N-(hydroxyalkyl(hetero)aryl)tetrahydrofurancarboxamides as modulators of sodium channels

Abstract

Compounds of formula I and pharma- ceutically acceptable salts thereof are provided that are useful as inhibitors of sodium channels.Also provided are pharmaceutical compositions comprising the compounds or pharma- ceutically acceptable salts, and methods of using the compounds, pharma- ceutically acceptable salts, and pharmaceutical compositions in the treatment of various disorders, including pain.In yet another aspect, the invention relates to a method of inhibiting voltage-gated sodium channels in a subject by administering a compound, a pharma- ceutically acceptable salt, or a pharmaceutical composition to the subject. JPEG2024522292000158.jpg5870

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 196,946, filed June 4, 2021, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and prevent further damage to injured tissue. Nevertheless, there are many conditions in which pain persists beyond its usefulness or in which patients would benefit from pain inhibition. Neuropathic pain is a form of chronic pain caused by sensory nerve damage (Dieleman, JP, et al., Incidence rates and treatment of neuropathic pain conditions in the general population. Pain, 2008. 137(3):pp. 681-688). Neuropathic pain can be divided into two categories: pain caused by systemic metabolic damage to nerves and pain caused by discrete nerve damage. Metabolic neuropathies include postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Indications for discrete nerve damage include nerve entrapment injuries, such as pain after amputation surgery, postoperative nerve injury pain, and neuropathic back pain.

[0003] Voltage-gated sodium channels (Na V ) is involved in pain signaling. V Sodium channel receptors (SCRs) are biological mediators of electrical signaling and mediate the rapid upstroke of action potentials in many excitable cell types (e.g., neurons, skeletal muscle cells, cardiac myocytes). Evidence for a role for these channels in normal physiology, pathological conditions resulting from mutations in sodium channel genes, preclinical studies in animal models, and clinical pharmacology of known sodium channel modulators all support the role of Na in pain sensation. V(Rush, A. M. and T. R. Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Na V 1.8 Sodium Channels.Mol.Interv.,2007.7(4):p.192-5), England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin. Investig. Drugs 17(12), p.1849-64 (2008), Krafte, DSand Bannon, AW, Sodium channels and Nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol.8(1), p.50-56(2008)). Na V Na mediates the rapid upstroke of action potentials in many excitable cell types (e.g., neurons, skeletal muscle cells, cardiac myocytes) and is therefore involved in the initiation of signal transduction in those cells (Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). Na plays a key role in the initiation and propagation of neuronal signals. V Because of the role played by Na V Antagonists that reduce current can prevent or reduce nerve signaling, VIt has been thought that these channels may potentially reduce pain in conditions where hyperexcitability is observed (Chahine, M., Chatelier, A., Babich, O., and Krupp, JJ, Voltage-gated sodium channels in neurological disorders. CNS Neurol. Disord. Drug Targets 7 (2), p. 144-58 (2008)). Several clinically useful analgesics are known to be sodium-gated. V Local anesthetics such as lidocaine have been identified as inhibitors of the Na channel. V Other compounds, such as carbamazepine, lamotrigine, and tricyclic antidepressants, which block pain by inhibiting channels and have been shown to be effective in reducing pain, have also been suggested to act by blocking sodium channels (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. Eur. J. Pain 6 Suppl. A, p. 3-9 (2002); Wang, GK, Mitchell, J., and Wang, SY, Block of persistent late Na + currents by antidepressant sertraline and paroxetine.J.Membr.Biol.222(2),p.79-90(2008)).

[0004] Na V form a subfamily of the voltage-gated ion channel superfamily and V 1.1~Na V It contains nine isoforms designated 1.1 and 1.9. The tissue localization of the nine isoforms varies. V 1.4 is the primary sodium channel in skeletal muscle, and Na V 1.5 is the primary sodium channel in cardiac myocytes. Na V 1.7, 1.8, and 1.9 are primarily localized in the peripheral nervous system, and Na V1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the central and peripheral nervous systems. The functional behavior of the nine isoforms is similar, but they differ in the details of their voltage dependence and kinetic behavior (Catterall, WA, Goldin, AL, and Waxman, SG, International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57(4), p. 397 (2005)).

[0005] At the time of their discovery, Na V The 1.8 channel was identified as a likely target for analgesia (Akopian, AN, L. Sivilotti, and JN Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562):pp. 257-62). Subsequently, Na V 1.8 has been shown to be a carrier of the sodium current that sustains action potential firing in small dorsal root ganglion (DRG) neurons in nociceptive sensory neurons (Blair, NT and BP Bean, Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current). + current, and Ca 2+ current in the action potentials of nociceptive sensory neurons.J.Neurosci.,2002.22(23):p.10277-90). Na V 1.8 is involved in spontaneous firing in injured neurons, such as those that cause neuropathic pain (Roza, C., et al., The tetrodotoxin-resistant Na+ channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice.J.Physiol.,2003.550(Pt 3):p.921-6、Jarvis,M.F.,et al.,A-803467,a potent and selective Na V 1.8 sodium channel blocker,attenuates neuropathic and inflammatory pain in the rat.Proc.Natl.Acad.Sci.U S A,2007.104(20):p.8520-5、Joshi,S.K.,et al.,Involvement of the TTX-resistant sodium channel Na V 1.8 in inflammatory and neuropathic,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,Na V 1.8.Pain,2002.95(1-2):p.143-52、Dong,X.W.,et al.,Small interfering RNA-mediated selective knockdown of Na V1.8 tetrodotoxin-resistant sodium channel reverses mechanical 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 sodium channel 1.8(Na V 1.8)mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats.J.Biol.Chem.286(46):p.39836-47)。Na VThe small DRG neurons in which Na1.8 is expressed contain nociceptors involved in pain signaling. V 1.8 mediates large amplitude action potentials in small neurons of the dorsal root ganglion (Blair, NT and BP Bean, Roles of tetrodotoxin (TTX)-sensitive Na + Current, TTX-resistant Na + current, and Ca 2+ current in the action potentials of nociceptive sensory neurons.J.Neurosci.,2002.22(23):p.10277-90). Na V 1.8 is required for rapid repetitive action potentials in nociceptors and for spontaneous activity of injured neurons. (Choi, JS and SG Waxman, Physiological interactions between Na V 1.7 and Na V 1.8 sodium channels: a computer simulation study.J.Neurophysiol.106(6):p.3173-84, Renganathan, M., TRCummins, and SGWaxman, Contribution of Na( V )1.8 sodium channels to action potential electrogenesis in DRG neurons.J.Neurophysiol.,2001.86(2):p.629-40, Roza,C.,et al.,The tetrodotoxin-resistant Na + Channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550(Pt 3): pp. 921-926. In depolarized or damaged DRG neurons, Na V1.8 appears to be a driver of hyperexcitability (Rush, AM, 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, Na V 1.8 mRNA expression levels have been shown to increase in DRG (Sun, W., et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats. Brain, 135(Pt 2): pp. 359-75; Strickland, IT, et al., Changes in the expression of Na V 1.7,Na V 1.8 and Na V 1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain.Eur.J.Pain,2008.12(5):p.564-72, Qiu,F.,et al.,Increased expression of tetrodotoxin-resistant sodium channels Na V 1.8 and Na V 1.9 within dorsal root ganglia in a rat model of bone cancer pain.Neurosci.Lett.,512(2):p.61-6). The present inventors have found that some voltage-gated sodium channel inhibitors, for example, have a poor therapeutic window (e.g., Na VIt has been discovered that selective Na V There remains a need to develop selective voltage-gated sodium channel inhibitors, such as 1.8 inhibitors. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Dieleman,JP,et al.,Incidence rates and treatment of neuropathic pain conditions in the general population.Pain,2008.137(3):p.681-8 [Non-patent document 2] Rush, AMand TRCummins, Painful Research:Identification of a Small-Molecule Inhibitor that Selectively Targets NaV1.8 Sodium Channels.Mol.Interv.,2007.7(4):p.192-5) [Non-patent document 3] England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin. Investig. Drugs 17(12), p.1849-64 (2008) [Non-patent document 4] Krafte, DSand Bannon, AW, Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol.8(1), p.50-56(2008) [Non-patent document 5] Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001) [Non-patent document 6] Chahine, M., Chatelier, A., Babich, O., and Krupp, JJ, Voltage-gated sodium channels in neurological disorders.CNS Neurol.Disord.Drug Targets 7 (2), p.144-58(2008) [Non-Patent Document 7] Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action.Eur.J.Pain 6 Suppl.A, p.3-9(2002) [Non-patent document 8] Wang, GK, Mitchell, J., and Wang, SY, Block of persistent late Na+ currents by antidepressant sertraline and paroxetine.J.Membr.Biol.222(2),p.79-90(2008) [Non-Patent Document 9] Catterall, WA, Goldin, AL, and Waxman, SG, International Union of Pharmacology.XLVII.Nomenclature and structure-function relationships of voltage-gated sodium channels.Pharmacol.Rev.57(4), p.397(2005) [Non-Patent Document 10] 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 [Non-Patent Document 11] Blair, N.T. and B.P. Bean, Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002. 22(23): p. 10277-90 [Non-Patent Document 12] 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 [Non-Patent Document 13] 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 [Non-Patent Document 14] Joshi, S.K., et al., Involvement of the TTX-resistant sodium channel NaV1.8 in inflammatory and neuropathic, but not post-operative, pain states. Pain, 2006. 123(1-2): pp. 75-82

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

[0008] In another aspect, the invention relates to pharmaceutical compositions comprising the compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or vehicles.

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

[0010] In yet another aspect, the present invention relates to methods of treating or lessening the severity in a subject of various diseases, disorders, or conditions, including, but not limited to, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia, by administering a compound, pharmaceutically acceptable salt, or pharmaceutical composition to the subject. [Brief explanation of the drawings]

[0011] [Figure 1] 1 shows an XRPD pattern characteristic of amorphous Compound 1. [Figure 2] 1 shows an XRPD pattern characteristic of amorphous Compound 7. [Figure 3] 1 shows an XRPD pattern characteristic of amorphous Compound 8. [Figure 4] 1 shows an XRPD pattern characteristic of compound 16 in crystalline form. [Figure 5] 1 shows an XRPD pattern characteristic of amorphous compound 21. [Figure 6] 1 shows an XRPD pattern characteristic of amorphous compound 35. DETAILED DESCRIPTION OF THE INVENTION

[0012] In one aspect, the present invention provides a compound of formula (I): [ka] , or a pharmaceutically acceptable salt thereof, X 2a is N, N + -O - , or CR 2a and X 3a is N or N + -O - and X 5a is N, N +-O - , or CR 5a and X 6a is N, N + -O - , or CR 6a and R d is (CH2) m (CHR e ) n (CH2) p H, m, n, and p are each independently 0 or 1; R e is H, OH, halo, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 2a and R 6a are each independently H, halo, C-C alkyl, or C-C haloalkyl; R 5a is H, halo, CHOH, C-C alkyl, or C-C haloalkyl; R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; R 5b1 and R 5b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; X 3c is N or CR 3c and X 4c is N or CR 4c and X 5c is N or CR 5c and X 6c is N or CR 6c and R 2c is H, OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2-(C3-C6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; L 1 is a bond or O, L 2 is a bond or C1-C6 alkylene; R 3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl, or X 3c is CR 3c and R 2c and R 3c together with the carbon atoms to which they are attached form a ring of the formula: [ka] ; Z1 and Z2 are each independently O or CH2; each R is independently H or halo; R 4c is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 5c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 6c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; However, X 2a , X 3a , X 5a , and X 6a Two or fewer of these are N or N + -O - and X 3c , X 4c , X 5c , and X 6c The condition is that at most one of

[0013] For the purposes of this invention, chemical elements are defined as follows:th Further, general principles of organic chemistry are identified in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5 th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0014] As used herein, the term "compounds of the invention" refers to compounds of formula (I) described herein, and all of its embodiments (e.g., formula (IA), etc.), and compounds identified in Table A.

[0015] As described herein, the compounds of the present invention may contain multiple variables (e.g., R 1 , X 3a , R 5b As one of ordinary skill in the art will recognize, combinations of groups envisioned by the present invention are those that result in the formation of stable or chemically feasible compounds. The term "stable" in this context refers to compounds that do not substantially change when subjected to conditions that allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or a chemically viable compound is one that does not substantially change when kept at a temperature of 40° C. or less for at least one week in the absence of moisture or other chemically reactive conditions.

[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), (IA), (IB), and (IC), X 2a and X 3a are connected by a single bond, and X 5a and X 6aare connected by a double bond, and X 4c and X 5c are joined by a single bond, but the bond between these groups may be hidden by atom labels in the chemical structure. Using different ChemDraw styles, formula (I) may be drawn as follows to show the bonds in question: [ka] Additionally, a substituent designated in a chemical structure as "CF3" or "F3C" refers to a trifluoromethyl substituent, regardless of where that depiction appears in the chemical structure.

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

[0018] As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing no unsaturation and having the specified number of carbon atoms, which is attached to the remainder of the molecule by a single bond. For example, a "C1-C6 alkyl" group is an alkyl group having from 1 to 6 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 a 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 from 2 to 6 carbon atoms.

[0020] As used herein, the term "cycloalkyl" refers to a stable non-aromatic monocyclic or bicyclic (fused, bridged, or spiro) saturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having the specified number of carbon ring atoms, which is attached to the remainder of the molecule by a single bond. For example, a "C3-C8 cycloalkyl" group is a cycloalkyl group having from 3 to 8 carbon atoms.

[0021] As used herein, the term "haloalkyl" refers to an alkoxy group having a specified number of carbon atoms, in which one or more of the alkyl group's hydrogen atoms are replaced by a halo group. For example, a "C1-C6 haloalkyl" group is an alkyl group having 1 to 6 carbon atoms, in which one or more of the alkyl group's hydrogen atoms are replaced by a halo group.

[0022] As used herein, the term "alkoxy" refers to a group of the formula -OR a where R a is an alkyl group having the specified number of carbon atoms. For example, a "C1-C6 alkoxy" group is a group of the formula -OR a where R a is an alkyl group having 1 to 6 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 alkyl group's hydrogen atoms is replaced by a halo group.

[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, without unsaturation and having the specified number of carbon 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 from 1 to 6 carbon atoms.

[0025] As used herein, the term "optionally substituted" refers to a group that is unsubstituted or substituted with the substituent(s) specified thereafter. For example, an "optionally substituted group with 1 to 2 halo" is either unsubstituted, substituted with one halo group, or substituted with two halo groups.

[0026] As used herein, "*2" and "*3" in the following structures represent R 2c Groups and R3c Indicates the carbon atom to which the group is attached. [ka]

[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. Furthermore, single stereoisomers, double bond isomers, conformational isomers, and tautomers, and 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 straight, non-bold bond attached to a stereogenic center of a compound, such as in the formula: [ka] , Indicates that the configuration of a stereocenter is unspecified. The compound may have any configuration or a mixture of configurations at the stereocenter.

[0029] As used herein, in any chemical structure or formula, a bold or dashed straight bond attached to a stereogenic center of a compound, such as in the formula: [ka] , A bold or dashed linear bond indicates the relative stereochemistry of a chiral center relative to the other stereocenter to which it is attached.

[0030] As used herein, in any chemical structure or formula, a bold or dashed wedge bond attached to a stereogenic center of a compound, such as in the formula: [ka] , A bold or dashed wedge bond indicates the absolute stereochemistry of a stereocenter relative to the other stereocenter to which it is attached, as well as the relative stereochemistry of the stereocenter.

[0031] As used herein, the prefix "rac-" when used in reference to a chiral compound refers to a racemic mixture of the compound. In compounds bearing the "rac-" prefix, the (R)- and (S)- designators in the chemical name reflect the relative stereochemistry of the compound.

[0032] As used herein, the prefix "rel-", when used in reference to a chiral compound, refers to a single enantiomer of unknown absolute configuration. In compounds with the "rel-" prefix, the (R) and (S)- designators in the chemical name reflect the relative stereochemistry of the compound, but not necessarily the absolute stereochemistry of the compound. If the relative stereochemistry of a given stereocenter is unknown, no stereochemical designator is provided. In some instances, the absolute configurations of some stereocenters are known, while only the relative configurations of other stereocenters are known. In these instances, the stereochemical designators associated with 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. Unmarked stereochemical designators associated with stereocenters of unknown absolute configuration reflect the relative stereochemistry of those stereocenters relative to other stereocenters of unknown absolute configuration, but not necessarily relative to stereocenters of known absolute configuration.

[0033] As used herein, the term "compound," when referring to a compound of the present invention, refers to a collection of molecules having the same chemical structure except that isotopic variations may exist among the constituent atoms of the molecule. The term "compound" includes a collection of such molecules regardless of the purity of a given sample containing the collection of molecules. Thus, the term "compound" includes a collection of such molecules in pure form, in a mixture with one or more other substances (e.g., a solution, suspension, colloid, or pharmaceutical composition or dosage form), or in the form of a hydrate, solvate, or co-crystal.

[0034] As used herein, the term "amorphous" refers to a solid material that does not have long-range order in the positions of its molecules. Amorphous solids are generally glasses or supercooled liquids in which the molecules are randomly arranged, such that there is no well-defined arrangement, e.g., no molecular packing, and no long-range order. Amorphous solids are generally rather isotropic, i.e., they exhibit similar properties in all directions, and do not have a distinct melting point. Instead, they typically exhibit a glass transition temperature that indicates the transition from a glassy amorphous state to a supercooled liquid amorphous state upon heating. For example, an amorphous substance is a solid material that does not have sharp, characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) are observed in its XRPD pattern. Broad peaks are characteristic of amorphous solids. For a comparison of XRPD of amorphous and crystalline materials, see US2004 / 0006237. In some embodiments, a solid material may comprise an amorphous compound; for example, the solid material may be characterized by the lack of sharp, characteristic crystalline peaks in its XRPD spectrum (i.e., the solid material is not crystalline, but is amorphous as determined by XRPD). Instead, one or several broad peaks (e.g., halos) may be observed in the XRPD pattern of the solid material. For a representative comparison of XRPD of amorphous and crystalline materials, see US2004 / 0006237. A solid material comprising an amorphous compound may be characterized, for example, by a broader temperature range of melting of the solid material compared to the melting range of a pure crystalline solid. Other techniques, such as, for example, solid-state NMR, may also be used to characterize crystalline or amorphous forms.

[0035] As used herein, the term "crystalline" refers to a crystalline structure (or polymorph) having a particular molecular packing arrangement within a crystal lattice. Crystalline forms can be identified by, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, and solid-state nuclear magnetic resonance (e.g., 13 C. 19 F, 15 N, and 31They can be identified and distinguished from one another by one or more characterization techniques, including P SSNMR.

[0036] In this specification and claims, unless otherwise specified, any atom not specifically designated as a particular isotope of any compound of the invention is intended to represent any stable isotope of the specified element. In the examples, when an atom is not specifically designated as a particular isotope of any compound of the invention, no effort was made to enrich that atom in a particular isotope, and therefore, one of ordinary skill in the art would understand that such atom was likely present in about 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, isotopes whose decay mode is not identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley 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, i.e. 1 Includes H and D. In the examples, when an atom is designated as "H," no attempt has been made to enrich that atom in a particular isotope of hydrogen, and thus, one of skill in the art will understand that such hydrogen atom was likely present in about the natural abundance isotopic composition of hydrogen.

[0039] As used herein, " 1 "H" refers to protium. When an atom in a compound of the invention or a pharmaceutically acceptable salt thereof is designated as protium, protium is present at the designated position at least at the natural abundance concentration of protium.

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

[0041] In some embodiments, the compounds of the invention and pharmaceutically acceptable salts thereof comprise each constituent atom at about the natural abundance isotopic composition of the specified element.

[0042] In some embodiments, the compounds of the present invention and pharmaceutically acceptable salts thereof contain one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the most abundant isotope of the specified element ("isotopically labeled" compounds and salts). Examples of stable isotopes that are commercially available and suitable for the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, e.g., 2 H, 13 C. 15 N, 18 O. 17 O, and 31 Examples include, but are not limited to, P.

[0043] Isotopically labeled compounds and salts can be used in several beneficial ways, including as pharmaceuticals. In some embodiments, isotopically labeled compounds and salts contain deuterium ( 2 H) labeled with deuterium ( 2 H) The labeled compounds and salts are therapeutically useful and non- 2 3H-labeled compounds have potential therapeutic advantages over H-labeled compounds. 2 H) Labeled compounds and salts may have higher metabolic stability compared to non-isotopically labeled counterparts due to kinetic isotope effects, as described below. Higher metabolic stability translates directly into increased in vivo half-life or lower dosages, which under most circumstances represent preferred embodiments of the present invention. Isotopically labeled compounds and salts can generally be prepared by following the procedures disclosed in the synthetic schemes, examples, and related description, substituting readily available isotopically labeled reactants for non-isotopically labeled reactants.

[0044] deuterium( 2 H) labeled compounds and salts can manipulate the rate of oxidative metabolism of a compound through the primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction resulting from the exchange of an isotope nucleus, which in turn is caused by a change in the ground state energy of the covalent bond involved in the reaction. The exchange of a heavier isotope usually results in a lowering of the ground state energy of the chemical bond and therefore a decrease in the rate-limiting bond scission. If the bond scission occurs within or near a saddle point region along the configuration of a multi-product reaction, the product distribution ratio can change significantly. For example, if deuterium is attached to a carbon atom at a non-exchangeable position, k H / k D A rate difference of 2 to 7 is typical. For further discussion, see S.L. Harbeson and R.D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417, which is incorporated herein by reference in its entirety.

[0045] The concentration of an isotope (e.g., deuterium) incorporated at a given position in an isotopically labeled compound of the present invention or a pharmaceutically acceptable salt thereof can be defined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the abundance of an isotope at a given position in an isotopically labeled compound (or salt) and the natural abundance of the isotope.

[0046] When 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 (about 45% deuterium incorporation). In some embodiments, the isotopic enrichment factor is at least 3500 (about 52.5% deuterium incorporation), at least 4000 (about 60% deuterium incorporation), at least 4500 (about 67.5% deuterium incorporation), at least 5000 (about 75% deuterium incorporation), at least 5500 (about 82.5% deuterium incorporation), at least 6000 (about 90% deuterium incorporation), at least 6333.3 (about 95% deuterium incorporation), at least 6466.7 (about 97% deuterium incorporation), at least 6600 (about 99% deuterium incorporation), or at least 6633.3 (about 99.5% deuterium incorporation).

[0047] In some embodiments, the present invention provides a compound of formula (IA): [ka] , or a pharmaceutically acceptable salt thereof, wherein X 2a , X 3a , X 5a , X 6a , R d , R 4b1 , R 4b2 , R 5b1 , R 5b2 , X 3c , X 4c , X 5c , X 6c , and R 2c is defined as set forth above in relation to formula (I).

[0048] In some embodiments, the present invention provides a compound of formula (IA-1): [ka] , or a pharmaceutically acceptable salt thereof, wherein R d , R 4b1 , R 4b2, R 5b1 , R 5b2 , R 2c , R 3c , and R 4c is defined as set forth above in relation to formula (I).

[0049] In some embodiments, the present invention provides a compound of formula (IA-2): [ka] , or a pharmaceutically acceptable salt thereof, wherein R d , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 2c , R 3c , and R 4c is defined as set forth above in relation to formula (I).

[0050] In some embodiments, the present invention provides a compound of formula (IA-3): [ka] , or a pharmaceutically acceptable salt thereof, wherein R d , R 4b2 , R 2c , R 3c , and R 4c is defined as set forth above in relation to formula (I).

