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

Abstract

This invention provides compounds and their pharmaceutically acceptable salts, which can be used as inhibitors of sodium channels. This invention also provides pharmaceutical compositions comprising such compounds or pharmaceutically acceptable salts, and methods of treating various conditions, including pain, using such compounds, pharmaceutically acceptable salts, and pharmaceutical compositions.

Description

Prior technology

[0001] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and prevent further damage to damaged tissue. In many cases, however, the pain persists beyond its utility, or the patient would benefit from inhibition of the pain. Neuropathic pain is a form of chronic pain caused by damage to sensory nerves (Dieleman, J.P. 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 damage to individual nerves. Metabolic neuropathy includes postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Individual nerve injury indications include post amputation pain, postoperative nerve injury pain, and nerve entrapment injuries such as neuropathic back pain.

[0002] Voltage-gated sodium channels (NaV) are involved in pain signaling. NaVs are biological mediators of electrical signaling because they mediate the rapid upstroke of action potentials that excite a variety of cell types (eg, neurons, skeletal muscle cells, cardiomyocytes). Evidence for the role of these channels in normal physiology, pathological states caused by mutations in sodium channel genes, preclinical studies in animal models, and clinical pharmacology of known sodium channel modulators all suggest a role for NaV in pain perception. Main effect (Rush, A.M. and T.R. Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets NaV1.8 Sodium Channels. Mol. Interv., 2007.7(4): pp. 192-195; England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin. Investig. Drugs17(12), pp. 1849-1864 (2008); Krafte, D. S. and Bannon, A. W., Sodium channels and nociception: recent concepts and therapy eutic opportunities. Curr. Opin. Pharmacol. 8(1), pp. 50-56 (2008)). NaV mediates the rapid upward stroke of action potentials that excite a variety of cell types (e.g., neurons, skeletal muscle cells, cardiomyocytes) and is thus involved in the initiation of signaling in these cells (Hille, Bertil, Ion Channels of Excitable Membranes, Third Edition (Sinauer Associates, Inc., Sunderland, MA, 2001)). Due to the role of NaV in the initiation and propagation of neuronal signaling, antagonists that reduce NaV currents can prevent or reduce neural signaling, and NaV channels have been considered as a potential for reducing pain under conditions where overexcitation is observed Targets (Chahine, M., Chatelier, A., Babich, O. and Krupp, J. J., Voltage-gated sodium channels in neurological disorders. CNS Neurol. Disord. Drug Targets7(2), pp. 144-158 (2008)) . Several clinically useful analgesics have been identified as inhibitors of NaV channels. Local anesthetics (such as lidocaine) block pain by inhibiting NaV channels, and other compounds (such as carbamazepine, lamotrigine) that have been shown to be effective in reducing pain have also been proposed and tricyclic antidepressants) act through sodium channel inhibition (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. Eur. J. Pain6 Supplement A, pp. 3-9 (2002); Wang, G. K., Mitchell, J. and Wang, S. Y., Block of persistent late Na+currents by antidepressant sertraline and paroxetine. J. Membr. Biol. 222(2), pp. 79-90 (2008)).

[0003] NaVs form a subfamily of the voltage-gated ion channel superfamily and include nine isoforms named NaV1.1-NaV1.9. The tissue localization of the nine isotypes differs. NaV1.4 is the major sodium channel of skeletal muscle and NaV1.5 is the major sodium channel of cardiomyocytes. NaV1.7, 1.8 and 1.9 are mainly located in the peripheral nervous system, while NaV1.1, 1.2, 1.3 and 1.6 are neuronal channels found in the central and peripheral nervous system. The functional behavior of the nine isoforms is similar, but the details of their voltage dependence and kinetic behavior differ (Catterall, W. A., Goldin, A. L. and Waxman, S. G., International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage - gated sodium channels. Pharmacol. Rev. 57(4), p. 397 (2005)).

[0004] Following its discovery, the NaV1.8 channel was identified as a possible target for analgesia (Akopian, A.N., L. Sivilotti and J.N. Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996.379 (6562): pp. 257-262). Since then, NaV1.8 has been shown to be a sodium current carrier that sustains action potential generation in small dorsal root ganglion (DRG) neurons (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): pp. 10277-10290). NaV1.8 is involved in spontaneous production in damaged neurons, such as those contributing to neuropathic pain (Roza, C. et al., The tetrodotoxin-resistant Na+channel NaV1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003.550(Pt 3): pp. 921-926; 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.US A, 2007.104(20): pp. 8520-8525; 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; Lai, J. et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8.Pain, 2002.95(1-2): pages 143-152; Dong, X.W. et al., Small interfering RNA-mediated selective knockdown of NaV1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. Neuroscience, 2007.146 (2): No. Pages 812-821; 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): pp. 644-653; Coward, K. et al., Immunolocalization of SNS / PN3 and NaN / SNS2 sodium channels in human pain states.Pain, 2000.85(1-2): pages 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): pp. 249-252; Ruangsri, S. et al., Relationship of axonal voltage-gated sodium channel 1.8 (NaV1.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats. J. Biol. Chem. 286(46): pp. 39836-39847). Small DRG neurons expressing NaV1.8 include nociceptors involved in pain signaling. NaV1.8 mediates large-amplitude action potentials in small neurons of the dorsal root ganglion (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): pp. 10277-10290). NaV1.8 is required for fast repetitive action potentials in nociceptors and for spontaneous activity of damaged neurons. (Choi, J.S. and S.G. Waxman, Physiological interactions between NaV1.7 and NaV1.8 sodium channels: a computer simulation study. J. Neurophysiol.106(6): pp. 3173-3184; Renganathan, M., T.R. Cummins and S.G. Waxman, Contribution of Na(V)1.8 sodium channels to action potential electrogenesis in DRG neurons. J. Neurophysiol., 2001.86(2): pp. 629-640; 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): pp. 921-926). NaV1.8 appears to be a driver of hyperexcitability in depolarized or damaged DRG neurons (Rush, A.M. et al., A single sodium channel mutation produces hyper-or hypoexcitability in different types of neurons. Proc. Natl. Acad . Sci. USA, 2006.103(21): pp. 8245-8250). In some animal pain models, it has been shown that the NaV1.8 mRNA expression level in DRG increases (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. 359-375; Strickland, I.T. et al., Changes in the expression of NaV1.7, NaV1.8 and NaV1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. Eur. J. Pain, 2008.12(5): pp. 564-572; Qiu, F. et al., Increased expression of tetrodotoxin-resistant sodium channels NaV1.8 and NaV1.9 within dorsal root ganglia in a rat model of bone cancer pain. Neurosci. Lett., 512(2): pp. 61-66).

[0005] The present inventors have discovered that some voltage-gated sodium channel inhibitors have potential as therapeutic agents due to, for example, a poor therapeutic window (eg, due to lack of NaV isoform selectivity, low efficacy, and / or other reasons). limitations. Therefore, there is still a need in the art to develop selective voltage-gated sodium channel inhibitors, such as selective NaV1.8 inhibitors.

Content of invention

[0006] In one aspect, the invention relates to a compound described herein, or a pharmaceutically acceptable salt thereof.

[0007] In another aspect, the present invention relates to a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or vehicles.

[0008] In another aspect, the present invention relates to a method of inhibiting a voltage-gated sodium channel in an individual by administering the compound, pharmaceutically acceptable salt, or pharmaceutical composition to the individual .

[0009] In another aspect, the present invention relates to a method of treating or lessening the severity of various diseases, conditions, or disorders in a subject by administering to the subject the compound, a pharmaceutically acceptable salt thereof diseases, conditions or conditions including but not limited to chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, surgical Posterior pain (eg, bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome syndrome), incontinence, pathological cough and cardiac arrhythmia.

Implementation

[0011] In one aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: X2a is N, N+-O- or C-R2a; X3a is N or N+- O-; X5a is N, N+-O- or C-R5a; X6a is N, N+-O- or C-R6a; Rd is (CH2)m(CHRe)n(CH2)pH; m, n and p are each 0 or 1 independently; Re is H, OH, halo, C1-C6 alkoxy or C1-C6 haloalkoxy; R2a and R6a are each independently H, halo, C1-C6 alkyl or C1 -C6 haloalkyl; R5a is H, halo, CH2OH, C1-C6 alkyl or C1-C6 haloalkyl; R4b1 and R4b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 haloalkyl; R5b1 and R5b2 are independently H, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 haloalkyl; X3c is N or C-R3c; X4c is N or C- R4c; X5c is N or C-R5c; X6c is N or C-R6c; R2c is H, OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkane Oxygen, C1-C6 haloalkoxy or -L1-L2-(C3-C6 cycloalkyl), wherein the cycloalkyl is optionally substituted by 1-2 halo; L1 is a bond or O; L2 is a bond Or C1-C6 alkylene; R3c is H, halo, C1-C6 alkyl or C1-C6 haloalkyl; or X3c is C-R3c, and R2c and R3c together form the following formula Ring:; Z1 and Z2 are each independently O or CH2; each R is independently H or halo; R4c is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; R5c is H, halo, C1-C6 alkyl or C1-C6 haloalkyl; and R6c is H, halo, C1-C6 alkyl or C1-C6 haloalkyl ; The restriction is that no more than two of X2a, X3a, X5a and X6a are N or N+-O-; and the restriction is that no more than one of X3c, X4c, X5c and X6c is N.

[0012] For the purposes of the present invention, the chemical elements are identified according to the Periodic Table of the Elements, CAS Edition, Handbook of Chemistry and Physics, 75th Edition. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th edition, editors: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, which is hereby incorporated by reference in its entirety.

[0013] As used herein, the term "compound of the present invention" refers to the compound of formula (I) as described herein and all its embodiments (such as formula (I-A) etc.), and the compound identified in Table A.

[0014] As described herein, the compounds of the present invention comprise a plurality of variable groups (eg, R1, X3a, R5b, etc.). As will be recognized by those skilled in the art, combinations of groups contemplated by the present invention result in the formation of those combinations which are stable or chemically feasible compounds. In this context, the term "stable" means that compounds are not stable when subjected to conditions for one or more of the purposes disclosed herein to allow their production, detection and preferably their recovery, purification and use. No substantive changes have taken place. In some embodiments, a stable compound or a chemically feasible compound is one that does not substantially change when maintained at a temperature of 40° C. or lower for at least one week in the absence of moisture or other chemically reactive conditions.

[0015] The understanding of the chemical structures depicted herein is intended to be that of those skilled in the art. For example, with respect to formulas (I), (I-A), (I-B) and (I-C), X2a and X3a are linked by a single bond, X5a and X6a are linked by a double bond, and X4c and X5c are linked by a single bond, However, bonds between such groups can be masked by atomic labels in the chemical structure. Using different ChemDraw styles, formula (I) can be drawn as follows to show the bond in question: In addition, substituents drawn as "CF3" or "F3C" in chemical structures refer to trifluoromethyl substituents, and chemical The representations appearing in the structure are irrelevant.

[0016] As used herein, the term "halo" means F, Cl, Br or I.

[0017] As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, free of unsaturation, and having the specified number of carbon atoms, which is formed by a single Bonds connect the rest of the molecule. For example, "C1-C6 alkyl" is an alkyl group having one to six carbon atoms.

[0018] As used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, containing one or more carbon-carbon double bonds and having the specified number of carbon atoms , which is connected to the rest of the molecule by a single bond. For example, "C2-C6 alkenyl" is an alkenyl group having two to six carbon atoms.

[0019] As used herein, the term "cycloalkyl" refers to a stable, non-aromatic, monocyclic or bicyclic (fused, bridged or spiro) saturated hydrocarbon group consisting only of carbon atoms and hydrogen atoms, having a designated carbon The number of ring atoms and is connected to the rest of the molecule by a single bond. For example, "C3-C8 cycloalkyl" is a cycloalkyl group having three to eight carbon atoms.

[0020] As used herein, the term "haloalkyl" refers to an alkyl group having the indicated number of carbon atoms in which one or more hydrogen atoms of the alkyl group are replaced by a halo group. For example, "C1-C6 haloalkyl" is an alkyl group having one to six carbon atoms, wherein one or more hydrogen atoms of the alkyl group are replaced by a halo group.

[0021] As used herein, the term "alkoxy" refers to a group of formula -ORa, wherein Ra is an alkyl group having the specified number of carbon atoms. For example, "C1-C6 alkoxy" is a group of formula -ORa, where Ra is an alkyl group having one to six carbon atoms.

[0022] As used herein, the term "haloalkoxy" refers to an alkoxy group having the indicated number of carbon atoms in which one or more hydrogen atoms of the alkyl group are replaced by a halo group.

[0023] As used herein, the term "alkylene" refers to a divalent, straight or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, free of unsaturation and having a specified number of carbon atoms , which is connected to the rest of the molecule by two single bonds. For example, "C1-C6 alkylene" is an alkylene group having one to six carbon atoms.

[0024] As used herein, the term "optionally substituted" refers to a group that is unsubstituted or substituted with a subsequently identified substituent. For example, a group "optionally substituted with 1-2 halo" is unsubstituted, substituted with 1 halo, or substituted with 2 halo.

[0025] As used herein, "*2" and "*3" in the following structures indicate the carbon atoms to which the R2c and R3c groups are attached, respectively.

[0026] Unless otherwise specified, the compounds of the present invention (whether identified by chemical name or chemical structure) include all stereoisomers (e.g., mirror image isomers) of the compounds identified by the chemical names and chemical structures provided herein and diastereomers), double bond isomers (eg (Z) and (E)), conformational isomers and tautomers. In addition, single stereoisomers, double bond isomers, conformational isomers and tautomers, and combinations of stereoisomers, double bond isomers, conformational isomers and tautomers Mixtures are within the scope of the invention.

[0027] As used herein, in any chemical structure or formula, a non-bold straight bond attached to a stereogenic center of a compound, such as in , indicates that the configuration of that stereogenic center is not specified. The compound may have any configuration or mixture of configurations at the stereogenic center.

[0028] As used herein, in any chemical structure or formula, a bold or hashed direct bond to a stereogenic center of a compound, such as in , indicates that the stereogenic center is relative to the bold or hashed direct bond. The relative stereochemistry of the other stereogenic center to which the bond is attached.

[0029] As used herein, in any chemical structure or formula, a bold or hashed wedge bond attached to a stereogenic center of a compound, such as in , denotes the absolute stereochemistry of a stereogenic center, and stereoisomerism Relative stereochemistry of centers relative to other stereoisomeric centers attached by bold or hashed wedge bonds.

[0030] As used herein, the prefix "rac-" when used in connection with a chiral compound refers to a racemic mixture of the compound. In compounds with the "rac-" prefix, the (R)- and (S)- designators in the chemical name reflect the relative stereochemistry of the compound.

[0031] As used herein, the prefix "rel-" when used in connection with a chiral compound refers to a single enantiomer whose absolute configuration is unknown. In compounds with a "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 stereogenic center is unknown, no stereochemical designator is provided. In some cases, the absolute configuration of some stereogenic centers is known, while only the relative configuration of other stereogenic centers is known. In such cases, the stereochemical designators associated with stereogenic centers of known absolute configuration are marked with an asterisk (*), such as (R*)- and (S*)-, and those associated with unknown absolute configuration. Stereochemical designators associated with stereogenic centers are unlabeled. Unlabeled stereochemical designators associated with stereogenic centers of unknown absolute configuration reflect the relative stereochemistry of those stereogenic centers relative to other stereogenic centers of unknown absolute configuration, but not necessarily relative to Relative stereochemistry of stereogenic centers of known absolute configuration.

[0032] As used herein, when referring to compounds of the present invention, the term "compound" refers to a collection of molecules having a consistent chemical structure, except for possible isotopic variations 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 compounds in pure form, in admixture with one or more other substances (such as solutions, suspensions, colloids, or pharmaceutical compositions, or dosage forms) or in the form of hydrates, solvates, or co-crystals. collection of such molecules.

[0033] As used herein, the term "amorphous" refers to a solid material that has no long-range order in molecular positions. Amorphous solids are typically glasses or supercooled liquids in which the molecules are arranged in a random manner such that no definite arrangement (eg, molecular packing) and no long-range order exists. Amorphous solids are generally isotropic, that is, exhibit similar properties in all directions and do not have a defined melting point. Instead, they typically exhibit a glass transition temperature, which marks the transition from a glassy amorphous state to a supercooled liquid amorphous state upon heating. For example, an amorphous material is a solid material that does not have sharp characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern (ie, is not crystalline as determined by XRPD). Instead, one or several broad peaks (eg halos) appear in its XRPD pattern. The broad peak is characteristic of an amorphous solid. For a comparison of XRPD of amorphous and crystalline materials see US 2004 / 0006237. In some embodiments, a solid material may comprise an amorphous compound, and the material may be characterized, for example, by the absence of sharp characteristic crystalline peaks in its XRPD spectrum (i.e., the material is not crystalline as determined by XRPD , but is amorphous). Instead, one or several broad peaks (eg halos) may appear in the XRPD pattern of the material. See US 2004 / 0006237 for a representative comparison of XRPD of amorphous versus crystalline materials. A solid material comprising an amorphous compound may, for example, be characterized by a wider range of melting temperatures for the solid material compared to the melting range of a pure crystalline solid. Crystalline or amorphous forms can also be characterized using other techniques such as solid-state NMR.

[0034] As used herein, the term "crystalline" refers to a crystal structure (or polymorph) having a specific packing arrangement of molecules in a crystal lattice. Crystalline forms can be identified and distinguished from one another by one or more characterization techniques including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, and solid-state NMR (e.g., 13C, 19F, 15N and 31P SSNMR).

[0035] In this specification and claims, unless otherwise specified, any atom in any compound of the present invention not specifically indicated as a particular isotope is intended to represent any stable isotope of the specified element. In an example, if an atom is not specifically designated as a particular isotope in any compound of the invention, no attempt has been made to enrich that atom for a particular isotope, and thus those skilled in the art will understand that such atoms may be approximately the same as the specified element The isotopic composition of the natural abundance exists.

[0036] As used herein, the term "stable" when referring to an isotope means an isotope that has not been known to undergo spontaneous radioactive decay. Stable isotopes include (but are not limited to) those identified in the absence of V.S. Shirley and C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980) Isotope of decay mode.

[0037] As used herein, in this specification and claims, "H" refers to hydrogen, and includes any stable isotope of hydrogen, namely 1H and D. In instances where an atom is indicated as "H," no attempt has been made to enrich the atom in a particular isotope of hydrogen, and thus those skilled in the art will appreciate that such hydrogen atoms may be present in approximately the isotopic composition of hydrogen in its natural abundance.

[0038] As used herein, "1H" refers to protium. Where an atom in a compound of the invention, or a pharmaceutically acceptable salt thereof, is indicated as protium, then protium is present in at least the naturally abundant concentration of protium at the indicated position.

[0039] As used herein, "D", "d" and "2H" refer to deuterium.

[0040] In some embodiments, the compounds of the invention, and pharmaceutically acceptable salts thereof, include each constituent atom at approximately the isotopic composition in its natural abundance for the indicated element.

[0041] In some embodiments, the compounds of the present invention and pharmaceutically acceptable salts thereof include 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, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, such as 2H, 13C, 15N, 18O, 17O, and 31P, respectively.

[0042] Isotopically labeled compounds and salts can be used in a variety of beneficial ways, including as pharmaceuticals. In some embodiments, isotopically labeled compounds and salts are deuterium (2H) labeled. Deuterium (2H)-labeled compounds and salts are therapeutically useful, with potential therapeutic advantages over non-2H-labeled compounds. In general, deuterium (2H)-labeled compounds and salts may have greater metabolic stability than non-isotopically-labeled compounds and salts due to the kinetic isotope interactions described below. Higher metabolic stability translates directly into increased half-life in vivo or lower dosage, which in most cases will represent a preferred embodiment of the invention. Isotopically labeled compounds and salts can generally be prepared by performing the procedures disclosed in the Synthetic Schemes, Examples and associated description, substituting readily available isotopically labeled reactants for non-isotopically labeled reactants.

[0043] Compounds and salts labeled with deuterium (2H) can manipulate the rate of oxidative metabolism of the compound through the first-order kinetic isotope effect. First order kinetic isotope effects are changes in the rate of chemical reactions resulting from the exchange of isotopic nuclei resulting from changes in the ground state energy of the covalent bonds participating in the reaction. The exchange of heavier isotopes generally results in a reduction in the ground state energy of chemical bonds, and thus in a reduction in the rate-limiting bond scission. If bond breaking occurs in or near the saddle region along the multi-product reaction coordinates, the product distribution ratios can be altered substantially. For example, if deuterium is bonded to a carbon atom at a non-exchangeable position, a rate difference of kH / kD=2-7 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 hereby incorporated by reference in its entirety.

[0044] The concentration of an isotope (eg, deuterium) incorporated at a given position in an isotopically-labeled compound of the invention, or a pharmaceutically acceptable salt thereof, can be defined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the abundance of an isotope at a given position in an isotopically labeled compound (or salt) and the natural abundance of that isotope.

[0045] If an atom in a compound of the present invention or a pharmaceutically acceptable salt thereof is denoted as deuterium, the isotopic enrichment factor of such compound (or salt) for such atom is at least 3000 (approximately 45% deuterium incorporated). 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) 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).

[0046] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X2a, X3a, X5a, X6a, Rd, R4b1, R4b2, R5b1, R5b2, X3c, X4c, X5c, X6c and R2c are defined as stated above in connection with formula (I).

[0047] In some embodiments, the present invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein Rd, R4b1, R4b2, R5b1, R5b2, R2c, R3c and R4c are as above In conjunction with the stated definitions of formula (I).

[0048] In some embodiments, the present invention relates to a compound of formula (I-A-2), or a pharmaceutically acceptable salt thereof, wherein Rd, R4b1, R4b2, R5b1, R5b2, R2c, R3c and R4c are as above In conjunction with the stated definitions of formula (I).

[0049] In some embodiments, the present invention relates to a compound of formula (I-A-3), or a pharmaceutically acceptable salt thereof, wherein Rd, R4b2, R2c, R3c and R4c are as described above in conjunction with formula (I) State the definition.

[0050] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X2a, X3a, X5a, X6a, Rd, R4b1, R4b2, R5b1, R5b2, X3c, X4c, X5c, X6c and R2c are defined as stated above in connection with formula (I).

[0051] In some embodiments, the present invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein Rd, R4b1, R4b2, R5b1, R5b2, R2c, R3c and R4c are as above In conjunction with the stated definitions of formula (I).

[0052] In some embodiments, the present invention relates to a compound of formula (I-B-2), or a pharmaceutically acceptable salt thereof, wherein Rd, R4b1, R4b2, R5b1, R5b2, R2c, R3c and R4c are as above In conjunction with the stated definitions of formula (I).

[0053] In some embodiments, the present invention relates to a compound of formula (I-B-3), or a pharmaceutically acceptable salt thereof, wherein Rd, R4b2, R2c, R3c and R4c are as described above in conjunction with formula (I) State the definition.

[0054] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X2a, X3a, X5a, X6a, Rd, R4b1, R4b2, R5b1, R5b2, X3c, X4c, X5c, X6c and R2c are defined as stated above in connection with formula (I).

[0055] In some embodiments, the present invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein Rd, R4b1, R4b2, R5b1, R5b2, R2c, R3c and R4c are as above In conjunction with the stated definitions of formula (I).

[0056] In some embodiments, the present invention relates to a compound of formula (I-C-2), or a pharmaceutically acceptable salt thereof, wherein Rd, R4b1, R4b2, R5b1, R5b2, R2c, R3c and R4c are as above In conjunction with the stated definitions of formula (I).

[0057] In some embodiments, the present invention relates to a compound of formula (I-C-3), or a pharmaceutically acceptable salt thereof, wherein Rd, R4b2, R2c, R3c and R4c are as described above in conjunction with formula (I) State the definition.

[0058] In some embodiments, the present invention relates to a compound of any one of formula (I), (I-A), (I-B) and (I-C), or a pharmaceutically acceptable salt thereof, wherein X2a is C- R2a. In other embodiments, X2a is C-R2a; and R2a is H.

[0059] In some embodiments, the present invention relates to a compound of any one of formula (I), (I-A), (I-B) and (I-C), or a pharmaceutically acceptable salt thereof, wherein X3a is N. In other embodiments, X3a is N+-O-.

[0060] In some embodiments, the present invention relates to a compound of any one of formula (I), (I-A), (I-B) and (I-C), or a pharmaceutically acceptable salt thereof, wherein X5a is N or C-R5a; and R5a is H, halo or CH2OH. In other embodiments, X5a is N. In other embodiments, X5a is C-R5a. In other embodiments, X5a is C-R5a; and R5a is H, halo, or CH2OH. In other embodiments, X5a is C-R5a; and R5a is H, F, or CH2OH. In other embodiments, X5a is C-R5a; and R5a is H. In other embodiments, X5a is C-R5a; and R5a is halo. In other embodiments, X5a is C-R5a; and R5a is F. In other embodiments, X5a is C-R5a; and R5a is CH2OH.

[0061] In some embodiments, the present invention relates to a compound of any one of formula (I), (I-A), (I-B) and (I-C), or a pharmaceutically acceptable salt thereof, wherein X6a is N or C-R6a; and R6a is H. In other embodiments, X6a is N. In other embodiments, X6a is C-R6a. In other embodiments, X6a is C-R6a; and R6a is H.

[0062] In some embodiments, the present invention relates to formula (I), (I-A), (I-A-1), (I-A-2), (I-B), (I-B-1), (I-B-2), The compound of any one of (I-C), (I-C-1) and (I-C-2), or a pharmaceutically acceptable salt thereof, wherein R4b1 is H or C1-C6 alkyl. In other embodiments, R4b1 is H. In other embodiments, R4b1 is C1-C6 alkyl. In other embodiments, R4b1 is H or CH3. In other embodiments, R4b1 is CH3.

[0063] In some embodiments, the present invention relates to formula (I), (I-A), (I-A-1), (I-A-2), (I-A-3), (I-B), (I-B-1), The compound of any one of (I-B-2), (I-B-3), (I-C), (I-C-1), (I-C-2) and (I-C-3) or a pharmaceutically acceptable salt thereof, wherein R4b2 is H or C1-C6 alkyl. In other embodiments, R4b2 is H. In other embodiments, R4b2 is C1-C6 alkyl. In other embodiments, R4b2 is H or CH3. In other embodiments, R4b2 is CH3.

[0064] In some embodiments, the present invention relates to formula (I), (I-A), (I-A-1), (I-A-2), (I-B), (I-B-1), (I-B-2), The compound of any one of (I-C), (I-C-1) and (I-C-2), or a pharmaceutically acceptable salt thereof, wherein R5b1 is C1-C6 alkyl or C1-C6 haloalkyl. In other embodiments, R5b1 is C1-C6 alkyl. In other embodiments, R5b1 is C1-C6 haloalkyl. In other embodiments, R5b1 is CH3 or CF3. In other embodiments, R5b1 is CH3. In other embodiments, R5b1 is CF3.

[0065] In some embodiments, the present invention relates to formula (I), (I-A), (I-A-1), (I-A-2), (I-B), (I-B-1), (I-B-2), The compound of any one of (I-C), (I-C-1) and (I-C-2), or a pharmaceutically acceptable salt thereof, wherein R5b2 is C1-C6 alkyl or C1-C6 haloalkyl. In other embodiments, R5b2 is C1-C6 alkyl. In other embodiments, R5b2 is C1-C6 haloalkyl. In other embodiments, R5b2 is CH3 or CF3. In other embodiments, R5b2 is CH3. In other embodiments, R5b2 is CF3.

