Substituted tetrahydrofurans as modulators of sodium channels.

Abstract

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

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 944,869, filed December 6, 2019, which is incorporated herein by reference in its entirety. [Background technology]

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

[0003] Voltage-gated sodium channels (Na V ) is involved in pain signaling. VSodium channels are biological mediators of electrical signaling because they mediate the rapid rise of action potentials in many excitable cell types (e.g., neurons, skeletal muscle cells, cardiac myocytes). Evidence for the role of these channels in normal physiology, pathological conditions resulting from mutations in sodium channel genes, preclinical studies in animal models, and clinical pharmacology of known sodium channel modulators all support the role of Na in pain sensation. V (Rush, AM and TR Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Na V 1.8 Sodium Channels. Mol. Interv., 2007. 7(4): p. 192-5), England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics.Expert Opin. Investig. Drugs 17 (12), p. 1849-64 (2008), Krafte, DS and Bannon, AW, Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8 (1), p. 50-56 (2008)). Na V Na mediates the rapid rise of action potentials in many excitable cell types (e.g., neurons, skeletal muscle cells, cardiac myocytes) and is therefore involved in the initiation of signal transduction in these cells (Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). V Due to the role that Na plays in the initiation and propagation of neuronal signals, VAntagonists that decrease the current can disrupt or decrease nerve signaling, and Na V Channels are considered promising targets for reducing pain in conditions where hyperexcitability is observed. (Chahine, M., Chatelier, A., Babich, O., and Krupp, JJ, Voltage-gated sodium channels in neurological disorders. CNS Neurol. Disord. Drug Targets 7 (2), p. 144-58 (2008)). Several clinically useful analgesics target sodium. V Local anesthetics such as lidocaine have been identified as inhibitors of the Na channel. V Other compounds that block pain by inhibiting the channel, such as carbamazepine, lamotrigine, and tricyclic antidepressants that have been shown to be effective in reducing pain, have also been suggested to act by blocking sodium channels (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. Eur. J. Pain 6 Suppl. A, p. 3-9 (2002); Wang, GK, Mitchell, J., and Wang, SY, Block of persistent late Na + currents by antidepressant sertraline and paroxetine. J. Membr. Biol. 222 (2), p. 79-90 (2008)).

[0004] Na V form a subfamily of the voltage-gated ion channel superfamily and V 1.1~Na V It contains nine isoforms, designated 1.1 and 1.9. The tissue localization of the nine isoforms varies. V 1.4 is the major sodium channel in skeletal muscle and is the Na V1.5 is the major sodium channel in cardiac myocytes. V 1.7, 1.8, and 1.9 are primarily localized in the peripheral nervous system, and Na V 1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the central and peripheral nervous systems. The nine isoforms have similar functional behavior, but differ in the characteristics of their voltage-dependence and kinetic behavior (Catterall, WA, Goldin, AL, and Waxman, SG, International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57 (4), p. 397 (2005)).

[0005] Upon their discovery, Na V The 1.8 channel was identified as a promising target for analgesia (Akopian, AN, L. Sivilotti, and JN Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562): pp. 257-62). Since then, Na V 1.8 has been shown to be a carrier of sodium currents that sustain action potential firing in small dorsal root ganglion (DRG) neurons (Blair, NT and BP Bean, Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, + current, and Ca 2+ current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002. 22(23): p. 10277-90). Na V1.8 is involved in the spontaneous firing of injured neurons, such as those responsible for neuropathic pain (Roza, C., et al., The tetrodotoxin-resistant Na + Channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550(Pt 3): p. 921-6;Jarvis, MF, et al., A-803467, a potent and selective Na V 1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat.Proc. Natl. Acad. Sci. USA, 2007. 104(20): p. 8520-5, Joshi, SK, et al., Involvement of the TTX-resistant sodium channel Na V 1.8 in inflammatory and neuropathic, but not post-operative, pain states. Pain, 2006. 123(1-2): pp. 75-82, Lai, J., et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, Na V 1.8. Pain, 2002. 95(1-2): p. 143-52, Dong, XW, et al., Small interfering RNA-mediated selective knockdown of Na V1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. Neuroscience, 2007. 146(2): p. 812-21、Huang, H.L., et al., Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves. Mol. Pain, 2008. 4: p. 33、Black, J.A., et al., Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann. Neurol., 2008. 64(6): p. 644-53、Coward, K., et al., Immunolocalization of SNS / PN3 and NaN / SNS2 sodium channels in human pain states. Pain, 2000. 85(1-2): p. 41-50、Yiangou, Y., et al., SNS / PN3 and SNS2 / NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. FEBS Lett., 2000. 467(2-3): p. 249-52、Ruangsri, S., et al.,Relationship of axonal voltage-gated sodium channel 1.8 (Na V 1.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats. J. Biol. Chem. 286(46): p. 39836-47)。Na VSmall DRG neurons expressing 1.8 contain nociceptors involved in pain signaling. V 1.8 mediates large-amplitude action potentials in small neurons of the dorsal root ganglion (Blair, NT and BP Bean, Roles of tetrodotoxin (TTX)-sensitive Na + current, TTX-resistant Na + current, and Ca 2+ current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002. 22(23): p. 10277-90). Na V 1.8 is necessary for rapid repetitive action potentials in nociceptors and for spontaneous activity of injured neurons. (Choi, JS and SG Waxman, Physiological interactions between Na V 1.7 and Na V 1.8 sodium channels: a computer simulation study. J. Neurophysiol. 106(6): p. 3173-84, Renganathan, M., TR Cummins, and SG Waxman, Contribution of Na( V )1.8 sodium channels to action potential electrogenesis in DRG neurons. J. Neurophysiol., 2001. 86(2): p. 629-40, Roza, C., et al., The tetrodotoxin-resistant Na + Channel Na V1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550(Pt 3): pp. 921-926. In depolarized or damaged DRG neurons, Na V 1.8 appears to be a driver of hyperexcitability (Rush, AM, et al., A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc. Natl. Acad. Sci. USA, 2006. 103(21): p. 8245-50). In some animal pain models, Na V 1.8 mRNA expression levels have been shown to increase in DRG (Sun, W., et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats. Brain, 135(Pt 2): pp. 359-75; Strickland, IT, et al., Changes in the expression of Na V 1.7, Na V 1.8 and Na V 1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. Eur. J. Pain, 2008. 12(5): p. 564-72, Qiu, F., et al., Increased expression of tetrodotoxin-resistant sodium channels Na V 1.8 and NaV 1.9 within dorsal root ganglia in a rat model of bone cancer pain. Neurosci. Lett., 512(2): p. 61-6). Some known Na V The major drawback of the inhibitors is their poor therapeutic window, which is likely a result of their lack of isoform selectivity. V 1.8 is primarily restricted to pain-sensing neurons and is therefore a selective Na V 1.8 Blockers are non-selective Na V It is unlikely to induce the adverse events common to blockers. V Channel regulators, preferably Na V There is a continuing need to develop highly potent and selective modulators of 1.8. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Dieleman, JP, et al., Incidence rates and treatment of neuropathic pain conditions in the general population. Pain, 2008. 137(3): p. 681-8 [Non-patent document 2] Rush, AM and TR Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets NaV1.8 Sodium Channels. Mol. Interv., 2007. 7(4): p. 192-5 [Non-patent document 3] England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics.Expert Opin. Investig. Drugs 17 (12), p. 1849-64 (2008) [Non-patent document 4] Krafte, DS and Bannon, AW, Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8 (1), p. 50-56 (2008) [Non-Patent Document 5] Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001) [Non-patent document 6] Chahine, M., Chatelier, A., Babich, O., and Krupp, JJ, Voltage-gated sodium channels in neurological disorders. CNS Neurol. Disord. Drug Targets 7 (2), p. 144-58 (2008) [Non-Patent Document 7] Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action.Eur. J. Pain 6 Suppl. A, p. 3-9 (2002) [Non-patent document 8] Wang, GK, Mitchell, J., and Wang, SY, Block of persistent late Na+ currents by antidepressant sertraline and paroxetine.J. Membr. Biol. 222 (2), p. 79-90 (2008) [Non-Patent Document 9] Catterall, WA, Goldin, AL, and Waxman, SG, International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels.Pharmacol. Rev. 57 (4), p. 397 (2005) [Non-Patent Document 10] Akopian, AN, L. Sivilotti, and JN Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562): p. 257-62 Summary of the Invention

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

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

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

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

[0011] [Figure 1] Compound 7, Form A, exhibits a characteristic XRPD pattern.

[0012] [Figure 2] 1 shows a characteristic TGA thermogram for Compound 7, Form A.

[0013] [Figure 3] 1 shows a characteristic DSC thermogram for Compound 7, Form A.

[0014] [Figure 4] Compound 7, Form B, exhibits a characteristic XRPD pattern.

[0015] [Figure 5] 1 shows a characteristic solid-state 13C NMR spectrum of Compound 7, Form B.

[0016] [Figure 6] 1 shows a characteristic solid-state 19F NMR spectrum of Compound 7, Form B.

[0017] [Figure 7] 1 shows a characteristic TGA thermogram for Compound 7, Form B.

[0018] [Figure 8]1 shows a characteristic DSC thermogram for Compound 7, Form B.

[0019] [Figure 9] 1 shows a characteristic IR spectrum for Compound 7, Form B.

[0020] [Figure 10] 1 shows a characteristic thermal ellipsoid plot for Compound 7, Form B.

[0021] [Figure 11] 1 shows a characteristic thermal vibration ellipsoid plot for Compound 9, Form A.

[0022] [Figure 12] Compound 11, Form A, exhibits a characteristic XRPD pattern.

[0023] [Figure 13] Compound 11, Form B, exhibits a characteristic XRPD pattern.

[0024] [Figure 14] 1 shows a characteristic thermal vibration ellipsoid plot for Compound 11, Form A.

[0025] [Figure 15] Compound 19, Form A, exhibits a characteristic XRPD pattern.

[0026] [Figure 16] 1 shows a characteristic solid-state 13C NMR spectrum of Compound 19, Form A.

[0027] [Figure 17] 1 shows a characteristic solid-state 19F NMR spectrum of Compound 19, Form A.

[0028] [Figure 18] 1 shows a characteristic thermal vibration ellipsoid plot for Compound 19, Form A.

[0029] [Figure 19] 2 shows a characteristic XRPD pattern for Compound 22, Form A.

[0030] [Figure 20] 1 shows a characteristic solid-state 13C NMR spectrum of Compound 22, Form A.

[0031] [Figure 21] 1 shows a characteristic solid-state 19F NMR spectrum of Compound 22, Form A.

[0032] [Figure 22] Compound 23, Form A, exhibits a characteristic XRPD pattern.

[0033] [Figure 23] 1 shows a characteristic solid-state 13C NMR spectrum of Compound 23, Form A.

[0034] [Figure 24] 1 shows a characteristic solid-state 19F NMR spectrum of Compound 23, Form A.

[0035] [Figure 25] 1 shows a characteristic thermal vibration ellipsoid plot for Compound 23, Form A.

[0036] [Figure 26] 2 shows a characteristic XRPD pattern for Compound 25, Form A. DETAILED DESCRIPTION OF THE INVENTION

[0037] In one aspect, the present invention provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein X 2a is N, N + -O -, or CR 2a and; X 4a is N, N + -O - , or CR 4a and; X 5a is N, N + -O - or CR 5a and; X 6a is N, N + -O - or CR 6a and; each R is independently H or C1-C6 alkyl; R 2a , R 4a , R 5a , and R 6a are each independently H, halo, C-C alkyl, or C-C haloalkyl; R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; R 5b1 and R 5b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; X 3c is N or CR 3c and; X 4c is N or CR 4c and; X 5c is N or CR 5c and; X 6c is N or CR 6c and; R 2c is H, OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2-(C3-C6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; L 1 is a bond or O; L 2 is a bond or C1-C6 alkylene; R 3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 4c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 5c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 6c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; However, X 2a , X 4a , X 5a , and X 6a N or N + -O - provided that there are not more than two such X 3c , X 4c , X 5c , and X 6c (Provided that not more than one of these is N).

[0038] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 2a is CR 2a and X 5a is CR 5a and X 6a is CR 6a and;R 4b1 and R 4b2 are each independently H, C-C alkyl, or C-C haloalkyl; R 5b1 and R 5b2 are each independently H, C-C alkyl, or C-C haloalkyl; X 3c is CR 3c and X4c is CR 4c and X 5c is CR 5c and X 6c is CR 6c and;R 2c is H, OH, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0039] For the purposes of this invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. Further, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5 th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001.

[0040] As used herein, the term "compounds of the invention" refers to compounds of formula (I), (IA), (IA-1), (IB), (IB-1), (IC), and (IC-1), and all embodiments thereof described herein, and those identified in Tables A, B, and C.

[0041] As described herein, the compounds of the present invention may be substituted with a number of variables (e.g., R, X 4a , R 5bAs one of skill in the art will recognize, combinations of groups contemplated by the present invention are those that result in the formation of stable or chemically feasible compounds. The term "stable" in this context refers to a compound that remains substantially unchanged when subjected to conditions that allow for the compound's production, detection, and preferably the compound's recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that remains substantially unchanged when kept at a temperature of 40° C. or less, in the absence of moisture or other chemically reactive conditions, for at least one week.

[0042] The chemical structures depicted herein are intended to be understood as one of ordinary skill in the art would understand. For example, with respect to formulas (I), (IA), (IB), and (IC), one of ordinary skill in the art would understand that X 5a and X 6a are connected by a double bond, and X 4c and X 5c are connected by a single bond, even if the bond between these groups is hidden by the atom labels in the chemical structure. Furthermore, one of ordinary skill in the art will understand that a substituent designated in a chemical structure as "CF3" or "F3C" refers to a trifluoromethyl substituent, regardless of which depiction appears in the chemical structure.

[0043] As used herein, the term "halo" means F, Cl, Br, or I.

[0044] As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing no unsaturation, having the specified number of carbon atoms, and attached to the remainder of the molecule by a single bond. For example, a "C1-C6 alkyl" group is an alkyl group having from 1 to 6 carbon atoms.

[0045] As used herein, the term "haloalkyl" refers to an alkyl group having a specified number of carbon atoms, in which one or more of the alkyl group's hydrogen atoms have been replaced with a halo group. For example, a "C1-C6 haloalkyl" group is an alkyl group having 1 to 6 carbon atoms, in which one or more of the alkyl group's hydrogen atoms have been replaced with a halo group.

[0046] As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds, having a specified number of carbon atoms, and attached to the rest of the molecule by a single bond. For example, a "C2-C6 alkenyl" group is an alkenyl group having from 2 to 6 carbon atoms.

[0047] As used herein, the term "cycloalkyl" refers to a stable, non-aromatic, monocyclic or bicyclic (fused, bridged, or spiro) saturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having the specified number of carbon ring atoms, and attached to the remainder of the molecule by a single bond. For example, a "C3-C8 cycloalkyl" group is a cycloalkyl group having from 3 to 8 carbon atoms.

[0048] As used herein, the term "alkylene" refers to a divalent straight or branched hydrocarbon chain radical group, consisting solely of carbon and hydrogen atoms, containing no unsaturation, having the specified number of carbon atoms, and attached to the rest of the molecule by two single bonds. For example, a "C1-C6 alkylene" group is an alkylene group having from 1 to 6 carbon atoms.

[0049] 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 that is "optionally substituted with 1 to 2 halo" is unsubstituted, substituted with 1 halo group, or substituted with 2 halo groups.

[0050] Unless otherwise specified, the compounds of the invention, whether identified by chemical name or chemical structure, include all stereoisomers (e.g., enantiomers and diastereomers), double bond isomers (e.g., (Z) and (E)), conformational isomers, and tautomers of the compounds identified by the chemical names and chemical structures provided herein. Additionally, single stereoisomers, double bond isomers, conformational isomers, and tautomers, as well as mixtures of stereoisomers, double bond isomers, conformational isomers, and tautomers, are within the scope of the invention.

[0051] As used herein, in any chemical structure or formula, e.g., [ka] A bold or dashed linear bond attached to a stereocenter of a compound, such as in [ka] ) indicates the relative stereochemistry of a stereocenter relative to the other stereocenter(s) to which the bold or dashed linear bond is attached.

[0052] As used herein, in any chemical structure or formula, e.g., [ka] A bold or dashed wedge bond attached to a stereocenter of a compound, such as in [ka] ) indicates the absolute stereochemistry of the stereocenter as well as the relative stereochemistry of the stereocenter relative to the other stereocenter(s) to which the bold or dashed wedge bond is attached.

[0053] As used herein, the prefix "rac-," when used in reference to a chiral compound, refers to a racemic mixture of the compound. In compounds prefixed with "rac-," the (R)- and (S)-designators in the chemical name reflect the relative stereochemistry of the compounds.

[0054] As used herein, the prefix "rel-", when used in reference to a chiral compound, refers to a single enantiomer of unknown absolute configuration. In compounds prefixed with "rel-", the (R)- and (S)- designators in the chemical name reflect the relative stereochemistry of the compounds, but do not necessarily reflect the absolute stereochemistry of the compounds.

[0055] As used herein, the term "compound," when referring to a compound of the present invention, refers to a collection of molecules that have the same chemical structure, except that there may be isotopic variations between the constituent atoms of the molecule. The term "compound" includes a collection of molecules, regardless of the purity of a given sample containing the collection of molecules. Thus, the term "compound" includes such a collection of molecules in pure form, in a mixture with one or more other substances (e.g., a solution, suspension, colloid, or pharmaceutical composition or dosage form), or in the form of a hydrate, solvate, or co-crystal.

[0056] In this specification and claims, unless otherwise specified, any atom not specifically designated as a particular isotope in any compound of the present invention is meant to represent any stable isotope of the designated element. In the examples, when an atom in any compound of the present invention is not specifically designated as a particular isotope, no effort has been made to enrich that atom in a particular isotope, and therefore, one skilled in the art will understand that such atom likely existed in approximately the natural abundance isotopic composition of the designated element.

[0057] As used herein, the term "stable," when referring to an isotope, means that the isotope is not known to undergo spontaneous radioactive decay. Stable isotopes include, but are not limited to, isotopes whose decay mode has not been identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0058] As used in this specification and claims, "H" refers to hydrogen and includes any stable isotope of hydrogen, i.e., 1 Includes H and D. In the examples, where an atom is designated as "H," no effort has been made to enrich that atom in a particular isotope of hydrogen, and thus, one of skill in the art will understand that such hydrogen atom likely existed in approximately the natural abundance isotopic composition of hydrogen.

[0059] As used herein, " 1 "H" refers to protium. When an atom in a compound of the invention, or a pharmaceutically acceptable salt thereof, is referred to as protium, protium is present at the specified position at least at the natural abundance of protium.

[0060] As used herein, "D", "d", and " 2 "H" refers to deuterium.

[0061] In some embodiments, the compounds of the present invention, and pharmaceutically acceptable salts thereof, contain each constituent atom in an isotopic composition at about the natural abundance of the specified element.

[0062] In some embodiments, the compounds of the present invention, and pharmaceutically acceptable salts thereof, contain one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the most abundant isotope of the specified element ("isotopically labeled" compounds and salts). Examples of stable isotopes that are commercially available and suitable for the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, e.g., 2 H, 13 C. 15 N, 18 O. 17 O, and 31 Examples include, but are not limited to, P.

[0063] Isotopically labeled compounds and salts can be used in a number of beneficial ways, including as pharmaceuticals. In some embodiments, isotopically labeled compounds and salts are deuterium ( 2 H) labeled with deuterium ( 2 H) The labeled compounds and salts are therapeutically useful and non- 2 have potential therapeutic advantages over H-labeled compounds. Generally, deuterium ( 2 H) Labeled compounds and salts may have higher metabolic stability compared to non-isotopically labeled counterparts due to the kinetic isotope effect described below. Higher metabolic stability translates directly into increased in vivo half-life or lower dosages, which under most circumstances will represent a preferred embodiment of the present invention. Isotopically labeled compounds and salts can generally be prepared by following the procedures disclosed in the synthetic schemes, examples, and related description, substituting readily available isotopically labeled reactants for non-isotopically labeled reactants.

[0064] deuterium( 2H) labeled compounds and salts can manipulate the rate of oxidative metabolism of a compound through the primary kinetic isotope effect. Primary kinetic isotope effect is a change in the rate of a chemical reaction due to the exchange of an isotope nucleus, which is caused by a change in the ground state energy of the covalent bond involved in the reaction. The exchange of a heavier isotope usually results in a lowering of the ground state energy of the chemical bond, thereby causing a decrease in rate-limiting bond scission. If bond scission occurs in or near a saddle point region along the coordinate of a multi-product reaction, the distribution ratio of the products can be substantially altered. For example, if deuterium is attached to a carbon atom at a non-exchangeable position, k H / k D A rate difference of 2 to 7 is typical. For further discussion, see SL Harbeson and RD Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417, which is incorporated herein by reference in its entirety.

[0065] The concentration of an isotope (e.g., deuterium) incorporated at a given position in an isotopically labeled compound of the present invention or a pharmaceutically acceptable salt thereof can be defined by the isotopic enrichment factor. The term "isotopic enrichment factor," as used herein, refers to the ratio between the abundance of an isotope at a given position in an isotopically labeled compound (or salt) and the natural abundance of that isotope.

[0066] When an atom in a compound of the invention, or a pharmaceutically acceptable salt thereof, is designated as deuterium, such compound (or salt) has an isotopic enrichment factor for such atom of at least 3000 (about 45% deuterium incorporation). In some embodiments, the isotopic enrichment factor is at least 3500 (about 52.5% deuterium incorporation), at least 4000 (about 60% deuterium incorporation), at least 4500 (about 67.5% deuterium incorporation), at least 5000 (about 75% deuterium incorporation), at least 5500 (about 82.5% deuterium incorporation), at least 6000 (about 90% deuterium incorporation), at least 6333.3 (about 95% deuterium incorporation), at least 6466.7 (about 97% deuterium incorporation), at least 6600 (about 99% deuterium incorporation), or at least 6633.3 (about 99.5% deuterium incorporation).

[0067] In some embodiments, the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts thereof, wherein each R is H. In other embodiments, each R is independently H or CH. In other embodiments, N(R) is NHCH.

[0068] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 2a is N. In other embodiments, X 2a is CR 2a In some embodiments, R 2a is H, D, halo, or C-C alkyl. In other embodiments, R 2a is H, D, F, or CH3. In some embodiments, X 2a is N, CH, CD, C-(C-C alkyl), or C-halo. 2a is N, CH, CD, C-CH3, or CF.

[0069] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 2a is CR2a and;R 2a is H.

[0070] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4a is N. In other embodiments, X 4a is N + -O - In another embodiment, X 4a is CR 4a In some embodiments, R 4a is halo. In other embodiments, R 4a is H or halo. In other embodiments, R 4a is H or F. In other embodiments, X 4a is CF. In some embodiments, X 4a is N, N + -O - , CH, or C-halo. 4a is N, N + -O - , CH, or CF.

[0071] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4a is CR 4a and;R 4a is a halo.

[0072] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 5a is N. In other embodiments, X 5a is CR 5a In some embodiments, R 5a is H, D, halo, or C-C alkyl. In other embodiments, R 5a is H, D, F, or CH3. In some embodiments, X 5a is N, CH, CD, C-(C-C alkyl), or C-halo. 5ais N, CH, CD, C-CH3, or CF.

[0073] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 5a is CR 5a and;R 5a is H.

[0074] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 6a is N. In other embodiments, X 6a is CR 6a In some embodiments, R 6a is H, D, halo, or C-C alkyl. In other embodiments, R 6a is H, D, F, or CH3. In some embodiments, X 6a is N, CH, CD, C-(C-C alkyl), or C-halo. 6a is N, CH, CD, C-CH3, or CF.

[0075] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 6a is CR 6a and;R 6a is H.

[0076] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 4b1 and R 4b2 are each independently H or C1-C6 alkyl. In other embodiments, R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. 4b1 and R 4b2 are each independently H or CH. In other embodiments, R 4b1 and R 4b2are each independently H, CH, CHCH, or cyclopropyl. 4b1 is C1-C6 alkyl, and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is C1-C6 alkyl. In other embodiments, R 4b1 is CH3 and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is CH3.

[0077] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5b1 and R 5b2 are each independently C1-C6 alkyl or C1-C6 haloalkyl. 5b1 and R 5b2 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl. 5b1 and R 5b2 are each independently H, CH, or CF. In other embodiments, R 5b1 and R 5b2 are each independently H, CH, CHCH, CH(CH), C(CH), CHF, CFCH, CHCF, or CF. 5b1 is C1-C6 alkyl, and R 5b2 is C1-C6 haloalkyl. In other embodiments, R 5b1 is C1-C6 haloalkyl, and R 5b2 is C1-C6 alkyl. In other embodiments, R 5b1 is CH3 and R 5b2 is CF3. In other embodiments, R 5b1 is CF3 and R 5b2 is CH3.

[0078] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2cis OH, C1-C6 alkoxy, or C1-C6 haloalkoxy. 2c is OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), where the cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R 2c is H. In other embodiments, R 2c is C1-C6 alkoxy. In other embodiments, R 2c is C1-C6 haloalkoxy. In other embodiments, R 2c -L 1 -L 2 -(C3-C6 cycloalkyl), where the cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R 2c is OH, OCH, OCD, OCHCH, or OCHF. In other embodiments, R 2c are H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCHF2, [ka] In other embodiments, R 2c is OH. In other embodiments, R 2c is OCH3. In other embodiments, R 2c is OCD3. In other embodiments, R 2c is OCH2CH3. In other embodiments, R 2c is OCHF2.