[0051] In some embodiments, the present invention provides a compound of formula (IB): [ka] , or a pharmaceutically acceptable salt thereof, wherein X 2a , X 3a , X 5a , X 6a , R d , R 4b1 , R 4b2 , R 5b1 , R 5b2, X 3c , X 4c , X 5c , X 6c , and R 2c is defined as set forth above in relation to formula (I).

[0052] In some embodiments, the present invention provides a compound of formula (IB-1): [ka] , or a pharmaceutically acceptable salt thereof, wherein R d , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 2c , R 3c , and R 4c is defined as set forth above in relation to formula (I).

[0053] In some embodiments, the present invention provides a compound of formula (IB-2): [ka] , or a pharmaceutically acceptable salt thereof, wherein R d , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 2c , R 3c , and R 4c is defined as set forth above in relation to formula (I).

[0054] In some embodiments, the present invention provides a compound of formula (IB-3): [ka] , or a pharmaceutically acceptable salt thereof, wherein R d , R 4b2 , R 2c , R 3c , and R 4cis defined as set forth above in relation to formula (I).

[0055] In some embodiments, the present invention provides a compound of formula (IC): [ka] , or a pharmaceutically acceptable salt thereof, wherein X 2a , X 3a , X 5a , X 6a , R d , R 4b1 , R 4b2 , R 5b1 , R 5b2 , X 3c , X 4c , X 5c , X 6c , and R 2c is defined as set forth above in relation to formula (I).

[0056] In some embodiments, the present invention provides a compound of formula (IC-1): [ka] , or a pharmaceutically acceptable salt thereof, wherein R d , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 2c , R 3c , and R 4c is defined as set forth above in relation to formula (I).

[0057] In some embodiments, the present invention provides a compound of formula (IC-2): [ka] , or a pharmaceutically acceptable salt thereof, wherein R d , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R2c , R 3c , and R 4c is defined as set forth above in relation to formula (I).

[0058] In some embodiments, the present invention provides a compound of formula (IC-3): [ka] , or a pharmaceutically acceptable salt thereof, wherein R d , R 4b2 , R 2c , R 3c , and R 4c is defined as set forth above in relation to formula (I).

[0059] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof, wherein X 2a is CR 2a In another embodiment, X 2a is CR 2a and R 2a is H.

[0060] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof, wherein X 3a is N. In other embodiments, X 3a is N + -O - is.

[0061] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof, wherein X 5a is N or CR 5a and R 5a is H, halo, or CHOH. In other embodiments, X 5a is N. In other embodiments, X 5a is CR5a In another embodiment, X 5a is CR 5a and R 5a is H, halo, or CHOH. In other embodiments, X 5a is CR 5a and R 5a is H, F, or CHOH. In other embodiments, X 5a is CR 5a and R 5a is H. In other embodiments, X 5a is CR 5a and R 5a is halo. In other embodiments, X 5a is CR 5a and R 5a is F. In other embodiments, X 5a is CR 5a and R 5a is CH2OH.

[0062] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof, wherein X 6a is N or CR 6a and R 6a is H. In other embodiments, X 6a is N. In other embodiments, X 6a is CR 6a In another embodiment, X 6a is CR 6a and R 6a is H.

[0063] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IA-2), (IB), (IB-1), (IB-2), (IC), (IC-1), and (IC-2), or a pharmaceutically acceptable salt thereof, wherein R 4b1 is H or C1-C6 alkyl. In other embodiments, R 4b1 is H. In other embodiments, R 4b1is C1-C6 alkyl. In other embodiments, R 4b1 is H or CH. In other embodiments, R 4b1 is CH3.

[0064] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IB), (IB-1), (IB-2), (IB-3), (IC), (IC-1), (IC-2), and (IC-3), or a pharmaceutically acceptable salt thereof, wherein R 4b2 is H or C1-C6 alkyl. In other embodiments, R 4b2 is H. In other embodiments, R 4b2 is C1-C6 alkyl. In other embodiments, R 4b2 is H or CH. In other embodiments, R 4b2 is CH3.

[0065] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IA-2), (IB), (IB-1), (IB-2), (IC), (IC-1), and (IC-2), or a pharmaceutically acceptable salt thereof, wherein R 5b1 is C1-C6 alkyl or C1-C6 haloalkyl. In other embodiments, R 5b1 is C1-C6 alkyl. In other embodiments, R 5b1 is C1-C6 haloalkyl. In other embodiments, R 5b1 is CH3 or CF3. In other embodiments, R 5b1 is CH3. In other embodiments, R 5b1 is CF3.

[0066] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IA-2), (IB), (IB-1), (IB-2), (IC), (IC-1), and (IC-2), or a pharmaceutically acceptable salt thereof, wherein R 5b2is C1-C6 alkyl or C1-C6 haloalkyl. In other embodiments, R 5b2 is C1-C6 alkyl. In other embodiments, R 5b2 is C1-C6 haloalkyl. In other embodiments, R 5b2 is CH3 or CF3. In other embodiments, R 5b2 is CH3. In other embodiments, R 5b2 is CF3.

[0067] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IB), (IB-1), (IB-2), (IB-3), (IC), (IC-1), (IC-2), and (IC-3), or a pharmaceutically acceptable salt thereof, wherein R 2c is OH, halo, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. 2c is OH. In other embodiments, R 2c is halo. In other embodiments, R 2c is C1-C6 alkyl. In other embodiments, R 2c is C1-C6 alkoxy. In other embodiments, R 2c is C1-C6 haloalkoxy. In other embodiments, R 2c is OH, Cl, CH, OCH, OCD, OCHCH, OCH(CH), OCHCHF, or OCHCHF. 2c is Cl. In other embodiments, R 2c is CH3. In other embodiments, R 2c is OCH3. In other embodiments, R 2c is OCD3. In other embodiments, R 2c is OCH2CH3. In other embodiments, R 2c is OCH(CH). In other embodiments, R 2c is OCH2CH2F. In other embodiments, R 2c is OCH2CHF2.

[0068] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof, wherein X 3c is N or CR 3c and R 3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl. 3c is N. In other embodiments, X 3c is CR 3c In another embodiment, X 3c is CR 3c and R 3c is H. In other embodiments, X 3c is CR 3c and R 3c is halo. In other embodiments, X 3c is CR 3c and R 3c is C1-C6 alkyl. In other embodiments, X 3c is CR 3c and R 3c is C1-C6 haloalkyl. In other embodiments, X 3c is CR 3c and R 3c is H, F, CH3, CHF2, or CF3. In other embodiments, X 3c is CR 3c and R 3c is F. In other embodiments, X 3c is CR 3c and R 3c is CH3. In other embodiments, X 3c is CR 3c and R 3c is CHF2. In another embodiment, X 3c is CR 3c and R 3c is CF3.

[0069] In some embodiments, the present invention relates to a compound of any one of formulas (IA-1), (IA-2), (IA-3), (IB-1), (IB-2), (IB-3), (IC-1), (IC-2), and (IC-3), or a pharmaceutically acceptable salt thereof, wherein R 3c is H, halo, C-C alkyl, or C-C haloalkyl. 3c is H. In other embodiments, R 3c is halo. In other embodiments, R 3c is C1-C6 alkyl. In other embodiments, R 3c is C1-C6 haloalkyl. In other embodiments, R 3c is H, F, CH3, CHF2, or CF3. In other embodiments, R 3c is F. In other embodiments, R 3c is CH3. In other embodiments, R 3c is CHF2. In another embodiment, R 3c is CF3.

[0070] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof, wherein X 3c is CR 3c and R 2c and R 3c together with the carbon atoms to which they are attached form a ring of the formula: [ka] . In other embodiments, the ring is of the formula: [ka] .

[0071] In some embodiments, the present invention relates to a compound of any one of formulas (IA-1), (IA-2), (IA-3), (IB-1), (IB-2), (IB-3), (IC-1), (IC-2), and (IC-3), or a pharmaceutically acceptable salt thereof, wherein R 2c and R 3c together with the carbon atoms to which they are attached form a ring of the formula: [ka] . In other embodiments, the ring is of the formula: [ka] .

[0072] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof, wherein X 4c is CR 4c and R 4c is H, halo, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. 4c is CR 4c In another embodiment, X 4c is CR 4c and R 4c is H. In other embodiments, X 4c is CR 4c and R 4c is halo. In other embodiments, X 4c is CR 4c and R 4c is C1-C6 haloalkyl. In other embodiments, X 4c is CR 4c and R 4c is C1-C6 alkoxy. In other embodiments, X 4c is CR 4c and R 4c is C1-C6 haloalkoxy. In other embodiments, X4c is CR 4c and R 4c is H, F, CHF2, OCH2CH3, OCHF2, OCF3. In other embodiments, X 4c is CR 4c and R 4c is F. In other embodiments, X 4c is CR 4c and R 4c is CHF2. In another embodiment, X 4c is CR 4c and R 4c is OCH2CH3. In another embodiment, X 4c is CR 4c and R 4c is OCHF2. In another embodiment, X 4c is CR 4c and R 4c is OCF3.

[0073] In some embodiments, the present invention relates to a compound of any one of formulas (IA-1), (IA-2), (IA-3), (IB-1), (IB-2), (IB-3), (IC-1), (IC-2), and (IC-3), or a pharmaceutically acceptable salt thereof, wherein R 4c is H, halo, C-C haloalkyl, C-C alkoxy, or C-C haloalkoxy. 4c is H. In other embodiments, R 4c is halo. In other embodiments, R 4c is C1-C6 haloalkyl. In other embodiments, R 4c is C1-C6 alkoxy. In other embodiments, R 4c is C1-C6 haloalkoxy. In other embodiments, R 4c is H, F, CHF2, OCH2CH3, OCHF2, OCF3. In other embodiments, R 4c is F. In other embodiments, R 4c is CHF2. In another embodiment, R 4c is OCH2CH3. In other embodiments, R4c is OCHF2. In other embodiments, R 4c is OCF3.

[0074] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof, wherein X 5c is CR 5c and R 5c is H.

[0075] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof, wherein X 6c is CR 6c and R 6c is H.

[0076] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IB), (IB-1), (IB-2), (IB-3), (IC), (IC-1), (IC-2), and (IC-3), or a pharmaceutically acceptable salt thereof, wherein R d is (CH2) p H. In other embodiments, R d is H or CH. In other embodiments, R d is (CHR e ) n (CH2) p H. In other embodiments, R d is CHF, CHOH, or CH(OH)CH. In other embodiments, R d is (CH2) m (CHR e ) n H. In another embodiment, R d is CH2OCH3 or CH2CH2OCH3.

[0077] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IB), (IB-1), (IB-2), (IB-3), (IC), (IC-1), (IC-2), and (IC-3), or any embodiment thereof, i.e., a non-salt form of the compound.

[0078] In some embodiments, the present invention relates to a compound selected from Table A, or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to a compound selected from Table A, i.e., a compound in non-salt form.

[0079] Table A. Compound structures and names. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15]

[0080] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0081] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0082] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof, the compound has the absolute and relative stereochemistry corresponding to the first-eluting isomer when the two diastereoisomers of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide are separated by SFC, as described in Step 15 of Example 1. In another embodiment, the present invention relates to the aforementioned compound in non-salt form. Such compounds are considered to be "compounds of the invention," as that term is used herein.

[0083] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof, the compound has the absolute and relative stereochemistry corresponding to the second-eluting isomer when the two diastereoisomers of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide are separated by SFC, as described in Step 15 of Example 1. In another embodiment, the present invention relates to the aforementioned compound in non-salt form. Such compounds are considered to be "compounds of the invention," as that term is used herein.

[0084] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0085] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0086] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof, the compound has the absolute and relative stereochemistry of the first eluting isomer when rac-(2R,3S,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-N-(6-(hydroxymethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide is separated by SFC as described in Example 6. In another embodiment, the present invention relates to the aforementioned compound in non-salt form. Such compounds are considered to be "compounds of the invention," as that term is used herein.

[0087] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof, the compound has the absolute and relative stereochemistry of the second eluting isomer when rac-(2R,3S,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-N-(6-(hydroxymethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide is separated by SFC as described in Example 6. In another embodiment, the present invention relates to the aforementioned compound in non-salt form. Such compounds are considered to be "compounds of the invention," as that term is used herein.

[0088] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0089] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0090] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0091] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof, 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)methylbenzo are separated by SFC, as described in Example 6. In another embodiment, the present invention relates to the aforementioned compound in non-salt form. Such compounds are considered to be "compounds of the invention," as that term is used herein.

[0092] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof, has the absolute and relative stereochemistry corresponding to the second-eluting isomer when the two enantiomers of rac-(5-((2R,3S,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyrimidin-2-yl)methylbenzo are separated by SFC, as described in Example 6. In another embodiment, the present invention relates to the aforementioned compound in non-salt form. Such compounds are considered to be "compounds of the invention," as that term is used herein.

[0093] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0094] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0095] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0096] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0097] In some embodiments, the present invention relates to the 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, which compound is available in two diastereoisomers rel-(2S,3R,4R,5S)—N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, as described in Example 5. When 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 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, they have the absolute and relative stereochemistry corresponding to the first-eluting isomer. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0098] In some embodiments, the present invention relates to the 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, which compound is a mixture of two diastereoisomers rel-(2S,3R,4R,5S)—N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin- When separated by SFC, 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 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 have the absolute and relative stereochemistry of the second eluting isomer. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0099] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0100] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0101] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0102] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof, the compound has the absolute and relative stereochemistry corresponding to the first-eluting isomer when the two enantiomers of rac-(2R,3S,4S,5R)—N-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide are separated by SFC, as described in Example 9. In another embodiment, the present invention relates to the aforementioned compound in non-salt form. Such compounds are considered to be "compounds of the invention," as that term is used herein.

[0103] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof, the compound has the absolute and relative stereochemistry corresponding to the second-eluting isomer when the two enantiomers of rac-(2R,3S,4S,5R)—N-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide are separated by SFC, as described in Example 9. In another embodiment, the present invention relates to the aforementioned compound in non-salt form. Such compounds are considered to be "compounds of the invention," as that term is used herein.

[0104] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0105] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0106] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof, the compound has the absolute and relative stereochemistry corresponding to the first-eluting isomer when the two diastereoisomers of (2R,3S,4S,5R)—N-(6-(1-((tert-butyldimethylsilyl)oxy)-2-methoxyethyl)pyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide are separated by SFC, as described in Step 2 of Example 2. In another embodiment, the present invention relates to the aforementioned compound in non-salt form. Such compounds are considered to be "compounds of the invention," as that term is used herein.

[0107] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof, the compound had the absolute and relative stereochemistry corresponding to the second-eluting isomer when the two diastereoisomers of (2R,3S,4S,5R)—N-(6-(1-((tert-butyldimethylsilyl)oxy)-2-methoxyethyl)pyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide were separated by SFC as described in Step 2 of Example 2. In another embodiment, the present invention relates to the aforementioned compound in non-salt form. Such compounds are considered to be "compounds of the invention," as that term is used herein.

[0108] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0109] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0110] In some embodiments, the present invention relates to the compound rel-(2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((1R,2R)-1,2-dihydroxypropyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, or a pharmaceutically acceptable salt thereof, which compound is present in two diastereoisomers rel-(2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, as described in Example 1. When rel-(2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-N-(6-((4S,5S)-2,2,5-trimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)tetrahydrofuran-2-carboxamide and rel-(2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-N-(6-((4S,5S)-2,2,5-trimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)tetrahydrofuran-2-carboxamide are separated by SFC, they have the absolute and relative stereochemistry corresponding to the first-eluting isomer. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0111] In some embodiments, the present invention relates to the compound rel-(2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((1S,2S)-1,2-dihydroxypropyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the compound is rel-(2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-N-(6-((4 When the two diastereoisomers of R,5R)-2,2,5-trimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)tetrahydrofuran-2-carboxamide and rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-N-(6-((4S,5S)-2,2,5-trimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)tetrahydrofuran-2-carboxamide are separated by SFC, they have the absolute and relative stereochemistry corresponding to the second-eluting isomer. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention," as that term is used herein.

[0112] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0113] In some embodiments, the present invention provides a compound of the following formula: [ka] , or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0114] In some embodiments, the present invention relates to the 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, which compound can be obtained in two diastereomers, rel-(2R,3S,5R)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-N-(6-((R*)-2,2-dihydroxyethyl)pyridin-3-yl), as described in Example 8. When 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, they have the absolute and relative stereochemistry corresponding to the first-eluting isomer. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0115] In some embodiments, the present invention relates to the 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, which compound can be obtained in two diastereomers rel-(2R,3S,5R)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-N-(6-((R*)-2,2-dihydroxyethyl)pyridin-3-yl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, as described in Example 8. When 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, they have the absolute and relative stereochemistry corresponding to the second-eluting isomer. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0116] Salts, Compositions, Uses, Formulations, Administration, and Additional Agents Pharmaceutically Acceptable Salts and Compositions As discussed herein, the present invention provides compounds and pharmaceutically acceptable salts thereof that are inhibitors of voltage-gated sodium channels. Accordingly, the present compounds and pharmaceutically acceptable salts thereof are useful for treating diseases, disorders, and conditions, including, but not limited to, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia. Accordingly, in another aspect of the present invention, pharmaceutical compositions are provided, which comprise a compound described herein, or a pharmaceutically acceptable salt thereof, and optionally, 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.

[0117] As used herein, the term "pharmaceutically acceptable" refers to a salt that is, 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 that is commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" of a compound of the invention includes any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of the present disclosure or an inhibitory active metabolite or residue thereof. The salt may be in pure form, a mixture with one or more other substances (e.g., a solution, suspension, or colloid), or in the form of a hydrate, solvate, or co-crystal. As used herein, the term "inhibitorily active metabolite or residue thereof" means that the metabolite or residue thereof is also an inhibitor of voltage-gated sodium channels.

[0118] Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or 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, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, methylpropional ... Salts derived from appropriate bases include sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, where appropriate.

[0119] As used herein, a pharmaceutically acceptable composition of the present invention additionally includes pharmaceutically acceptable carriers, adjuvants, or vehicles, including any and all solvents, diluents, or other liquid vehicles, dispersing or suspending aids, surfactants, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as used herein, appropriate for 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 their preparation. Except insofar as any conventional carrier medium is incompatible with the compounds of the present invention, for example, by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, its use is contemplated within the scope of the present disclosure.Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates, glycine, sorbic acid, and potassium sorbate, etc.), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., carboxymethylcellulose), and the like. sodium, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository waxes), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (e.g., propylene glycol and polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solution, and other non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium 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.

[0120] In another aspect, the invention features a pharmaceutical composition including a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0121] In another aspect, the invention features a pharmaceutical composition including a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

[0122] Uses of the compounds and pharmaceutically acceptable salts and compositions In another aspect, the invention features a method of inhibiting a voltage-gated sodium channel in a subject, the method including administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. V It is 1.8.

[0123] In yet another aspect, the invention features a method of treating or lessening the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-surgical pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia in a subject, the method includes administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0124] In yet another aspect, the invention features a method of treating or lessening the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-surgical pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, or cardiac arrhythmia in a subject, the method comprising administering an effective amount of a compound, 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 of intestinal pain in a subject, including inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain, the method comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0126] In yet another aspect, the invention features a method for treating or reducing the severity of neuropathic pain in a subject, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some aspects, neuropathic pain includes 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.

[0127] In yet another aspect, the invention features a method of treating or lessening the severity of neuropathic pain in a subject, including postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, pain after amputation surgery, phantom limb pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, medication-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia; pain after spinal cord injury, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic headache, the method comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0128] In yet another aspect, the invention features a method for treating or lessening the severity of musculoskeletal pain in a subject, 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 includes osteoarthritis.

[0129] In yet another aspect, the invention features a method of treating or lessening the severity of musculoskeletal pain in a subject, including osteoarthritis, back pain, cold pain, burn pain, or dental pain, the method comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0130] In yet another aspect, the invention features a method of treating or lessening the severity of inflammatory pain in a subject, including rheumatoid arthritis pain or vulvodynia, the method comprising 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 of inflammatory pain in a subject, including rheumatoid arthritis pain, the method comprising 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 of idiopathic pain in a subject, including fibromyalgia pain, the method comprising 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 for treating or reducing the severity of pathological cough in a subject, the method comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0134] In yet another aspect, the invention features a method for treating or lessening the severity of acute pain in a subject, 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 includes acute post-surgical pain.

[0135] In yet another aspect, the invention features a method for treating or reducing the severity of post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain) in a subject, 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 for treating or reducing the severity of bunionectomy pain in a subject, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0137] In yet another aspect, the invention features a method of treating herniorrhaphy or reducing the severity of pain in a subject, 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 a method for treating or reducing the severity of abdominoplasty pain in a subject, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0139] In yet another aspect, the invention features a method for treating or lessening the severity of visceral pain in a subject, 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 includes abdominoplasty visceral pain.

[0140] In yet another aspect, the invention features a method for treating or lessening the severity of a neurodegenerative disease in a subject, 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 neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt-Hopkins syndrome (PTHS).

[0141] In yet another aspect, the invention features a method in which a subject is treated with one or more additional therapeutic agents administered simultaneously with, before, or after treatment with an effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0142] In another aspect, the invention features a method of inhibiting voltage-gated sodium channels in a biological sample, the method including contacting the biological sample with an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. V It is 1.8.

[0143] In another aspect, the present invention provides a method for treating acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, algesic pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain in multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis, post-herpetic neuralgia, diabetic neuropathic pain, and rheumatoid arthritis. rheumatoid arthropathy, radicular pain, sciatica, back pain, unspecified chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), cancer pain including chronic cancer pain and cancer breakthrough pain, stroke (e.g., post-stroke central neuropathic pain), traumatic neck syndrome, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus Degenerative joint disease, epidermolysis bullosa, gout, juvenile idiopathic arthritis, osteomyelitis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic osteophytosis, degenerative / herniated disc pain, radiculopathy, facet joint syndrome, failed spinal surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylodiscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmopathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy-induced orthostatic hypoplasia The present invention features a method for treating or lessening the severity of oral mucositis, Charcot arthropathy, temporomandibular joint disorders, painful knee replacement, non-cardiac chest pain, pudendal pain, renal colic, biliary tract disease, 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, palpitations, hypertension, or abnormal gastrointestinal motility in a subject, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0144] In another aspect, the present invention provides a method for treating femoral 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; splenic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headache; 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 neuroma; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiotherapy-induced neuropathic pain; persistent / chronic postoperative pain (e.g., after amputation, thoracotomy, cardiac surgery), post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; phantom limb pain (e.g., after lower limb, upper limb, or mastectomy); intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tenosynovitis; injury pain; movement pain; acute visceral pain. Pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, burn pain, traumatic pain; acute intermittent pain, endometriosis; acute shingles pain; sickle cell disease; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; toothache; multiple sclerosis (MS) pain; depression pain; leprosy pain; Behcet's disease pain; adiposity pain; phlebitis pain; Guillain-Barré syndrome pain; sore legs and moving toes; Haglund's syndrome syndrome; erythromelalgia pain; Fabry disease pain; bladder and genitourinary disorders; urinary incontinence, pathological cough; overactive bladder; bladder pain syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain in a subject, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0145] Compounds, Pharmaceutically Acceptable Salts, and Compositions for Use - Patent application 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.

[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 inhibiting a voltage-gated sodium channel in a subject. V It is 1.8.

[0147] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or lessening the severity in a subject of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-surgical pain (e.g., herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia.

[0148] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or lessening the severity in a subject of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-surgical pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, or cardiac arrhythmia.

[0149] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or reducing the severity of intestinal pain in a subject, wherein the intestinal pain includes inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain.

[0150] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or reducing the severity of neuropathic pain in a subject. In some aspects, neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some aspects, neuropathic pain includes 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.