[0066] In some embodiments, the present invention relates to formula (I), (I-A), (I-A-1), (I-A-2), (I-A-3), (I-B), (I-B-1), The compound of any one of (I-B-2), (I-B-3), (I-C), (I-C-1), (I-C-2) and (I-C-3) or a pharmaceutically acceptable salt thereof, wherein R2c is OH, halo, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy. In other embodiments, R2c is OH. In other embodiments, R2c is halo. In other embodiments, R2c is C1-C6 alkyl. In other embodiments, R2c is C1-C6 alkoxy. In other embodiments, R2c is C1-C6 haloalkoxy. In other embodiments, R2c is OH, Cl, CH3, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCH2CH2F, or OCH2CHF2. In other embodiments, R2c is Cl. In other embodiments, R2c is CH3. In other embodiments, R2c is OCH3. In other embodiments, R2c is OCD3. In other embodiments, R2c is OCH2CH3. In other embodiments, R2c is OCH(CH3)2. In other embodiments, R2c is OCH2CH2F. In other embodiments, R2c is OCH2CHF2.

[0067] In some embodiments, the present invention relates to a compound of any one of formula (I), (I-A), (I-B) and (I-C), or a pharmaceutically acceptable salt thereof, wherein X3c is N or C-R3c; and R3c is H, halo, C1-C6 alkyl or C1-C6 haloalkyl. In other embodiments, X3c is N. In other embodiments, X3c is C-R3c. In other embodiments, X3c is C-R3c; and R3c is H. In other embodiments, X3c is C-R3c; and R3c is halo. In other embodiments, X3c is C-R3c; and R3c is C1-C6 alkyl. In other embodiments, X3c is C-R3c; and R3c is C1-C6 haloalkyl. In other embodiments, X3c is C-R3c; and R3c is H, F, CH3, CHF2 or CF3. In other embodiments, X3c is C-R3c; and R3c is F. In other embodiments, X3c is C-R3c; and R3c is CH3. In other embodiments, X3c is C-R3c; and R3c is CHF2. In other embodiments, X3c is C-R3c; and R3c is CF3.

[0068] In some embodiments, the present invention relates to formulas (I-A-1), (I-A-2), (I-A-3), (I-B-1), (I-B-2), (I-B-3), The compound of any one of (I-C-1), (I-C-2) and (I-C-3), or a pharmaceutically acceptable salt thereof, wherein R3c is H, halo, C1-C6 alkyl or C1-C6 Haloalkyl. In other embodiments, R3c is H. In other embodiments, R3c is halo. In other embodiments, R3c is C1-C6 alkyl. In other embodiments, R3c is C1-C6 haloalkyl. In other embodiments, R3c is H, F, CH3, CHF2 or CF3. In other embodiments, R3c is F. In other embodiments, R3c is CH3. In other embodiments, R3c is CHF2. In other embodiments, R3c is CF3.

[0069] In some embodiments, the present invention relates to a compound of any one of formula (I), (I-A), (I-B) and (I-C), or a pharmaceutically acceptable salt thereof, wherein X3c is C- R3c; and R2c and R3c form a ring of the following formula together with the carbon atoms to which they are attached:.

[0070] In other embodiments, the ring has the formula: .

[0071] In some embodiments, the present invention relates to formulas (I-A-1), (I-A-2), (I-A-3), (I-B-1), (I-B-2), (I-B-3), The compound of any one of (I-C-1), (I-C-2) and (I-C-3) or a pharmaceutically acceptable salt thereof, wherein R2c and R3c form a ring of the following formula together with the carbon atom to which they are attached: .

[0072] In other embodiments, the ring has the formula: .

[0073] In some embodiments, the present invention relates to a compound of any one of formula (I), (I-A), (I-B) and (I-C), or a pharmaceutically acceptable salt thereof, wherein X4c is C- R4c; and R4c is H, halo, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy. In other embodiments, X4c is C-R4c. In other embodiments, X4c is C-R4c; and R4c is H. In other embodiments, X4c is C-R4c; and R4c is halo. In other embodiments, X4c is C-R4c; and R4c is C1-C6 haloalkyl. In other embodiments, X4c is C-R4c; and R4c is C1-C6 alkoxy. In other embodiments, X4c is C-R4c; and R4c is C1-C6 haloalkoxy. In other embodiments, X4c is C-R4c; and R4c is H, F, CHF2, OCH2CH3, OCHF2, OCF3. In other embodiments, X4c is C-R4c; and R4c is F. In other embodiments, X4c is C-R4c; and R4c is CHF2. In other embodiments, X4c is C-R4c; and R4c is OCH2CH3. In other embodiments, X4c is C-R4c; and R4c is OCHF2. In other embodiments, X4c is C-R4c; and R4c is OCF3.

[0074] In some embodiments, the present invention relates to formulas (I-A-1), (I-A-2), (I-A-3), (I-B-1), (I-B-2), (I-B-3), The compound of any one of (I-C-1), (I-C-2) and (I-C-3), or a pharmaceutically acceptable salt thereof, wherein R4c is H, halo, C1-C6 haloalkyl, C1- C6 alkoxy or C1-C6 haloalkoxy. In other embodiments, R4c is H. In other embodiments, R4c is halo. In other embodiments, R4c is C1-C6 haloalkyl. In other embodiments, R4c is C1-C6 alkoxy. In other embodiments, R4c is C1-C6 haloalkoxy. In other embodiments, R4c is H, F, CHF2, OCH2CH3, OCHF2, OCF3. In other embodiments, R4c is F. In other embodiments, R4c is CHF2. In other embodiments, R4c is OCH2CH3. In other embodiments, R4c is OCHF2. In other embodiments, R4c is OCF3.

[0075] In some embodiments, the present invention relates to a compound of any one of formula (I), (I-A), (I-B) and (I-C), or a pharmaceutically acceptable salt thereof, wherein X5c is C- R5c; and R5c is H.

[0076] In some embodiments, the present invention relates to a compound of any one of formula (I), (I-A), (I-B) and (I-C), or a pharmaceutically acceptable salt thereof, wherein X6c is C- R6c; and R6c is H.

[0077] In some embodiments, the present invention relates to formula (I), (I-A), (I-A-1), (I-A-2), (I-A-3), (I-B), (I-B-1), The compound of any one of (I-B-2), (I-B-3), (I-C), (I-C-1), (I-C-2) and (I-C-3) or a pharmaceutically acceptable salt thereof, wherein Rd is (CH2)pH. In other embodiments, Rd is H or CH3. In other embodiments, Rd is (CHRe)n(CH2)pH. In other embodiments, Rd is CH2F, CH2OH or CH(OH)CH3. In other embodiments, Rd is (CH2)m(CHRe)nH. In other embodiments, Rd is CH2OCH3 or CH2CH2OCH3.

[0078] In some embodiments, the present invention relates to formula (I), (I-A), (I-A-1), (I-A-2), (I-A-3), (I-B), (I-B-1), The compound of any one of (I-B-2), (I-B-3), (I-C), (I-C-1), (I-C-2) and (I-C-3), or any embodiment thereof, also presents Compounds in non-salt form.

[0079] In some embodiments, the present invention relates to a compound selected from Table A or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to compounds selected from Table A, ie in non-salt form. Table A. Compound structures and names.

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

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

[0082] In some embodiments, the present invention relates to a compound of formula, or a pharmaceutically acceptable salt thereof, wherein when separated by SFC as described in step 15 of Example 1 (2R, 3S, 4S, 5R) -3-(3,4-Difluoro-2-methoxyphenyl)-N-(6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine When the two diastereomers of -3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide are two diastereomers, the compound has the corresponding first eluting isomer Absolute and relative stereochemistry of substances. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the invention," as that term is used herein.

[0083] In some embodiments, the present invention relates to a compound of formula, or a pharmaceutically acceptable salt thereof, wherein when separated by SFC as described in step 15 of Example 1 (2R, 3S, 4S, 5R) -3-(3,4-Difluoro-2-methoxyphenyl)-N-(6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine When the two diastereomers of -3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide are two diastereomers, the compound has the corresponding second eluting isomer Absolute and relative stereochemistry of substances. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the invention," as that term is used herein.

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

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

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

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

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

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

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

[0091] In some embodiments, the present invention relates to a compound of formula, or a pharmaceutically acceptable salt thereof, wherein when rac-benzoic acid (5-((2R, 3S,4S,5R)-3-(3-(Difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- When there are two enantiomers of 2-formamido)pyrimidin-2-yl)methyl ester, the compound has the absolute and relative stereochemistry corresponding to the first eluting isomer. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the invention," as that term is used herein.

[0092] In some embodiments, the present invention relates to a compound of formula, or a pharmaceutically acceptable salt thereof, wherein when rac-benzoic acid (5-((2R, 3S,4S,5R)-3-(3-(Difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- When there are two enantiomers of 2-formamido)pyrimidin-2-yl)methyl ester, the compound has the absolute and relative stereochemistry corresponding to the second eluting isomer. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the invention," as that term is used herein.

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

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

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

[0096] In some embodiments, the present invention relates to a compound of the following formula, or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "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)pyridine-3- Base)-3-(4-fluoro-2-methoxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide or its medicine A pharmaceutically acceptable salt wherein when the two diastereomers rel-(2S,3R,4R,5S)-N-(6-((R*)-2 ,2-Dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-3-(4-fluoro-2-methoxy-3-methylphenyl)- 4,5-Dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide 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, In the case of 5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, this compound has the absolute and relative stereochemistry corresponding to the first eluting isomer. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "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)pyridine-3- Base)-3-(4-fluoro-2-methoxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide or its medicine A pharmaceutically acceptable salt wherein when the two diastereomers rel-(2S,3R,4R,5S)-N-(6-((R*)-2 ,2-Dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-3-(4-fluoro-2-methoxy-3-methylphenyl)- 4,5-Dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide 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, In the case of 5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, this compound has the absolute and relative stereochemistry of the second eluting isomer. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the invention," as that term is used herein.

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

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

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

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

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

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

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

[0106] In some embodiments, the present invention relates to a compound of formula, or a pharmaceutically acceptable salt thereof, wherein when separated by SFC as described in step 2 of Example 2 (2R, 3S, 4S, 5R) -N-(6-(1-((tert-butyldimethylsilyl)oxy)-2-methoxyethyl)pyridin-3-yl)-3-(3,4-difluoro- When two diastereomers of 2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide, the compound has the corresponding Absolute and relative stereochemistry of isomers. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the invention," as that term is used herein.

[0107] In some embodiments, the present invention relates to a compound of formula, or a pharmaceutically acceptable salt thereof, wherein when separated by SFC as described in step 2 of Example 2 (2R, 3S, 4S, 5R) -N-(6-(1-((tert-butyldimethylsilyl)oxy)-2-methoxyethyl)pyridin-3-yl)-3-(3,4-difluoro- When the two diastereomers of 2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide, the compound has the corresponding Absolute and relative stereochemistry of isomers. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the invention," as that term is used herein.

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

[0109] In some embodiments, the present invention relates to a compound of the following formula, or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "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-formamide or a pharmaceutically acceptable salt thereof, wherein when the two diastereomers rel-(2R*, 3S*, 4S*, 5R*)-3-(3, 4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-N-(6-((4R,5R)-2,2,5-tri Methyl-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, When 5-trimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)tetrahydrofuran-2-carboxamide, the compound has the absolute and relative stereochemistry. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "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-formamide or a pharmaceutically acceptable salt thereof, wherein when the two diastereomers rel-(2R*, 3S*, 4S*, 5R*)-3-(3, 4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-N-(6-((4R,5R)-2,2,5-tri Methyl-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, When 5-trimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)tetrahydrofuran-2-carboxamide, the compound has the absolute and relative stereochemistry. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the invention," as that term is used herein.

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

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

[0114] In some embodiments, the 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 its pharmaceutically acceptable salt , wherein when the two diastereomers were separated by SFC as described in Example 8 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-(tri Fluoromethyl)tetrahydrofuran-2-formamide 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- In the case of formamide, the compound has the absolute and relative stereochemistry corresponding to the first eluting isomer. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the invention," as that term is used herein.

[0115] In some embodiments, the 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 its pharmaceutically acceptable salt , wherein when the two diastereomers were separated by SFC as described in Example 8 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-(tri Fluoromethyl)tetrahydrofuran-2-formamide 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- In the case of formamide, the compound has the absolute and relative stereochemistry corresponding to the second eluting isomer. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the invention," as that term is used herein. Salts, Compositions, Uses, Formulations, Administration and Additional Agents Pharmaceutically Acceptable Salts and Compositions

[0116] As discussed herein, the present invention provides compounds and pharmaceutically acceptable salts thereof that are inhibitors of voltage-gated sodium channels, and thus compounds of the present invention and pharmaceutically acceptable salts thereof are useful in the treatment of Diseases, disorders, and disorders, including (but not limited to) chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-surgical pain (e.g. bunion resection pain, Hernia suture pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Chuck-Marley-Dousse syndrome, incontinence, pathological cough, or cardiac arrhythmia. Accordingly, in another aspect of the present invention, there are provided pharmaceutical compositions, wherein the compositions comprise a compound as described herein, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier agent, adjuvant or vehicle. In certain embodiments, such 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 salt" means, within the scope of sound medical judgment, suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reaction and the like and in association with A reasonable benefit / risk ratio should be taken with a grain of salt. A "pharmaceutically acceptable salt" of a compound of the present invention includes any non-toxic salt that, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present invention or its inhibitory active metabolites or residues. A salt may be in pure form, in admixture with one or more other substances such as a solution, suspension or colloid, or in the form of a hydrate, solvate or co-crystal. As used herein, the term "its inhibitory active metabolite or residue" means that its metabolite or residue 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. describe 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 this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino groups with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphor salt, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate Salt, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl Sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotine, nitrate, oleate, oxalate, palmitate, Pamoate, Pectate, Persulfate, 3-Phenylpropionate, Phosphate, Picrate, Pivalate, Propionate, Stearate, Succinate, Sulfate , tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Where appropriate, other pharmaceutically acceptable salts include those formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates. Non-toxic ammonium, quaternary ammonium and amine cations.

[0119] As set forth herein, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle suitable for the particular desired dosage form, which, as used herein, includes any and All solvents, diluents or other liquid vehicles, dispersion or suspension aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like. Remington's Pharmaceutical Sciences, 16th Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation. Unless any conventional carrier medium is incompatible with the compounds of the present invention, such as by producing any undesired biological effects or otherwise interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, in the present invention Any conventional carrier medium is contemplated to be used within the scope of the present invention. Some examples of materials that may serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate; lecithin; serum proteins such as human serum albumin; buffer substances such as phosphoric acid Salt, glycine, sorbic acid or potassium sorbate; mixtures of partial glycerides of saturated vegetable fatty acids; water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; Colloidal silicon dioxide; Magnesium trisilicate; Polyvinylpyrrolidone; Polyacrylates; Waxes; Polyethylene-polyoxypropylene block polymers; Lanolin; Sugars, such as lactose, glucose, and sucrose; Starches, such as cornstarch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered gum tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes ; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; Buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffered saline; and other nontoxic compatible lubricants, such as laurel Sodium hydroxysulfate and magnesium stearate; as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions according to the judgment of the formulator.

[0120] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0121] In another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or vehicles . Uses of compounds, pharmaceutically acceptable salts and compositions

[0122] In another aspect, the present invention relates to a method of inhibiting voltage-gated sodium channels in a subject comprising administering to the subject a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof . In another aspect, the voltage-gated sodium channel is NaV1.8.

[0123] In another aspect, the invention relates to treating chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-surgical pain ( eg bunionectomy pain, Hernia suture pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Chuck-Marley-Dousse syndrome, incontinence, pathological cough, or arrhythmia A method of severity comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0124] In another aspect, the invention relates to the treatment of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-surgical pain, Hernia suture pain, bunionectomy pain, multiple sclerosis, Chuck-Marley-Dousse syndrome, incontinence, or arrhythmia or a method of reducing the severity thereof comprising administering an effective amount of the present invention Compound, its pharmaceutically acceptable salt or its pharmaceutical composition.

[0125] In another aspect, the invention relates to a method of treating or lessening the severity of intestinal pain in a subject, wherein the intestinal pain comprises inflammatory bowel disease pain, Crohn's disease pain, or interstitial pain Cystitis pain, wherein the method comprises administering an effective amount of the compound of the present invention, its pharmaceutically acceptable salt or its pharmaceutical composition.

[0126] In another aspect, the present invention relates to a method of treating or lessening the severity of neuropathic pain in a subject comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. combination. In some aspects, the neuropathic pain comprises postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some aspects, neuropathic pain comprises diabetic neuropathy (eg, diabetic peripheral neuropathy). As used herein, the phrase "idiopathic small fiber neuropathy" should be understood to include any small fiber neuropathy.

[0127] In another aspect, the invention relates to a method of treating or lessening the severity of neuropathic pain in a subject, wherein the neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy , trigeminal neuralgia, burning mouth syndrome, amputation pain, phantom limb pain, painful neuroma; traumatic neuroma; Morton's neuroma (Morton's neuroma); nerve entrapment injury, spinal stenosis, carpal tunnel syndrome , radicular pain, sciatica; nerve tear injury, brachial plexus tear injury; complex regional pain syndrome, drug therapy-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, wherein the method comprises administering an effective amount of a compound of the invention, its pharmaceutical acceptable salts or pharmaceutical compositions thereof.

[0128] In another aspect, the invention relates to a method of 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 pharmaceutically acceptable salt thereof. combination. In some aspects, musculoskeletal pain comprises osteoarthritic pain.

[0129] In another aspect, the invention relates to a method of treating or lessening the severity of musculoskeletal pain in a subject, wherein the musculoskeletal pain comprises osteoarthritic pain, back pain, cold pain, burn pain, or dental pain , wherein the method comprises administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0130] In another aspect, the invention relates to a method of treating or lessening the severity of inflammatory pain in a subject, wherein the inflammatory pain comprises rheumatoid arthritis pain or vulvodynia, wherein the method comprises administering an effective amount of the compound of the present invention, its pharmaceutically acceptable salt or its pharmaceutical composition.

[0131] In another aspect, the present invention is directed to a method of treating or lessening the severity of inflammatory pain in a subject, wherein the inflammatory pain comprises rheumatoid arthritis pain, wherein the method comprises administering an effective amount of the present invention The compound, its pharmaceutically acceptable salt or its pharmaceutical composition.

[0132] In another aspect, the present invention relates to a method of treating or lessening the severity of idiopathic pain in a subject, wherein the idiopathic pain comprises fibromyalgia, wherein the method comprises administering an effective amount of Compound, its pharmaceutically acceptable salt or its pharmaceutical composition.

[0133] In another aspect, the invention relates to a method of treating or lessening the severity of pathological cough in a subject, wherein the method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or Its pharmaceutical composition.

[0134] In another aspect, the present invention relates to a method of treating or reducing the severity of acute pain in a subject comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical combination thereof things. In some aspects, acute pain comprises acute postoperative pain.

[0135] In another aspect, the invention relates to treating post-surgical pain (e.g., joint replacement pain, soft tissue surgery pain, Hernia suture pain, bunion excision pain, or abdominoplasty pain) in an individual Or a method of reducing its severity, which comprises administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0136] In another aspect, the present invention is directed to a method of treating or reducing the severity of bunionectomy pain in a subject comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt or its pharmaceutical composition.

[0137] In another aspect, the present invention relates to a method of treating or reducing the severity of Hernia suture pain in a subject comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof or its pharmaceutical composition.

[0138] In another aspect, the invention relates to a method of treating or lessening 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 Pharmaceutical composition.

[0139] In another aspect, the present invention relates to a method of treating or reducing the severity of visceral pain in a subject comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical combination thereof things. In some aspects, the visceral pain comprises visceral pain from abdominoplasty.

[0140] In another aspect, the present invention relates to a method of treating or lessening the severity of a neurodegenerative disease in a subject comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or Pharmaceutical composition. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt Hopkins Syndrome (PTHS).

[0141] In another aspect, the invention relates to a method wherein an individual is treated with one or more additional therapeutic agents in an effective amount of a compound, pharmaceutically acceptable Simultaneously with, prior to, or subsequent to treatment with the salt or pharmaceutical composition received. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0142] In another aspect, the present invention relates to a method of inhibiting a voltage-gated sodium channel in a biological sample, which comprises subjecting the biological sample to an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof or its pharmaceutical composition. In another aspect, the voltage-gated sodium channel is NaV1.8.

[0143] In another aspect, the invention relates to a method of treating or reducing the severity of the following pain in a subject: acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, nociceptive pain Pain, Arthritis, Migraine, Cluster Headache, Trigeminal Neuralgia, Herpetic Neuralgia, General Neuralgia, Epilepsy, Epilepsy Conditions, Neurodegenerative Disorders, Psychiatric Disorders, Anxiety Disorders, Depression, Bipolar Disorders, Myotonia , cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain in multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic Neuropathy, radicular pain, sciatica, back pain, nonspecific chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (eg, joint replacement pain, soft tissue surgery pain, Hernia suture pain, bunionectomy pain or abdominoplasty pain), cancer pain (including chronic cancer pain and fulminant cancer pain), stroke (such as post-stroke central neuropathic pain ), whiplash associated disorder, fragility fracture, spinal fracture, adhesive spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, bullous epidermis Lysis, gout, juvenile idiopathic arthritis, cereus-like osteopathy, polymyalgia rheumatica, pyoderma gangrenosum, chronic generalized pain, diffuse idiopathic hyperostosis, disc degeneration / herniation pain , Radiculopathy, Facet Syndrome, Post-Surgery Decay Syndrome, Burns, Carpal Tunnel Syndrome, Paget's Disease Pain, Spinal Stenosis, Discitis, Transverse Myelitis, Eden's Disease Ehlers-Danlos syndrome, Fabry's disease, obesity cell disease, neurofibromatosis, ocular neuropathic pain, sarcoidosis, laminectomy, spondylolisthesis, chemotherapy-induced Oral mucositis, Charcot neuropathic osteoarthropathy, temporomandibular joint disorders, painful arthroplasty, noncardiac chest pain, genital pain, renal colic, biliary tract disease, vascular leg Ulcers, Parkinson's disease pain, Alzheimer's disease pain, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced Angina pectoris, palpitations, hypertension or abnormal gastrointestinal motility, the method includes administering an effective amount of the compound of the present invention, its pharmaceutically acceptable salt or its pharmaceutical composition.

[0144] In another aspect, the invention relates to a method of treating or lessening the severity of the following pain in a subject: 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; pancreatic pain; IBS pain; chronic and acute headache; migraine; tension headache; cluster headache; Chronic and acute neuropathic pain, postherpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Chuck-Marley-Dousse neuropathy; hereditary sensory neuropathy; peripheral nerve injury; pain Neuroma; Ectopic proximal and distal discharges; Radiculopathy; Chemotherapy-induced neuropathic pain; Radiation therapy-induced neuropathic pain; Persistent / chronic postoperative pain (eg, post-amputation, post-thoracotomy , cardiac surgery), post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; Acute postoperative pain; acute musculoskeletal pain; arthralgia; mechanical low back pain; neck pain; tendonitis; traumatic pain; movement pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; Chest pain, cardiac pain; pelvic pain, renal colic, acute labor pain, labor pain; caesarean section pain; acute inflammatory pain, burn pain, traumatic pain; acute intermittent pain, endometriosis; acute banding Herpes Pain; Sickle Cell Anemia; Acute Pancreatitis; Breakthrough Pain; Orofacial Pain; Sinus Pain; Dental Pain; Multiple Sclerosis (MS) Pain; Depression Pain; Leprosy Pain; Bessett's Behcet's disease pain; painful obesity; phlebitis pain; Guillain-Barre pain; leg pain and toe movement; Haglund syndrome; extremity pain Pain in Fabry disease; Bladder and genitourinary disorders; Urinary incontinence, pathological cough; Overactive bladder; Painful bladder syndrome; Interstitial cystitis (IC); Prostatitis; Type I complex area Pain syndrome (CRPS), type II complex regional pain syndrome (CRPS); generalized pain, paroxysmal pain, pruritus, tinnitus or colic-induced pain, the method includes administering an effective amount of the compound of the present invention, Its pharmaceutically acceptable salt or its pharmaceutical composition. Compounds, pharmaceutically acceptable salts and compositions for use

[0145] In another aspect, the present invention relates to a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use as a medicament.

[0146] In another aspect, the present invention relates to a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting a voltage-gated sodium channel in a subject. In another aspect, the voltage-gated sodium channel is NaV1.8.

[0147] In another aspect, the present invention relates to a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in the treatment of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, Pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-surgical pain (e.g. Hernia suture pain, bunionectomy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, In a method of reducing or lessening the severity of Chuck-Marley-Dousse syndrome, incontinence, pathological cough, or cardiac arrhythmias.

[0148] In another aspect, the present invention relates to a compound of the present invention, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, for use in the treatment of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, Pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, Hernia suture pain, bunionectomy pain, multiple sclerosis, Chuck-Marley-Dousse syndrome, Incontinence or cardiac arrhythmias or methods of alleviating their severity.

[0149] In another aspect, the present invention relates to 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 of intestinal pain in a subject, wherein Bowel pain includes inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis pain.

[0150] In another aspect, the invention relates to 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 of neuropathic pain in a subject. In some aspects, the neuropathic pain comprises postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some aspects, neuropathic pain comprises diabetic neuropathy (eg, diabetic peripheral neuropathy). As used herein, the phrase "idiopathic small fiber neuropathy" should be understood to include any small fiber neuropathy.

[0151] In another aspect, the present invention relates to a compound of the present 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, Among them, neuropathic pain includes postherpetic neuralgia, diabetic neuralgia, painful HIV-related sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom limb pain, painful neuroma; traumatic neuroma ; Morton's neuroma; Nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica; nerve tear injury, brachial plexus tear injury; complex regional pain syndrome, drug therapy-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 sexual headache.

[0152] In another aspect, the invention relates to 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 of musculoskeletal pain in a subject. In some aspects, musculoskeletal pain comprises osteoarthritic pain.

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

[0154] In another aspect, the present invention relates to 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 of inflammatory pain in a subject, Wherein inflammatory pain includes rheumatoid arthritis pain or vulvodynia.

[0155] In another aspect, the present invention relates to 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 of inflammatory pain in a subject, Wherein inflammatory pain includes rheumatoid arthritis pain.

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

[0157] In another aspect, the present invention relates to 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 of pathological cough in a subject.

[0158] In another aspect, the invention relates to 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 of acute pain in a subject. In some aspects, acute pain comprises acute postoperative pain.

[0159] In another aspect, the present invention relates to a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of postoperative pain (e.g., joint replacement pain, soft tissue surgery pain) in a subject , Hernia suture pain, bunionectomy pain, or abdominoplasty pain) or in a method to reduce its severity.

[0160] In another aspect, the present invention relates to a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating or reducing the severity of bunionectomy pain in a subject in the method.

[0161] In another aspect, the present invention relates to a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating or reducing the severity of Hernia suture pain in a subject. method.

[0162] In another aspect, the invention relates to 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 abdominoplasty pain in a subject .

[0163] In another aspect, the present invention relates to 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 of visceral pain in a subject. In some aspects, the visceral pain comprises visceral pain from abdominoplasty.

[0164] In another aspect, the present invention relates to a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or lessening 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 present invention relates to a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method wherein an individual is treated with one or more additional therapeutic agents, The one or more additional therapeutic agents are administered concurrently with, prior to, or subsequent to treatment with an effective amount of the compound, pharmaceutically acceptable salt, or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0166] In another aspect, the present invention relates to a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting a voltage-gated sodium channel in a biological sample, the The method comprises contacting the biological sample with an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another aspect, the voltage-gated sodium channel is NaV1.8.