[0079] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 3c is N. In other embodiments, X 3c is CR 3c In another embodiment, R 3cis H, halo, C-C alkyl, or C-C haloalkyl. 3c is H, CH3, CH2CH3, CHF2, CF3, F, or Cl. In some embodiments, X 3c is N, CH, C-CH3, C-CH2CH3, C-CHF2, C-CF3, CF, or C-Cl.

[0080] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 3c is CR 3c and;R 3c is H, halo, or C-C alkyl. In other embodiments, R 3c is halo. In other embodiments, R 3c is C1-C6 alkyl. In other embodiments, R 3c is H, F, Cl, or CH. In other embodiments, R 3c is H. In other embodiments, R 3c is F. In other embodiments, R 3c is C1. In other embodiments, R 3c is CH3.

[0081] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4c is N. In other embodiments, X 4c is CR 4c In another embodiment, R 4c is H, halo, or C1-C6 haloalkyl. In other embodiments, R 4c is H, CHF2, CF3, or F. In some embodiments, X 4c is N, CH, C-CHF2, C-CF3, or CF.

[0082] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4c is CR 4c and;R 4cis halo. In other embodiments, R 4c is F.

[0083] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 5c is N. In other embodiments, X 5c is CR 5c In other embodiments, R 5c is H or halo. In other embodiments, R 5c is H, D, or Cl. In some embodiments, X 5c is N, CH, CD, or C-Cl.

[0084] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 5c is CR 5c and;R 5c is H.

[0085] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 6c is N. In other embodiments, X 6c is CR 6c In other embodiments, R 6c is H or halo. In other embodiments, R 6c is H or F. In some embodiments, X 6c is N, CH, or CF.

[0086] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 6c is H.

[0087] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 2a is N, CH, CD, C—(C1-C6 alkyl), or C-halo; X 4a is N, N + -O- , CH, or C-halo; X 5a is N, CH, CD, C—(C1-C6 alkyl), or C-halo; X 6a is N, CH, CD, C—(C1-C6 alkyl), or C-halo; each R is H or CH3; R 4b1 and R 4b2 are each independently H, C-C alkyl, or C-C cycloalkyl; R 5b1 and R 5b2 are each independently H, C-C alkyl, or C-C haloalkyl; R 2c is OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; X 3c is CR 3c and;R 3c is H, halo, C-C alkyl, or C-C haloalkyl; X 4c is CR 4c and;R 4c is H, halo, or C1-C6 haloalkyl; X 5c is CR 5c and;R 5c is H or halo; X 6c is CR 6c and;R 6c is H or halo.

[0088] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6aand;R 6a is H;R 4b1 and R 4b2 are each independently H or C1-C6 alkyl; R 5b1 and R 5b2 are each independently C1-C6 alkyl or C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0089] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 2a is N, CH, CD, C-CH3, or CF; X 4a is N, N + -O - , CH, or CF; X 5a is N, CH, CD, C-CH3 or CF; X 6a is N, CH, CD, C-CH3, or CF; each R is H or CH3; R 4b1 and R 4b2 are each independently H, CH, CHCH, or cyclopropyl; R 5b1 and R 5b2 are each independently H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CHF2, CF2CH3, CH2CF3, or CF3; R 2c are H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCHF2, [ka] and X 3c is N, CH, C-CH3, C-CH2CH3, C-CHF2, C-CF3, CF, or C-Cl; X 4c is N, CH, C-CHF2, C-CF3, or CF; X 5c is N, CH, CD, or C-Cl; X 6c is N, CH, or CF.

[0090] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 4b1 and R 4b2 are each independently H or CH; R 5b1 and R 5b2 are each independently H, CH3, or CF3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0091] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 4b1 is C1-C6 alkyl; R 4b2 is H;R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0092] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 4b1 is H;R 4b2 is C1-C6 alkyl; R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2cis OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0093] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 4b1 is C1-C6 alkyl; R 4b2 is H;R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0094] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 4b1 is H;R 4b2 is C1-C6 alkyl; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0095] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 5b1 is CH3; R 5b2 is CF3; R 4b1 is CH3; R4b2 is H;R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0096] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 5b1 is CH3; R 5b2 is CF3; R 4b1 is H;R 4b2 is CH3; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0097] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 5b1 is CF3; R 5b2 is CH3; R 4b1 is CH3; R 4b2 is H;R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0098] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 5b1 is CF3; R 5b2 is CH3; R 4b1 is H and R 4b2is CH3; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0099] In some embodiments, the present invention relates to compounds of formula (I) (including any of the foregoing embodiments thereof), ie, compounds in non-salt form.

[0100] In some embodiments, the present invention provides a compound of formula (IA): [ka] or a pharmaceutically acceptable salt thereof, wherein X 2a is N, N + -O - , or CR 2a and; X 4a is N, N + -O - , or CR 4a and; X 5a is N, N + -O - , or CR 5a and; X 6a is N, N + -O - , or CR 6a and; each R is independently H or C1-C6 alkyl; R 2a , R 4a , R 5a, and R 6a are each independently H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; R 5b1 and R 5b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; X 3c is N or CR 3c and; X 4c is N or CR 4c and; X 5c is N or CR 5c and; X 6c is N or CR 6c and; R 2c is H, OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; L 1 is a bond or O; L 2 is a bond or C1-C6 alkylene; R 3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 4c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 5c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 6c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; However, X2a , X 4a , X 5a , and X 6a N or N + -O - provided that there are not more than two such X 3c , X 4c , X 5c , and X 6c (Provided that not more than one of these is N).

[0101] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 2a is CR 2a and X 5a is CR 5a and X 6a is CR 6a and;R 4b1 and R 4b2 are each independently H, C-C alkyl, or C-C haloalkyl; R 5b1 and R 5b2 are each independently H, C-C alkyl, or C-C haloalkyl; X 3c is CR 3c and X 4c is CR 4c and X 5c is CR 5c and X 6c is CR 6c and;R 2c is H, OH, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0102] In some embodiments, the present invention relates to compounds of formula (IA), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently H or CH. In other embodiments, N(R) is NHCH.

[0103] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 2a is N. In other embodiments, X 2a is CR 2a In some embodiments, R 2a is H, D, halo, or C-C alkyl. In other embodiments, R 2a is H, D, F, or CH3. In some embodiments, X 2a is N, CH, CD, C-(C-C alkyl), or C-halo. 2a is N, CH, CD, C-CH3, or CF.

[0104] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 2a is CR 2a and;R 2a is H.

[0105] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 4a is N. In other embodiments, X 4a is N + -O - In another embodiment, X 4a is CR 4a In some embodiments, R 4a is halo. In other embodiments, R 4a is H or halo. In other embodiments, R 4a is H or F. In other embodiments, X 4a is CF. In some embodiments, X 4a is N, N + -O - , CH, or C-halo. 4a is N, N + -O - , CH, or CF.

[0106] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 4a is CR 4a and;R 4a is a halo.

[0107] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 5a is N. In other embodiments, X 5a is CR 5a In some embodiments, R 5a is H, D, halo, or C-C alkyl. In other embodiments, R 5a is H, D, F, or CH3. In some embodiments, X 5a is N, CH, CD, C-(C-C alkyl), or C-halo. 5a is N, CH, CD, C-CH3, or CF.

[0108] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 5a is CR 5a and;R 5a is H.

[0109] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 6a is N. In other embodiments, X 6a is CR 6a In some embodiments, R 6a is H, D, halo, or C-C alkyl. In other embodiments, R 6a is H, D, F, or CH3. In some embodiments, X 6a is N, CH, CD, C-(C-C alkyl), or C-halo. 6a is N, CH, CD, C-CH3, or CF.

[0110] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 6a is CR 6a and;R 6a is H.

[0111] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein R 4b1 and R 4b2 are each independently H or C1-C6 alkyl. In other embodiments, R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. 4b1 and R 4b2 are each independently H or CH. In other embodiments, R 4b1 and R 4b2 are each independently H, CH, CHCH, or cyclopropyl. 4b1 is C1-C6 alkyl, and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is C1-C6 alkyl. In other embodiments, R 4b1 is CH3 and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is CH3.

[0112] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein R 5b1 and R 5b2 are each independently C1-C6 alkyl or C1-C6 haloalkyl. 5b1 and R 5b2 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl. 5b1 and R 5b2are each independently H, CH, or CF. In other embodiments, R 5b1 and R 5b2 are each independently H, CH, CHCH, CH(CH), C(CH), CHF, CFCH, CHCF, or CF. 5b1 is C1-C6 alkyl, and R 5b2 is C1-C6 haloalkyl. In other embodiments, R 5b1 is C1-C6 haloalkyl, and R 5b2 is C1-C6 alkyl. In other embodiments, R 5b1 is CH3 and R 5b2 is CF3. In other embodiments, R 5b1 is CF3 and R 5b2 is CH3.

[0113] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy. 2c is OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), where the cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R 2c is H. In other embodiments, R 2c is C1-C6 alkoxy. In other embodiments, R 2c is C1-C6 haloalkoxy. In other embodiments, R 2c -L 1 -L 2 -(C3-C6 cycloalkyl), where the cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R 2c is OH, OCH, OCD, OCHCH, or OCHF. In other embodiments, R 2care H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCHF2, [ka] In other embodiments, R 2c is OH. In other embodiments, R 2c is OCH3. In other embodiments, R 2c is OCD3. In other embodiments, R 2c is OCH2CH3. In other embodiments, R 2c is OCHF2.

[0114] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 3c is N. In other embodiments, X 3c is CR 3c In another embodiment, R 3c is H, halo, C-C alkyl, or C-C haloalkyl. 3c is H, CH3, CH2CH3, CHF2, CF3, F, or Cl. In some embodiments, X 3c is N, CH, C-CH3, C-CH2CH3, C-CHF2, C-CF3, CF, or C-Cl.

[0115] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 3c is CR 3c and;R 3c is H, halo, or C-C alkyl. In other embodiments, R 3c is halo. In other embodiments, R 3c is C1-C6 alkyl. In other embodiments, R 3c is H, F, Cl, or CH. In other embodiments, R 3c is H. In other embodiments, R 3c is F. In other embodiments, R 3cis C1. In other embodiments, R 3c is CH3.

[0116] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 4c is N. In other embodiments, X 4c is CR 4c In another embodiment, R 4c is H, halo, or C1-C6 haloalkyl. In other embodiments, R 4c is H, CHF2, CF3, or F. In some embodiments, X 4c is N, CH, C-CHF2, C-CF3, or CF.

[0117] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 4c is CR 4c and;R 4c is halo. In other embodiments, R 4c is F.

[0118] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 5c is N. In other embodiments, X 5c is CR 5c In other embodiments, R 5c is H or halo. In other embodiments, R 5c is H, D, or Cl. In some embodiments, X 5c is N, CH, CD, or C-Cl.

[0119] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 5c is CR 5c and;R 5c is H.

[0120] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 6c is N. In other embodiments, X 6c is CR 6c In other embodiments, R 6c is H or halo. In other embodiments, R 6c is H or F. In some embodiments, X 6c is N, CH, or CF.

[0121] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein R 6c is H.

[0122] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 2a is N, CH, CD, C—(C1-C6 alkyl), or C-halo; X 4a is N, N + -O - , CH, or C-halo; X 5a is N, CH, CD, C—(C1-C6 alkyl), or C-halo; X 6a is N, CH, CD, C—(C1-C6 alkyl), or C-halo; each R is H or CH3; R 4b1 and R 4b2 are each independently H, C-C alkyl, or C-C cycloalkyl; R 5b1 and R 5b2 are each independently H, C-C alkyl, or C-C haloalkyl; R 2c is OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; X 3c is CR 3c and;R3c is H, halo, C-C alkyl, or C-C haloalkyl; X 4c is CR 4c and;R 4c is H, halo, or C1-C6 haloalkyl; X 5c is CR 5c and;R 5c is H or halo; X 6c is CR 6c and;R 6c is H or halo.

[0123] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 4b1 and R 4b2 are each independently H or C1-C6 alkyl; R 5b1 and R 5b2 are each independently C1-C6 alkyl or C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0124] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 2a is N, CH, CD, C-CH3, or CF; X 4a is N, N + -O - , CH, or CF; X 5a is N, CH, CD, C-CH3 or CF; X 6a is N, CH, CD, C-CH3, or CF; each R is H or CH3; R 4b1 and R 4b2 are each independently H, CH, CHCH, or cyclopropyl; R 5b1 and R 5b2 are each independently H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CHF2, CF2CH3, CH2CF3, or CF3; R 2c are H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCHF2, [ka] and X 3c is N, CH, C-CH3, C-CH2CH3, C-CHF2, C-CF3, CF, or C-Cl; X 4c is N, CH, C-CHF2, C-CF3, or CF; X 5c is N, CH, CD, or C-Cl; X 6c is N, CH, or CF.

[0125] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR6a and;R 6a is H;R 4b1 and R 4b2 are each independently H or CH; R 5b1 and R 5b2 are each independently H, CH3, or CF3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0126] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 4b1 is C1-C6 alkyl; R 4b2 is H;R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4cis a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0127] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 4b1 is H;R 4b2 is C1-C6 alkyl; R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0128] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 4b1 is C1-C6 alkyl; R 4b2 is H;R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0129] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 4b1 is H;R 4b2 is C1-C6 alkyl; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3cis H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0130] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 5b1 is CH3; R 5b2 is CF3; R 4b1 is CH3; R 4b2 is H;R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0131] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2aand;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 5b1 is CH3; R 5b2 is CF3; R 4b1 is H;R 4b2 is CH3; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0132] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 5b1 is CF3; R 5b2 is CH3; R 4b1 is CH3; R 4b2 is H;R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3cis H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0133] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 5b1 is CF3; R 5b2 is CH3; R 4b1 is H and R 4b2 is CH3; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0134] In some embodiments, the present invention relates to compounds of formula (IA) (including any of the foregoing embodiments thereof), ie, compounds in non-salt form.

[0135] In some embodiments, the present invention provides a compound of formula (IA-1): [ka] or a pharmaceutically acceptable salt thereof, wherein X 4a is N, N + -O - , or CR 4a and; each R is independently H or C1-C6 alkyl; R 4a is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl; R 5b1 and R 5b2 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl; R 2c is H, OH, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 4c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl).

[0136] In some embodiments, the present invention relates to a compound of formula (IA-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N. In other embodiments, X 4a is N + -O - In another embodiment, X 4a is CR 4a In another embodiment, X 4a is CF.

[0137] In some embodiments, the present invention relates to a compound of formula (IA-1), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently H or CH. In other embodiments, N(R) is NHCH.

[0138] In some embodiments, the present invention relates to a compound of formula (IA-1), or a pharmaceutically acceptable salt thereof, wherein R 4a is a halo.

[0139] In some embodiments, the present invention relates to a compound of formula (IA-1), or a pharmaceutically acceptable salt thereof, wherein R 4b1 and R 4b2 are each independently H or C1-C6 alkyl. In other embodiments, R 4b1 and R 4b2 are each independently H or CH. In other embodiments, R 4b1 is C1-C6 alkyl, and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is C1-C6 alkyl. In other embodiments, R 4b1 is CH3 and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is CH3.

[0140] In some embodiments, the present invention relates to a compound of formula (IA-1), or a pharmaceutically acceptable salt thereof, wherein R 5b1 and R 5b2 are each independently C1-C6 alkyl or C1-C6 haloalkyl. 5b1 and R 5b2 are each independently H, CH, or CF. In other embodiments, R 5b1 is C1-C6 alkyl, and R 5b2 is C1-C6 haloalkyl. In other embodiments, R 5b1 is C1-C6 haloalkyl, and R 5b2is C1-C6 alkyl. In other embodiments, R 5b1 is CH3 and R 5b2 is CF3. In other embodiments, R 5b1 is CF3 and R 5b2 is CH3.

[0141] In some embodiments, the present invention relates to a compound of formula (IA-1), or a pharmaceutically acceptable salt thereof, wherein R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy. 2c is C1-C6 alkoxy. In other embodiments, R 2c is C1-C6 haloalkoxy. In other embodiments, R 2c is OH, OCH, OCD, OCHCH, or OCHF. In other embodiments, R 2c is OH. In other embodiments, R 2c is OCH3. In other embodiments, R 2c is OCD3. In other embodiments, R 2c is OCH2CH3. In another embodiment, R 2c is OCHF2.

[0142] In some embodiments, the present invention relates to a compound of formula (IA-1), or a pharmaceutically acceptable salt thereof, wherein R 3c is H, halo, or C-C alkyl. In other embodiments, R 3c is halo. In other embodiments, R 3c is C1-C6 alkyl. In other embodiments, R 3c is H, F, Cl, or CH. In other embodiments, R 3c is H. In other embodiments, R 3c is F. In other embodiments, R 3c is C1. In other embodiments, R 3c is CH3.

[0143] In some embodiments, the present invention relates to a compound of formula (IA-1), or a pharmaceutically acceptable salt thereof, wherein R 4c is halo. In other embodiments, R 4c is F.

[0144] In some embodiments, the present invention relates to a compound of formula (IA-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 and R 4b2 are each independently H or C1-C6 alkyl; R 5b1 and R 5b2 are each independently C1-C6 alkyl or C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0145] In some embodiments, the present invention relates to a compound of formula (IA-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 and R 4b2 are each independently H or CH; R 5b1 and R 5b2 are each independently H, CH3, or CF3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0146] In some embodiments, the present invention relates to a compound of formula (IA-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is C1-C6 alkyl; R 4b2 is H;R 5b1 is C1-C6 alkyl; R 5b2is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0147] In some embodiments, the present invention relates to a compound of formula (IA-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H;R 4b2 is C1-C6 alkyl; R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0148] In some embodiments, the present invention relates to a compound of formula (IA-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is C1-C6 alkyl; R 4b2 is H;R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0149] In some embodiments, the present invention relates to a compound of formula (IA-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H;R 4b2 is C1-C6 alkyl; R 5b1 is C1-C6 haloalkyl; R5b2 is C1-C6 alkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0150] In some embodiments, the present invention relates to a compound of formula (IA-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is CH3; R 4b2 is H;R 5b1 is CH3; R 5b2 is CF3; R 2c is OH, C-C alkoxy, or C-C haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0151] In some embodiments, the present invention relates to a compound of formula (IA-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H;R 4b2 is CH3; R 5b1 is CH3; R 5b2 is CF3; R 2c is OH, C-C alkoxy, or C-C haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0152] In some embodiments, the present invention relates to a compound of formula (IA-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is CH3; R 4b2 is H;R 5b1 is CF3; R 5b2 is CH3; R 2cis OH, C-C alkoxy, or C-C haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0153] In some embodiments, the present invention relates to a compound of formula (IA-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H;R 4b2 is CH3; R 5b1 is CF3; R 5b2 is CH3; R 2c is OH, C-C alkoxy, or C-C haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0154] In some embodiments, the present invention relates to compounds of formula (IA-1), including any of the foregoing embodiments thereof, ie, the compounds in non-salt form.

[0155] In some embodiments, the present invention provides a compound of formula (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein X 2a is N, N + -O - , or CR 2a and; X 4a is N, N + -O - , or CR 4a and; X 5a is N, N + -O - , or CR 5a and; X 6a is N, N + -O -, or CR 6a and; each R is independently H or C1-C6 alkyl; R 2a , R 4a , R 5a , and R 6a are each independently H, halo, C-C alkyl, or C-C haloalkyl; R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; R 5b1 and R 5b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; X 3c is N or CR 3c and; X 4c is N or CR 4c and; X 5c is N or CR 5c and; X 6c is N or CR 6c and; R 2c is H, OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; L 1 is a bond or O; L 2 is a bond or C1-C6 alkylene; R 3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 4c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R5c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 6c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; However, X 2a , X 4a , X 5a , and X 6a N or N + -O - provided that there are not more than two such X 3c , X 4c , X 5c , and X 6c (Provided that not more than one of these is N).

[0156] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 2a is CR 2a and X 5a is CR 5a and X 6a is CR 6a and;R 4b1 and R 4b2 are each independently H, C-C alkyl, or C-C haloalkyl; R 5b1 and R 5b2 are each independently H, C-C alkyl, or C-C haloalkyl; X 3c is CR 3c and X 4c is CR 4c and X 5c is CR 5c and X 6c is CR 6c and;R 2c is H, OH, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0157] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently H or CH. In other embodiments, N(R) is NHCH.

[0158] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 2a is N. In other embodiments, X 2a is CR 2a In some embodiments, R 2a is H, D, halo, or C-C alkyl. In other embodiments, R 2a is H, D, F, or CH3. In some embodiments, X 2a is N, CH, CD, C-(C-C alkyl), or C-halo. 2a is N, CH, CD, C-CH3, or CF.

[0159] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 2a is CR 2a and;R 2a is H.

[0160] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 4a is N. In other embodiments, X 4a is N + -O - In another embodiment, X 4a is CR 4a In some embodiments, R 4a is halo. In other embodiments, R 4a is H or halo. In other embodiments, R 4a is H or F. In other embodiments, X 4a is CF. In some embodiments, X 4a is N, N +-O - , CH, or C-halo. 4a is N, N + -O - , CH, or CF.

[0161] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 4a is CR 4a and;R 4a is a halo.

[0162] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 5a is N. In other embodiments, X 5a is CR 5a In some embodiments, R 5a is H, D, halo, or C-C alkyl. In other embodiments, R 5a is H, D, F, or CH3. In some embodiments, X 5a is N, CH, CD, C-(C-C alkyl), or C-halo. 5a is N, CH, CD, C-CH3, or CF.

[0163] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 5a is CR 5a and;R 5a is H.

[0164] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 6a is N. In other embodiments, X 6a is CR 6a In some embodiments, R 6a is H, D, halo, or C-C alkyl. In other embodiments, R 6ais H, D, F, or CH3. In some embodiments, X 6a is N, CH, CD, C-(C-C alkyl), or C-halo. 6a is N, CH, CD, C-CH3, or CF.

[0165] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 6a is CR 6a and;R 6a is H.

[0166] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein R 4b1 and R 4b2 are each independently H or C1-C6 alkyl. In other embodiments, R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. 4b1 and R 4b2 are each independently H or CH. In other embodiments, R 4b1 and R 4b2 are each independently H, CH, CHCH, or cyclopropyl. 4b1 is C1-C6 alkyl, and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is C1-C6 alkyl. In other embodiments, R 4b1 is CH3 and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is CH3.

[0167] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein R 5b1 and R 5b2are each independently C1-C6 alkyl or C1-C6 haloalkyl. 5b1 and R 5b2 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl. 5b1 and R 5b2 are each independently H, CH, or CF. In other embodiments, R 5b1 and R 5b2 are each independently H, CH, CHCH, CH(CH), C(CH), CHF, CFCH, CHCF, or CF. 5b1 is C1-C6 alkyl, and R 5b2 is C1-C6 haloalkyl. In other embodiments, R 5b1 is C1-C6 haloalkyl, and R 5b2 is C1-C6 alkyl. In other embodiments, R 5b1 is CH3 and R 5b2 is CF3. In other embodiments, R 5b1 is CF3 and R 5b2 is CH3.

[0168] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy. 2c is OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), where the cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R 2c is H. In other embodiments, R 2c is C1-C6 alkoxy. In other embodiments, R 2c is C1-C6 haloalkoxy. In other embodiments, R 2c -L 1 -L2 -(C3-C6 cycloalkyl), where the cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R 2c is OH, OCH, OCD, OCHCH, or OCHF. In other embodiments, R 2c are H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCHF2, [ka] In other embodiments, R 2c is OH. In other embodiments, R 2c is OCH3. In other embodiments, R 2c is OCD3. In other embodiments, R 2c is OCH2CH3. In other embodiments, R 2c is OCHF2.

[0169] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 3c is N. In other embodiments, X 3c is CR 3c In another embodiment, R 3c is H, halo, C-C alkyl, or C-C haloalkyl. 3c is H, CH3, CH2CH3, CHF2, CF3, F, or Cl. In some embodiments, X 3c is N, CH, C-CH3, C-CH2CH3, C-CHF2, C-CF3, CF, or C-Cl.

[0170] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 3c is CR 3c and;R 3c is H, halo, or C-C alkyl. In other embodiments, R 3c is halo. In other embodiments, R3c is C1-C6 alkyl. In other embodiments, R 3c is H, F, Cl, or CH. In other embodiments, R 3c is H. In other embodiments, R 3c is F. In other embodiments, R 3c is C1. In other embodiments, R 3c is CH3.

[0171] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 4c is N. In other embodiments, X 4c is CR 4c In another embodiment, R 4c is H, halo, or C1-C6 haloalkyl. In other embodiments, R 4c is H, CHF2, CF3, or F. In some embodiments, X 4c is N, CH, C-CHF2, C-CF3, or CF.

[0172] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 4c is CR 4c and;R 4c is halo. In other embodiments, R 4c is F.

[0173] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 5c is N. In other embodiments, X 5c is CR 5c In other embodiments, R 5c is H or halo. In other embodiments, R 5c is H, D, or Cl. In some embodiments, X 5c is N, CH, CD, or C—Cl.

[0174] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 5c is CR 5c and;R 5c is H.

[0175] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 6c is N. In other embodiments, X 6c is CR 6c In other embodiments, R 6c is H or halo. In other embodiments, R 6c is H or F. In some embodiments, X 6c is N, CH, or CF.

[0176] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein R 6c is H.