[0151] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or lessening the severity of neuropathic pain in a subject, where neuropathic pain includes postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, pain after amputation surgery, phantom limb pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, medication-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia; pain after spinal cord injury, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic headache.

[0152] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or reducing the severity of musculoskeletal pain in a subject. In some aspects, the musculoskeletal pain includes osteoarthritis.

[0153] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or reducing the severity of musculoskeletal pain in a subject, wherein musculoskeletal pain includes osteoarthritis, back pain, cold pain, burn pain, or dental pain.

[0154] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or reducing the severity of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain or vulvodynia.

[0155] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or reducing the severity of inflammatory pain in a subject, wherein inflammatory pain includes rheumatoid arthritis pain.

[0156] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or lessening the severity of idiopathic pain in a subject, wherein the idiopathic pain includes the pain of fibromyalgia.

[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 for treating or reducing the severity of pathological cough in a subject.

[0158] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or reducing the severity of acute pain in a subject. In some aspects, the acute pain includes acute post-operative pain.

[0159] In yet another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating or reducing the severity of post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain) in a subject.

[0160] 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 for treating or reducing the severity of bunionectomy pain in a subject.

[0161] 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 for treating herniorrhaphy or reducing the severity of the pain in a subject.

[0162] 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 for treating or reducing the severity of abdominoplasty pain in a subject.

[0163] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or reducing the severity of visceral pain in a subject. In some aspects, the visceral pain includes abdominoplasty visceral pain.

[0164] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or reducing the severity of a neurodegenerative disease in a subject. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt-Hopkins syndrome (PTHS).

[0165] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method in which a subject is treated with an effective amount of one or more additional therapeutic agents administered simultaneously with, before, or after treatment with the compound, pharmaceutically acceptable salt, or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0166] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of inhibiting a voltage-gated sodium channel in a biological sample, the method 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. V It is 1.8.

[0167] In another aspect, the present invention provides a method for treating acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, algesic pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain in multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis, post-herpetic neuralgia, diabetic neuropathic pain, and rheumatoid arthritis. pain, radicular pain, sciatica, back pain, unspecified chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), cancer pain including chronic cancer pain and cancer breakthrough pain, stroke (e.g., central neuropathic pain after stroke), traumatic neck syndrome, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic Lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, osteomyelitis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic osteophytosis, degenerative / herniated disc pain, radiculopathy, facet joint syndrome, failed spinal surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylodiscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmopathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy The present invention features a compound of the present 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 exercise-induced oral mucositis, Charcot arthropathy, temporomandibular joint disorders, painful knee replacement surgery, non-cardiac chest pain, pudendal pain, renal colic, biliary tract disease, 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, palpitations, hypertension, or abnormal gastrointestinal motility.

[0168] In another aspect, the present invention provides a method for treating femoral 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; splenic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral neuropathy. Peripheral nerve injury; painful neuroma; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiotherapy-induced neuropathic pain; persistent / chronic postoperative pain (e.g., after amputation, thoracotomy, cardiac surgery), postmastectomy pain; central pain; spinal cord injury pain; poststroke pain; thalamic pain; phantom limb pain (e.g., after lower limb, upper limb, or mastectomy); intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tenosynovitis; injury pain; movement pain; acute internal pain Visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; Caesarean section pain; acute inflammatory pain, burn pain, traumatic pain; acute intermittent pain, endometriosis; acute shingles pain; sickle cell disease; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; toothache; pain from multiple sclerosis (MS); pain from depression; pain from leprosy; pain from Behcet's disease; adiposity; pain from phlebitis; pain from Guillain-Barré syndrome; painful legs and moving toes; The present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating or reducing the severity in a subject of Haglund's syndrome; erythromelalgia pain; Fabry disease pain; bladder and genitourinary disorders; urinary incontinence, pathological cough; overactive bladder; bladder pain syndrome; interstitial cystitis (IC); prostatitis; regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain.

[0169] 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, migraine treated with Botox, cervical spondylotic radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioinguinal neuralgia, pudendal neuralgia, femoral neuropathy, dysesthesias of the thigh, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain, or pain following amputation surgery.

[0170] Drug manufacturing In another aspect, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament.

[0171] In another aspect, the present invention provides the use of a compound of the present 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. V It is 1.8.

[0172] In yet another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity in a subject of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain (e.g., herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia.

[0173] In yet another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity in a subject of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, or cardiac arrhythmia.

[0174] In yet another aspect, the present invention provides the use of a compound, pharmaceutically acceptable salt, or pharmaceutical composition as described herein for the manufacture of a medicament for use in treating or reducing the severity of intestinal pain in a subject, wherein intestinal pain includes inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain.

[0175] In yet another aspect, the present invention provides a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of neuropathic pain in a subject. In some aspects, neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some aspects, neuropathic pain includes diabetic neuropathy (e.g., diabetic peripheral neuropathy).

[0176] In yet another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of neuropathic pain in a subject, wherein the neuropathic pain includes post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, pain after amputation surgery, phantom limb pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, medication-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia; pain after spinal cord injury, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal-autonomic neuropathy.

[0177] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of musculoskeletal pain in a subject. In some aspects, the musculoskeletal pain includes osteoarthritis.

[0178] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of musculoskeletal pain in a subject, wherein musculoskeletal pain includes osteoarthritis, back pain, cold pain, burn pain, or dental pain.

[0179] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain or vulvodynia.

[0180] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of inflammatory pain in a subject, wherein inflammatory pain includes rheumatoid arthritis pain.

[0181] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of idiopathic pain in a subject, wherein idiopathic pain includes fibromyalgia pain.

[0182] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of pathological cough in a subject.

[0183] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of acute pain in a subject, hi some aspects, acute pain includes acute post-operative pain.

[0184] In yet another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of post-operative pain in a subject (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain).

[0185] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating herniorrhaphy pain or reducing the severity thereof in a subject.

[0186] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of bunionectomy pain in a subject.

[0187] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of abdominoplasty pain in a subject.

[0188] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of visceral pain in a subject, hi some aspects, the visceral pain includes abdominoplasty visceral pain.

[0189] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of a neurodegenerative disease in a subject. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt-Hopkins syndrome (PTHS).

[0190] In yet another aspect, the present invention provides use of a compound of the present 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 simultaneously with, before, or after treatment with the compound or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0191] In another aspect, the present invention provides a method for treating acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, algesic pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain in multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis, post-herpetic neuralgia, diabetic neuropathy, and rheumatoid arthritis. Neuropathy, radicular pain, sciatica, back pain, unspecified chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), cancer pain including chronic cancer pain and cancer breakthrough pain, stroke (e.g., central neuropathic pain after stroke), traumatic neck syndrome, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic Lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, osteomyelitis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic osteophytosis, degenerative / herniated disc pain, radiculopathy, facet joint syndrome, failed spinal surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylodiscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmopathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemosis and the like. The present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in the treatment or lessening of the severity of chemotherapy-induced oral mucositis, Charcot arthropathy, temporomandibular joint disorder, painful knee replacement surgery, non-cardiac chest pain, pudendal pain, renal colic, biliary tract disease, 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, palpitations, hypertension, or abnormal gastrointestinal motility.

[0192] In another aspect, the present invention provides a method for treating femoral 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; splenic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headache; 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 neuroma; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiotherapy-induced neuropathic pain; persistent / chronic postoperative pain (e.g., after amputation, thoracotomy, cardiac surgery), post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; phantom limb pain (e.g., after lower limb, upper limb, or mastectomy); intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tenosynovitis; injury pain; movement pain; acute Visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, burn pain, traumatic pain; acute intermittent pain, endometriosis; acute shingles pain; sickle cell disease; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; toothache; multiple sclerosis (MS) pain; depression pain; leprosy pain; Behcet's disease pain; adiposity pain; phlebitis pain; Guillain-Barré syndrome pain; sore and moving legs Provided is use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of: pain in the toes; Haglund's syndrome; pain in erythromelalgia; pain in Fabry's disease; bladder and genitourinary disorders; urinary incontinence, pathological cough; overactive bladder; bladder pain syndrome; interstitial cystitis (IC); prostatitis; regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain.

[0193] In another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in the treatment or reduction of the severity of trigeminal neuralgia, migraine treated with Botox, cervical spondylotic radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioinguinal neuralgia, pudendal neuralgia, femoral neuropathy, dysesthesias of the femoral nerve, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain, or following amputation surgery.

[0194] Administration of Compounds, Pharmaceutically Acceptable Salts, and Compositions In certain embodiments of the present invention, an "effective amount" of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is that amount effective to treat or lessen the severity of one or more of the conditions listed above.

[0195] The compounds, salts, and compositions of the present invention can be administered in any amount and via any route of administration effective for treating or reducing the severity of one or more of the pain or non-pain disorders listed herein. The exact amount required will vary from subject to subject, depending on the subject's species, age, and general condition, the severity of the condition, the specific drug, its mode of administration, and the like. The compounds, salts, and compositions of the present invention are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, the term "unit dosage form" refers to a physically discrete pharmaceutical unit appropriate for the subject being treated. However, it will be understood that the total daily dosage of the compounds, salts, and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular subject or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound or salt used; the particular composition used; the age, weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the particular compound or salt used; the duration of treatment; drugs used in combination with or concomitantly with the particular compound or salt used, and similar factors well known in the medical arts. As used herein, the term "subject" or "patient" means an animal, preferably a mammal, and most preferably a human.

[0196] The pharmaceutically acceptable compositions of the invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powder, ointment, or drops), buccally as an oral or nasal spray, etc., depending on the severity of the condition being treated. In certain embodiments, the compounds, salts, and compositions of the invention may be administered orally or parenterally, one or more times daily, at dosage levels of about 0.001 mg / kg to about 1000 mg / kg effective to obtain the desired therapeutic effect.

[0197] 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, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and fragrances.

[0198] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution (USP), and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil, including synthetic monoglycerides or diglycerides, may be used. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables.

[0199] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0200] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the compound-to-polymer ratio and the nature of the particular polymer used, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0201] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound or salt of the invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or a suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

[0202] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound or salt is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar, carbonate, cellulose, cellulose acetate, cellulose acetate, cellulose stearate, cellulose acetate, cellulose acetate stearate ... Calcium, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retardants such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0203] Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient 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 used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0204] The active compound or salt may also be in microencapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound or salt may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. These dosage forms may also contain, as is common practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient(s) only, or preferentially, in a delayed manner, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0205] Dosage forms for topical or transdermal administration of the compounds or salts of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers, as may be required. Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of the present invention. The present invention also contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound into the body. Such dosage forms are prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0206] As generally described above, the compounds of the present invention are useful as inhibitors of voltage-gated sodium channels. In one embodiment, the compounds V1.8 inhibitors, and therefore, without wishing to be bound by any particular theory, the compounds, salts, and compositions V These compounds are particularly useful for treating or lessening the severity of a disease, condition, or disorder in which activation or overactivity of Na 1.8 is implicated. V When activation or overactivity of 1.8 is involved in a particular disease, condition, or disorder, the disease, condition, or disorder may also be associated with Na V 1.8-mediated disease, condition, or disorder. V The present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation or overactivity of 1.8 is implicated in the disease state.

[0207] Na V The activity of the compounds utilized in this invention as inhibitors of 1.8 may be assayed according to the methods generally described in WO 2014 / 120808A9 and U.S. 2014 / 0213616A1 (both of which are incorporated by reference in their entireties), the methods described herein, as well as other methods known and available to those of skill in the art.

[0208] Additional medications It will also be understood that the compounds, salts, and pharmaceutically acceptable compositions of the present invention can be used in combination therapy, i.e., the compounds, salts, and pharmaceutically acceptable compositions can be administered simultaneously with, prior to, or after one or more other desired therapies or medical treatments. The particular combination of therapies (treatments or procedures) used in a combination regimen will take into account the compatibility of the desired therapeutic agents and / or treatments and the desired therapeutic effect to be achieved. It will also be understood that the therapies used can achieve the desired effect for the same disorder (e.g., a compound of the present invention can be administered simultaneously with another agent used to treat the same disorder) or can achieve a different effect (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease or condition refer to those known to be appropriate for the disease or condition being treated. For example, exemplary additional therapeutic agents include, but are not limited to, non-opioid analgesics (indoles, e.g., etodolac, indomethacin, sulindac, tolmetin; naphthylalkanones, e.g., nabumetone; oxicams, e.g., piroxicam; para-aminophenol derivatives, e.g., acetaminophen; propionic acids, e.g., fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, oxaprozin; salicylates, e.g., aspirin, choline magnesium trisalicylate, diflunisal; fenamates, e.g., , meclofenamic acid, mefenamic acid; and pyrazoles, e.g., phenylbutazone), or opioid (anesthetic) agonists (e.g., codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine). Additionally, non-drug analgesic approaches may be utilized in conjunction with the administration of one or more compounds of the present invention. For example, anesthesiology (spinal injection, nerve blockade), neurosurgery (neuroablation of CNS pathways), neurostimulation (transcutaneous electrical nerve stimulation, dorsal column stimulation), physical therapy (physical therapy, orthotic devices, diathermy), or psychology (cognitive methods—hypnosis, biofeedback, or behavioral methods) approaches may also be utilized.Additional suitable therapeutic agents or approaches are generally described in The Merck Manual, Nineteenth Edition, 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 incorporated herein by reference.

[0209] In another embodiment, the additional suitable therapeutic agent is selected from the following:

[0210] (1) Opioid analgesics, such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, levalorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, pentazocine, or difelikefalin; (2) nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen (including but not limited to intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketorolac (including but not limited to 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) barbiturates, such as amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal, or thiopental; (4) benzodiazepines with sedative effects, such as chlordiazepoxide, clorazepate, diazepam, flazepam, lorazepam, oxazepam, temazepam, or triazolam; (5) sedating histamine (H1) antagonists, such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine, or chlorcyclizine; (6) sedatives, such as glutethimide, meprobamate, methaqualone, or dichloralphenazone; (7) Skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphenadrine; (8) NMDA receptor antagonists, such as dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), a combination formulation of morphine and dextromethorphan, topiramate, neramexane, or perzinfotel (including NR2B antagonists, such as ifenprodil, traxoprodil, or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-l-piperidinyl]-l-hydroxyethyl-3,4-dihydro-2(lH)-quinolinone); (9) alpha-adrenergic agonists, such as doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinolin-2-yl)-5-(2-pyridyl)quinazoline; (10) Tricyclic antidepressants, such as desipramine, imipramine, amitriptyline, or nortriptyline; (11) Anticonvulsants, such as carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®), or valproate; (12) Tachykinin (NK) antagonists, particularly NK-3, NK-2, or NK-1 antagonists, such as (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[l,4]diazocino[2,lg][l,7]-naphthyridine-6-13-dione (TAK-637), 5-[[(2R,3S) -2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-l,2-dihydro-3H-l,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant, or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine(2S,3S); (13) Muscarinic antagonists, such as oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine, and ipratropium; (14) COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib; (15) Coal-tar analgesics, especially paracetamol; (16) Neuroleptics, 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, meclineltant, Miraxion®, or sarizotan; (17) Vanilloid receptor agonists (e.g., resiniferatoxin or civamide) or antagonists (e.g., capsazepine, GRC-15300); (18) beta-adrenergics, such as propranolol; (19) Local anesthetics, e.g., mexiletine; (20) Corticosteroids, e.g., dexamethasone; (21) 5-HT receptor agonists or antagonists, especially 5-HT 1B / 1D agonists, such as eletriptan, sumatriptan, naratriptan, zolmitriptan, or rizatriptan; (22)5-HT 2A Receptor antagonists, such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907); (23) Cholinergic (nicotinic) analgesics, such as isoprenicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), or nicotine; (24) Tramadol®, tramadol ER (Ultram ER®), IV tramadol, tapentadol ER (Nucynta®); (25) PDE5 inhibitors, such as 5-[2-ethoxy-5-(4-methyl-l-piperazinyl-sulfonyl)phenyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',l':6,l]-pyrido[3,4-b ]indole-l,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-l-yl-l-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,lf][l,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(l-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4, 3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-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-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine- 7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-l-yl]-N-(pyrimidin-2-ylmethyl)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) Alpha-2-delta ligands, such as gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methylgabapentin, (1[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]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(l-aminomethyl-3,4-dimethyl-cyclopentyl)-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-amino-4,5-dimethyl-octanoic acid; (27) Cannabinoids, such as KHK-6188; (28) metabotropic glutamate subtype 1 receptor (mGluRl) antagonists; (29) Serotonin reuptake inhibitors, such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ioxetine, cyanodothiepin, ritoxetine, dapoxetine, nefazodone, cericlamine, and trazodone; (30) noradrenaline (norepinephrine) reuptake inhibitors, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, the bupropion metabolite hydroxybupropion, nomifensine, and viloxazine (Vivalan®), in particular selective noradrenaline reuptake inhibitors, such as reboxetine, in particular (S,S)-reboxetine; (31) Dual serotonin-norepinephrine reuptake inhibitors, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran, and imipramine; (32) Inducible nitric oxide synthase (iNOS) inhibitors, 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,5Z)-2-amino-2-methyl-7-[(l-iminoethyl)amino]-5-heptenoic acid, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile; 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5- (thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN-462, or guanidinoethyl disulfide; (33) Acetylcholinesterase inhibitors, for example, donepezil; (34) Prostaglandin E2 subtype 4 (EP4) antagonists, such as N-[({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)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid; (35) Leukotriene B4 antagonists, 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) 5-lipoxygenase inhibitors, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504); (37) Sodium channel blockers, such as lidocaine, lidocaine + tetracaine cream (ZRS-201), or eslicarbazepine acetate; (38)Na V1.7 Blockers, 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 WO2011 / 140425 (US2011 / 306607); WO2012 / 106499 (US2012 / 196869); WO2012 / 112743 (US2012 / 245 136); those disclosed in WO2012 / 125613 (US2012 / 264749), WO2012 / 116440 (US2014 / 187533), WO2011 / 026240 (US2012 / 220605), US8883840, US8466188, WO2013 / 109521 (US2015 / 005304), WO2020 / 117626, and CN111217776 (the entire contents of each application are incorporated herein by reference); (38a)Na V1.7 Blockers, such as (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl)-(4-isopropoxy-3-methyl-phenyl)methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]- 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'-piperidin]-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-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[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'-piperidin]-1'-yl]methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-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'-piperidin]-6-yl]ethanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-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]methanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 1-[(3S)-2,3-dimethyl-1'-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[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'-piperidin]-1'-yl]-[3-methoxy-4-[(1R)-1-methylpropoxy]phenyl]methanone, 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'-piperidin]-6-yl]ethanone, 1-[1'-[ 4-Methoxy-3-(trifluoromethyl)benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-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'-piperidin]-1'-yl]methanone, [2-methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-Piperidin]-1'-yl]-[4-(3,3,3-trifluoropropoxymethyl)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]pyrazine-1,4'-piperidin]-1'-yl]methanone. (39)Na V 1.8 blockers, such as PF-04531083, PF-06372865, as well as, for example, WO2008 / 135826 (US2009048306), WO2006 / 011050 (US2008312235), WO2013 / 061205 (US2014296313), US2013 / 0303535, WO2013 / 131018, US8466188, WO2013 / 114250(US2013 / 274243), WO2014 / 120808(US2014 / 213616), WO2014 / 120815(US2014 / 228371), WO20 14 / 120820(US2014 / 221435), WO2015 / 010065(US20160152561), WO2015 / 089361(US20150166589), WO2 019 / 014352(US2019 / 0016671), WO2018 / 213426, WO2020 / 146682, WO2020 / 146612, WO2020 / 014243, WO 2020 / 014246, WO2020 / 092187, WO2020 / 092667(US2020140411), WO2020 / 261114, WO2020 / 140959, WO20 20 / 151728, WO2021 / 032074, CN112390745, CN111808019, CN112225695, CN112457294, CN112300051, CN112300069, CN112441969, and CN112479996 (WO2021 / 047622) (the entire contents of each application are incorporated herein by reference); (39a)Na V1.8 Blockers, such as 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)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-dihydropyridin-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-dihydropyridin-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-(trifluoromethyl)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-fluoro phenoxy)-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-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide (4-(2-(4-fluoro-2-(methyl-d3)phenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate, 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-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-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide)picolinic acid, 2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide, 3-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoline-3-carboxamide, N-(3-sulfamoylphenyl)-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide, 3-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)quinoxaline- 2-carboxamide, 5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide)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-Sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, N-(4-carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide)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-dimethoxyphenoxy)-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-methoxyphenoxy)-4-(perfluoroethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)benzoic acid, 5-(4,5-dicolinic acid 4-(2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 4-(2-(2-chloro-4-fluorophenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(perfluoroethyl)benzamido)benzoic 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-methylphenoxy)benzamido)benzoic acid, 5-(4,5- Dichloro-2-(2,4-dimethoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(2-chloro-4-fluorophenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)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)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)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-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-chloro-2-methyl 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-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-Dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-Dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-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-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)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)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteromethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl, N-(3-carbamoyl-4-fluorophenyl)-3-(trifluoromethoxy)benzamide, 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, 4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, 4-[[2-fluoro-6-[2-(trideuteromethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluorophenyl)-3 -(Difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, 4-[[2-fluoro-6-[2-(trideuteromethoxy)-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-(difluoromethoxy)-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] )phenoxy]-3-(trifluoromethyl)benzamide, N-(4-carbamoyl-3-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[2-fluoro-6-[2-(trideuteromethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-pentafluoroethyl)benzamide, 4-[[4-(difluoromethoxy)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[4-cyclopropyl-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoro N-(3-carbamoyl-4-fluorophenyl)-2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzamide, 4-(2-fluoro-6-(2-methoxy-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzamido)picolinamide, or 4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide; (40) Combined Na V 1.7 and Na V 1.8 Blockers, such as DSP-2230, Lohocla201, or BL-1021; (41) 5-HT3 antagonists, such as ondansetron; (42) TPRV1 receptor agonists, such as capsaicin (NeurogesX®, Qutenza®), and pharmaceutically acceptable salts and solvates thereof; (43) Nicotinic receptor antagonists, such as varenicline; (44) N-type calcium channel antagonists, such as Z-160; (45) Nerve growth factor antagonists, such as tanezumab; (46) Endopeptidase stimulators, such as senrebotase; (47) Angiotensin II antagonists, such as EMA-401; (48) Acetaminophen (including but not limited to intravenous acetaminophen (e.g., Ofirmev®)); (49) Bupivacaine (including, but not limited to, bupivacaine liposomal injectable suspension (e.g., Exparel®), bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll), and transdermal bupivacaine (Eladur®)); and (50) Combination of bupivacaine and meloxicam (e.g., HTX-011).

[0211] In one embodiment, the additional suitable therapeutic agent is selected from V-116517, pregabalin, extended-release pregabalin, ezogabine (Potiga®), ketamine / amitriptyline topical cream (Amiket®), AVP-923, perampanel (E-2007), ralfinamide, transdermal bupivacaine (Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561, or ARC-4558.

[0212] In another embodiment, the additional suitable therapeutic agent is 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.

[0213] In another embodiment, the additional therapeutic agent is selected from a GlyT2 / 5HT2 inhibitor, e.g., Operanserin (VVZ149), a TRPV modulator, e.g., CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101, MDR16523, or MDR652, an EGR1 inhibitor, e.g., Brivoglide (AYX1), an NGF inhibitor, e.g., Tanezumab, Fasinumab, ASP6294, MEDI7352, a Mu opioid agonist, e.g., Cebranopadol, NKTR181 (Oxycodegol), a CB-1 agonist, e.g., NEO1940 (AZN1940), an imidazoline 12 agonist, e.g., CR4056, or a p75NTR-Fc modulator, e.g., LEVI-04.