[0167] In another aspect, the present invention relates to a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or reducing the severity of the following pain in a subject: acute Pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, nociceptive pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epilepsy symptoms, neurodegenerative disorders, psychiatric disorders, anxiety disorders, depression, bipolar disorders, myotonia, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, and central neuropathy in irritable bowel syndrome Pain, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, nonspecific chronic back pain, headache, neck pain, moderate pain , severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (eg, joint replacement pain, soft tissue surgery pain, Hernia suture pain, bunion excision pain, or abdominoplasty pain), Cancer pain (including chronic cancer pain and fulminant cancer pain), stroke (such as post-stroke central neuropathic pain), whiplash-related conditions, fragility fractures, spinal fractures, adhesive spondylitis, pemphigus, Raynaud's disease , Scleroderma, Systemic Lupus Erythematosus, Epidermolysis Bullosa, Gout, Juvenile Idiopathic Arthritis, Cerebral Osteopathy, Polymyalgia Rheumatica, Pyoderma Gangrenosum, Chronic Generalized Pain , Diffuse idiopathic hyperostosis, disc degeneration / herniation pain, radiculopathy, facet joint syndrome, post-surgery decay syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, discitis, Transverse myelitis, Angle-Dan syndrome, Fabry's disease, obesity cell disease, neurofibromatosis, ocular neuropathic pain, sarcoidosis, laminopathy, spondylolisthesis, chemotherapy-induced Oral mucositis, Charcot neuropathic osteoarthropathy, temporomandibular joint disorders, painful arthroplasty, noncardiac chest pain, vulva, renal colic, biliary tract disease, vascular leg ulcers, Parkinson's disease Pain, Alzheimer's pain, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, high blood pressure, or abnormal gastrointestinal motility.

[0168] In another aspect, the present invention relates to 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 of the following pain in a subject: Cancer pain; nonmalignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreas Visceral pain; IBS pain; chronic and acute headache; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, postherpetic neuralgia; diabetic neuropathy; HIV-related neuropathy; trigeminal neuralgia; Ke-Marie-Dousse neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuroma; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiation therapy-induced Neuropathic pain; persistent / chronic post-operative pain (eg, post-amputation, post-thoracotomy, post-cardiac surgery), post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; hallucinations Extremity pain (eg, after removal of lower extremity, upper extremity, breast); intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; traumatic pain pain with movement; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, heart pain; Burn Pain, Traumatic Pain; Acute Intermittent Pain, Endometriosis; Acute Herpes Zoster Pain; Sickle Cell Anemia; Acute Pancreatitis; Breakthrough Pain; Orofacial Pain; Sinus Pain; Dental Pain ; multiple sclerosis (MS) pain; depression pain; leprosy pain; Behcet's disease pain; obesity pain; phlebitis pain; Guillain-Barré pain; Lund syndrome; extremity red pain; Fabry's disease pain; bladder and genitourinary diseases; urinary incontinence, pathological cough; overactive bladder; painful bladder syndrome; interstitial cystitis (IC); Prostatitis; type I complex regional pain syndrome (CRPS), type II complex regional pain syndrome (CRPS); generalized pain, paroxysmal severe pain, pruritus, tinnitus, or colic-induced pain. manufacturing potions

[0169] In another aspect, the present invention provides the use of the compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition for the manufacture of a medicament.

[0170] In another aspect, the present invention provides the use of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for inhibiting voltage-gated sodium channels. In another aspect, the voltage-gated sodium channel is NaV1.8.

[0171] In another aspect, the present invention provides the use of the compound of the present invention, its pharmaceutically acceptable salt, or its pharmaceutical composition for the manufacture of chronic pain, intestinal pain, neuropathy Sexual pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-surgical pain (eg, Hernia suture pain, bunionectomy pain, or abdominoplasty pain), visceral pain , multiple sclerosis, Chuck-Marley-Dousse syndrome, incontinence, pathological cough or arrhythmia or reducing the severity of the drug.

[0172] In another aspect, the present invention provides the use of the compound of the present invention, its pharmaceutically acceptable salt, or its pharmaceutical composition for the manufacture of chronic pain, intestinal pain, neuropathy Sexual Pain, Musculoskeletal Pain, Acute Pain, Inflammatory Pain, Cancer Pain, Idiopathic Pain, Post-Surgical Pain, Hernia Suture Pain, Bunionectomy Pain, Multiple Sclerosis, Chuck-Marley - Medications for Duce's syndrome, incontinence or cardiac arrhythmias or for the alleviation of their severity.

[0173] In another aspect, the present invention provides the use of a compound, a pharmaceutically acceptable salt, or a pharmaceutical composition described herein for the manufacture of a drug for treating or reducing the severity of intestinal pain in a subject. A medicament, wherein the intestinal pain comprises inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis pain.

[0174] In another aspect, the present invention provides a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a drug for treating or reducing the severity of neuropathic pain in an individual. potion. In some aspects, the neuropathic pain comprises postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some aspects, neuropathic pain comprises diabetic neuropathy (eg, diabetic peripheral neuropathy).

[0175] 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 in the manufacture of a neuropathic pain for the treatment of an individual or to reduce its severity Neuropathic pain includes postherpetic neuralgia, diabetic neuralgia, painful HIV-related sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom limb pain, painful neuroma; Traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, nerve root pain, sciatica; nerve tear injury, brachial plexus tear injury; complex regional pain syndrome, Drug therapy-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.

[0176] 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 musculoskeletal pain for the treatment of an individual or to reduce its severity level of medicine. In some aspects, musculoskeletal pain comprises osteoarthritic pain.

[0177] 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 musculoskeletal pain for the treatment of an individual or to reduce its severity Degree of medication, wherein musculoskeletal pain includes osteoarthritis pain, back pain, cold pain, burn pain or dental pain.

[0178] 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 an inflammatory pain for the treatment of an individual or for reducing its severity The medicament of degree, wherein the inflammatory pain includes rheumatoid arthritis pain or vulvodynia.

[0179] 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 an inflammatory pain for the treatment of an individual or for reducing its severity Degree of medicament, wherein inflammatory pain includes rheumatoid arthritis pain.

[0180] In another aspect, the present invention provides a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the manufacture of idiopathic pain for the treatment of an individual or for alleviating it Agents of severity, wherein idiopathic pain includes fibromyalgia.

[0181] In another aspect, the present invention provides a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the manufacture of a pathological cough for treating an individual or reducing its severity level of medicine.

[0182] 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, in the manufacture of a compound for treating acute pain in a subject or reducing its severity medicine. In some aspects, acute pain comprises acute postoperative pain.

[0183] 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 in the manufacture of a drug for the treatment of postoperative pain (such as joint replacement) in an individual. pain, soft tissue surgery pain, Hernia suture pain, bunionectomy pain, or abdominoplasty pain) or an agent that lessens its severity.

[0184] In another aspect, the present invention provides a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the manufacture of Hernia suture pain or Drugs to lessen its severity.

[0185] In 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 pain in bunion excision for the treatment of an individual or drugs to lessen its severity.

[0186] 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 abdominoplasty pain for the treatment of an individual or for alleviating it. Medicines for seriousness.

[0187] 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 drug for treating or reducing the severity of visceral pain in an individual medicine. In some aspects, the visceral pain comprises visceral pain from abdominoplasty.

[0188] In another aspect, the present invention relates to a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in the manufacture of a neurodegenerative disease or lessening its severity in an individual medicine. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt Hopkins Syndrome (PTHS).

[0189] 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 combination with one or more additional therapeutic agents , the one or more additional therapeutic agents are administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0190] In 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 treating or reducing the severity of the following pains : Acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, nociceptive pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, Epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety disorders, depression, bipolar disorders, myotonia, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis and central neuropathy in irritable bowel syndrome Sexual pain, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, nonspecific chronic back pain, headache, neck pain, moderate Pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (eg, joint replacement pain, soft tissue surgery pain, Hernia suture pain, bunion excision pain, or abdominoplasty pain) , cancer pain (including chronic cancer pain and fulminant cancer pain), stroke (such as central neuropathic pain after stroke), whiplash-related conditions, fragility fractures, spinal fractures, adhesive spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, cerebral bone disease, polymyalgia rheumatica, pyoderma gangrenosum, chronic generalized Pain, diffuse idiopathic hyperostosis, disc degeneration / herniation pain, radiculopathy, facet joint syndrome, post-back surgery decay syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, discitis , Transverse myelitis, Angler-Dan syndrome, Fabry's disease, obesity cell disease, neurofibromatosis, ocular neuropathic pain, sarcoidosis, laminopathy, spondylolisthesis, chemotherapy Induced oral mucositis, Charcot neuropathic osteoarthropathy, temporomandibular joint disorders, painful arthroplasty, noncardiac chest pain, vulva, renal colic, biliary disorders, vascular leg ulcers, Parkinson's disease pain, Alzheimer's disease pain, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, high blood pressure, or abnormal gastrointestinal motility.

[0191] In 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 treating or reducing the severity of the following pains : 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 Pancreatic pain; IBS pain; Chronic and acute headache; Migraine; Tension headache; Cluster headache; Chronic and acute neuropathic pain, postherpetic neuralgia; Diabetic neuropathy; HIV-related neuropathy; Trigeminal neuralgia ; Chuck-Marley-Dousse neuropathy; Hereditary sensory neuropathy; Peripheral nerve injury; Painful neuroma; Ectopic proximal and distal discharges; Radiculopathy; Chemotherapy-induced neuropathic pain; Radiation therapy Evoked neuropathic pain; persistent / chronic postoperative pain (eg, postamputation, postthoracotomy, postcardiac surgery), postmastectomy pain; central pain; spinal cord injury pain; poststroke pain; thalamic pain ; phantom limb pain (eg, after removal of lower extremity, upper extremity, breast); intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury Sexual pain; movement pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, heart pain; Pain, burn pain, traumatic pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinus pain; Dental Pain; Multiple Sclerosis (MS) Pain; Depression Pain; Leprosy Pain; Behcet's Disease Pain; Obesity Pain; Phlebitis Pain; Hegglund's syndrome; extremity red pain; Fabry's disease pain; bladder and genitourinary disorders; urinary incontinence, pathological cough; overactive bladder; painful bladder syndrome; interstitial cystitis (IC ); prostatitis; type I complex regional pain syndrome (CRPS), type II complex regional pain syndrome (CRPS); generalized pain, paroxysmal severe pain, pruritus, tinnitus or colic-induced pain. Administration of Compounds, Pharmaceutically Acceptable Salts, and Compositions

[0192] 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 effective for treating one of the diseases listed above or more or less serious.

[0193] According to the methods of the present invention, the compounds, salts, and compositions may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the pain or non-pain conditions listed herein . The exact amount required will vary from individual to individual, depending on the individual's species, age, and general condition, the severity of the disorder, the particular agent, its mode of administration, and the like. The compounds, salts, and compositions of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, the expression "unit dosage form" refers to physically discrete units of dosage suitable for the individual to be treated. It should be understood, however, 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 individual or organism will depend on many factors, including the condition being treated and the severity of the condition; the activity of the particular compound or salt employed; the particular composition employed; The age, weight, general health, sex, and diet of the individual; the time of administration, route of administration, and rate of excretion of the specific compound or salt employed; duration of treatment; drugs used in combination or concurrently with the specific compound or salt employed; Similar factors are well known in the art. As used herein, the term "individual" or "patient" means an animal, preferably a mammal and most preferably a human.

[0194] The pharmaceutically acceptable composition of the present invention can be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, externally (such as by powder, ointment or drops), buccally, as an oral or nasal spray, or the like, to humans and other animals. In certain embodiments, the compounds, salts and compositions of the present invention may be administered orally or parenterally one or more times per day at dosage levels of about 0.001 mg / kg to about to about 1000 mg / kg effective to achieve the desired therapeutic effect. vote with.

[0195] 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 also contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl Alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil) , glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan fatty acid esters and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0196] Injectable preparations, such as sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0197] Injectable formulations can be sterilized, for example, by filtration through bacteria-retaining filters 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.

[0198] In order to prolong the effect of the compounds of the invention, it is generally desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility. Thus, the rate of absorption of the compound depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.

[0199] Compositions for rectal or vaginal administration are preferably: suppositories, which can be obtained by combining the compound or salt of the present invention with a suitable non-irritating excipient or carrier (such as cocoa butter, polyethylene glycol alcohol); or suppository waxes, which are solid at ambient temperature but liquid at body temperature and thus melt in the rectum or vaginal cavity and release the active compound.

[0200] Solid dosage forms for oral administration include capsules, lozenges, pills, powders, and granules. In such solid dosage forms, the active compound or salt is admixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or: a) a filler or bulking agents such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia gum (acacia ), c) humectants, such as glycerin, d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) slowing agents, such as paraffin, f) absorption Accelerators, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glycerol monostearate, h) adsorbents, such as kaolin and bentonite, and i) lubricants, such as talc, Calcium stearate, magnesium stearate, macrogol solid, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0201] Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition to release the active ingredient(s) in a delayed manner only, or preferentially, as the case may be, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be employed as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols and the like.

[0202] The active compounds or salts can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and others well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound or salt may be admixed with at least one inert diluent such as sucrose, lactose or starch. As is common practice, such dosage forms may also contain 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 form may also comprise buffering agents. They may optionally contain opacifying agents and may also be of a composition to release the active ingredient(s) in a delayed manner only, or preferentially, as the case may be, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0203] Dosage forms for topical or transdermal administration of a compound or salt of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed, if necessary, with a pharmaceutically acceptable carrier and any necessary preservatives or buffers under sterile conditions. Ophthalmic formulations, ear drops and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of controlled delivery of compounds to the body. Such dosage forms are prepared by dissolving or distributing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. Rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0204] As outlined above, the compounds of the present invention are useful as inhibitors of voltage-gated sodium channels. In one embodiment, the compound is an inhibitor of NaV1.8, and thus, without wishing to be bound by any particular theory, the compounds, salts and compositions are particularly useful in the treatment of diseases, disorders in which activation or hyperactivity of NaV1.8 or lessen the severity of a disease, disorder or condition associated with a medical condition. When the activation or hyperactivity of NaV1.8 is associated with a specific disease, disease or condition, the disease, disease or condition may also be referred to as "NaV1.8-mediated disease, disease or condition". Accordingly, in another aspect, the present invention provides a method of treating or lessening the severity of a disease, disorder or condition, wherein the disease state is associated with activation or hyperactivity of NaV1.8.

[0205] The activity of the compounds used as NaV1.8 inhibitors in the present invention can be determined according to International Publication No. WO 2014 / 120808 A9 and U.S. Publication No. 2014 / 0213616 A1 (both of which are cited in their entirety) methods outlined in ), the methods described herein, and other methods known and available to those skilled in the art. additional therapeutic agent

[0206] It should also be understood that the compounds, salts, and pharmaceutically acceptable compositions of the present invention may be used in combination therapy, that is, such compounds, salts, and pharmaceutically acceptable compositions may be combined with one or more Concomitant with, prior to, or subsequent to, another desired therapeutic agent or medical procedure. The particular combination of therapies (therapeutics or procedures) to be used in a combination regimen will take into account the desired compatibility of the therapeutics and / or procedures and the desired therapeutic effect to be achieved. It is also understood that the therapy employed may achieve a desired effect for the same condition (e.g., a compound of the invention may be administered concurrently with another agent used to treat the same condition), or it may achieve a different effect (e.g., control any adverse effects ). As used herein, an additional therapeutic agent generally administered to treat or prevent a particular disease or condition is said to be "appropriate for the disease or condition being treated." Exemplary additional therapeutic agents include, but are not limited to, by way of example: non-opioid pain relievers (indoles such as Etodolac, Indomethacin, Sulindac, Tolmetin; Nabumetone, such as Nabumetone; Oxicam, such as Piroxicam; P-aminophenol derivatives, such as Acetaminophen; Propionic acid, such as non Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen Sodium, Oxaprozin; salts, such as Aspirin, choline magnesium trisalinate, Diflunisal; fenamates, such as meclofenamic acid, Mefenamic acid acid); and pyrazoles, such as Phenylbutazone); or opioid (narcotic) agonists (such as Codeine, Fentanyl, Hydromorphone , Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Butylmorphine ( Buprenorphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine). Additionally, drug-free analgesic methods may be used in conjunction with the administration of one or more compounds of the invention. For example, anesthesiological methods (intraspinal infusion, nerve block), neurosurgical methods (neurolysis of CNS pathways), neurostimulation methods (transcutaneous electrical nerve stimulation, dorsal column stimulation), physical Therapeutic methods (physiotherapy, orthotics, diathermy) or psychotherapeutic methods (cognitive methods - hypnosis, biofeedback or behavioral methods). Other suitable therapeutic agents or methods are outlined in The Merck Manual, Nineteenth Edition, edited by Robert S. Porter and Justin L. Kaplan, Merck Sharp & Dohme Corp. (a subsidiary of Merck & Co., Inc.), 2011 and Food & Drug The Agency's website at www.fda.gov, the entire contents of which are incorporated herein by reference.

[0207] In another embodiment, the additional suitable therapeutic agent is selected from the following: (1) Opioid analgesics such as morphine, heroin, hydromorphone, oxymorphone, levopernam, allyl levola Levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene (nalmefene), nalorphine, naloxone, naltrexone, butylprocaffeine, butorphanol, nalbuphine, pentazocin, 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 (eg, Toradol®), meclofenamic acid, mefenamic acid, meloxicam, intravenous meloxicam (eg, Anjeso®), nabumetone , naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine ), sulindac, timemetine, or zomepirac; (3) barbiturate sedatives, such as amobarbital, aprobarbital, secobutyl butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital ( phenobarbital), secobarbital, talbutal, thiamylal or thiopental; (4) benzodiazepines with sedative effects, such as chlorine Chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam; (5) Histamine (H1) antagonists with sedative effects, such as diphenhydramine, pyrilamine, promethazine, and chlorfenyl chlorpheniramine or chlorcyclizine; (6) sedatives such as glutethimide, meprobamate, methaqualone, or dichloralphenazone; (7 ) skeletal muscle relaxants such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or diphenhydramine ( orphenadrine); (8) NMDA receptor antagonists, such as dextromethorphan (dextromethorphan) ((+)-3-hydroxyl-N-methylmorphinan) or its metabolite dextromethorphan (dextrorphan) ((+ )-3-hydroxy-N-methylmorphinane), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2 - Picolinate, budipine, EN-3231 (MorphiDex®, a combination formulation of morphine and dextromethorphan), topiramate, neramexane, or drugs including NR2B antagonists Perzinfotel, an NR2B antagonist such as ifenprodil, traxoprodil, or (-)-(R)-6-{2-[4-(3-fluorobenzene yl)-4-hydroxy-1-hexahydropyridyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone; (9) α-adrenergic, such as doxazole 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, in particular NK-3, NK-2 or NK-1 antagonists, such as (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9 ,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazepine[2,1-g][1,7]-naphthyridine- 6-13-Diketone (TAK-637), 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy- 3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), Ari aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]- 2-Phenylhexahydropyridine (2S,3S); (13) Muscarinic antagonists such as oxybutynin, tolterodine, propiverine, trospike tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium; (14) COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiraxib (15) coal tar analgesics, especially paracetamol; (16) antipsychotics such as droperidol, chlorpromazine, haloperidol (haloperidol), perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, Olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, soneprazole ), blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, a Asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant , rimonabant, meclinertant, Miraxion®, or sarizotan; (17) vanilloid receptor agonists (such as resinferatoxin or zuca civamide) or antagonists (e.g. capsazepine, GRC-15300); (18) beta-adrenergics such as propranolol; (19) local anesthetics such as mexiletine (mexiletine); (20) corticosteroids, such as dexamethasone (dexamethasone); (21) 5-HT receptor agonists or antagonists, in particular 5-HT1B / 1D agonists, such as eletripl eletriptan, sumatriptan, naratriptan, zolmitriptan, or rizatriptan; (22) 5-HT2A receptor antagonist Agents such as R(+)-α-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-hexahydropyridinemethanol (MDL-100907 ); (23) Cholinergic (nicotine) analgesics such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridyl)-3-butane (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-1-hexahydropyrazinyl-sulfonyl Base) phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil (sildenafil)) , (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2' ,1':6,1]-pyrido[3,4-b]indole-1,4-dione (IC-351 or tadalafil), 2-[2-ethoxy- 5-(4-Ethyl-hexahydropyrazin-1-yl-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][ 1,2,4] Triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridyl)-3-ethyl-2- (1-Ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-acetyl-2 -propoxy-3-pyridyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylhexahydropyrazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl- 2-[2-Methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 4-[(3-chloro-4-methoxy Benzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3- (1-Methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide; (26) α-2-δ ligands such as gabapentin (gabapentin) (Neurontin®), gabapentin GR (Gralise ®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methylgabapentin, (1[α],3[α],5[α]) (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 acid, (2S,4S)-4-(3-fluorobenzyl)-proline, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl ]acetic acid, 3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-yl Methyl)-cycloheptyl]-methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-amine Methyl-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 (mGluR1) antagonists; (29) serotonin reuptake inhibitors, such as sertraline, sertraline metabolites Methylsertraline, fluoxetine, norfluoxetine (fluoxetine demethyl metabolite), fluvoxamine, paroxetine, west Citalopram, citalopram metabolites desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, efusiline Ifoxetine, cyanodothiepin, ritoxetine, dapoxetine, nefazodone, cericlamine, and trazodone ); (30) Norepinephrine (norepinephrine) reuptake inhibitors such as maprotiline, lofepramine, mirtazepine, oxaprotiline , fezolamine, tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion, nomifensine ( nomifensine) and viloxazine (Vivalan®), especially selective norepinephrine reuptake inhibitors such as reboxetine, in particular (S,S)-reboxetine; (31 ) dual serotonin-norepinephrine reuptake inhibitors such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine ), the clomipramine metabolites desmethylclomipramine, duloxetine (Cymbalta®), milnacipran, and imipramine; (32) Inducible nitric oxide synthase (iNOS) inhibitors such as S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[ (1-iminoethyl)-amino]ethyl]-4,4-dioxy-L-cysteine, S-[2-[(1-iminoethyl)amino ]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5 - Heptenoic acid, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile; 2-[[(1R,3S)-3-Amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amine Base-4-[[2-chloro-5-(trifluoromethyl)phenyl]sulfanyl]-5-thiazobutanol, 2-[[(1R,3S)-3-amino-4-hydroxy- 1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1 -(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine , NXN-462 or guanidinoethyl disulfide; (33) acetylcholinesterase inhibitors, such as donepezil (donepezil); (34) prostaglandin E2 subtype 4 (EP4) antagonists, such as N -[({2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)- Carbonyl]-4-tosylamide or 4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl] Benzoic acid; (35) Leukotriene B4 antagonists such as 1-(3-biphenyl-4-ylmethyl-4-hydroxy-alkan-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-pentanoic 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-quinolinone (ZD-2138) or 2,3,5-trimethyl-6-(3- (37) Sodium channel blockers such as lidocaine, lidocaine plus tetracaine cream (ZRS-201) or Eslicarbazepine acetate (38) NaV1.7 blocker, such as XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893 BIIB-074 (Vixotrigine )), BIIB-095, ASP-1807, DSP-3905, OLP-1002, RQ-00432979, FX-301, DWP-1706, DWP-17061, IMB-110, IMB-111, IMB-112 and applications such as the following Those blockers disclosed in the case: WO2011 / 140425 (US2011 / 306607); WO2012 / 106499 (US2012196869); WO2012 / 112743 (US2012245136); WO2012 / 125613 (US2012264749), WO2012 / 116440 (US2014187533), WO2011026240 ( US2012220605), US8883840, US8466188, WO2013 / 109521 (US2015005304), WO2020 / 117626 and CN111217776, the entire contents of each application are incorporated herein by reference; (38a) NaV1.7 blocking agents, such as ( 2-Benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-hexahydropyridin]-1'-yl)-(4-isopropoxy-3- Methyl-phenyl)methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl Base]-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-hexahydropyridin]-6-yl]ethanone, [8 -Fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-hexahydropyridin]-1'-yl ]-(4-isobutoxy-3-methoxy-phenyl)methanone, 1-(4-benzhydrylhexahydropyrazin-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'-hexahydropyridin]-1'-yl]methanone, [8-fluoro-2-methyl-6-( Trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-hexahydropyridinyl]-1'-yl]-(5-isopropoxy-6 -Methyl-2-pyridyl)methanone, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoro Ethyl) spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-hexahydropyridin]-1'-yl]methanone, 5-[2-methyl-4 -[2-Methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-hexahydropyridine ]-1'-carbonyl]phenyl]pyridine-2-carbonitrile, (4-isopropoxy-3-methyl-phenyl)-[6-(trifluoromethyl)spiro[3,4-di Hydrogen-2H-pyrrolo[1,2-a]pyrazine-1,4'-hexahydropyridin]-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'-hexahydropyridin]-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'-hexahydropyridin]-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'-hexahydropyridin]-6-yl]ethanone, (4-isopropoxy-3-methoxy-phenyl)-[2-methyl-6-(tri Fluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-hexahydropyridin]-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'-Hexahydropyridin]-6-yl]ethanone, 1-[(3S)-2,3-dimethyl-1'-[4-(3,3,3-trifluoropropoxy Methyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-hexahydropyridinyl]-6-yl]-2,2,2-tri Fluoro-ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-hexahydro Pyridin]-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'-Hexahydropyridin]-6-yl]ethanone, 1-[1'-[4-methoxy-3-(trifluoromethyl)benzoyl]-2-methyl-spiro[3 ,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-hexahydropyridin]-6-yl]-2,2-dimethyl-propan-1-one, (4-iso Propoxy-3-methyl-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4 '-Hexahydropyridine]-1'-yl]methanone, [2-methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[1,2-a]pyridine Oxazine-1,4'-hexahydropyridinyl]-1'-yl]-[4-(3,3,3-trifluoropropoxymethyl)phenyl]methanone, 4-bromo-N-(4 -Bromophenyl)-3-[(1-methyl-2-oxo-4-hexahydropyridyl)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'-Hexahydropyridin]-1'-yl]methanone. (39) NaV1.8 blockers such as PF-04531083, PF-06372865 and such blockers as disclosed in the following applications: WO2008 / 135826 (US2009048306), WO2006 / 011050 (US2008312235), WO2013 / 061205 (US2014296313), US20130303535, WO2013131018, US8466188, WO2013114250 (US2013274243), WO2014 / 120808 (US2014213616), WO2014 / 120815 (US201422837 1), WO2014 / 120820 (US2014221435), WO2015 / 010065 (US20160152561), WO2015 / 089361 (US20150166589), WO2019 / 014352 (US20190016671), WO2018 / 213426, WO2020 / 146682, WO2020 / 146612, WO2020 / 014243, WO2020 / 014246, WO2020 / 092187, WO2020 / 092667 (US20 20140411), WO2020 / 261114, WO2020 / 140959, WO2020 / 151728, WO2021 / 032074, CN112390745, CN111808019, CN112225695, CN112457294, CN112300051, CN112300069, CN112441969 and CN112479996 (WO2021 / 047622), the entire content of each application are incorporated herein by reference; (39a) NaV1.8 block Broken agent, such as 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzene Formamide, 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, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzoyl Amine, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzene Formamide, 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 ) Oxygen)-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-dihydropyridine -4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-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, dihydrogen phosphate [4-[[2-(4-fluoro-2-methyl- Phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl ester, 2-(4-fluoro-2-(methyl- d3) phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, dihydrogen phosphoric acid (4-(2 -(4-fluoro-2-(methyl-d3)phenoxy)-4-(trifluoromethyl)benzamido)-2-side oxypyridin-1(2H)-yl)methyl Esters, 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-formamide, 3-(2-chloro -4-fluorophenoxy)-N-(3-aminosulfonylphenyl)quinoxaline-2-formamide, 3-(2-chloro-4-methoxyphenoxy)-N- (3-aminosulfonylphenyl)quinaline-2-formamide, 3-(4-chloro-2-methoxyphenoxy)-N-(3-aminosulfonylphenyl)quinoline Pyridine-2-formamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-formamido)picolinic acid, 2-(2,4-di Fluorophenoxy)-N-(3-aminosulfonylphenyl)quinoline-3-formamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-amine Sulfonylphenyl)quinoline-3-formamide, 3-(2,4-difluorophenoxy)-N-(3-aminosulfonylphenyl)quinoxaline-2-formamide , N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoline-3-carboxamide, N-(3-sulfamoylphenyl) )-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-formamide, 3-(4-chloro-2-methylphenoxy)-N-(3-amine Sulfonylphenyl)quinoxaline-2-formamide, 5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-formamido)picolinic acid, 3 -(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)quinoxaline-2 -Formamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4-yl)quinoxaline-2-formamide, 3-(4-fluorophenoxy )-N-(3-aminosulfonylphenyl)quinoxaline-2-formamide, N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy )quinoxaline-2-formamide, N-(4-aminoformylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-formamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-formamido)benzoic acid, N-(4-cyanophenyl)-3-(4-fluoro -2-methoxyphenoxy)quinoxaline-2-formamide, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamide base) 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)benzyl Amino)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-dichloro-2-(4-fluoro-2-methoxy phenylphenoxy)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)pyridinecarboxylic 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)pyridinecarboxylic acid, 5-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy yl)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-aminosulfonylphenyl )-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide Amine, 2-(2-chloro-4-fluorophenoxy)-N-(3-aminosulfonylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenyl Oxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3- Aminosulfonylphenyl)-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-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2 -Methoxyphenoxy)-N-(3-aminosulfonylphenyl)-5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methyl Phenoxy)-N-(3-aminosulfonylphenyl)benzamide, 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3 -sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzene Formamide, 2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro -2-Methoxyphenoxy)-N-(3-aminosulfonylphenyl)-4,6-bis(trifluoromethyl)benzamide, 2-(4-fluoro-2-methyl phenyloxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide, 5-chloro-2-(2-chloro-4-fluorobenzene Oxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl) -4-(trifluoromethoxy)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoro Methyl) benzamide, 4,5-Dichloro-2-(4-fluorophenoxy)-N-(3-aminosulfonylphenyl)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-aminosulfonylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, N-(3-aminomethanol Acyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteromethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl) Benzamide, N-(3-aminoformyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]- 3-(Trifluoromethyl)benzamide, N-(3-Aminoformyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteromethoxy)-4- (Trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzamide, 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy Base)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, 4-[[3-chloro-2-fluoro-6-[2-methoxy Base-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, 4-[[2-fluoro-6-[2-(trideuteromethoxy )-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-formamide, N-(3-aminoformyl- 4-fluoro-phenyl)-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-formamide, N-(3-aminoformyl-4-fluoro-phenyl)-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro -3-(trifluoromethyl)benzamide, N-(3-aminoformyl-4-fluoro-phenyl)-2-fluoro-6-[2-methyl-4-(trifluoromethyl Oxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-aminoformyl-4-fluoro-phenyl)-2,3,4-trifluoro-6- [2-Methoxy-4-(trifluoromethoxy)phenoxy]benzamide, N-(2-aminoformyl-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-formamide, N-(3-aminomethanide Acyl-4-fluoro-phenyl)-6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N -(3-Aminoformyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide , N-(4-aminoformyl-3-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(three Fluoromethyl)benzamide, 4-[[2-fluoro-6-[2-(trideuteromethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl Base) benzoyl] amino] pyridine-2-carboxamide, N-(3-aminoformyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-4-( Trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-aminoformyl-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-amine Formyl-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-formyl Amine, N-(3-aminoformyl-4-fluoro-phenyl)-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-( Trifluoromethyl)benzamide, 5-[[2-fluoro-6-[2-(trideuteromethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoro Methyl)benzoyl]amino]pyridine-2-formamide, N-(3-aminoformyl-4-fluoro-phenyl)-2-fluoro-6-(4-fluorophenoxy )-3-(trifluoromethyl)benzamide or 4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]- 3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide; (40) combined NaV1.7 and NaV1.8 blockers, such as DSP-2230, Lohocla201 or BL-1021 (41) 5-HT3 antagonists, such as ondansetron (ondansetron); (42) TPRV 1 receptor agonists, such as capsaicin (capsaicin) (NeurogesX®, Qutenza®); Accepted salts and solvates; (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) vasoconstrictor peptide II antagonists such as EMA-401; (48) acetaminophen ( including, but not limited to, intravenous acetaminophen (eg, Ofermev®); (49) bupivacaine (including, but not limited to, bupivacaine liposome injectable suspension (eg, Exparel®), Bupivacaine ER (Posimir), Bupivacaine Collagen (Xaracoll) and Transdermal Bupivacaine (Eladur®); and (50) Bupivacaine and Met Loxicam combination (eg HTX-011). ,

