-; Retention time: 2.92 min- utes (Precursor was the second eluting peak by SFC on (R,R)‑Whelk-O1 column, rt = 4.18min) 34 rel‑(2S,3R,5S)-N-(6‑((R*)‑1,2-dihydroxyethyl) pyridin‑3-yl)‑3‑(2-ethoxy‑3,4-difluorophe- nyl)‑5-methyl‑5‑(trifluoromethyl)tetrahydrofura n‑2-carboxamide ESI-MS m / z calc. 490.1527, found 491.4 (M+1)+; 489.5 (M‑1)-; Retention time: 2.93 min- utes(Precursor was the first eluting peak by SFC on (R,R)-Whelk-O1 column, rt = 3.62 min) 35 rel‑(2R,3S,5R)‑N-(6‑((R*)‑1,2-dihydroxyethyl) pyridin‑3-yl)‑3‑(2-ethoxy‑3,4-difluorophe- nyl)‑5-methyl‑5‑(trifluoromethyl)tetrahydrofura n‑2-carboxamide ESI-MS m / z calc. 490.1527, found 491.4 (M+1)+; 489.5 (M‑1)-; Retention time: 2.92 min- utes (Precursor was the second eluting peak by SFC on (R,R)-Whelk-O1 column, rt = 4.18min)

[0299] Compound 35 was analyzed by X-ray powder diffraction analysis Method B and determined to be amorphous (see Fig. 6). Example 4 (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-hydroxyphenyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoro- methyl)tetrahydrofuran‑2-carboxamide (36) and (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2‑(2-fluoroethoxy)phenyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(tri- fluoromethyl)tetrahydrofuran‑2-carboxamide (37)

[0300] 77 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 Step 1:

[0301] A stirred solution of (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3- yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (1, 343.7mg, 0.7008mmol) inDCM(9mL)wasplaced under a nitrogen atmosphere and cooled down with an ice bath. Boron tribromide (in DCM) (2.2 mL of 1 M, 2.200 mmol) was added and the reactionmixturewas stirred for 2h. The reactionwas quenched by addition ofMeOH (2mL) and stirred overnight at ambient temperature. Themixturewas concentrated in vacuo.The residuewasdissolved inMeOH(3mL)and the pH was adjusted to pH 9 with a 2M aqueous sodium hydroxide solution. Purification by reverse phase preparative HPLC (Waters Sunfire C18, 10 µM, 100 Å column, 0% to 100% MeCN in water containing 0.1% ammonia) gave (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-hydroxyphenyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoro- methyl)tetrahydrofuran‑2-carboxamide (36, 259.8mg, 78%). 1HNMR (500MHz,DMSO-d6) δ10.45 (s, 1H), 10.40 (s, 1H), 8.65 (d, J=2.2Hz,1H), 8.00 (dd, J=8.7, 2.3Hz, 1H), 7.42 (d, J=8.6Hz, 1H), 7.03 (t, J=6.8Hz,1H), 6.85 (q, J=8.6Hz,1H), 5.33 (d, J = 4.9Hz, 1H), 5.09 (d, J = 10.3Hz, 1H), 4.64 (t, J = 5.9Hz, 1H), 4.57 - 4.50 (m, 1H), 4.28 - 4.19 (m, 1H), 3.66 - 3.57 (m,1H), 3.49 -3.38 (m,1H), 2.83 (p, J=7.4Hz, 1H), 1.58 (s, 3H), 0.70 (d, J=6.4Hz,3H)ppm.ESI-MSm / zcalc. 476.13705, found 477.3 (M+1)+; Retention time: 2.46 minutes.

[0302] Step 2:

[0303] K2CO3 (18 mg, 0.1302 mmol) was added to a mixture of 1-fluoro‑2-iodoethane (10 µL, 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‑(trifluoro- methyl)tetrahydrofuran‑2-carboxamide (36, 40 mg, 0.08396 mmol) in DMF (2 mL). The mixture was stirred at 60 °C for 6h30. Themixture was diluted with MeOH and purified by reverse phase preparative HPLC (Waters Sunfire C18, 10 µM, 100 Å column, 0% to 100% MeCN in water containing 0.1% ammonia) to give (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2‑(2- fluoroethoxy)phenyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-car- boxamide (37, 18.48mg, 41%). 1HNMR (500MHz, DMSO-d6) δ 10.35 (s, 1H), 8.64 (dd, J = 2.5, 0.8 Hz, 1H), 8.00 (dd, J = 8.5, 2.5 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.27 - 7.09 (m, 2H), 5.32 (d, J = 4.9 Hz, 1H), 5.11 (d, J = 10.6 Hz, 1H), 4.79 (dt, J = 4.9, 2.4Hz, 1H), 4.69 (dt, J = 5.0, 2.4Hz, 1H), 4.63 (t, J =5.9Hz, 1H), 4.54 (dt, J = 6.8, 4.5Hz, 1H), 4.49 - 4.27 (m, 3H), 3.70 - 3.59 (m,1H), 3.45 (ddd, J=10.9, 6.8, 5.7Hz,1H), 2.78 (p, J=7.4Hz,1H), 1.59 (s, 3H), 0.81 -0.68 (m,3H)ppm.ESI-MSm / z calc. 522.15894, found 523.3 (M+1)+; Retention time: 3.0 minutes.

[0304] The following compound was made using the method described in Example 4, except that 2-bromo‑1,1- difluoroethane was used in place of 1-fluoro‑2-iodoethane in the alkylation step 2: 78 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 38 (2R,3S,4S,5R)‑3‑(2‑(2,2-difluor- oethoxy)‑3,4-difluorophe- nyl)‑N‑(6‑((R)‑1,2-dihydroxyethyl) pyridin‑3-yl)‑4,5-dimethyl‑5‑(tri- fluoromethyl)tetrahydrofura n‑2- carboxamide ESI-MS m / z calc. 1H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.64 (dd, J = 2.5, 0.8 Hz, 1H), 8.00 (dd, J = 8.6, 2.5 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.32 - 6.98 (m, 2H), 6.39 (tt, J = 53.9, 2.9 Hz, 1H), 5.32 (d, J = 4.9 Hz, 1H), 5.11 (d, J = 10.6 Hz, 1H), 4.63 (t, J = 5.9 Hz, 1H), 4.58 - 4.34 (m, 3H), 4.29 (dd, J = 10.6, 7.3 Hz, 1H), 3.63 (ddd, J = 10.6, 6.1, 4.2 Hz, 1H), 3.44 (ddd, J = 11.0, 6.9, 5.8 Hz, 1H), 2.78 (p, J = 7.4 Hz, 1H), 1.59 (s, 3H), 0.73 (d, J = 7.3 Hz, 3H) ppm. 540.14954, found 541.2 (M+1)+; 539.1 (M‑1)-; Retention time: 3.07 minutes