[0214] In another embodiment, the additional therapeutic agent is oliceridine or ropivacaine (TLC590).

[0215] In another embodiment, the additional therapeutic agent is Na V 1.7 blockers, such as ST-2427 or ST-2578, and those disclosed in WO2010 / 129864, WO2015 / 157559, WO2017 / 059385, WO2018 / 183781, WO2018 / 183782, WO2020 / 072835, and WO2022 / 036297 (the entire contents of each application are incorporated herein by reference). In some embodiments, the additional therapeutic agent is a Na V In some embodiments, the additional therapeutic agent is a Na 1.7 blocker. V It is a 1.7 blocker.

[0216] In another embodiment, the additional therapeutic agent is selected from the group consisting of ASP18071, CC-8464, ANP-230, ANP-231, NOC-100, NTX-1175, ASN008, NW3509, AM-6120, AM-8145, AM-0422, BL-017881, NTM-006, opilanserin (Unafra™), bribolizide, 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.

[0217] 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.

[0218] In another embodiment, the additional therapeutic agent is any of WO2021 / 257490, WO2021 / 257420, WO2021 / 257418, WO2020 / 014246, WO2020 / 092187, WO2020 / 092667, WO2020 / 261114, CN112457294, CN112225695, CN111808019, WO2021 / 032074, WO2020 / 151728, WO2020 / 140959, WO2022 / 037641, WO2022 / 037647, CN112300051, CN112300069, WO2014 / 120808, WO2015 / 089361, WO2019 / 014352, WO2021 / 113627, WO2013 / 086229, WO2013 / 134518, WO2014 / 211173, WO2014 / 201206, WO2016 / 141035, WO2021 / 252818, WO2021 / 252822, and WO2021 / 252820.

[0219] In some embodiments, the additional therapeutic agent is a compound disclosed in WO2013 / 086229. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2013 / 134518. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2014 / 211173. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2014 / 201206. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2016 / 141035. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2021 / 252818. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2021 / 252822. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2021 / 252820. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2020 / 072835. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2022 / 036297.

[0220] In another embodiment, the additional therapeutic agent is a NaV 1.7 and Na V and sodium channel inhibitors (also known as sodium channel blockers), such as 1.8 blockers.

[0221] The amount of additional therapeutic agent present in the compositions of the invention may be up to the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. The amount of additional therapeutic agent in the presently disclosed compositions may range from about 10% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0222] The compounds and salts of the present invention, or pharmaceutically acceptable compositions thereof, may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents, and catheters. Accordingly, in another aspect, the present invention includes compositions for coating implantable devices, comprising a compound or salt of the present invention, generally as described above, and the classes and subclasses herein, and a carrier suitable for coating the implantable device. In yet another aspect, the present invention includes an implantable device coated with a composition comprising a compound or salt of the present invention, generally as described above, and the classes and subclasses herein, and a carrier suitable for coating the implantable device. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Patent Nos. 6,099,562, 5,886,026, and 5,304,121. The coating is typically a biocompatible polymeric material, such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable top coating of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart sustained release characteristics in the composition.

[0223] Another aspect of the present invention is to detect Na in a biological sample or subject. VWith respect to inhibiting 1.8 activity, the method includes administering to a subject or contacting the biological sample with a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof, biopsies obtained from mammals or extracts thereof, as well as blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[0224] Na in biological samples V Inhibition of 1.8 activity is useful for a variety of purposes known to those of skill in the art, including, but not limited to, the study of sodium channels in biological and pathological phenomena and the comparative evaluation of new sodium channel inhibitors.

[0225] Synthesis of Compounds of the Invention The compounds of the present invention can be prepared from known materials by the methods described in the examples, other analogous methods, and other methods known to those skilled in the art. As will be understood by those skilled in the art, functional groups of intermediate compounds in the methods described below may need to be protected by suitable protecting groups. Protecting groups may be added or removed according to standard techniques 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).

[0226] Radiolabeled Analogues of the Compounds of the Invention In another aspect, the present invention relates to radiolabeled analogues of the compounds of the present invention.As used herein, the term "radiolabeled analogues of the compounds of the present invention" refers to compounds that are identical to the compounds of the present invention described herein, including all embodiments thereof, except that one or more atoms are replaced with radioactive isotopes of the atoms present in the compounds of the present invention.

[0227] 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: 3 H, 14 C. 32 P, 35 S, 18 F, 36 Cl, etc., as well as isotopes whose decay modes are identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0228] Radiolabeled analogs can be used in several beneficial ways, including various types of assays such as substrate tissue distribution assays. For example, tritium (3 H ) labeling and / or carbon-14 ( 14 C) Labeled compounds can be useful in various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detectability.

[0229] In another aspect, the invention relates to a pharmaceutically acceptable salt of a radiolabeled analog according to any of the embodiments described herein in connection with the compounds of the invention.

[0230] In another aspect, the invention relates to a pharmaceutical composition comprising a radiolabeled analog or a pharmaceutically acceptable salt thereof according to any of the embodiments described herein with respect to the compounds of the invention, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0231] In another aspect, the present invention relates to methods for inhibiting voltage-gated sodium channels in a subject, and for treating or lessening the severity of various diseases and disorders, including pain, comprising administering an effective amount of a radiolabeled analogue, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, according to any of the embodiments described herein with reference to the compounds of the invention.

[0232] In another aspect, the invention relates to radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use according to any of the embodiments described herein in connection with the compounds of the invention.

[0233] In another aspect, the invention relates to the use of a radiolabeled analogue, or a pharmaceutically acceptable salt thereof, according to any of the embodiments described herein with reference to the compounds of the invention, for the manufacture of a medicament, and pharmaceutical compositions thereof.

[0234] In another aspect, the radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof may be used in combination therapy according to any of the embodiments described herein in connection with the compounds of the invention.

[0235] Enumerated Embodiments Further embodiments of the present disclosure are described in the following numbered clauses: 1. A compound of formula (I), [ka] , or a pharmaceutically acceptable salt thereof, wherein: X 2a But, N, N + -O - , or CR 2a and X 3a But N or N + -O - and X 5a But, N, N + -O -, or CR 5a and X 6a But, N, N + -O - , or CR 6a and R d But (CH2) m (CHR e ) n (CH2) p H, m, n, and p are each independently 0 or 1; R e is H, OH, halo, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 2a and R 6a are each independently H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 5a is H, halo, CHOH, C-C alkyl, or C-C haloalkyl; R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; R 5b1 and R 5b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; X 3c But N or CR 3c and X 4c But N or CR 4c and X 5c But N or CR 5c and X 6c But N or CR 6c and R 2c is H, OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2-(C3-C6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; L 1 is a bond or O, L 2 is a bond or C1-C6 alkylene; R 3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl, or X 3c But, CR 3c and R 2c and R 3c together with the carbon atoms to which they are attached form a ring of the formula: [ka] ; Z1 and Z2 are each independently O or CH2; each R is independently H or halo; R 4c is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 5c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 6c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; However, X 2a , X 3a , X 5a , and X 6a Two or fewer of these are N or N + -O - and X 3c , X 4c , X 5c , and X 6c A compound of formula (I), or a pharmaceutically acceptable salt thereof, provided that not more than one of: 2. The compound has the formula (IA) [ka] , 2. The compound according to clause 1, or a pharmaceutically acceptable salt thereof, having the formula: 3. The compound is represented by the formula (IA-1) [ka] , 2. The compound according to clause 1, or a pharmaceutically acceptable salt thereof, having the formula: 4. The compound has the formula (IB) [ka] , 2. The compound according to clause 1, or a pharmaceutically acceptable salt thereof, having the formula: 5. The compound is represented by the formula (IB-1) [ka] , 2. The compound according to clause 1, or a pharmaceutically acceptable salt thereof, having the formula: 6.X 2a But, CR 2a and R 2a A compound according to any one of clauses 1, 2 and 4, or a pharmaceutically acceptable salt thereof, wherein: 7.X 3a A compound according to any one of clauses 1, 2, 4 and 6, or a pharmaceutically acceptable salt thereof, wherein is N. 8.X 3a But, N + -O - 7. The compound according to any one of clauses 1, 2, 4 and 6, wherein: 9.X 5a But N or CR 5a and R 5a is H, halo, or CH2OH, or a pharmaceutically acceptable salt thereof. 10.X 5a is N, or a pharmaceutically acceptable salt thereof. 11.X 5a But, CR 5a and R 5a10. The compound according to item 9, or a pharmaceutically acceptable salt thereof, wherein is H, F, or CH2OH. 12.X 6a But N or CR 6a and R 6a is H, or a pharmaceutically acceptable salt thereof. 13.X 6a But, CR 6a and R 6a 13. The compound according to item 12, wherein is H, or a pharmaceutically acceptable salt thereof. 14.R 4b1 14. The compound according to any one of items 1 to 13, or a pharmaceutically acceptable salt thereof, wherein is H or C1-C6 alkyl. 15.R 4b1 is H or CH3, or a pharmaceutically acceptable salt thereof. 16.R 4b2 16. The compound according to any one of items 1 to 15, or a pharmaceutically acceptable salt thereof, wherein is H or C1-C6 alkyl. 17.R 4b2 17. The compound according to clause 16, or a pharmaceutically acceptable salt thereof, wherein is H or CH3. 18.R 5b1 18. The compound according to any one of clauses 1 to 17, or a pharmaceutically acceptable salt thereof, wherein is C1-C6 alkyl or C1-C6 haloalkyl. 19.R 5b1 19. The compound according to clause 18, or a pharmaceutically acceptable salt thereof, wherein is CH3 or CF3. 20.R 5b2 20. The compound according to any one of clauses 1 to 19, or a pharmaceutically acceptable salt thereof, wherein is C1-C6 alkyl or C1-C6 haloalkyl. 21.R 5b2 21. The compound according to clause 20, or a pharmaceutically acceptable salt thereof, wherein is CH3 or CF3. 22.R 2c22. The compound according to any one of clauses 1 to 21, or a pharmaceutically acceptable salt thereof, wherein is OH, halo, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. 23.R 2c 23. The compound of clause 22, or a pharmaceutically acceptable salt thereof, wherein is OH, Cl, CH3, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCH2CH2F, or OCH2CHF2. 24.X 3c But N or CR 3c and R 3c 24. The compound according to any one of clauses 1 to 23, or a pharmaceutically acceptable salt thereof, wherein is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl. 25.X 3c 25. The compound according to clause 24, wherein is N, or a pharmaceutically acceptable salt thereof. 26.X 3c But, CR 3c and R 3c 25. The compound of clause 24, or a pharmaceutically acceptable salt thereof, wherein is H, F, CH3, CHF2, or CF3. 27.X 3c But, CR 3c and R 2c and R 3c taken together with the carbon atoms to which they are attached form a ring of the formula: or a pharmaceutically acceptable salt thereof. [ka] . 28. The compound according to clause 27, wherein the ring is of the formula: or a pharmaceutically acceptable salt thereof. [ka] . 29.X 4c But, CR 4c and R 4c29. The compound according to any one of clauses 1 to 28, or a pharmaceutically acceptable salt thereof, wherein is H, halo, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. 30.X 4c But, CR 4c and R 4c 29. The compound according to clause 29, wherein is H, F, CHF2, OCH2CH3, OCHF2, OCF3, or a pharmaceutically acceptable salt thereof. 31.X 5c But, CR 5c and R 5c 31. The compound according to any one of clauses 1 to 30, wherein is H, or a pharmaceutically acceptable salt thereof. 32.X 6c But, CR 6c and R 6c 32. The compound according to any one of clauses 1 to 31, wherein is H, or a pharmaceutically acceptable salt thereof. 33.R d But (CH2) p 33. The compound according to any one of clauses 1 to 32, wherein R is H, or a pharmaceutically acceptable salt thereof. 34.R d is H or CH3, or a pharmaceutically acceptable salt thereof. 35.R d However, (CHR e ) n (CH2) p 33. The compound according to any one of clauses 1 to 32, wherein R is H, or a pharmaceutically acceptable salt thereof. 36.R d 36. The compound of clause 35, or a pharmaceutically acceptable salt thereof, wherein is CH2F, CH2OH, or CH(OH)CH3. 37.R d But (CH2) m (CHR e ) n 33. The compound according to any one of clauses 1 to 32, wherein R is H, or a pharmaceutically acceptable salt thereof. 38.R d 38. The compound according to clause 37, or a pharmaceutically acceptable salt thereof, wherein is CH2OCH3 or CH2CH2OCH3. 39. A compound selected from Table A, or a pharmaceutically acceptable salt thereof. 40. The compound according to any one of clauses 1 to 39, in non-salt form. 41. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of clauses 1 to 39 or a pharmaceutically acceptable salt thereof, or a compound according to clause 40, and one or more pharmaceutically acceptable carriers or vehicles. 42. A pharmaceutical composition comprising a compound according to any one of clauses 1 to 39 or a pharmaceutically acceptable salt thereof, or a compound according to clause 40, and one or more pharmaceutically acceptable carriers or vehicles. 43. A method of inhibiting voltage-gated sodium channels in a subject, the method comprising administering to the subject a compound according to any one of clauses 1 to 39 or a pharmaceutically acceptable salt thereof, a compound according to clause 40, or a pharmaceutical composition according to clause 41 or 42. 44. Voltage-gated sodium channels are V 1.8. The method according to clause 43. 45. A method for treating or lessening the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia in a subject, said method comprising administering to the subject an effective amount of a compound according to any one of clauses 1 to 39 or a pharmaceutically acceptable salt thereof, a compound according to clause 40, or a pharmaceutical composition according to clause 41 or 42. 46. ​​The method of clause 45, wherein the method comprises treating or reducing the severity of neuropathic pain in the subject. 47. The method according to clause 46, wherein the neuropathic pain comprises postherpetic neuralgia. 48. The method of clause 46, wherein the neuropathic pain comprises small fiber neuropathy. 49. The method of item 46, wherein the neuropathic pain comprises idiopathic small fiber neuropathy. 50. The method according to clause 46, wherein the neuropathic pain includes diabetic neuropathy. 51. The method according to clause 50, wherein the diabetic neuropathy includes diabetic peripheral neuropathy. 52. The method of clause 45, wherein the method comprises treating or reducing the severity of musculoskeletal pain in a subject. 53. The method according to clause 52, wherein the musculoskeletal pain comprises osteoarthritis pain. 54. The method of clause 45, wherein the method comprises treating or reducing the severity of acute pain in the subject. 55. The method according to clause 54, wherein the acute pain comprises acute post-operative pain. 56. The method of clause 45, wherein the method comprises treating or reducing the severity of post-operative pain in the subject. 57. The method of clause 56, wherein the postoperative pain comprises bunionectomy pain. 58. The method according to clause 56, wherein the postoperative pain includes abdominoplasty pain. 59. The method according to clause 56, wherein the postoperative pain includes pain from herniorrhaphy. 60. The method of clause 45, wherein the method comprises treating or reducing the severity of visceral pain in the subject. 61. The method of any one of clauses 43-60, wherein the subject is treated with one or more additional therapeutic agents administered simultaneously with, before, or after treatment with the compound, pharmaceutically acceptable salt, or pharmaceutical composition. 62. Use of a compound according to any one of clauses 1 to 39 or a pharmaceutically acceptable salt thereof, a compound according to clause 40, or a pharmaceutical composition according to clause 41 or 42 as a medicament. [Example]

[0236] General method. 1 1 H NMR spectra were obtained as solutions in a suitable deuterated solvent such as dimethylsulfoxide-d6 (DMSO-d6).

[0237] Compound purity, retention time, and electrospray mass spectrometry (ESI-MS) data were determined by LC / MS analysis.

[0238] LC / MS method: LC / MS analysis was performed using a Waters Acquity UPLC BEH C8 column (50 x 2.1 mm, 1.7 μm particles) (pn: 186002877) with a (2.1 x 5 mm, 1.7 μm particles) guard column (pn: 186003978) and a dual gradient run of 2 to 98% mobile phase B over 4.45 min. Mobile phase A = HO (10 mM ammonium formate with 0.05% ammonium hydroxide). Mobile phase B = acetonitrile. Flow rate = 0.6 mL / min, injection volume = 2 μL, and column temperature = 45 °C.

[0239] X-ray Powder Diffraction Analysis Method A: X-ray powder diffraction (XRPD) analysis was performed in transmission mode at room temperature using a PANalytical Empyrean system equipped with a sealed-tube source and a PIXcel 1D Medipix-2 detector (Malvern PANalytical Inc, Westborough, Massachusetts). The X-ray generator was operated with copper radiation (1.54060 Å) at a voltage of 45 kV and a current of 40 mA. Powder samples were placed on a 96-well sample holder with Mylar film and loaded into the instrument. Samples were scanned over the range of approximately 5° to approximately 40° 2θ with a step size of 0.0131303° and 8.67 seconds per step × 5 (unstable omega = 0, ±1, ±2).

[0240] X-ray Powder Diffraction Analysis Method B: X-ray powder diffraction (XRPD) analysis was performed in transmission mode at room temperature using a PANalytical Empyrean system equipped with a sealed-tube source and a PIXcel 3D Medipix-3 detector (Malvern PANalytical Inc, Westborough, Massachusetts). The X-ray generator was operated with copper radiation (1.54060 Å) at a voltage of 45 kV and a current of 40 mA. Powder samples were placed on a 96-well sample holder with Mylar film and loaded into the instrument. Samples were scanned over the range of approximately 3° to approximately 40° 2θ with a step size of 0.0131303° and 49 seconds per step.

[0241] Abbreviation Unless otherwise specified, or where the context dictates otherwise, the following abbreviations shall be understood to have the following meanings: [Table 2-1] [Table 2-2] Example 1 [ka]

[0242] Step 1: NEt (7.7 mL, 55.2 mmol) was added to a solution of ethyl 2-diazo-3-oxo-pentanoate (6.69 g, 39.3 mmol) in DCM (80 mL) with stirring at 0 °C under nitrogen. Trimethylsilyl trifluoromethanesulfonate (8.5 mL, 47.0 mmol) was added dropwise over 5 min, and the mixture was stirred at 0 °C for an additional 30 min. The reaction mixture was diluted with pentane (100 mL), the layers were separated, and the organic phase was washed with dilute aqueous sodium bicarbonate (100 mL) followed by brine (100 mL). The organic layer was dried (MgSO) and concentrated in vacuo to give ethyl (Z)-2-diazo-3-trimethylsilyloxy-pent-3-enoate (9.4 g, 99%) as a red oil. 1H NMR (500 MHz, chloroform-d) δ 5.33 (q, J = 7.0 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 1.67 (d, J = 7.0 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 0.22 (s, 9H) ppm.

[0243] Step 2: To a stirred solution of 1,1,1-trifluoropropan-2-one (8 mL, 89.4 mmol) in DCM (80 mL) at −78° C., TiCl (70 mL of 1 M in DCM, 70.00 mmol) was added 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 minutes. After stirring for 100 minutes, the reaction was carefully quenched with water, the temperature was allowed to slowly rise, and then extracted with DCM. The combined organic layers were dried (MgSO), filtered, and concentrated in vacuo. Purification by silica gel chromatography (330 g SiO, 0–20% EtOAc in heptane) gave ethyl rac-(4R,5R)-2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxohexanoate (8.82 g, 67%) as the major diastereoisomer, which was stored as a solution in toluene. 1 H NMR (500 MHz,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 = 7.1 Hz, 3H), 1.31 (dq, J = 7.0, 1.4 Hz, 3H) ppm. ESI-MS m / z calculated value 282.08273, measured value 283.1 (M+1) + ; 281.0 (M-1) - .

[0244] Step 3: After heating a solution of rhodium tetraacetate (245 mg, 0.55 mmol) in benzene (32 mL) at reflux for 10 minutes, 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 an addition funnel while refluxing for 60 minutes. 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 residue containing residual catalyst and a mixture of epimers adjacent to the ester. This material was used in the next step without further purification. 1 H NMR (500 MHz, chloroform-d) δ 4.83–4.57 (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.

[0245] Step 4: 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., DIPEA (29.680 g, 40 mL, 229.64 mmol) was added. A solution of trifluoromethylsulfonyl trifluoromethanesulfonate (53.440 g, 32 mL, 189.41 mmol) in DCM (200 mL) was added to the reaction mixture over 1 h at the same temperature. The reaction mixture was stirred at 0° C. for 30 min and then quenched with 100 mL of saturated aqueous NaHCO3 solution. The organic layer was separated, and the aqueous layer was 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%). 1 H NMR (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.

[0246] Step 5: To a stirred solution of ethyl rac-(4R,5R)-2,3-dimethyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (26 g, 67.311 mmol) in toluene (130.00 mL) under an argon atmosphere, (3,4-difluoro-2-methoxy-phenyl)boronic acid (14 g, 74.5 mmol) was added, followed by KPO (100 mL of 2 M, 200.00 mmol). The reaction was degassed, and then 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 with water, and the aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were concentrated in vacuo. Purification by silica gel chromatography (SiO, 0-10% EtOAc in heptane) gave ethyl 4-(3,4-difluoro-2-methoxy-phenyl)-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-methoxyphenyl)-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate. Major isomer: 1 H 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 = 7.4 Hz, 1H), 1.67 (s, 3H), 1.12 (t, J = 7.4 Hz, 3H), 1.06 (dd, J = 5.4, 2.7 Hz, 3H) ppm. Trace isomers: 1H NMR (400 MHz, chromohol-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 = 7.4 Hz, 3H), 0.99 (dd, J = 5.4, 2.7 Hz, 3H) ppm. ESI-MS m / z calcd: 380.1047, found: 381.02 (M+1) + .

[0247] ステップ6: To an ice-cold solution of ethyl rac-(4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (110 g, 243.0 mmol) in DCM (360 mL) was added BBr3 (370 mL of 1 M, 370.0 mmol) dropwise. Upon completion of the addition, the mixture was quenched by the addition of aqueous sodium bicarbonate. The aqueous layer was extracted with DCM, and the combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was dissolved in DCM (430 mL) at ambient temperature, and TFA (40 mL, 519.2 mmol) was added. The reaction was heated to 45°C. Upon completion of the reaction, the mixture was quenched by the addition of aqueous sodium bicarbonate, and the aqueous layer was extracted with DCM, dried (MgSO), filtered, and concentrated in vacuo to give the desired product as a 5:1 mixture of diastereomers. Recrystallization was performed by solubilizing the crude material in the minimum amount of DCM possible and adding a layer of heptane over the solution (liquid-liquid diffusion). After approximately 1 hour, 56.5 g (97:3 syn:anti dr) was obtained from the first and second crystallizations, and an additional 4.6 g (96:4 syn:anti dr) was obtained from the third crystallization. The first, second, and third recrystallization batches were 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 calculated 320.04718, found 321.5 (M+1). + ; 319.6 (M-1) - .

[0248] Step 7: 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 × 3 cm, from Regis Technologies on a MultiGram III SFC instrument from Berger Instruments using a mobile phase consisting of MeOH (containing 5 mM ammonia) and CO:

[0249] First eluting isomer (retention time = 1.85 min): (1R,2S)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3-c]chromen-4-one (analytical sample only collected). 1 H NMR (400 MHz, DMSO-d6) δ 7.57 (ddd, J = 9.0, 5.5, 2.0 Hz, 1H), 7.51 (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 calculated value 320.04718, measured value 321.3 (M+1) + ; 319.4 (M-1) - .

