Substituted tetrahydrofurans as modulators of sodium channels

Abstract

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

Description

SUBSTITUTED TETRAHYDROFURANS AS MODULATORS OF SODIUM CHANNELS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.62 / 944,869, filed December 6, 2019, which is incorporated by reference in its entirety. BACKGROUND

[0002] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and to prevent further damage to injured tissue. Nonetheless there are many conditions where pain persists beyond its usefulness, or where patients would benefit from inhibition of pain. Neuropathic pain is a form of chronic pain caused by an injury to the sensory nerves (Dieleman, J.P., et al., Incidence rates and treatment of neuropathic pain conditions in the general population. Pain, 2008.137(3): p.681-8). Neuropathic pain can be divided into two categories, pain caused by generalized metabolic damage to the nerve and pain caused by a discrete nerve injury. The metabolic neuropathies include post-herpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Discrete nerve injury indications include post-amputation pain, post-surgical nerve injury pain, and nerve entrapment injuries like neuropathic back pain.

[0003] Voltage-gated sodium channels (NaVs) are involved in pain signaling. NaVs are biological mediators of electrical signaling as they mediate the rapid upstroke of the action potential of many excitable cell types (e.g. neurons, skeletal myocytes, cardiac myocytes). The evidence for the role of these channels in normal physiology, the pathological states arising from mutations in sodium channel genes, preclinical work in animal models, and the clinical pharmacology of known sodium channel modulating agents all point to the central role of NaVs in pain sensation (Rush, A.M. and T.R. Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets NaV1.8 Sodium Channels. Mol. Interv., 2007.7(4): p.192-5); England, S., Voltage-gated sodium channels: the search for subtype- selective analgesics. Expert Opin. Investig. Drugs 17 (12), p.1849-64 (2008); Krafte, D. S. and Bannon, A. W., Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol.8 (1), p.50-56 (2008)). NaVs mediate the rapid upstroke of the action potential of many excitable cell types (e.g. neurons, skeletal myocytes, cardiac myocytes), and thus are involved in the initiation of signaling in those cells (Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). Because of the role NaVs play in the initiation and propagation of neuronal signals, antagonists that reduce NaVcurrents can prevent or reduce neuralsignaling and NaVchannels have been considered likely targets to reduce pain in conditions where hyper- excitability is observed (Chahine, M., Chatelier, A., Babich, O., and Krupp, J. J., Voltage-gated sodium channels in neurological disorders. CNS Neurol. Disord. Drug Targets 7 (2), p.144-58 (2008)). Several clinically useful analgesics have been identified as inhibitors of NaVchannels. The local anesthetic drugs such as lidocaine block pain by inhibiting NaVchannels, and other compounds, such as carbamazepine, lamotrigine, and tricyclic antidepressants that have proven effective at reducing pain have also been suggested to act by sodium channel inhibition (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. Eur. J. Pain 6 Suppl. A, p.3-9 (2002); Wang, G. K., Mitchell, J., and Wang, S. Y., Block of persistent late Na+currents by antidepressant sertraline and paroxetine. J. Membr. Biol.222 (2), p.79-90 (2008)).

[0004] The NaVs form a subfamily of the voltage-gated ion channel super-family and comprises 9 isoforms, designated NaV1.1 – NaV1.9. The tissue localizations of the nine isoforms vary. NaV1.4 is the primary sodium channel of skeletal muscle, and NaV1.5 is primary sodium channel of cardiac myocytes. NaVs 1.7, 1.8 and 1.9 are primarily localized to the peripheral nervous system, while NaVs 1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the central and peripheral nervous systems. The functional behaviors of the nine isoforms are similar but distinct in the specifics of their voltage-dependent and kinetic behavior (Catterall, W. A., Goldin, A. L., and Waxman, S. G., International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57 (4), p.397 (2005)).