[0208] In one embodiment, the additional suitable therapeutic agent is selected from the group consisting of V-116517, pregabalin, controlled release pregabalin, Ezogabine (Potiga®), ketamine / amitriptyline topical cream (Amiket®), AVP-923, Perampanel (E-2007), Ralfinamide, Transdermal Bupivacaine (Eladur®), CNV1014802, JNJ-10234094 (Carimide Carisbamate), BMS-954561 or ARC-4558.

[0209] In another embodiment, additional suitable therapeutic agents are selected from N-(6-amino-5-(2,3,5-trichlorophenyl)pyridin-2-yl)acetamide; N- (6-amino-5-(2-chloro-5-methoxyphenyl)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; or 3-((4 -(4-(Trifluoromethoxy)phenyl)-1H-imidazol-2-yl)methyl)oxetan-3-amine.

[0210] In another embodiment, the additional therapeutic agent is selected from GlyT2 / 5HT2 inhibitors, such as Operanserin (VVZ149); TRPV modulators, such as CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101 , MDR16523 or MDR652; EGR1 inhibitors such as Brivoglide (AYX1); NGF inhibitors such as tanizumab, Fasinumab, ASP6294, MEDI7352; Mu opioid agonists , such as Sibupadol (Cebranopadol), NKTR181 (oxycodegol); CB-1 agonists, such as NEO1940 (AZN1940); imidazoline 12 agonists, such as CR4056; or p75NTR-Fc modulators, Such as LEVI-04.

[0211] In another embodiment, the additional therapeutic agent is oliceridine or ropivacaine (TLC590).

[0212] In another embodiment, the additional therapeutic agent is a NaV1.7 blocking agent, such as ST-2427 or ST-2578 and WO2010129864, WO2015157559, WO2017059385, WO2018183781, WO2018183782, WO2020072835 and WO202203629 Those barriers revealed in 7 The entire content of each application is incorporated herein by reference.

[0213] In another embodiment, the additional therapeutic agent is ASP18071, CC-8464, ANP-230, ANP-231, NOC-100, NTX-1175, ASN008, NW3509, AM-6120, AM-8145, AM- 0422, BL-017881, NTM-006, Opiranserin (UnafraTM), Brivoligide, SR419, NRD.E1, LX9211, LY3016859, ISC-17536, NFX-88, LAT-8881, AP-235, NYX 2925, CNTX-6016, S-600918, S-637880, RQ-00434739, KLS-2031, MEDI 7352, or XT-150.

[0214] In another embodiment, the additional therapeutic agent is a sodium channel inhibitor (also known as a sodium channel blocker), such as the NaV1.7 and NaV1.8 blockers identified above.

[0215] The additional therapeutic agent may be present in the compositions of the invention in an amount no greater than that which would normally be administered in a composition comprising that therapeutic agent as the sole active agent. The amount of additional therapeutic agent in the compositions disclosed herein can range from about 10% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0216] The compounds and salts of the present invention, or pharmaceutically acceptable compositions thereof, may also be incorporated into implantable medical devices (such as prostheses, artificial valves, vascular grafts, stents, and catheters) for coating in the composition. Accordingly, in another aspect, the invention includes a composition for coating an implantable device comprising a compound or salt of the invention as outlined above and within classes and subclasses herein, and a suitable A vehicle that coats the implantable device. In another aspect, the invention includes an implantable device coated with a composition comprising a compound or salt of the invention as summarized above and within classes and subclasses herein, and suitable A vehicle that coats the implantable device. Suitable coatings and general preparation of coated implantable devices are described in US Patents 6,099,562, 5,886,026 and 5,304,121. Coatings are typically biocompatible polymeric materials such as hydrogel polymers, polymethicone, polycaprolactone, polyethylene glycol, polylactic acid, ethylene / vinyl acetate, and mixtures thereof. The coating can optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharide, polyethylene glycol, phospholipid or combinations thereof to impart controlled release characteristics to the composition.

[0217] Another aspect of the present invention relates to inhibiting NaV1.8 activity in a biological sample or an individual, the method comprising administering to the individual a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, or The biological sample is contacted with a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. The term "biological sample" as used herein includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from mammals or extracts thereof; and blood, saliva, urine, feces, semen, tears or Other bodily fluids or their extracts.

[0218] Inhibition of NaV1.8 activity in a biological sample can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, the study of sodium channels in biological and pathological phenomena; and the comparative evaluation of novel sodium channel inhibitors. Synthesize the compound of the present invention

[0219] The compounds of this invention may be prepared from known materials by the methods illustrated in the Examples, other analogous methods, and other methods known to those skilled in the art. As will be appreciated by those skilled in the art, functional groups of intermediate compounds in the processes described below may need to be protected by suitable protecting groups. Protecting groups can 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 edition, 2006). Radiolabeled Analogs of Compounds of the Invention

[0220] In another aspect, the invention pertains to radiolabeled analogs of the compounds of the invention. As used herein, the term "radiolabeled analogs of the compounds of the invention" refers to compounds of the invention as described herein, except that one or more atoms have been replaced by radioactive isotopes of atoms present in the compounds of the invention. The same compound as the compound (including all examples thereof).

[0221] As used herein, the term "radioactive isotope" refers to an isotope of an element known to undergo spontaneous radioactive decay. Examples of radioisotopes include 3H, 14C, 32P, 35S, 18F, 36Cl, and the like, and identify decays in V.S. Shirley and C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980) The isotope of the pattern.

[0222] Radiolabeled analogs can be used to advantage in a variety of ways, including in various types of assays, such as substrate tissue distribution assays. For example, compounds labeled with tritium (3H) and / or carbon-14 (14C) can be used in various types of analysis, such as substrate tissue distribution analysis, due to their relative simplicity of preparation and excellent detectability.

[0223] In another aspect, according to any of the embodiments described herein with respect to a compound of the invention, the invention relates to a pharmaceutically acceptable salt of a radiolabeled analog.

[0224] In another aspect, according to any of the embodiments described herein with respect to compounds of the invention, the invention relates to pharmaceutical compositions comprising a radiolabeled analog or a pharmaceutically acceptable salt thereof and A pharmaceutically acceptable carrier, adjuvant or vehicle.

[0225] In another aspect, the present invention relates to methods of inhibiting voltage-gated sodium channels and the treatment of various diseases and conditions (including pain) or A method of lessening the severity thereof comprising administering an effective amount of a radiolabeled analogue, a pharmaceutically acceptable salt thereof, and pharmaceutical compositions thereof.

[0226] In another aspect, the invention relates to radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical combinations thereof for use according to any of the embodiments described herein with respect to the compounds of the invention thing.

[0227] In another aspect, the invention relates to the use of radiolabeled analogs or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, according to any of the embodiments described herein with respect to the compounds of the invention , which is used in the manufacture of medicaments.

[0228] In another aspect, radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof may be used in combination therapy according to any of the embodiments described herein for the compounds of the invention. Examples listed

[0229] Other embodiments of the disclosure are set forth in the following numbered clauses: 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: X2a is N, N+-O- or C-R2a; X3a is N or N+-O-; X5a is N, N+-O- or C-R5a; X6a is N, N+-O- or C-R6a; Rd is (CH2)m(CHRe)n(CH2)pH; m, n and p are each independently 0 or 1; Re is H, OH, halo, C1-C6 alkoxy or C1-C6 haloalkoxy; R2a and R6a are each independently H, halo, C1 - C6 alkyl or C1-C6 haloalkyl; R5a is H, halo, CH2OH, C1-C6 alkyl or C1-C6 haloalkyl; R4b1 and R4b2 are each independently H, C1-C6 alkyl, C3 - C6 cycloalkyl or C1-C6 haloalkyl; R5b1 and R5b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 haloalkyl; X3c is N or C-R3c; X4c is N or C-R4c; X5c is N or C-R5c; X6c is N or C-R6c; R2c is H, OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkane Base, C1-C6 alkoxy, C1-C6 haloalkoxy or -L1-L2-(C3-C6 cycloalkyl), wherein the cycloalkyl is optionally substituted by 1-2 halo; L1 is a bond Or O; L2 is a bond or C1-C6 alkylene; R3c is H, halo, C1-C6 alkyl or C1-C6 haloalkyl; or X3c is C-R3c, and R2c and R3c are connected to the carbon The atoms together form a ring of the following formula: Z1 and Z2 are each independently O or CH2; each R is independently H or halo; R4c is H, halo, C1-C6 alkyl, C1-C6 haloalkyl , C1-C6 alkoxy or C1-C6 haloalkoxy; R5c is H, halo, C1-C6 alkyl or C1-C6 haloalkyl; and R6c is H, halo, C1-C6 alkyl or C1-C6 haloalkyl; the restriction is that no more than two of X2a, X3a, X5a, and X6a are N or N+-O-; and the restriction is that no more than one of X3c, X4c, X5c, and X6c is N. 2. The compound according to clause 1, wherein the compound has formula (I-A), or a pharmaceutically acceptable salt thereof. 3. The compound according to clause 1, wherein the compound has formula (I-A-1), or a pharmaceutically acceptable salt thereof. 4. The compound according to clause 1, wherein the compound has formula (I-B), or a pharmaceutically acceptable salt thereof. 5. The compound according to clause 1, wherein the compound has formula (I-B-1), or a pharmaceutically acceptable salt thereof. 6. The compound according to any one of clauses 1, 2 and 4, or a pharmaceutically acceptable salt thereof, wherein X2a is C-R2a; and R2a is H. 7. The compound according to any one of clauses 1, 2, 4 and 6, or a pharmaceutically acceptable salt thereof, wherein X3a is N. 8. The compound according to any one of clauses 1, 2, 4 and 6, or a pharmaceutically acceptable salt thereof, wherein X3a is N+-O-. 9. The compound according to any one of clauses 1, 2, 4 and 6 to 8, or a pharmaceutically acceptable salt thereof, wherein X5a is N or C-R5a; and R5a is H, halo or CH2OH. 10. The compound according to clause 9, or a pharmaceutically acceptable salt thereof, wherein X5a is N. 11. The compound according to clause 9 or a pharmaceutically acceptable salt thereof, wherein X5a is C-R5a; and R5a is H, F or CH2OH. 12. The compound according to any one of clauses 1, 2, 4 and 6 to 11, or a pharmaceutically acceptable salt thereof, wherein X6a is N or C-R6a; and R6a is H. 13. The compound according to clause 12, or a pharmaceutically acceptable salt thereof, wherein X6a is C-R6a; and R6a is H. 14. The compound according to any one of clauses 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R4b1 is H or C1-C6 alkyl. 15. The compound according to clause 14, or a pharmaceutically acceptable salt thereof, wherein R4b1 is H or CH3. 16. The compound according to any one of clauses 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R4b2 is H or C1-C6 alkyl. 17. The compound according to clause 16, or a pharmaceutically acceptable salt thereof, wherein R4b2 is H or CH3. 18. The compound according to any one of clauses 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R5b1 is C1-C6 alkyl or C1-C6 haloalkyl. 19. The compound according to clause 18, or a pharmaceutically acceptable salt thereof, wherein R5b1 is CH3 or CF3. 20. The compound according to any one of clauses 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R5b2 is C1-C6 alkyl or C1-C6 haloalkyl. 21. The compound according to clause 20 or a pharmaceutically acceptable salt thereof, wherein R5b2 is CH3 or CF3. 22. The compound according to any one of clauses 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R2c is OH, halo, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy base. 23. The compound according to clause 22 or a pharmaceutically acceptable salt thereof, wherein R2c is OH, Cl, CH3, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCH2CH2F or OCH2CHF2. 24. The compound according to any one of clauses 1 to 23, or a pharmaceutically acceptable salt thereof, wherein X3c is N or C-R3c; and R3c is H, halo, C1-C6 alkyl or C1-C6 halo alkyl. 25. The compound according to clause 24, or a pharmaceutically acceptable salt thereof, wherein X3c is N. 26. The compound according to clause 24, or a pharmaceutically acceptable salt thereof, wherein X3c is C-R3c; and R3c is H, F, CH3, CHF2 or CF3. 27. The compound according to any one of clauses 1 to 23, or a pharmaceutically acceptable salt thereof, wherein X3c is C-R3c; and R2c and R3c together with the carbon atoms to which they are attached form a ring of the formula: . 28. The compound according to clause 27, or a pharmaceutically acceptable salt thereof, wherein the ring has the following formula: . 29. The compound according to any one of clauses 1 to 28, or a pharmaceutically acceptable salt thereof, wherein X4c is C-R4c; and R4c is H, halo, C1-C6 haloalkyl, C1-C6 alkoxy group or C1-C6 haloalkoxy group. 30. The compound according to clause 29 or a pharmaceutically acceptable salt thereof, wherein X4c is C-R4c; and R4c is H, F, CHF2, OCH2CH3, OCHF2, OCF3. 31. The compound according to any one of clauses 1 to 30, or a pharmaceutically acceptable salt thereof, wherein X5c is C-R5c; and R5c is H. 32. The compound according to any one of clauses 1 to 31, or a pharmaceutically acceptable salt thereof, wherein X6c is C-R6c; and R6c is H. 33. The compound according to any one of clauses 1 to 32, or a pharmaceutically acceptable salt thereof, wherein Rd is (CH2)pH. 34. The compound according to clause 33, or a pharmaceutically acceptable salt thereof, wherein Rd is H or CH3. 35. The compound according to any one of clauses 1 to 32, or a pharmaceutically acceptable salt thereof, wherein Rd is (CHRe)n(CH2)pH. 36. The compound according to clause 35, or a pharmaceutically acceptable salt thereof, wherein Rd is CH2F, CH2OH or CH(OH)CH3. 37. The compound according to any one of clauses 1 to 32, or a pharmaceutically acceptable salt thereof, wherein Rd is (CH2)m(CHRe)nH. 38. The compound according to clause 37, or a pharmaceutically acceptable salt thereof, wherein Rd is CH2OCH3 or CH2CH2OCH3. 39. A compound selected from Table A or a pharmaceutically acceptable salt thereof. 40. The compound according to any one of clauses 1 to 39, which is 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 acceptable carrier or vehicle. 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 medium. 43. A method of inhibiting voltage-gated sodium channels in a subject 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 compound according to clause 40. The pharmaceutical composition of clause 41 or 42. 44. The method of clause 43, wherein the voltage-gated sodium channel is NaV1.8. 45. A treatment for chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-surgical pain, visceral pain, multiple sclerosis, chuck- A method of or lessening the severity of Marley-Dousse syndrome, incontinence, pathological cough or arrhythmia comprising administering to the subject an effective amount of a compound according to any one of clauses 1 to 39 or a pharmaceutically acceptable A salt of , a compound according to item 40, or a pharmaceutical composition according to item 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 of clause 46, wherein the neuropathic pain comprises post-herpetic neuralgia. 48. The method of clause 46, wherein the neuropathic pain comprises small fiber neuropathy. 49. The method of clause 46, wherein the neuropathic pain comprises idiopathic small fiber neuropathy. 50. The method of clause 46, wherein the neuropathic pain comprises diabetic neuropathy. 51. The method of clause 50, wherein the diabetic neuropathy comprises diabetic peripheral neuropathy. 52. The method of clause 45, wherein the method comprises treating or reducing the severity of musculoskeletal pain in the individual. 53. The method of clause 52, wherein the musculoskeletal pain comprises osteoarthritis pain. 54. The method of clause 45, wherein the method comprises treating or reducing the severity of acute pain in the subject. 55. The method of clause 54, wherein the acute pain comprises acute postoperative pain. 56. The method of clause 45, wherein the method comprises treating or reducing the severity of post-surgical pain in the subject. 57. The method of clause 56, wherein the post-operative pain comprises bunionectomy pain. 58. The method of clause 56, wherein the post-operative pain comprises abdominoplasty pain. 59. The method of clause 56, wherein the postoperative pain comprises Hernia suture pain. 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 to 60, wherein the individual is treated with one or more additional therapeutic agents, the one or more additional therapeutic agents being administered with the compound, pharmaceutically acceptable salt or pharmaceutical The composition is administered concurrently with, prior to, or subsequent to treatment. 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

[0230] General Methods. 1H NMR spectra were obtained as solutions in an appropriate deuterated solvent, such as dimethylsulfoxide-d6 (DMSO-d6).

[0231] Compound purity, retention time and electrospray mass spectrometry (ESI-MS) data were determined by LC / MS analysis.

[0232] LC / MS method: use the Acquity UPLC BEH C8 column (50 × 2.1 mm, 1.7 μm particles) (pn: 186002877) manufactured by Waters to carry out LC / MS analysis, the column has (2.1 × 5 mm, 1.7 μm particles) guard the column (pn: 186003978) and run a dual gradient from 2%-98% mobile phase B over 4.45 minutes. Mobile phase A=H2O (10 mM ammonium formate containing 0.05% ammonium hydroxide). Mobile phase B = acetonitrile. Flow rate = 0.6 mL / min, injection volume = 2 μL, and column temperature = 45 °C.

[0233] X-ray Powder Diffraction Analysis Method A: X-rays were performed in transmission mode at room temperature using a PANalytical Empyrean system (Malvern PANalytical Inc, Westborough, Massachusetts) equipped with a sealed tube source and PIXcel 1D Medipix-2 detector Powder Diffraction (XRPD) Analysis. The X-ray generator was operated at a voltage of 45 kV and a current of 40 mA using copper radiation (1.54060 Å). Powder samples were placed in 96-well sample holders with mylar film and loaded into the instrument. Scan the sample over a range of about 5° to about 40° 2Θ with a step size of 0.0131303° and 8.67 s x 5 per step (swing Ω = 0, ±1, ±2).

[0234] X-ray Powder Diffraction Analysis Method B: X-rays were performed in transmission mode at room temperature using a PANalytical Empyrean system (Malvern PANalytical Inc, Westborough, Massachusetts) equipped with a sealed tube source and a PIXcel 3D Medipix-3 detector Powder Diffraction (XRPD) Analysis. The X-ray generator was operated at a voltage of 45 kV and a current of 40 mA using copper radiation (1.54060 Å). Powder samples were placed in 96-well sample holders with Mylar membranes and loaded into the instrument. The sample was scanned from about 3° to about 40° 2Θ with a step size of 0.0131303° and 49 s per step. abbreviation

[0235] Unless otherwise stated or the context dictates otherwise, the following abbreviations shall be understood to have the following meanings: abbreviation meaning NMR nuclear magnetic resonance ESI-MS electrospray mass spectrometry LC / MS Liquid Chromatography-Mass Spectrometry UPLC ultra-high performance liquid chromatography HPLC / MS / MS High Performance Liquid Chromatography / Tandem Mass Spectrometry IS internal standard HPLC HPLC SFC supercritical fluid chromatography ESI electrospray ionization g gram mg mg kg Kilogram L liter mL ml µL microliter nL Nasho mol mole mmol millimolar hr, h Hour min minute ms millisecond mm mm μm Micron nm Nano MHz megahertz Hz hertz N Equivalent (concentration) m Mole (concentration) mM millimolar (concentration) μM micromole (concentration) ppm parts per million %w / v weight-volume concentration %w / w weight-weight concentration t-BuOH tertiary butanol CDI 1,1'-Carbonyldiimidazole DAST Diethylaminosulfur trifluoride DCM DCE Dichloromethane Dichloroethane DIEA, DIPEA N,N-Diisopropylethylamine DMA N,N-Dimethylacetamide DMAP N,N-Dimethylaminopyridine DMF N,N-Dimethylformamide DMSO DRG Dimethyridine dorsal root ganglia EDC.HCl Ethylcarbodiimide hydrochloride EtOH ethanol EtOAc ethyl acetate HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HOB Hydroxybenzotriazole EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide T3P Propylphosphonic anhydride, also known as 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide KOAc Potassium acetate m-CPBA m-chloroperoxybenzoic acid MeOH Methanol MTBE Methyl tertiary butyl ether NaOH sodium hydroxide NBS N-Bromosuccinimide NMP N-Methylpyrrolidone NMO N-methylmorpholine N-oxide PPTS Pyridinium p-toluenesulfonate TBAB Tetra-n-butylammonium bromide TBAF Tetra-n-butylammonium fluoride TBSCl tertiary butyldimethylsilyl chloride TBSOT tertiary butyldimethylsilyl trifluoromethanesulfonate THF Tetrahydrofuran TEA Triethylamine TFA Trifluoroacetate RB Round-bottomed flask) RT room temperature ca. About (approximately) E-VIPR Electrical Stimulation Voltage Ion Probe Reader HEK human embryonic kidney KIR2.1 Inwardly rectifying potassium channels 2.1 DMEM Dulbecco's Modified Eagle's Medium FBS fetal bovine serum NEAA non-essential amino acids HEPES 2-[4-(2-Hydroxyethyl)hexahydropyrazin-1-yl]ethanesulfonic acid DiSBAC 6 (3) Bis-(1,3-dihexyl-thiobarbituric acid) trimethyloxin CC2-DMPE Chlorocoumarin-2-dimyristylphosphatidylethanolamine VABSC-1 Potentiometric Background Suppression Compounds HS human serum BSA bovine serum albumin Example 1 (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((R)-1,2-dihydroxyethyl) Pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (1), (2R,3S,4S,5R)-3-(3,4 -Difluoro-2-methoxyphenyl)-N-(6-((S)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-( Trifluoromethyl)tetrahydrofuran-2-formamide (2) step 1:

[0236] To a stirred solution of ethyl 2-diazo-3-oxo-pentanoate (6.69 g, 39.3 mmol) in DCM (80 mL) at 0 °C was added NEt3( 7.7 mL, 55.2 mmol). Trimethylsilyl triflate (8.5 mL, 47.0 mmol) was added dropwise over 5 min, and the mixture was stirred at 0 °C for another 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) and brine (100 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to give (Z)-2-diazo-3-trimethylsilyloxy-pent-3-enoic acid ethyl ester as a red oil ( 9.4 g, 99%). 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. Step 2:

[0237] To a stirred solution of 1,1,1-trifluoropropan-2-one (8 mL, 89.4 mmol) in DCM (80 mL) was added TiCl (70 mL, 1 M in DCM, 70.00 mmol). To the resulting solution was added dropwise (Z)-2-diazo-3-trimethylsilyloxy-pent-3-enoic acid ethyl ester (36.1 g, 31.3% w / w, 46.6 mmol) in DCM (40 mL). After stirring for 100 min, the reaction was carefully quenched with water, the temperature was allowed to rise slowly, and then extracted with DCM. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography (330 g SiO2, 0% to 20% EtOAc in heptane) afforded rac-(4R,5R)-2-diazo-6 as the major diastereomer, 6,6-Trifluoro-5-hydroxy-4,5-dimethyl-3-oxohexanoic acid ethyl ester (8.82 g, 67%), which was stored as a solution in toluene. 1H 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 calc. 282.08273, found 283.1 (M+1)+; 281.0 (M-1)-. Step 3: A solution of rhodium tetraacetate (245 mg, 0.55 mmol) in benzene (32 mL) was heated at reflux for 10 min, after which rac-(4R,5R)-2-diazo- A solution of ethyl 6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxohexanoate (10 g, 35.4 mmol) in benzene (13 mL) while refluxing 60 min. The mixture was concentrated in vacuo to give ethyl rac-(4R,5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (9.0 g, 100%) as a green residue containing residual catalyst and as a mixture of epimers adjacent to the ester. This material was used in the next step without further purification. 1H 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. Step 4:

[0239] Add rac-(4R,5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid ethyl ester (48 g , 188.83 mmol) in DCM (400 mL) was added DIPEA (29.680 g, 40 mL, 229.64 mmol). A solution of trifluoromethylsulfonyl triflate (53.440 g, 32 mL, 189.41 mmol) in DCM (200 mL) was added to the reaction mixture at the same temperature over 1 h. The reaction mixture was stirred at 0 °C for 30 min before quenching with 100 mL of saturated aqueous NaHCO3. 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 rac-(4R,5R)-2,3-dimethyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonium Acyloxy)-3H-furan-5-carboxylic acid ethyl ester (71 g, 97%). 1H 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. Step 5:

[0240] To rac-(4R,5R)-2,3-dimethyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan under argon atmosphere - To a stirred solution of ethyl 5-carboxylate (26 g, 67.311 mmol) in toluene (130.00 mL) was added (3,4-difluoro-2-methoxy-phenyl)boronic acid (14 g, 74.5 mmol ), followed by the addition of K3PO4 (100 mL, 2 M, 200.00 mmol). The reaction was degassed before adding tetrakis(triphenylphosphine)palladium(0) (4 g, 3.46 mmol). After further degassing, the reaction was heated at 100 °C for 2 h. The reaction was diluted in water, and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were concentrated in vacuo. Purification by silica gel chromatography (SiO2, 0% to 10% EtOAc in heptane) afforded 4-(3,4-difluoro-2-methoxy as a 6:1 diastereomeric mixture -phenyl)-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylic acid ethyl ester (24.4 g, 93%), the major isomer is believed to be rac- (4S,5R)-4-(3,4-Difluoro-2-methoxyphenyl)-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylic acid ethyl base ester. Major isomer: 1H NMR (400 MHz, chloroform-d) δ 6.88 -6.79 (m, 2H), 4.17 -4.09 (m, 2H), 3.90 (s, 3H), 3.46 (q, J = 7.4 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. Minor isomer: 1H NMR (400 MHz, chloroform-d) δ 6.88 -6.79 (m, 2H), 4.17 -4.09 (m, 2H), 3.88 (s, 3H), 3.76 -3.71 (m, 1H) , 1.51 (s, 3H), 1.12 (t, J = 7.4 Hz, 3H), 0.99 (dd, J = 5.4, 2.7 Hz, 3H) ppm. ESI-MS m / z calculated 380.1047, found 381.02 (M+1)+. Step 6:

[0241] to rac-(4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-2,3-dimethyl-2-(trifluoromethyl)-3H- To an ice-cooled solution of ethyl furan-5-carboxylate (110 g, 243.0 mmol) in DCM (360 mL) was added BBr3 (370 mL, 1 M, 370.0 mmol) dropwise. After the addition was complete, the mixture was quenched by the addition of water and 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) and TFA (40 mL, 519.2 mmol) was added at ambient temperature. The reaction was heated to 45°C. After the reaction was complete, the mixture was quenched by the addition of aqueous sodium bicarbonate and the aqueous layer was extracted with DCM, dried (MgSO4), filtered and concentrated in vacuo to give the desired product as a 5:1 mixture of diastereomeric isomers. Recrystallization was performed by dissolving the crude material in the smallest possible amount of DCM and adding a layer of heptane on top of this solution (liquid-liquid diffusion). After approximately 1 h, 56.5 g were obtained from the first and second crystallizations (d.r. 97:3 ipsi:different) and another 4.6 g from the third crystallization (d.r. 96:4 ipsi:different) . The first batch to the third batch were combined to obtain 6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1H-furo[2,3-c]methene-4 - Ketone (61 g, 78%), the major isomer is believed to be rac-(1S,2R)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)- 1,2-Dihydro-4H-furo[2,3-c]𠳭en-4-one. ESI-MS m / z calc. 320.04718, found 321.5 (M+1)+; 319.6 (M-1)-. Step 7:

[0242] On a MultiGram III SFC instrument from Berger Instruments, a (R,R)-Whelk-O1 column from Regis Technologies, 5 μm particle size, 15 cm x 3 cm, was used with MeOH (containing 5 mM ammonia ) and CO2, the separation of rac-(1S,2R)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2- Dihydro-4H-furo[2,3-c]𠳭en-4-one (1348 g, 4.366 mol) to give:

[0243] The first eluted isomer (rt = 1.85 min): (1R,2S)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2 -Dihydro-4H-furo[2,3-c]alen-4-one (analytical samples only). 1H 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 calc. 320.04718, found 321.3 (M+1)+; 319.4 (M-1)-.