[0250] Second eluting isomer (retention time = 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%). 1H NMR (400 MHz, DMSO-d6) δ 7.57 (ddd, J = 9.0, 5.5, 2.0 Hz, 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 calculated value 320.04518, measured value 321.4 (M+1) + ; 319.4 (M-1) - .

[0251] Step 8: 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 overnight under 40 psi of hydrogen. After overnight reaction, the reaction temperature was observed to rise to 37°C, and the mixture was cooled to 24°C. Hydrogenation was continued for a total of 48 hours. The mixture was filtered through Celite, washing with MeOH (20 L), and the filtrate was concentrated in vacuo. The residue was dissolved in toluene (4 L) and concentrated in vacuo, and the process was repeated. The residue was dried under vacuum at 40° C. overnight to give methyl (2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.0 kg at 91% purity, 100%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) 10.20 (br s, 1H), 6.94 (br t, J = 7.4 Hz, 1H), 6.79-6.69 (m, 1H), 5.10 (d, J = 6.0 Hz, 1H), 4.20 (dd, J = 6.1, 8.2 Hz, 1H), 3.43 (s, 3H), 2.94 (quin, J = 7.7 Hz, 1H), 1.46 (s, 3H), 0.77 (br d, J = 6.8 Hz, 3H) ppm.

[0252] Step 9: Potassium carbonate (2.0 kg, 14.4 mol) and iodomethane (800 mL, 12.8 mol) were added sequentially to a solution of methyl (2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.0 kg, 2.82 mol) in acetonitrile (10 L) with stirring at ambient temperature under nitrogen. After stirring overnight, additional iodomethane (120 mL, 2 mmol) was added. After stirring overnight, additional iodomethane (60 mL, 0.85 mmol) was added, and the mixture was stirred for an additional 3 days. The reaction mixture was diluted with MTBE (30 L), treated with 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 with MTBE (4 L), and the filtrate was concentrated in vacuo. The residue was dissolved in toluene (4 L) and concentrated in vacuo, and the process was repeated. The residue was dried under vacuum at 40° C. overnight to give 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, 8.4 Hz, 1H), 3.88 (d, J = 1.7 Hz, 3H), 2.97 (quin, J = 7.8 Hz, 1H), 1.48 (s, 3H), 0.72 (br d, J = 6.6 Hz, 3H) ppm.

[0253] Steps 10 and 11: Sodium methoxide (25% in methanol, 65 mL, 0.28 mol) was added to a solution of methyl (2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (0.98 kg, 2.66 mol) in THF (10 L) with 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 added sequentially, and the mixture was stirred overnight. The reaction mixture was poured into 1 M HCl (4.4 L, 4.4 mol) and then extracted with MTBE (20 L). The aqueous layer was further extracted with MTBE (2 × 5 L), and the combined organic layers were washed with brine (2 L), dried (NaSO), filtered, and then treated with activated carbon (50 g, 5% w / w) with stirring for 1 h. The mixture was filtered through Celite, washing with MTBE (2 × 4 L), and the filtrate was concentrated in vacuo. The residue was dissolved in toluene (4 L), concentrated in vacuo, then dissolved in MTBE (4 L) and concentrated in vacuo again to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1.06 kg at 77.7% purity) as an amber oil, which was used without further purification.

[0254] Step 12: Crude (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (2.09 kg, 4.54 mol at 77% purity) was dissolved in MTBE (25 L) in a 100 L Chemglass reactor and then stirred at ambient temperature and 84 rpm. A mixture of (R)-1-phenylethylamine (0.704 kg, 5.81 mol) and MTBE (2 L) was added to the reactor, followed by additional MTBE to achieve a total volume of 30 L in the reactor. After 2 hours, additional MTBE (2 L) was added to the reaction. After a total of 3.5 hours, the mixture was filtered, washing with MTBE (2 L). The reactor was rinsed with MTBE (4 L) and used to rinse the solids, which were then compressed and dried on a Buchner funnel for 2 hours. The solid product cake was loosened and then dried overnight under nitrogen flow and vacuum on a Buchner funnel. The isolated solid was dried in a convection oven at 40° C. for 24 hours to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-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. 1 H NMR, 400 MHz, 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 = 9.9 Hz, 1H), 4.23 (q, J = 6.7 Hz, 1H), 3.99 (dd, J = 7.8, 9.8 Hz, 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.

[0255] Step 13: To a suspension of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1R)-1-phenylethanamine salt (10.6 g, 22.29 mmol) in MTBE (250 mL) was added HCl (200 mL of 2 M, 400.0 mmol). The layers were separated, and the organic layer was washed with water (200 mL), dried (MgSO), filtered, and concentrated in vacuo to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (8.4 g, 99%) as an oil. 1 H NMR (400 MHz,chloroform-d) δ 6.96 (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.

[0256] Steps 14 and 15: 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, 4.234 mmol) and DMF (31 μL, 0.4004 mmol) in dichloromethane (10 mL). After stirring at ambient temperature for 30 minutes, the solution was concentrated in vacuo. The residue was redissolved in dichloromethane (10 mL) and a mixture of rac-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine (904 mg, 4.654 mmol) and triethylamine (706 μL, 5.065 mmol) was added. The mixture was stirred at ambient temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate (30 mL) and water (30 mL). The aqueous layer was further extracted with EtOAc (50 mL). The combined organic extracts were washed with brine (1 × 20 mL), dried (MgSO), 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 with 0.1% ammonia) afforded, after lyophilization, a mixture of two diastereoisomers of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide.

[0257] A mixture of two diastereoisomers of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide was separated by chiral SFC on a Minigram SFC instrument from Berger Instruments using a Chiralcel OJ-H column from Daicel, 5 μm particle size, 25 cm × 10 mm (mobile phase: 12% MeOH (with 20 mM ammonia), 88% CO. Flow rate: 10 mL / min):

[0258] First eluting isomer (retention time = 2.99 min): (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (700 mg, 60%). ESI-MS m / z calculated 530.184, found 531.2 (M+1). + ;Retention time: 3.56 minutes.

[0259] Second eluting isomer (retention time = 3.63 min): (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 (700 mg, 60%). ESI-MS m / z calculated 530.184, found 531.2 (M+1). + ;Retention time: 3.56 minutes.

[0260] Step 16: TFA (1.743 mL, 22.62 mmol) was added to a solution of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (600 mg, 1.112 mmol) (first eluting isomer from SFC separation) in DCM (20 mL), and the mixture was stirred at ambient temperature for 2 hours. The mixture was concentrated in vacuo and lyophilized from MeCN and water to give a white solid. Purification by reverse-phase preparative HPLC (Waters Sunfire C18, 10 μM, 100 Å column, 0% to 100% MeCN in water with 0.1% ammonia) gave, after lyophilization, (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, 304 mg, 55%). 1 H 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 = 10.3 Hz, 1H), 4.61 (s, 1H), 4.25 (dd, J = 10.3, 7.6 Hz, 1H), 3.95 (d, J = 2.1 Hz, 3H), 3.63 (dd, J = 11.0, 4.4 Hz, 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 calculated value 490.1527, measured value 491.6 (M+1) + ;Retention time: 2.98 minutes.

[0261] (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) (the second eluting isomer from the SFC separation) was treated in the same manner to give, after lyophilization, (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((S)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (2, 340 mg, 61%). 1 H 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 = 8.5 Hz, 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, 4.4 Hz, 1H), 4.24 (dd, J = 10.3, 7.7 Hz, 1H), 3.95 (d, J = 2.1 Hz, 3H), 3.63 (ddd, J = 11.0, 6.0, 4.1 Hz, 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-MS m / z calculated value 490.1527, measured value 491.6 (M+1) + ;Holding time: 2.99 minutes.

[0262] The absolute stereochemistry of 1 and 2 was determined by analysis of the single crystal X-ray crystallography of 1 .

[0263] Compound 1 was analyzed by X-ray powder diffraction analysis method A and determined to be amorphous (see Figure 1).

[0264] The following compound was 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 instead of rac-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine in the amide coupling step 14. In step 15, purification was carried out by chiral SFC using a Chiralcel OD-H column from Daicel Corporation, 5 μm particle size, 25 cm × 10 mm (mobile phase: 12% MeOH (with 20 mM ammonia), 88% CO. Flow rate: 10 mL / min) on a Minigram SFC instrument from Berger Instruments. [Table 3]

[0265] The following compounds were 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 instead of (1S,2R)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3-c]chromen-4-one in 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. SFC separation step 15 was not required: [Table 4]

[0266] The following compounds were made using the method described in Example 1, except that ethyl iodide was used instead of methyl iodide in alkylation step 9. The conditions used in epimerization / hydrolysis steps 10 and 11 followed the first part of the conditions described in step 4 of Example 5. 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 used as coupling partners for compounds 6 and 7, respectively. The SFC separation step 15 was not required: [Table 5]

[0267] Compound 7 was analyzed by X-ray powder diffraction analysis method B and determined to be amorphous (see Figure 2).

[0268] The following compounds were made using methods similar to those described in Example 1, except that iodomethane-d3 and methyl iodide were used in alkylation step 9, and the conditions carried out for amide coupling step 14 followed those described in Step 1 of Example 2 using (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine as the coupling partner. SFC separation step 15 was not required: [Table 6]

[0269] Compound 8 was analyzed by X-ray powder diffraction analysis method B and determined to be amorphous (see Figure 3).

[0270] The following compound was made using the method described in Example 1, except that 2-iodopropane was used instead of methyl iodide in step 9 and the reaction was carried out at 75°C. Epimerization / hydrolysis steps 10 and 11 were carried out in one step according to the conditions described in step 3 of Example 6. Steps 12 and 13 were omitted, and 2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrimidin-5-amine was used as the coupling partner in the amide coupling step 14. In step 15, purification was carried out by chiral SFC using a Chiralpak IB column from Daicel Corporation, 5 um particle size, 25 cm x 20 mm (mobile phase: 20% MeOH (with 20 mM ammonia), 80% CO2; flow rate: 100 mL / min) on a Berger Instruments Minigram SFC instrument. [Table 7]

[0271] The following compound was made using the method described in Example 1, except that steps 12 and 13 were omitted and 2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrimidin-5-amine was used as the coupling partner in the amide coupling step 14. In step 15, purification was carried out by chiral SFC using a Chiralcel OD-H column from Daicel Corporation, 5 um particle size, 25 cm x 10 mm (mobile phase: 22% MeOH (with 20 mM ammonia), 78% CO. Flow rate: 10 mL / min) on a Minigram SFC instrument from Berger Instruments. [Table 8]

[0272] The following compound was made using the method described in Example 1, except that (3-fluoro-2-methoxyphenyl)boronic acid was used instead of (3,4-difluoro-2-methoxyphenyl)boronic acid in Suzuki step 5. In the amide coupling step 14, (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine was used instead of 6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine, and the coupling conditions were those used in step 1 of Example 2. The compound did not require the chiral SFC separation step 15. [Table 9]

[0273] The following compound was made using the method described in Example 1, except that 6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-amine was used as the coupling partner in the amide coupling step 14. The SFC separation step 15 was not required, and the deprotection step 16 was carried out using excess HCl in MeOH (37% w / v) as the solvent for 3 days at ambient temperature. [Table 10]

[0274] The following compound was made using the method described in Example 1, except that methyl (5-aminopyrimidin-2-yl)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 excess 2 M sodium hydroxide solution and 1,4-dioxane as the solvent. [Table 11]

[0275] 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 from Daicel, 5 μm particle size, 25 cm × 20 mm (mobile phase: 5% IPA (with 20 mM ammonia), 95% CO . Flow rate: 100 mL / min) on a Prep-100 SFC instrument from Waters. The conditions used for the deprotection step 16 were those described in Step 3 of Example 2, utilizing THF as the solvent rather than 2-MeTHF.

[0276] Compound 16 was analyzed by X-ray powder diffraction analysis method B and determined to be crystalline (see Figure 4). [Table 12] Example 2 [ka]

[0277] Step 1: 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-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (130 mg, 0.3486 mmol), rac-6-(1-((tert-butyldimethylsilyl)oxy)-2-methoxyethyl)pyridin-3-amine (108 mg, 0.3824 mmol), and Et3N (100 μL, 0.7175 mmol) in EtOAc (1.5 mL). The clear mixture was stirred at ambient temperature for 2 h. The mixture was partitioned between EtOAc and water and passed through a phase separation cartridge. The organic filtrate was concentrated in vacuo to give a clear oil. Purification by silica gel chromatography (12 g SiO, 0-30% EtOAc in hexanes) afforded a mixture of two diastereoisomers of (2R,3S,4S,5R)-N-(6-(1-((tert-butyldimethylsilyl)oxy)-2-methoxyethyl)pyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (211 mg, 92%) as a clear oil. ESI-MS m / z calculated 618.2548, found 619.0 (M+1). + ; 617.0 (M-1) - ;Retention time: 4.3 minutes.

[0278] Step 2: The two diastereoisomers of (2R,3S,4S,5R)-N-(6-(1-((tert-butyldimethylsilyl)oxy)-2-methoxyethyl)pyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (210 mg, 0.3191 mmol) were separated on a Minigram SFC instrument from Berger Instruments using a Chiralcel OD-H column from Daicel, 5 μm particle size, 25 cm × 10 mm (mobile phase: 15% MeOH (with 20 mM ammonia), 85% CO. Flow rate: 10 mL / min):

[0279] First eluting isomer (retention time = 2.24 min): 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 (83 mg, 84%). ESI-MS m / z calculated 618.2548, found 619.0 (M+1). + ; 617.0 (M-1) - ;Retention time: 4.3 minutes.

[0280] Second eluting isomer (retention time = 3.01 min): 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 (82 mg, 83%). ESI-MS m / z calculated 618.2548, found 619.0 (M+1). + ; 617.0 (M-1) - ;Retention time: 4.3 minutes.

[0281] Step 3: A THF solution of TBAF (650 μL of 1 M, 0.6500 mmol) was added to a stirred solution of rel-(2R*,3S*,4S*,5R*)-N-(6-(1-((tert-butyldimethylsilyl)oxy)-2-methoxyethyl)pyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (80 mg, 0.1293 mmol) (first eluting isomer from SFC separation) in 2-MeTHF (4 mL) at 0° C. The reaction was stirred at ambient temperature over the weekend (expedient). The reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL), stirred for 10 minutes, and extracted with ethyl acetate (2×10 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 with 0.1% ammonia) gave, after lyophilization, 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 (400 MHz, 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 = 5.0 Hz, 1H), 5.09 (d, J = 10.3 Hz, 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, ESI-MS m / z calculated value 504.16837, measured value 505.0 (M+1) + ; 503.0 (M-1) - ;Retention time: 3.16 minutes.

[0282] 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) (the second eluting isomer from the SFC separation) was treated in the same manner to give, after lyophilization, 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 (21, 54 mg, 82%). 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.68 (dd, J = 2.5, 0.7 Hz, 1H), 7.99 (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 = 4.4 Hz, 1H), 5.09 (d, J = 10.3 Hz, 1H), 4.69 (d, J = 6.2 Hz, 1H), 4.24 (dd, J = 10.3, 7.7 Hz, 1H), 3.95 (d, J = 2.2 Hz, 3H), 3.57 (dd, J = 10.0, 3.9 Hz, 1H), 3.44 (dd, J = 10.0, 6.9 Hz, 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 calculated value 504.16837, measured value 505.0 (M+1) + ;503.0 (M-1) - ;Retention time: 3.16 minutes.

[0283] Compound 21 was analyzed by X-ray powder diffraction analysis method B and determined to be amorphous (see Figure 5).

[0284] The following compounds were made using the method described in Example 2, except that in the amide coupling step 1, 6-(1-((tert-butyldimethylsilyl)oxy)-3-methoxypropyl)pyridin-3-amine was used as the coupling partner. In step 2, purification was carried out by chiral SFC using a Chiralpak IB column from Daicel, 5 μm particle size, 25 cm × 20 mm (mobile phase: 5% MeOH (with 20 mM ammonia), 95% CO. Flow rate: 100 mL / min) on a Prep-100 SFC instrument from Waters. [Table 13] Example 3 [ka]

[0285] Step 1: Triethylamine (8.05 g, 11.2 mL, 78.8 mmol) was added to a stirred solution of ethyl 2-diazo-3-oxobutanoate (5.0 g, 31.4 mmol) in DCM (50 mL) at 0 °C. TBSOTf (9.24 g, 8.2 mL, 34.3 mmol) was added slowly, and the reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was washed with 30% NaHCO solution (200 mL). The organic layer was separated, washed with water (500 mL), dried (MgSO), 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.

[0286] Step 2: A solution of 1,1,1-trifluoropropan-2-one (33.8 g, 27 mL, 301.2 mmol) in DCM (150 mL) was cooled to −78° C. TiCl (56.8 g, 33 mL, 299.2 mmol) was added dropwise to the stirred reaction mixture. The reaction was maintained at −78° C. for 10 minutes, after which a solution of ethyl 3-((tert-butyldimethylsilyl)oxy)-2-diazobut-3-enoate (64 g, 236.7 mmol) in DCM (150 mL) was added. The reaction was maintained at −78° C. for 1 hour. Saturated NaHCO solution was added and the mixture was diluted with DCM. The organic layer was separated, dried (MgSO), filtered, and concentrated in vacuo. Purification by silica gel chromatography (SiO2, 0-30% EtOAc in hexanes) gave ethyl 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.

[0287] Step 3: Rhodium(II) acetate (643 mg, 1.45 mmol) was charged to an oven-dried two-neck flask. Toluene (970 mL) was added, and the solution was stirred at 100° C. for 10 minutes. The solution was briefly removed from the oil bath, while a solution of ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-5-methyl-3-oxohexanoate (39 g, 145.4 mmol) in toluene (200 mL) was added dropwise. The reaction mixture was heated at reflux for 1 hour. The mixture was filtered through filter paper, and the filtrate was concentrated in vacuo to give ethyl 5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (30.89 g, 88%) as a mixture of epimers adjacent to the ester. 1 H 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.

[0288] Step 4: Trifluoromethanesulfonic anhydride (6.0 mL, 35.7 mmol) was added dropwise to a solution of ethyl 5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (6.5 g, 27.1 mmol) and DIPEA (14 mL, 80.4 mmol) in DCM (150 mL) at −78° C. The reaction mixture was stirred for 2.5 h, after which saturated aqueous NH4Cl (75 mL) was added. The mixture was allowed to warm to ambient temperature. The aqueous layer was extracted with DCM (2 × 30 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to give ethyl 5-methyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (10.1 g), which was used directly in the next reaction.

[0289] Step 5: K3PO4 (13 mL of a 2 M aqueous solution, 26.0 mmol) was added to a stirred solution of (3,4-difluoro-2-methoxyphenyl)boronic acid (2.0 g, 10.6 mmol) and ethyl 5-methyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (3 g, 7.90 mmol) in toluene (80 mL). The mixture was degassed by bubbling nitrogen through the solution for 20 minutes. Pd(PPh3)4 (466 mg, 0.40 mmol) was added, and the reaction was heated at 100 °C for 1 hour. The mixture was filtered through a pad of Celite. The filtrate was diluted with water (50 mL), and the aqueous phase was separated. The aqueous layer was extracted with EtOAc (50 × 2 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography (SiO, 0–2% EtOAc in hexanes) afforded ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (2.5 g, 85%) as a light yellow liquid. 1H NMR (400 MHz,chloroform-d) δ 6.87 (pd, J = 8.8, 6.2 Hz, 2H), 4.15 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.42 (d, J = 17.4 Hz, 1H), 2.93 (d, J = 17.4 Hz,1H), 1.65 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H) ppm. ESI-MS m / z calculated value 366.08905, measured value 367.4 (M+1) + ;Holding time: 1.01 minutes.

[0290] Step 6: EtOH (200 mL) was added to a mixture of ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (5.51 g, 15.0 mmol) and Pd / C (10 wt % loading, 2.2 g, 2.067 mmol). The mixture was degassed and stirred under a balloon of H for 96 h. The catalyst was removed by filtration, and the solids were washed with EtOH (50 mL). The filtrate was concentrated in vacuo. An additional portion of Pd / C (10 wt % loading, 2.2 g, 2.07 mmol) was added to the residue, followed by EtOH (200 mL). The reaction mixture was stirred at ambient temperature for 24 h under a balloon of H. The catalyst was removed by filtration, and the solids were washed with EtOH (50 mL). The filtrate was concentrated in vacuo. An additional portion of Pd / C (10 wt % loading, 2.2 g, 2.07 mmol) was added to the residue, followed by EtOH (200 mL), and the reaction mixture was stirred at ambient temperature under a balloon of H for 4 days. The catalyst was removed by filtration, and the solids were washed with EtOH (50 mL). The filtrate was 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 = 8.9 Hz, 1H), 4.23 (dt, J = 13.0, 7.6 Hz, 1H), 4.08 (d, J = 2.9 Hz, 3H), 3.85 - 3.71 (m, 2H), 2.82 (t, J = 12.5 Hz, 1H), 2.04 (dd, J = 12.0, 6.7 Hz, 1H), 1.53 (s, 3H), 0.94 (t, J = 7.1 Hz, 3H) ppm; 19 F NMR (471 MHz, chloroform-d) δ −80.15, −136.84 (d, J = 19.4 Hz), −154.77 (d, J = 19.6 Hz) ppm.

[0291] Step 7: Ethyl rac-(2S,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (5.19 g, 14.09 mmol) was dissolved in ethanol (100 mL). CsCO (7.1 g, 21.79 mmol) was added, and the suspension was stirred at 50 °C for 2 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between 1 M HCl and MTBE. The aqueous layer was extracted twice with MTBE. The combined organic extracts were dried (MgSO), filtered, and concentrated in vacuo to give rac-(2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (5.1063 g, 96%) as a colorless oil. 1H NMR (500 MHz, クロロホルム-d) δ 6.99 - 6.96 (m, 1H), 6.92 - 6.87 (m, 1H), 4.68 (d, J = 10.5 Hz, 1H), 4.00 (d, J = 2.7 Hz, 3H), 3.90 (ddd, J = 12.0, 10.6, 8.2 Hz, 1H), 2.58 (t, J = 12.5 Hz, 1H), 2.31 (dd, J = 13.0, 8.2 Hz, 1H), 1.60 (s, 3H) ppm; 19 F NMR (471 MHz, chromohol-d) δ -81.56, -136.40 (d, J = 19.6 Hz), -153.60 (d, J = 19.5 Hz) ppm. ESI-MS m / z calcd: 340.0734, found: 339.5 (M-1) - ; Holding time: 0.52 minutes.

[0292] ステップ8: Oxalyl chloride (70 μL, 0.8024 mmol) was carefully added to an ice-cold 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 (50 μL of a 0.86 M 2-methyl-THF solution, 0.04300 mmol) in 2-methyltetrahydrofuran (5 mL). The reaction mixture was stirred and allowed to warm to room temperature over 45 minutes. The reaction mixture was concentrated in vacuo, and the residue was dissolved in 2-methyltetrahydrofuran (5 mL). This solution was added to an ice-cold 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 allowed to warm to ambient temperature over 1 h. The reaction mixture was quenched with water (2 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (2 × 5 mL). The combined organic extracts were dried (MgSO), filtered, and concentrated in vacuo. Purification by silica gel chromatography (24 g SiO, 0–100% EtOAc in heptane, loaded from DCM) afforded 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 two diastereoisomers. 1H NMR (500 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.70 - 8.69 (m, 1H), 8.03 (dt, J = 8.4, 2.6 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.22 - 7.15 (m, 2H), 5.07 (t, J = 6.8 Hz, 1H), 4.65 (d, J = 10.1 Hz, 1H), 4.33 (dd, J = 8.2, 6.7 Hz, 1H), 4.05 (q, J = 10.0 Hz, 1H), 3.87 (d, J = 2.0 Hz, 3H), 3.83 (ddd, J = 8.0, 19F NMR (471 MHz, DMSO-d6) δ -80.12, -138.13 (d, J = 21.1 Hz), -154.77 (d, J = 21.2 Hz) ppm.ESI-MS m / z calculated value 516.16833, measured value 517.5(M+1) + ; 515.6(M-1) - ;Retention time: 0.99 minutes.