[0005] Upon their discovery, NaV1.8 channels were identified as likely targets for analgesia (Akopian, A.N., L. Sivilotti, and J.N. Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996.379(6562): p.257-62). Since then, NaV1.8 has been shown to be a carrier of the sodium current that maintains action potential firing in small dorsal root ganglia (DRG) neurons (Blair, N.T. and B.P. Bean, Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+current, and Ca2+current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002. 22(23): p.10277-90). NaV1.8 is involved in spontaneous firing in damaged neurons, like those that drive neuropathic pain (Roza, C., et al., The tetrodotoxin-resistant Na+channel NaV1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003.550(Pt 3): p. 921-6; Jarvis, M.F., et al., A-803467, a potent and selective NaV1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc. Natl. Acad. Sci. U S A, 2007.104(20): p.8520-5; Joshi, S.K., et al., Involvement of the TTX-resistant sodium channel NaV1.8 in inflammatory andneuropathic, but not post-operative, pain states. Pain, 2006.123(1-2): pp.75-82; Lai, J., et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8. Pain, 2002.95(1-2): p.143-52; Dong, X.W., et al., Small interfering RNA-mediated selective knockdown of NaV1.8 tetrodotoxin-resistant sodium channel 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 (NaV1.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats. J. Biol. Chem.286(46): p.39836-47). The small DRG neurons where NaV1.8 is expressed include the nociceptors involved in pain signaling. NaV1.8 mediates large amplitude action potentials in small neurons of the dorsal root ganglia (Blair, N.T. and B.P. Bean, Roles of tetrodotoxin (TTX)-sensitive Na+current, TTX-resistant Na+current, and Ca2+current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002.22(23): p.10277-90). NaV1.8 is necessary for rapid repetitive action potentials in nociceptors, and for spontaneous activity of damaged neurons. (Choi, J.S. and S.G. Waxman, Physiological interactions between NaV1.7 and NaV1.8 sodium channels: a computer simulation study. J. Neurophysiol.106(6): p.3173-84; Renganathan, M., T.R. Cummins, and S.G. 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 NaV1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003.550(Pt 3): p.921-6). In depolarized or damaged DRG neurons, NaV1.8 appears to be a driver of hyper-excitablility (Rush, A.M., et al., A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc. Natl. Acad. Sci. USA, 2006.103(21): p.8245-50). In some animal pain models, NaV1.8 mRNA expression levels have been shown to increase in the DRG (Sun, W., et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats. Brain, 135(Pt 2): p.359-75; Strickland, I.T., et al., Changes in the expression of NaV1.7, NaV1.8 and NaV1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in 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 NaV1.8 and NaV1.9 within dorsal root ganglia in a rat model of bone cancer pain. Neurosci. Lett., 512(2): p.61-6).

[0006] The primary drawback to some known NaVinhibitors is their poor therapeutic window, and this is likely a consequence of their lack of isoform selectivity. Since NaV1.8 is primarily restricted to the neurons that sense pain, selective NaV1.8 blockers are unlikely to induce the adverse events common to non-selective NaVblockers. Accordingly, there remains a need to develop additional NaVchannel modulators, preferably those that are highly potent and selective for NaV1.8. SUMMARY

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

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

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

[0010] In yet another aspect, the invention relates to a method of treating or lessening the severity in a subject of a variety of diseases, disorders, or conditions, including, but not limited to, chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomy pain, herniorrhaphy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, and cardiac arrhythmia, by administering the compound, pharmaceutically acceptable salt, or pharmaceutical composition to the subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 depicts an XRPD pattern characteristic of Compound 7, Form A.

[0012] Figure 2 depicts TGA thermogram characteristic of Compound 7, Form A.

[0013] Figure 3 depicts DSC thermogram characteristic of Compound 7, Form A.

[0014] Figure 4 depicts an XRPD pattern characteristic of Compound 7, Form B.

[0015] Figure 5 depicts a solid state13C NMR spectrum characteristic of Compound 7, Form B.

[0016] Figure 6 depicts a solid state19F NMR spectrum characteristic of Compound 7, Form B.

[0017] Figure 7 depicts a TGA thermogram characteristic of Compound 7, Form B.

[0018] Figure 8 depicts a DSC thermogram characteristic of Compound 7, Form B.