[0305] The following compound was made using the method described in Example 4 step 1, except that (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-methoxyphenyl)‑N‑(2‑(hydroxymethyl)pyrimidin‑5-yl)‑4,5-dimethyl‑5‑(trifluoromethyl) tetrahydrofuran‑2-carboxamide (15) was used as the starting material: Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 39 (2R,3S,4S,5R)‑3‑(3,4-difluoro‑2-hydroxy- phenyl)‑N‑(2‑(hydroxymethyl)pyrimidin‑5- yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahy- drofura n‑2-carboxamide ESI-MS m / z calc. 1HNMR (500MHz, DMSO-d6) δ 10.53 (s, 1H), 10.40 (s, 1H), 8.99 (s, 2H), 7.05 (ddd, J = 8.3, 5.7, 1.9 Hz, 1H), 6.87 - 6.78 (m, 1H), 5.26 (t, J = 6.5 Hz, 1H), 5.15 (d, J = 10.3 Hz, 1H), 4.56 (d, J = 5.4 Hz, 2H), 4.25 (dd, J = 10.3, 7.6 Hz, 1H), 2.84 (t, J = 7.5 Hz, 1H), 1.61 (s, 3H), 0.77 - 0.65 (m, 3H) ppm. 447.12173, found 448.6 (M+1)+; 446.5 (M‑1)-; Retention time: 2.46 minutes Example 5 rel‑(2R,3S,4S,5R)‑N‑(6‑((R*)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑3‑(2-ethoxy‑4-fluoro‑3-methylphenyl)‑4,5-dimethyl‑5‑(tri- fluoromethyl)tetrahydrofuran‑2-carboxamide (40) and rel‑(2S,3R,4R,5S)‑N‑(6‑((R*)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑3‑(2-ethoxy‑4-fluoro‑3-methylphenyl)‑4,5-dimethyl‑5‑(tri- fluoromethyl)tetrahydrofuran‑2-carboxamide (41)

[0306] 79 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 Step 1:

[0307] To a 2 L three necked round bottom flask, flanked with a thermometer, was added a mixture of ethyl rac‑(4R,5R)‑4,5-dimethyl‑5‑(trifluoromethyl)‑3‑(((trifluoromethyl)sulfonyl)oxy)‑4,5-dihydrofuran‑2-carboxylate (39.05 g, 101.1 mmol), (4-fluoro‑2-methoxy‑3-methylphenyl)boronic acid (20.4 g, 110.9 mmol) and PdCl2(PPh3)2 (1.4 g, 1.995 mmol) in a saturated solution of NaHCO3 (120 mL) and dioxane (400 mL). The orange mixture was heated to 50 °C internally for 20min. The reactionmixture was cooled to ambient temperature and diluted with EtOAc (100mL) and water (100 mL). The layers were separated and the aqueous phase was extracted with EtOAc (4 x 100 mL). The combined organic extracts were washed with brine (1 x 50 mL), dried (MgSO4), filtered and concentrated in vacuo to an approximative volume of 100 mL. Charcoal (10 g) was added and the mixture was stirred for 2 h. The mixture was filtered and the residual cake was washed further with EtOAc. The filtrates were collected and concentrated in vacuo to give 50 g of crude product. Purification by flash chromatography (330 g SiO2, 0 to 30%EtOAc in heptane) gave ethyl rac- (4S,5R)‑3‑(4-fluoro‑2-methoxy‑3-methylphenyl)‑4,5-dimethyl‑5‑(trifluoromethyl)‑4,5-dihydrofuran‑2-carboxylate (27.348 g, 72%) as a pale yellow oil. 1HNMR (500MHz, Chloroform-d) δ 6.98 - 6.88 (m, 1H), 6.81 (t, J = 8.7Hz, 1H), 4.20 - 4.07 (m, 2H), 3.66 (s, 3H), 3.58 - 3.49 (m, 1H), 2.21 (d, J = 2.1Hz, 3H), 1.7 (s, 3H), 1.12 (t, J = 7.1Hz, 3H), 1.06 (dq, J = 7.2, 2.3 Hz, 3H) ppm. ESI-MS m / z calc. 376.12976, found 377.5 (M+1)+; Retention time: 1.09 minutes. Step 2:

[0308] 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 (200mL). The reactionmixture was cooled to 5 °Cwith an ice bath. Boron tribromide (112mL, 1M solution in DCM, 112.0 mmol)was added via cannula over 30min, keeping the internal temperature around5 °C. The reactionmixturewas 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 x50mL). The combinedorganic extractswerewashedwith a saturated sodiumbicarbonate solution (5 x 100mL), dried (MgSO4), 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 throughapadof celite. Thefiltrateswerecollected, dried (MgSO4), filteredandconcentrated in vacuo togivea~1:1 mixture of rac‑(1S,2R)‑7-fluoro‑1,2,6-trimethyl‑2‑(trifluoromethyl)‑1,2-dihydro‑4H-furo[2,3‑c]chromen‑4-one and ethyl rac‑(4S,5R)‑3‑(4-fluoro‑2-hydroxy‑3-methylphenyl)‑4,5-dimethyl‑5‑(trifluoromethyl)‑4,5-dihydrofuran‑2-carboxylate (27.7 g) as a waxy solid.

[0309] Themixture was dissolved in DCM (200mL) and TFA (9.8 mL, 127.2 mmol) was added at ambient temperature under stirring. The reaction mixture was heated at reflux and stirred for 2.5 h. The mixture was cooled to ambient temperature and quenched with a saturated aqueous sodium bicarbonate solution (100 mL). The organic phase was 80 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 washed with saturated aqueous sodium bicarbonate solution (4 x 100 mL), dried (Na2SO4) and concentrated in vacuo to give a waxy solid. The waxy solid was re-dissolved in EtOAc (200 mL) and activated charcoal (10 g) was added. The mixture was stirred at ambient temperature overnight. The mixture was filtered through a celite cartridge, washing with EtOAc (3 x 100 mL). The filtrates were concentrated in vacuo to give a waxy solid. Purification by flash chromatography (120 g SiO2, 50% EtOAc in heptane) gave rac‑(1S,2R)‑7-fluoro‑1,2,6-trimethyl‑2‑(trifluoromethyl)‑1,2-dihydro‑4H-furo [2,3-c]chromen‑4-one (24.18 g, 100%). 1H NMR (500 MHz, Chloroform-d) δ 7.25 - 7.23 (m, 1H), 7.05 (t, J = 8.7 Hz, 1H), 3.65 (q, J = 7.4 Hz, 1H), 2.39 (d, J = 2.0 Hz, 3H), 1.67 (q, J = 1.0 Hz, 3H), 1.58 (t, J = 2.2 Hz, 3H) ppm. ESI-MS m / z calc. 316.07227, found 317.4 (M+1)+; 315.4 (M‑1)-; Retention time: 0.94 minutes. Step 3:

[0310] 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 inEtOAc (20mL) and stirredwith activated charcoal (300mg, 24.98mmol) for 18 h. Themixturewas 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 reactionmixture was filtered through a celite cartridge, washing with MeOH. The filtrates were concentrated in vacuo to give a mixture of isomers of methyl 3‑(4-fluoro‑2-hydroxy‑3- methylphenyl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxylate (939.3 mg, 82%) as an off-white solid, of which methyl rac‑(2S,3S,4S,5R)‑3‑(4-fluoro‑2-hydroxy‑3-methylphenyl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofur- an‑2-carboxylate was the major isomer. 1H NMR (500 MHz, Chloroform-d) δ 7.20 (t, J = 7.7 Hz, 1H), 6.57 (t, J = 8.9 Hz, 1H), 4.88 (d, J = 6.1Hz, 2H), 4.28 (dd, J = 8.4, 6.1Hz, 1H), 3.56 (s, 3H), 2.81 (p, J = 7.8Hz, 1H), 2.14 (d, J = 1.6Hz, 3H), 1.4 (3H), 0.92 (dq, J = 7.6, 1.9 Hz, 3H) ppm; alcohol OH not observed. ESI-MS m / z calc. 350.11414, found 349.0 (M‑1)-; Retention time: 0.95 minutes. Step 4:

[0311] 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)tetra- hydrofuran‑2-carboxylate was the major isomer, in tetrahydrofuran (125 mL) at 0 °C. After 15 minutes, the mixture was quenched by the addition of 1MHCl (350mL) and diluted with saturated brine (100mL) and DCM (100mL). The aqueous layerwasextractedwithDCM(3 x100mL). The combinedorganic extractswere dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in DCM (71mL) and treated with TFA (26.62 g, 17.99mL, 233.5mmol). The reaction mixturewasstirredatambient temperature for2h.Themixturewasconcentrated in vacuoand the residueazeotropedwith DCM (2 x 50 mL). The residue was partitioned between DCM (100 mL) and water (50 mL) and the layers separated. The organic layer was washed with water (3 x 50 mL) and the organic extracts dried (MgSO4), filtered and concentrated in vacuo to give 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‑(tri- fluoromethyl)tetrahydrofuran‑2-carboxylic acid (9.753 g, 100%) as a brown oil, which was used as is in the next step. ESI-MS m / z calc. 336.09848, found 335.5 (M‑1)-; Retention time: 0.56 minutes. Step 5:

[0312] K2CO3 (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. The vial was sealed and heated to 80 °C for 5 h. The reactionmixturewas cooled down to ambient temperature anddilutedwithDCM.Themixturewas filtered and the solid washed further with DCM. The filtrates were collected and concentrated in vacuo to give 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 ethyl rac‑(2S,3S,4S,5R)‑3‑(2-ethoxy‑4-fluoro‑3-methylphenyl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-car- boxylate (1.038 g, 89%). ESI-MS m / z calc. 392.16107, found 393.6 (M+1)+; Retention time: 0.99 minutes. 81 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 Step 6:

[0313] 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). The mixture was stirred at ambient temperature for 18 h. The MeOH was removed in vacuo and diluted with 1M HCl to pH 1. The mixture was extracted with DCM (2 x 10 mL). The combinedorganicextractsweredriedbypassing throughaphaseseparatingcartridgeandconcentrated in vacuo to givea 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)tetrahydro- furan‑2-carboxylic acid (778.9mg, 84%). ESI-MSm / z calc. 364.12976, found 363.6 (M‑1)-; Retention time: 0.62minutes. Step 7:

[0314] DMF (2.5 µL, 0.0323 mmol) and oxalyl chloride (27.5 µL, 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. After the end of the addition, the mixture was stirred at ambient temperature for 2h.The reactionmixturewasconcentrated in vacuo.The residuewas taken in2-MeTHF (2mL) and added dropwise to a solution of (R)‑6‑(2,2-dimethyl‑1,3-dioxolan‑4-yl)pyridin‑3-amine (48.8 mg, 0.2512 mmol) and TEA (90µL, 0.6457mmol). The reactionmixturewas stirredat ambient temperature for 2 h. Themixturewasconcentrated in vacuo and loaded onto solid support. Purification by flash chromatography (SiO2, 0 to 100%EtOAc in heptane) gave a mixture of isomers: First Eluting Isomers: 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-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (23mg, 41%). 1HNMR (400MHz,Chloroform-d) δ 8.54 (dd, J = 2.6, 0.7Hz, 1H), 8.35 (s, 1H), 8.12 (dd, J =8.6, 2.6Hz, 1H), 7.47 (d, J = 8.5Hz, 1H), 7.19 (dd, J =8.7, 6.3Hz, 1H), 6.86 (t, J = 8.7 Hz, 1H), 5.16 (t, J = 6.7Hz, 1H), 5.00 (d, J = 11.1 Hz, 1H), 4.42 (ddd, J = 8.0, 6.8, 1.1 Hz, 1H), 4.13 (dd, J = 11.0, 7.9 Hz, 1H), 3.95 - 3.75 (m,3H), 2.76 (p, J =7.7Hz, 1H), 2.20 (d, J =2.1Hz, 3H), 1.69 (s, 3H), 1.51 (dd, J=1.5, 0.7Hz, 3H), 1.48 (t, J = 0.7 Hz, 3H), 1.39 (t, J = 7.0 Hz, 3H), 0.83 - 0.76 (m, 3H) ppm. ESI-MS m / z calc. 540.22473, found 541.2 (M+1)+; 539.3 (M‑1)-; Retention time: 1.09 minutes.