[0293] Step 9: The two diastereoisomers of rel-(2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide were separated by chiral SFC using a Chiralpak IA column from Daicel, 5 μm particle size, 25 cm × 20 mm (mobile phase: 15% MeOH (with 20 mM ammonia), 85% CO. Flow rate: 100 mL / min) on a Prep-100 SFC instrument from Waters:

[0294] First eluting isomer (retention time = 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 calculated 516.16833, found 517.2 (M+1). + ; 515.3 (M-1) - ;Retention time: 3.41 minutes.

[0295] Second eluting isomer (retention time = 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 calculated 516.16833, found 517.2 (M+1). + ; 515.3(M-1) - ;Retention time: 3.41 minutes.

[0296] Step 10: TFA (225 μL, 2.920 mmol) was added to a solution of rel-(2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((R*)-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (42 mg, 0.081 mmol) (first eluting isomer from the SFC separation) in DCM (5 mL), and the mixture was stirred at ambient temperature for 18 h. The mixture was concentrated in vacuo and azeotroped twice with DCM. Reverse-phase preparative HPLC (Waters Sunfire) was used. Purification on a C18, 10 μM, 100 Å column (0% to 100% MeCN in water with 0.1% ammonia) gave, after lyophilization, 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, 24.6 mg, 62%) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.64 (d, J = 2.2 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 = 6.6, 4.5 Hz, 1H), 4.05 (q, J = 10.1 Hz, 1H), 3.88 (d, J = 1.9 Hz, 3H), 3.63 (ddd, J = 10.3, 6.0, 4.2 Hz, 1H), 3.48 - 3.43 (m, 1H), 2.47 (s, 1H), 2.45 (s, 1H), 1.56 (s, 3H) ppm; 19F NMR (471 MHz, DMSO-d6) δ -80.12, -138.14 (d, J = 21.0 Hz), -154.77 (d, J = 21.0 Hz) ppm.ESI-MS m / z calculated value 476.13705, measured value 474.4 (M+1) + ; 475.5(M-1) - ;Retention time: 2.77 minutes.

[0297] 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) (the second eluting isomer from the SFC separation) was treated in the same manner to give, after lyophilization, rel-(2S,3R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-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. 1 H NMR (500 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.65 (d, J = 2.5 Hz, 1H), 7.96 (dd, J = 8.5, 2.5 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 = 10.0 Hz, 1H), 3.88 (d, J = 1.9 Hz, 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; 19F NMR (471 MHz, DMSO-d6) δ -80.12, -138.14 (d, J = 21.1 Hz), -154.77 (d, J = 21.1 Hz) ppm.ESI-MS m / z calculated value 476.13705, measured value 477.4(M+1) + ;475.4(M-1) - ;Retention time: 2.77 minutes.

[0298] The following compound was 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 instead of (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine in the amide coupling step 8. In step 9, purification was carried out by chiral SFC using a Chiralpak IA column from Daicel Corporation, 5 μm particle size, 25 cm×20 mm, on a Prep-100 SFC instrument from Waters: [Table 14]

[0299] The following compound was made using the method described in Example 3, except that rac-2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrimidin-5-amine was used instead 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(PPh) was used as a catalyst with NaCO as the base and a mixture of toluene, water, and methanol as the solvent, and the reaction was carried out at 80 °C for 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, with 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 subjected to chiral SFC using a Chiralcel OJ column from Daicel Corporation, 5 μm particle size, 25 cm × 21.2 mm, on a Prep-100 SFC instrument from Waters (40 °C; mobile phase: 6% MeOH (20 mM NH), 94% CO; flow rate: 70 mL / min). [Table 15-1] [Table 15-2]

[0300] The following compounds were made using the method described in Example 3, except that 2-(2-ethoxy-3,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of (3,4-difluoro-2-methoxyphenyl)boronic acid in the Suzuki coupling in step 5. For compounds 32 and 33, (S)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine was used instead of (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine in the amide coupling step 8. In Suzuki coupling step 5, Pd(PPh) was used as a catalyst together with NaCO as the base and a mixture of toluene, water, and methanol as the solvent, and the reaction was carried out at 80 °C for 16 hours. In step 9, purification was carried out by chiral SFC using a (R,R)-Whelk-O1 column from Daicel, 5 um particle size, 25 cm x 21.1 mm (mobile phase: 30% MeOH (with 20 mM ammonia), 70% CO2. Flow rate: 100 mL / min) on a Minigram SFC instrument from Berger Instruments. The deprotection step 10 was carried out at ambient temperature for 1.5 hours using 12 M HCl in THF as solvent: [Table 16-1] [Table 16-2]

[0301] Compound 35 was analyzed by X-ray powder diffraction analysis method B and determined to be amorphous (see Figure 6). Example 4 [ka]

[0302] Step 1: 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, 343.7 mg, 0.7008 mmol) in DCM (9 mL) was placed under a nitrogen atmosphere and cooled in an ice bath. Boron tribromide (in DCM) (2.2 mL of 1 M, 2.200 mmol) was added and the reaction mixture was stirred for 2 hours. The reaction was quenched by the addition of MeOH (2 mL) and stirred at ambient temperature overnight. The mixture was concentrated in vacuo. The residue was dissolved in MeOH (3 mL) and the pH was adjusted to pH 9 with 2 M aqueous sodium hydroxide solution. Purification by reverse-phase preparative HPLC (Waters Sunfire C18, 10 μM, 100 Å column, 0% to 100% MeCN in water with 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-(trifluoromethyl)tetrahydrofuran-2-carboxamide (36, 259.8 mg, 78%). 1H NMR (500 MHz, DMSO-d6) δ 10.45 (s, 1H), 10.40 (s, 1H), 8.65 (d, J = 2.2 Hz, 1H), 8.00 (dd, J = 8.7, 2.3 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.03 (t, J = 6.8 Hz, 1H), 6.85 (q, J = 8.6 Hz, 1H), 5.33 (d, J = 4.9 Hz, 1H), 5.09 (d, J = 10.3 Hz, 1H), 4.64 (t, J = 5.9 Hz, 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 = 7.4 Hz, 1H), 1.58 (s, 3H), 0.70 (d, J = 6.4 Hz, 3H) ppm. ESI-MS m / z calcd. 476.13705, found 477.3 (M+1) + ; Holding time: 2.46 minutes.

[0303] ステップ2: KCO (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-(trifluoromethyl)tetrahydrofuran-2-carboxamide (36, 40 mg, 0.08396 mmol) in DMF (2 mL). The mixture was stirred at 60 °C for 6 h 30 min. The mixture 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 with 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-carboxamide (37, 18.48 mg, 41%). 1 H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.64 (dd, J = 2.5, 0.8 Hz, 1H), 8.00 (dd, J = 8.5, 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, 2.4 Hz, 1H), 4.69 (dt, J = 5.0, 2.4 Hz, 1H), 4.63 (t, J = 5.9 Hz, 1H), 4.54 (dt, J = 6.8, 4.5 Hz, 1H), 4.49 - 4.27 (m, 3H), 3.70 - 3.59 (m, 1H), 3.45 (ddd, J = 10.9, 6.8, 5.7 Hz, 1H), 2.78 (p, J = 7.4 Hz, 1H), 1.59 (s, 3H), 0.81 - 0.68 (m, 3H) ppm. ESI-MS m / z calculated value 522.15894, measured value 523.3 (M+1)+ ;Holding time: 3.0 minutes.

[0304] The following compounds were made using the method described in Example 4, except that 2-bromo-1,1-difluoroethane was used instead of 1-fluoro-2-iodoethane in alkylation step 2. [Table 17]

[0305] The following compound was made using the method described in Step 1 of Example 4, 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. [Table 18] Example 5 [ka]

[0306] Step 1: In a 2 L three-necked round-bottom flask equipped with a thermometer, 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 PdCl(PPh) were added to a solution of saturated NaHCO (120 mL) and dioxane (400 mL). 2(A mixture of 1.4 g (1.995 mmol) of methylparaben (NaOH, HCl) was added. The orange mixture was heated internally to 50° C. for 20 minutes. The reaction mixture was cooled to ambient temperature and diluted with EtOAc (100 mL) and water (100 mL). The layers were separated and the aqueous phase was extracted with EtOAc (4×100 mL). The combined organic extracts were washed with brine (1×50 mL), dried (MgSO), filtered, and concentrated in vacuo to a volume of approximately 100 mL. Charcoal (10 g) was added and the mixture was stirred for 2 hours. The mixture was filtered and the residual cake was washed further with EtOAc. The filtrate was collected and concentrated in vacuo to give 50 g of crude product. Purification by flash chromatography (330 g SiO, 0 to 30% EtOAc in heptane) afforded 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. 1 H NMR (500 MHz,chloroform-d) δ 6.98 - 6.88 (m, 1H), 6.81 (t, J = 8.7 Hz, 1H), 4.20 - 4.07 (m, 2H), 3.66 (s, 3H), 3.58 - 3.49 (m, 1H), 2.21 (d, ESI-MS m / z calculated value 376.12976, measured value 377.5 (M+1) + ;Retention time: 1.09 minutes.

[0307] Step 2: To a 1 L three-neck flask equipped with a thermometer was added ethyl rac-(4S,5R)-3-(4-fluoro-2-methoxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (27.35 g, 72.67 mmol), followed by DCM (200 mL). The reaction mixture was cooled to 5° C. in an ice bath. Boron tribromide (112 mL, 1 M solution in DCM, 112.0 mmol) was added via cannula over 30 minutes, maintaining an internal temperature of approximately 5° C. The reaction mixture was stirred for 1 hour. The mixture was quenched by the slow addition of water (100 mL) (causing effervescence) and saturated sodium bicarbonate solution (100 mL). The mixture was stirred for 30 minutes. The aqueous phase was collected and washed with DCM (3×50 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution (5 × 100 mL), dried (MgSO), filtered, and concentrated in vacuo to give a yellow waxy solid. The waxy solid was redissolved in EtOAc (100 mL). Charcoal (15 g) was added, and the mixture was stirred at ambient temperature overnight. The mixture was filtered through a pad of Celite. The filtrate was collected, dried (MgSO), filtered, and concentrated in vacuo to give an approximately 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.

[0308] The mixture was dissolved in DCM (200 mL) and TFA (9.8 mL, 127.2 mmol) was added with stirring at ambient temperature. The reaction mixture was heated at reflux and stirred for 2.5 h. The mixture was cooled to ambient temperature and quenched with saturated aqueous sodium bicarbonate (100 mL). The organic phase was washed with saturated aqueous sodium bicarbonate (4 x 100 mL), dried (Na2SO4), and concentrated in vacuo to give a waxy solid. The waxy solid was redissolved 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 filtrate was concentrated in vacuo to give a waxy solid. Purification by flash chromatography (120 g of SiO, 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%). 1 H 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 calculated value 316.07227, measured value 317.4 (M+1) + ; 315.4 (M-1) - ;Retention time: 0.94 minutes.

[0309] Step 3: rac-(1S,2R)-7-Fluoro-1,2,6-trimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3-c]chromen-4-one (1.5 g, 3.273 mmol) was dissolved in EtOAc (20 mL) and stirred with activated carbon (300 mg, 24.98 mmol) for 18 hours. The mixture was filtered through a pad of Celite. The liquid was 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 atmospheric pressure of hydrogen for 120 hours. The mixture was filtered through a Celite cartridge, washing with MeOH. The filtrate was concentrated in vacuo to a volume of approximately 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 balloon atmosphere of hydrogen for 12 hours. The reaction mixture was filtered through a Celite cartridge, washing with MeOH. The filtrate was 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)tetrahydrofuran-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 = 6.1 Hz, 2H), 4.28 (dd, J = 8.4, 6.1 Hz, 1H), 3.56 (s, 3H), 2.81 (p, J = 7.8 Hz, 1H), 2.14 (d, J = 1.6 Hz, 3H), 1.4 (3H), 0.92 (dq, J = 7.6, 1.9 Hz, 3H) ppm; no alcohol OH observed. ESI-MS m / z calculated 350.11414, found 349.0 (M-1). - ;Holding time: 0.95 minutes.

[0310] Step 4: Potassium tert-butoxide (11.40 g, 101.6 mmol) was added to a stirred solution of a mixture of isomers of methyl 3-(4-fluoro-2-hydroxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (8.896 g, 25.39 mmol), of which methyl rac-(2S,3S,4S,5R)-3-(4-fluoro-2-hydroxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate was the major isomer in tetrahydrofuran (125 mL) at 0 °C. After 15 min, the mixture was quenched by the addition of 1 M HCl (350 mL) and diluted with saturated brine (100 mL) and DCM (100 mL). The aqueous layer was extracted with DCM (3 × 100 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The residue was dissolved in DCM (71 mL) and treated with TFA (26.62 g, 17.99 mL, 233.5 mmol). The reaction mixture was stirred at ambient temperature for 2 h. The mixture was concentrated in vacuo, and the residue was azeotroped with DCM (2 x 50 mL). The residue was partitioned between DCM (100 mL) and water (50 mL), and the layers were separated. The organic layer was washed with water (3 × 50 mL), and the organic extract was dried (MgSO), 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-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (9.753 g, 100%) as a brown oil, which was used directly in the next step. ESI-MS m / z calculated 336.09848, found 335.5 (M−1). - ;Retention time: 0.56 minutes.

[0311] Step 5: KCO (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 at 80 °C for 5 h. The reaction mixture was cooled to ambient temperature and diluted with DCM. The mixture was filtered, and the solid was further washed with DCM. The filtrate was 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-carboxylate (1.038 g, 89%). ESI-MS m / z calculated 392.16107, found 393.6 (M+1). + ;Retention time: 0.99 minutes.

[0312] Step 6: 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 hours. MeOH was removed in vacuo and diluted to pH 1 with 1 M HCl. The mixture was extracted with DCM (2 × 10 mL). The combined organic extracts were dried by passing through a phase separation cartridge and concentrated in vacuo to give 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 (778.9 mg, 84%). ESI-MS m / z calculated 364.12976, found 363.6 (M-1). - ;Retention time: 0.62 minutes.

[0313] Step 7: 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. Upon completion of the addition, the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in 2-MeTHF (2 mL) 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 (90 μL, 0.6457 mmol). The reaction mixture was stirred at ambient temperature for 2 h. The mixture was concentrated in vacuo and loaded onto a solid support. Purification by flash chromatography (SiO, 0-100% EtOAc in heptane) gave a mixture of isomers:

[0314] First eluting isomer: 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-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (23 mg, 41%). 1H NMR (400 MHz,chloroform-d) δ 8.54 (dd, J = 2.6, 0.7 Hz, 1H), 8.35 (s, 1H), 8.12 (dd, J = 8.6, 2.6 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.7, 6.3 Hz, 1H), 6.86 (t, J = 8.7 Hz, 1H), 5.16 (t, J = 6.7 Hz, 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 = 7.7 Hz, 1H), 2.20 (d, J = 2.1 Hz, 3H), 1.69 (s, 3H), 1.51 (dd, J = 1.5, 0.7 Hz, 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 calculated value 540.22473, measured value 541.2 (M+1) + ; 539.3 (M-1) - ;Retention time: 1.09 minutes.

[0315] Second eluting isomer: 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-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (13.3 mg, 24%). 1H NMR (400 MHz,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, 6.7 Hz, 1H), 6.63 (td, J = 8.8, 1.7 Hz, 1H), 5.15 (t, J = 6.7 Hz, 1H), 4.92 (d, J = 6.6 Hz, 1H), 4.41 (ddd, J = 8.3, 6.7, 1.5 Hz, 1H), 4.36 (dd, J = 8.8, 6.6 Hz, 1H), 4.01 - 3.79 (m, 3H), 2.90 (p, J = 7.8 Hz, 1H), 2.17 (d, J = 2.1 Hz, 3H), 1.59 (d, J = ESI-MS m / z calculated value 540.22473, measured value 541.2 (M+1) + ; 539.3 (M-1) - Retention time: 1.06 min. These isomers were separated by chiral SFC.

[0316] Step 8: A 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-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (23 mg, 0.042 mmol) (first eluting isomer from step 7) was purified by Minigram chromatography (Berger Instruments). Separation was performed by chiral SFC using a Lux i-Cellulose-5 column from Phenomenex, Inc., 5 um particle size, 25 cm x 20 mm (mobile phase: 15% MeOH (with 20 mM ammonia), 85% CO2. Flow rate: 100 mL / min) on an SFC instrument:

[0317] First eluting isomer (retention time = 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 calculated 540.22473, found 541.2 (M+1). + ; 539.3 (M-1) - ;Retention time: 3.73 minutes.

[0318] Second eluting isomer (retention time = 4.48 min): 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 calculated 540.22473, found 541.2 (M+1). + ; 539.3 (M-1) - ;Retention time: 3.73 minutes.

[0319] Step 9: TFA (10 μL, 0.130 mmol) was added to a solution of rel-(2R,3S,4S,5R)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (10 mg, 0.0185 mmol) (first eluting isomer from SFC separation) in THF (800 μL) and water (200 μL). The reaction mixture was stirred at 60° C. for 6 hours and at 40° C. for an additional 16 hours. The mixture was concentrated in vacuo. Purification by reverse-phase HPLC-MS using an X-bridge C18 OBD column (Waters) (150 × 19 mm, 5 mm particle size) 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-(trifluoromethyl)tetrahydrofuran-2-carboxamide (40, 2.5 mg, 27%). 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 = 8.5, 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 = 10.8 Hz, 1H), 4.71 (dd, J = 6.7, 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 (dq, J = 7.4, 2.3 Hz, 3H) ppm; alcohol OH and amide NH not observed. ESI-MS m / z calculated 500.19342, found 501.2 (M+1). + ; 499.2 (M-1) - ;Retention time: 3.17 minutes.

[0320] 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, 0.01665 mmol) (the second eluting isomer from the SFC separation) was treated in the same manner 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, 7.9 Hz, 1H), 3.98 - 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 = 7.2, 2.4 Hz, 3H) ppm; alcohol OH and amide NH not observed. ESI-MS m / z calculated 500.19342, found 501.3 (M+1). + ; 499.3 (M-1) - ;Retention time: 3.19 minutes.

[0321] The following compound was made using the method described in Example 5, except that (S)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine was used instead of (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine in step 7. In step 8, purification was carried out by chiral SFC using a Lux i-cellulose-5 column from Daicel Corporation, 5 mm particle size, 25 cm × 20 mm (mobile phase: 15% MeOH (with 20 mM ammonia), 85% CO. Flow rate: 100 mL / min) on a Prep-100 SFC instrument from Waters. [Table 19]

[0322] The following compounds were made using the method described in Example 5, except that hydrogenation step 3 was carried out using 60 psi of hydrogen. In step 5, methyl iodide was used as the alkylating agent instead of ethyl iodide. In step 7, for compounds 44 and 45, (S)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine was used instead of (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine. In step 8, purification was carried out by chiral SFC using a Daicel (R,R)-Whelk-O1 column, 5 um particle size, 25 cm x 21.1 mm, on a Berger Instruments Minigram SFC instrument (mobile phase: 5-25% MeOH (with 20 mM ammonia), 95-75% CO2, flow rate: 100 mL / min). In step 9, DCM was used as the solvent instead of a mixture of THF and water: [Table 20-1] [Table 20-2] Example 6 [ka]

[0323] Step 1: A mixture of ethyl rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (1.44 g, 3.169 mmol), 2-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (900 mg, 2.592 mmol), Pd(Ph) (148 mg, 0.1281 mmol), and aqueous KCO (2.6 mL of 2 M, 5.200 mmol) in 1,4-dioxane (25 mL) was heated at 100 °C for 2 h. The mixture was concentrated in vacuo and loaded onto a solid support. Purification by flash chromatography (SiO, 0–25% EtOAc in heptane) afforded ethyl rac-(4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (708 mg, 66%) as a colorless oil. 1 H NMR (400 MHz,chloroform-d)δ 7.25 (ddt, J = 7.3, 6.2, 1.2 Hz, 1H), 6.95 (td, J = 53.6, 0.7 Hz, 1H), 6.94 (tt, J = 8.7, 0.9 Hz, 1H), 4.17 (qd, J = 7.1, 1.3 Hz, 2H), 3.77 (s, 3H), 3.62 - 3.53 (m, 1H), 1.71 (q, J = 1.0 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H), 1.07 (dq, J = 7.1, 2.2 Hz, 3H) ppm. ESI-MS m / z calculated 412.11093, observed 413.2 (M+1) + ;Holding time: 1.05 minutes.

[0324] Step 2: A solution of ethyl rac-(4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (3.5 g, 8.488 mmol) in MeOH (100 mL) was added to a two-necked flask containing magnesium (2.07 g, 85.17 mmol). The reaction mixture was heated at 70 °C for 3 h. The mixture was concentrated in vacuo and partitioned between aqueous AcOH and EtOAc. The aqueous layer was separated and extracted twice with EtOAc. The combined organic phases were washed with aqueous NaHCO and twice with water. The organic phase was dried (MgSO4) and concentrated in vacuo to give a mixture of methyl rac-(2S,3S,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate and methyl rac-(2R,3R,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (2.87 g, 84%) as an orange oil. 1 H NMR (400 MHz, 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 = 10.2 Hz, 1H), 4.21–4.15 (m, 1H), 3.84 (s, 3H), 3.71 (s, 3H), 2.73 (p, J = 7.7 Hz, 1H), 1.63 (q, J = 1.2 Hz, 3H), 0.78 (ddq, J = 7.2, 4.7, 2.3 Hz, 3H) ppm.

[0325] Step 3: Potassium tert-butoxide (1.66 g, 14.79 mmol) was added to a solution of a mixture of methyl rac-(2S,3S,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate and methyl rac-(2R,3R,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (2.87 g, 7.169 mmol) in 2-MeTHF (35 mL) in a water bath at ambient temperature. An exotherm of approximately 3° was observed during the addition. The reaction mixture was stirred for 2 hours, after which an additional portion of potassium tert-butoxide (860 mg) was added. The mixture was stirred at ambient temperature for an additional 1 hour. The reaction was quenched with dilute HCl solution. The aqueous layer was separated, washed with EtOAc, dried (MgSO), 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. 1 H NMR (400 MHz, chloroform-d) δ 7.43 - 7.35 (m, 1H), 6.98 (ddd, J = 13.4, 9.3, 4.2 Hz, 1H), 6.93 (t, J = 53.6 Hz, 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; no OH acid observed. ESI-MS m / z calculated 386.09528, found 385.1 (M-1). - ;Retention time: 0.57 minutes.

[0326] Step 4: 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-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid and rac-(2S,3R,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (100 mg, 0.2589 mmol), (S)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine (78 mg, 0.4016 mmol), and triethylamine (110 μL, 0.7892 mmol) in ethyl acetate (2 mL). The reaction mixture was stirred at 50°C for 30 minutes and then at ambient temperature overnight. The reaction mixture was partitioned between EtOAc and water and passed through a Whatmann phase separation filter. The organic phase was concentrated in vacuo and loaded onto silica. Purification by flash chromatography (SiO, 0–75% EtOAc in heptane) afforded a mixture of 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 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)tetrahydrofuran-2-carboxamide (50 mg, 34%). 1H NMR (400 MHz,chloroform-d) δ 8.56 (t, J = 2.5 Hz, 1H), 8.38 (s, 1H), 8.13 (dt, J = 8.7, 2.9 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.11 - 6.76 (m, 2H), 5.18 (t, J = 6.7 Hz, 1H), 5.01 (d, J = 10.6 Hz, 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), 1.50 - 1.45 (m, 6H), 0.84 - 0.75 (m, 3H) ppm; no NH amide observed. ESI-MS m / z calculated 562.19025, found 563.2 (M+1). + ; 561.3 (M-1) - ;Holding time: 1.02 minutes.