[0177] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 2a is N, CH, CD, C—(C1-C6 alkyl), or C-halo; X 4a is N, N + -O - , CH, or C-halo; X 5a is N, CH, CD, C—(C1-C6 alkyl), or C-halo; X 6a is N, CH, CD, C—(C1-C6 alkyl), or C-halo; each R is H or CH3; R 4b1 and R 4b2 are each independently H, C-C alkyl, or C-C cycloalkyl; R 5b1 and R 5b2 are each independently H, C-C alkyl, or C-C haloalkyl; R 2cis OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; X 3c is CR 3c and;R 3c is H, halo, C-C alkyl, or C-C haloalkyl; X 4c is CR 4c and;R 4c is H, halo, or C1-C6 haloalkyl; X 5c is CR 5c and;R 5c is H or halo; X 6c is CR 6c and;R 6c is H or halo.

[0178] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 4b1 and R 4b2 are each independently H or C1-C6 alkyl; R 5b1 and R 5b2 are each independently C1-C6 alkyl or C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4cand;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0179] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 2a is N, CH, CD, C-CH3, or CF; X 4a is N, N + -O - , CH, or CF; X 5a is N, CH, CD, C-CH3 or CF; X 6a is N, CH, CD, C-CH3, or CF; each R is H or CH3; R 4b1 and R 4b2 are each independently H, CH, CHCH, or cyclopropyl; R 5b1 and R 5b2 are each independently H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CHF2, CF2CH3, CH2CF3, or CF3; R 2c are H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCHF2, [ka] and X 3c is N, CH, C-CH3, C-CH2CH3, C-CHF2, C-CF3, CF, or C-Cl; X 4c is N, CH, C-CHF2, C-CF3, or CF; X 5c is N, CH, CD, or C-Cl; X 6c is N, CH, or CF.

[0180] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 4b1 and R 4b2 are each independently H or CH; R 5b1 and R 5b2 are each independently H, CH3, or CF3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0181] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 4b1 is C1-C6 alkyl; R 4b2 is H;R 5b1is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0182] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 4b1 is H;R 4b2 is C1-C6 alkyl; R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6cand;R 6c is H.

[0183] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 4b1 is C1-C6 alkyl; R 4b2 is H;R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0184] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 4b1 is H;R 4b2 is C1-C6 alkyl; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0185] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 5b1 is CH3; R 5b2 is CF3; R 4b1 is CH3; R 4b2 is H;R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c ;and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X6c is CR 6c and;R 6c is H.

[0186] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 5b1 is CH3; R 5b2 is CF3; R 4b1 is H;R 4b2 is CH3; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0187] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R5b1 is CF3; R 5b2 is CH3; R 4b1 is CH3; R 4b2 is H;R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0188] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 5b1 is CF3; R 5b2 is CH3; R 4b1 is H and R 4b2 is CH3; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR6c and;R 6c is H.

[0189] In some embodiments, the present invention relates to compounds of formula (IB) (including any of the foregoing embodiments thereof), ie, the compounds in non-salt form.

[0190] In some embodiments, the present invention provides a compound of formula (IB-1): [ka] or a pharmaceutically acceptable salt thereof, wherein X 4a is N, N + -O - , or CR 4a and; each R is independently H or C1-C6 alkyl; R 4a is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl; R 5b1 and R 5b2 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl; R 2c is H, OH, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 4c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl).

[0191] In some embodiments, the present invention relates to a compound of formula (IB-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N. In other embodiments, X4a is N + -O - In another embodiment, X 4a is CR 4a In some embodiments, R 4a is halo. In other embodiments, X 4a is CF.

[0192] In some embodiments, the present invention relates to a compound of formula (IB-1), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently H or CH. In other embodiments, N(R) is NHCH.

[0193] In some embodiments, the present invention relates to a compound of formula (IB-1), or a pharmaceutically acceptable salt thereof, wherein R 4a is a halo.

[0194] In some embodiments, the present invention relates to a compound of formula (IB-1), or a pharmaceutically acceptable salt thereof, wherein R 4b1 and R 4b2 are each independently H or C1-C6 alkyl. In other embodiments, R 4b1 and R 4b2 are each independently H or CH. In other embodiments, R 4b1 is C1-C6 alkyl, and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is C1-C6 alkyl. In other embodiments, R 4b1 is CH3 and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is CH3.

[0195] In some embodiments, the present invention relates to a compound of formula (IB-1), or a pharmaceutically acceptable salt thereof, wherein R 5b1 and R 5b2are each independently C1-C6 alkyl or C1-C6 haloalkyl. 5b1 and R 5b2 are each independently H, CH, or CF. In other embodiments, R 5b1 is C1-C6 alkyl, and R 5b2 is C1-C6 haloalkyl. In other embodiments, R 5b1 is C1-C6 haloalkyl, and R 5b2 is C1-C6 alkyl. In other embodiments, R 5b1 is CH3 and R 5b2 is CF3. In other embodiments, R 5b1 is CF3 and R 5b2 is CH3.

[0196] In some embodiments, the present invention relates to a compound of formula (IB-1), or a pharmaceutically acceptable salt thereof, wherein R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy. 2c is C1-C6 alkoxy. In other embodiments, R 2c is C1-C6 haloalkoxy. In other embodiments, R 2c is OH, OCH, OCD, OCHCH, or OCHF. In other embodiments, R 2c is OH. In other embodiments, R 2c is OCH3. In other embodiments, R 2c is OCD3. In other embodiments, R 2c is OCH2CH3. In another embodiment, R 2c is OCHF2.

[0197] In some embodiments, the present invention relates to a compound of formula (IB-1), or a pharmaceutically acceptable salt thereof, wherein R 3c is H, halo, or C-C alkyl. In other embodiments, R 3c is halo. In other embodiments, R 3c is C1-C6 alkyl. In other embodiments, R 3cis H, F, Cl, or CH. In other embodiments, R 3c is H. In other embodiments, R 3c is F. In other embodiments, R 3c is C1. In other embodiments, R 3c is CH3.

[0198] In some embodiments, the present invention relates to a compound of formula (IB-1), or a pharmaceutically acceptable salt thereof, wherein R 4c is halo. In other embodiments, R 4c is F.

[0199] In some embodiments, the present invention relates to a compound of formula (IB-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 and R 4b2 are each independently H or C1-C6 alkyl; R 5b1 and R 5b2 are each independently C1-C6 alkyl or C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0200] In some embodiments, the present invention relates to a compound of formula (IB-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 and R 4b2 are each independently H or CH; R 5b1 and R 5b2 are each independently H, CH3, or CF3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0201] In some embodiments, the present invention relates to a compound of formula (IB-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is C1-C6 alkyl; R 4b2 is H;R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0202] In some embodiments, the present invention relates to a compound of formula (IB-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H;R 4b2 is C1-C6 alkyl; R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0203] In some embodiments, the present invention relates to a compound of formula (IB-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is C1-C6 alkyl; R 4b2 is H;R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0204] In some embodiments, the present invention relates to a compound of formula (IB-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H;R 4b2 is C1-C6 alkyl; R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0205] In some embodiments, the present invention relates to a compound of formula (IB-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is CH3; R 4b2 is H;R 5b1 is CH3; R 5b2 is CF3; R 2c is OH, C-C alkoxy, or C-C haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0206] In some embodiments, the present invention relates to a compound of formula (IB-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H;R 4b2 is CH3; R 5b1 is CH3; R 5b2 is CF3; R 2c is OH, C-C alkoxy, or C-C haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0207] In some embodiments, the present invention relates to a compound of formula (IB-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is CH3; R 4b2 is H;R 5b1 is CF3; R 5b2 is CH3; R 2c is OH, C-C alkoxy, or C-C haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0208] In some embodiments, the present invention relates to a compound of formula (IB-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H;R 4b2 is CH3; R 5b1 is CF3; R 5b2 is CH3; R 2c is OH, C-C alkoxy, or C-C haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0209] In some embodiments, the present invention relates to compounds of formula (IB-1), including any of the foregoing embodiments thereof, ie, the compounds in non-salt form.

[0210] In some embodiments, the present invention provides a compound of formula (IC): [ka] or a pharmaceutically acceptable salt thereof, wherein X 2a is N, N + -O - , or CR 2a and; X 4a is N, N + -O- , or CR 4a and; X 5a is N, N + -O - , or CR 5a and; X 6a is N, N + -O - , or CR 6a and; each R is independently H or C1-C6 alkyl; R 2a , R 4a , R 5a , and R 6a are each independently H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; R 5b1 and R 5b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; X 3c is N or CR 3c and; X 4c is N or CR 4c and; X 5c is N or CR 5c and; X 6c is N or CR 6c and; R 2c is H, OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; L 1 is a bond or O; L2 is a bond or C1-C6 alkylene; R 3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 4c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 5c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 6c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; However, X 2a , X 4a , X 5a , and X 6a N or N + -O - provided that there are not more than two such X 3c , X 4c , X 5c , and X 6c (Provided that not more than one of these is N).

[0211] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 2a is CR 2a and X 5a is CR 5a and X 6a is CR 6a and;R 4b1 and R 4b2 are each independently H, C-C alkyl, or C-C haloalkyl; R 5b1 and R 5b2 are each independently H, C-C alkyl, or C-C haloalkyl; X 3c is CR 3c and X 4c is CR 4c and X 5c is CR 5c and X 6c is CR 6c and;R2c is H, OH, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0212] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently H or CH. In other embodiments, N(R) is NHCH.

[0213] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 2a is N. In other embodiments, X 2a is CR 2a In some embodiments, R 2a is H, D, halo, or C-C alkyl. In other embodiments, R 2a is H, D, F, or CH3. In some embodiments, X 2a is N, CH, CD, C-(C-C alkyl), or C-halo. 2a is N, CH, CD, C-CH3, or CF.

[0214] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 2a is CR 2a and;R 2a is H.

[0215] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 4a is N. In other embodiments, X 4a is N + -O - In another embodiment, X 4a is CR 4a In some embodiments, R 4a is halo. In other embodiments, R 4ais H or halo. In other embodiments, R 4a is H or F. In other embodiments, X 4a is CF. In some embodiments, X 4a is N, N + -O - , CH, or C-halo. 4a is N, N + -O - , CH, or CF.

[0216] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 4a is CR 4a and;R 4a is a halo.

[0217] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 5a is N. In other embodiments, X 5a is CR 5a In some embodiments, R 5a is H, D, halo, or C-C alkyl. In other embodiments, R 5a is H, D, F, or CH3. In some embodiments, X 5a is N, CH, CD, C-(C-C alkyl), or C-halo. 5a is N, CH, CD, C-CH3, or CF.

[0218] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 5a is CR 5a and;R 5a is H.

[0219] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 6a is N. In other embodiments, X 6ais CR 6a In some embodiments, R 6a is H, D, halo, or C-C alkyl. In other embodiments, R 6a is H, D, F, or CH3. In some embodiments, X 6a is N, CH, CD, C-(C-C alkyl), or C-halo. 6a is N, CH, CD, C-CH3, or CF.

[0220] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 6a is CR 6a and;R 6a is H.

[0221] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein R 4b1 and R 4b2 are each independently H or C1-C6 alkyl. In other embodiments, R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. 4b1 and R 4b2 are each independently H or CH. In other embodiments, R 4b1 and R 4b2 are each independently H, CH, CHCH, or cyclopropyl. 4b1 is C1-C6 alkyl, and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is C1-C6 alkyl. In other embodiments, R 4b1 is CH3 and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is CH3.

[0222] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein R 5b1 and R 5b2 are each independently C1-C6 alkyl or C1-C6 haloalkyl. 5b1 and R 5b2 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl. 5b1 and R 5b2 are each independently H, CH, or CF. In other embodiments, R 5b1 and R 5b2 are each independently H, CH, CHCH, CH(CH), C(CH), CHF, CFCH, CHCF, or CF. 5b1 is C1-C6 alkyl, and R 5b2 is C1-C6 haloalkyl. In other embodiments, R 5b1 is C1-C6 haloalkyl, and R 5b2 is C1-C6 alkyl. In other embodiments, R 5b1 is CH3 and R 5b2 is CF3. In other embodiments, R 5b1 is CF3 and R 5b2 is CH3.

[0223] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy. 2c is OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), where the cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R 2c is H. In other embodiments, R 2cis C1-C6 alkoxy. In other embodiments, R 2c is C1-C6 haloalkoxy. In other embodiments, R 2c -L 1 -L 2 -(C3-C6 cycloalkyl), where the cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R 2c is OH, OCH, OCD, OCHCH, or OCHF. In other embodiments, R 2c are H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCHF2, [ka] In other embodiments, R 2c is OH. In other embodiments, R 2c is OCH3. In other embodiments, R 2c is OCD3. In other embodiments, R 2c is OCH2CH3. In other embodiments, R 2c is OCHF2.

[0224] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 3c is N. In other embodiments, X 3c is CR 3c In another embodiment, R 3c is H, halo, C-C alkyl, or C-C haloalkyl. 3c is H, CH3, CH2CH3, CHF2, CF3, F, or Cl. In some embodiments, X 3c is N, CH, C-CH3, C-CH2CH3, C-CHF2, C-CF3, CF, or C-Cl.

[0225] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 3cis CR 3c and;R 3c is H, halo, or C-C alkyl. In other embodiments, R 3c is halo. In other embodiments, R 3c is C1-C6 alkyl. In other embodiments, R 3c is H, F, Cl, or CH. In other embodiments, R 3c is H. In other embodiments, R 3c is F. In other embodiments, R 3c is C1. In other embodiments, R 3c is CH3.

[0226] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 4c is N. In other embodiments, X 4c is CR 4c In another embodiment, R 4c is H, halo, or C1-C6 haloalkyl. In other embodiments, R 4c is H, CHF2, CF3, or F. In some embodiments, X 4c is N, CH, C-CHF2, C-CF3, or CF.

[0227] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 4c is CR 4c and;R 4c is halo. In other embodiments, R 4c is F.

[0228] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 5c is N. In other embodiments, X 5c is CR 5c In other embodiments, R 5c is H or halo. In other embodiments, R 5cis H, D, or Cl. In some embodiments, X 5c is N, CH, CD, or C—Cl.

[0229] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 5c is CR 5c and;R 5c is H.

[0230] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 6c is N. In other embodiments, X 6c is CR 6c In other embodiments, R 6c is H or halo. In other embodiments, R 6c is H or F. In some embodiments, X 6c is N, CH, or CF.

[0231] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein R 6c is H.

[0232] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 2a is N, CH, CD, C—(C1-C6 alkyl), or C-halo; X 4a is N, N + -O - , CH, or C-halo; X 5a is N, CH, CD, C—(C1-C6 alkyl), or C-halo; X 6a is N, CH, CD, C—(C1-C6 alkyl), or C-halo; each R is H or CH3; R 4b1 and R 4b2 are each independently H, C-C alkyl, or C-C cycloalkyl; R 5b1 and R 5b2are each independently H, C-C alkyl, or C-C haloalkyl; R 2c is OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; X 3c is CR 3c and;R 3c is H, halo, C-C alkyl, or C-C haloalkyl; X 4c is CR 4c and;R 4c is H, halo, or C1-C6 haloalkyl; X 5c is CR 5c and;R 5c is H or halo; X 6c is CR 6c and;R 6c is H or halo.

[0233] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 4b1 and R 4b2 are each independently H or C1-C6 alkyl; R 5b1 and R 5b2 are each independently C1-C6 alkyl or C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3cis H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0234] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 2a is N, CH, CD, C-CH3, or CF; X 4a is N, N + -O - , CH, or CF; X 5a is N, CH, CD, C-CH3 or CF; X 6a is N, CH, CD, C-CH3, or CF; each R is H or CH3; R 4b1 and R 4b2 are each independently H, CH, CHCH, or cyclopropyl; R 5b1 and R 5b2 are each independently H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CHF2, CF2CH3, CH2CF3, or CF3; R 2c are H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCHF2, [ka] and X 3c is N, CH, C-CH3, C-CH2CH3, C-CHF2, C-CF3, CF, or C-Cl; X 4c is N, CH, C-CHF2, C-CF3, or CF; X 5c is N, CH, CD, or C-Cl; X 6c is N, CH, or CF.

[0235] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 4b1 and R 4b2 are each independently H or CH; R 5b1 and R 5b2 are each independently H, CH3, or CF3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0236] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 4b1 is C1-C6 alkyl; R 4b2is H;R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0237] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 4b1 is H;R 4b2 is C1-C6 alkyl; R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6cis CR 6c and;R 6c is H.

[0238] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 4b1 is C1-C6 alkyl; R 4b2 is H;R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0239] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R6a is H;R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 4b1 is H;R 4b2 is C1-C6 alkyl; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0240] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 5b1 is CH3; R 5b2 is CF3; R 4b1 is CH3; R 4b2 is H;R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R5c is H;X 6c is CR 6c and;R 6c is H.

[0241] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 5b1 is CH3; R 5b2 is CF3; R 4b1 is H;R 4b2 is CH3; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0242] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R6a is H;R 5b1 is CF3; R 5b2 is CH3; R 4b1 is CH3; R 4b2 is H;R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0243] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 5b1 is CF3; R 5b2 is CH3; R 4b1 is H and R 4b2 is CH3; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X6c is CR 6c and;R 6c is H.

[0244] In some embodiments, the present invention relates to compounds of formula (IC) (including any of the foregoing embodiments thereof), ie, the compounds in non-salt form.

[0245] In some embodiments, the present invention provides a compound of formula (IC-1): [ka] or a pharmaceutically acceptable salt thereof, wherein X 4a is N, N + -O - , or CR 4a and; each R is independently H or C1-C6 alkyl; R 4a is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl; R 5b1 and R 5b2 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl; R 2c is H, OH, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 4c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl).

[0246] In some embodiments, the present invention relates to a compound of formula (IC-1), or a pharmaceutically acceptable salt thereof, wherein X 4ais N. In other embodiments, X 4a is N + -O - In another embodiment, X 4a is CR 4a In some embodiments, R 4a is halo. In other embodiments, X 4a is CF.

[0247] In some embodiments, the present invention relates to a compound of formula (IC-1), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently H or CH. In other embodiments, N(R) is NHCH.

[0248] In some embodiments, the present invention relates to a compound of formula (IC-1), or a pharmaceutically acceptable salt thereof, wherein R 4a is a halo.

[0249] In some embodiments, the present invention relates to a compound of formula (IC-1), or a pharmaceutically acceptable salt thereof, wherein R 4b1 and R 4b2 are each independently H or C1-C6 alkyl. In other embodiments, R 4b1 and R 4b2 are each independently H or CH. In other embodiments, R 4b1 is C1-C6 alkyl, and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is C1-C6 alkyl. In other embodiments, R 4b1 is CH3 and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is CH3.

[0250] In some embodiments, the present invention relates to a compound of formula (IC-1), or a pharmaceutically acceptable salt thereof, wherein R 5b1 and R 5b2are each independently C1-C6 alkyl or C1-C6 haloalkyl. 5b1 and R 5b2 are each independently H, CH, or CF. In other embodiments, R 5b1 is C1-C6 alkyl, and R 5b2 is C1-C6 haloalkyl. In other embodiments, R 5b1 is C1-C6 haloalkyl, and R 5b2 is C1-C6 alkyl. In other embodiments, R 5b1 is CH3 and R 5b2 is CF3. In other embodiments, R 5b1 is CF3 and R 5b2 is CH3.

[0251] In some embodiments, the present invention relates to a compound of formula (IC-1), or a pharmaceutically acceptable salt thereof, wherein R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy. 2c is C1-C6 alkoxy. In other embodiments, R 2c is C1-C6 haloalkoxy. In other embodiments, R 2c is OH, OCH, OCD, OCHCH, or OCHF. In other embodiments, R 2c is OH. In other embodiments, R 2c is OCH3. In other embodiments, R 2c is OCD3. In other embodiments, R 2c is OCH2CH3. In another embodiment, R 2c is OCHF2.

[0252] In some embodiments, the present invention relates to a compound of formula (IC-1), or a pharmaceutically acceptable salt thereof, wherein R 3c is H, halo, or C-C alkyl. In other embodiments, R 3c is halo. In other embodiments, R 3c is C1-C6 alkyl. In other embodiments, R 3cis H, F, Cl, or CH. In other embodiments, R 3c is H. In other embodiments, R 3c is F. In other embodiments, R 3c is C1. In other embodiments, R 3c is CH3.

[0253] In some embodiments, the present invention relates to a compound of formula (IC-1), or a pharmaceutically acceptable salt thereof, wherein R 4c is halo. In other embodiments, R 4c is F.

[0254] In some embodiments, the present invention relates to a compound of formula (IC-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 and R 4b2 are each independently H or C1-C6 alkyl; R 5b1 and R 5b2 are each independently C1-C6 alkyl or C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0255] In some embodiments, the present invention relates to a compound of formula (IC-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 and R 4b2 are each independently H or CH; R 5b1 and R 5b2 are each independently H, CH3, or CF3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0256] In some embodiments, the present invention relates to a compound of formula (IC-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is C1-C6 alkyl; R 4b2 is H;R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0257] In some embodiments, the present invention relates to a compound of formula (IC-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H;R 4b2 is C1-C6 alkyl; R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0258] In some embodiments, the present invention relates to a compound of formula (IC-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is C1-C6 alkyl; R 4b2 is H;R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0259] In some embodiments, the present invention relates to a compound of formula (IC-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H;R 4b2 is C1-C6 alkyl; R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0260] In some embodiments, the present invention relates to a compound of formula (IC-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is CH3; R 4b2 is H;R 5b1 is CH3; R 5b2 is CF3; R 2c is OH, C-C alkoxy, or C-C haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0261] In some embodiments, the present invention relates to a compound of formula (IC-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H;R 4b2 is CH3; R 5b1 is CH3; R 5b2 is CF3; R 2c is OH, C-C alkoxy, or C-C haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0262] In some embodiments, the present invention relates to a compound of formula (IC-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is CH3; R 4b2 is H;R 5b1 is CF3; R 5b2 is CH3; R 2c is OH, C-C alkoxy, or C-C haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0263] In some embodiments, the present invention relates to a compound of formula (IC-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H;R 4b2 is CH3; R 5b1 is CF3; R 5b2 is CH3; R 2c is OH, C-C alkoxy, or C-C haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0264] In some embodiments, the present invention relates to compounds of formula (IC-1), including any of the foregoing embodiments thereof, ie, the compounds in non-salt form.

[0265] In some embodiments, the present invention relates to a compound selected from Table A, or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to a compound selected from Table A in non-salt form.

[0266] [Table 1-1] [Table 1-2]

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

[0267] In some embodiments, the present invention relates to a compound selected from Table B, or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to a compound selected from Table B in non-salt form.

[0268] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

[0269] In some embodiments, the present invention relates to a compound selected from Table C, or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to a compound selected from Table C in non-salt form.

[0270] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11]

Table 3-12

Table 3-13

Table 3-14

Table 3-15

Table 3-16

Table 3-17

Table 3-18

Table 3-19

Table 3-20

Table 3-21

Table 3-22

Table 3-23

Table 3-24

Table 3-25

Table 3-26

Table 3-27

Table 3-28

Table 3-29

Table 3-30

Table 3-31

Table 3-32

Table 3-33

Table 3-34

Table 3-35

Table 3-36

Table 3-37

Table 3-38

Table 3-39

Table 3-40

Table 3-41

Table 3-42

Table 3-43

Table 3-44

Table 3-45

Table 3-46

Table 3-47

Table 3-48

Table 3-49

Table 3-50

Table 3-51

Table 3-52

Table 3-53

Table 3-54

Table 3-55

Table 3-56

Table 3-57

Table 3-58

Table 3-59

Table 3-60

Table 3-61

Table 3-62

Table 3-63

Table 3-64

Table 3-65

Table 3-66

Table 3-67

Table 3-68

Table 3-69

Table 3-70

Table 3-71

Table 3-72

Table 3-73

Table 3-74

Table 3-75

Table 3-76

Table 3-77

Table 3-78

Table 3-79

Table 3-80

[0271] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry of the first eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 1, Step 6. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0272] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof, which compound has the absolute stereochemistry of the second eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 1, Step 6. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0273] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof, the compound has the absolute stereochemistry of the first eluting isomer when the racemic mixture of enantiomers is separated by SFC (Chiralpak AS-H column) as described in Example 1. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0274] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof, the compound has the absolute stereochemistry of the second eluting isomer when the racemic mixture of enantiomers is separated by SFC (Chiralpak AS-H column) as described in Example 1. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0275] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry of the first eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 2, Step 10. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0276] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof, which compound has the absolute stereochemistry of the second eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 2, Step 10. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0277] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof, which compound has the absolute stereochemistry of the first eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 3, Step 13. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0278] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof, which compound has the absolute stereochemistry of the second eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 3, Step 13. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0279] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0280] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0281] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry of the first eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 3. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0282] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry of the second eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 3. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0283] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0284] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0285] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0286] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0287] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0288] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof, the compound has the absolute stereochemistry of the first eluting isomer when the racemic mixture of enantiomers is separated by SFC (Chiralpak AS-H column) as described in Example 1. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0289] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof, the compound has the absolute stereochemistry of the second eluting isomer when the racemic mixture of enantiomers is separated by SFC (Chiralpak AS-H column) as described in Example 1. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0290] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry of the first eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 4, Step 4. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0291] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof, which compound has the absolute stereochemistry of the second eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 4, Step 4. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0292] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry of the first eluting isomer when the racemic mixture of enantiomers is separated by SFC (Chiralpak AS-H column) as described in Example 4, Step 4. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0293] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof, which compound has the absolute stereochemistry of the second eluting isomer when the racemic mixture of enantiomers is separated by SFC (Chiralpak AS-H column) as described in Example 4, Step 4. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0294] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0295] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0296] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof, the compound has the absolute stereochemistry of the first eluting isomer when the mixture of racemic diastereomers (epimers at the 5-position) is separated by SFC as described in Example 6, Step 7. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0297] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof, which has the absolute stereochemistry of the second eluting isomer when the mixture of racemic diastereomers (epimers at the 5-position) is separated by SFC as described in Example 6, Step 7. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0298] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0299] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof, which has the absolute stereochemistry of the third eluting isomer when the racemic diastereomeric mixture (epimers at the 5-position) is separated by SFC as described in Example 6, Step 7. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0300] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof, the compound has the absolute stereochemistry of the fourth eluting isomer when the mixture of racemic diastereomers (epimers at the 5-position) is separated by SFC as described in Example 6, Step 7. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0301] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0302] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof, which compound has the absolute stereochemistry of the first eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 7, Step 11. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0303] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof, which compound has the absolute stereochemistry of the second eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 7, Step 11. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0304] In some embodiments, the present invention provides a compound of formula [ka] or a pharmaceutically acceptable salt thereof. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0305] Solid Forms of the Compounds of the Invention In another aspect, the present invention relates to a solid form of a compound of the present invention, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present invention, or a pharmaceutically acceptable salt thereof, is in a crystalline solid form.