[0019] Figure 9 depicts an IR spectrum characteristic of Compound 7, Form B.

[0020] Figure 10 depicts a thermal ellipsoid plot characteristic of Compound 7, Form B.

[0021] Figure 11 depicts a thermal ellipsoid plot characteristic of Compound 9, Form A.

[0022] Figure 12 depicts an XRPD pattern characteristic of Compound 11, Form A.

[0023] Figure 13 depicts an XRPD pattern characteristic of Compound 11, Form B.

[0024] Figure 14 depicts a thermal ellipsoid plot characteristic of Compound 11, Form A.

[0025] Figure 15 depicts an XRPD pattern characteristic of Compound 19, Form A.

[0026] Figure 16 depicts a solid state13C NMR spectrum characteristic of Compound 19, Form A.

[0027] Figure 17 depicts a solid state19F NMR spectrum characteristic of Compound 19, Form A.

[0028] Figure 18 depicts a thermal ellipsoid plot characteristic of Compound 19, Form A.

[0029] Figure 19 depicts an XRPD pattern characteristic of Compound 22, Form A.

[0030] Figure 20 depicts a solid state13C NMR spectrum characteristic of Compound 22, Form A.

[0031] Figure 21 depicts a solid state19F NMR spectrum characteristic of Compound 22, Form A.

[0032] Figure 22 depicts an XRPD pattern characteristic of Compound 23, Form A.

[0033] Figure 23 depicts a solid state13C NMR spectrum characteristic of Compound 23, Form A.

[0034] Figure 24 depicts a solid state19F NMR spectrum characteristic of Compound 23, Form A.

[0035] Figure 25 depicts a thermal ellipsoid plot characteristic of Compound 23, Form A.

[0036] Figure 26 depicts an XRPD pattern characteristic of Compound 25, Form A. DETAILED DESCRIPTION

[0037] In one aspect, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: X2ais N, N+-O-, or C-R2a; X4ais N, N+-O-, or C-R4a; X5ais N, N+-O-, or C-R5a; X6ais N, N+-O-, or C-R6a; each R is independently H or C1-C6alkyl; R2a, R4a, R5a, and R6aare each independently H, halo, C1-C6alkyl, or C1-C6haloalkyl; R4b1and R4b2are each independently H, C1-C6alkyl, C3-C6cycloalkyl, or C1-C6haloalkyl; R5b1and R5b2are each independently H, C1-C6alkyl, C3-C6cycloalkyl, or C1-C6haloalkyl; X3cis N or C-R3c; X4cis N or C-R4c; X5cis N or C-R5c; X6cis N or C-R6c; R2cis H, OH, halo, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, or –L1-L2-(C3-C6cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo; L1is a bond or O; L2is a bond or C1-C6alkylene; R3cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; R4cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; R5cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; and R6cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; provided that no more than two of X2a, X4a, X5a, and X6aare N or N+-O-; and provided that no more than one of X3c, X4c, X5c, and X6care N.

[0038] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X2ais C-R2a; X5ais C-R5a; X6ais C-R6a; R4b1and R4b2are eachindependently H, C1-C6alkyl, or C1-C6haloalkyl; R5b1and R5b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl; X3cis C-R3c; X4cis C-R4c; X5cis C-R5c; X6cis C-R6c; and R2cis H, OH, halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0039] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry,” 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0040] As used herein, the term “compounds of the invention” refers to the compounds of formulas (I), (I-A), (I-A-1), (I-B), (I-B-1), (I-C), and (I-C-1), and all of the embodiments thereof, as described herein, and to the compounds identified in Table A, Table B, and Table C.

[0041] As described herein, the compounds of the invention comprise multiple variable groups (e.g., R, X4a, R5b, etc.). As one of ordinary skill in the art will recognize, combinations of groups envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds. The term “stable,” in this context, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 ^C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

[0042] The chemical structures depicted herein are intended to be understood as they would be understood by one of ordinary skill in the art. For example, with respect to formulas (I), (I-A), (I-B), and (I-C), one of ordinary skill in the art would understand that X5aand X6aare connected by a double bond and that X4cand X5care connected by a single bond, even though the bonds between these groups may be obscured by the atom labels in the chemical structures. Moreover, one of ordinary skill would understand that a substituent depicted as “CF3” or “F3C” in a chemical structure refers to a trifluoromethyl substituent, regardless of which depiction appears in the chemical structure.