[0244] The second elution isomer (rt = 2.38 min): (1S,2R)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2 - Dihydro-4H-furo[2,3-c]𠳭en-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 calc. 320.04518, found 321.4 (M+1)+; 319.4 (M-1)-. Step 8:

[0245] (1S,2R)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3- c] A solution of methen-4-one (0.89 kg, 2.78 mol) and 20% palladium hydroxide on carbon (50% wet, 0.39 kg, 0.278 mol) in MeOH (12 L) was stirred under 40 psi hydrogen pressure overnight. After reacting overnight, the reaction temperature was observed to increase to 37°C, and the mixture was allowed to cool to 24°C. Hydrogenation was continued for a total of 48 h. The mixture was filtered through celite, washed 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 (2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl as a beige solid - Methyl 5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.0 kg, 91% purity, 100%). 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. Step 9:

[0246] At ambient temperature, potassium carbonate (2.0 kg, 14.4 mol) and methyl iodide (800 mL, 12.8 mol) were added sequentially to (2S, 3S, 4S, 5R)- 3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid methyl ester (1.0 kg, 2.82 mol) in acetonitrile (10 L) in solution. 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), washed 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 (2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-di Methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (0.99 kg, 90% purity, 95%). 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. Steps 10 and 11:

[0247] Under nitrogen, sodium methoxide (25% in methanol, 65 mL, 0.28 mol) was added to (2S,3S,4S,5R)-3-(3,4 -Difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid methyl ester (0.98 kg, 2.66 mol) in THF (10 L) in solution. 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), followed by extraction with MTBE (20 L). The aqueous layer was further extracted with MTBE (2 x 5 L), and the combined organic layers were washed with brine (2 L), dried (Na2SO4), filtered, and then treated with activated carbon (50 g, 5% w / w) And stir for 1 h. The mixture was filtered through Celite, washed with MTBE (2 x 4 L), and the filtrate was concentrated in vacuo. The residue was dissolved in toluene (4 L) and concentrated in vacuo, then dissolved in MTBE (4 L) and concentrated again in vacuo to give (2R,3S,4S,5R) as an amber oil. 3-(3,4-Difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1.06 kg, 77.7% purity), which Used without further purification. Step 12:

[0248] In a 100 L Chemglass reactor, the crude (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl - 5-(Trifluoromethyl)tetrahydrofuran-2-carboxylic acid (2.09 kg, 77% purity, 4.54 mol) was dissolved in MTBE (25 L) followed by stirring at 84 rpm at ambient temperature. A mixture of (R)-1-phenylethylamine (0.704 kg, 5.81 mol) and MTBE (2 L) was added to the reactor followed by MTBE to give a total volume of 30 L in the reactor. After 2 h, additional MTBE (2 L) was added to the reaction. After a total of 3.5 h, the mixture was filtered, washing with MTBE (2 L). The reactor was rinsed with MTBE (4 L) to rinse the solids, then the solids were pressed and dried on a Büchner funnel for 2 h. The solid product cake was allowed to loosen, then dried overnight on a Buchner funnel under a stream of nitrogen and under vacuum. The isolated solid was dried in a convection oven at 40 °C for 24 h to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl) as an off-white solid -4,5-Dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (R)-1-phenylethan-1-amine salt (1.86 kg, 95.7% purity, 74% by 3 steps ). 1H 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. Step 13:

[0249] to (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl) To a suspension of tetrahydrofuran-2-carboxylic acid (1R)-1-phenylethylamine salt (10.6 g, 22.29 mmol) in MTBE (250 mL) was added HCl (200 mL, 2 M, 400.0 mmol). The layers were separated, and the organic layer was washed with water (200 mL), dried (MgSO 4 ), filtered and concentrated in vacuo to give (2R,3S,4S,5R)-3-(3,4-di Fluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (8.4 g, 99%). 1H 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. Steps 14 and 15:

[0250] Oxalyl chloride (738 µL, 8.460 mmol) was added dropwise to (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 min, the solution was concentrated in vacuo. The residue was redissolved in dichloromethane (10 mL), and 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). The mixture was stirred at ambient temperature for 1 h. 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 x 20 mL), dried (MgSO4), filtered, and concentrated in vacuo. Purification by reverse-phase preparative HPLC (Waters Sunfire C18, 10 μM, 100 Å column, 0% to 100% MeCN in water containing 0.1% ammonia) gave after lyophilization (2R,3S,4S,5R )-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-(2,2-dimethyl-1,3-dioxolan-4-yl) Mixture of 2 diastereomers of pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide.

[0251] On a Minigram SFC instrument from Berger Instruments, Chiralcel OJ-H column from Daicel was used by chiral SFC, 5 μm particle size, 25 cm × 10 mm (mobile phase: 12% MeOH (containing 20 mM Ammonia), 88% CO2. Flow rate: 10 mL / min.) Separation 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 - Mixture of 2 diastereomers of formamide:

[0252] The first eluted isomer (rt=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-(trifluoromethane base) tetrahydrofuran-2-carboxamide (700 mg, 60%). ESI-MS m / z calculated 530.184, found 531.2 (M+1)+; retention time: 3.56 minutes.

[0253] The second eluting isomer (rt=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 base) tetrahydrofuran-2-carboxamide (700 mg, 60%). ESI-MS m / z calculated 530.184, found 531.2 (M+1)+; retention time: 3.56 minutes. Step 16:

[0254] TFA (1.743 mL, 22.62 mmol) was added to (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-Formamide (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 h. 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 containing 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-formamide (1,304 mg, 55%). 1H NMR (500 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.73 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.23 -7.13 (m, 2H), 5.11 (d, J = 10.3 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 490.1527, found 491.6 (M+1)+; retention time: 2.98 minutes.

[0255] Treat (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-formamide ( 600 mg, 1.106 mmol) (second eluted isomer from SFC separation), after lyophilization to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy Phenyl)-N-(6-((S)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- Formamide (2,340 mg, 61%). 1H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.67 (dd, J = 2.5, 0.7 Hz, 1H), 7.98 (dd, J = 8.5, 2.6 Hz, 1H), 7.43 (d, J = 8.5 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 490.1527, found 491.6 (M+1)+; retention time: 2.99 minutes.

[0256] The absolute stereochemistry of 1 and 2 was determined by single crystal X-ray crystallographic analysis of 1.

[0257] Compound 1 was analyzed by X-ray Powder Diffraction Analysis Method A and determined to be amorphous (see Figure 1).

[0258] The following compounds were prepared 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 instead of rac-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3- amine. In step 15, Chiralcel OD-H column from Daicel Corporation, 5 μm particle size, 25 cm × 10 mm (mobile phase: 12% MeOH ( Contains 20 mM ammonia), 88% CO2. Flow rate: 10 mL / min.) Perform purification: Compound number Compound name LC / MS NMR (shift, ppm) 3 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-formamide (The first elution peak of the former system on the Chiralcel OD-H column by SFC, rt = 4.36 min) ESI-MSm / z calculated value 504.16837, experimental value 505.0 (M+1) + ;503.1 (M-1) - ;Dwell time: 3.08 minutes 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.37 (s, 1H), 8.68 (d, J = 2.2 Hz, 1H), 7.97 (dd, J = 8.5, 2.5 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.20 -7.13 (m, 2H), 5.20 (d, J = 5.3 Hz, 1H), 5.09 (d, J = 10.3 Hz, 1H), 4.46 (d, J = 5.5 Hz, 1H), 4.30 (t, J = 5.2 Hz , 1H), 4.25 (dd, J = 10.1, 7.8 Hz, 1H), 3.95 (d, J = 2.1 Hz, 3H), 3.81 -3.75 (m, 1H), 2.77 (p, J = 7.2 Hz, 1H) , 1.61 (s, 3H), 0.94 (d, J = 6.4 Hz, 3H), 0.74 (d, J = 7.3 Hz, 3H) ppm. 4 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-formamide (The second elution peak of the former system on the Chiralcel OD-H column by SFC, rt = 5.28 min) ESI-MSm / z calculated value 504.16837, experimental value 505.0 (M+1) + ;503.1 (M-1) - ;Dwell time: 3.08 minutes 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.37 (s, 1H), 8.65 (d, J = 2.5 Hz, 1H), 7.99 (dd, J = 8.6, 2.5 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.20 -7.13 (m, 2H), 5.20 (d, J = 5.3 Hz, 1H), 5.09 (d, J = 10.3 Hz, 1H), 4.45 (d, J = 5.5 Hz, 1H), 4.30 (t, J = 5.2 Hz , 1H), 4.25 (dd, J = 10.4, 7.6 Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 3.81 -3.75 (m, 1H), 2.80 -2.73 (m, 1H), 1.61 ( s, 3H), 0.94 (d, J = 6.4 Hz, 3H), 0.73 (d, J = 6.5 Hz, 3H) ppm.

[0259] The following compounds were prepared using the method described in Example 1 except that (1R,2S)-6,7-difluoro-1,2-dimethyl-2-(trifluoro Methyl)-1,2-dihydro-4H-furo[2,3-c]alken-4-one instead of (1S,2R)-6,7-difluoro-1,2-dimethyl- 2-(Trifluoromethyl)-1,2-dihydro-4H-furo[2,3-c]𠳭en-4-one and (S)-6-(2,2- Dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine as coupling partner. SFC separation step 15 not required: Compound number Compound name LC / MS NMR (shift, ppm) 5 (2S,3R,4R,5S)-3-(3,4-Difluoro-2-methoxyphenyl)-N-(6-((S)-1,2-dihydroxyethyl)pyridine- 3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide ESI-MSm / z calculated value 490.1527, experimental value 491.2 (M+1) + ;489.2 (M-1) - ;Dwell time: 2.97 minutes 1H NMR (400 MHz, DMSO-d 6 ) δ 10.39 (s, 1H), 8.65 (dd, J = 2.5, 0.7 Hz, 1H), 8.00 (dd, J = 8.6, 2.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.17 (dd, J = 8.6, 5.2 Hz, 2H), 5.33 (d, J = 4.9 Hz, 1H), 5.10 (d, J = 10.3 Hz, 1H), 4.63 (t, J = 5.9 Hz, 1H), 4.54 (dt, J = 6.9, 4.5 Hz, 1H), 4.24 (dd, J = 10.3, 7.6 Hz, 1H), 3.95 (d, J = 2.2 Hz, 3H), 3.63 (ddd, J = 10.9, 6.0, 4.1 Hz, 1H), 3.44 (ddd, J = 10.9, 6.8, 5.8 Hz, 1H), 2.77 (t, J = 7.5 Hz, 1H), 1.61 (s, 3H), 0.80 -0.68 (m, 3H) ppm.

[0260] The following compounds were prepared using the method described in Example 1 except that in the alkylation step 9 ethyl iodide was used instead of methyl iodide. The conditions used in the epimerization / hydrolysis steps 10 and 11 followed the first part of the conditions described in Example 5, Step 4. In step 14, (S)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine and (R)-6-(2 , 2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine as the coupling partner of compounds 6 and 7, respectively. SFC separation step 15 not required: Compound number Compound name LC / MS NMR (shift, ppm) 6 (2R,3S,4S,5R)-N-(6-((S)-1,2-dihydroxyethyl)pyridin-3-yl)-3-(2-ethoxy-3,4-di Fluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide ESI-MSm / z calculated value 504.16837, experimental value 505.4 (M+1) + ;503.5 (M-1) - ;Dwell time: 3.12 minutes 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.36 (s, 1H), 8.65 (s, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.16 (dd, J = 8.5, 4.6 Hz , 2H), 5.31 (s, 1H), 5.08 (d, J = 10.6 Hz, 1H), 4.62 (t, J = 5.7 Hz, 1H), 4.53 (s, 1H), 4.27 (dd, J = 10.5, 7.5 Hz, 1H), 4.24 -4.09 (m, 2H), 3.62 (s, 1H), 3.44 (d, J = 9.8 Hz, 1H), 2.74 (p, J = 7.4 Hz, 1H), 1.60 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H), 0.73 (d, J = 7.3 Hz, 3H) ppm. 7 (2R,3S,4S,5R)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-3-(2-ethoxy-3,4-di Fluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide ESI-MSm / z calculated value 504.16837, experimental value 505.4 (M+1) + ;503.5 (M-1) - ;Dwell time: 3.11 minutes 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.36 (s, 1H), 8.63 (dd, J = 2.5, 0.8 Hz, 1H), 7.99 (dd, J = 8.5, 2.6 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.21 -7.08 (m, 2H), 5.31 (d, J = 4.9 Hz, 1H), 5.08 (d, J = 10.5 Hz, 1H), 4.62 (t, J = 5.9 Hz, 1H), 4.53 (dt, J = 6.8, 4.5 Hz, 1H), 4.27 (dd, J = 10.5, 7.5 Hz, 1H), 4.24 -4.08 (m, 2H), 3.62 (ddd, J = 10.9, 6.0, 4.1 Hz, 1H), 3.44 (ddd , J = 11.0, 6.8, 5.8 Hz, 1H), 2.74 (p, J = 7.5 Hz, 1H), 1.60 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H), 0.77 -0.67 (m, 3H) ppm.

[0261] Compound 7 was analyzed by X-ray Powder Diffraction Analysis Method B and determined to be amorphous (see Figure 2).

[0262] The following compounds were prepared using a method similar to that described in Example 1, except that methyl iodide-d3 was used instead of methyl iodide in the alkylation step 9, and the conditions for the amide coupling step 14 followed that of Example 2, step 1 Conditions described in , using (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine as the coupling partner. SFC separation step 15 not required: Compound number Compound name LC / MS NMR (shift, ppm) 8 (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d 3 )phenyl)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2 - formamide ESI-MSm / z calculated value 493.17154, experimental value 494.3 (M+1) + ;492.3 (M-1) - ;Dwell time: 2.99 minutes 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.37 (s, 1H), 8.65 (dd, J = 2.6, 0.7 Hz, 1H), 8.00 (dd, J = 8.5, 2.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.18 -7.13 (m, 2H), 5.32 (d, J = 4.9 Hz, 1H), 5.09 (d, J = 10.3 Hz, 1H), 4.62 (t, J = 5.9 Hz, 1H), 4.54 (dt, J = 6.8, 4.5 Hz, 1H), 4.24 (dd, J = 10.3, 7.6 Hz, 1H), 3.63 (ddd, J = 11.0, 6.1, 4.2 Hz, 1H), 3.48 -3.42 (m, 1H), 2.77 (t , J = 7.5 Hz, 1H), 1.61 (s, 3H), 0.76 -0.71 (m, 3H) ppm.

[0263] Compound 8 was analyzed by X-ray Powder Diffraction Analysis Method B and determined to be amorphous (see Figure 3).

[0264] The following compounds were prepared 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. Following the conditions described in Example 6, Step 3, epimerization / hydrolysis steps 10 and 11 were performed in one step. Omit steps 12 and 13 and use 2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrimidin-5-amine as coupling partner in amide coupling step 14 things. In step 15, a Chiralpak IB column from Daicel Corporation, 5 um particle size, 25 cm x 20 mm was used by chiral SFC on a Minigram SFC instrument from Berger Instruments (mobile phase: 20% MeOH (containing 20 mM ammonia), 80% CO2. Flow rate: 100 mL / min.) to perform purification: Compound number Compound name LC / MS NMR (shift, ppm) 9 rel-(2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-isopropoxyphenyl)-N-(2-(1,2-dihydroxyethyl )pyrimidin-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The first elution peak of the former system on the Chiralpak IB column by SFC, rt = 0.80 min) ESI-MSm / z calculated value 519.17926, experimental value 520.3 (M+1) + ;518.2 (M-1) - ;Dwell time: 3.2 minutes 1 H NMR (400 MHz, methanol-d 4 ) δ 9.02 (s, 2H), 7.14 (ddd, J = 8.4, 5.6, 2.1 Hz, 1H), 6.97 (ddd, J = 9.9, 8.9, 7.5 Hz, 1H), 5.08 (d, J = 10.7 Hz, 1H), 4.78 (dd, J = 6.0, 4.6 Hz, 1H), 4.66 (pd, J = 6.1, 1.2 Hz, 1H), 4.37 (dd, J = 10.7, 7.9 Hz, 1H), 3.94 -3.78 (m , 2H), 2.78 (p, J = 7.6 Hz, 1H), 1.67 (d, J = 1.2 Hz, 3H), 1.40 (dd, J = 6.2, 1.0 Hz, 3H), 1.25 (d, J = 6.1 Hz , 3H), 0.79 (dt, J = 7.4, 2.3 Hz, 3H) ppm; alcohol OH and amide NH were not observed. 10 rel-(2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-isopropoxyphenyl)-N-(2-(1,2-dihydroxyethyl )pyrimidin-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The second elution peak of the former system on the Chiralpak IB column by SFC, rt = 0.95 min) ESI-MSm / z calculated value 519.17926, experimental value 520.3 (M+1) + ;518.2 (M-1) - ;Dwell time: 3.19 minutes 1 H NMR (400 MHz, methanol-d 4 ) δ 9.02 (s, 2H), 7.14 (ddd, J = 8.3, 5.6, 2.1 Hz, 1H), 6.97 (ddd, J = 9.9, 8.9, 7.6 Hz, 1H), 5.08 (d, J = 10.7 Hz, 1H), 4.78 (dd, J = 6.0, 4.6 Hz, 1H), 4.66 (pd, J = 6.2, 1.3 Hz, 1H), 4.37 (dd, J = 10.7, 7.9 Hz, 1H), 3.94 -3.77 (m , 2H), 2.78 (p, J = 7.6 Hz, 1H), 1.67 (d, J = 1.1 Hz, 3H), 1.40 (dd, J = 6.1, 0.9 Hz, 3H), 1.25 (d, J = 6.1 Hz , 3H), 0.80 (dt, J = 7.6, 2.3 Hz, 3H) ppm; alcohol OH and amide NH were not observed.

[0265] The following compounds were prepared using the method described in Example 1, except steps 12 and 13 were omitted, and in amide coupling step 14, 2-(2,2-dimethyl-1,3-di Oxolan-4-yl)pyrimidin-5-amine as coupling partner. In step 15, Chiralcel OD-H column from Daicel Corporation, 5 um particle size, 25 cm × 10 mm was used by chiral SFC on a Minigram SFC instrument from Berger Instruments (mobile phase: 22% MeOH ( Contains 20 mM ammonia), 78% CO2. Flow rate: 10 mL / min.) Perform purification: Compound number Compound name LC / MS NMR (shift, ppm) 11 rel-(2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(1,2-dihydroxyethyl) Pyrimidin-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The first elution peak of the former system on the Chiralcel OD-H column by SFC, rt = 2.91 min) ESI-MSm / z calculated value 491.14795, experimental value 492.0 (M+1) + ;490.1 (M-1) - ;Dwell time: 2.94 minutes 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.50 (s, 1H), 8.99 (s, 2H), 7.19 -7.16 (m, 2H), 5.17 (d, J = 6.0 Hz, 1H), 5.14 (d, J = 10.4 Hz, 1H), 4.59 (dt, J = 12.6, 6.0 Hz, 2H), 4.25 (dd, J = 10.3, 7.7 Hz, 1H), 3.95 (d, J = 2.1 Hz, 3H), 3.71 (dt, J = 11.5, 6.0 Hz, 1H), 3.65 -3.61 (m, 1H), 2.80 -2.75 (m, 1H), 1.62 (s, 3H), 0.74 (d, J = 7.4 Hz, 3H) ppm. 12 rel-(2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(1,2-dihydroxyethyl) Pyrimidin-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The second elution peak of the former system on the Chiralcel OD-H column by SFC, rt = 3.79 min) ESI-MSm / z calculated value 491.14795, experimental value 492.0 (M+1) + ;490.1 (M-1) - ;Dwell time: 2.94 minutes 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.50 (s, 1H), 8.99 (s, 2H), 7.19 -7.14 (m, 2H), 5.17 (br s, 1H), 5.15 (d, J = 10.2 Hz, 1H), 4.61 -4.58 (m , 2H), 4.25 (dd, J = 10.3, 7.6 Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 3.73 -3.70 (m, 1H), 3.65 -3.61 (m, 1H), 2.80 - 2.74 (m, 1H), 1.62 (s, 3H), 0.74 (d, J = 7.4 Hz, 3H) ppm.

[0266] The following compounds were prepared 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 amide coupling step 14, use (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine 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. This compound does not require chiral SFC separation Step 15: Compound number Compound name LC / MS NMR (shift, ppm) 13 (2R,3S,4S,5R)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-3-(3-fluoro-2-methoxyphenyl )-4,5-Dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.40 (s, 1H), 8.63 (d,J= 2.0 Hz, 1H), 7.99 (dd,J= 2.0, 6.8 Hz, 1H), 7.42 (d,J= 6.8 Hz, 1H), 7.24-7.06 (m, 3H), 5.31 (d,J= 4.0 Hz, 1H), 5.08 (d,J= 8.4 Hz, 1H), 4.61 (t,J= 4.8 Hz, 1H), 4.52 (m, 1H), 4.29 (dd,J= 4.8, 8.4 Hz, 1H), 3.86 (s, 3H), 3.60 (m, 1H), 3.43 (m, 1H), 2.76 (qint,J= 6.0 Hz, 1H), 1.59 (s, 3H), 0.71 (d,J= 5.2 Hz, 3H) ppm.

[0267] The following compounds were prepared using the method described in Example 1 except that 6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine-3 was used in amide coupling step 14 -Amines as coupling partners. SFC separation step 15 was not required, and deprotection step 16 was performed at ambient temperature for 3 days using excess HCl in MeOH (37% w / v) as solvent: Compound number Compound name LC / MS NMR (shift, ppm) 14 (2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxyphenyl)-N-(6-(hydroxymethyl)pyridin-3-yl)-4,5- Dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide ESI-MSm / z calculated value 460.14215, experimental value 461.7 (M+1) + ;459.6 (M-1) - ;Dwell time: 3.11 minutes 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.37 (s, 1H), 8.68 (d, J = 2.5 Hz, 1H), 8.03 (dd, J = 8.5, 2.5 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.18 (dd , J = 9.9, 6.5 Hz, 2H), 5.36 (t, J = 5.8 Hz, 1H), 5.10 (d, J = 10.3 Hz, 1H), 4.52 (d, J = 5.8 Hz, 2H), 4.26 (dd , J = 10.3, 7.7 Hz, 1H), 3.97 (d, J = 2.0 Hz, 3H), 2.78 (t, J = 7.5 Hz, 1H), 1.62 (s, 3H), 0.77 -0.73 (m, 3H) ppm.

[0268] The following compounds were prepared using the method described in Example 1 except that (5-aminopyrimidin-2-yl)methyl benzoate was used as the coupling partner in the amide coupling step 14. SFC separation step 15 was not required and deprotection step 16 was performed overnight at ambient temperature using 2 M sodium hydroxide solution (in excess) and 1,4-dioxane as solvent: Compound number Compound name LC / MS NMR (shift, ppm) 15 (2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxyphenyl)-N-(2-(hydroxymethyl)pyrimidin-5-yl)-4,5- Dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide ESI-MSm / z calculated value 461.1374, experimental value 462.6 (M+1) + ;460.5 (M-1) - ;Dwell time: 3.09 minutes 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.47 (s, 1H), 8.98 (s, 2H), 7.20 -7.13 (m, 2H), 5.25 (t, J = 6.3 Hz, 1H), 5.14 (d, J = 10.3 Hz, 1H), 4.55 (d, J = 6.1 Hz, 2H), 4.25 (dd, J = 10.3, 7.5 Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.77 (dq, J = 7.5, 7.5 Hz, 1H) , 1.62 (s, 3H), 0.73 (d, J = 6.2 Hz, 3H) ppm.