[0306] Solid forms of compound 7 In some embodiments, the present invention provides a compound of formula [ka] wherein the compound has the absolute stereochemistry of the second eluting isomer when the racemic mixture of enantiomers is separated by SFC as described in Example 3, Step 13, and the compound is in a crystalline solid form.

[0307] In some embodiments, the crystalline solid form is Form A.

[0308] In some embodiments, Form A is characterized by an XRPD pattern with diffractions at angles of 9.9, 13.9, 15.7, and 19.0 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern with at least one, at least two, or at least three diffractions at angles of 9.9, 13.9, 15.7, and 19.0 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern with diffractions at angles of 7.3, 9.9, 13.9, 15.7, 19.0, 20.1, 20.3, and 25.4 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, at least five, at least six, or at least seven diffractions at angles of 7.3, 9.9, 13.9, 15.7, 19.0, 20.1, 20.3, and 25.4 (2-theta ±0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern substantially similar to that shown in FIG.

[0309] In some embodiments, Form A is characterized by a DSC thermogram with an onset of melting at 186°C and a peak at 187°C.

[0310] In some embodiments, Form A can be obtained by crystallization from methanol at 60°C.

[0311] In some embodiments, the crystalline solid form is Form B.

[0312] In some embodiments, Form B is characterized by an XRPD pattern with diffractions at angles of 12.8, 14.1, 15.2, 18.5, and 20.3 (2-theta ± 0.2 degrees). In other embodiments, Form B is characterized by an XRPD pattern with at least one, at least two, at least three, or at least four diffractions at angles of 12.8, 14.1, 15.2, 18.5, and 20.3 (2-theta ± 0.2 degrees). In other embodiments, Form B is characterized by an XRPD pattern with diffractions at angles of 12.0, 12.8, 14.1, 15.2, 16.9, 18.4, 18.5, 18.7, 19.3, and 20.3 (2-theta ± 0.2 degrees). In other embodiments, Form B is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine diffractions at angles of 12.0, 12.8, 14.1, 15.2, 16.9, 18.4, 18.5, 18.7, 19.3, and 20.3 (2 theta ±0.2 degrees). In other embodiments, Form B is characterized by an XRPD pattern with diffraction at angles (2 theta ±0.2 degrees) of 7.6, 9.2, 12.0, 12.8, 14.1, 15.1, 15.2, 16.2, 16.9, 17.6, 18.4, 18.5, 18.7, 19.3, 20.3, 21.7, 22.0, 22.2, 22.9, 23.6, 24.0, 24.2, 25.2, 26.9, 27.0, 27.4, 28.6, and 28.9.In other embodiments, Form B has at least one, at least two, at least three, at least four, or at least two or more of the following angles (2 theta ±0.2 degrees): 7.6, 9.2, 12.0, 12.8, 14.1, 15.1, 15.2, 16.2, 16.9, 17.6, 18.4, 18.5, 18.7, 19.3, 20.3, 21.7, 22.0, 22.2, 22.9, 23.6, 24.0, 24.2, 25.2, 26.9, 27.0, 27.4, 28.6, and 28.9. In another embodiment, Form B is characterized by an XRPD pattern having at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, or at least 27 diffractions. In another embodiment, Form B is characterized by an XRPD pattern substantially similar to that of FIG.

[0313] In some embodiments, Form B is a solid having peaks at chemical shifts of 172.5, 172.1, 168.5, 168.3, 168.0, 151.5, 148.3, 147.8, 127.7, 122.7, 116.6, 115.1, 110.6, 86.5, 80.2, 63.2, 44.3, 23.0, and 13.1 ppm. 13 In some embodiments, Form B is characterized by a solid state image substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0314] In some embodiments, Form B is a solid having peaks at chemical shifts of −137.1 and −152.8 ppm. 19 In some embodiments, Form B is characterized by a solid state image substantially similar to that shown in FIG. 19 Characterized by F NMR spectrum.

[0315] In some embodiments, Form B is characterized by a DSC thermogram with an onset of melting at 182°C with a peak at 183°C.

[0316] In some embodiments, Form B has peaks of 3501, 3356, 1684, 1565, 1505, and 1122 cm -1 In some embodiments, Form B is characterized by an IR spectrum substantially similar to that of FIG.

[0317] In some embodiments, Form B is characterized by an orthorhombic crystalline system as determined by single crystal X-ray analysis. In other embodiments, Form B is characterized by a P212121 space group as determined by single crystal X-ray analysis. In other embodiments, Form B is characterized by a unit cell with the following dimensions as determined by single crystal X-ray analysis: a=7.3929(2) Å; b=14.5827(4) Å; c=18.9312(6) Å; α=90°; β=90°; and γ=90°.

[0318] In some embodiments, Form B can be obtained by dissolving the compound in ethyl acetate and then crystallizing the compound by adding n-heptane as an anti-solvent. In other embodiments, Form B can be obtained by the procedure described in Example 3.

[0319] In some embodiments, the present invention provides a compound of formula [ka] With respect to the compound of formula (I), the compound is in a crystalline solid form.

[0320] In some embodiments, the crystalline solid form is Form A.

[0321] In some embodiments, Form A is characterized by an XRPD pattern with diffractions at angles of 9.9, 13.9, 15.7, and 19.0 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern with at least one, at least two, or at least three diffractions at angles of 9.9, 13.9, 15.7, and 19.0 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern with diffractions at angles of 7.3, 9.9, 13.9, 15.7, 19.0, 20.1, 20.3, and 25.4 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, at least five, at least six, or at least seven diffractions at angles of 7.3, 9.9, 13.9, 15.7, 19.0, 20.1, 20.3, and 25.4 (2-theta ±0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern substantially similar to that shown in FIG.

[0322] In some embodiments, Form A is characterized by a DSC thermogram with an onset of melting at 186°C and a peak at 187°C.

[0323] In some embodiments, Form A can be obtained by crystallization from methanol at 60°C.

[0324] In some embodiments, the crystalline solid form is Form B.

[0325] In some embodiments, Form B is characterized by an XRPD pattern with diffractions at angles of 12.8, 14.1, 15.2, 18.5, and 20.3 (2-theta ± 0.2 degrees). In other embodiments, Form B is characterized by an XRPD pattern with at least one, at least two, at least three, or at least four diffractions at angles of 12.8, 14.1, 15.2, 18.5, and 20.3 (2-theta ± 0.2 degrees). In other embodiments, Form B is characterized by an XRPD pattern with diffractions at angles of 12.0, 12.8, 14.1, 15.2, 16.9, 18.4, 18.5, 18.7, 19.3, and 20.3 (2-theta ± 0.2 degrees). In other embodiments, Form B is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine diffractions at angles of 12.0, 12.8, 14.1, 15.2, 16.9, 18.4, 18.5, 18.7, 19.3, and 20.3 (2 theta ±0.2 degrees). In other embodiments, Form B is characterized by an XRPD pattern with diffraction at angles (2 theta ±0.2 degrees) of 7.6, 9.2, 12.0, 12.8, 14.1, 15.1, 15.2, 16.2, 16.9, 17.6, 18.4, 18.5, 18.7, 19.3, 20.3, 21.7, 22.0, 22.2, 22.9, 23.6, 24.0, 24.2, 25.2, 26.9, 27.0, 27.4, 28.6, and 28.9.In other embodiments, Form B has at least one, at least two, at least three, at least four, or at least two or more of the following angles (2 theta ±0.2 degrees): 7.6, 9.2, 12.0, 12.8, 14.1, 15.1, 15.2, 16.2, 16.9, 17.6, 18.4, 18.5, 18.7, 19.3, 20.3, 21.7, 22.0, 22.2, 22.9, 23.6, 24.0, 24.2, 25.2, 26.9, 27.0, 27.4, 28.6, and 28.9. In another embodiment, Form B is characterized by an XRPD pattern having at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, or at least 27 diffractions. In another embodiment, Form B is characterized by an XRPD pattern substantially similar to that of FIG.

[0326] In some embodiments, Form B is a solid having peaks at chemical shifts of 172.5, 172.1, 168.5, 168.3, 168.0, 151.5, 148.3, 147.8, 127.7, 122.7, 116.6, 115.1, 110.6, 86.5, 80.2, 63.2, 44.3, 23.0, and 13.1 ppm. 13 In another embodiment, Form B is characterized by a solid state image substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0327] In some embodiments, Form B is a solid having peaks at chemical shifts of −137.1 and −152.8 ppm. 19 In another embodiment, Form B is characterized by a solid state image substantially similar to that shown in FIG. 19 Characterized by F NMR spectrum.

[0328] In some embodiments, Form B is characterized by a DSC thermogram with an onset of melting at 182°C with a peak at 183°C.

[0329] In some embodiments, Form B has peaks of 3501, 3356, 1684, 1565, 1505, and 1122 cm -1 9. In another embodiment, Form B is characterized by an IR spectrum substantially similar to that of FIG.

[0330] In some embodiments, Form B is characterized by an orthorhombic crystalline system as determined by single crystal X-ray analysis. In other embodiments, Form B is characterized by a P212121 space group as determined by single crystal X-ray analysis. In other embodiments, Form B is characterized by a unit cell with the following dimensions as determined by single crystal X-ray analysis: a=7.3929(2) Å; b=14.5827(4) Å; c=18.9312(6) Å; α=90°; β=90°; and γ=90°.

[0331] In some embodiments, Form B can be obtained by dissolving the compound in ethyl acetate and then crystallizing the compound by adding n-heptane as an anti-solvent. In other embodiments, Form B can be obtained by the procedure described in Example 3.

[0332] Solid forms of compound 9 In some embodiments, the present invention provides a compound of formula [ka] With respect to the compound of formula (I), the compound is in a crystalline solid form.

[0333] In some embodiments, the crystalline solid form is Form A.

[0334] In some embodiments, Form A is characterized by an orthorhombic crystalline system as determined by single crystal X-ray analysis. In other embodiments, Form A is characterized by a I222 space group as determined by single crystal X-ray analysis. In other embodiments, Form A is characterized by a unit cell with the following dimensions as determined by single crystal X-ray analysis: a=12.0172(5) Å; b=15.6682(6) Å; c=24.1406(11) Å; α=90°; β=90°; and γ=90°.

[0335] In some embodiments, Form A can be obtained by dissolving the compound in a 10 / 90 dichloromethane / dichloroethane solution followed by vapor diffusion with pentane. In some embodiments, Form A can be obtained by the procedure described in Example 3.

[0336] Solid forms of compound 11 In some embodiments, the present invention provides a compound of formula [ka] With respect to the compound of formula (I), the compound is in a crystalline solid form.

[0337] In some embodiments, the crystalline solid form is Form A.

[0338] In some embodiments, Form A is characterized by an XRPD pattern with diffractions at angles of 10.1, 13.7, 14.1, 16.3, and 20.0 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern with at least one, at least two, at least three, or at least four diffractions at angles of 10.1, 13.7, 14.1, 16.3, and 20.0 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern with diffractions at angles of 7.3, 10.1, 13.7, 14.1, 16.0, 16.3, 20.0, 20.4, 23.7, and 24.8 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine diffractions at angles (2-theta ± 0.2 degrees) of 7.3, 10.1, 13.7, 14.1, 16.0, 16.3, 20.0, 20.4, 23.7, and 24.8. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (2-theta ± 0.2 degrees) of 7.1, 7.3, 10.1, 13.7, 14.1, 16.0, 16.3, 17.6, 18.5, 18.9, 20.0, 20.4, 21.5, 23.7, 24.8, 25.7, and 26.1. In other embodiments, Form A is characterized by an XRPD pattern having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16 diffractions at angles of 7.1, 7.3, 10.1, 13.7, 14.1, 16.0, 16.3, 17.6, 18.5, 18.9, 20.0, 20.4, 21.5, 23.7, 24.8, 25.7, and 26.1 (2-theta ±0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern substantially similar to that of FIG.

[0339] In some embodiments, Form A can be obtained by suspending the compound in water. In other embodiments, Form A can be obtained by the procedure described in Example 4.

[0340] In some embodiments, the crystalline solid form is Form B.

[0341] In some embodiments, Form B is characterized by an XRPD pattern with diffractions at angles of 6.8, 13.2, 16.1, 20.6, and 21.3 degrees (2-theta ± 0.2 degrees). In other embodiments, Form B is characterized by an XRPD pattern with at least one, at least two, at least three, or at least four diffractions at angles of 6.8, 13.2, 16.1, 20.6, and 21.3 degrees (2-theta ± 0.2 degrees). In other embodiments, Form B is characterized by an XRPD pattern with diffractions at angles of 6.8, 11.5, 13.2, 13.6, 14.4, 16.1, 16.3, 18.8, 20.6, and 21.3 degrees (2-theta ± 0.2 degrees). In other embodiments, Form B is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine diffractions at angles (2-theta ± 0.2 degrees) of 6.8, 11.5, 13.2, 13.6, 14.4, 16.1, 16.3, 18.8, 20.6, and 21.3. In other embodiments, Form B is characterized by an XRPD pattern having diffractions at angles (2-theta ± 0.2 degrees) of 6.8, 11.5, 13.2, 13.6, 14.4, 15.6, 16.1, 16.3, 17.6, 18.0, 18.8, 19.4, 20.6, 21.3, 22.3, 23.3, 24.2, and 27.4. In other embodiments, Form B is characterized by an XRPD pattern having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, or at least 17 diffractions at angles of 6.8, 11.5, 13.2, 13.6, 14.4, 15.6, 16.1, 16.3, 17.6, 18.0, 18.8, 19.4, 20.6, 21.3, 22.3, 23.3, 24.2, and 27.4 (2-theta ± 0.2 degrees). In other embodiments, Form B is characterized by an XRPD pattern substantially similar to that of FIG.

[0342] In some embodiments, Form A is characterized by a monoclinic crystalline system as determined by single crystal X-ray analysis. In other embodiments, Form A is characterized by a P21 space group as determined by single crystal X-ray analysis. In other embodiments, Form A is characterized by a unit cell with the following dimensions as determined by single crystal X-ray analysis: a=12.0863(2) Å; b=7.48310(10) Å; c=23.9904(4) Å; α=90°; β=90.0130(10)°; and γ=90°.

[0343] In some embodiments, Form B can be obtained by recrystallization from acetonitrile. In other embodiments, Form B can be obtained by the procedure described in Example 4.

[0344] Solid forms of compound 19 In some embodiments, the present invention provides a compound of formula [ka] With respect to the compound of formula (I), the compound is in a crystalline solid form.

[0345] In some embodiments, the crystalline solid form is Form A.

[0346] In some embodiments, Form A is characterized by an XRPD pattern having diffractions at angles of 13.7, 15.2, and 18.2 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one or at least two diffractions at angles of 13.7, 15.2, and 18.2 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles of 13.7, 15.2, 18.2, 18.3, 20.8, and 23.8 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, or at least five diffractions at angles of 13.7, 15.2, 18.2, 18.3, 20.8, and 23.8 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern with diffractions at angles of 13.7, 14.3, 15.2, 18.2, 18.3, 20.8, 22.5, 23.8, and 25.8 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight diffractions at angles of 13.7, 14.3, 15.2, 18.2, 18.3, 20.8, 22.5, 23.8, and 25.8 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern with diffraction at angles of 6.8, 13.7, 14.3, 15.2, 16.1, 18.2, 18.3, 19.1, 20.6, 20.8, 22.5, 23.8, 24.0, 25.8, 26.3, and 26.6 (2-theta ±0.2 degrees).In other embodiments, Form A is characterized by an XRPD pattern having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 15 diffractions at angles of 6.8, 13.7, 14.3, 15.2, 16.1, 18.2, 18.3, 19.1, 20.6, 20.8, 22.5, 23.8, 24.0, 25.8, 26.3, and 26.6 (2-theta ±0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern substantially similar to that of FIG.

[0347] In some embodiments, Form A is a solid having peaks at chemical shifts of 171.4, 141.6, 118.0, 112.2, 23.0, and 11.6 ppm. 13 In other embodiments, Form A is characterized by a C NMR spectrum having peaks at chemical shifts of 171.4, 164.2, 151.8, 149.5, 148.4, 146.6, 144.0, 141.6, 138.7, 126.2, 123.8, 118.0, 112.2, 86.4, 78.8, 63.3, 47.6, 43.8, 23.0, and 11.6 ppm. 13 In another embodiment, Form A is characterized by a solid state image substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0348] In some embodiments, Form A is a solid having peaks at chemical shifts of −74.6, −141.5, and −154.6 ppm. 19 In another embodiment, Form A is characterized by a solid state image substantially similar to that shown in FIG. 19 Characterized by F NMR spectrum.

[0349] In some embodiments, Form A is characterized by a monoclinic crystalline system as determined by single crystal X-ray analysis. In other embodiments, Form A is characterized by a P21 space group as determined by single crystal X-ray analysis. In other embodiments, Form A is characterized by a unit cell with the following dimensions as determined by single crystal X-ray analysis: a=11.2266(3) Å; b=7.3948(2) Å; c=13.1432(4) Å; α=90°; β=100.3980(1)°; and γ=90°.

[0350] In some embodiments, Form A can be obtained by precipitation from methanol by adding a heptane anti-solvent. In other embodiments, Form A can be obtained from a suspension of the compound in ethanol, acetonitrile, and water by lyophilization. In other embodiments, Form A can be obtained by dissolving the compound in methanol and slowly diffusing the heptane anti-solvent. In other embodiments, Form A can be obtained by the procedure described in Example 5.

[0351] Solid forms of compound 22 In some embodiments, the present invention provides a compound of formula [ka] wherein the compound has the absolute stereochemistry of the third eluting isomer when the mixture of racemic diastereomers (epimers at the 5-position) is separated by SFC as described in Example 6, Step 7, and the compound is in a crystalline solid form.

[0352] In some embodiments, the crystalline solid form is Form A.

[0353] In some embodiments, Form A is characterized by an XRPD pattern having diffractions at angles of 9.2, 10.4, and 15.7 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one or at least two diffractions at angles of 9.2, 10.4, and 15.7 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles of 7.7, 9.2, 10.4, 12.9, 15.7, and 18.4 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, or at least five diffractions at angles of 7.7, 9.2, 10.4, 12.9, 15.7, and 18.4 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern with diffractions at angles (2-theta ± 0.2 degrees) of 7.7, 9.2, 10.4, 12.9, 15.7, 18.4, 19.8, 21.7, and 24.0. In other embodiments, Form A is characterized by an XRPD pattern with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight diffractions at angles (2-theta ± 0.2 degrees) of 7.7, 9.2, 10.4, 12.9, 15.7, 18.4, 19.8, 21.7, and 24.0. In other embodiments, Form A is characterized by an XRPD pattern with diffractions at angles (2-theta ± 0.2 degrees) of 7.7, 9.2, 10.4, 12.9, 13.8, 14.7, 15.7, 16.1, 18.4, 19.8, 21.7, 22.3, and 24.0. In other embodiments, Form A is characterized by an XRPD pattern with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least 11, or at least 12 diffractions at angles (2-theta ± 0.2 degrees) of 7.7, 9.2, 10.4, 12.9, 13.8, 14.7, 15.7, 16.1, 18.4, 19.8, 21.7, 22.3, and 24.0. In other embodiments, Form A is characterized by an XRPD pattern substantially similar to that in FIG.

[0354] In some embodiments, Form A is a solid having peaks at chemical shifts of 167.7, 126.0, 115.9, 43.5, and 20.3 ppm. 13 In other embodiments, Form A is characterized by a C NMR spectrum having peaks at chemical shifts of 172.6, 167.7, 158.7, 156.8, 151.8, 148.7, 128.6, 126.0, 115.9, 113.1, 112.3, 88.0, 85.5, 62.0, 60.5, 55.6, 43.5, 37.7, 29.6, 21.1, and 20.3 ppm. 13 In another embodiment, Form A is characterized by a solid state image substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0355] In some embodiments, Form A is a solid having peaks at chemical shifts of −82.2, −83.1, −111.7, and −114.4 ppm. 19 In another embodiment, Form A is characterized by a solid state image substantially similar to that shown in FIG. 19 Characterized by F NMR spectrum.

[0356] In some embodiments, Form A can be obtained by slow evaporation of a 1:1 2-methyltetrahydrofuran / heptane solution. In other embodiments, Form A can be obtained by the procedure described in Example 6.

[0357] Solid forms of compound 23 In some embodiments, the present invention provides a compound of formula [ka] With respect to the compound of formula (I), the compound is in a crystalline solid form.

[0358] In some embodiments, the crystalline solid form is Form A.

[0359] In some embodiments, Form A is characterized by an XRPD pattern having diffractions at angles of 17.2, 19.3, and 22.3 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one or at least two diffractions at angles of 17.2, 19.3, and 22.3 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles of 14.2, 15.8, 17.2, 19.3, 22.3, and 30.6 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, or at least five diffractions at angles of 14.2, 15.8, 17.2, 19.3, 22.3, and 30.6 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern with diffractions at angles of 12.2, 14.2, 15.8, 17.2, 19.3, 22.3, 25.0, 25.1, and 30.6 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight diffractions at angles of 12.2, 14.2, 15.8, 17.2, 19.3, 22.3, 25.0, 25.1, and 30.6 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern with diffraction at angles of 11.3, 12.2, 13.2, 14.2, 15.2, 15.8, 16.6, 17.2, 19.3, 21.1, 22.3, 22.8, 23.7, 24.6, 25.0, 25.1, 25.9, 27.1, 27.9, 30.6, 34.4, and 39.4 (2-theta ±0.2 degrees).In other embodiments, Form A is characterized by an XRPD pattern having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 diffractions at angles of 11.3, 12.2, 13.2, 14.2, 15.2, 15.8, 16.6, 17.2, 19.3, 21.1, 22.3, 22.8, 23.7, 24.6, 25.0, 25.1, 25.9, 27.1, 27.9, 30.6, 34.4, and 39.4 (2 theta ±0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern substantially similar to that in FIG.

[0360] In some embodiments, Form A is a solid having peaks at chemical shifts of 171.1, 149.3, 123.3, 41.6, and 20.0 ppm. 13 In other embodiments, Form A is characterized by a C NMR spectrum having peaks at chemical shifts of 171.1, 166.7, 156.8, 155.5, 151.9, 149.3, 147.3, 131.5, 123.3, 119.0, 114.2, 112.8, 86.0, 85.0, 61.7, 61.0, 44.4, 41.6, and 20.0 ppm. 13 In another embodiment, Form A is characterized by a solid state image substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0361] In some embodiments, Form A is a solid having peaks at chemical shifts of −78.2, −113.5, and −115.1 ppm. 19 In another embodiment, Form A is characterized by a solid state image substantially similar to that shown in FIG. 19 Characterized by F NMR spectrum.

[0362] In some embodiments, Form A is characterized by a monoclinic crystalline system as determined by single crystal X-ray analysis. In other embodiments, Form A is characterized by a P21 space group as determined by single crystal X-ray analysis. In other embodiments, Form A is characterized by a unit cell with the following dimensions as determined by single crystal X-ray analysis: a=7.8661(3) Å; b=7.9167(3) Å; c=16.8777(7) Å; α=90°; β=98.487(2)°; and γ=90°.

[0363] In some embodiments, Form A can be obtained by slow evaporation of a 1:1 2-methyltetrahydrofuran / heptane solution. In other embodiments, Form A can be obtained by dissolving the compound in methanol and slowly diffusing heptane vapor. In other embodiments, Form A can be obtained by the procedure described in Example 6.

[0364] Solid forms of compound 25 In some embodiments, the present invention provides a compound of formula [ka] wherein the compound has the absolute stereochemistry of the second eluting isomer when the racemic mixture of enantiomers is separated by SFC as described in Example 7, Step 11, and the compound is in a crystalline solid form.

[0365] In some embodiments, the crystalline solid form is Form A.