[0327] Step 5: A mixture of 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 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)tetrahydrofuran-2-carboxamide (50 mg, 0.089 mmol) was run on a Minigram SFC instrument from Berger Instruments using a Daicel Separation was by chiral SFC using a Chiralpak AS-H column from Corporation, 5 um particle size, 25 cm x 10 mm (mobile phase: 15% MeOH (containing 20 mM ammonia), 85% CO2, flow rate: 10 mL / min).

[0328] First eluting isomer (retention time = 2.14 min): 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 calculated 562.19025, found 563.2 (M+1). + ; 561.2 (M-1) - ;Holding time: 3.5 minutes.

[0329] Second eluting isomer (retention time = 3.60 min): 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, 48%). ESI-MS m / z calculated 562.19025, found 563.2 (M+1). + ; 561.2 (M-1) - ;Holding time: 3.49 minutes.

[0330] Step 6: 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)tetrahydrofuran-2-carboxamide (15 mg, 0.02667 mmol) (first eluting isomer from SFC separation) in THF (800 μL) and water (200 μL). The reaction mixture was stirred at 60° C. overnight. The mixture was concentrated in vacuo. Purification by reverse-phase HPLC-MS using an X-bridge C18 OBD column (Waters) (150 × 19 mm, 5 mm particle size) gave rel-(2S,3R,4R,5S)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-N-(6-((S*)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (48, 6 mg, 41%). 1H NMR (400 MHz,methanol-d4) δ 8.71 (dd, J = 2.6, 0.8 Hz, 1H), 8.08 (dd, J = 8.5, 2.5 Hz, 1H), 7.64 - 7.58 (m, 1H), 7.55 (dt, J = 8.6, 0.7 Hz, 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; alcohol OH and amide NH not observed. ESI-MS m / z calculated 522.15894, found 522.9 (M+1). + ; 521.0 (M-1) - ;Retention time: 3.04 minutes.

[0331] 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) (the second eluting isomer from the SFC separation) was treated in the same manner 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-carboxamide (49, 4 mg, 34%). 1H NMR (400 MHz, methanol-d4) δ 8.69 (dd, J = 2.6, 0.8 Hz, 1H), 8.06 (dd, J = 8.5, 2.5 Hz, 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 = 10.4 Hz, 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; alcohol OH and amide NH not observed. ESI-MS m / z calculated 522.15894, found 522.9 (M+1). + ; 521.0 (M-1) - ;Retention time: 3.01 minutes.

[0332] The following compound was made using the method described in Example 6, except that (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine was used instead of (S)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine in the amide coupling step 4. In step 5, purification was carried out by chiral SFC using a (R,R)-Whelk-O1 column from Daicel, 5 um particle size, 25 cm x 21.1 mm (mobile phase: 5-55% MeOH, 95-45% CO2. Flow rate: 100 mL / min) on a Minigram SFC instrument from Berger Instruments. The conditions used in step 6 were similar to those described in step 16 of Example 1: [Table 21]

[0333] The following compounds were made using the method described in Example 6. The product of Step 1 was prepared in three steps using the conditions described in Steps 1, 2, and 3 of Example 11, where the coupling partner was 1-bromo-3-(difluoromethyl)-4-fluoro-2-methoxybenzene. In the amide coupling Step 4, methyl 5-aminopicolinate was used as the amine coupling partner. The ester formed in Step 4 was reduced overnight at 50° C. using excess NaBH in MeOH as the solvent, conditions well known in the art. The deprotection Step 6 was not required: [Table 22]

[0334] The following compounds were made using the method described in Example 6. The product of Step 1 was prepared in three steps using the conditions described in Steps 1, 2, and 3 of Example 11, where the coupling partner was 1-bromo-3-(difluoromethyl)-4-fluoro-2-methoxybenzene. In the amide coupling Step 4, methyl (5-aminopyrimidin-2-yl)benzoate was used as the amine coupling partner. The chiral SFC separation Step 5 was carried out on a Prep-100 SFC instrument from Waters using a ChiralPak IG column from Daicel, 5 μm particle size, 25 cm × 20 mm (mobile phase: 17% MeOH (with 20 mM ammonia), 83% CO , flow rate: 100 mL / min). The deprotection Step 6 was carried out at 30° C. for 16 hours using excess 2 M LiOH solution in MeOH as the solvent, conditions well known in the art: [Table 23]

[0335] The following compounds were made using the method described in Example 6. The product of Step 1 was prepared in three steps using the conditions described in Steps 1, 2, and 3 of Example 11, where the coupling partner was 1-bromo-3-(difluoromethyl)-4-fluoro-2-methoxybenzene. In the amide coupling Step 4, 1-(5-aminopyridin-2-yl)ethan-1-one was used as the amine coupling partner. The chiral SFC separation Step 5 was carried out on a Minigram SFC instrument from Berger Instruments using a ChiralPak IG column from Daicel, 5 μm particle size, 25 cm × 10 mm (mobile phase: 25% IPA (with 20 mM ammonia), 75% CO , flow rate: 10 mL / min). The deprotection Step 6 was carried out at ambient temperature for 30 minutes and was replaced by a ketone reduction step using 3 equivalents of NaBH in MeOH as solvent, conditions well known in the art. The first eluting isomer in the SFC separation (Step 5) was a mixture of epimers at the hydroxyethyl position, which was not further separated and is referred to herein as Compound 56. The second eluting isomer in the SFC separation (Step 5) was a mixture of epimers at the hydroxyethyl position, Compounds 57 and 58, which were further separated by chiral SFC on a Minigram SFC instrument from Berger Instruments using a Chiralpak IG column from Daicel, 5 μm particle size, 25 cm × 10 mm (mobile phase: 25% IPA (with 20 mM ammonia), 75% CO. Flow rate: 10 mL / min): [Table 24-1] [Table 24-2] Example 7 [ka]

[0336] Step 1: A solution of rel-(2R,3S,4S,5R)-N-(6-((S*)-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 (11.5 mg, 0.02184 mmol), prepared as described for the precursor of compound 45 in Example 5, in DCM (2 mL) was cooled in an ice bath. m-CPBA (19.9 mg, 0.08072 mmol) was added in one portion, and the mixture was placed in an ice bath and slowly warmed. The reaction mixture was stirred for 24 hours. The reaction mixture was quenched with saturated bicarbonate (2 ml). The aqueous layer was washed with DCM (3 × 2 ml). The organic phases were combined and passed through a phase separator cartridge. The liquid was concentrated in vacuo to give rel-2-((S*)-2,2-dimethyl-1,3-dioxolan-4-yl)-5-((2R,3S,4S,5R)-3-(4-fluoro-2-methoxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridine 1-oxide (15.4 mg, 100%) as a yellow solid which was used directly in the next step. ESI-MS m / z calculated 542.204, found 543.7 (M+1). + ; 541.6 (M-1) - ;Retention time: 0.97 minutes.

[0337] Step 2: TFA (25 μL, 0.3245 mmol) was added to a stirred solution of rel-2-((S*)-2,2-dimethyl-1,3-dioxolan-4-yl)-5-((2R,3S,4S,5R)-3-(4-fluoro-2-methoxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridine 1-oxide (15.4 mg, 0.02441 mmol) in DCM (500 μL). The reaction mixture was stirred at ambient temperature for 24 hours. Purification by reverse-phase preparative HPLC (base elution) afforded rel-2-((S*)-1,2-dihydroxyethyl)-5-((2R,3S,4S,5R)-3-(4-fluoro-2-methoxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridine 1-oxide (3.2 mg, 24%) as a white solid. 1 H NMR (500 MHz, methanol-d4) δ 8.96 (d, J = 1.9 Hz, 1H), 7.78 - 7.73 (m, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.22 (dd, J = 8.7, 6.4 Hz, 1H), 6.91 (t, J = 8.8 Hz, 1H), 5.28 (dd, J = 5.4, 3.5 Hz, 1H), 5.06 (d, J = 10.6 Hz, 1H), 4.38 (dd, J = 10.6, 8.0 Hz, 1H), 3.93 (dd, J = 11.3, 3.4 Hz, 1H), 3.83 - 3.72 (m, 4H), 2.81 (p, J = 7.6 Hz, 1H), 2.25 (d, J = 2.0 Hz, 3H), 1.70 (s, 3H), 0.84 (dd, J = 6.9, 2.6 Hz, 3H) ppm; alcohol OH and amide NH not observed. 19 F NMR (471 MHz, methanol-d4) δ -75.62, -117.82 ppm. ESI-MS m / z calculated 502.1727, found 503.6 (M+1) + ; 501.6 (M-1) - ;Retention time: 2.9 minutes.

[0338] Using 1 as the starting material, the following compounds were made using the methods described in Example 7: [Table 25] Example 8 [ka]

[0339] Step 1: Tetrakis(triphenylphosphine)palladium(0) (1.3 g, 1.125 mmol) was added to a mixture of (2-chloro-4-(trifluoromethoxy)phenyl)boronic acid (5 g, 20.80 mmol), ethyl 5-methyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (8 g, 21.49 mmol), and aqueous sodium carbonate (28.2 mL of 2 M, 56.40 mmol) in dioxane (85 mL). The reaction mixture was heated at 100° C. for 3 h. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried (MgSO), filtered, and concentrated in vacuo. Purification by flash chromatography (120 g SiO, 0 to 40% EtOAc in heptane) gave ethyl 3-(2-chloro-4-(trifluoromethoxy)phenyl)-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (6.46 g, 74%). 1 H NMR (500 MHz,chloroform-d) δ 7.34 (dd, J = 2.3, 1.0 Hz, 1H), 7.32 - 7.24 (m, 1H), 7.16 (dtd, J = 8.5, 2.0, 0.9 Hz, 1H), 4.14 (q, J = 7.2 Hz, ESI-MS m / z calculated value 418.04065, actual value 418.8 (M+1)+ ;Retention time: 1.13 minutes.

[0340] Step 2: A pressure tube was charged with magnesium powder (2.35 g, 96.69 mmol) and purged with nitrogen. To the reaction vessel was added MeOH (20 mL), followed by a solution of ethyl 3-(2-chloro-4-(trifluoromethoxy)phenyl)-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (2 g, 4.777 mmol) in MeOH (20 mL). The reaction mixture was degassed with nitrogen, and then a few drops of 1,2-dibromoethane (80 mg, 0.4258 mmol) were added. The reaction mixture was vigorously stirred and heated at 50° C. for 5 hours. The mixture was cooled to ambient temperature and quenched by slowly pouring it into a cold 1 M HCl solution. The mixture was stirred for 30 minutes until a clear solution was obtained. The mixture was partitioned with TBME. The separated aqueous layer was washed with TBME (×3). The combined organic phase was passed through a phase separator cartridge. The filtrate was concentrated in vacuo to give a mixture of diastereoisomers, the two major diastereoisomers being methyl rac-(2S,3S,5R)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate and methyl rac-(2R,3R,5R)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (2.85 g, 73%), which was used directly in the next step. ESI-MS m / z calculated 406.04065, retention times: 1.09 and 1.11 min for the two major diastereoisomers.

[0341] Step 3: Sodium methoxide (310 μL of 25% w / v in MeOH, 1.435 mmol) was added to a stirred solution containing a mixture of methyl rac-(2S,3S,5R)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate and methyl rac-(2R,3R,5R)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (3.8 g, 9.343 mmol) in THF (40 mL) under nitrogen at ambient temperature. After 5 h, methanol (0.2 mL) and LiOH (7.3 mL of a 2 M aqueous solution, 14.60 mmol) were added, and the reaction mixture was stirred at ambient temperature overnight. The reaction was poured into 1 M HCl solution. The mixture was extracted with TBME (2 × 30 mL). The combined organic layers were washed with brine, dried (NaSO), filtered, and concentrated in vacuo to give a mixture containing two major diastereoisomers, rac-(2R,3S,5R)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid and rac-(2S,3R,5R)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (3.244 g, 88%). ESI-MS m / z calculated 392.025, found 391.0 (M-1). - Retention times: 0.63 and 0.66 min for the two major diastereoisomers.

[0342] Step 4: Dimethylformamide (0.3 μL, 0.003874 mmol) and oxalyl chloride (78 μL, 0.8941 mmol) were added to an ice-cooled, stirred solution of a diastereomeric mixture containing rac-(2R,3S,5R)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid and rac-(2S,3R,5R)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (167 mg, 0.4253 mmol) in 2-methyltetrahydrofuran (2 mL). The reaction mixture was stirred and allowed to warm to ambient temperature over 1.5 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in 2-methyltetrahydrofuran (2 mL) and added to an ice-cold solution of (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine (90 mg, 0.4634 mmol) and TEA (178 μL, 1.277 mmol) in a mixture of 2-methyltetrahydrofuran (2 mL) and NMP (0.1 mL). The resulting mixture was stirred and allowed to warm to ambient temperature over 18 hours. The reaction mixture was quenched with water (5 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (2×10 mL). The combined organic extracts were washed with brine (5 mL), dried (MgSO), filtered, and concentrated in vacuo. Purification by column chromatography (12 g SiO, 0-50% EtOAc in heptane) gave a mixture of isomers:

[0343] First eluting isomer: A mixture of rel-(2R,3S,5R)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide and rel-(2S,3R,5S)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (95 mg, 28%) as a white solid and as an approximately 3:1 mixture with dechlorination by-products. ESI-MS m / z calculated 568.12, observed 570.1 (M+1) + ;Retention time: 1.09 minutes.

[0344] Second eluting isomer: A mixture of rel-(2S,3R,5R)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide and rel-(2R,3S,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 (59 mg, 21%) as a white solid. 1H NMR (500 MHz,chloroform-d) δ 8.58 (dd, J = 22.6, 2.5 Hz, 1H), 8.32 (d, J = 2.9 Hz, 1H), 8.12 (ddd, J = 25.0, 8.6, 2.6 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.33 (dd, J = 2.5, 1.0 Hz, 1H), 7.24 - 7.16 (m, 1H), 5.22 (t, J = 6.7 Hz, 1H), 4.97 (dd, J = 9.5, 1.3 Hz, 1H), 4.46 (dd, J = 8.4, 6.7 Hz, 1H), 4.22 (dt, J = 11.4, 8.9 Hz, 1H), 3.96 (dd, J = 8.3, 6.7 Hz, 1H), 2.95 (dd, J = 13.9, 8.4 Hz, 1H), 2.27 - 2.15 (m, 1H), 1.69 - 1.62 (m, 3H), 1.54 (s, 3H), 1.51 (s, 3H) ppm. ESI-MS m / z calculated value 568.12, measured value 570.1 (M+1) + retention time: 1.09 min. The SFC separation and deprotection of these second eluting isomers is illustrated in the table following Example 8.

[0345] Step 5: A mixture of rel-(2R,3S,5R)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide and rel-(2S,3R,5S)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (95 mg, 0.120 mmol) (first eluting isomer from step 4) was purified by Minigram chromatography (Berger Instruments). Separation was performed by chiral SFC using a (R,R)-Whelk-O1 column from Daicel, 5 um particle size, 25 cm x 21.1 mm (mobile phase: 30% MeOH (with 20 mM ammonia), 70% CO2. Flow rate: 100 mL / min) on an SFC instrument:

[0346] First eluting isomer (retention time = 2.66 min): 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 (28 mg, 36%) as a colorless oil. 1H NMR (500 MHz,chloroform-d) δ 8.55 (d, J = 2.5 Hz, 1H), 8.27 (s, 1H), 8.14 (dd, J = 8.6, 2.6 Hz, 1H), 7.54 - 7.49 (m, 2H), 7.32 (dd, J = 2.5, 1.0 Hz, 1H), 7.22 (ddd, J = 8.7, 2.5, 1.1 Hz, 1H), 5.19 (t, J = 6.7 Hz, 1H), 4.83 (d, J = 10.6 Hz, 1H), 4.45 (dd, J = 8.3, 6.7 Hz, 1H), 4.12 (td, J = 11.2, 8.2 Hz, 1H), 3.94 (dd, J = 8.3, 6.7 Hz, 1H), 2.55 (dd, J = 13.2, 8.2 Hz, 1H), 2.46 (dd, J = 13.2, 11.7 Hz, 1H), 1.69 (s, 3H), 1.54 (s, 3H), 1.51 (s, 3H) ppm. ESI-MS m / z calculated value 568.12, measured value 569.2 (M+1) + ; 567.1 (M-1) - ;Holding time: 1.12 minutes.

[0347] Second eluting isomer (retention time = 3.76 min): rel-(2R,3S,5R)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (27 mg, 38%) as a colorless oil. 1H NMR (500 MHz, クロロホルム-d) δ 8.46 (d, J = 2.4 Hz, 1H), 8.18 (s, 1H), 8.04 (dd, J = 8.6, 2.6 Hz, 1H), 7.42 (dd, J = 8.7, 1.8 Hz, 2H), 7.22 (dd, J = 2.5, 1.0 Hz, 1H), 7.13 (ddd, J = 8.6, 2.5, 1.1 Hz, 1H), 5.10 (t, J = 6.7 Hz, 1H), 4.74 (d, J = 10.5 Hz, 1H), 4.35 (dd, J = 8.3, 6.7 Hz, 1H), 4.03 (td, δ (d, J = 11.2, 8.2 Hz, 1H), 3.84 (dd, J = 8.3, 6.8 Hz, 1H), 2.46 (dd, J = 13.3, 8.2 Hz, 1H), 2.36 (dd, J = 13.2, 11.7 Hz, 1H), 1.59 (s, 3H), 1.44 (s, 3H), 1.41 (s, 3H) ppm. ESI-MS m / z calcd. 568.12, found 569.2 (M+1) + ; 567.1 (M-1) - ; Holding time: 1.12 minutes.

[0348] ステップ6: TFA (200 μL, 2.596 mmol) was added to a solution of 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 (32 mg, 0.04950 mmol) (first eluting isomer from SFC separation) in DCM (3 mL). The reaction mixture was stirred at ambient temperature for 18 hours. The mixture was concentrated in vacuo. Purification by reverse-phase preparative HPLC (Waters Sunfire C18, 10 μM, 100 Å column, 0% to 100% MeCN in water with 0.1% ammonia) gave 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 (61, 7.9 mg, 26%). 1 H NMR (500 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.62 (d, J = 2.5 Hz, 1H), 7.94 (dd, J = 8.5, 2.6 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.62 - 7.57 (m, 1H), 7.48 - 7.44 (m, 1H), 7.43 (d, J = 8.5 Hz, 1H), 5.32 (d, J = 4.9 Hz, 1H), 4.73 (d, J = 9.9 Hz, 1H), 4.64 (t, J = 5.9 Hz, 1H), 4.56 - 4.51 (m, 1H), 4.28 - 4.18 (m, 1H), 3.64 (ddd, J = 10.5, 6.0, 4.2 Hz, 1H), 3.45 (dt, J = 11.0, 6.2 Hz, 1H), 2.59 (dd, J = 13.0, 8.1 Hz, 1H), 2.44 (t, J = 12.3 Hz, 1H), 1.59 (s, 3H) ppm; 19F NMR (471 MHz, DMSO-d6) δ -56.96, -79.96 ppm. ESI-MS m / z calculated 528.0887, found 529.2 (M+1) + ; 527.1 (M-1) - ;Holding time: 3.15 minutes.

[0349] rel-(2R,3S,5R)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (27 mg, 0.04604 mmol) (the second eluting isomer from the SFC separation) was treated in the same manner to give 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 (62, 8.1 mg, 33%). 1 H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.61 (d, J = 2.5 Hz, 1H), 7.95 (dd, J = 8.5, 2.5 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 2.6 Hz, 1H), 7.52 - 7.44 (m, 1H), 7.43 (d, J = 8.5 Hz, 1H), 5.33 (d, J = 4.5 Hz, 1H), 4.73 (d, J = 9.9 Hz, 1H), 4.64 (t, J = 5.9 Hz, 1H), 4.54 (dt, J = 7.4, 4.0 Hz, 1H), 4.24 (td, J = 10.7, 10.2, 8.2 Hz, 1H), 3.68 - 3.58 (m, 1H), 3.45 (dt, J = 11.4, 5.9 Hz, 1H), 2.59 (dd, J = 13.0, 8.1 Hz, 1H), 2.48 - 2.39 (m, 1H), 1.59 (s, 3H) ppm; 19F NMR (471 MHz, DMSO-d6) δ -56.96, -79.96 ppm. ESI-MS m / z calculated 528.0887, found 529.2 (M+1) + ; 527.1 (M-1) - ;Holding time: 3.15 minutes.

[0350] The second eluting isomer obtained from the column chromatography in amide coupling step 4 was used to make the following compounds using the method described in Example 8. In step 5, purification was carried out by chiral SFC using a Chiralcel OD-H column from Daicel, 5 um particle size, 25 cm x 10 mm (mobile phase: 15% MeOH (with 20 mM ammonia), 85% CO2. Flow rate: 10 mL / min) on a Minigram SFC instrument from Berger Instruments. [Table 26] Example 9 [ka]

[0351] Step 1: Ethyl rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (42 g, 108.7 mmol) and 1,4-dioxane (500 mL) were added to a 1-liter, three-necked flask equipped with a thermometer and an air-conditioning condenser. The stirred mixture was degassed and flushed with nitrogen. KOAc (32 g, 326.1 mmol) was added, followed by bis(pinacolato)diboron (32 g, 126.0 mmol). The reaction mixture was evacuated and backfilled with nitrogen (×3). Pd(dppf)Cl2 (4 g, 5.467 mmol) was added, and the mixture was heated at 80 °C for 20 h. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate (300 mL) and water (100 mL). The mixture was filtered through a pad of Celite, washing with ethyl acetate (5 x 100 mL) until no more product remained. The filtrate phases were separated. The aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layers were passed through Whatmann phase separation filter paper. The filtrate was concentrated in vacuo to give 47 g of a brown oil. Purification by flash chromatography (Florisil, 100% heptane) gave ethyl rac-(4S,5R)-4,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (47 g, 95%) as a thick, viscous yellow oil. 1 H NMR (500 MHz,chloroform-d) δ 4.33 - 4.23 (m, 2H), 3.27 - 3.18 (m, 1H), 1.55 (d, J = 1.1 Hz, 3H), 1.32 (s, 12H), 1.28 (d, J = 2.3 Hz, 3H), 1.24 (s, 3H) ppm. ESI-MS m / z calculated value 364.1669, measured value 365.3 (M+1) + ;Holding time: 1.1 minutes.

[0352] Step 2: An aqueous solution of KPO (8 mL of 2 M, 16.00 mmol) was added to a solution of rac-(4S,5R)-4,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (3 g, 7.414 mmol), 1-bromo-3,4-difluoro-2-methylbenzene (1.4 g, 6.763 mmol), and Pd(dppf)Cl.CHCl (350 mg, 0.4286 mmol) in 1,4-dioxane (60 mL). The mixture was degassed and placed under a nitrogen atmosphere. The reaction was stirred at 100 °C for 2 hours. The mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The organic phases were combined and passed through a Whatmann phase separator filter paper. The filtrate was concentrated in vacuo to give a brown oil, which was purified by flash chromatography (24 g SiO, 0 to 100% EtOAc in heptane) to give ethyl rac-(4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (2.213 g, 67%) as a pale yellow oil. 1 H NMR (500 MHz, methanol-d4) δ 7.10 (dt, J = 10.3, 8.4 Hz, 1H), 6.90 (s, 1H), 4.14 - 4.00 (m, 2H), 3.54 (d, J = 8.2 Hz, 1H), 2.19 (d, J = 2.7 ESI-MS m / z calculated value 364.10977, measured value 365.2 (M+1) + ;Retention time: 1.08 minutes.