[0269] The following compound was prepared using the method described in Example 1, except that 6-(1-((tert-butyldimethylsilyl)oxy)-2-fluoro was used in amide coupling step 14 Ethyl)pyridin-3-amine as coupling partner. On a Prep-100 SFC instrument from Waters, a Chiralpak IB column from Daicel was used, 5 μm particle size, 25 cm × 20 mm (mobile phase: 5% IPA with 20 mM ammonia), 95% CO2. Flow rate: 100 mL / min.) for chiral SFC separation step 15. The conditions used for deprotection step 16 were those described in Example 2, step 3, using THF as solvent instead of 2-MeTHF:

[0270] Compound 16 was analyzed by X-ray Powder Diffraction Analysis Method B and determined to be crystalline (see Figure 4). Compound number Compound name LC / MS NMR (shift, ppm) 16 rel-(2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-(2-fluoro-1-hydroxyethyl )pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The first elution peak of the former system on the Chiralpak IB column by SFC, rt = 0.46 min) ESI-MSm / z calculated value 492.1484, experimental value 493.3 (M+1) + ;491.3 (M-1) - ;Dwell time: 3.28 minutes 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.41 (s, 1H), 8.70 (d, J = 2.4 Hz, 1H), 8.06 (dd, J = 8.6, 2.5 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.23 -7.07 (m, 2H), 5.86 (d, J = 5.2 Hz, 1H), 5.10 (d, J = 10.2 Hz, 1H), 4.81 (dtd, J = 20.5, 5.8, 3.3 Hz, 1H), 4.73 -4.55 ( m, 1H), 4.55 -4.36 (m, 1H), 4.25 (dd, J = 10.3, 7.7 Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.77 (p, J = 7.5 Hz, 1H ), 1.61 (s, 3H), 0.74 (dd, J = 7.4, 2.5 Hz, 3H) ppm. 17 rel-(2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-(2-fluoro-1-hydroxyethyl )pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The second elution peak of the former system on the Chiralpak IB column by SFC, rt = 0.75 min) ESI-MSm / z calculated value 492.1484, experimental value 493.3 (M+1) + ;491.3 (M-1) - ;Dwell time: 3.28 minutes 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.37 (s, 1H), 8.67 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 8.5, 2.5 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.19 -7.05 (m, 2H), 5.82 (s, 1H), 5.05 (d, J = 10.3 Hz, 1H), 4.76 (ddd, J = 20.5, 6.3, 3.2 Hz, 1H), 4.59 (ddd, J = 47.6, 9.4 , 3.3 Hz, 1H), 4.45 (ddd, J = 47.9, 9.3, 6.3 Hz, 1H), 4.20 (dd, J = 10.3, 7.6 Hz, 1H), 3.91 (d, J = 2.0 Hz, 3H), 2.73 (q, J = 7.5 Hz, 1H), 1.56 (s, 3H), 0.69 (dd, J = 7.3, 2.5 Hz, 3H) ppm. Example 2 rel-(2R*, 3S*, 4S*, 5R*)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-(1-hydroxyl-2-methyl Oxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (20), and rel-(2R*,3S*,4S *,5R*)-3-(3,4-Difluoro-2-methoxyphenyl)-N-(6-(1-hydroxy-2-methoxyethyl)pyridin-3-yl)- 4,5-Dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (21) Step 1:

[0271] T3P (1000 µL, 50% w / v, 1.571 mmol) was added to (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 a mixture of 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 SiO2, 0% to 30% EtOAc in hexanes) afforded (2R,3S,4S,5R)-N-(6-(1-( (Tertiary butyldimethylsilyl)oxy)-2-methoxyethyl)pyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4 , A mixture of 2 diastereomers of 5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (211 mg, 92%). ESI-MS m / z calculated 618.2548, found 619.0 (M+1)+; 617.0 (M-1)-; retention time: 4.3 minutes. Step 2:

[0272] On a Minigram SFC instrument from Berger Instruments, by using a Chiralcel OD-H column from Daicel, 5 μm particle size, 25 cm × 10 mm (mobile phase: 15% MeOH (containing 20 mM ammonia), 85% CO2. Flow rate: 10 mL / min.) Separation of (2R,3S,4S,5R)-N-(6-(1-((tert-butyldimethylsilyl)oxy)-2-methyl Oxyethyl)pyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2 -Two diastereomers of formamide (210 mg, 0.3191 mmol):

[0273] The first dissolved isomer (rt = 2.24 min): rel-(2R*, 3S*, 4S*, 5R*)-N-(6-(1-((tertiary butyldimethyl Silyl)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.

[0274] The second dissolved isomer (rt = 3.01 min): rel-(2R*, 3S*, 4S*, 5R*)-N-(6-(1-((tertiary butyldimethyl Silyl)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. Step 3:

[0275] Add TBAF in THF (650 µL, 1 M, 0.6500 mmol) to 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-formamide (80 mg, 0.1293 mmol) (first eluting isomer from SFC separation) in 2-MeTHF (4 mL) in the stirred solution. The reaction was stirred at ambient temperature over weekend (convenient). The reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL), stirred for 10 min and extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by reverse-phase preparative HPLC (Waters Sunfire C18, 10 μM, 100 Å column, 0% to 100% MeCN in water containing 0.1% ammonia) gave rel-(2R*,3S* after lyophilization ,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, 1H), 3.44 (dd, J = 10.1, 7.0 Hz, 1H), 3.24 (s, 3H), 2.78 (q, J = 7.5 Hz, 1H), 1.61 (s, 3H), 0.74 (d, J = 6.7 Hz, 3H) ppm. ESI-MS m / z calculated 504.16837, found 505.0 (M+1)+; 503.0 (M-1)-; retention time: 3.16 minutes.

[0276] Treat rel-(2R*, 3S*, 4S*, 5R*)-N-(6-(1-((tertiary butyldimethylsilyl)oxy)-2-methanol in the same way Oxyethyl)pyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2 -Formamide (80 mg, 0.1293 mmol) (second eluted isomer from SFC separation), after lyophilization to give 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 504.16837, found 505.0 (M+1)+; 503.0 (M-1)-; retention time: 3.16 minutes.

[0277] Compound 21 was analyzed by X-ray Powder Diffraction Analysis Method B and determined to be amorphous (see Figure 5).

[0278] The following compounds were prepared using the method described in Example 2, except that 6-(1-((tert-butyldimethylsilyl)oxy)-3-methanol was used in amide coupling step 1 Oxypropyl)pyridin-3-amine as coupling partner. In step 2, Chiralpak IB column from Daicel, 5 μm particle size, 25 cm × 20 mm (mobile phase: 5% MeOH (containing 20 mM ammonia), 95% CO2. Flow rate: 100 mL / min.) to perform purification: Compound number Compound name LC / MS NMR (shift, ppm) twenty two rel-(2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-(1-hydroxy-3-methoxy Propyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The first elution peak of the former system on the Chiralpak IB column by SFC, rt = 0.37 min) ESI-MSm / z calculated value 518.184, experimental value 519.0 (M+1) + ;517.0 (M-1) - ;Dwell time: 3.20 minutes 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.37 (s, 1H), 8.64 (dd, J = 2.6, 0.7 Hz, 1H), 8.01 (dd, J = 8.5, 2.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.17 (dd, J = 9.0, 6.3 Hz, 2H), 5.32 (d, J = 5.2 Hz, 1H), 5.09 (d, J = 10.4 Hz, 1H), 4.61 (dt, J = 9.0, 4.7 Hz, 1H) , 4.25 (dd, J = 10.3, 7.6 Hz, 1H), 3.95 (d, J = 2.2 Hz, 3H), 3.46 (ddd, J = 9.4, 7.5, 6.7 Hz, 1H), 3.38 -3.33 (m, 1H ), 3.20 (s, 3H), 2.77 (p, J = 7.5 Hz, 1H), 1.96 (dtd, J = 14.4, 7.4, 4.3 Hz, 1H), 1.73 (dddd, J = 13.6, 8.6, 6.7, 5.1 Hz, 1H), 1.61 (s, 3H), 0.77 -0.70 (m, 3H) ppm. twenty three rel-(2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-(1-hydroxy-3-methoxy Propyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The second elution peak of the former system on the Chiralpak IB column by SFC, rt = 0.75 min) ESI-MSm / z calculated value 518.184, experimental value 519.0 (M+1) + ;517.0 (M-1) - ;Dwell time: 3.20 minutes 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.36 (s, 1H), 8.67 (dd, J = 2.6, 0.7 Hz, 1H), 7.99 (dd, J = 8.5, 2.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.22 -7.13 (m, 2H), 5.32 (d, J = 5.2 Hz, 1H), 5.09 (d, J = 10.3 Hz, 1H), 4.61 (dt, J = 9.0, 4.7 Hz, 1H), 4.25 (dd, J = 10.3, 7.6 Hz, 1H), 3.95 (d, J = 2.2 Hz, 3H), 3.46 (dt, J = 9.4, 7.2 Hz, 1H), 3.39 -3.32 (m, 1H), 3.21 (s, 3H ), 2.77 (p, J = 7.5 Hz, 1H), 1.96 (dtd, J = 14.2, 7.4, 4.2 Hz, 1H), 1.80 -1.67 (m, 1H), 1.61 (s, 3H), 0.77 -0.70 ( m, 3H) ppm. Example 3 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-formamide (24), and rel-(2S,3R,5S)-3-(3,4- Difluoro-2-methoxyphenyl)-N-(6-((R*)-1,2-dihydroxyethyl)pyridin-3-yl)-5-methyl-5-(trifluoromethyl base) tetrahydrofuran-2-formamide (25) step 1:

[0279] Triethylamine (8.05 g, 11.2 mL, 78.8 mmol) was added to ethyl 2-diazo-3-oxobutanoate (5.0 g, 31.4 mmol) in DCM (50 mL) in a stirred solution. 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% NaHCO3 solution (200 mL). The organic layer was separated, washed with water (500 mL), dried (MgSO 4 ), filtered and concentrated in vacuo to give 3-((t-butyldimethylsilyl)oxy)-2-diazobutan-3 - Ethyl enoate (8.22 g, 97%), which was used in the next step without further purification. Step 2:

[0280] 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. TiCl4 (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 min, after which ethyl 3-((tert-butyldimethylsilyl)oxy)-2-diazobut-3-enoate (64 g , 236.7 mmol) in DCM (150 mL). The reaction was maintained at -78 °C for 1 h. A saturated solution of NaHCO3 was added, and the mixture was diluted with DCM. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. Purification by silica gel chromatography (SiO2, 0% to 30% EtOAc in hexanes) afforded 2-diazo-6,6,6-trifluoro-5-hydroxy-5- Ethyl methyl-3-oxohexanoate (39 g, 61%). 1H NMR (400 MHz, chloroform-d) δ 4.92 (s, 1H), 4.32 (q, J = 7.1 Hz, 2H), 3.63 (d, J = 15.5 Hz, 1H), 2.84 (d, J = 15.5 Hz , 1H), 1.41 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H) ppm. Step 3:

[0281] Charge rhodium(II) acetate (643 mg, 1.45 mmol) into an oven-dried two-necked flask. Toluene (970 mL) was added, and the solution was stirred at 100 °C for 10 min. The solution was briefly withdrawn from the oil bath while ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-5-methyl-3-oxohexanoate (39 g, 145.4 mmol) in toluene (200 mL). The reaction mixture was heated at reflux for 1 h. 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%) which It is in the form of a mixture of epimers at the position adjacent to the ester. 1H NMR (400 MHz, chloroform-d) δ 4.68 (s, 1H), 4.35 -4.17 (m, 2H), 2.89 (d, J = 18.8, 1H), 2.58 (d, J = 18.8, 1H), 1.70 (s, 3H), 1.30 (t, J = 7.2, Hz, 3H) ppm. Step 4:

[0282] Trifluoromethanesulfonic anhydride (6.0 mL, 35.7 mmol) was added dropwise to ethyl 5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate at -78°C In a solution of the base ester (6.5 g, 27.1 mmol) and DIPEA (14 mL, 80.4 mmol) in DCM (150 mL). The reaction mixture was stirred for 2.5 h, after which saturated aqueous NH 4 Cl (75 mL) was added. The mixture was allowed to warm to ambient temperature. The aqueous layer was extracted with DCM (2 x 30 mL). The combined organic extracts were dried (MgSO 4 ), filtered and concentrated in vacuo to afford 5-methyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy )-Ethyl 4,5-dihydrofuran-2-carboxylate (10.1 g), which was used directly in the next reaction. Step 5:

[0283] K3PO4 (13 mL, 2 M in water, 26.0 mmol) was added to (3,4-difluoro-2-methoxyphenyl)boronic acid (2.0 g, 10.6 mmol) and 5-methyl-5- (Trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylic acid ethyl ester (3 g, 7.90 mmol) in toluene (80 mL) in a stirred solution. The mixture was degassed by bubbling nitrogen through the solution for 20 min. Pd(PPh3)4 (466 mg, 0.40 mmol) was added, and the reaction was heated to 100 °C for 1 h. The mixture was filtered through a pad of celite. The filtrate was diluted with water (50 mL), and the phases were separated. The aqueous layer was extracted with EtOAc (50 x 2 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by silica gel chromatography (SiO2, 0% to 2% EtOAc in hexanes) afforded 3-(3,4-difluoro-2-methoxyphenyl)-5- Ethyl methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (2.5 g, 85%). 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 366.08905, found 367.4 (M+1)+; retention time: 1.01 minutes. Step 6:

[0284] EtOH (200 mL) was added to 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)-4,5-dihydro In a mixture of ethyl furan-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 H2 balloon for 96 h. The catalyst was removed by filtration, and the solid was washed with EtOH (50 mL). The filtrate was concentrated in vacuo. Another 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 under a balloon of H2 for 24 h. The catalyst was removed by filtration, and the solid was washed with EtOH (50 mL). The filtrate was concentrated in vacuo. To the residue was added another portion of Pd / C (10 wt.% loading, 2.2 g, 2.07 mmol), followed by EtOH (200 mL), and the reaction mixture was stirred at ambient temperature under a balloon of H2 for 4 days. The catalyst was removed by filtration, and the solid was washed with EtOH (50 mL). The filtrate was concentrated in vacuo to afford rac-(2S,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl) Ethyl tetrahydrofuran-2-carboxylate (5.19 g, 94%) as a white solid in the form of 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; 19F NMR (471 MHz, chloroform-d) δ -80.15, -136.84 (d, J = 19.4 Hz), -154.77 ( d, J = 19.6 Hz) ppm. Step 7:

[0285] rac-(2S,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2- Ethyl formate (5.19 g, 14.09 mmol) was dissolved in ethanol (100 mL). Cs2CO3 (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 (MgSO4), filtered and concentrated in vacuo to afford rac-(2R,3S,5R)-3-(3,4-difluoro-2-methoxy as a colorless oil phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (5.1063 g, 96%). 1H NMR (500 MHz, chloroform-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; 19F NMR (471 MHz, chloroform-d) δ -81.56, -136.40 (d, J = 19.6 Hz), -153.60 (d, J = 19.5 Hz) ppm. ESI-MS m / z calc. 340.0734, found 339.5 (M-1)-; retention time: 0.52 minutes. Step 8:

[0286] Carefully add oxalyl chloride (70 µL, 0.8024 mmol) to rac-(2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methanol Base-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (150 mg, 0.3968 mmol) and DMF (2-methyl-THF solution, 50 µL, 0.86 M, 0.04300 mmol) in 2-methyltetrahydrofuran (5 mL) in ice-cooled solution. The reaction mixture was stirred and warmed to room temperature over 45 min. The reaction mixture was concentrated in vacuo, and the residue was dissolved in 2-methyltetrahydrofuran (5 mL). This solution was added to (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 an ice-cooled solution in 2-methyltetrahydrofuran (5 mL). The resulting mixture was stirred and warmed to ambient temperature over 1 h. The reaction mixture was quenched with water (2 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (2 x 5 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by silica gel chromatography (24 g SiO2, 0% to 100% EtOAc in heptane, loaded with DCM) gave rel-(2R,3S,5R)-3-(3,4-difluoro-2 -Methoxyphenyl)-N-(6-((R*)-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)- 5-Methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (120.4 mg, 59%) as a white solid as a mixture of 2 diastereomers. 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, 6.7, 1.2 Hz, 1H), 2.46 (d, J = 10.5 Hz, 2H), 1.57 (s , 3H), 1.43 (s, 3H), 1.40 (s, 3H) ppm; 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 516.16833, found 517.5 (M+1)+; 515.6 (M-1)-; retention time: 0.99 minutes. Step 9:

[0287] On a Prep-100 SFC instrument from Waters, by chiral SFC using a Chiralpak IA column from Daicel, 5 μm particle size, 25 cm × 20 mm (mobile phase: 15% MeOH (containing 20 mM ammonia ), 85% CO2. Flow: 100 mL / min.) Separation 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- Two diastereomers of 2-formamide:

[0288] The first eluting isomer (rt=0.73 min): rel-(2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6 -((R*)-2,2-Dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-5-methyl-5-(trifluoromethyl) Tetrahydrofuran-2-carboxamide (42 mg, 60%) as a white solid. ESI-MS m / z calculated 516.16833, found 517.2 (M+1)+; 515.3 (M-1)-; retention time: 3.41 minutes.

[0289] The second eluting isomer (rt=0.95 min): rel-(2S,3R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6 -((R*)-(2,2-Dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-5-methyl-5-(trifluoromethyl ) Tetrahydrofuran-2-carboxamide (51 mg, 73%) as a white solid. ESI-MS m / z calcd. 516.16833, found 517.2 (M+1)+; 515.3 (M-1)-; retention time : 3.41 minutes.Step 10:

[0290] TFA (225 µL, 2.920 mmol) was added to 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-Formamide (42 mg, 0.081 mmol) (first eluting isomer from SFC separation) was in solution 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. Purified by reverse phase preparative HPLC (Waters Sunfire C18, 10 μM, 100 Å column, 0% to 100% MeCN in water containing 0.1% ammonia). 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-formamide (24, 24.6 mg, 62%).1H 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 476.13705, found 474.4 (M+1)+; 475.5 (M-1)-;

[0291] Treat 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-formamide (51 mg, 0.099 mmol) (second eluted isomer from SFC separation), 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 -Formamide (25, 32.0 mg, 66%).1H NMR (500 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.65 (d, J = 2.5 Hz, 1H), 7.96 (dd, J = 8.5, 2.5 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- ( M-1)-; residence time: 2.77 minutes.

[0292] The following compounds were prepared using the method described in Example 3, except that (S)-6-(2,2-dimethyl-1,3-dioxolane was used in amide coupling step 8 Alk-4-yl)pyridin-3-amine instead of (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine. In step 9, purification was performed by chiral SFC on a Prep-100 SFC instrument from Waters using a Chiralpak IA column from Daicel Corporation, 5 μm particle size, 25 cm x 20 mm: Compound number Compound name LC / MS NMR (shift, ppm) 26 rel-(2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((S*)-1,2-dihydroxyethyl)pyridine -3-yl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The first elution peak of the former system on the Chiralpak IA column by SFC, rt = 0.70 min) ESI-MSm / z calculated value 476.13705, experimental value 477.4 (M+1) + ;475.5 (M-1) - ;Dwell time: 2.78 minutes 1 H NMR (500 MHz, DMSO-d 6) δ 10.08 (s, 1H), 8.65 (d, J = 2.3 Hz, 1H), 7.96 (dd, J = 8.5, 2.5 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.21 -7.15 (m, 2H), 5.32 (d, J = 4.9 Hz, 1H), 4.66 -4.62 (m, 2H), 4.54 (dt, J = 6.7, 4.5 Hz, 1H), 4.08 -4.02 (m, 1H), 3.87 (d, J = 1.8 Hz, 3H), 3.64 (ddd, J = 10.5, 6.0, 4.4 Hz, 1H), 3.48 -3.43 (m, 1H), 2.47 (s, 1H), 2.45 (s, 1H) , 1.57 (s, 3H) ppm. 27 rel-(2S,3R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((S*)-1,2-dihydroxyethyl)pyridine -3-yl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The second elution peak of the former system on the Chiralpak IA column by SFC, rt = 0.87 min) ESI-MSm / z calculated value 476.13705, experimental value 477.3 (M+1) + ;475.5 (M-1) - ;Dwell time: 2.78 minutes 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.09 (s, 1H), 8.64 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 8.5, 2.5 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.22 -7.15 (m, 2H), 5.32 (d, J = 4.9 Hz, 1H), 4.66 -4.62 (m, 2H), 4.54 (dt, J = 6.7, 4.5 Hz, 1H), 4.05 (q, J = 10.1 Hz, 1H), 3.88 (d, J = 1.9 Hz, 3H), 3.63 (ddd, J = 10.4, 6.0, 4.2 Hz, 1H), 3.45 (ddd, J = 11.0, 6.9, 5.8 Hz, 1H), 2.47 (s , 1H), 2.45 (s, 1H), 1.57 (s, 3H) ppm.

[0293] The following compounds were prepared using the method described in Example 3, except that rac-2-(2,2-dimethyl-1,3-dioxolane- 4-yl)pyrimidin-5-amine instead of (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine. In Suzuki coupling step 5, Pd(PPh3)4 was used as catalyst and Na2CO3 as base and a mixture of toluene, water and methanol as solvent, and the reaction was carried out at 80 °C for 16 h. In step 9, Chiralcel OJ column from Daicel Corporation, 5 μm particle size, 25 cm × 21.2 mm (40°C; mobile phase: 6% MeOH (20 mM NH3), 94% CO2; flow: 70 mL / min.) for rel-(2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N -Mixture of four stereoisomers of (2-(1,2-dihydroxyethyl)pyrimidin-5-yl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide , the mixture has a known relative stereochemistry for the THF ring (ie (2R,3S,5R)), but an unknown relative stereochemistry between the THF ring and the dihydroxyethyl substituent: Compound number Compound name LC / MS NMR (shift, ppm) 28 rel-(2S,3R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(1,2-dihydroxyethyl)pyrimidin-5-yl) -5-Methyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The first elution peak of the former system on the Chiralcel OJ column by SFC, rt = 4.75 min) ESI-MSm / z calculated value 477.13232, experimental value 478.0 (M+1) + ;476.0 (M-1) - ;Dwell time: 2.78 minutes 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.25 (s, 1H), 8.96 (s, 2H), 7.23 -7.15 (m, 2H), 5.17 (d, J = 6.0 Hz, 1H), 4.68 (d, J = 10.1 Hz, 1H), 4.60 (dt, J = 10.2, 5.9 Hz, 2H), 4.04 (q, J = 10.3 Hz, 1H), 3.88 (d, J = 2.0 Hz, 3H), 3.72 (dt, J = 11.6, 6.0 Hz, 1H) , 3.64 (dt, J = 11.2, 6.0 Hz, 1H), 1.58 (s, 3H) ppm. 2 protons are hidden by the DMSO signal. 29 rel-(2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(1,2-dihydroxyethyl)pyrimidin-5-yl) -5-Methyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The second elution peak of the former system on the Chiralcel OJ column by SFC, rt = 5.42 min) ESI-MSm / z calculated value 477.13232, experimental value 478.0 (M+1) + ;476.0 (M-1) - ;Dwell time: 2.78 minutes 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.25 (s, 1H), 8.96 (s, 2H), 7.23 -7.15 (m, 2H), 5.17 (d, J = 6.0 Hz, 1H), 4.68 (d, J = 10.2 Hz, 1H), 4.60 (dt, J = 11.4, 5.9 Hz, 2H), 4.04 (q, J = 10.1 Hz, 1H), 3.89 (d, J = 2.0 Hz, 3H), 3.72 (dt, J = 11.5, 6.0 Hz, 1H) , 3.64 (dt, J = 11.0, 5.9 Hz, 1H), 1.58 (s, 3H) ppm. 2 protons are hidden by the DMSO signal. 30 rel-(2S,3R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(1,2-dihydroxyethyl)pyrimidin-5-yl) -5-Methyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The third elution peak of the former system on the Chiralcel OJ column by SFC, rt = 10.45 min) ESI-MSm / z calculated value 477.13232, experimental value 477.8 (M+1) + ;476.0 (M-1) - ;Dwell time: 2.78 minutes 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.25 (s, 1H), 8.96 (s, 2H), 7.23-7.15 (m, 2H), 5.17 (d, J = 6.0 Hz, 1H), 4.68 (d, J = 10.1 Hz, 1H), 4.62 -4.57 (m, 2H), 4.04 (q, J = 11.0, 10.5 Hz, 1H), 3.88 (d, J = 1.9 Hz, 3H), 3.72 (dt, J = 11.5, 6.0 Hz, 1H), 3.64 ( dt, J = 11.1, 6.0 Hz, 1H), 1.58 (s, 3H) ppm. 2 protons are hidden by the DMSO signal. 31 rel-(2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(1,2-dihydroxyethyl)pyrimidin-5-yl) -5-Methyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The fourth elution peak of the former system by SFC on the Chiralcel OJ column, rt = 12.17 min) ESI-MSm / z calculated value 477.13232, experimental value 478.0 (M+1) + ;476.0 (M-1) - ;Dwell time: 2.78 minutes 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.25 (s, 1H), 8.96 (s, 2H), 7.23 -7.15 (m, 2H), 5.17 (d, J = 6.0 Hz, 1H), 4.68 (d, J = 10.1 Hz, 1H), 4.62 -4.57 (m, 2H), 4.04 (q, J = 10.2 Hz, 1H), 3.88 (d, J = 1.9 Hz, 3H), 3.72 (dt, J = 11.5, 5.9 Hz, 1H), 3.64 (dt, J = 11.0, 5.9 Hz, 1H), 1.58 (s, 3H) ppm. 2 protons are hidden by the DMSO signal.

[0294] The following compounds were prepared using the method described in Example 3, except that 2-(2-ethoxy-3,4-difluoro-phenyl)-4,4,5 was used in Suzuki coupling step 5 ,5-Tetramethyl-1,3,2-dioxaborolane instead of (3,4-difluoro-2-methoxyphenyl)boronic acid. In the case of compounds 32 and 33, (S)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine-3 was used in amide coupling step 8 -amine instead of (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine. In Suzuki coupling step 5, Pd(PPh3)4 was used as catalyst and Na2CO3 as base and a mixture of toluene, water and methanol as solvent, and the reaction was carried out at 80 °C for 16 h. In step 9, a (R,R)-Whelk-O1 column from Daicel, 5 um particle size, 25 cm × 21.1 mm was used by chiral SFC on a Minigram SFC instrument from Berger Instruments (mobile phase: 30% MeOH (with 20 mM ammonia), 70% CO2. Flow: 100 mL / min.) for purification. Deprotection step 10 was performed at ambient temperature over 1.5 h using 12 M HCl in THF as solvent: Compound number Compound name LC / MS NMR (shift, ppm) 32 rel-(2S,3R,5S)-N-(6-((S*)-1,2-dihydroxyethyl)pyridin-3-yl)-3-(2-ethoxy-3,4- Difluorophenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The first elution peak of the former system on the (R,R)-Whelk-O1 column by SFC, rt = 3.62 min) ESI-MSm / z calculated value 490.1527, experimental value 491.4 (M+1) + ;489.5 (M-1) - ;Dwell time: 2.93 minutes 33 rel-(2R,3S,5R)-N-(6-((S*)-1,2-dihydroxyethyl)pyridin-3-yl)-3-(2-ethoxy-3,4- Difluorophenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The second elution peak of the former system on the (R,R)-Whelk-O1 column by SFC, rt = 4.18 min) ESI-MSm / z calculated value 490.1527, experimental value 491.4 (M+1) + ;489.5 (M-1) - ;Dwell time: 2.92 minutes 34 rel-(2S,3R,5S)-N-(6-((R*)-1,2-dihydroxyethyl)pyridin-3-yl)-3-(2-ethoxy-3,4- Difluorophenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The first elution peak of the former system on the (R,R)-Whelk-O1 column by SFC, rt = 3.62 min) ESI-MSm / z calculated value 490.1527, experimental value 491.4 (M+1) + ;489.5 (M-1) - ;Dwell time: 2.93 minutes 35 rel-(2R,3S,5R)-N-(6-((R*)-1,2-dihydroxyethyl)pyridin-3-yl)-3-(2-ethoxy-3,4- Difluorophenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The second elution peak of the former system on the (R,R)-Whelk-O1 column by SFC, rt = 4.18 min) ESI-MSm / z calculated value 490.1527, experimental value 491.4 (M+1) + ;489.5 (M-1) - ;Dwell time: 2.92 minutes

[0295] Compound 35 was analyzed by X-ray Powder Diffraction Analysis Method B and determined to be amorphous (see Figure 6). Example 4 (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-N-(6-((R)-1,2-dihydroxyethyl)pyridine- 3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (36), and (2R,3S,4S,5R)-3-(3,4- Difluoro-2-(2-fluoroethoxy)phenyl)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl -5-(Trifluoromethyl)tetrahydrofuran-2-formamide (37) step 1:

[0296] (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((R)-1,2-dihydroxyethyl (1,343.7 mg, 0.7008 mmol) in DCM (9 mL) was stirred The solution was placed under a nitrogen atmosphere and cooled with an ice bath. Boron tribromide in DCM (2.2 mL, 1 M, 2.200 mmol) was added, and the reaction mixture was stirred for 2 h. The reaction was quenched by the addition of MeOH (2 mL), and stirred overnight at ambient temperature. 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. (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 calculated 476.13705, found 477.3 (M+1)+; retention time: 2.46 minutes. Step 2:

[0297] Add K2CO3 (18 mg, 0.1302 mmol) to 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) In a mixture of tetrahydrofuran-2-carboxamide (36, 40 mg, 0.08396 mmol) in DMF (2 mL). The mixture was stirred at 60 °C for 6h30. 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 containing 0.1% ammonia) to give (2R,3S,4S ,5R)-3-(3,4-difluoro-2-(2-fluoroethoxy)phenyl)-N-(6-((R)-1,2-dihydroxyethyl)pyridine-3 -yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (37, 18.48 mg, 41%). 1H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.64 (dd, J = 2.5, 0.8 Hz, 1H), 8.00 (dd, J = 8.5, 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 calc. 522.15894, found 523.3 (M+1)+; retention time: 3.0 minutes.