[0366] In some embodiments, Form A is characterized by an XRPD pattern having diffractions at angles of 6.8, 7.9, and 13.8 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one or at least two diffractions at angles of 6.8, 7.9, and 13.8 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles of 6.8, 7.9, 11.0, 13.7, 13.8, and 27.4 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, or at least five diffractions at angles of 6.8, 7.9, 11.0, 13.7, 13.8, and 27.4 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern with diffractions at angles 6.8, 7.9, 11.0, 13.7, 13.8, 15.9, 16.3, 23.2, and 27.4 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight diffractions at angles 6.8, 7.9, 11.0, 13.7, 13.8, 15.9, 16.3, 23.2, and 27.4 (2-theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern with diffraction at angles of 3.2, 6.8, 7.9, 11.0, 11.8, 13.7, 13.8, 15.1, 15.9, 16.3, 17.5, 18.6, 19.0, 19.5, 21.6, 21.9, 23.2, 27.0, 27.4, 29.4, and 30.3 (2-theta ±0.2 degrees).In other embodiments, Form A is characterized by an XRPD pattern having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 diffractions at angles of 3.2, 6.8, 7.9, 11.0, 11.8, 13.7, 13.8, 15.1, 15.9, 16.3, 17.5, 18.6, 19.0, 19.5, 21.6, 21.9, 23.2, 27.0, 27.4, 29.4, and 30.3 (2 theta ±0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern substantially similar to that of Figure 26.

[0367] In some embodiments, Form A can be obtained by slow evaporation of a 1:1 2-methyltetrahydrofuran / heptane solution. In other embodiments, Form A can be obtained by the procedure described in Example 7.

[0368] Salts, Compositions, Uses, Formulations, Administration and Additional Agents Pharmaceutically Acceptable Salts and Compositions As discussed herein, the present invention provides compounds and pharmaceutically acceptable salts thereof that are inhibitors of voltage-gated sodium channels. Accordingly, the compounds of the present invention and pharmaceutically acceptable salts thereof are useful for treating diseases, disorders, and conditions, including, but not limited to, chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia. Accordingly, another aspect of the present invention provides pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0369] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. 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 an inhibitory active metabolite or residue thereof. The salt may be in pure form, a mixture with one or more other substances (e.g., a solution, suspension, or colloid), or in the form of a hydrate, solvate, or co-crystal. As used herein, the term "inhibitorily active metabolite or residue thereof" means that the metabolite or residue thereof is also an inhibitor of voltage-gated sodium channels.

[0370] Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanesulfonate. Salts derived from appropriate bases include salts of alkali metals, alkaline earth metals, ammonium, and N-methyl-N ... + (C 1-4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further non-limiting examples of pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0371] As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any solvent, diluent, or other liquid vehicle, dispersing or suspending aid, surfactant, isotonic agent, thickener or emulsifier, preservative, solid binder, lubricant, and the like, suitable for the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for their preparation. Except insofar as any conventional carrier medium is incompatible with the compounds of the present invention, such as by producing any undesirable biological effects or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated 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 phosphates, glycine, sorbates, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose. The following lubricants may be used: cellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository wax; 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; ethyl alcohol, and phosphate buffers; and other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening agents, flavoring and perfuming agents, preservatives, and antioxidants, may also be present in the composition, at the discretion of the formulator.

[0372] In another aspect, the invention features a pharmaceutical composition including a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0373] In another aspect, the invention features a pharmaceutical composition including a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

[0374] Uses of the Compounds and Pharmaceutically Acceptable Salts and Compositions In another aspect, the invention features a method of inhibiting a voltage-gated sodium channel in a subject, the method comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. V It is 1.8.

[0375] In yet another aspect, the invention features a method of treating or lessening the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia in a subject, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0376] In yet another aspect, the invention features a method of treating or lessening the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-surgical pain, bunionectomy pain, herniorrhaphy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia in a subject comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0377] In yet another aspect, the invention features a method of treating or lessening the severity of intestinal pain in a subject, including inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain, the method comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0378] In yet another aspect, the invention features a method for treating or reducing the severity of neuropathic pain in a subject, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, or idiopathic small fiber neuropathy. As used herein, the phrase "idiopathic small fiber neuropathy" should be understood to include any small fiber neuropathy. In some aspects, neuropathic pain includes diabetic neuropathy.

[0379] In yet another aspect, the invention features a method for treating or lessening the severity of neuropathic pain in a subject, including post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated 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 avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, medication-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia; post-spinal cord injury pain, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic cephalalgia, the method comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0380] In yet another aspect, the invention features 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 pharmaceutical composition thereof. In some embodiments, the musculoskeletal pain includes osteoarthritis pain.

[0381] In yet another aspect, the invention features a method of treating or lessening the severity of musculoskeletal pain in a subject, including osteoarthritis pain, back pain, cold pain, burn pain, or dental pain, the method comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0382] In yet another aspect, the invention features a method of treating or lessening the severity of inflammatory pain in a subject, where the inflammatory pain includes rheumatoid arthritis pain or vulvodynia, the method comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0383] In yet another aspect, the invention features a method of treating or lessening the severity of inflammatory pain in a subject, including rheumatoid arthritis pain, the method comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0384] In yet another aspect, the invention features a method of treating or lessening the severity of idiopathic pain in a subject, including fibromyalgia pain, the method comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0385] In yet another aspect, the invention features a method of treating or lessening the severity of pathological cough in a subject, the method comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0386] In yet another aspect, the invention features a method of treating or lessening the severity of acute pain in a subject, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the acute pain comprises acute post-operative pain.

[0387] In yet another aspect, the invention features a method of treating or lessening the severity of post-surgical pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain) in a subject comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0388] In yet another aspect, the invention features a method of treating or lessening the severity of bunionectomy pain in a subject comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0389] In yet another aspect, the invention features a method of treating or lessening the severity of herniorrhaphy pain in a subject comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0390] In yet another aspect, the invention features 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 a pharmaceutical composition thereof.

[0391] In yet another aspect, the invention features a method of treating or lessening the severity of visceral pain in a subject, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the visceral pain includes abdominoplasty visceral pain.

[0392] In yet another aspect, the invention features a method for treating or reducing the severity of a neurodegenerative disease in a subject, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt-Hopkins syndrome (PTHS).

[0393] In yet another aspect, the invention features a method of treating a subject with one or more additional therapeutic agents administered simultaneously with, before, or after treatment with an effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0394] In another aspect, the invention features a method for inhibiting a voltage-gated sodium channel in a biological sample, comprising contacting the biological sample with an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. V It is 1.8.

[0395] In another aspect, the present invention provides a method for treating acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritic pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe pain, The present invention features a method for treating or lessening the severity of intractable pain, refractory pain, nociceptive pain, breakthrough pain, post-operative pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal motility in a subject, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0396] In another aspect, the present invention provides a method for treating femoral cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuroma; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiation therapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; Post-stroke pain; Thalamic pain; Complex regional pain syndrome; Phantom limb pain; Intractable pain; Acute pain, acute post-operative pain; Acute musculoskeletal pain; Arthral pain; Mechanical low back pain; Neck pain; Tendonitis; Injury pain; Pain from exercise; Acute visceral pain; Pyelonephritis; Appendicitis; Cholecystitis; Intestinal obstruction; Hernia; Chest pain, cardiac pain; Pelvic pain, renal colic, acute obstetric pain, labor pain; Caesarean section pain; Acute inflammatory pain, burning pain, trauma pain; Acute intermittent pain, endometriosis; Acute herpes pain; Sickle cell anemia; Acute pancreatitis; Breakthrough pain; Orofacial pain; Sinusitis pain; Toothache; Pain from multiple sclerosis (MS); Pain in depression; Leprosy pain; Behçet's disease pain; Painful adiposity; Phlebitis pain; Guillain-Barré pain; Painful legs and moving toes legs and moving toes); Haglund's syndrome; erythromelalgia pain; Fabry disease pain; bladder and genitourinary disorders; urinary incontinence, pathological cough; overactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal extreme pain, pruritus, tinnitus, or angina-induced pain in a subject, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0397] Compounds, pharmaceutically acceptable salts and compositions for use In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a pharmaceutical.

[0398] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of inhibiting a voltage-gated sodium channel in a subject. V It is 1.8.

[0399] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method to treat or lessen the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-surgical pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia in a subject.

[0400] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method to treat or lessen the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-surgical pain, bunionectomy pain, herniorrhaphy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia in a subject.

[0401] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or lessening the severity of intestinal pain in a subject, where the intestinal pain includes inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain.

[0402] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or reducing the severity of neuropathic pain in a subject. In some aspects, the neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, or idiopathic small fiber neuropathy. As used herein, the phrase "idiopathic small fiber neuropathy" should be understood to include any small fiber neuropathy. In some aspects, the neuropathic pain includes diabetic neuropathy.

[0403] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or lessening the severity of neuropathic pain in a subject, where neuropathic pain includes post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated 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 avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, medication-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia; post-spinal cord injury pain, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic cephalalgia.

[0404] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or lessening the severity of musculoskeletal pain in a subject. In some embodiments, the musculoskeletal pain includes osteoarthritis pain.

[0405] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or lessening the severity of musculoskeletal pain in a subject, where musculoskeletal pain includes osteoarthritis pain, back pain, cold pain, burn pain, or dental pain.

[0406] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or lessening the severity of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain or vulvodynia.

[0407] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or lessening the severity of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain.

[0408] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or lessening the severity of idiopathic pain in a subject, wherein the idiopathic pain includes fibromyalgia pain.

[0409] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or lessening the severity of pathological cough in a subject.

[0410] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or lessening the severity of acute pain in a subject. In some aspects, the acute pain includes acute post-operative pain.

[0411] In yet another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or lessening the severity of post-surgical pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain) in a subject.

[0412] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or lessening the severity of bunionectomy pain in a subject.

[0413] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or lessening the severity of herniorrhaphy pain in a subject.

[0414] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or lessening the severity of abdominoplasty pain in a subject.

[0415] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or lessening the severity of visceral pain in a subject. In some aspects, the visceral pain includes abdominoplasty visceral pain.

[0416] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or reducing the severity of a neurodegenerative disease in a subject. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt-Hopkins syndrome (PTHS).

[0417] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating a subject with one or more additional therapeutic agents administered simultaneously with, before, or after 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.

[0418] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for inhibiting a voltage-gated sodium channel in a biological sample, the method comprising contacting the biological sample with an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. V It is 1.8.

[0419] In another aspect, the present invention provides a method for treating acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritic pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe pain, The present invention features 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 pain in a subject suffering from rheumatoid arthritis, inflammatory bowel disease, refractory pain, nociceptive pain, breakthrough pain, post-operative pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal motility.

[0420] In another aspect, the present invention provides a method for treating femoral cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuroma; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiation therapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; Post-stroke pain; Thalamic pain; Complex regional pain syndrome; Phantom limb pain; Intractable pain; Acute pain, acute post-operative pain; Acute musculoskeletal pain; Arthral pain; Mechanical low back pain; Neck pain; Tendonitis; Injury pain; Pain from exercise; Acute visceral pain; Pyelonephritis; Appendicitis; Cholecystitis; Intestinal obstruction; Hernia; Chest pain, cardiac pain; Pelvic pain, renal colic, acute obstetric pain, labor pain; Caesarean section pain; Acute inflammatory pain, burning pain, trauma pain; Acute intermittent pain, endometriosis; Acute herpes pain; Sickle cell anemia; Acute pancreatitis; Breakthrough pain; Orofacial pain; Sinusitis pain; Toothache; Pain from multiple sclerosis (MS); Pain in depression; Leprosy pain; Behçet's disease pain; Painful adiposity; Phlebitis pain; Guillain-Barré pain; Painful legs and moving toes legs and moving toes); Haglund's syndrome; erythromelalgia pain; Fabry disease pain; bladder and genitourinary disorders; urinary incontinence, pathological cough; overactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal extreme pain, pruritus, tinnitus, or angina-induced pain.

[0421] Pharmaceutical manufacturing In another aspect, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament.

[0422] In another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in inhibiting a voltage-gated sodium channel. V It is 1.8.

[0423] In yet another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or lessening the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia in a subject.

[0424] In yet another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for treating or lessening the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, bunionectomy pain, herniorrhaphy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia in a subject.

[0425] In yet another aspect, the present invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or lessening the severity of intestinal pain in a subject, wherein the intestinal pain includes inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain.

[0426] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of neuropathic pain in a subject. In some aspects, the neuropathic pain includes post-herpetic neuralgia, small fiber neuropathy, or idiopathic small fiber neuropathy. In some aspects, the neuropathic pain includes diabetic neuropathy.

[0427] In yet another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or lessening the severity of neuropathic pain in a subject, wherein neuropathic pain includes post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated 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 avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, medication-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia; post-spinal cord injury pain, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic neuropathy.

[0428] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of musculoskeletal pain in a subject. In some embodiments, the musculoskeletal pain includes osteoarthritis pain.

[0429] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or lessening the severity of musculoskeletal pain in a subject, wherein musculoskeletal pain includes osteoarthritis pain, back pain, cold pain, burn pain, or dental pain.

[0430] In yet another aspect, the present invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or lessening the severity of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain or vulvodynia.

[0431] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or lessening the severity of inflammatory pain in a subject, wherein inflammatory pain includes rheumatoid arthritis pain.

[0432] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or lessening the severity of idiopathic pain in a subject, wherein idiopathic pain includes fibromyalgia pain.

[0433] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or lessening the severity of pathological cough in a subject.

[0434] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity of acute pain in a subject. In some embodiments, the acute pain comprises acute post-operative pain.

[0435] In yet another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or lessening the severity of post-operative pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain) in a subject.

[0436] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or lessening the severity of bunionectomy pain in a subject.

[0437] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or lessening the severity of herniorrhaphy pain in a subject.

[0438] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or lessening the severity of abdominoplasty pain in a subject.

[0439] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity of visceral pain in a subject. In some embodiments, the visceral pain includes abdominoplasty visceral pain.

[0440] In another aspect, the invention features a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of a neurodegenerative disease in a subject. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt-Hopkins syndrome (PTHS).

[0441] In another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in combination with one or more additional therapeutic agents administered simultaneously with, before, or after treatment with the compound or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0442] In another aspect, the present invention provides a method for treating acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritic pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe pain, and the like. The present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity of inflammatory bowel disease (IGN), intractable pain, nociceptive pain, breakthrough pain, post-operative pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal motility.

[0443] In another aspect, the present invention provides a method for treating femoral cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuroma; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiation therapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain. ;Post-stroke pain;Thalamic pain;Complex regional pain syndrome;Phantom limb pain;Intractable pain;Acute pain, acute post-operative pain;Acute musculoskeletal pain;Arthral pain;Mechanical low back pain;Neck pain;Tendonitis;Injury pain;Movement pain;Acute visceral pain;Pyelonephritis;Appendicitis;Cholecystitis;Intestinal obstruction;Hernia;Chest pain, cardiac pain;Pelvic pain, renal colic, acute obstetric pain, labor pain;Cesarean section pain;Acute inflammation, burning pain, trauma pain;Acute intermittent pain, endometriosis;Acute herpes pain;Sickle cell anemia;Acute pancreatitis;Breakthrough pain;Oro-facial pain;Sinusitis pain;Toothache;Pain from multiple sclerosis (MS);Pain in depression;Leprosy pain;Behcet's disease pain;Painful adiposity;Phlebitis pain;Guillain-Barré pain;Painful legs and moving toes legs and moving toes); Haglund's syndrome; erythromelalgia pain; Fabry disease pain; bladder and genitourinary disorders; urinary incontinence, pathological cough; overactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal extreme pain, pruritus, tinnitus, or angina-induced pain.

[0444] Administration of Pharmaceutically Acceptable Salts and Compositions In certain embodiments of the present invention, an "effective amount" of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is an amount effective to treat or lessen the severity of one or more of the conditions noted above.

[0445] The compounds, salts, and compositions of the present invention can be administered in any amount and using any route of administration effective to treat or reduce the severity of one or more pain or non-pain disorders described herein. The exact amount required will vary from subject to subject, depending on the subject's species, age, and general condition, the severity of the condition, the specific drug, its mode of administration, and the like. The compounds, salts, and compositions of the present invention are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. The term "unit dosage form," as used herein, refers to a physically discrete unit of drug appropriate for the subject being treated. However, it will be understood that the total daily usage of the compounds, salts, and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular subject or organism will depend on a variety of factors, including the disorder or severity of the disorder being treated; the activity of the specific compound or salt used; the specific composition used; the age, weight, health, sex, and diet of the subject; the time of administration, route of administration, and excretion rate of the specific compound or salt used; the duration of treatment; drugs used in combination with or concurrently with the specific compound or salt used, and similar factors well known in the medical field. The term "subject" or "patient," as used herein, means an animal, preferably a mammal, and most preferably a human.

[0446] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powder, ointment, or drops), buccally, as an oral or nasal spray, or the like, depending on the severity of the condition being treated. In certain embodiments, the compounds, salts, and compositions of the present invention may be administered orally or parenterally, one or more times daily, at a dosage level of from about 0.001 mg / kg to about 100 mg / kg of the subject's body weight, or from about 0.01 mg / kg to about 50 mg / kg of the subject's body weight per day, effective to obtain the desired therapeutic effect.

[0447] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound or salt, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0448] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating, fixed oil can be used, including synthetic mono- or diglycerides. Additionally, fatty acids such as oleic acid can be used in the preparation of injectables.

[0449] Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0450] To prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. In this case, the rate of absorption of the compound depends on its dissolution rate, which may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0451] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound or salt of the invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax, which is solid at ordinary temperatures but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active ingredient.

[0452] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound or salt is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retardants such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) humectants such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0453] Solid compositions of a similar type can also be utilized as fillers in soft and hard-filled gelatin capsules using lactose or milk sugar, high molecular weight polyethylene glycols, and similar excipients. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical arts. These may optionally contain opacifying agents and may also be of a composition that optionally releases the active compound(s) only, or preferentially, in a certain part of the intestinal tract, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be utilized as fillers in soft and hard-filled gelatin capsules using lactose or milk sugar, high molecular weight polyethylene glycols, and similar excipients.

[0454] The active compound or salt may also be in microencapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical arts. In such solid dosage forms, the active compound or salt may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. As is customary, 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 forms may also contain buffering agents. They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally with a delay. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0455] Dosage forms for topical or transdermal administration of the compounds or salts of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, as needed. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. Furthermore, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0456] As generally described above, the compounds of the present invention are useful as inhibitors of voltage-gated sodium channels. In one embodiment, the compounds are V 1.8 inhibitors, and therefore, without wishing to be bound by any particular theory, the compounds, salts, and compositions may inhibit Na V These compounds are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of 1.8 is implicated in the disease, condition, or disorder. V When activation or hyperactivity of 1.8 is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder is referred to as "Na V 1.8-mediated disease, condition, or disorder." Accordingly, in another aspect, the present invention provides a method for treating a Na V Where activation or hyperactivity of 1.8 is implicated in the pathology, methods for treating or lessening the severity of the disease, condition, or disorder are provided.

[0457] Na VThe activity of the compounds utilized in the present invention as inhibitors of 1.8 can be assayed according to the methods generally described in International Publication No. WO2014 / 120808A9 and U.S. Publication No. 2014 / 0213616A1, both of which are incorporated by reference in their entireties, the methods described herein, and other methods known and available to those of skill in the art.

[0458] Additional therapeutic agents It will also be understood that the compounds, salts, and pharmaceutically acceptable compositions of the present invention can be used in combination therapy, i.e., the compounds, salts, and pharmaceutically acceptable compositions can be administered simultaneously with, before, or after one or more other desired therapies or medical treatments. The particular combination of therapies (therapies or treatments) to use in a combination regimen will take into account the compatibility of the desired therapies and / or treatments and the desired therapeutic effect to be achieved. It will also be understood that the therapies used can achieve a desired effect for the same disorder (e.g., a compound of the present invention can be administered simultaneously with another agent used to treat the same disorder), or they can achieve a different effect (e.g., control of adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease or condition are known as "appropriate for the disease or condition being treated." For example, exemplary additional therapeutic agents include, but are not limited to, non-opioid analgesics (indoles such as etodolac, indomethacin, sulindac, tolmetin; naphthylalkanones such as nabumetone; oxicams such as piroxicam; para-aminophenol derivatives such as acetaminophen; propionic acids such as fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, oxaprozin; salicylates such as aspirin, choline magnesium trisalicylate, diflunisal; fenamates such as meclofenamic acid, mefenamic acid; and pyrazoles such as phenylbutazone); or opioid (narcotic) agonists (such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine). Additionally, non-drug analgesic approaches can be utilized in conjunction with the administration of one or more compounds of the present invention.For example, anesthetic (intraspinal injections, nerve blockade), neurosurgical (neurolysis of CNS pathways), neurostimulatory (transcutaneous electrical nerve stimulation, dorsal column stimulation), physical therapy (physical therapy, orthotic devices, diathermy), or psychological (cognitive techniques - hypnosis, biofeedback, or behavioral methods) approaches may be utilized. Additional suitable therapeutic agents or approaches are generally described in The Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and on the Food and Drug Administration website, www.fda.gov, the entire contents of which are incorporated herein by reference.

[0459] In another embodiment, the additional suitable therapeutic agent is selected from the following:

[0460] (1) Opioid analgesics, such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, pentazocine, or difelikefalin;

[0461] (2) nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen (including but not limited to intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketorolac (including but not limited to ketorolac tromethamine (e.g., Toradol®)), meclofenamic acid, mefenamic acid, meloxicam, IV meloxicam (e.g., Anjeso®), nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, or zomepirac;

[0462] (3) barbiturate sedatives, such as amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal, or thiopental;

[0463] (4) benzodiazepines with sedative properties, such as chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam;

[0464] (5) sedating histamine (H1) antagonists, such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine, or chlorcyclizine;

[0465] (6) sedatives, e.g., glutethimide, meprobamate, methaqualone, or dichloralphenazone;

[0466] (7) skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphenadrine;

[0467] (8) NMDA receptor antagonists, such as dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), a combination preparation of morphine and dextromethorphan, topiramate, neramexane, or perzinfotel; examples of NR2B antagonists include ifenprodil, traxoprodil, or (-)-(R)-6-{2-[4-(3-fluoro-phenyl)-4-hydroxy-l-piperidinyl]-l-hydroxyethyl-3,4-dihydro-2(lH)-quinolinone;

[0468] (9) α-adrenergic agonists, such as doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinolin-2-yl)-5-(2-pyridyl)quinazoline;

[0469] (10) Tricyclic antidepressants, such as desipramine, imipramine, amitriptyline, or nortriptyline;

[0470] (11) Anticonvulsants, such as carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®) or valproate;

[0471] (12) Tachykinin (NK) antagonists, in particular NK-3 antagonists, NK-2 antagonists 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]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione (TAK-637), 5-[[(2R,3S)-2-[( lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant, or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine(2S,3S);

[0472] (13) Muscarinic antagonists, such as oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

[0473] (14) COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

[0474] (15) Coal tar analgesics, especially paracetamol;

[0475] (16) Neuroleptics, such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclineltant, Miraxion® or sarizotan;

[0476] (17) Vanilloid receptor agonists (e.g., resiniferatoxin or civamide) or antagonists (e.g., capsazepine, GRC-15300);

[0477] (18) beta-adrenergic agonists, such as propranolol;

[0478] (19) Local anesthetics, e.g., mexiletine;

[0479] (20) Corticosteroids, e.g., dexamethasone;

[0480] (21) 5-HT receptor agonists or antagonists, especially 5-HT 1B / 1D agonists, such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

[0481] (22)5-HT 2A Receptor antagonists, such as R(+)-α-(2,3-dimethoxy-phenyl)-l-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);

[0482] (23) Cholinergic (nicotinic) analgesics, such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-l-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), or nicotine;

[0483] (24) Tramadol®, Tramadol ER (Ultram ER®), IV Tramadol, tapentadol ER (Nucynta®);

[0484] (25) PDE5 inhibitors, such as 5-[2-ethoxy-5-(4-methyl-l-piperazinyl-sulfonyl)phenyl]-l-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',l':6,l]-pyrido[3,4-b] Indole-1,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-l-yl-l-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4 ,3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-l-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine- 7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-l-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(l-methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(l-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;

[0485] (26) Alpha-2-delta ligands, such as 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, (2S,4S)-4-(3-fluorobenzyl)-proline amine, [(lR,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(l-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(l-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;

[0486] (27) Cannabinoids, such as KHK-6188;

[0487] (28) metabotropic glutamate subtype 1 receptor (mGluR1) antagonist;

[0488] (29) Serotonin reuptake inhibitors, such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, ritoxetine, dapoxetine, nefazodone, cericlamine, and trazodone;

[0489] (30) noradrenaline (norepinephrine) reuptake inhibitors, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion, nomifensine, and viloxazine (Vivalan®), in particular, selective noradrenaline reuptake inhibitors, such as reboxetine, in particular (S,S)-reboxetine;

[0490] (31) Dual serotonin-norepinephrine reuptake inhibitors, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran, and imipramine;

[0491] (32) Inducible nitric oxide synthase (iNOS) inhibitors, such as S-[2-[(l-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(l-iminoethyl)amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(l-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(l-iminoethyl)amino]-5-heptenoic acid, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile; 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5 -thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(lR,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamide, NXN-462 or guanidinoethyl disulfide;

[0492] (33) Acetylcholinesterase inhibitors, for example, donepezil;

[0493] (34) Prostaglandin E2 subtype 4 (EP4) antagonists, such as N-[({2-[4-(2-ethyl-4,6-dimethyl-lH-imidazo[4,5-c]pyridin-l-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[(15)-l-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;

[0494] (35) Leukotriene B4 antagonists; for example, l-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870;

[0495] (36) 5-lipoxygenase inhibitors, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-l-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-l,4-benzoquinone (CV-6504);

[0496] (37) Sodium channel blockers, such as lidocaine, lidocaine + tetracaine cream (ZRS-201), or eslicarbazepine acetate;

[0497] (38)Na V 1.7 Blockers, such as XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893, BIIB-074 (Vixotrigine), BIIB-095, ASP-1807, DSP-3905, OLP-1002, RQ-00432979, FX-301, DWP-17061, IMB-110, IMB-111, IMB-112, and examples thereof, including those disclosed in WO20140101, the entire contents of each of which are incorporated herein by reference. 1 / 140425 (US2011 / 306607); WO2012 / 106499 (US2012196869); WO2012 / 112743 (US2012245136); WO2012 / 125613 (US2012264749), WO2012 / 116440 (US2014187533), WO2011026240 (US2012220605), US8883840, US8466188, or WO2013 / 109521 (US2015005304).