[0315] Second Eluting Isomers: mixture of rel‑(2S,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‑(2R,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-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (13.3mg, 24%). 1HNMR (400MHz,Chloroform-d) δ 8.45 (ddd, J = 18.1, 2.6, 0.7 Hz, 1H), 8.22 (d, J = 2.8 Hz, 1H), 7.85 (ddd, J = 24.6, 8.5, 2.6 Hz, 1H), 7.44 (dd, J = 8.6, 1.1 Hz, 1H), 7.12 (dd, J =8.7, 6.7Hz, 1H), 6.63 (td, J = 8.8, 1.7Hz, 1H), 5.15 (t, J = 6.7Hz, 1H), 4.92 (d, J = 6.6Hz, 1H), 4.41 (ddd, J =8.3, 6.7, 1.5Hz,1H), 4.36 (dd, J=8.8, 6.6Hz,1H), 4.01 -3.79 (m,3H), 2.90 (p, J=7.8Hz,1H), 2.17 (d, J=2.1Hz,3H), 1.59 (d, J=1.1 Hz, 4H), 1.50 (s, 3H), 1.48 (d, J =0.7Hz, 3H), 1.44 (t, J =7.0Hz, 3H), 0.88 - 0.82 (m, 3H)ppm.ESI-MSm / z calc. 540.22473, found 541.2 (M+1)+; 539.3 (M‑1)-; Retention time: 1.06 minutes. These isomers were not separated by chiral SFC. Step 8:

[0316] 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-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (23 mg, 0.042 mmol) (First Eluting Isomers from Step 7) were separated by chiral SFC using a Lux i-Cellulose‑5 column, 5um particle size, 25 cm x 20 mm from Phenomenex, Inc. (Mobile phase: 15%MeOH (containing 20mMAmmonia), 85%CO2. Flow: 100mL / min.) on aMinigramSFC instrument from Berger Instruments to give: First Eluting Isomer (rt = 3.41 min): 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, 87%). ESI-MS m / z calc. 540.22473, found 541.2 (M+1)+; 539.3 (M‑1)-; Retention time: 3.73 minutes.

[0317] SecondEluting Isomer (rt=4.48min): 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-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (9 mg, 78%). ESI-MS m / z calc. 540.22473, found 541.2 (M+1)+; 539.3 (M‑1)-; Retention time: 3.73 minutes. 82 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 Step 9:

[0318] TFA (10µL, 0.130mmol) 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 (10mg,0.0185mmol) (FirstEluting Isomer fromSFCseparation) inTHF(800µL)andwater (200µL).The reactionmixture was stirred at 60 °C for 6 h and for a further 16 h at 40 °C. Themixture was concentrated in vacuo.Purification by reversed phase HPLC-MS using a X-bridge C18 OBD column (150 × 19 mm, 5 mm particle size) from Waters gave rel- (2R,3S,4S,5R)‑N-(6‑((R*)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑3‑(2-ethoxy‑4-fluoro‑3-methylphenyl)‑4,5-dimethyl‑5‑(tri- fluoromethyl)tetrahydrofuran‑2-carboxamide (40, 2.5 mg, 27%). 1H NMR (400MHz, Methanol-d4) δ 8.67 (dd, J = 2.5, 0.7 Hz, 1H), 8.04 (dd, J = 8.6, 2.5 Hz, 1H), 7.52 (dt, J = 8.5, 0.7 Hz, 1H), 7.20 (dd, J = 8.7, 6.3 Hz, 1H), 6.86 (t, J = 8.8 Hz, 1H), 5.03 (d, J =10.8Hz, 1H), 4.71 (dd, J=6.7, 4.2Hz, 1H), 4.34 (dd, J=10.8, 7.9Hz, 1H), 3.96 - 3.82 (m, 2H), 3.79 (dd, J =11.3, 4.2Hz, 1H), 3.65 (dd, J=11.3, 6.7Hz, 1H), 2.77 (p, J =7.6Hz, 1H), 2.19 (d, J =2.1Hz, 3H), 1.67 (d, J=1.1Hz, 3H), 1.43 (t, J = 7.0 Hz, 3H), 0.80 (dq, J = 7.4, 2.3 Hz, 3H) ppm; alcohols OH and amide NH not observed. ESI-MSm / z calc. 500.19342, found 501.2 (M+1)+; 499.2 (M‑1)-; Retention time: 3.17 minutes.

[0319] 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-methylphe- nyl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (9 mg, 0.01665 mmol) (Second Eluting Isomer from SFC separation) was treated in the sameway to give rel-(2S,3R,4R,5S)‑N‑(6‑((R*)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑3‑(2- ethoxy‑4-fluoro‑3-methylphenyl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (41, 2.2 mg, 26%). 1H NMR (400 MHz, Methanol-d4) δ 8.67 (dd, J = 2.5, 0.7 Hz, 1H), 8.04 (dd, J = 8.5, 2.5 Hz, 1H), 7.52 (dt, J = 8.6, 0.7 Hz, 1H), 7.20 (dd, J = 8.7, 6.3 Hz, 1H), 6.86 (t, J = 8.8 Hz, 1H), 5.03 (d, J = 10.8 Hz, 1H), 4.71 (dd, J = 6.6, 4.2 Hz, 1H), 4.35 (dd, J = 10.8, 7.9Hz, 1H), 3.98 - 3.82 (m, 2H), 3.79 (dd, J =11.3, 4.2Hz, 1H), 3.65 (dd, J = 11.3, 6.7Hz, 1H), 2.77 (p, J = 7.6Hz, 1H), 2.19 (d, J = 2.1Hz, 3H), 1.67 (d, J = 1.1Hz, 3H), 1.43 (t, J = 7.0Hz, 3H), 0.80 (dt, J = 7.2, 2.4 Hz, 3H) ppm; alcoholsOHand amide NH not observed. ESI-MS m / z calc. 500.19342, found 501.3 (M+1)+; 499.3 (M‑1)-; Retention time: 3.19 minutes.