[0298] The following compounds were prepared using the method described in Example 4, except that 2-bromo-1,1-difluoroethane was used instead of 1-fluoro-2-iodoethane in the alkylation step 2: Compound number Compound name LC / MS NMR (shift, ppm) 38 (2R,3S,4S,5R)-3-(2-(2,2-Difluoroethoxy)-3,4-difluorophenyl)-N-(6-((R)-1,2 -Dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide ESI-MSm / z calculated value 540.14954, experimental value 541.2 (M+1) + ;539.1 (M-1) - ;Dwell time: 3.07 minutes 1 H NMR (500 MHz, DMSO-d 6) δ 10.35 (s, 1H), 8.64 (dd, J = 2.5, 0.8 Hz, 1H), 8.00 (dd, J = 8.6, 2.5 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.32 -6.98 (m, 2H), 6.39 (tt, J = 53.9, 2.9 Hz, 1H), 5.32 (d, J = 4.9 Hz, 1H), 5.11 (d, J = 10.6 Hz, 1H), 4.63 (t, J = 5.9 Hz, 1H), 4.58 -4.34 (m, 3H), 4.29 (dd, J = 10.6, 7.3 Hz, 1H), 3.63 (ddd, J = 10.6, 6.1, 4.2 Hz, 1H), 3.44 (ddd , J = 11.0, 6.9, 5.8 Hz, 1H), 2.78 (p, J = 7.4 Hz, 1H), 1.59 (s, 3H), 0.73 (d, J = 7.3 Hz, 3H) ppm.

[0299] The following compounds were prepared 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) as starting material: Compound number Compound name LC / MS NMR (shift, ppm) 39 (2R,3S,4S,5R)-3-(3,4-Difluoro-2-hydroxyphenyl)-N-(2-(hydroxymethyl)pyrimidin-5-yl)-4,5-dimethyl Amyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide ESI-MSm / z calculated value 447.12173, experimental value 448.6 (M+1) + ;446.5 (M-1) - ;Dwell time: 2.46 minutes 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.53 (s, 1H), 10.40 (s, 1H), 8.99 (s, 2H), 7.05 (ddd, J = 8.3, 5.7, 1.9 Hz, 1H), 6.87 -6.78 (m, 1H), 5.26 ( t, J = 6.5 Hz, 1H), 5.15 (d, J = 10.3 Hz, 1H), 4.56 (d, J = 5.4 Hz, 2H), 4.25 (dd, J = 10.3, 7.6 Hz, 1H), 2.84 ( t, J = 7.5 Hz, 1H), 1.61 (s, 3H), 0.77 -0.65 (m, 3H) ppm. Example 5 rel-(2R,3S,4S,5R)-N-(6-((R*)-1,2-dihydroxyethyl)pyridin-3-yl)-3-(2-ethoxy- 4-fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (40), and rel-(2S,3R,4R,5S )-N-(6-((R*)-1,2-dihydroxyethyl)pyridin-3-yl)-3-(2-ethoxy-4-fluoro-3-methylphenyl)- 4,5-Dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (41) Step 1:

[0300] Add rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)-3-(((trifluoromethyl) Methyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylic acid ethyl ester (39.05 g, 101.1 mmol), (4-fluoro-2-methoxy-3-methylphenyl ) a mixture of boronic acid (20.4 g, 110.9 mmol) and PdCl2(PPh3)2 (1.4 g, 1.995 mmol) in a saturated solution of NaHCO3 (120 mL) and dioxane (400 mL). The orange mixture was heated internally to 50 °C for 20 min. 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 x 100 mL). The combined organic extracts were washed with brine (1 x 50 mL), dried (MgSO4), filtered and concentrated in vacuo to a volume of approximately 100 mL. Charcoal (10 g) was added, and the mixture was stirred for 2 h. The mixture was filtered, and the residual filter cake was further washed with EtOAc. The filtrate was collected and concentrated in vacuo to give 50 g of crude product. Purification by flash chromatography (330 g SiO2, 0% to 30% EtOAc in heptane) afforded rac-(4S,5R)-3-(4-fluoro-2-methoxyl as a pale yellow oil Ethyl-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (27.348 g, 72%). 1H 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, J = 2.1 Hz, 3H), 1.7 (s, 3H), 1.12 (t, J = 7.1 Hz, 3H), 1.06 (dq, J = 7.2, 2.3 Hz, 3H ) ppm. ESI-MS m / z calc. 376.12976, found 377.5 (M+1)+; retention time: 1.09 minutes. Step 2:

[0301] Add rac-(4S,5R)-3-(4-fluoro-2-methoxy-3-methylphenyl)-4,5-dimethyl to a 1 L three-necked flask equipped with a thermometer Ethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (27.35 g, 72.67 mmol) followed by the addition of DCM (200 mL). The reaction mixture was cooled to 5°C using an ice bath. Boron tribromide (112 mL, 1 M solution in DCM, 112.0 mmol) was added via cannula over 30 min, keeping the internal temperature around 5 °C. The reaction mixture was stirred for 1 h. The mixture was quenched by the slow addition of water (100 mL), which caused effervescence, and saturated sodium bicarbonate solution (100 mL). The mixture was stirred for 30 min. The aqueous phase was collected and washed with DCM (3 x 50 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution (5 x 100 mL), dried (MgSO4), 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 overnight at ambient temperature. The mixture was filtered through a pad of celite. The filtrate was collected, dried (MgSO4), filtered and concentrated in vacuo to give rac-(1S,2R)-7-fluoro-1,2,6-trimethyl-2-(trifluoromethyl) as a waxy solid )-1,2-dihydro-4H-furo[2,3-c]alken-4-one and rac-(4S,5R)-3-(4-fluoro-2-hydroxy-3-methyl Phenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylic acid ethyl ester about 1:1 mixture (27.7 g).

[0302] 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 overnight at ambient temperature. The mixture was filtered through a plug of celite, washing with EtOAc (3 x 100 mL). The filtrate was concentrated in vacuo to give a waxy solid. Purification by flash chromatography (120 g SiO2, 50% EtOAc in heptane) afforded rac-(1S,2R)-7-fluoro-1,2,6-trimethyl-2-(trifluoromethane yl)-1,2-dihydro-4H-furo[2,3-c]𠳭en-4-one (24.18 g, 100%). 1H NMR (500 MHz, chloroform-d) δ 7.25 -7.23 (m, 1H), 7.05 (t, J = 8.7 Hz, 1H), 3.65 (q, J = 7.4 Hz, 1H), 2.39 (d, J = 2.0 Hz, 3H), 1.67 (q, J = 1.0 Hz, 3H), 1.58 (t, J = 2.2 Hz, 3H) ppm. ESI-MS m / z calc. 316.07227, found 317.4 (M+1)+; 315.4 (M-1)-; retention time: 0.94 min. Step 3:

[0303] rac-(1S,2R)-7-fluoro-1,2,6-trimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3 -c] 𠳭en-4-one (1.5 g, 3.273 mmol) was dissolved in EtOAc (20 mL) and stirred with activated charcoal (300 mg, 24.98 mmol) for 18 h. The mixture was filtered through a pad of celite. The liquid was concentrated in vacuo to give a yellow solid. This solid was dissolved in methanol (20 mL) and added to a 100 mL flask containing dihydroxypalladium (460 mg, 20% w / w, 0.6551 mmol). The resulting mixture was stirred under hydrogen atmosphere for 120 h. The mixture was filtered through a plug of Celite, 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, 20% w / w, 0.3276 mmol). The resulting mixture was stirred under a balloon of hydrogen for 12 h. The reaction mixture was filtered through a plug of celite, washing with MeOH. The filtrate was concentrated in vacuo to afford 3-(4-fluoro-2-hydroxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2 as an off-white solid -Isomer mixture of methyl formate (939.3 mg, 82%), in which rac-(2S,3S,4S,5R)-3-(4-fluoro-2-hydroxyl-3-methylphenyl)- Methyl 4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate is 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; alcoholic OH was not observed. ESI-MS m / z calc. 350.11414, found 349.0 (M-1)-; retention time: 0.95 minutes. Step 4:

[0304] Potassium tert-butoxide (11.40 g, 101.6 mmol) was added to 3-(4-fluoro-2-hydroxy-3-methylphenyl)-4,5-dimethyl-5 at 0°C -Isomer mixture of methyl (trifluoromethyl)tetrahydrofuran-2-carboxylate (8.896 g, 25.39 mmol, where rac-(2S,3S,4S,5R)-3-(4-fluoro-2-hydroxy -3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid methyl ester as the major isomer) in tetrahydrofuran (125 mL) in a stirred solution . 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 x 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 x 50 mL) and the organic extracts were dried (MgSO 4 ), filtered and concentrated in vacuo to give 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)- A mixture of 3-(4-fluoro-2-hydroxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (9.753 g, 100%), It was used as such in the next step. ESI-MS m / z calc. 336.09848, found 335.5 (M-1)-; retention time: 0.56 min. Step 5:

[0305] K2CO3 (1.65 g, 11.94 mmol) and iodoethane (1 mL, 12.50 mmol) were added to 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 -A mixture of 2-hydroxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1 g, 2.974 mmol) in acetonitrile (10 mL) in the solution. The vial was sealed and heated to 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 rac-(2R,3S,4S,5R)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl- 5-(Trifluoromethyl)tetrahydrofuran-2-carboxylic acid ethyl ester and rac-(2S,3S,4S,5R)-3-(2-ethoxy-4-fluoro-3-methylphenyl)- Mixture of ethyl 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. Step 6:

[0306] LiOH (3.3 mL, 2 M, 6.600 mmol) was added to rac-(2R,3S,4S,5R)-3-(2-ethoxy-4-fluoro-3-methylphenyl)- 4,5-Dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid ethyl ester and rac-(2S,3S,4S,5R)-3-(2-ethoxy-4-fluoro- A mixture of ethyl 3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1 g, 2.549 mmol) in methanol (15 mL) and water ( 4 mL) in a stirred solution. The mixture was stirred at ambient temperature for 18 h. The MeOH was removed in vacuo and diluted to pH 1 with 1 M HCl. The mixture was extracted with DCM (2 x 10 mL). The combined organic extracts were dried by passing through a phase separation cartridge and concentrated in vacuo to afford rac-(2R,3S,4S,5R)-3-(2-ethoxy-4-fluoro-3-methylbenzene base)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid and rac-(2S,3S,4S,5R)-3-(2-ethoxy-4-fluoro- A mixture of 3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (778.9 mg, 84%). ESI-MS m / z calc. 364.12976, found 363.6 (M-1)-; retention time: 0.62 min. Step 7:

[0307] DMF (2.5 µL, 0.0323 mmol) and oxalyl chloride (27.5 µL, 0.315 mmol) were added to 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-( A mixture of 2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (76 mg, 0.209 mmol) in DCM (2 mL) in solution. After the addition was complete, the mixture was stirred at ambient temperature for 2 h. The reaction mixture was concentrated in vacuo. The residue was taken up in 2-MeTHF (2 mL) and added dropwise to (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine -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 (SiO2, 0% to 100% EtOAc in heptane) afforded the following mixture of isomers:

[0308] The first eluting isomer: rel-(2R,3S,4S,5R)-N-(6-((R*)-2,2-dimethyl-1,3-dioxane Pentane-4-yl)pyridin-3-yl)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl ) Tetrahydrofuran-2-formamide and rel-(2S,3R,4R,5S)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolane -4-yl)pyridin-3-yl)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran - Mixture of 2-formamide (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 540.22473, found 541.2 (M+1)+; 539.3 (M-1)-; retention time: 1.09 minutes.

[0309] The second eluting isomer: rel-(2S, 3S, 4S, 5R)-N-(6-((R*)-2,2-dimethyl-1,3-dioxane Pentane-4-yl)pyridin-3-yl)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl ) Tetrahydrofuran-2-formamide and rel-(2R,3R,4R,5S)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolane -4-yl)pyridin-3-yl)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran - Mixture of 2-formamide (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 = 1.1 Hz, 4H), 1.50 (s, 3H), 1.48 (d, J = 0.7 Hz, 3H), 1.44 (t, J = 7.0 Hz, 3H), 0.88 -0.82 (m, 3H) ppm. ESI-MS m / z calculated 540.22473, found 541.2 (M+1)+; 539.3 (M-1)-; retention time: 1.06 minutes. The isomers were not separated by chiral SFC. Step 8:

[0310] On the Minigram SFC instrument from Berger Instruments, by chiral SFC using a Luxi-Cellulose-5 column from Phenomenex, Inc., 5 um particle size, 25 cm × 20 mm (mobile phase: 15% MeOH (with 20 mM ammonia), 85% CO2. Flow rate: 100 mL / min.) Separation of rel-(2R,3S,4S,5R)-N-(6-((R*)-2,2-dimethyl Base-1,3-dioxolan-4-yl)pyridin-3-yl)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-di Methyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide 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 - Mixture of 5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (23 mg, 0.042 mmol) (first eluted isomer from step 7) to give:

[0311] The first eluted isomer (rt = 3.41 min): rel-(2R,3S,4S,5R)-N-(6-((R*)-2,2-dimethyl-1, 3-dioxolan-4-yl)pyridin-3-yl)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-5 -(trifluoromethyl)tetrahydrofuran-2-carboxamide (10 mg, 87%). ESI-MS m / z calculated 540.22473, found 541.2 (M+1)+; 539.3 (M-1)-; retention time: 3.73 minutes.

[0312] The second eluted isomer (rt = 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. Step 9:

[0313] TFA (10 µL, 0.130 mmol) was added to rel-(2R,3S,4S,5R)-N-(6-((R*)-2,2-dimethyl-1,3-di Oxolane-4-yl)pyridin-3-yl)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-5-(tri Fluoromethyl)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 h and at 40 °C for a further 16 h. The mixture was concentrated in vacuo. Purified by reverse-phase HPLC-MS using an X-bridge C18 OBD column (150 × 19 mm, 5 mm particle size) from Waters to obtain 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 were not observed. ESI-MS m / z calc. 500.19342, found 501.2 (M+1)+; 499.2 (M-1)-; retention time: 3.17 minutes.

[0314] Treat rel-(2S,3R,4R,5S)-N-(6-((R*)-2,2-dimethyl-1,3-dioxolane-4 in the same manner -yl)pyridin-3-yl)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2 -Formamide (9 mg, 0.01665 mmol) (second eluted isomer from SFC separation) 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-(trifluoromethane base) 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 were not observed. ESI-MS m / z calc. 500.19342, found 501.3 (M+1)+; 499.3 (M-1)-; retention time: 3.19 minutes.

[0315] The following compounds were prepared using the method described in Example 5, except that (S)-6-(2,2-dimethyl-1,3-dioxolane-4 was used in Step 7 -yl)pyridin-3-amine instead of (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine. In step 8, on a Prep-100 SFC instrument from Waters, by chiral SFC using a Luxi-Cellulose-5 column from Daicel Corporation, 5 mm particle size, 25 cm × 20 mm (mobile phase: 15 % MeOH (with 20 mM ammonia), 85% CO2. Flow: 100 mL / min.) Purification was performed: Compound number Compound name LC / MS NMR (shift, ppm) 42 rel-(2R,3S,4S,5R)-N-(6-((S*)-1,2-dihydroxyethyl)pyridin-3-yl)-3-(2-ethoxy-4- Fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The first elution peak of the former system on the Chiralpak IC column by SFC, rt = 0.85 min) ESI-MSm / z calculated value 500.19342, experimental value 501.3 (M+1) + ;499.3 (M-1) - ;Dwell time: 3.19 minutes 1 H NMR (400 MHz, methanol-d 4) δ 8.67 (dd, J = 2.6, 0.7 Hz, 1H), 8.04 (dd, J = 8.6, 2.5 Hz, 1H), 7.52 (dt, J = 8.6, 0.7 Hz, 1H), 7.20 (dd, J = 8.7, 6.3 Hz, 1H), 6.86 (t, J = 8.8 Hz, 1H), 5.02 (d, J = 10.8 Hz, 1H), 4.71 (dd, J = 6.6, 4.2 Hz, 1H), 4.34 (dd, J = 10.8, 7.9 Hz, 1H), 3.96 -3.82 (m, 2H), 3.79 (dd, J = 11.3, 4.2 Hz, 1H), 3.65 (dd, J = 11.3, 6.7 Hz, 1H), 2.77 (p , J = 7.6 Hz, 1H), 2.19 (d, J = 2.1 Hz, 3H), 1.67 (d, J = 1.1 Hz, 3H), 1.43 (t, J = 7.0 Hz, 3H), 0.80 (dt, J = 7.4, 2.4 Hz, 3H) ppm; alcohol OH and amide NH were not observed. 43 rel-(2S,3R,4R,5S)-N-(6-((S*)-1,2-dihydroxyethyl)pyridin-3-yl)-3-(2-ethoxy-4- Fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The second elution peak of the former system on the Chiralpak IC column by SFC, rt = 1.00 min) ESI-MSm / z calculated value 500.19342, experimental value 501.3 (M+1) + ;499.2 (M-1) - ;Dwell time: 3.19 minutes 1 H NMR (400 MHz, methanol-d 4 ) δ 8.67 (dd, J = 2.5, 0.7 Hz, 1H), 8.04 (dd, J = 8.6, 2.5 Hz, 1H), 7.52 (dt, J = 8.6, 0.7 Hz, 1H), 7.20 (dd, J = 8.8, 6.3 Hz, 1H), 6.86 (t, J = 8.8 Hz, 1H), 5.03 (d, J = 10.8 Hz, 1H), 4.71 (dd, J = 6.6, 4.2 Hz, 1H), 4.34 (dd, J = 10.8, 7.9 Hz, 1H), 3.96 -3.82 (m, 2H), 3.79 (dd, J = 11.3, 4.2 Hz, 1H), 3.65 (dd, J = 11.3, 6.6 Hz, 1H), 2.77 (p , J = 7.6 Hz, 1H), 2.19 (d, J = 2.1 Hz, 3H), 1.67 (d, J = 1.2 Hz, 3H), 1.43 (t, J = 7.0 Hz, 3H), 0.80 (dt, J = 7.5, 2.4 Hz, 3H) ppm; alcohol OH and amide NH were not observed.

[0316] The following compounds were prepared using the method described in Example 5, except that 60 psi of hydrogen was used for hydrogenation step 3. In step 5, methyl iodide was used instead of ethyl iodide as the alkylating agent. In step 7, in the case of compounds 44 and 45, (S)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine was used Instead of (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine. In step 8, a (R,R)-Whelk-O1 column from Daicel, 5 um particle size, 25 cm × 21.1 mm was used by chiral SFC on a Minigram SFC instrument from Berger Instruments (mobile phase: 5% to 25% MeOH (with 20 mM ammonia), 95% to 75% CO2. Flow: 100 mL / min.) for purification. In step 9, use DCM as solvent instead of THF and water mixture: Compound number Compound name LC / MS NMR (shift, ppm) 44 rel-(2S,3R,4R,5S)-N-(6-((S*)-1,2-dihydroxyethyl)pyridin-3-yl)-3-(4-fluoro-2-methoxy yl-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The first elution peak of the former system on the (R,R)-Whelk-O1 column by SFC, rt = 1.31 min) ESI-MSm / z calculated value 486.1778, experimental value 487.6 (M+1) + ;485.6 (M-1) - ;Dwell time: 3.02 minutes 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.40 (s, 1H), 8.65 (d, J = 2.4 Hz, 1H), 8.01 (dd, J = 8.6, 2.6 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.25 -7.06 (m, 2H), 7.01 -6.94 (m, 1H), 5.05 (d, J = 10.6 Hz, 1H), 4.55 (dd, J = 6.8, 4.2 Hz, 1H), 4.28 (dd, J = 10.7, 7.6 Hz, 1H), 3.72 (s, 3H), 3.62 (dd, J = 11.0, 4.2 Hz, 1H), 3.44 (dd, J = 11.0, 6.8 Hz, 2H), 2.73 (p, J = 7.4 Hz, 1H ), 2.16 (d, J = 2.0 Hz, 3H), 1.62 (s, 3H), 0.73 (d, J = 7.4 Hz, 3H) ppm. 45 rel-(2R,3S,4S,5R)-N-(6-((S*)-1,2-dihydroxyethyl)pyridin-3-yl)-3-(4-fluoro-2-methoxy yl-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The second elution peak of the former system on the (R,R)-Whelk-O1 column by SFC, rt = 2.20 min) ESI-MSm / z calculated value 486.1778, experimental value 487.6 (M+1) + ;485.6 (M-1) - ;Dwell time: 3.02 minutes 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.36 (s, 1H), 8.68 -8.59 (m, 1H), 7.95 (dd, J = 8.5, 2.5 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.7, 6.5 Hz, 1H), 6.97 (t, J = 8.8 Hz, 1H), 5.30 (d, J = 4.9 Hz, 1H), 5.03 (d, J = 10.6 Hz, 1H), 4.61 (t, J = 5.9 Hz, 1H), 4.52 (dt, J = 6.7, 4.5 Hz, 1H), 4.27 (dd, J = 10.7, 7.6 Hz, 1H), 3.71 (s, 3H), 3.61 (ddd, J = 10.4, 6.0 , 4.1 Hz, 1H), 3.43 (ddd, J = 10.9, 6.9, 5.8 Hz, 1H), 2.71 (p, J = 7.5 Hz, 1H), 2.14 (d, J = 2.0 Hz, 3H), 1.60 (s , 3H), 0.77 -0.68 (m, 3H) ppm. 46 rel-(2S,3R,4R,5S)-N-(6-((R*)-1,2-dihydroxyethyl)pyridin-3-yl)-3-(4-fluoro-2-methoxy yl-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The first elution peak of the former system on the (R,R)-Whelk-O1 column by SFC, rt = 1.26 min) ESI-MSm / z calculated value 486.1778, experimental value 487.6 (M+1) + ;485.6 (M-1) - ;Dwell time: 3.02 minutes 47 rel-(2R,3S,4S,5R)-N-(6-((R*)-1,2-dihydroxyethyl)pyridin-3-yl)-3-(4-fluoro-2-methoxy yl-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The second elution peak of the former system on the (R,R)-Whelk-O1 column by SFC, rt = 2.10 min) ESI-MSm / z calculated value 486.1778, experimental value 487.6 (M+1) + ;485.6 (M-1) - ;Dwell time: 3.02 minutes 1 H NMR (500 MHz, DMSO-d 6) δ 10.37 (s, 1H), 8.63 (d, J = 2.5 Hz, 1H), 7.99 (dd, J = 8.6, 2.6 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.20 (dd , J = 8.7, 6.5 Hz, 1H), 6.98 (t, J = 8.8 Hz, 1H), 5.31 (d, J = 4.9 Hz, 1H), 5.04 (d, J = 10.6 Hz, 1H), 4.62 (t , J = 5.9 Hz, 1H), 4.53 (dt, J = 7.0, 4.5 Hz, 1H), 4.28 (dd, J = 10.6, 7.5 Hz, 1H), 3.72 (s, 3H), 3.62 (ddd, J = 10.5, 6.1, 4.2 Hz, 1H), 3.49 -3.39 (m, 1H), 2.72 (p, J = 7.5 Hz, 1H), 2.15 (d, J = 2.0 Hz, 3H), 1.61 (s, 3H), 0.73 (d, J = 7.0 Hz, 3H) ppm. Example 6 rel-(2S, 3R, 4R, 5S)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-N-(6-((S*)- 1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (48), and rel-(2R,3S ,4S,5R)-3-(3-(Difluoromethyl)-4-fluoro-2-methoxyphenyl)-N-(6-((S*)-1,2-dihydroxyethyl )pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (49) step 1:

[0317] rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5 -Dihydrofuran-2-carboxylic acid ethyl ester (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(Ph3)4 (148 mg, 0.1281 mmol) and K2CO3 aqueous solution (2.6 mL, 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 (SiO2, 0% to 25% EtOAc in heptane) afforded rac-(4S,5R)-3-(3-(difluoromethyl)-4 as a colorless oil -Fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylic acid ethyl ester (708 mg, 66%) . 1H 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, found 413.2 (M+1)+; retention time: 1.05 minutes. Step 2:

[0318] rac-(4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoro A solution of ethyl methyl)-4,5-dihydrofuran-2-carboxylate (3.5 g, 8.488 mmol) in MeOH (100 mL) was added to a two-necked flask containing magnesium (2.07 g, 85.17 mmol) . The reaction mixture was heated at 70 °C for 3 h. The mixture was concentrated in vacuo and partitioned between aq. AcOH and EtOAc. The aqueous layer was separated and extracted twice with EtOAc. The combined organic phases were washed with aqueous NaHCO3 and twice with water. The organic phase was dried (MgSO4) and concentrated in vacuo to give rac-(2S,3S,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2- as an orange oil Methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid methyl ester and rac-(2R,3R,4S,5R)-3-(3-( A mixture of difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid methyl ester (2.87 g, 84 %). 1H 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. Step 3:

[0319] Potassium tert-butoxide (1.66 g, 14.79 mmol) was added to rac-(2S,3S,4S,5R)-3-(3-(difluoromethyl)-4 in a water bath at ambient temperature -Fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid methyl ester and rac-(2R,3R,4S,5R)-3 -Mixtures of (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). During the addition, an exotherm of about 3° was observed. The reaction mixture was stirred for 2 h before another portion of potassium tert-butoxide (860 mg) was added. The mixture was stirred for another 1 h at ambient temperature. The reaction was quenched with dilute HCl solution. The aqueous layer was separated and washed with EtOAc, dried (MgSO4) and concentrated in vacuo to give rac-(2R,3S,4S,5R)-3-(3-(difluoromethyl)-4- as an orange oil Fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid and rac-(2S,3R,4S,5R)-3-(3- Mixture of (difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (3.32 g, 74%) . 1H 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; OH acids not observed. ESI-MS m / z calc. 386.09528, found 385.1 (M-1)-; retention time: 0.57 minutes. Step 4:

[0320] Add T3P (310 µL, 50% w / w, 0.5208 mmol) to 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-(difluoromethane A mixture of -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 solution in ethyl acetate (2 mL). The reaction mixture was stirred at 50 °C for 30 min, and then at ambient temperature overnight. The reaction mixture was partitioned between EtOAc and water and passed through Whatmann phase separation filter paper. The organic phase was concentrated in vacuo and loaded onto silica. Purification by flash chromatography (SiO2, 0% to 75% EtOAc in heptane) afforded 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-formamide and rel-(2S,3R,4R,5S)-3-(3-(difluoromethyl)-4 -Fluoro-2-methoxyphenyl)-N-(6-((S*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridine-3- base)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (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; NH amides were not observed. ESI-MS m / z calculated 562.19025, found 563.2 (M+1)+; 561.3 (M-1)-; retention time: 1.02 minutes. Step 5:

[0321] On a Minigram SFC instrument from Berger Instruments, by chiral SFC using a Chiralpak AS-H column from Daicel Corporation, 5 um particle size, 25 cm × 10 mm (mobile phase: 15% MeOH (containing 20 mM ammonia), 85% CO2. Flow: 10 mL / min.) separation of rel-(2R,3S,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxy Phenyl)-N-(6-((S*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5-di Methyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide and rel-(2S,3R,4R,5S)-3-(3-(difluoromethyl)-4-fluoro-2-methanol Oxyphenyl)-N-(6-((S*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5 - A mixture of dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (50 mg, 0.089 mmol) to give:

[0322] The first eluted isomer (rt = 2.14 min): rel-(2S,3R,4R,5S)-3-(3-(difluoromethyl)-4-fluoro-2-methoxy Phenyl)-N-(6-((S*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5-di Methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (15 mg, 60%). ESI-MS m / z calculated 562.19025, found 563.2 (M+1)+; 561.2 (M-1)-; retention time: 3.5 minutes.