[0498] (38a) Na V1.7 Blockers, such as (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl)-(4-isopropoxy-3-methyl-phenyl)methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]ethanone, 1-(4-benzhydrylpiperazin-1-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy]propan-2-ol, (4-butoxy-3-methoxyphenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro [3,4-Dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]-(5-isopropoxy-6-methyl-2-pyridyl)methanone, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone, 5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4 '-Piperidine]-1'-carbonyl]phenyl]pyridine-2-carbonitrile, (4-isopropoxy-3-methyl-phenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]ethanone, 2,2,2-Trifluoro-1-[1'-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-3,3-dimethyl-spiro[2,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]ethanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]ethanone, (4-isopropoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl) spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 1-[(3S)-2,3-dimethyl-1'-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6- yl]-2,2,2-trifluoro-ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]-[3-methoxy-4-[(1R)-1-methylpropoxy]phenyl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]ethanone, 1-[1'-[ 4-Methoxy-3-(trifluoromethyl)benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]-2,2-dimethyl-propan-1-one, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone, [2-methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]-[4-(3,3,3-trifluoropropoxymethyl)phenyl]methanone, 4-bromo-N-(4-bromophenyl)-3-[(1-methyl-2-oxo-4-piperidyl)sulfamoyl]benzamide or (3-chloro-4-isopropoxy-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone.

[0499] (39)Na V 1.8 Blockers, such as PF-04531083, PF-06372865, and WO2008 / 135826 (US2009048306), WO2006 / 011050 (US2008312235), WO2013 / 061205 (US2014296313), US20130303535, WO2013131018, US8466188, WO2013114250 (US2013274243), WO2014 / 120808 (US2014213616), WO2014 / 12081 5 (US2014228371), WO2014 / 120820 (US2014221435), WO2015 / 010065 (US20160152561), WO2015 / 089361 (US20150166589), WO2019014352 (US20190016671), WO2018 / 213426, WO2020 / 146682, WO2020 / 146612, WO2020 / 014243, WO2020 / 014246, WO2020 / 092187, and WO2020 / 092667 (US2020140411).

[0500] (39a)Na V1.8 Blockers, such as 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide, 5-chloro-2-(4 -fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)- 5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-((5-fluoro-2-hydroxybenzyl)oxy)-N-(2-oxo-1,2-Dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide, 2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide, [4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate, 2-(4-fluoro-2-(methyl-d3)phenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)-5-(trifluoromethyl)benzamide yl)-4-(trifluoromethyl)benzamide, (4-(2-(4-fluoro-2-(methyl-d3)phenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate, 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-methoxyphenoxy)-N- (3-Sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide)picolinic acid, 2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide, 3-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoline-3-carboxamide, N-(3-sulfamoylphenyl)-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide, 3-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)quinoxaline- 2-carboxamide, 5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide)picolinic acid, 3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)quinoxaline-2-carboxamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4-yl)quinoxaline-2-carboxamide, 3-(4-fluorophenoxy)-N -(3-Sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, N-(4-carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide)benzoic acid, N-(4-cyanophenyl)-3-(4 -fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 5-(2-(2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)benzoic acid, 5-(4,5-dicolinic acid 4-(2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 4-(2-(2-chloro-4-fluorophenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)benzoic acid, 4-(4, 5-Dichloro-2-(4-chloro-2-methylphenoxy)benzamido)benzoic acid, 5-(4-(tert-butyl)-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)benzoic acid, 5-(4,5- Dichloro-2-(2,4-dimethoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(2-chloro-4-fluorophenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4-Difluorophenoxy)benzamido)picolinic acid, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-chloro-2-methyl 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-Dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-Dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6-Bis(trifluoromethyl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide 2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3-sulfamoylphenyl)benzamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fu, N-(3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzamide N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2,3,4-Trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, N-(2-carbamoyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide, 4-[[6-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy) phenoxy]-3-(trifluoromethyl)benzamide, N-(4-carbamoyl-3-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-pentafluoroethyl)benzamide, 4-[[4-(difluoromethoxy)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[4-cyclopropyl-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-5-fluoro-2-[2 -Methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide, 5-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzamide, or 4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide;

[0501] (40) Combined Na V 1.7 and Na V 1.8 blockers, for example DSP-2230, Lohocla201 or BL-1021;

[0502] (41) 5-HT3 antagonists, e.g., ondansetron;

[0503] (42) TPRV 1 receptor agonists (e.g., capsaicin (NeurogesX®, Qutenza®)); and pharmaceutically acceptable salts and solvates thereof;

[0504] (43) Nicotinic receptor antagonists, e.g., varenicline;

[0505] (44) N-type calcium channel antagonists, such as Z-160;

[0506] (45) Nerve growth factor antagonists, e.g., tanezumab;

[0507] (46) Endopeptidase stimulators, e.g., senrebotase;

[0508] (47) Angiotensin II antagonists, e.g., EMA-401;

[0509] (48) Acetaminophen (including but not limited to intravenous acetaminophen (e.g., Ofirmev®));

[0510] (49) Bupivacaine (including, but not limited to, bupivacaine liposomal injectable suspension (e.g., Exparel®), bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll), and transdermal bupivacaine (Eladur®)); and

[0511] (50) Combination of bupivacaine and meloxicam (e.g., HTX-011).

[0512] In one embodiment, the additional suitable therapeutic agent is selected from the following: V-116517, pregabalin, controlled-release pregabalin, ezogabine (Potiga®), ketamine / amitriptyline topical cream (Amiket®), AVP-923, perampanel (E-2007), ralfinamide, transdermal bupivacaine (Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561, or ARC-4558.

[0513] In another embodiment, the additional suitable therapeutic agent is selected from: N-(6-amino-5-(2,3,5-trichlorophenyl)pyridin-2-yl)acetamide; N-(6-amino-5-(2-chloro-5-methoxyphenyl)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; or 3-((4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)methyl)oxetan-3-amine.

[0514] In another embodiment, the additional therapeutic agent is selected from GlyT2 / 5HT2 inhibitors, e.g., operanserin (VVZ149), TRPV modulators, e.g., CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101, MDR16523, or MDR652, EGR1 inhibitors such as Brivoglide (AYX1), NGF inhibitors, e.g., tanezumab, fasinumab, ASP6294, MEDI7352, Mu opioid agonists, e.g., cebranopadol, NKTR181 (oxycodegol), CB-1 agonists, e.g., NEO1940 (AZN1940), imidazoline 12 agonists such as CR4056, or p75NTR-Fc modulators such as LEVI-04.

[0515] In another embodiment, the additional therapeutic agent is oliceridine or ropivacaine (TLC590).

[0516] In another embodiment, the additional therapeutic agent is Na V 1.7 Blockers, such as ST-2427, and those disclosed in WO2010129864, WO2015157559, WO2017059385, WO2018183781, WO2018183782, and WO2020072835, the entire contents of each of which are incorporated herein by reference.

[0517] 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, opilanserin (Unafra™), brivolizide, SR419, NRD.E1, LX9211, LY3016859, ISC-17536, NFX-88, LAT-8881, AP-235, NYX2925, CNTX-6016, S-600918, S-637880, RQ-00434739, KLS-2031, MEDI 7352, or XT-150.

[0518] In another embodiment, the additional therapeutic agent is any of the Na V 1.7 and Na V and sodium channel inhibitors (also known as sodium channel blockers), such as 1.8 blockers.

[0519] The amount of additional therapeutic agent present in the compositions of the invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. The amount of additional therapeutic agent in the compositions of the present disclosure can range from about 10% to 100% of the amount that would normally be present in a composition comprising that therapeutic agent as the only therapeutically active agent.

[0520] The compounds and salts of the present invention, or pharmaceutically acceptable compositions thereof, may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, artificial blood vessels, stents, and catheters. Accordingly, in another aspect, the present invention includes compositions for coating implantable devices, comprising a compound or salt of the present invention, as generally described above in the classes and subclasses herein, and a carrier suitable for coating the implantable device. In yet another aspect, the present invention includes an implantable device coated with a composition comprising a compound or salt of the present invention, as generally described above in the classes and subclasses herein, and a carrier suitable for coating the implantable device. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Patent Nos. 6,099,562; 5,886,026; and 5,304,121. The coating is typically a biocompatible polymeric material, such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

[0521] Another aspect of the present invention relates to inhibiting NaV1.8 activity in a biological sample or a subject, the method comprising administering to the subject a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, or contacting the biological sample with a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsies or extracts thereof obtained from mammals; and blood, saliva, urine, feces, sperm, tears, or other bodily fluids or extracts thereof.

[0522] Na in biological samples VInhibition of 1.8 activity is useful for a variety of purposes known to those skilled in the art, including, but not limited to, the study of sodium ion channels in biological and pathological phenomena, and the comparative evaluation of novel sodium ion channel inhibitors.

[0523] Synthesis of Compounds of the Invention The compounds of the present invention can be prepared from known materials by the methods described in the examples, other similar methods, and other methods known to those skilled in the art. As will be understood by those skilled in the art, functional groups of intermediate compounds 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 TGM Wuts et al., Greene's Protective Groups in Organic Synthesis (4th ed. 2006).

[0524] Radiolabeled Analogs of the Compounds of the Invention In another aspect, the present invention relates to radiolabeled analogs of the compounds of the present invention. As used herein, the term "radiolabeled analogs of the compounds of the present invention" refers to compounds that are identical to the compounds of the present invention (including all embodiments thereof) described herein, except that one or more atoms are replaced with a radioisotope of the atom present in the compounds of the present invention.

[0525] As used herein, the term "radioisotope" refers to an isotope of an element that is known to undergo spontaneous radioactive decay. Examples of radioisotopes include: 3 H, 14 C. 32 P, 35 S, 18 F, 36Cl, etc., and isotopes whose decay modes are identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0526] Radiolabeled analogs can be used in several beneficial ways, including various types of assays such as substrate tissue distribution assays. For example, tritium ( 3 H) labeled compounds and / or carbon-14( 14 C) Labeled compounds are useful in various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detectability.

[0527] In another aspect, the invention relates to a pharmaceutically acceptable salt of a radiolabeled analogue according to any of the embodiments described herein in relation to the compounds of the invention.

[0528] In another aspect, the invention relates to a pharmaceutical composition comprising a radiolabeled analogue, or a pharmaceutically acceptable salt thereof, according to any of the embodiments described herein with respect to the compounds of the invention, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0529] In another aspect, the present invention relates to methods of inhibiting voltage-gated sodium channels according to any of the embodiments described herein in connection with the compounds of the invention, and methods of treating or lessening the severity of various diseases and disorders, including pain, in a subject, comprising administering an effective amount of a radiolabeled analogue, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.

[0530] In another aspect, the invention relates to radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof for use according to any of the embodiments described herein in connection with the compounds of the invention.

[0531] In another aspect, the invention relates to the use of a radiolabeled analogue, or a pharmaceutically acceptable salt thereof, according to any of the embodiments described herein with respect to the compounds of the invention, for the manufacture of a medicament, and pharmaceutical compositions thereof.

[0532] In another aspect, the radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof can be used in combination therapy according to any of the embodiments described herein in connection with the compounds of the invention. [Example]

[0533] Common method. 1 H NMR (400 MHz) spectra were obtained as solutions in appropriate deuterated solvents such as dimethylsulfoxide-d6 (DMSO-d6).

[0534] Analytical supercritical fluid chromatography (SFC) separation of various isomeric mixtures was achieved using a Waters UPC2-SFC instrument consisting of a convergence manager, sample manager, binary solvent manager, column manager-30S, PDA detector, isocratic solvent manager, and QDa detector. Columns used included those manufactured by Regis Technologies (e.g., R'R Whelk 0-1, 3.5 μm particle size, 5.0 cm × 3.0 mm size). The mobile phase consisted of Solvent A: liquid CO₂ (58–60 bar / 40°C) and Solvent B: HPLC-grade methanol containing 20 mM NH₃, with a flow rate of 2 ml / min and an injection volume of 2 μl. Gradient: 0 min (95:5) A:B, 3.5 min (50:50) A:B, 3.55 min (40:60) A:B, 3.95 min (40:60) A:B and 4.0 min (95:5) A:B. Samples for analytical SFC were dissolved in methanol at a concentration of approximately 0.5 mg / ml.

[0535] Preparative SFC used the same stationary and mobile phases as described above for analytical SFC, but samples were purified using different equipment and gradient methods as follows: Preparative SFC separation of various isomeric mixtures was achieved using a Waters Prep-100 SFC instrument consisting of a backpressure regulator, a 2767 sample manager, a 2545 quaternary gradient module, a column oven, a 2998 PDA detector, an isocratic solvent manager, a P-200 CO2 pump, an SFC flow splitter-100, three heat exchangers, a Series III LC pump, and a QDa detector. Columns used included those manufactured by Regis Technologies (e.g., R'R Whelk 0-1, 5.0 μm particle size, 25.0 cm × 21.1 mm size), with a mobile phase of Solvent A: liquid CO2 (58-60 bar / 40 °C) and Solvent B: HPLC-grade methanol containing 20 mM NH3, with a flow rate of 100 ml / min and an injection volume of 500 μl (crude load 50 mg). A 2:1 ratio of methanol to dichloroethane was used for crude compound solubilization and SFC injection. The following methods were used for 500 μl / 50 mg load injections: isocratic: 0 min to 7.6 min (80:20) A:B, gradient: 8.1 min (75:25) A:B, isocratic 8.2 to 10.6 min (75:25) (A:B), gradient: 10.7 min (80:20) A:B, and isocratic: 11 min (80:20) (A:B). The following methods were used for injections of 1500 μl / 150 mg load volume: isocratic: 0 min to 7.5 min (80:20) A:B, gradient: 7.6 min (75:25) A:B, gradient: 8.1 min (60:40) A:B, isocratic: 8.7 min to 10.6 min (60:40) A:B, gradient: 10.7 min (80:20) A:B, and isocratic: 12 min (80:20) A:B.

[0536] LC / MS Method: LC / MS analysis was performed using a Waters Acquity UPLC BEH C8 column (50 × 2.1 mm, 1.7 μm particles) (pn: 186002877) equipped with a (2.1 × 5 mm, 1.7 μm particles) guard column (pn: 186003978). A dual gradient was run from 2 to 98% mobile phase B over 4.45 min. Mobile phase A = HO (10 mM ammonium formate with 0.05% ammonium hydroxide). Mobile phase B = acetonitrile. Flow rate = 0.6 mL / min, injection volume = 2 μL, and column temperature = 45 °C.

[0537] X-ray powder diffraction (XRPD) analysis was performed in transmission mode at room temperature using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel 1D Medipix-3 detector (Malvern PANalytical Inc, Westborough, Massachusetts). The X-ray generator was operated at 45 kV and 40 mA, using copper wire (1.54060 Å). Powder samples were placed in a 96-well sample holder with Mylar film and loaded into the instrument. Samples were scanned from approximately 3° to approximately 40° 2θ with a step size of 0.0131303° and 49 seconds per step.

[0538] Solid-state NMR analysis was performed on a Bruker-Biospin 400 MHz wide-aperture spectrometer equipped with a Bruker-Biospin 4 mm HFX probe. Samples were packed in a 4 mm ZrO2 rotor and spun under magic angle spinning (MAS) conditions with the spinning speed typically set at 12.5 kHz. Proton relaxation times were determined as 1 Measured using a H MAS T1 saturation recovery relaxation experiment 13 An appropriate recycle delay for the C cross-polarization (CP) MAS experiment was set. The fluorine relaxation time was 19 F measured using a MAS T1 saturation recovery relaxation experiment 19An appropriate recycle delay was set for the F MAS experiment. The CP contact time for the carbon CPMAS experiment was set to 2 ms. A linear gradient (50% to 100%) of the CP proton pulse was used. The carbon Hartmann-Hahn match was optimized with an external reference sample (glycine). Both the carbon and fluorine spectra were recorded with proton decoupling using the TPPM15 decoupling sequence with a field strength of approximately 100 kHz.

[0539] Thermogravimetric analysis (TGA) data were collected on a TA Discovery thermogravimetric analyzer or equivalent. Samples weighing approximately 1-5 mg were scanned from 25°C to 350°C at a heating rate of 10°C / min. Data were collected using Thermal Advantage Q Series™ software and analyzed using Trios and / or Universal Analysis software (TA Instruments, New Castle, DE).

[0540] Differential scanning calorimetry (DSC) data were acquired using a TA Instruments Q2000 or equivalent instrument. Samples weighing 1–10 mg were weighed into aluminum pans. The pans were placed in the sample position of the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a stream of nitrogen was passed through the cell. A heating program was set to heat the sample to a temperature of 300°C at a heating rate of 10°C / min. Upon completion of the run, data were analyzed using Trios and / or Universal Analysis software (TA Instruments, New Castle, DE).

[0541] Infrared (IR) spectra were collected using a Thermo Scientific Nicolet iS50 spectrometer equipped with a diamond ATR sampling accessory.

[0542] X-ray diffraction data were analyzed using Cu K αThe diffraction patterns were obtained on a Bruker diffractometer equipped with a 1.5478 Å radiation beam and a CCD detector. The structure was solved and refined using the SHELX program (Sheldrick, GM, Acta Cryst., (2008) A64, 112-122).

[0543] Abbreviation Unless otherwise specified, or unless the context indicates 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 High Performance Liquid Chromatography SFC Supercritical Fluid Chromatography MDAP mass directed automatic purification ESI electrospray ionization LED Light Emitting Diode g grams mg milligram L liter(s) mL milliliter μL microliter nL nanoliter mmol millimole hr, h hours min ms milliseconds mm millimeters μm micrometer nm nanometer MHz Megahertz Hz Hertz N normality (concentration) M moles (concentration) mmmmol(concentration) μm micromolar (concentration) ppm parts per million % w / v weight-volume concentration ArBPin 2-[2-(difluoromethoxy)-4-fluoro-phenyl ]-4,4,5,5-tetramethyl-1,3,2-dioxabo Loran t-BuOH tert-butyl alcohol DAST Diethylaminosulfur trifluoride DCM dichloromethane DCE Dichloroethane DIEA, DIPEA N,N-Diisopropylethylamine DMA N,N-dimethylacetamide DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DRG dorsal root ganglion EtOH ethanol EtOAc ethyl acetate HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3 -Triazolo[4,5-b]pyridinium 3-oxide hexa Fluorophosphate EDCI 1-ethyl-3-(3-dimethylpropyl)carbodiimide T3P Propylphosphonic anhydride, i.e., 2,4,6-triplo Pyr-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide TCFH N,N,N',N'-Tetramethylchloroformamidinium Hexafluorophosphate MeOH Methanol MTBE Methyl tert-butyl ether NMP N-methylpyrrolidone THF tetrahydrofuran TEA Triethylamine RB round bottom (flask) RT room temperature ca. about (approximately) E-VIPR Electrical Stimulation Voltage Ion Probe Reader HEK Human Embryonic Kidney KIR2.1 inwardly rectifying potassium ion channel 2.1 DMEM Dulbecco's Modified Eagle's Medium FBS Fetal Bovine Serum NEAA Non-Essential Amino Acids HEPES 2-[4-(2-hydroxyethyl)piperazin-1-yl] Ethanesulfonic acid DiSBAC6(3) Bis-(1,3-dihexyl-thiobarbituric acid) Trimethine Oxonol CC2-DMPE Chlorocoumarin-2-dimyristoylphosphatidyl Ethanolamine VABSC-1 Potential Assay Background Inhibitory Compounds HS human serum BSA Bovine serum albumin

[0544] Example 1 rel-(2S,3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (1) and rel-(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (2) [ka] Step 1:

[0545] A mixture of ethyl rac-(2S,3R)-2,3-dimethyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (3.0 g, 7.77 mmol), 2-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane ("ArBPin", 2.33 g, 8.09 mmol), Pd(PPh3)4 (380 mg, 0.33 mmol), and sodium carbonate (2 M 16 mL, 32.00 mmol) in dioxane (60 mL) was heated at 100° C. for 1 h. The solution was diluted with EtOAc and water, the layers were separated, and the organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography (220 g SiO, 0–30% EtOAc in petroleum ether) gave ethyl rac-(2S,3R)-4-[2-(difluoromethoxy)-4-fluoro-phenyl]-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (2.0 g, 65%). 1 H NMR (500 MHz, chloroform-d) δ 7.19 (dd, J = 8.5, 6.4 Hz, 1H), 6.99 - 6.89 (m, 2H), 6.44 (t, J = 73.3 Hz, 1H), 4.14 (qd, J = 7.1, 1.7 Hz, 2H), 3.45 (q, J = 7.4 Hz, 1H), 1.72 - 1.65 (m, 3H), 1.14 (t, J = 7.1 Hz, 3H), 1.12 - 1.08 (m, 3H) ppm. ESI-MS m / z calculated value 398.09528, measured value 399.0 (M+1) + .

[0546] Step 2:

[0547] Magnesium turnings (3.5 g, 144.0 mmol) were crushed in a mortar and added to a solution of ethyl rac-(2S,3R)-4-[2-(difluoromethoxy)-4-fluoro-phenyl]-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (2.0 g, 5.02 mmol) in MeOH (60 mL). The flask was purged with nitrogen, and the reaction was stirred at ambient temperature until the observed exotherm ceased (30 min). The reaction was then heated at 90 °C for 3 h, then cooled to 0 °C and quenched and acidified by the careful addition of 2 M HCl. The mixture was concentrated under reduced pressure and extracted with DCM (3 × 100 mL). The combined organic layers were dried (MgSO), filtered, and concentrated under reduced pressure to give methyl rac-(3R,4R,5S)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.7 g, 88%) as a mixture of epimers adjacent to the ester (stereochemical assignment tentative). ESI-MS m / z calculated 386.09528, found 387.0 (M+1). + .

[0548] Step 3:

[0549] To a solution of methyl rac-(3R,4R,5S)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (3.2 g, 8.28 mmol) in t-BuOH (80 mL) was added K0t-Bu (4.25 g, 37.87 mmol). The reaction was stirred overnight at ambient temperature and then quenched by the addition of saturated aqueous NH4Cl and diluted with EtOAc. The aqueous layer was separated and extracted with EtOAc, and the combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was dissolved in EtOH (20 mL) and LiOH (2 M, 15 mL, 30.00 mmol), and the mixture was stirred at 110 °C for 1 h. The reaction was quenched by the addition of saturated aqueous NH4Cl and diluted with EtOAc. The aqueous layer was separated and extracted with EtOAc, and the combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. Purification by flash chromatography (80 g SiO, 0–100% EtOAc in heptane) afforded rac-(3R,4R,5S)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (2.2 g, 71%) as a mixture of epimers adjacent to the ester (stereochemical assignment tentative). ESI-MS m / z calculated 372.07962, found 371.2 (M-1). - .

[0550] Step 4:

[0551] To a solution of rac-(3R,4R,5S)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (650 mg, 1.75 mmol) in DCM (24 mL) stirred at 0 °C was added DMF (50 μL, 0.65 mmol) and oxalyl chloride (400 μL, 4.59 mmol). The reaction was allowed to warm to ambient temperature over 30 min and then concentrated under reduced pressure. The residue was dried under high vacuum for an additional 5 min to give a white foam, which was dissolved in DCM (24 mL) and added dropwise to a solution of methyl 4-aminopyridine-2-carboxylate (305 mg, 2.01 mmol) and NEt (800 μL, 5.74 mmol) in DCM (9 mL) stirred at 0 °C. The reaction was allowed to warm to ambient temperature over 4 h, then quenched by the addition of MeOH (2 mL) and concentrated under reduced pressure. Purification by flash chromatography (loaded on 12 g of SiO, 0–70% EtOAc in heptane, DCM) afforded methyl rac-(3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (840 mg, 95%) as an 85:15 mixture of epimers adjacent to the amide (stereochemical assignment tentative). ESI-MS m / z calculated 506.12766, found 507.9 (M+1). + .

[0552] Step 5:

[0553] A solution of methyl rac-(3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (740 mg, 1.46 mmol) in methanolic ammonia (7 M 15 mL, 105.0 mmol) was stirred in a sealed vessel at 100° C. for 16 hours. The solution was concentrated under reduced pressure to give rac-(3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (700 mg, 98%) as a mixture of epimers adjacent to the amide (stereochemical assignment tentative). ESI-MS m / z calculated 491.12796, observed 491.7 (M+1) + .

[0554] Step 6:

[0555] Purification of rac-(3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (400 mg, 0.81 mmol) by chiral SFC using a Daicel Chiralpak IC column, 5 um particle size, 25 cm x 20 mm to give:

[0556] First eluting isomer (rt=3.40 min): rel-(2S,3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (1, 150 mg, 74%) (stereochemical assignment tentative). 1H NMR (500 MHz, methanol-d4) δ 8.48 (d, J = 5.5 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.90 (dd, J = 5.5, 2.2 Hz, 1H), 7.49 (dd, J = 9.0, 6.3 Hz, 1H), 7.01 (dd, J = 9.0, 6.7 Hz, 2H), 7.14 - 6.74 (m, 1H), 5.14 (d, J = 10.3 Hz, 1H), 4.33 (dd, J = 10.3, 7.9 Hz, 1H), 2.83 (p, J = 7.6 Hz, 1H), 1.66 (s, 3H), 0.83 (dd, J = 7.7, 2.3 Hz, 3H) ppm. ESI-MS m / z calculated 491.12796, found 492.2 (M+1) + ;490.3 (M-1) - .