[0353] Step 3: A pressure tube was charged with magnesium powder (200 mg, 8.229 mmol) and purged with nitrogen. A solution of ethyl rac-(4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (2.02 g, 5.545 mmol) in MeOH (30 mL) was added to the pressure vessel. The mixture was degassed and placed under a nitrogen atmosphere. A few drops of 1,2-dibromoethane (5 μL, 0.058 mmol) were added. The reaction mixture was vigorously stirred and heated at 70° C. for 6 hours. Three additional successive portions of magnesium powder (200 mg, 8.229 mmol) were added, followed by one drop of 1,2-dibromoethane (5 μL, 0.058 mmol). The mixture was stirred overnight at 70°C for 88 hours. The reaction mixture was cooled to 0°C before opening the pressure vessel. The cooled mixture was added dropwise to ice-cold 1 M HCl solution. The reaction was stirred at 0°C for 30 minutes until all Mg solids were dissolved. The mixture was concentrated in vacuo to remove MeOH. The resulting aqueous solution was extracted with ethyl acetate (x3). The combined organic extracts were passed through a Whatmann phase separator filter. The filtrate was concentrated in vacuo to give a mixture of methyl rac-(2R,3R,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate and methyl rac-(2S,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.487 g, 76%) as a colorless oil. ESI-MS m / z calculated 352.10977, observed 353.3 (M+1) + retention times: 0.94, 1.00, 1.01, and 1.04 minutes.

[0354] Step 4: To a cooled solution of a mixture of methyl rac-(2R,3R,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate and methyl rac-(2S,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.487 g, 4.221 mmol) in 2-MeTHF (20 mL) was added potassium tert-butoxide (1.4 g, 12.48 mmol), causing a temperature increase of approximately 5 °C. The reaction mixture turned yellow upon addition of the potassium tert-butoxide. The reaction was stirred at ambient temperature for 1 hour. The reaction was diluted with ethyl acetate and 1N NaOH. The aqueous layer was separated. The organic layer was further washed with 1M NaOH (×2). The combined organic layers were passed through a Whatmann phase separator filter. The filtrate was concentrated in vacuo to give a mixture of two major diastereoisomers, rac-(2S,3R,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid and rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1.01 g, 71%) as a colorless oil. ESI-MS m / z calculated 338.09415, found 337.0 (M-1). - Retention times: 1.20 and 1.27 minutes for the two major diastereoisomers.

[0355] Step 5: DMF (2 μL, 0.026 mmol) and oxalyl chloride (154.2 mg, 106.0 μL, 1.215 mmol) were carefully added to an ice-cooled stirred solution of a mixture of rac-(2S,3R,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid and rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (200 mg, 0.591 mmol) in 2-MeTHF (5 mL). The mixture was allowed to warm to ambient temperature over 30 minutes. The reaction mixture was concentrated in vacuo. The residue was taken up in 2-MeTHF (5 mL) and added to an ice-cold solution of (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine (155 mg, 0.710 mmol) and triethylamine (384 μL, 2.755 mmol) in 2-methyltetrahydrofuran (5 mL). The resulting mixture was stirred and allowed to warm to ambient temperature over 18 hours. The reaction mixture was quenched by adding water (5 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic extracts were passed through a Whatmann phase separator filter paper. The filtrate was concentrated in vacuo to give an oil.Purification by flash chromatography (4 g of SiO, 0 to 50% EtOAc:EtOH (3:1) with 2% NHOH in heptane) gave rel-(2S,3R,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, rel-(2R,3S,4R,5S ... A mixture of diastereoisomers was obtained, including hydrofuran-2-carboxamide, rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-N-(6-((R*)-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-(3,4-difluoro-2-methylphenyl)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (191.4 mg, 63%). ESI-MS m / z calculated 514.1891, found 515.3 (M+1). + ; 513.4 (M-1) - ;Retention times: 3.60 and 3.67 min.

[0356] Step 6: The diastereoisomeric T mixture obtained in step 5 was separated by chiral SFC on a Minigram SFC instrument from Berger Instruments using a (R,R)-Whelk-O1 column, 5 um particle size, 25 cm x 21 mm mobile phase: 5-45% MeOH (containing 20 mM ammonia), 95-55% CO2. Flow rate: 100 mL / min):

[0357] First eluting isomer (retention time = 3.43 min): rel-(2S,3R,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (16 mg, 26%). ESI-MS m / z calculated 514.1891, found 515.0 (M+1). + ; 513.2 (M-1) - ;Retention time: 3.66 minutes.

[0358] Second eluting isomer (retention time = 3.98 min): rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (23 mg, 41%). ESI-MS m / z calculated 514.1891, found 515.1 (M+1). + ; 513.2 (M-1) - ;Retention time: 3.59 minutes.

[0359] Third eluting isomer (retention time = 5.29 min): rel-(2R,3S,4R,5S)-3-(3,4-difluoro-2-methylphenyl)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (14 mg, 27%). ESI-MS m / z calculated 514.1891, found 515.1 (M+1). + ; 513.2 (M-1) - ;Retention time: 3.66 minutes.

[0360] Fourth eluting isomer (retention time = 6.44 min): rel-(2S,3R,4R,5S)-3-(3,4-difluoro-2-methylphenyl)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (35 mg, 50%). ESI-MS m / z calculated 514.1891, found 515.2 (M+1). + ; 513.2 (M-1) - ;Retention time: 3.59 minutes.

[0361] Step 7: TFA (100 μL, 1.298 mmol) was added to a stirred solution of rel-(2S,3R,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-N-(6-((R*)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (16 mg, 0.025 mmol) (first eluting isomer from SFC separation) in DCM (5 mL). The reaction mixture was stirred at ambient temperature overnight. The mixture was concentrated in vacuo. The residue was azeotroped twice with DCM, quenched with 1 M NaOH solution, and partitioned with DCM. The aqueous layer was extracted with DCM (×3). The combined organic phases were passed through a phase separator cartridge and concentrated in vacuo. Purification by reverse-phase HPLC-MS using an X-bridge C18 OBD column (Waters) (150 × 19 mm, 5 mm particle size) gave rel-(2S,3R,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-N-(6-((R*)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (65, 6.4 mg, 51%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.61 (dd, J = 2.5, 0.8 Hz, 1H), 7.96 (dd, J = 8.5, 2.5 Hz, 1H), 7.48 - 7.38 (m, 2H), 7.32 (q, J = 9.1 Hz, 1H), 5.32 (d, J = 4.7 Hz, 1H), 4.68 - 4.59 (m, 2H), 4.56 - 4.49 (m, 1H), 3.83 - 3.73 (m, 1H), 3.62 (dt, J = 10.3, 4.9 Hz, 1H), 3.44 (dt, J = 11.9, ESI-MS m / z calculated value 474.1578, measured value 475.2 (M+1) + ; 473.2 (M-1) - ;Retention time: 2.93 minutes.

[0362] rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (23 mg, 0.038 mmol) (the second eluting isomer from the SFC separation) was treated in the same manner to give rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-N-(6-((R*)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (66, 10.6 mg, 55%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.65 (dd, J = 2.5, 0.8 Hz, 1H), 7.99 (dd, J = 8.5, 2.5 Hz, 1H), 7.45 - 7.38 (m, 1H), 7.26 (q, J = 9.0 Hz, 1H), 7.17 (dd, J = 8.8, 3.5 Hz, 1H), 5.33 (d, J = 4.8 Hz, 1H), 5.16 (d, J = 10.4 Hz, 1H), 4.63 (t, J = 5.9 Hz, 1H), 4.58 - 4.50 (m, 1H), 4.17 (dd, J = 10.5, 7.5 Hz, 1H), 3.67 - 3.57 (m, 1H), 3.49 - 3.38 (m, 1H), 2.85 (p, J = 7.5 Hz, 1H), 2.28 (d, J = 1.9 Hz, 3H), 1.63 (s, 3H), 0.68 (d, J = 7.4 Hz, 3H) ppm. ESI-MS m / z calculated value 474.1578, measured value 475.2 (M+1) + ; 473.2 (M-1) - ;Retention time: 3.02 minutes.

[0363] rel-(2R,3S,4R,5S)-3-(3,4-difluoro-2-methylphenyl)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (14 mg, 0.025 mmol) (the third eluting isomer from the SFC separation) was treated in the same manner to give rel-(2R,3S,4R,5S)-3-(3,4-difluoro-2-methylphenyl)-N-(6-((R*)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (67, 7.5 mg, 63%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.61 (dd, J = 2.6, 0.7 Hz, 1H), 7.97 (dd, J = 8.5, 2.5 Hz, 1H), 7.48 - 7.37 (m, 2H), 7.32 (q, J = 9.1 Hz, 1H), 5.32 (s, 1H), 4.64 (d, J = 9.3 Hz, 2H), 4.53 (s, 1H), 3.83 - 3.73 (m, 1H), 3.66 - 3.59 (m, 1H), 3.44 (dt, J = 11.1, 5.8 Hz, 1H), 2.58 (m, 1H), 2.25 (d, J = 1.9 Hz, 3H), 1.60 (s, 3H), 0.95 (d, J = 7.0 Hz, 3H) ppm. ESI-MS m / z calculated value 474.1578, measured value 475.2 (M+1) + ; 473.2 (M-1) - ;Retention time: 2.93 minutes.

[0364] rel-(2S,3R,4R,5S)-3-(3,4-difluoro-2-methylphenyl)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (35 mg, 0.047 mmol) (the fourth eluting isomer from the SFC separation) was treated in the same manner to give rel-(2S,3R,4R,5S)-3-(3,4-difluoro-2-methylphenyl)-N-(6-((R*)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (68, 9.6 mg, 42%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.67 (dd, J = 2.6, 0.7 Hz, 1H), 7.97 (dd, J = 8.5, 2.5 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.26 (q, J = 9.1 Hz, 1H), 7.17 (dd, J = 8.8, 3.5 Hz, 1H), 5.32 (d, J = 4.9 Hz, 1H), 5.16 (d, J = 10.5 Hz, 1H), 4.63 (t, J = 5.9 Hz, 1H), 4.54 (dt, J = 6.8, 4.5 Hz, 1H), 4.17 (dd, J = 10.5, 7.5 Hz, 1H), 3.62 (ddd, J = 10.5, 6.0, 4.1 Hz, 1H), 3.44 (ddd, J = 10.9, 6.9, 5.8 Hz, 1H), 2.85 (p, J = 7.5 Hz, 1H), 2.28 (d, J = 1.9 Hz, 3H), 1.63 (s, 3H), 0.68 (d, J = 6.6 Hz, 3H) ppm. ESI-MS m / z calcd. 474.1578, found 475.2 (M+1) + ; 473.2 (M-1) - ; Holding time: 3.01 minutes.

[0365] The following compounds were made using the method described in Example 9, except that the product of Step 2 was prepared by the reaction of ethyl rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate and (2-methoxy-3-(trifluoromethyl)phenyl)boronic acid using Suzuki conditions in Step 2 with KCO as the base. In Step 6, purification was carried out by chiral SFC using a Daicel (R,R)-Whelk-O1 column, 5 um particle size, 25 cm x 21.1 mm (mobile phase: 5-20% MeOH (with 20 mM ammonia), 95-80% CO. Flow rate: 100 mL / min) on a Berger Instruments Minigram SFC instrument. [Table 27]

[0366] The following compounds were made using the method described in Example 9, except that the product of Step 2 was prepared by the reaction of ethyl rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate and (2-methoxy-3-(trifluoromethyl)phenyl)boronic acid using Suzuki conditions in Step 2 with KCO as the base. In the amide coupling Step 5, 2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrimidin-5-amine was used as the coupling partner. In Step 6, purification was performed by chiral SFC using a Daicel Chiralcel OJ column, 5 μm particle size, 25 cm × 20 mm, on a Waters Prep-100 SFC instrument (mobile phase: 2-7% MeOH (with 20 mM ammonia), 98-93% CO; flow rate: 75 mL / min). [Table 28-1] [Table 28-2]

[0367] The following compounds were made using the method described in Example 9, except that 4-bromo-2,2,7-trifluorobenzo[d][1,3]dioxole was used instead of 1-bromo-3,4-difluoro-2-methylbenzene in Suzuki coupling step 2. The conditions used in step 3 were those described in step 3 of example 5: In deprotection step 7, 2-MeTHF was used as the solvent instead of DCM, and the reaction was carried out in a sealed tube at 60° C. for 72 hours: [Table 29]

[0368] The following compounds were made using the method described in Example 9, except that 6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-amine was used as the coupling partner in the amide coupling step 5. In step 6, purification was carried out by chiral SFC using a Daicel (R,R)-Whelk-O1 column, 5 μm particle size, 25 cm × 21.1 mm (mobile phase: 5-15% IPA (with 20 mM ammonia), 95-85% CO. Flow rate: 100 mL / min) on a Berger Instruments Minigram SFC instrument. [Table 30-1] [Table 30-2]

[0369] The following compounds were made using the method described in Example 9, except that the product of Step 2 was prepared by the reaction of ethyl rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate and (2-methoxy-3-(trifluoromethyl)phenyl)boronic acid using Suzuki conditions in Step 2 with KCO as the base. The amine used in the amide coupling Step 5 was 6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-amine. In Step 6, purification was carried out by chiral SFC using a Daicel (R,R)-Whelk-O1 column, 5 μm particle size, 25 cm × 21.1 mm (mobile phase: 40% MeOH (with 20 mM ammonia), 60% CO. Flow rate: 100 mL / min) on a Berger Instruments Minigram SFC instrument. [Table 31] Example 10 [ka]

[0370] Step 1: To an ice-cold solution of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (2390 mg, 6.409 mmol) (see Step 13 of Example 1) in 2-methyltetrahydrofuran (20 mL) was added DMF (60 μL, 0.775 mmol), followed by careful addition of oxalyl chloride (1.1 mL, 12.61 mmol). The reaction mixture was warmed to room temperature and stirred for 90 minutes. The reaction mixture was concentrated in vacuo, and the residue was dissolved in 2-methyltetrahydrofuran (10 mL). This solution was added to an ice-cold solution of ammonium hydroxide (10 mL of 28% w / v, 79.90 mmol) in 2-methyltetrahydrofuran (10 mL). The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was quenched with water (15 mL) and partitioned with ethyl acetate (15 mL). The layers were separated, and the organic phase was washed with brine (15 mL), passed through a phase separation cartridge, and concentrated under reduced pressure to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (2.34 g, 98%) as a pale yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.51 (s, 1H), 7.33 (s, 1H), 7.23 - 7.04 (m, 2H), 4.83 (d, J = 10.7 Hz, 1H), 4.11 - 3.97 (m, 1H), 3.94 (d, J = 2.2 Hz, 3H), 2.66 (p, J = 7.5 Hz, 1H), 1.56 (d, J = 1.2 Hz, 3H), 0.75 - 0.63 (m, 3H) ppm. ESI-MS m / z calculated value 353.10504, measured value 354.0 (M+1) + ;Retention...

Claims

1. A compound of formula (I), 【Chemical 1】 ， or a pharmaceutically acceptable salt thereof, wherein X ２ａ is N, N ＋ -O － or C-R ２ａ wherein X ３ａ is N or N ＋ -O － and X ５ａ is N, N ＋ -O － or C-R ５ａ wherein X ６ａ is N, N ＋ -O － or C-R ６ａ and R ｄ is (CH ２ ) ｍ (CHR ｅ ) ｎ (CH ２ ) ｐ H, and m, n, and p are each independently 0 or 1, R ｅ is H, OH, halo, C １ -C ６ alkoxy, or C １ -C ６ haloalkoxy, and R ２ａ and R ６ａ are each independently H, halo, C １ -C ６ -alkyl, or C １ -C ６ -haloalkyl, R ５ａ is H, halo, CH ２ OH, C １ -C ６ alkyl, or C １ -C ６ haloalkyl, and R ４ｂ１ and R ４ｂ２ are each independently H, C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, or C １ -C ６ haloalkyl, and R ５ｂ１ and R ５ｂ２ are each independently H, C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, or C １ -C ６ haloalkyl, and X ３ｃ is N or C—R ３ｃ and X ４ｃ is N or C—R ４ｃ and X ５ｃ is N or C—R ５ｃ wherein X ６ｃ is N or C—R ６ｃ wherein R ２ｃ is H, OH, halo, C １ -C ６ alkyl, C ２ -C ６ alkenyl, C １ -C ６ haloalkyl, C １ -C ６ alkoxy, C １ -C ６ haloalkoxy, or -L １ -L ２ -(C ３ -C ６ cycloalkyl), where the cycloalkyl is optionally substituted with 1 to 2 halos, L １ is either a bond or O, L ２ is a bond or C １ -C ６ alkylene, and R ３ｃ is H, halo, C １ -C ６ -alkyl, or C １ -C ６ -haloalkyl, or X ３ｃ is C-R ３ｃ and R ２ｃ and R ３ｃ together with the carbon atom to which they are attached form a ring of the following formula, [Chemical Formula 2] ； Z １ and Z ２ each independently is O or CH ２ and each R is independently H or halo, R ４ｃ is H, halo, C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ alkoxy, or C １ -C ６ haloalkoxy, and R ５ｃ is H, halo, C １ -C ６ -alkyl, or C １ -C ６ -haloalkyl, and R ６ｃ is H, halo, C １ -C ６ -alkyl, or C １ -C ６ -haloalkyl, and However, X ２ａ X ３ａ X ５ａ and X ６ａ Among them, two or less are N or N ＋ -O － and X ３ｃ , X ４ｃ , X ５ｃ , and X ６ｃ wherein one or less of them is N, a compound of formula (I), or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (I-A) 【Chemical Formula 3】 ，

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

4. 【Chemical Formula 4】 ， The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (I-B)

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (I-B-1) [Chemical Formula 5] ，

6.

7.

8. 【Chemical Formula 6】 ，

9.

10. X ２ａ is C—R ２ａ wherein R ２ａ is H, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. X ３ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is N.

12. X ５ａ is N or C—R ５ａ where R ５ａ is H, halo, or CH ２ OH, Optionally, X ５ａ is C-R ５ａ wherein R ５ａ is H, F, or CH ２ OH, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

13. X ６ａ is N or C—R ６ａ where R ６ａ is H Optionally, X ６ａ is C-R ６ａ wherein R ６ａ is H, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

14. R ４ｂ１ is H or C １ -C ６ alkyl, and Optionally, R ４ｂ１ is H or CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

15. R ４ｂ２ is H or C １ -C ６ is alkyl, Optionally, R ４ｂ２ is H or CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

16. R ５ｂ１ is C １ -C ６ alkyl or C １ -C ６ haloalkyl, Optionally, R ５ｂ１ is CH ３ or CF ３ and the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

17. R ５ｂ２ is C １ -C ６ alkyl or C １ -C ６ haloalkyl, Optionally, R ５ｂ２ is CH ３ or CF ３ and the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

18. R ２ｃ is OH, halo, C １ -C ６ alkyl, C １ -C ６ alkoxy, or C １ -C ６ haloalkoxy, and Optionally, R ２ｃ is OH, Cl, CH ３ , OCH ３ , OCD ３ , OCH ２ CH ３ , OCH(CH ３ ), ２ , OCH ２ CH ２ F, or OCH ２ CHF ２ and the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

19. X ３ｃ is N or C—R ３ｃ where R ３ｃ is H, halo, C １ —C ６ alkyl, or C １ —C ６ haloalkyl, Optionally, X ３ｃ is C—R ３ｃ wherein R ３ｃ is H, F, CH ３ , CHF ２ , or CF ３ and the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

20. X ４ｃ is C-R ４ｃ where R ４ｃ is H, halo, C １ -C ６ haloalkyl, C １ -C ６ alkoxy, or C １ -C ６ haloalkoxy, Optionally, X ４ｃ is C—R ４ｃ wherein R ４ｃ is H, F, CHF ２ , OCH ２ CH ３ , OCHF ２ , OCF ３ and the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

21. X ５ｃ is C—R ５ｃ and R ５ｃ is H, the compound according to claim 1, or a pharmaceutically acceptable salt thereof. A compound selected from, or a pharmaceutically acceptable salt thereof. X ６ｃ is C-R ６ｃ wherein R ６ｃ is H, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

23. R ｄ is (CH ２ ) ｐ H and Optionally, R ｄ is H or CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof. A compound selected from the following, R ｄ is (CHR ｅ ) ｎ (CH ２ ) ｐ H and Optionally, R ｄ is CH ２ F, CH ２ OH, or CH(OH)CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is as defined above. or a pharmaceutically acceptable salt thereof. R ｄ is (CH ２ ) ｍ (CHR ｅ ) ｎ H and Optionally, R ｄ is CH ２ OCH ３ or CH ２ CH ２ OCH ３ and the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

22. 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】

24. Formula: A compound of, or a pharmaceutically acceptable salt thereof.

25. Formula: 【Chemical Formula 7-1】 【Chemical Formula 7-2】 A compound of, or a pharmaceutically acceptable salt thereof.

26. Formula: 【Chemical Formula 8】 A compound of, or a pharmaceutically acceptable salt thereof.

27. Formula: 【Chemical Formula 9】 A compound of, or a pharmaceutically acceptable salt thereof.

28. Formula: 【Chemical Formula 10】 A compound of, or a pharmaceutically acceptable salt thereof.

29. Formula: 【Chemical 11】 A compound of, or a pharmaceutically acceptable salt thereof.

30. 【Chemical 12】 The compound according to any one of claims 1 to 29 in non-salt form.

31. A compound of formula: 【Chemical 13】 in non-salt form.

32. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or vehicles.

33. 【Chemical Formula 14】 A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or vehicles.

34. A composition for use in a method of inhibiting voltage-dependent sodium channels in a subject, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof,

35. ​ ​ ​ Optionally, the voltage-dependent sodium channel is Na Ｖ 1.8, a composition. ​ A composition for use in a method of treating chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia or reducing the severity thereof in a subject, the composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

36. wherein the method comprises treating the neuropathic pain or reducing the severity thereof in the subject, optionally, wherein the neuropathic pain comprises postherpetic neuralgia or wherein the neuropathic pain comprises small fiber neuropathy or wherein the neuropathic pain comprises idiopathic small fiber neuropathy or wherein the neuropathic pain comprises diabetic neuropathy, optionally, wherein the diabetic neuropathy comprises diabetic peripheral neuropathy, the composition according to claim 35.

37. wherein the method comprises treating the musculoskeletal pain or reducing the severity thereof in the subject, optionally, wherein the musculoskeletal pain comprises pain of osteoarthritis, the composition according to claim 35.

38. wherein the method comprises treating the acute pain or reducing the severity thereof in the subject, optionally, wherein the acute pain comprises acute postoperative pain, the composition according to claim 35.

39. wherein the method comprises treating postoperative pain or reducing the severity thereof in the subject, optionally, wherein the postoperative pain comprises pain of aponeurotoma resection or wherein the postoperative pain comprises pain of abdominoplasty or wherein the postoperative pain comprises pain of hernia suture, the composition according to claim 35.

40. wherein the method comprises treating visceral pain or reducing the severity thereof in the subject, the composition according to claim 34.

41. The composition according to claim 35, wherein the subject is treated with one or more additional therapeutic agents administered simultaneously with, before, or after treatment with the composition.

42. A composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof for use as a medicament.

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