[0323] The second eluted isomer (rt = 3.60 min): rel-(2R,3S,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxy Phenyl)-N-(6-((S*)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5-di Methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (12 mg, 48%). ESI-MS m / z calc. 562.19025, found 563.2 (M+1)+; 561.2 (M-1)-; retention time: 3.49 minutes. Step 6:

[0324] TFA (10 µL, 0.1298 mmol) was added to 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) middle. The reaction mixture was stirred overnight at 60 °C. The mixture was concentrated in vacuo. 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 were not observed. ESI-MS m / z calculated 522.15894, found 522.9 (M+1)+; 521.0 (M-1)-; retention time: 3.04 minutes.

[0325] Treat rel-(2R, 3S, 4S, 5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-N-(6-( (S*)-2,2-Dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl ) tetrahydrofuran-2-carboxamide (12 mg, 0.02133 mmol) (second eluted isomer from SFC separation) to give rel-(2R,3S,4S,5R)-3-(3-(difluoro Methyl)-4-fluoro-2-methoxyphenyl)-N-(6-((S*)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl 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 were not observed. ESI-MS m / z calculated 522.15894, found 522.9 (M+1)+; 521.0 (M-1)-; retention time: 3.01 minutes.

[0326] The following compounds were prepared using the method described in Example 6, except that (R)-6-(2,2-dimethyl-1,3-dioxolane was used in amide coupling step 4 Alk-4-yl)pyridin-3-amine instead of (S)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine. In step 5, a (R,R)-Whelk-O1 column from Daicel, 5 um particle size, 25 cm × 21.1 mm was used by chiral SFC on a Minigram SFC instrument from Berger Instruments (mobile phase: 5% to 55% MeOH, 95% to 45% CO2. Flow: 100 mL / min.) for purification. The conditions used in Step 6 were similar to those set forth in Example 1 Step 16: Compound number Compound name LC / MS NMR (shift, ppm) 50 rel-(2S,3R,4R,5S)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-N-(6-((R*)-1, 2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The first elution peak of the former system on the (R,R)-Whelk-O1 column by SFC, rt = 1.16 min) ESI-MSm / z calculated value 522.15894, experimental value 523.2 (M+1) + ;521.1 (M-1) - ;Dwell time: 2.97 minutes 1 H NMR (500 MHz, chloroform-d) δ 8.67 (s, 1H), 8.57 (s, 1H), 8.18 (d, J = 8.6 Hz, 1H), 7.59 -7.49 (m, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.10 -6.80 (m, 2H), 5.02 (d, J = 10.6 Hz, 1H), 4.83 (s, 1H), 4.15 (dd, J = 10.6, 8.4 Hz, 1H), 3.92 (dd, J = 11.3, 3.7 Hz, 1H), 3.84 (s, 3H), 3.76 (dd, J = 11.4, 5.3 Hz, 1H), 2.78 (p, J = 7.7 Hz, 1H), 1.69 (s , 3H), 0.81 (dd, J = 7.6, 2.4 Hz, 3H) ppm; alcoholic OH was not observed. 51 rel-(2R,3S,4S,5R)-3-(3-(Difluoromethyl)-4-fluoro-2-methoxyphenyl)-N-(6-((R*)-1, 2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The second elution peak of the former system on the (R,R)-Whelk-O1 column by SFC, rt = 1.78 min) ESI-MSm / z calculated value 522.15894, experimental value 523.2 (M+1) + ;521.1 (M-1) - ;Dwell time: 2.97 minutes 1 H NMR (500 MHz, chloroform-d) δ 8.69 (s, 1H), 8.23 ​​(dd,J= 8.6, 2.3 Hz, 1H), 7.53 (dd,J= 8.9, 5.8 Hz, 1H), 7.39 (d, J= 8.6 Hz, 1H), 7.05 -6.79 (m, 2H), 5.02 (d,J= 10.6 Hz, 1H), 4.85 (t,J= 4.6 Hz, 1H), 4.15 (dt,J= 10.8, 7.9 Hz, 1H), 3.92 (dd,J= 11.5, 3.8 Hz, 1H), 3.84 (s, 3H), 3.76 (dd,J= 11.4, 5.4 Hz, 1H), 2.78 (p,J= 7.7 Hz, 1H ), 1.70 (d,J= 3.6 Hz, 3H), 0.81 (dt,J= 7.8, 2.1 Hz, 3H) ppm; alcohol OH and amide NH were not observed.

[0327] The following compounds were prepared using the method described in Example 6, except that the product of Step 1 was prepared in 3 steps using the conditions described in Example 11 Steps 1, 2 and 3, and the coupling partner was 1-bromo -3-(Difluoromethyl)-4-fluoro-2-methoxybenzene. In 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 NaBH4 in MeOH as solvent, conditions well known in the art. No need to deprotect step 6: Compound number Compound name LC / MS NMR (shift, ppm) 52 rel-(2S,3R,4R,5S)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-N-(6-(hydroxymethyl)pyridine-3 -yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The first elution peak by SFC on a Chiralpak AS-H column 10 × 250 mm (mobile phase: 20% MeOH (containing 20 mM ammonia), 80% CO 2 . Flow rate: 10 mL / min. ), rt = 1.99 min) ESI-MSm / z calculated value 492.14838, experimental value 493.4 (M+1) + ;491.3 (M-1) - ;Dwell time: 2.76 minutes 1 H NMR (500 MHz, methanol-d 4 ) δ 9.03 (d, J = 2.4 Hz, 1H), 8.37 (dd, J = 8.8, 2.3 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.60 (dd, J = 8.8, 6.1 Hz , 1H), 7.19 -6.88 (m, 2H), 5.12 (d, J = 10.4 Hz, 1H), 4.81 (s, 2H), 4.36 (dd, J = 10.5, 8.2 Hz, 1H), 3.86 (s, 3H), 2.83 (p, J = 7.7 Hz, 1H), 1.69 (d, J = 1.2 Hz, 3H), 0.84 (dt, J = 7.6, 2.4 Hz, 3H) ppm; alcohol OH and amide were not observed NH. 53 rel-(2R,3S,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-N-(6-(hydroxymethyl)pyridine-3 -yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (Second elution peak by SFC on Chiralpak AS-H column 10 × 250 mm (mobile phase: 20% MeOH (containing 20 mM ammonia), 80% CO 2 . Flow rate: 10 mL / min. ), rt = 3.05 min) ESI-MSm / z calculated value 492.14838, experimental value 493.4 (M+1) + ;Dwell time: 2.77 minutes 1 H NMR (500 MHz, methanol-d 4 ) δ 8.67 (d, J = 2.5 Hz, 1H), 8.07 (dd, J = 8.5, 2.5 Hz, 1H), 7.59 (dd, J = 8.8, 6.0 Hz, 1H), 7.50 (d, J = 8.5 Hz , 1H), 7.15 -6.90 (m, 2H), 5.08 (d, J = 10.4 Hz, 1H), 4.64 (s, 2H), 4.34 (dd, J = 10.5, 8.2 Hz, 1H), 3.86 (s, 3H), 2.82 (p, J = 7.7 Hz, 1H), 1.68 (d, J = 1.2 Hz, 3H), 0.83 (dt, J = 7.5, 2.3 Hz, 3H) ppm; alcohol OH and amide were not observed NH.

[0328] The following compounds were prepared using the method described in Example 6, except that the product of Step 1 was prepared in 3 steps using the conditions described in Example 11 Steps 1, 2 and 3, and the coupling partner was 1-bromo -3-(Difluoromethyl)-4-fluoro-2-methoxybenzene. In amide coupling step 4, (5-aminopyrimidin-2-yl)methyl benzoate was used as the amine coupling partner. On a Prep-100 SFC instrument from Waters, a Chiralpak IG column from Daicel was used, 5 μm particle size, 25 cm × 20 mm (mobile phase: 17% MeOH with 20 mM ammonia), 83% CO2. Flow rate: 100 mL / min.) for chiral SFC separation step 5. Deprotection step 6 was carried out at 30 °C for 16 h using an excess of 2 M LiOH in MeOH as solvent, under conditions well known in the art: Compound number Compound name LC / MS NMR (shift, ppm) 54 rel-(2R,3S,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-N-(2-(hydroxymethyl)pyrimidine-5 -yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The first elution peak of the former system on the Chiralpak IG column by SFC, rt = 1.31 min) ESI-MSm / z calculated value 493.14362, experimental value 494.6 (M+1) + ;492.5 (M-1) - ;Dwell time: 3.06 minutes 1 H NMR (500 MHz, methanol-d 4 ) δ 9.04 (s, 2H), 7.60 (dd, J = 8.9, 6.1 Hz, 1H), 7.27 -6.80 (m, 2H), 5.11 (d, J = 10.4 Hz, 1H), 4.72 (s, 2H) , 4.35 (dd, J = 10.4, 8.2 Hz, 1H), 3.86 (s, 3H), 2.83 (p, J = 7.7 Hz, 1H), 1.69 (d, J = 1.2 Hz, 3H), 0.83 (dq, J = 7.5, 2.3 Hz, 3H) ppm; alcohol OH and amide NH were not observed. 55 rel-(2S,3R,4R,5S)-3-(3-(Difluoromethyl)-4-fluoro-2-methoxyphenyl)-N-(2-(Hydroxymethyl)pyrimidine-5 -yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The second elution peak of the former system on the Chiralpak IG column by SFC, rt = 1.47 min) ESI-MSm / z calculated value 493.14362, experimental value 494.6 (M+1) + ;492.5 (M-1) - ;Dwell time: 3.06 minutes 1 H NMR (500 MHz, methanol-d 4 ) δ 9.04 (s, 2H), 7.60 (dd, J = 8.8, 6.0 Hz, 1H), 7.21 -6.86 (m, 2H), 5.11 (d, J = 10.4 Hz, 1H), 4.72 (s, 2H) , 4.35 (dd, J = 10.4, 8.2 Hz, 1H), 3.86 (s, 3H), 2.83 (p, J = 7.7 Hz, 1H), 1.69 (d, J = 1.4 Hz, 3H), 0.83 (dt, J = 7.5, 2.4 Hz, 3H) ppm; alcohol OH and amide NH were not observed.

[0329] The following compounds were prepared using the method described in Example 6, except that the product of Step 1 was prepared in 3 steps using the conditions described in Example 11 Steps 1, 2 and 3, and the coupling partner was 1-bromo -3-(Difluoromethyl)-4-fluoro-2-methoxybenzene. In amide coupling step 4, 1-(5-aminopyridin-2-yl)ethan-1-one was used as the amine coupling partner. Chiralpak IG column from Daicel, 5 μm particle size, 25 cm × 10 mm (mobile phase: 25% IPA with 20 mM ammonia), 75% CO2 was used on a Minigram SFC instrument from Berger Instruments. Flow rate: 10 mL / min.) to chiral SFC separation step 5. The deprotection step 6 was replaced by a ketone reduction step at ambient temperature over 30 min using 3 equivalents of NaBH4 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 isolated 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, namely compounds 57 and 58, by manual analysis on a Minigram SFC instrument from Berger Instruments. A Chiralpak IG column from Daicel, 5 μm particle size, 25 cm × 10 mm (mobile phase: 25% IPA (containing 20 mM ammonia), 75% CO2. Flow rate: 10 mL / min.) was used to further separate the and other compounds: Compound number Compound name LC / MS NMR (shift, ppm) 56 rel-(2R,3S,4S,5R)-3-(3-(Difluoromethyl)-4-fluoro-2-methoxyphenyl)-N-(6-(1-hydroxyethyl)pyridine -3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (mixture of epimers at the hydroxyethyl position) (The first elution peak of the former system on the Chiralpak IG column by SFC, rt = 2.51 min; no epimers were separated) ESI-MSm / z calculated value 506.16403, experimental value 507.6 (M+1) + ;505.5 (M-1) - ;Dwell time: 3.23 minutes 1 H NMR (500 MHz, methanol-d 4) δ 8.66 (dt, J = 2.6, 0.8 Hz, 1H), 8.06 (ddd, J = 8.5, 2.5, 0.9 Hz, 1H), 7.62 -7.57 (m, 1H), 7.53 -7.48 (m, 1H), 7.14 -6.91 (m, 2H), 5.07 (d, J = 10.4 Hz, 1H), 4.82 (q, J = 6.6 Hz, 1H), 4.34 (dd, J = 10.4, 8.2 Hz, 1H), 3.86 (s , 3H), 2.82 (p, J = 7.6 Hz, 1H), 1.68 (d, J = 1.2 Hz, 3H), 1.43 (d, J = 6.5 Hz, 3H), 0.86 -0.80 (m, 3H) ppm; Alcohol OH and amide NH were not observed. 57 rel-(2S,3R,4R,5S)-3-(3-(Difluoromethyl)-4-fluoro-2-methoxyphenyl)-N-(6-(1-hydroxyethyl)pyridine -3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The second elution peak of the former system on the Chiralpak IG column by SFC, rt = 3.51 min; the first elution peak of the last step on the Chiralpak IG column by SFC, rt = 3.44 min) ESI-MSm / z calculated value 506.16403, experimental value 507.4 (M+1) + ;505.3 (M-1) - ;Dwell time: 3.21 minutes 1 H NMR (500 MHz, methanol-d 4 ) δ 8.66 (d, J = 2.5 Hz, 1H), 8.05 (dd, J = 8.5, 2.5 Hz, 1H), 7.59 (dd, J = 8.9, 6.1 Hz, 1H), 7.51 (d, J = 8.6 Hz , 1H), 7.16 -6.91 (m, 2H), 5.07 (d, J = 10.4 Hz, 1H), 4.86 -4.79 (m, 1H), 4.34 (dd, J = 10.4, 8.2 Hz, 1H), 3.86 ( s, 3H), 2.82 (p, J = 7.7 Hz, 1H), 1.68 (d, J = 1.3 Hz, 3H), 1.43 (d, J = 6.6 Hz, 3H), 0.83 (dq, J = 7.4, 2.4 Hz, 3H) ppm; alcohol OH and amide NH were not observed. 58 rel-(2S,3R,4R,5S)-3-(3-(Difluoromethyl)-4-fluoro-2-methoxyphenyl)-N-(6-(1-hydroxyethyl)pyridine -3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (The second elution peak of the former system on the Chiralpak IG column by SFC, rt = 3.51 min; the second elution peak of the last step on the Chiralpak IG column by SFC, rt = 4.33 min) ESI-MSm / z calculated value 506.16403, experimental value 507.4 (M+1) + ;505.3 (M-1) - ;Dwell time: 3.21 minutes 1 H NMR (500 MHz, methanol-d 4 ) δ 8.66 (d, J = 2.5 Hz, 1H), 8.05 (dd, J = 8.5, 2.5 Hz, 1H), 7.59 (dd, J = 8.8, 6.0 Hz, 1H), 7.51 (d, J = 8.6 Hz , 1H), 7.14 -6.91 (m, 2H), 5.07 (d, J = 10.4 Hz, 1H), 4.86 -4.79 (m, 1H), 4.34 (dd, J = 10.4, 8.2 Hz, 1H), 3.86 ( s, 3H), 2.82 (p, J = 7.7 Hz, 1H), 1.68 (d, J = 1.2 Hz, 3H), 1.43 (d, J = 6.6 Hz, 3H), 0.83 (dq, J = 7.4, 2.3 Hz, 3H) ppm; alcohol OH and amide NH were not observed. Example 7 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-formamido)pyridine 1-oxide (59) Step 1:

[0330] Make rel-(2R,3S,4S,5R)-N-(6-((S*)-2,2-dimethyl-1,3-dioxolane- 4-yl)pyridin-3-yl)-3-(4-fluoro-2-methoxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- A solution of 2-formamide (11.5 mg, 0.02184 mmol, prepared as described in Example 5 for the compound 45 precursor) in DCM (2 mL) was cooled. m-CPBA (19.9 mg, 0.08072 mmol) was added in one portion and the mixture was allowed to warm moderately slowly using an ice bath. The reaction mixture was stirred for 24 h. The reaction mixture was quenched with saturated bicarbonate (2 ml). The aqueous layer was washed with DCM (3 x 2 ml). The organic phases were combined and passed through a phase separation column. The liquid was concentrated in vacuo to afford 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- Formamido)pyridine 1-oxide (15.4 mg, 100%) was used as such in the next step. ESI-MS m / z calculated 542.204, found 543.7 (M+1)+; 541.6 (M-1)-; retention time: 0.97 min. Step 2:

[0331] TFA (25 µL, 0.3245 mmol) was added to 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- In a stirred solution of 2-formamido)pyridine 1-oxide (15.4 mg, 0.02441 mmol) in DCM (500 µL). The reaction mixture was stirred at ambient temperature for 24 h. Purification by reverse phase preparative HPLC (basic eluent) 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-formamido) Pyridine 1-oxide (3.2 mg, 24%). 1H 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 were not observed. 19F 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.

[0332] The following compounds were prepared using the method described in Example 7, using 1 as starting material: Compound number Compound name LC / MS NMR (shift, ppm) 60 5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-formamido)-2-((R)-1,2-dihydroxyethyl)pyridine 1-oxide ESI-MSm / z calculated value 506.1476, experimental value 507.3 (M+1) + ;505.3 (M-1) - ;Dwell time: 2.84 minutes 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.46 (s, 1H), 8.66 (d, J = 1.9 Hz, 1H), 7.54 (dd, J = 8.8, 2.0 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.17 (dd , J = 11.2, 6.6 Hz, 2H), 5.64 (d, J = 5.4 Hz, 1H), 5.08 (d, J = 10.1 Hz, 1H), 5.03 -4.98 (m, 1H), 4.77 (t, J = 6.0 Hz, 1H), 4.24 (dd, J = 10.1, 7.7 Hz, 1H), 3.95 (d, J = 2.1 Hz, 3H), 3.66 (ddd, J = 10.9, 6.0, 3.4 Hz, 1H), 3.46 ( dt, J = 10.9, 6.0 Hz, 1H), 2.76 (q, J = 7.6 Hz, 1H), 1.60 (s, 3H), 0.73 (d, J = 7.1 Hz, 3H) ppm. Example 8 rel-(2S,3R,5S)-3-(2-chloro-4-(trifluoromethoxy)phenyl)-N-(6-((R*)-1,2-dihydroxyethyl Base) pyridin-3-yl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide (61), and rel-(2R,3S,5R)-3-(2-chloro -4-(trifluoromethoxy)phenyl)-N-(6-((R*)-1,2-dihydroxyethyl)pyridin-3-yl)-5-methyl-5-(tri Fluoromethyl)tetrahydrofuran-2-carboxamide (62) Step 1:

[0333] Tetrakis(triphenylphosphine)palladium(0) (1.3 g, 1.125 mmol) was added to (2-chloro-4-(trifluoromethoxy)phenyl)boronic acid (5 g, 20.80 mmol), 5-Methyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylic acid ethyl ester (8 g, 21.49 mmol) and aqueous sodium carbonate (28.2 mL, 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 (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (120 g SiO2, 0% to 40% EtOAc in heptane) gave 3-(2-chloro-4-(trifluoromethoxy)phenyl)-5-methyl- Ethyl 5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (6.46 g, 74%). 1H 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, 2H), 3.43 (d, J = 17.5 Hz, 1H), 3.07 -2.96 (m, 1H), 1.71 (d, J = 1.0 Hz, 3H), 1.08 (t, J = 7.1 Hz, 3H) ppm. ESI-MS m / z calculated 418.04065, found 418.8 (M+1)+; retention time: 1.13 minutes. Step 2:

[0334] A pressure tube was loaded with magnesium powder (2.35 g, 96.69 mmol) and purged with nitrogen. To the reaction vessel was added MeOH (20 mL) followed by 3-(2-chloro-4-(trifluoromethoxy)phenyl)-5-methyl-5-(trifluoromethyl)-4,5 - A solution of ethyl dihydrofuran-2-carboxylate (2 g, 4.777 mmol) in MeOH (20 mL). The reaction mixture was degassed with nitrogen, after which a few drops of 1,2-dibromoethane (80 mg, 0.4258 mmol) were added. The reaction mixture was stirred vigorously and heated at 50 °C for 5 h. The mixture was cooled to ambient temperature and quenched by pouring it slowly onto cooled 1 M HCl solution. The mixture was stirred for 30 min until a clear solution was obtained. The mixture was partitioned with TBME. The separated aqueous layer was washed with TBME (x 3). Pass the combined organic phases through a phase separation column. The filtrate was concentrated in vacuo to give a mixture of diastereomers, the two main diastereomers being rac-(2S,3S,5R)-3-(2-chloro-4-(trifluoromethoxy base)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid methyl ester and rac-(2R,3R,5R)-3-(2-chloro-4-(trifluoro Methoxy)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid methyl ester (2.85 g, 73%) was used as such in the next step. ESI-MS m / z calculated 406.04065, retention time: 1.09 and 1.11 min for the 2 major diastereomers. Step 3:

[0335] Sodium methoxide (310 µL, 25% w / v in MeOH, 1.435 mmol) was added to the solution containing rac-(2S,3S,5R)-3-(2-chloro-4 -(trifluoromethoxy)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid methyl ester and rac-(2R,3R,5R)-3-(2-chloro -A mixture of methyl 4-(trifluoromethoxy)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (3.8 g, 9.343 mmol) in THF (40 mL) in the stirred solution. After 5 h, methanol (0.2 ml) and LiOH (7.3 mL, 2 M aq, 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 x 30 ml). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give 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-( Mixture of 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 time: 0.63 and 0.66 minutes for the two main diastereomers. Step 4:

[0336] Dimethylformamide (0.3 µL, 0.003874 mmol) and oxalyl chloride (78 µL, 0.8941 mmol) were added to a 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 diastereomer mixture (167 mg, 0.4253 mmol) in 2-methyltetrahydrofuran (2 mL) in an ice-cold stirred solution. The reaction mixture was stirred and allowed to warm to ambient temperature over 1.5 h. The reaction mixture was concentrated in vacuo. The residue was taken up in 2-methyltetrahydrofuran (2 mL) and added to (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine In an ice-cooled solution of 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 h. The reaction mixture was quenched with water (5 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (5 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (12 g SiO2, 0% to 50% EtOAc in heptane) afforded the following mixture of isomers:

[0337] The first eluting isomer: 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-methyl Amide a...

Claims

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

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has: (i) formula (IA), or (ii) formula (IB).

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has: (i) formula (IA-1), or (ii) formula (IB-1).

4. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: (i) X2a is C-R2a; and R2a is H; and / or (ii) X3a is N; and / or (iii) X5a is N or C-R5a; and R5a is H, a halogen or CH2OH; and / or (iv) X6a is N or C-R6a; and R6a is H.

5. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: (i) X2a is C-R2a; and R2a is H; and / or (ii) X3a is N; and / or (iii) X5a is N or C-R5a; and R5a is H, F or CH2OH; and / or (iv) X6a is N or C-R6a; and R6a is H.

6. A compound or a pharmaceutically acceptable salt thereof, as described in any of claims 1 to 3, wherein: (i) R4b1 is H or C1-C6 alkyl; and / or (ii) R4b2 is H or C1-C6 alkyl; and / or (iii) R5b1 is C1-C6 alkyl or C1-C6 haloalkyl; and / or (iv) R5b2 is C1-C6 alkyl or C1-C6 haloalkyl; and / or (v) R2c is OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; and / or (vi) X3c is N or C-R3c; and R3c is H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; and / or (vii) X4c is C-R4c; and R4c is H, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; and / or (viii) X5c is C-R5c; and R5c is H; and / or (ix) X6c is C-R6c; and R6c is H; and / or (x) Rd is: (a) Rd is (CH2)pH; or (b) Rd is (CHRe)n(CH2)pH; or (c) Rd is (CH2)m(CHRe)nH.

7. A compound or a pharmaceutically acceptable salt thereof, as described in any of claims 1 to 3, wherein: (i) R4b1 is H or CH3; and / or (ii) R4b2 is H or CH3; and / or (iii) R5b1 is CH3 or CF3; and / or (iv) R5b2 is CH3 or CF3; and / or (v) R2c is OH, Cl, CH3, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCH2CH2F, or OCH2CHF2; and / or (vi) X3c is N or C-R3c; and R3c is H, F, CH3, CHF2, or CF3; and / or (vii) X4c is C-R4c; and R4c is H, F, CHF2, OCH2CH3, OCHF2, or OCF3; and / or (viii) X5c is C-R5c; and R5c is H; and / or (ix) X6c is C-R6c; and R6c is H; and / or (x) Rd is: (a) Rd is H or CH3; or (b) Rd is CH2F, CH2OH or CH(OH)CH3; or (c) Rd is CH2OCH3 or CH2CH2OCH3.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is selected from: , or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is selected from: , , , , , , , , , , , , , , , , , ; or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is selected from: , , , , , , , , , , , , , and; or a pharmaceutically acceptable salt thereof.

11. A compound of a certain formula or a pharmaceutically acceptable salt thereof.

12. A compound of a certain formula or a pharmaceutically acceptable salt thereof.

13. A compound of the formula or a pharmaceutically acceptable salt thereof.

14. The compound or its pharmaceutically acceptable salt thereof of any one of claims 1 to 3, 8, 9 and 11 to 13, wherein the compound or its pharmaceutically acceptable salt is in a non-salt form.

15. A compound in a non-salt form.

16. A pharmaceutical composition comprising a compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or a compound of claims 14 or 15 and one or more pharmaceutically acceptable carriers or mediators.

17. Use of a compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 16, in the preparation of a medicament for inhibiting voltage-gated sodium channels in an individual.

18. As requested in claim 17, wherein the voltage-gated sodium channel is NaV1.

8.

19. Use of any compound of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 16, in the preparation of a medicament for treating an individual’s 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 syndrome, incontinence, pathological cough, or arrhythmia, or for reducing their severity.

20. The use as claimed in claim 19, wherein the drug is used to treat or reduce the severity of neuropathic pain in the individual, wherein the neuropathic pain includes: postherpetic neuralgia, small fiber neuropathy, idiopathic small fiber neuropathy, or diabetic neuropathy.

21. As claimed in claim 20, wherein the diabetic neuropathy includes diabetic peripheral neuropathy.

22. The use as claimed in claim 19, wherein the drug is used to treat or reduce the severity of musculoskeletal pain in the individual, wherein the musculoskeletal pain includes osteoarthritis pain.

23. The use as claimed in claim 19, wherein the drug is used to treat or reduce the severity of acute pain in the individual, wherein the acute pain includes acute postoperative pain.

24. As claimed in claim 19, wherein the drug is used to treat or reduce the severity of postoperative pain in the individual, wherein the postoperative pain includes pain from excision of the thumb tip, pain from abdominoplasty, or pain from herniorrhaphy suture.

25. As claimed in claim 19, wherein the drug is used to treat visceral pain in the individual or to reduce its severity.

26. As claimed in claims 17 or 19, wherein the individual is treated with one or more additional therapeutic agents, which are administered concurrently, before or after treatment with the compound, a pharmaceutically acceptable salt or a pharmaceutical composition.

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