[0557] Second eluting isomer (rt=4.28 min): The second eluting isomer was further purified by reverse-phase preparative HPLC (basic eluent) to afford rel-(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (2, 100 mg, 50%) (stereochemical assignment tentative). 1H NMR (500 MHz, methanol-d4) δ 8.49 (d, J = 5.5 Hz, 1H), 8.27 - 8.23 ​​(m, 1H), 7.90 (dd, J = 5.5, 2.2 Hz, 1H), 7.49 (dd, J = 9.1, 6.4 Hz, 1H), 7.06 - 6.99 (m, 2H), 7.16 - 6.69 (m, 1H), 5.14 (d, J = 10.3 Hz, 1H), 4.33 (dd, J = 10.3, 7.9 Hz, 1H), 2.83 (p, J = 7.6 Hz, 1H), 1.66 (d, J = 1.3 Hz, 3H), 0.83 (dd, J = 7.6, 2.3 Hz, 3H) ppm. ESI-MS m / z calculated 491.12796, found 492.1 (M+1)+.

[0558] The following compounds were made using methods similar to those described in Example 1, however, the SFC separation step 6 was not performed at the end of the synthesis and the compounds were isolated as racemates. [Table 4]

[0559] The following compounds were made using a method similar to that described in Example 1, but using methylamine at 40° C. in step 5. The conditions used for epimerization / hydrolysis step 3 followed those described in step 5 of Example 11. Purification in step 6 was performed by chiral SFC using a Daicel Chiralpak AS-H column, 5 μm particle size, 25 cm×10 mm, on a Berger Instruments Minigram SFC instrument. [Table 5]

[0560] The following compound was made using a method similar to that described in Example 1, except that 5-amino-2-fluorobenzamide was used as the coupling partner in Step 4 and Step 5 was omitted. The conditions used for epimerization / hydrolysis Step 3 followed those described in Step 5 of Example 11. Purification in Step 6 was performed by chiral SFC using a Daicel Chiralpak AS-H column, 5 um particle size, 25 cm x 10 mm on a Berger Instruments Minigram SFC instrument. [Table 6]

[0561] The following compounds were prepared using a method similar to that described in Example 1, but using catalytic 1,2-dibromoethane to activate the magnesium in step 2 and without separation of the racemate by chiral SFC in step 6. [Table 7-1] [Table 7-2]

[0562] The following compounds were made using a method similar to that described in Example 1, except that catalytic 1,2-dibromoethane was used to activate magnesium in step 2 and LiOH / EtOH was not added in step 3. Purification in step 6 was carried out by SFC using a Princeton Chromatography Inc. DEAP column, 5 μm particle size, 25 cm × 21.2 mm, on a Waters Corp. SFC 100 instrument, followed by chiral SFC using a Daicel Chiralpak AS-H column, 5 μm particle size, 25 cm × 10 mm, on a Berger Instruments Minigram SFC instrument. Compound 3a was further purified by chiral SFC using a Daicel Chiralpak OD-H column, 5 μm particle size, 25 cm × 10 mm, on a Berger Instruments Minigram SFC instrument. Compounds 38 and 39 were separated by chiral SFC using a Regis Technologies (R,R)-Whelk-O1 column, 5 μm particle size, 25 cm×21.2 mm. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4]

[0563] The following compounds were made using a method similar to that described in Example 1, except that catalytic 1,2-dibromoethane was used to activate magnesium in step 2 and LiOH / EtOH was not added in step 3. Purification in step 6 was performed by SFC on a Waters Corp. SFC 100 instrument using a Phenomenex Lux Cellulose-2 column, 5 μm particle size, 25 cm × 10 mm, on a Berger Instruments Minigram SFC instrument. [Table 9]

[0564] The following compounds were made using a method similar to that described in Example 1, but without the addition of LiOH / EtOH in step 3. The amide coupling step 4 was carried out using T3P as the activating agent rather than oxalyl chloride. Purification in step 6 was carried out by SFC on a Waters Corp. SFC 100 instrument, a Berger Instruments Minigram SFC instrument, and a Phenomenex Lux i-Cellulose-5 column, 5 μm particle size, 25 cm × 10 mm. [Table 10]

[0565] The following compounds were made using a method similar to that described in Example 1, except that methylamine was used instead of ammonia in step 5. Purification in step 6 was performed by chiral SFC using a Daicel Chiralpak AS-H column, 5 μm particle size, 25 cm × 10 mm on a Berger Instruments Minigram SFC instrument. [Table 11]

[0566] Example 2 rel-(2S,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (4) and rel-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (5) [ka] Step 1:

[0567] To a solution of ethyl 2-diazo-3-oxobutanoate (5.0 g, 31.4 mmol) in DCM (50 mL) stirred at 0 °C, triethylamine (8.05 g, 11.2 mL, 78.8 mmol) was added. TBSOTf (9.24 g, 8.2 mL, 34.3 mmol) was slowly added, and the reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was washed with 30% NaHCO solution (200 mL). The organic layer was separated, washed with water (500 mL), and then dried over MgSO. The solvent was evaporated to give ethyl 3-[tert-butyl(dimethyl)silyl]oxy-2-diazo-but-3-enoate (8.22 g, 97%), which was used in the next step without further purification.

[0568] Step 2:

[0569] A solution of 1,1,1-trifluoropropan-2-one (33.8 g, 27 mL, 301.2 mmol) in DCM (150 mL) was stirred at −78° C. and TiCl (56.8 g, 33 mL, 299.2 mmol) was added dropwise. The reaction was held at −78° C. for 10 minutes, after which a solution of ethyl 3-[tert-butyl(dimethyl)silyl]oxy-2-diazo-but-3-enoate (64 g, 236.7 mmol) in DCM (150 mL) was added dropwise. The reaction was held at −78° C. for 1 hour, then a saturated solution of NaHCO was added and the mixture was diluted with DCM. The organic layer was dried over MgSO4, concentrated under reduced pressure, and the residue was purified by column chromatography (0-30% EtOAc in hexanes) to give ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-5-methyl-3-oxo-hexanoate (39 g, 61%) as a pale yellow liquid. 1 H 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.

[0570] Step 3:

[0571] Rhodium(II) acetate (643 mg, 1.45 mmol) was charged to an oven-dried two-neck flask. Toluene (970 mL) was added, and the solution was stirred at 100° C. for 10 minutes. While the solution was briefly removed from the oil bath, a solution of ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-5-methyl-3-oxo-hexanoate (39 g, 145.4 mmol) in toluene (200 mL) was added dropwise, and the reaction was heated to reflux for 1 hour. The reaction mixture was filtered through filter paper, and the filtrate was concentrated under reduced pressure to give ethyl 5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (30.89 g, 88%). 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.

[0572] Step 4:

[0573] Trifluoromethanesulfonic anhydride (6.0 mL, 35.7 mmol) was added dropwise to a solution of ethyl 5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (6.5 g, 27.1 mmol) and DIPEA (14 mL, 80.4 mmol) in DCM (150 mL) at −78° C. The reaction was stirred for 2.5 h, after which saturated aqueous NH4Cl (75 mL) was added. The mixture was warmed to ambient temperature, the layers were separated, and the aqueous layer was extracted with DCM (2 × 30 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure to provide ethyl 2-methyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (10.1 g, 100%), which was used directly in the next reaction.

[0574] Step 5:

[0575] To a stirred solution of (3,4-difluoro-2-methoxy-phenyl)boronic acid (2.0 g, 10.6 mmol) and ethyl 2-methyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (3 g, 7.90 mmol) in toluene (80 mL) was added KPO (13 mL of a 2 M aqueous solution, 26.0 mmol). The mixture was degassed with N for 20 min, after which Pd(PPh) (466 mg, 0.40 mmol) was added and then heated at 100 °C for 1 h. The mixture was filtered through a Celite pad, the filtrate was diluted with water (50 mL), and the aqueous layer was extracted with EtOAc (50 × 2 mL). The organic layer was dried (MgSO), filtered, and evaporated. The residue was purified by column chromatography (SiO2, 0-2% EtOAc in hexanes) to give ethyl 4-(3,4-difluoro-2-methoxy-phenyl)-2-methyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (2.5 g, 85%) as a pale yellow liquid. 1 H NMR (400 MHz, chloroform-d) δ 6.87 (pd, J = 8.8, 6.2 Hz, 2H), 4.15 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.42 (d, J = 17.4 Hz, 1H), 2.93 (d, J = 17.4 Hz, 1H), 1.65 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H) ppm. ESI-MS m / z calculated value 366.089, measured value 367.2 (M+1) + .

[0576] Step 6:

[0577] EtOH (200 mL) was added to ethyl 4-(3,4-difluoro-2-methoxy-phenyl)-2-methyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (5.51 g, 15.0 mmol) and Pd / C (10 wt. % loading, 2.2 g, 2.067 mmol). The mixture was degassed and stirred under a balloon of H for 96 hours. The catalyst was removed by filtration, the solid was washed with EtOH (50 mL), and the filtrate was concentrated under reduced pressure. An additional portion of Pd / C (10 wt. % loading, 2.2 g, 2.07 mmol) was added to the residue, followed by EtOH (200 mL), and the reaction mixture was stirred at ambient temperature for 24 hours under a balloon of H. The catalyst was removed by filtration, the solid was washed with EtOH (50 mL), and the filtrate was concentrated under reduced pressure. An additional portion of Pd / C (10 wt.% loading, 2.2 g, 2.07 mmol) was added to the residue, followed by EtOH (200 mL), and the reaction mixture was stirred under a balloon of H at ambient temperature for 4 days. The catalyst was removed by filtration, the solid was washed with EtOH (50 mL), and the filtrate was concentrated under reduced pressure to give ethyl rac-(2S,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (5.19 g, 94%) as a white solid and as a single diastereomer. 1 H NMR (500 MHz, chloroform-d) δ 6.89 - 6.86 (m, 1H), 6.82 - 6.77 (m, 1H), 4.93 (d, J = 8.9 Hz, 1H), 4.23 (dt, J = 13.0, 7.6 Hz, 1H), 4.08 (d, J = 2.9 Hz, 3H), 3.85 - 3.71 (m, 2H), 2.82 (t, J = 12.5 Hz, 1H), 2.04 (dd, J = 12.0, 6.7 Hz, 1H), 1.53 (s, 3H), 0.94 (t, J = 7.1 Hz, 3H) ppm; 19 F NMR (471 MHz, chloroform-d) δ −80.15, −136.84 (d, J = 19.4 Hz), −154.77 (d, J = 19.6 Hz) ppm.

[0578] Step 7:

[0579] Ethyl rac-(2S,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (5.19 g, 14.09 mmol) was dissolved in ethanol (100 mL). Cesium carbonate (7.1 g, 21.8 mmol) was added, and the suspension was stirred at 50 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then partitioned between 1 M HCl and MTBE. The layers were separated, and the aqueous layer was extracted twice with MTBE. The combined organic extracts were dried (MgSO), filtered, and concentrated under reduced pressure to give rac-(2R,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (5.11 g, 96%) as a colorless oil and as a single diastereomer. 1 H 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; 19 F 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 calculated 340.0734, found 339.5 (M-1). - .

[0580] Step 8:

[0581] To a solution of rac-(2R,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1.5 g, 4.41 mmol) in DCM (30 mL) cooled to -10 °C was added DMF (5 μL, 0.065 mmol), followed by oxalyl chloride (620 μL, 7.11 mmol). The reaction was stirred for 4 h, and after it was warmed to ambient temperature, more oxalyl chloride (300 μL, 3.55 mmol) was added. The reaction was stirred for an additional 1 h before being concentrated under reduced pressure. The residue was dissolved in DCM (30 mL), and the solution was cooled in an ice bath. TEA (600 μL, 4.31 mmol) and methyl 4-aminopyridine-2-carboxylate (663.7 mg, 4.36 mmol) were added sequentially, and the resulting mixture was stirred for 30 min before being quenched with MeOH and concentrated under reduced pressure. Purification by flash chromatography (loaded on 40 g of SiO, 0–60% ethyl acetate in heptane, DCM) afforded methyl rac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (827.6 mg, 74%). 1 H NMR (500 MHz, chloroform-d) δ 8.63 (d, J = 5.5 Hz, 1H), 8.46 (s, 1H), 8.07 (d, J = 2.1 Hz, 1H), 7.94 (dd, J = 5.5, 2.2 Hz, 1H), 7.00 (ddd, J = 8.0, 5.5, 2.1 Hz, 1H), 6.90 (td, J = 9.1, 7.3 Hz, 1H), 4.75 (d, J = 10.7 Hz, 1H), 4.01 (s, 3H), 3.99 (d, J = 2.6 Hz, 3H), 3.83 (td, J = 11.4, 8.3 Hz, 1H), 2.61 (t, J = 12.5 Hz, 1H), 2.34 (dd, J = 13.1, 8.2 Hz, 1H), 1.65 (s, 3H) ppm. ESI-MS m / z calculated value 474.1214, measured value 474.7 (M+1) +and 473.2 (M-1) - .

[0582] Step 9:

[0583] Methyl rac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (1.9 g, 4.01 mmol) was dissolved in 7 M methanolic ammonia (20 mL, 140.0 mmol) and the reaction was stirred at ambient temperature overnight. Additional methanolic ammonia (5 mL, 7 M, 35.0 mmol) was added and the reaction was stirred at ambient temperature for an additional 3 hours before being concentrated under reduced pressure to give rac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (1.94 g, 99%). 1 H NMR (500 MHz, methanol-d4) δ 8.49 (dd, J = 5.5, 0.6 Hz, 1H), 8.26 (dd, J = 2.2, 0.6 Hz, 1H), 7.88 (dd, J = 5.5, 2.2 Hz, 1H), 7.14 (ddd, J = 8.3, 5.7, 2.3 Hz, 1H), 6.99 (ddd, J = 9.9, 8.9, 7.5 Hz, 1H), 4.67 (d, J = 10.3 Hz, 1H), 4.10 - 4.01 (m, 1H), 3.92 (d, J = 2.3 Hz, 3H), 3.35 (s, 3H), 2.62 (t, J = 12.4 Hz, 1H), 2.40 (dd, J = 12.8, 8.2 Hz, 1H), 1.63 (s, 3H) ppm. ESI-MS m / z calculated 459.12173, found 460.2 (M+1) + and 458.3 (M-1) - .

[0584] Step 10:

[0585] rac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (1.9 g, 3.89 mmol) was separated by chiral SFC using a Regis Technologies (R,R)-Whelk-O1 column, 5 μm particle size, 25 cm × 21.2 mm, to give two single isomers of unknown absolute configuration:

[0586] First eluting isomer (rt = 5.05 min): rel-(2S,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (4, 724 mg, 38%); ESI-MS m / z calculated 459.12173, found 460.2 (M+1). + and 458.3 (M-1) - . 1 H NMR (500 MHz, methanol-d4) δ 8.36 (d, J = 5.5 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 7.75 (dd, J = 5.5, 2.2 Hz, 1H), 7.00 (ddd, J = 8.2, 5.6, 2.2 Hz, 1H), 6.86 (td, J = 9.3, 7.5 Hz, 1H), 4.55 (d, J = 10.3 Hz, 1H), 3.92 (ddd, J = 12.2, 10.4, 8.2 Hz, 1H), 3.79 (d, J = 2.3 Hz, 3H), 3.22 (s, 1H), 2.49 (t, J = 12.4 Hz, 1H), 2.27 (dd, J = 12.8, 8.2 Hz, 1H), 1.50 (s, 3H) ppm.

[0587] Second eluting isomer (rt=7.36 min): rel-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (5, 749 mg, 39%); ESI-MS m / z calculated 459.12173, found 460.2 (M+1). + and 458.3 (M-1) - . 1 H NMR (500 MHz, methanol-d4) δ 8.36 (d, J = 5.5 Hz, 1H), 8.13 (d, J = 2.2 Hz, 1H), 7.75 (dd, J = 5.5, 2.2 Hz, 1H), 7.01 (ddd, J = 8.3, 5.6, 2.2 Hz, 1H), 6.86 (td, J = 9.4, 7.5 Hz, 1H), 4.55 (d, J = 10.2 Hz, 1H), 3.92 (ddd, J = 12.0, 10.4, 8.2 Hz, 1H), 3.79 (d, J = 2.3 Hz, 3H), 3.22 (s, 3H), 2.49 (t, J = 12.4 Hz, 1H), 2.27 (dd, J = 12.9, 8.2 Hz, 1H), 1.50 (s, 3H) ppm.

[0588] The following compound was made using a similar method to that described in Example 2, except that 5-amino-2-fluorobenzamide was used as the coupling partner in step 8 and step 9 was omitted. [Table 12]

[0589] Example 3 (2S,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (6) and (2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (7) [ka] Step 1:

[0590] NEt3 (7.7 mL, 55.2 mmol) was added to a solution of ethyl 2-diazo-3-oxo-pentanoate (6.69 g, 39.3 mmol) in DCM (80 mL) stirred under nitrogen at 0 °C. Trimethylsilyl trifluoromethanesulfonate (8.5 mL, 47.0 mmol) was added dropwise over 5 min, and the mixture was stirred at 0 °C for an additional 30 min. The reaction mixture was diluted with pentane (100 mL), the layers were separated, and the organic phase was washed with dilute aqueous sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to give ethyl (Z)-2-diazo-3-trimethylsilyloxy-pent-3-enoate (9.4 g, 99%) as a red oil. 1 H 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.

[0591] Step 2:

[0592] To a solution of 1,1,1-trifluoropropan-2-one (8 mL, 89.4 mmol) in DCM (80 mL) stirred at −78° C., TiCl (70 mL of 1 M in DCM, 70.00 mmol) was added via cannula. To the resulting solution, a solution of ethyl (Z)-2-diazo-3-trimethylsilyloxy-pent-3-enoate (31.3% w / w, 36.1 g, 46.6 mmol) in 40 mL of DCM was added dropwise over 15 min. After 100 min, the reaction was carefully quenched with water, the temperature was allowed to slowly rise, and then extracted with DCM. The combined organic layers were dried (MgSO), filtered, and concentrated under reduced pressure. Purification by flash chromatography (330 g SiO2, 0-20% EtOAc in heptane) gave ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxo-hexanoate (8.82 g, 67%), which was stored as a toluene solution. 1 H NMR (500 MHz, chloroform-d) δ 4.33 (q, J = 7.1 Hz, 2H), 4.14 (q, J = 7.0 Hz, 1H), 3.98 (s, 1H), 1.43 (q, J = 1.2 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H), 1.31 (dq, J = 7.0, 1.4 Hz, 3H) ppm. ESI-MS m / z calculated value 282.08273, measured value 283.1 (M+1) + ;281.0 (M-1) - .

[0593] Step 3:

[0594] After heating a solution of rhodium tetraacetate (245 mg, 0.55 mmol) in benzene (32 mL) at reflux for 10 minutes, a solution of ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxohexanoate (10 g, 35.4 mmol) in benzene (13 mL) was added slowly via an addition funnel while refluxing for 60 minutes. The mixture was then concentrated under reduced pressure 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 without further purification. 1 H NMR (500 MHz, chloroform-d) δ 4.83–4.57 (m, 1H), 4.38–4.16 (m, 2H), 2.60 (dddd, J = 9.3, 8.2, 5.6, 1.4 Hz, 1H), 1.73–1.63 (m, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.24 (ddq, J = 6.4, 4.1, 1.9 Hz, 3H) ppm.

[0595] Step 4:

[0596] To a stirred solution of ethyl rac-(4R,5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (48 g, 188.83 mmol) in DCM (400 mL) at -78 °C was added DIPEA (29.680 g, 40 mL, 229.64 mmol). A solution of trifluoromethylsulfonyl trifluoromethanesulfonate (53.440 g, 32 mL, 189.41 mmol) in DCM (200 mL) was added to the reaction mixture over 1 h at the same temperature. The reaction mixture was stirred at 0 °C for 30 min and then quenched with 100 mL of saturated aqueous NaHCO3. The organic layer was separated, and the aqueous layer was extracted with DCM (160 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give ethyl rac-(4R,5R)-2,3-dimethyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (71 g, 97%). 1 H NMR (400 MHz, chloroform-d) δ 4.38-4.32 (m, 2H), 3.29-3.23 (m, 1H), 1.64 (s, 3H), 1.37-1.33 (m, 6H) ppm.

[0597] Step 5:

[0598] To a stirred solution of ethyl rac-(4R,5R)-2,3-dimethyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (26 g, 67.311 mmol) in toluene (130.00 mL) was added (3,4-difluoro-2-methoxy-phenyl)boronic acid (14 g, 74.5 mmol), followed by KPO (2 M, 100 mL, 200.00 mmol) under an argon atmosphere. The reaction was degassed, and then tetrakis(triphenylphosphine)palladium(0) (4 g, 3.46 mmol) was added. After further degassing, the reaction was heated at 100 °C for 2 h. The reaction was diluted with water, and the aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were concentrated under reduced pressure. Purification by flash chromatography (SiO, 0-10% EtOAc in heptane) afforded ethyl 4-(3,4-difluoro-2-methoxy-phenyl)-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (24.4 g, 93%) as a 6:1 diastereomeric mixture, with the major isomer likely to be ethyl rac-(4R,5R)-4-(3,4-difluoro-2-methoxy-phenyl)-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate. Major isomer: 1 H NMR (400 MHz, chloroform-d) δ 6.88 - 6.79 (m, 2H), 4.17 - 4.09 (m, 2H), 3.90 (s, 3H), 3.46 (q, J = 7.4 Hz, 1H), 1.67 (s, 3H), 1.12 (t, J = 7.4 Hz, 3H), 1.06 (dd, J = 5.4, 2.7 Hz, 3H) ppm. minor isomer 1H NMR (400 MHz, chromophore-d) δ 6.88 - 6.79 (m, 2H), 4.17-4.09 (m, 2H), 3.88 (s, 3H), 3.76-3.71 (m, 1H), 1.51 (s, 3H), 1.12 (t, J = 7.4 Hz, 3H), 0.99 (dd, J = 5.4, 2.7 Hz, 3H) ppm. ESI-MS m / z calcd: 380.1047, found: 381.02 (M+1) + .

[0599] ステップ6:

[0600] To an ice-cold solution of ethyl 4-(3,4-difluoro-2-methoxy-phenyl)-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (110 g, 243.0 mmol) in DCM (360 mL) was added dropwise BBr3 (1 M 370 mL, 370.0 mmol). Upon completion, 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) and concentrated under reduced pressure. The residue was dissolved in DCM (430 mL) at ambient temperature, TFA (40 mL, 519.2 mmol) was added, and the reaction was then heated to 45 °C. Upon completion, the mixture was quenched by the addition of aqueous sodium bicarbonate, and the aqueous layer was extracted with DCM, dried (MgSO4), and concentrated under reduced pressure to give the desired product as a 5:1 mixture of diastereomers. Recrystallization was performed by solubilizing the crude product in the minimum amount of DCM possible and adding a layer of heptane on top of this solution (liquid-liquid diffusion). After approximately 1 hour, 56.5 g (97:3 syn:anti) was obtained from the first and second crystallizations, and an additional 4.6 g (96:4 syn:anti) was obtained from the third crystallization. The first, second, and third batches were combined to yield 6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1H-furo[2,3-c]chromen-4-one (61 g, 78%), with the major isomer being rac-(1S,2R)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1H-furo[2,3-c]chromen-4-one. ESI-MS m / z calculated 320.04718, found 321.5 (M+1). + ;319.6 (M-1) - .

[0601] Step 7:

[0602] rac-(1S,2R)-6,7-Difluoro-1,2-dimethyl-2-(trifluoromethyl)-1H-furo[2,3-c]chromen-4-one (30 g, 93.69 mmol) was dissolved in EtOAc (400 mL) and stirred with activated charcoal (6 g, 499.6 mmol) (0.2 g / g substrate) at ambient temperature for 4 hours and 30 minutes. The mixture was filtered through a pad of Celite and washed with EtOAc. The filtrate was concentrated under reduced pressure to give a white solid. The white solid was suspended in MeOH (600 mL) and added to a suspension of Pd(OH) (20% w / w 13.62 g, 19.40 mmol) in MeOH (150 mL) in a 2.25 L Parr bottle. The resulting mixture was shaken overnight in a Parr hydrogenator under 60 psi hydrogen pressure. The suspension was filtered through Celite under a nitrogen atmosphere, rinsed with MeOH and then EtOAc, and the resulting filtrate was concentrated under reduced pressure to give methyl rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (32.75 g, 99%). 1 H NMR (400 MHz, methanol-d4) δ 7.05 (ddq, J = 9.4, 5.9, 1.9 Hz, 1H), 6.57 (ddd, J = 10.0, 9.0, 7.6 Hz, 1H), 5.01 (d, J = 6.0 Hz, 1H), 4.34 (dd, J ppm. ESI-MS m / z calculated value 354.08905, measured value 353.3 (M-1) - .