[0320] The following compound was made using the method described in Example 5, except that (S)‑6‑(2,2- dimethyl‑1,3-dioxolan‑4-yl)pyridine‑3-aminewasused inplaceof (R)‑6‑(2,2-dimethyl‑1,3-dioxolan‑4-yl)pyridine‑3-amine in step 7. In step 8, purification was performed by chiral SFC using a Lux i-Cellulose‑5 column, 5mmparticle size, 25 cm x 20mm fromDaicel Corporation (Mobile phase: 15%MeOH (containing 20mMAmmonia), 85%CO2. Flow: 100mL / min.) on a Prep‑100 SFC instrument from Waters: Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 42 rel‑(2R,3S,4S,5R)‑N‑(6‑((S*)‑1,2-dihy- droxyethyl)pyridine‑3-yl)‑3‑(2-ethoxy‑4- fluoro‑3-methylphenyl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydro- fura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (400 MHz, Methanol-d4) δ 8.67 (dd, J = 2.6, 0.7 Hz, 1H), 8.04 (dd, J = 8.6, 2.5 Hz, 1H), 7.52 (dt, J = 8.6, 0.7 Hz, 1H), 7.20 (dd, J = 8.7, 6.3 Hz, 1H), 6.86 (t, J = 8.8 Hz, 1H), 5.02 (d, J = 10.8 Hz, 1H), 4.71 (dd, J = 6.6, 4.2 Hz, 1H), 4.34 (dd, J = 10.8, 7.9 Hz, 1H), 3.96 - 3.82 (m, 2H), 3.79 (dd, J = 11.3, 4.2 Hz, 1H), 3.65 (dd, J = 11.3, 6.7 Hz, 1H), 2.77 (p, J = 7.6 Hz, 1H), 2.19 (d, J = 2.1 Hz, 3H), 1.67 (d, J = 1.1 Hz, 3H), 1.43 (t, J = 7.0 Hz, 3H), 0.80 (dt, J = 7.4, 2.4 Hz, 3H) ppm; alcohols OH and amide NH not observed. 500.19342, found 501.3 (M+1)+; 499.3 (M‑1)-; Retention time: 3.19 minutes (Precursor was the first eluting peak by SFC on Chiralpak IC column, rt = 0.85 min) 83 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 43 rel‑(2S,3R,4R,5S)‑N‑(6‑((S*)‑1,2-dihy- droxyethyl)pyridin‑3-yl)‑3‑(2-ethoxy‑4- fluoro‑3-methylphenyl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydro- fura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (400 MHz, Methanol-d4) δ 8.67 (dd, J = 2.5, 0.7 Hz, 1H), 8.04 (dd, J = 8.6, 2.5 Hz, 1H), 7.52 (dt, J = 8.6, 0.7 Hz, 1H), 7.20 (dd, J = 8.8, 6.3 Hz, 1H), 6.86 (t, J = 8.8 Hz, 1H), 5.03 (d, J = 10.8 Hz, 1H), 4.71 (dd, J = 6.6, 4.2 Hz, 1H), 4.34 (dd, J = 10.8, 7.9 Hz, 1H), 3.96 - 3.82 (m, 2H), 3.79 (dd, J = 11.3, 4.2 Hz, 1H), 3.65 (dd, J = 11.3, 6.6 Hz, 1H), 2.77 (p, J = 7.6 Hz, 1H), 2.19 (d, J = 2.1 Hz, 3H), 1.67 (d, J = 1.2 Hz, 3H), 1.43 (t, J = 7.0 Hz, 3H), 0.80 (dt, J = 7.5, 2.4 Hz, 3H) ppm; alcohols OH and amide NH not observed. 500.19342, found 501.3 (M+1)+; 499.2 (M‑1)-; Retention time: 3.19 minutes (Precursor was the second eluting peak by SFC on Chiralpak IC column, rt = 1.00 min)

[0321] The following compounds were made using the method described in Example 5, except that the hydrogenation step 3 was carried out using 60 psi of hydrogen. In step 5, methyl iodide was used in place of ethyl iodide as the alkylating agent. In step 7, in the case of compounds 44 and 45, (S)‑6‑(2,2-dimethyl‑1,3-dioxolan‑4-yl)pyridine‑3-aminewas used in place of (R)‑6‑(2,2-dimethyl‑1,3-dioxolan‑4-yl)pyridine‑3-amine. In step 8, purificationwasperformed by chiral SFCusing a (R,R)‑Whelk-O1 column, 5 umparticle size, 25 cmx21.1mm fromDaicel (Mobile phase: 5 to 25%MeOH (containing 20 mM Ammonia), 95 to 75 % CO2. Flow: 100 mL / min.) on a Minigram SFC instrument from Berger Instruments. In step 9, DCM was used as the solvent rather than a mixture of THF and water: Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 44 rel‑(2S,3R,4R,5S)‑N‑(6‑((S*)‑1,2-dihy- droxyethyl)138yridine‑3-yl)‑3‑(4- fluoro‑2-methoxy‑3-methylphenyl)‑4,5- dimethyl‑5‑(trifluoromethyl)tetrahydro- fura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (500 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.65 (d, J = 2.4 Hz, 1H), 8.01 (dd, J = 8.6, 2.6 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.25 - 7.06 (m, 2H), 7.01 - 6.94 (m, 1H), 5.05 (d, J = 10.6 Hz, 1H), 4.55 (dd, J = 6.8, 4.2 Hz, 1H), 4.28 (dd, J = 10.7, 7.6 Hz, 1H), 3.72 (s, 3H), 3.62 (dd, J = 11.0, 4.2 Hz, 1H), 3.44 (dd, J = 11.0, 6.8 Hz, 2H), 2.73 (p, J = 7.4 Hz, 1H), 2.16 (d, J = 2.0 Hz, 3H), 1.62 (s, 3H), 0.73 (d, J = 7.4 Hz, 3H) ppm. 486.1778, found 487.6 (M+1)+; 485.6 (M‑1)-; Retention time: 3.02 minutes (Precursor was the first eluting peak by SFC on (R,R)‑Whelk-O1 column, rt = 1.31 min) 45 rel‑(2R,3S,4S,5R)‑N‑(6‑((S*)-1,2-dihy- droxyethyl)pyridin‑3-yl)‑3‑(4-fluoro‑2- methoxy‑3-methylphenyl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.68 - 8.59 (m, 1H), 7.95 (dd, J = 8.5, 2.5 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.7, 6.5 Hz, 1H), 6.97 (t, J = 8.8 Hz, 1H), 5.30 (d, J = 4.9 Hz, 1H), 5.03 (d, J = 10.6 Hz, 1H), 4.61 (t, J = 5.9 Hz, 1H), 4.52 (dt, J = 6.7, 4.5 Hz, 1H), 4.27 (dd, J = 10.7, 7.6 Hz, 1H), 3.71 (s, 3H), 3.61 (ddd, J = 10.4, 6.0, 4.1 Hz, 1H), 3.43 (ddd, J = 10.9, 6.9, 5.8 Hz, 1H), 2.71 (p, J = 7.5 Hz, 1H), 2.14 (d, J = 2.0 Hz, 3H), 1.60 (s, 3H), 0.77 - 0.68 (m, 3H) ppm. 486.1778, found 487.6 (M+1)+; 485.6 (M‑1)-; Retention time: 3.02 minutes (Precursor was the second eluting peak by SFC on (R,R)‑Whelk-O1 column, rt = 2.20 min) 84 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 46 rel‑(2S,3R,4R,5S)‑N‑(6‑((R*)‑1,2-dihy- droxyethyl)pyridin‑3-yl)‑3‑(4-fluoro‑2- methoxy‑3-methylphenyl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofura n‑2-carboxamide ESI-MS m / z calc. 486.1778, found 487.6 (M+1)+; 485.6 (M‑1)-; Retention time: 3.02 minutes (Precursor was the first eluting peak by SFC on (R,R)‑Whelk-O1 column, rt = 1.26 min) 47 rel‑(2R,3S,4S,5R)‑N‑(6‑((R*)‑1,2-dihy- droxyethyl)pyridin‑3-yl)‑3‑(4-fluoro‑2- methoxy‑3-methylphenyl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.63 (d, J = 2.5 Hz, 1H), 7.99 (dd, J = 8.6, 2.6 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.20 (dd, J = 8.7, 6.5 Hz, 1H), 6.98 (t, J = 8.8 Hz, 1H), 5.31 (d, J = 4.9 Hz, 1H), 5.04 (d, J = 10.6 Hz, 1H), 4.62 (t, J = 5.9 Hz, 1H), 4.53 (dt, J = 7.0, 4.5 Hz, 1H), 4.28 (dd, J = 10.6, 7.5 Hz, 1H), 3.72 (s, 3H), 3.62 (ddd, J = 10.5, 6.1, 4.2 Hz, 1H), 3.49 - 3.39 (m, 1H), 2.72 (p, J = 7.5 Hz, 1H), 2.15 (d, J = 2.0 Hz, 3H), 1.61 (s, 3H), 0.73 (d, J = 7.0 Hz, 3H) ppm. 486.1778, found 487.6 (M+1)+; 485.6 (M‑1)-; Retention time: 3.02 minutes (Precursor was the second eluting peak by SFC on (R,R)‑Whelk-O1 column, rt = 2.10 min) Example 6 rel‑(2S,3R,4R,5S)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methoxyphenyl)‑N‑(6‑((S*)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (48) and rel‑(2R,3S,4S,5R)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methoxyphenyl)‑N‑(6‑((S*)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (49)