[0603] Step 8:

[0604] A solution of methyl rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (60.8 g, 171.6 mmol) in THF (620 mL) was cooled to 1 °C, and potassium tert-butoxide (65.0472 g, 579.7 mmol) was added over 10 minutes, maintaining the internal temperature below 10 °C. The mixture was stirred at 0 °C for an additional 5 minutes, and then the mixture was allowed to warm slightly. Once the temperature reached 13 °C, the reaction was cooled again in an ice bath before adding 2 M HCl (365 mL, pH 1) while maintaining the internal temperature below 15 °C. Water (300 mL) was added, the layers were separated, and the aqueous layer was extracted with EtOAc (110 mL). The combined organic extracts were washed with brine (300 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to give rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (58.22 g, 100%). 1 H NMR (400 MHz, methanol-d4) δ 7.00 (ddd, J = 8.4, 5.6, 2.3 Hz, 1H), 6.69 (ddd, J = 10.1, 8.8, 7.5 Hz, 1H), 4.98 (d, J = 10.5 Hz, 1H), 4.18 (dd, J = 10.5, 7.6 Hz, 1H), 2.83 (p, J = 7.5 Hz, 1H), 1.59 (q, J = 1.2 Hz, 3H), 0.76 (dq, J = 7.2, 2.2 Hz, 3H) ppm. ESI-MS m / z calculated value 340.0734, measured value 339.0 (M-1) - .

[0605] Step 9:

[0606] To a solution of rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (58.39 g, 171.6 mmol) in acetonitrile (300 mL) was added KCO (82.6 g, 597.7 mmol) and MeI (37 mL, 594.3 mmol). The reaction was heated to 80 °C (internal temperature reached 61 °C) for 5 h, then cooled to ambient temperature and diluted with DCM (350 mL). The mixture was filtered, the filter cake washe...

Claims

1. Formula (I) 【Chemistry 107】 or a pharma- ceutically acceptable salt thereof, wherein X ２ａ is N, N ＋ -O － , or C-R ２ａ and X ４ａ is N, N ＋ -O － , or C-R ４ａ and X ５ａ is N, N ＋ -O － , or C-R ５ａ and X ６ａ is N, N ＋ -O － , or C-R ６ａ and Each R is independently H or C １ -C ６ is alkyl; R ２ａ , R ４ａ , R ５ａ , and R ６ａ are each independently H, halo, or C １ -C ６ Alkyl, or C １ -C ６ haloalkyl; R ４ｂ１ and R ４ｂ２ are each independently H, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ haloalkyl; R ５ｂ１ and R ５ｂ２ are each independently H, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ haloalkyl; X ３ｃ is N or C-R ３ｃ and X ４ｃ is N or C-R ４ｃ and X ５ｃ is N or C-R ５ｃ and X ６ｃ is N or C-R ６ｃ and R ２ｃ H, OH, halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ haloalkoxy, or -L １ -L ２ - (C ３ -C ６ cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo; L １ is a bond or O; L ２ is a bond or C １ -C ６ is alkylene; R ３ｃ H, halo, C １ -C ６ Alkyl, or C １ -C ６ haloalkyl; R ４ｃ H, halo, C １ -C ６ Alkyl, or C １ -C ６ haloalkyl; R ５ｃ H, halo, C １ -C ６ Alkyl, or C １ -C ６ haloalkyl; R ６ｃ H, halo, C １ -C ６ Alkyl, or C １ -C ６ haloalkyl; However, X ２ａ , X ４ａ , X ５ａ , and X ６ａ Of these, N or N ＋ -O － provided that there are not more than two of X ３ｃ , X ４ｃ , X ５ｃ , and X ６ｃ provided that not more than one of The compound, or a pharma- ceutically acceptable salt thereof.

2. 2. A compound of claim 1 or a pharma- ceutically acceptable salt thereof, comprising: X ２ａ is C-R ２ａ and X ５ａ is C-R ５ａ and X ６ａ is C-R ６ａ and R ４ｂ１ and R ４ｂ２ are each independently H, C １ -C ６ Alkyl, or C １ -C ６ haloalkyl; R ５ｂ１ and R ５ｂ２ are each independently H, C １ -C ６ Alkyl, or C １ -C ６ haloalkyl; X ３ｃ is C-R ３ｃ and X ４ｃ is C-R ４ｃ and X ５ｃ is C-R ５ｃ and X ６ｃ is C-R ６ｃ and R ２ｃ H, OH, halo, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, or C １ -C ６ haloalkoxy; The compound, or a pharma- ceutically acceptable salt thereof.

3. 3. The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein the compound has the formula (IA): 【Chemistry 108】 13. A compound having the formula:

4. 3. The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein the compound has the formula (IB): 【Chemistry 109】 13. A compound having the formula:

5. X ４ａ is C-R ４ａ and R ４ａ is H or halo; or X ４ａ The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein:

6. Each R is H or CH ３ 6. The compound according to any one of claims 1 to 5, which is: or a pharma- ceutically acceptable salt thereof.

7. X ２ａ is C-R ２ａ and R ２ａ is H, halo, or C １ -C ６ 7. The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

8. X ５ａ is C-R ５ａ and R ５ａ is H, halo, or C １ -C ６ The compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

9. X ６ａ is C-R ６ａ and R ６ａ is H, halo, or C １ -C ６ 9. The compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

10. Each R is H; X 2a is C-R 2a and R 2a is H; X 5a is C—R 5a and R 5a is H; and X 6a is C-R 6a and R 6a is H; 10. The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof.

11. R ４ｂ１ and R ４ｂ２ are independently H, C １ -C ６ Alkyl or C ３ -C ６ 11. The compound of any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, which is cycloalkyl.

12. R ５ｂ１ and R ５ｂ２ However, each independently H, C １ -C ６ Alkyl or C １ -C ６ 12. The compound of any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

13. R 4b1 and R 4b2 are each independently H or C 1 -C 6 alkyl; and R 5b1 and R 5b2 are each independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; 13. The compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof.

14. R ２ｃ But, OH, C １ -C ６ Alkoxy, or C １ -C ６ The compound of any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, which is haloalkoxy.

15. X ３ｃ is C-R ３ｃ and R ３ｃ is H, halo, or C １ -C ６ 15. The compound of any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, which is alkyl.

16. X ４ｃ is C-R ４ｃ and R ４ｃ is H, halo, or C １ -C ６ 16. The compound of any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

17. X ５ｃ is C-R ５ｃ and R ５ｃ The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein is H or halo.

18. X ６ｃ is C-R ６ｃ and R ６ｃ The compound of any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, wherein is H or halo.

19. The method of claim 1, wherein R 2c is C 1 -C 6 alkoxy; X 3c is C—R 3c and R 3c is halo; X 4c is C—R 4c and R 4c is halo; X 5c is C—R 5c and R 5c is H; and X 6c is C—R 6c and R 6c is H; 19. The compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof.

20. The compound 【Chemistry 201】 【Chemistry 202】 【Chemistry 203】 【Chemistry 204】 【Chemistry 205】 【Chemistry 206】 【Chemistry 207】 【Chemistry 208】 【Chemistry 209】 【Chemistry 210】 【Chemistry 211】 【Chemistry 212】 【Chemistry 213】 【Chemistry 214】 【Chemistry 215】 【Chemistry 216】 【Chemistry 217】 【Chemistry 218】 【Chemical 219】 【Chemistry 220】 【Chemistry 221】 【Chemical 222】 【Chemical 223】 【Chemical 224】 【Chemistry 225】 【Chemical 226】 【Chemical 227】 【Chemical 228】 【Chemical 229】 【Chemistry 230】 【Chemistry 231】 【Chemical 232】 【Chemistry 233】 【Chemical 234】 【Chemistry 235】 【Chemistry 236】 2. The compound of claim 1, selected from:

21. The compound 【Chemical 237】 【Chemical 238】 【Chemical 239】 【Chemistry 240】 【Chemical 241】 【Chemical 242】 【Chemical 243】 【Chemical 244】 【Chemistry 245】 【Chemical Formula 246】 【Chemical 247】 【Chemical 248】 【Chemical 249】 【Chemistry 250】 【Chemistry 251】 【Chemistry 252】 【Chemistry 253】 【Chemical 254】 【255】 (2R,3R,4R,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2R,3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2R,3R,4S,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2R,3S,4R,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2S,3R,4R,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2R,3R,4S,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2R,3S,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2S,3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2S,3R,4S,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2S,3S,4R,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2R,3S,4S,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2S,3R,4S,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2S,3S,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2S,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2S,3S,4S,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2R,3R,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3R,4R,5S)—N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3R,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3S,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3R,4R,5R)—N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3R,4S,5S)—N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3S,4R,5S)—N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3R,4R,5S)—N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3S,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3R,4S,5R)—N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3S,4R,5R)—N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3S,4S,5S)—N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3R,4S,5S)—N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3S,4R,5S)—N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3S,4S,5R)—N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3S,4S,5S)—N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3R,4R,5R)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5S)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5R)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5R)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5R)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5S)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5S)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5S)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5R)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5R)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5R)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5S)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5S)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5S)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5R)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5S)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5R)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5S)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5R)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5R)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5R)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5S)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5S)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5S)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5R)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5R)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5R)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5S)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5S)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5S)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5R)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5S)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5R)—N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3R,5S)—N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3S,5R)—N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3R,5R)—N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3S,5S)—N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3R,5S)—N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3S,5R)—N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3S,5S)—N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3R,4R,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3R,4R,5S)—N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3R,4S,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3S,4R,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3R,4R,5R)—N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3R,4S,5S)—N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3S,4R,5S)—N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3R,4R,5S)—N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3S,4S,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3R,4S,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3S,4R,5R)—N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3S,4S,5S)—N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3R,4S,5S)—N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3S,4R,5S)—N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3S,4S,5R)—N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3S,4S,5S)—N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2R,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2S,3R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2R,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2S,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2S,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2S,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2R,3R,4R,5R)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2R,3R,4R,5S)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2R,3R,4S,5R)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2R,3S,4R,5R)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2S,3R,4R,5R)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2R,3R,4S,5S)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2R,3S,4R,5S)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2S,3R,4R,5S)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2R,3S,4S,5R)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2S,3R,4S,5R)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2S,3S,4R,5R)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2R,3S,4S,5S)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2S,3R,4S,5S)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2S,3S,4R,5S)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2S,3S,4S,5R)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2S,3S,4S,5S)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2R,3R,4R,5R)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2R,3R,4R,5S)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2R,3R,4S,5R)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2R,3S,4R,5R)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2S,3R,4R,5R)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2R,3R,4S,5S)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2R,3S,4R,5S)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2S,3R,4R,5S)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2R,3S,4S,5R)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2S,3R,4S,5R)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2S,3S,4R,5R)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2R,3S,4S,5S)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2S,3R,4S,5S)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2S,3S,4R,5S)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2S,3S,4S,5R)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2S,3S,4S,5S)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, 4-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxide-pyridin-1-ium-2-carboxamide, (2R,3R,4R,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2R,3R,4R,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2R,3R,4S,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2R,3S,4R,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2S,3R,4R,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2R,3R,4S,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2R,3S,4R,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2S,3R,4R,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2R,3S,4S,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2S,3R,4S,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2S,3S,4R,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2R,3S,4S,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2S,3R,4S,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2S,3S,4R,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2S,3S,4S,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2S,3S,4S,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2R,3R,4R,5R)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5S)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5R)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5R)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5R)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5S)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5S)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5S)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5R)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5R)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5R)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5S)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5S)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5S)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5R)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5S)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5R)-4-[[5-tert-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5S)-4-[[5-tert-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5R)-4-[[5-tert-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5R)-4-[[5-tert-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5S)-4-[[5-tert-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5S)-4-[[5-tert-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5R)-4-[[5-tert-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5S)-4-[[5-tert-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5R)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5S)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5R)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5R)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5S)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5S)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5R)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5S)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5R)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5S)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5R)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5R)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5S)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5S)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5R)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5S)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5R)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5S)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5R)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5R)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5S)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5S)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5R)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5S)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5R)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5S)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5R)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5R)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5S)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5S)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5R)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5S)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5R)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5S)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5R)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5R)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5S)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5S)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5R)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5S)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5R)-4-[[5-(1,1-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5S)-4-[[5-(1,1-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5R)-4-[[5-(1,1-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5R)-4-[[5-(1,1-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5S)-4-[[5-(1,1-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5S)-4-[[5-(1,1-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5R)-4-[[5-(1,1-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5S)-4-[[5-(1,1-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5R)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5S)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5R)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5R)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5R)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5S)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5S)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5S)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5R)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5R)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5S)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5S)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5S)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5R)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5S)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5R)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5S)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5R)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5R)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5R)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5S)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5S)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5S)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5R)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5R)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5R)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5S)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5S)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5S)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5R)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5S)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5R)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5S)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5R)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5R)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5R)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5S)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5S)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5S)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5R)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5R)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5R)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5S)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5S)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5S)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5R)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5S)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5R)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,5S)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5R)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5R)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,5S)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,5S)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5R)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5S)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 6-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 6-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 6-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 6-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 6-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 6-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 6-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 6-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 6-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 6-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 6-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 6-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 6-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 6-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 6-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 5-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide, 5-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide, 5-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide, 5-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide, 5-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide, 5-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide, 5-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide, 5-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide, 5-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide, 5-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide, 5-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide, 5-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide, 5-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide, 5-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide, 5-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide, 5-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide, 4-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, 4-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, 4-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, 4-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, 4-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, 4-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, 4-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, 4-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, 4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, 4-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, 4-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, 4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, 4-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, 4-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, 4-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, 4-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, 2-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide, 2-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide, 2-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide, 2-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide, 2-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide, 2-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide, 2-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide, 2-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide, 2-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide, 2-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide, 2-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide, 2-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide, 2-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide, 2-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide, 2-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide, 2-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide, 6-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide, 6-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide, 6-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide, 6-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide, 6-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide, 6-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide, 6-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide, 6-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide, 6-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide, 6-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide, 6-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide, 6-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide, 6-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide, 6-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide, 6-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide, 6-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide, 4-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide, 4-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide, 4-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide, 4-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide, 4-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide, 4-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide, 4-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide, 4-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide, 4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide, 4-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide, 4-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide, 4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide, 4-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide, 4-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide, 4-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide, 4-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide, (2R,3R,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3R,4R,5S)—N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3R,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3S,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3R,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3R,4S,5S)—N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3S,4R,5S)—N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3R,4R,5S)—N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3S,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3R,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3S,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3S,4S,5S)—N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3R,4S,5S)—N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3S,4R,5S)—N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3S,4S,5R)—N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3S,4S,5S)—N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, 5-deuterio-4-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 5-deuterio-4-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 5-deuterio-4-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 5-deuterio-4-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 5-deuterio-4-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 5-deuterio-4-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 5-deuterio-4-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 5-deuterio-4-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 5-deuterio-4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 5-deuterio-4-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 5-deuterio-4-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 5-deuterio-4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 5-deuterio-4-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 5-deuterio-4-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 5-deuterio-4-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 5-deuterio-4-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide, 4-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide, 4-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide, 4-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide, 4-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide, 4-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide, 4-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide, 4-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide, 4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide, 4-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide, 4-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide, 4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide, 4-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide, 4-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide, 4-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide, 4-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide, 4-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide, 4-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide, 4-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide, 4-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide, 4-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide, 4-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide, 4-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide, 4-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide, 4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide, 4-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide, 4-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide, 4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide, 4-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide, 4-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide, 4-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide, 4-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide, 4-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide, 4-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide, 4-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide, 4-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide, 4-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide, 4-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide, 4-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide, 4-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide, 4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide, 4-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide, 4-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide, 4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide, 4-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide, 4-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide, 4-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide, 4-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide, 4-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide, 4-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide, 4-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide, 4-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide, 4-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide, 4-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide, 4-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide, 4-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide, 4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide, 4-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide, 4-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide, 4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide, 4-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide, 4-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide, 4-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide, 4-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide, 3-deuterio-4-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 3-deuterio-4-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 3-deuterio-4-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 3-deuterio-4-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 3-deuterio-4-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 3-deuterio-4-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 3-deuterio-4-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 3-deuterio-4-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 3-deuterio-4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 3-deuterio-4-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 3-deuterio-4-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 3-deuterio-4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 3-deuterio-4-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 3-deuterio-4-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 3-deuterio-4-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 3-deuterio-4-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-deuterio-4-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-deuterio-4-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-deuterio-4-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-deuterio-4-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-deuterio-4-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-deuterio-4-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-deuterio-4-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-deuterio-4-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-deuterio-4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-deuterio-4-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-deuterio-4-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-deuterio-4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-deuterio-4-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-deuterio-4-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-deuterio-4-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 6-deuterio-4-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5R)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5R)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5R)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5R)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5S)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5S)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5R)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5R)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5S)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5S)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5R)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5S)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5R)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5R)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5R)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5S)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5S)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5S)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5R)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5R)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5R)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5S)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5S)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5S)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5R)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5S)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5R)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5S)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5R)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5R)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5R)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5S)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5S)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5S)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5R)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5R)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5R)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5S)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5S)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5S)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5R)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5S)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5R)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5S)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5R)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5R)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5R)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5S)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5S)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5S)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5R)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5R)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5R)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5S)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5S)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5S)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5R)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5S)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5R)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5S)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5R)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5R)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5R)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5S)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5S)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5S)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5R)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5R)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5R)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5S)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5S)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5S)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5R)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5S)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5R)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5S)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5R)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5R)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5R)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5S)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5S)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5S)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5R)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5R)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5R)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5S)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5S)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5S)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5R)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5S)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5R)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5S)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5R)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5R)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5R)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4S,5S)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4R,5S)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4R,5S)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5R)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5R)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5R)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3S,4S,5S)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3R,4S,5S)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4R,5S)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5R)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5S)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4R,5R)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4R,5S)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4S,5R)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4R,5R)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4R,5R)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4S,5S)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4R,5S)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4R,5S)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4S,5R)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4S,5R)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4R,5R)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4S,5S)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4S,5S)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4R,5S)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4S,5R)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4S,5S)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4R,5R)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4R,5S)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4S,5R)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4R,5R)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4R,5R)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4S,5S)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4R,5S)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4R,5S)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4S,5R)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4S,5R)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4R,5R)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4S,5S)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4S,5S)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4R,5S)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4S,5R)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4S,5S)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4R,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4R,5S)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4S,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4R,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4R,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4S,5S)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4R,5S)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4R,5S)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4S,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4S,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4R,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4S,5S)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4S,5S)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4R,5S)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4S,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4S,5S)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (2R,3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (2R,3R,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (2R,3S,4R,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (2S,3R,4R,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (2R,3R,4S,5S)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (2R,3S,4R,5S)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (2S,3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (2S,3R,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (2S,3S,4R,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (2R,3S,4S,5S)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (2S,3R,4S,5S)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (2S,3S,4R,5S)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (2S,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (2S,3S,4S,5S)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide, 4-[[(2R,3R,4R,5R)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4R,5S)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4S,5R)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4R,5R)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4R,5R)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4S,5S)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4R,5S)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4R,5S)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4S,5R)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4S,5R)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4R,5R)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4S,5S)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4S,5S)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4R,5S)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4S,5R)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4S,5S)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4R,5R)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4R,5S)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4S,5R)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4R,5R)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4R,5R)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3R,4S,5S)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4R,5S)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4R,5S)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4S,5R)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4S,5R)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4R,5R)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2R,3S,4S,5S)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3R,4S,5S)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4R,5S)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, 4-[[(2S,3S,4S,5R)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, or 4-[[(2S,3S,4S,5S)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide 2. The compound of claim 1, selected from:

22. A compound according to any one of claims 1 to 21.

23. Formula 【Chemistry 110】 Compound.

24. 24. The compound of claim 23, wherein the compound is Form A of a crystalline solid, and Form A is characterized by an XRPD pattern having diffractions at angles of 9.9, 13.9, 15.7, and 19.0 (2 theta ± 0.2 degrees).

25. The compound described in claim 23, wherein the compound is form B of a crystalline solid, and form B is characterized by an XRPD pattern having diffractions at angles of 12.8, 14.1, 15.2, 18.5, and 20.3 (2 theta ±0.2 degrees).

26. The compound has the formula 【Chemistry 111】 23. The compound of claim 22, having the formula:

27. The compound is in crystalline solid form A, and form A is (a) Orthorhombic crystal system as determined by single crystal X-ray analysis; (b) the I222 space group and, as determined by single crystal X-ray analysis, (c) A unit cell of the following dimensions, as determined by single crystal X-ray analysis: a=12.0172(5) Å; b=15.6682(6) Å; c=24.1406(11) Å; α=90°; β=90°; and γ=90°.

27. The compound according to claim 26, characterized in that

28. The compound has the formula 【Chemistry 112】 23. The compound of claim 22, having the formula:

29. 30. The compound of claim 28, wherein the compound is Form A of a crystalline solid, and Form A is characterized by an XRPD pattern having diffractions at angles of 10.1, 13.7, 14.1, 16.3, and 20.0 (2 theta ± 0.2 degrees).

30. The compound described in claim 28, wherein the compound is form B of a crystalline solid, and form B is characterized by an XRPD pattern having diffractions at angles of 6.8, 13.2, 16.1, 20.6, and 21.3 (2 theta ±0.2 degrees).

31. The compound has the formula 【Chemistry 113】 23. The compound of claim 22, having the formula:

32. 32. The compound of claim 31, wherein the compound is Form A of a crystalline solid, and Form A is characterized by an XRPD pattern having diffractions at angles of 13.7, 15.2, and 18.2 (2 theta ± 0.2 degrees).

33. The compound has the formula 【Chemistry 114】 having 23. The compound of claim 22, wherein when the mixture of racemic diastereomers (epimers at the 5-position) is separated by chiral SFC using a 25 cm×21.2 mm (R,R)-WHELK-O® 1 (1-(3,5-dinitrobenzamide)-1,2,3,4-tetrahydrophenanthrene modified 5 μm silica) column, said compound has the absolute stereochemistry of the third eluting isomer.

34. 34. The compound of claim 33, wherein the compound is Form A of a crystalline solid, and Form A is characterized by an XRPD pattern having diffractions at angles of 9.2, 10.4, and 15.7 (2 theta ± 0.2 degrees).

35. The compound has the formula 【Chemistry 115】 23. The compound of claim 22, having the formula:

36. 36. The compound of claim 35, wherein the compound is Form A of a crystalline solid, and Form A is characterized by an XRPD pattern having diffractions at angles of 17.2, 19.3, and 22.3 (2 theta ±0.2 degrees).

37. The compound has the formula 【Chemistry 116】 having 23. The compound of claim 22, wherein when the racemic mixture of enantiomers is separated by chiral SFC using a 25 cm x 10 mm CHIRALPAK® AS-H (5 μm silica coated with amylose tris-[(S)-α-methylbenzylcarbamate]) column, said compound has the absolute stereochemistry of the second eluting isomer.

38. 38. The compound of claim 37, wherein the compound is Form A of a crystalline solid, and Form A is characterized by an XRPD pattern having diffractions at angles of 6.8, 7.9, and 13.8 (2 theta ± 0.2 degrees).

39. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, or a compound according to any one of claims 22 to 38, and one or more pharma- ceutically acceptable carriers or vehicles.

40. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, or a compound according to any one of claims 22 to 38, and one or more pharma- ceutically acceptable carriers or vehicles.

41. A compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, a composition comprising a compound according to any one of claims 22 to 38, or a pharmaceutical composition according to claim 39 or 40, for inhibiting voltage-gated sodium channels in a subject.

42. The composition or pharmaceutical composition of claim 41, wherein the voltage-gated sodium channel is Na V 1.

8.

43. 41. A compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, a composition comprising a compound according to any one of claims 22 to 38, or a pharmaceutical composition according to claim 39 or 40, for treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia in a subject.

44. 44. The composition or pharmaceutical composition of claim 43, wherein said composition or pharmaceutical composition is for treating or reducing the severity of neuropathic pain in said subject.

45. The composition or pharmaceutical composition of claim 43 or 44, wherein the neuropathic pain comprises post-herpetic neuralgia, small fiber neuropathy, idiopathic small fiber neuropathy, or diabetic neuropathy.

46. The composition or pharmaceutical composition described in claim 43, wherein the composition or pharmaceutical composition is for treating or reducing the severity of musculoskeletal pain in the subject.

47. A composition or pharmaceutical composition described in claim 43 or 46, wherein the musculoskeletal pain includes osteoarthritis pain.

48. The composition or pharmaceutical composition of claim 43, wherein the composition or pharmaceutical composition is for treating or reducing the severity of acute pain in the subject.

49. The composition or pharmaceutical composition of claim 41, wherein the acute pain comprises acute post-operative pain.

50. 44. The composition or pharmaceutical composition of claim 43, wherein said composition or pharmaceutical composition is for treating or reducing the severity of post-operative pain in said subject.

51. The composition or pharmaceutical composition of claim 43 or 50, wherein the postoperative pain comprises bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain.

52. 44. The composition or pharmaceutical composition of claim 43, wherein said composition or pharmaceutical composition is for treating or reducing the severity of visceral pain in said subject.

53. A compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, a composition comprising a compound according to any one of claims 22 to 38, or a pharmaceutical composition according to claim 39 or 40, for treating or reducing the severity of a subject in pain.

54. The composition or pharmaceutical composition of any one of claims 43 to 53, wherein the subject is treated with one or more additional therapeutic agents administered simultaneously with, prior to, or following treatment with the composition or pharmaceutical composition.

55. A compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, a composition comprising a compound according to any one of claims 22 to 38, or a pharmaceutical composition according to claim 39 or 40, for use as a medicament.

56. Formula: 【256】 or a pharma- ceutically acceptable salt thereof.

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