[0322] 85 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 Step 1:

[0323] Amixtureof ethyl rac‑(4R,5R)‑4,5-dimethyl‑5‑(trifluoromethyl)‑3‑(((trifluoromethyl)sulfonyl)oxy)‑4,5-dihydrofur- an‑2-carboxylate (1.44 g, 3.169 mmol), 2‑(3‑(difluoromethyl)‑4-fluoro‑2-methoxyphenyl)‑4,4,5,5-tetramethyl‑1,3,2-diox- aborolane (900 mg, 2.592 mmol), Pd(Ph3)4 (148 mg, 0.1281 mmol) and aqueous K2CO3 (2.6 mL of 2 M, 5.200 mmol) in 1,4-dioxane (25 mL) was heated at 100 °C for 2 h. Themixture was concentrated in vacuo and loaded onto solid support. Purification by flash chromatography (SiO2, 0 to 25% EtOAc in heptane) gave ethyl rac-(4S,5R)‑3‑(3‑(difluoromethyl)‑4- fluoro‑2-methoxyphenyl)‑4,5-dimethyl‑5‑(trifluoromethyl)‑4,5-dihydrofuran‑2-carboxylate (708mg, 66%) as a colourless oil. 1HNMR(400MHz,Chloroform-d) δ7.25 (ddt, J=7.3, 6.2, 1.2Hz, 1H), 6.95 (td, J=53.6, 0.7Hz, 1H), 6.94 (tt, J =8.7, 0.9 Hz, 1H), 4.17 (qd, J = 7.1, 1.3Hz, 2H), 3.77 (s, 3H), 3.62 - 3.53 (m, 1H), 1.71 (q, J = 1.0Hz, 3H), 1.15 (t, J = 7.1Hz, 3H), 1.07 (dq, J = 7.1, 2.2 Hz, 3H) ppm. ESI-MS m / z calc. 412.11093, found 413.2 (M+1)+; Retention time: 1.05 minutes. Step 2:

[0324] A solution of ethyl rac‑(4S,5R)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methoxyphenyl)‑4,5-dimethyl‑5‑(trifluoro- methyl)‑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. The mixture was concentrated in vacuo and partitioned between aqueous AcOH and EtOAc. The aqueous layer was separated and extracted twicewithEtOAc. The combined organic phaseswerewashedwith aqueousNaHCO3and twicewithwater. The organic phase was dried (MgSO4) and concentrated in vacuo to give a mixture of methyl rac‑(2S,3S,4S,5R)‑3‑(3‑(di- fluoromethyl)‑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-car- boxylate (2.87 g, 84%) as an orange oil. 1HNMR (400MHz, Chloroform-d) δ 7.43 - 7.32 (m, 1H), 7.01 - 6.95 (m, 1H), 7.09 - 6.80 (m, 1H), 4.89 (d, J =10.2Hz, 1H), 4.21 - 4.15 (m, 1H), 3.84 (s, 3H), 3.71 (s, 3H), 2.73 (p, J =7.7Hz, 1H), 1.63 (q, J =1.2 Hz, 3H), 0.78 (ddq, J = 7.2, 4.7, 2.3 Hz, 3H) ppm. Step 3:

[0325] 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‑(trifluoro- methyl)tetrahydrofuran‑2-carboxylate (2.87 g, 7.169 mmol) in 2-MeTHF (35 mL) in a water bath at ambient temperature. Duringaddition, a~3 ° exothermwasobserved.The reactionmixturewasstirred for 2h, afterwhich timea further portionof potassium tert-butoxide (860mg)wasadded.Themixturewasstirredatambient temperature fora further1h.The reaction was quenchedwith a diluted HCl solution. The aqueous layer was separated andwashedwith EtOAc, dried (MgSO4) and concentrated in vacuo to give 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 (3.32 g, 74%) as an orange oil. 1H NMR(400MHz,Chloroform-d) δ7.43 - 7.35 (m,1H), 6.98 (ddd, J=13.4, 9.3, 4.2Hz, 1H), 6.93 (t, J =53.6Hz, 1H), 4.93 (d, J = 10.3 Hz, 1H), 4.18 - 4.14 (m, 1H), 3.84 (s, 3H), 2.76 (p, J = 7.7 Hz, 1H), 1.67 - 1.62 (m, 3H), 0.82 - 0.75 (m, 3H) ppm; OH acid not observed. ESI-MS m / z calc. 386.09528, found 385.1 (M‑1)-; Retention time: 0.57 minutes. Step 4:

[0326] T3P (310 µL of 50 %w / w, 0.5208 mmol) was added to a solution of a mixture of rac-(2R,3S,4S,5R)‑3‑(3‑(di- fluoromethyl)‑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 (100mg, 0.2589mmol), (S)‑6‑(2,2-dimethyl‑1,3-dioxolan‑4-yl)pyridin‑3-amine (78mg, 0.4016mmol) and triethylamine (110µL, 0.7892mmol) in ethyl acetate (2mL). The reactionmixturewasstirredat 50 °C for 30minand thenat 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. Purification by flash chromatography (SiO2, 0 to 75% EtOAc in heptane) gave a mixture of re- l‑(2R,3S,4S,5R)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methoxyphenyl)‑N‑(6‑((S*)‑2,2-dimethyl‑1,3-dioxolan‑4-yl)pyridin‑3- yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide and rel‑(2S,3R,4R,5S)‑3‑(3‑(difluoromethyl)‑4- fluoro‑2-methoxyphenyl)‑N‑(6‑((S*)‑2,2-dimethyl‑1,3-dioxolan‑4-yl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahy- drofuran‑2-carboxamide (50mg, 34%). 1HNMR (400MHz,Chloroform-d) δ 8.56 (t, J = 2.5Hz, 1H), 8.38 (s, 1H), 8.13 (dt, J =8.7, 2.9Hz,1H), 7.50 (d, J=8.5Hz,1H), 7.11 -6.76 (m,2H), 5.18 (t, J =6.7Hz,1H), 5.01 (d, J=10.6Hz,1H), 4.43 (ddd, J= 8.4, 6.7, 0.8 Hz, 1H), 4.16 - 4.08 (m, 1H), 3.98 - 3.88 (m, 1H), 3.84 (d, J = 0.6 Hz, 4H), 2.78 (p, J = 7.7 Hz, 1H), 1.69 (s, 3H), 86 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 1.50 - 1.45 (m, 6H), 0.84 - 0.75 (m, 3H) ppm; NH amide not observed. ESI-MS m / z calc. 562.19025, found 563.2 (M+1)+; 561.3 (M‑1)-; Retention time: 1.02 minutes. Step 5:

[0327] The mixture of rel‑(2R,3S,4S,5R)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methoxyphenyl)‑N-(6‑((S*)‑2,2-di- methyl‑1,3-dioxolan‑4-yl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide and re- l‑(2S,3R,4R,5S)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methoxyphenyl)‑N‑(6‑((S*)‑2,2-dimethyl‑1,3-dioxolan‑4-yl)pyridin‑3- yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (50 mg, 0.089 mmol) were separated by chiral SFC using a Chiralpak AS-H column, 5um particle size, 25 cm x 10 mm from Daicel Corporation (Mobile phase: 15 % MeOH (containing 20 mM Ammonia), 85 % CO2. Flow: 10 mL / min.) on a Minigram SFC instrument from Berger Instruments to give: First Eluting Isomer (rt = 2.14min): rel‑(2S,3R,4R,5S)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methoxyphenyl)‑N-(6‑((S*)‑2,2- dimethyl‑1,3-dioxolan‑4-yl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (15 mg, 60%). ESI-MS m / z calc. 562.19025, found 563.2 (M+1)+; 561.2 (M‑1)-; Retention time: 3.5 minutes.

[0328] Second Eluting Isomer (rt = 3.60 min): rel‑(2R,3S,4S,5R)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methoxyphe- nyl)‑N‑(6‑((S*)‑2,2-dimethyl‑1,3-dioxolan‑4-yl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (12 mg, 48%). ESI-MS m / z calc. 562.19025, found 563.2 (M+1)+; 561.2 (M‑1)-; Retention time: 3.49 minutes. Step 6:

[0329] TFA (10 µL, 0.1298 mmol) was added to a solution of rel‑(2S,3R,4R,5S)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2- methoxyphenyl)‑N‑(6‑((S*)‑2,2-dimethyl‑1,3-dioxolan‑4-yl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofur- an‑2-carboxamide (15mg, 0.02667mmol) (First Eluting Isomer fromSFCseparation) in THF (800µL) andwater (200µL). The reaction mixture was stirred overnight at 60 °C. The mixture was concentrated in vacuo. Purification by reversed phase HPLC-MS using a X-bridge C18 OBD column (150 × 19 mm, 5 mm particle size) from Waters gave rel- (2S,3R,4R,5S)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methoxyphenyl)‑N‑(6‑((S*)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5-di- methyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (48, 6mg, 41%). 1HNMR (400MHz,Methanol-d4) δ 8.71 (dd, J =2.6, 0.8Hz,1H), 8.08 (dd, J=8.5, 2.5Hz,1H), 7.64 -7.58 (m,1H), 7.55 (dt, J=8.6,0.7Hz,1H), 7.21 -6.89 (m,2H), 5.09 (d, J = 10.4 Hz, 1H), 4.74 (dd, J = 6.6, 4.2 Hz, 1H), 4.36 (dd, J = 10.4, 8.1 Hz, 1H), 3.87 (s, 3H), 3.86 - 3.62 (m, 2H), 2.83 (p, J = 7.7 Hz, 1H), 1.70 (d, J = 1.2 Hz, 3H), 0.90 - 0.82 (m, 3H) ppm; alcohols OH and amide NH not observed. ESI-MSm / z calc. 522.15894, found 522.9 (M+1)+; 521.0 (M‑1)-; Retention time: 3.04 minutes.

[0330] rel‑(2R,3S,4S,5R)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2-methoxyphenyl)‑N‑(6‑((S*)‑2,2-dimethyl‑1,3-dioxolan‑4-yl) pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxamide (12 mg, 0.02133 mmol) (Second Eluting Isomer from SFC separation) was treated in the same way to give rel‑(2R,3S,4S,5R)‑3‑(3‑(difluoromethyl)‑4-fluoro‑2- methoxyphenyl)‑N‑(6‑((S*)‑1,2-dihydroxyethyl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(trifluoromethyl)tetrahydrofuran‑2-carboxa- mide (49, 4mg, 34%). 1HNMR (400MHz,Methanol-d4) δ8.69 (dd, J = 2.6, 0.8Hz, 1H), 8.06 (dd, J =8.5, 2.5Hz, 1H), 7.63 - 7.57 (m, 1H), 7.53 (dt, J = 8.6, 0.7 Hz, 1H), 7.20 - 6.87 (m, 2H), 5.08 (d, J = 10.4Hz, 1H), 4.72 (dd, J = 6.6, 4.2 Hz, 1H), 4.34 (dd, J = 10.4, 8.1 Hz, 1H), 3.86 (s, 3H), 3.84 - 3.61 (m, 2H), 2.82 (p, J = 7.7 Hz, 1H), 1.69 (d, J = 1.2 Hz, 3H), 0.88 - 0.80 (m, 3H) ppm; alcohols OH and amide NH not observed. ESI-MS m / z calc. 522.15894, found 522.9 (M+1)+; 521.0 (M‑1)-; Retention time: 3.01 minutes.

[0331] The following compounds were made using the method described in Example 6, except that (R)‑6‑(2,2- dimethyl‑1,3-dioxolan‑4-yl)pyridine‑3-aminewasused in place of (S)‑6‑(2,2-dimethyl‑1,3-dioxolan‑4-yl)pyridine‑3-amine in the amide coupling step 4. In 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 % CO2. 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: 87 EP 4 699 607 A2 5 10 15 20 25 30 35 40 45 50 55 Cmpd No. Compound Name LC / MS NMR (shifts in ppm) 50 rel‑(2S,3R,4R,5S)‑3‑(3‑(difluoromethyl)‑4- fluoro‑2-methoxyphenyl)‑N‑(6‑((R*)‑1,2-dihy- droxyethyl)pyridin‑3-yl)‑4,5-dimethyl‑5‑(tri- fluoromethyl)tetrahydrofura n‑2-carboxamide ESI-MS m / z calc. 1H NMR (500 MHz, Chloro- form‑d) δ 8.67 (s, 1H), 8.57 (s, 1H), 8.18 (d, J = 8.6 Hz, 1H), 7.59 - 7.49 (m, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.10 - 6.80 (m, 2H), 5.02 (d, J = 10.6 Hz, 1H), 4.83 (s, 1H), 4.15 (dd, J = 10.6, 8.4 Hz, 1H), 3.92 (dd, J = 11.3, 3.7 Hz, 1H), 3.84 (s, 3H), 3.76 (dd, J = 11.4, 5.3 Hz...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: X2a is N, N+-O-, or C-R2a; X3a is N or N+-O-; X5a is N, N+-O-, or C-R5a; X6a is N, N+-O-, or C-R6a; Rd is (CH2)m(CHRe)n(CH2)pH; m, n, and p are each independently 0 or 1; Re is H, OH, halo, C1-C6 alkoxy, or C1-C6 haloalkoxy; R2a and R6a are each independently H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R5a is H, halo, CH2OH, C1-C6 alkyl, or C1-C6 haloalkyl; R4b1 and R4b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; R5b1 and R5b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; X3c is N or C-R3c; X4c is N or C-R4c; X5c is N or C-R5c; X6c is N or C-R6c; R2c is H, OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L1-L2-(C3-C6 cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo; L1 is a bond or O; L2 is a bond or C1-C6 alkylene; R3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; or X3c is C-R3c, and R2c and R3c, together with the carbon atoms to which they are attached, form a ring of formula: Z1 and Z2 are each independently O or CH2; each R is independently H or halo; R4c is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; R5c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; and R6c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; provided that no more than two of X2a, X3a, X5a, and X6a are N or N+-O-; and provided that no more than one of X3c, X4c, X5c, and X6c is N.

2. The compound of claim 1, wherein the compound has formula (I-A) or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein the compound has formula (I-A-1) or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein the compound has formula (I-B) or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, wherein the compound has formula (I-B-1) or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1, 2, and 4, or a pharmaceutically acceptable salt thereof, wherein x2a is C-R2a; and R2a is H, and / or wherein X3a is N, and / or wherein X5a is N or C-R5a; and R5a is H, halo, or CH2OH, optionally wherein X5a is C-R5a; and R5a is H, F, or CH2OH, and / or wherein X6a is N or C-R6a; and R6a is H, optionally wherein X6a is C-R6a; and R6a is H.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R4b1 is H or C1-C6 alkyl, optionally wherein R4b1 is H or CH3, and / or wherein R4b2 is H or C1-C6 alkyl, optionally wherein R4b2 is H or CH3, and / or wherein R5b1 is C1-C6 alkyl or C1-C6 haloalkyl, optionally wherein R5b1 is CH3 or CF3, and / or wherein R5b2 is C1-C6 alkyl or C1-C6 haloalkyl, optionally wherein R5b2 is CH3 or CF3, and / or wherein R2c is OH, halo, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy, optionally wherein R2c is OH, Cl, CH3, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCH2CH2F, or OCH2CHF2, and / or wherein X3c is N or C-R3c; and R3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl, optionally wherein X3c is C-R3c; and R3c is H, F, CH3, CHF2, or CF3, and / or wherein X4c is C-R4c; and R4c is H, halo, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy, optionally wherein X4c is C-R4c; and R4c is H, F, CHF2, OCH2CH3, OCHF2, OCF3, and / or wherein X5c is C-R5c; and R5c is H, and / or wherein X6c is C-R6c; and R6c is H, and / or wherein Rd is (CH2)pH, optionally wherein Rd is H or CH3, and / or wherein Rd is (CHRe)n(CH2)pH, optionally wherein Rd is CH2F, CH2OH, or CH(OH)CH3, and / or wherein Rd is (CH2)m(CHRe)nH, optionally wherein Rd is CH2OCH3 or CH2CH2OCH3.

8. A compound selected from Table A, or a pharmaceutically acceptable salt thereof, or a compound selected from: and or a pharmaceutically acceptable salt thereof.

9. The compound of any one of claims 1-8 in non-salt form.

10. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or the compound of claim 9 and one or more pharmaceutically acceptable carriers or vehicles.

11. A pharmaceutical composition comprising the compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or the compound of claim 9 and one or more pharmaceutically acceptable carriers or vehicles.

12. A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject the compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, the compound of claim 9, or the pharmaceutical composition of claim 10 or 11, optionally wherein the voltage-gated sodium channel is NaV1.8.

13. 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 claims 1-8, or a pharmaceutically acceptable salt thereof, the compound of claim 9, or the pharmaceutical composition of claim 10 or 11, optionally (i) where the method comprises treating or lessening the severity in the subject of neuropathic pain, optionally wherein: the neuropathic pain comprises post-herpetic neuralgia; or the neuropathic pain comprises small-fiber neuropathy; or the neuropathic pain comprises idiopathic small-fiber neuropathy; or the neuropathic pain comprises diabetic neuropathy, optionally wherein the diabetic neuropathy comprises diabetic peripheral neuropathy, (ii) wherein the method comprises treating or lessening the severity in the subject of musculoskeletal pain, optionally wherein the musculoskeletal pain comprises osteoarthritis pain (iii) wherein the method comprises treating or lessening the severity in the subject of acute pain, optionally wherein the acute pain comprises acute post-operative pain (iv) wherein the method comprises treating or lessening the severity in the subject of postsurgical pain, optionally wherein: the postsurgical pain comprises bunionectomy pain; or the postsurgical pain comprises abdominoplasty pain; or the postsurgical pain comprises herniorrhaphy pain, or (v) wherein the method comprises treating or lessening the severity in the subject of visceral pain.

14. The method of any one of claims 12-13, wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound, pharmaceutically acceptable salt, or pharmaceutical composition.

15. Use of the compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, the compound of claim 9, or the pharmaceutical composition of claim 10 or 11, as a medicament.

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