[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, and having the specifiednumber of carbon atoms, which is attached to the rest of the molecule by a single bond. For example, a “C1-C6alkyl” group is an alkyl group having between one and six carbon atoms.

[0045] As used herein, the term “haloalkyl” refers to an alkyl group having the specified number of carbon atoms, wherein one or more of the hydrogen atoms of the alkyl group are replaced by halo groups. For example, a “C1-C6haloalkyl” group is an alkyl group having between one and six carbon atoms, wherein one or more of the hydrogen atoms of the alkyl group are replaced by halo groups.

[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, and having the specified number of carbon atoms, which is attached to the rest of the molecule by a single bond. For example, a “C2-C6alkenyl” group is an alkenyl group having between two and six carbon atoms.

[0047] As used herein, the term “cycloalkyl” refers to a stable, non-aromatic, mono- or bicyclic (fused, bridged, or spiro) saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, having the specified number of carbon ring atoms, and which is attached to the rest of the molecule by a single bond. For example, a “C3-C8cycloalkyl” group is a cycloalkyl group having between three and eight 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, and having the specified number of carbon atoms, which is attached to the rest of the molecule by two single bonds. For example, a “C1-C6alkylene” group is an alkylene group having between one and six carbon atoms.

[0049] As used herein, the term "optionally substituted” refers to a group that is either unsubstituted or substituted with the subsequently identified substituents. For example, a group that is “optionally substituted with 1-2 halo” is either unsubstituted, substituted with 1 halo group, or substituted with 2 halo groups.

[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. In addition, single stereoisomers, double bond isomers, conformational isomers, and tautomers as well as mixtures of stereoisomers, double bond isomers, conformational isomers, and tautomers are within the scope of the invention.

[0051] As used herein, in any chemical structure or formula, a bold or hashed straight bond (respectively) attached to a stereocenter of a compound, such as in, denotes the relative stereochemistry of the stereocenter, relative to other stereocenter(s) to which bold or hashed straight bonds are attached.

[0052] As used herein, in any chemical structure or formula, a bold or hashed wedge bond ( or , respectively) attached to a stereocenter of a compound, such as in, denotes the absolute stereochemistry of the stereocenter, as well as the relative stereochemistry of the stereocenter, relative to other stereocenter(s) to which bold or hashed wedge bonds are attached.

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

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

[0055] As used herein, the term “compound,” when referring to the compounds of the invention, refers to a collection of molecules having identical chemical structures, except that there may be isotopic variation among the constituent atoms of the molecules. The term “compound” includes such a collection of molecules without regard to the purity of a given sample containing the collection of molecules. Thus,the term “compound” includes such a collection of molecules in pure form, in a mixture (e.g., solution, suspension, colloid, or pharmaceutical composition, or dosage form) with one or more other substances, or in the form of a hydrate, solvate, or co-crystal.

[0056] In the specification and claims, unless otherwise specified, any atom not specifically designated as a particular isotope in any compound of the invention is meant to represent any stable isotope of the specified element. In the Examples, where an atom is not specifically designated as a particular isotope in any compound of the invention, no effort was made to enrich that atom in a particular isotope, and therefore a person of ordinary skill in the art would understand that such atom likely was present at approximately the natural abundance isotopic composition of the specified 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, the isotopes for which no decay mode is identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0058] As used herein in the specification and claims, “H” refers to hydrogen and includes any stable isotope of hydrogen, namely1H and D. In the Examples, where an atom is designated as “H,” no effort was made to enrich that atom in a particular isotope of hydrogen, and therefore a person of ordinary skill in the art would understand that such hydrogen atom likely was present at approximately the natural abundance concentration of hydrogen.

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

[0060] As used herein, “D,” “d,” and “2H” refer to deuterium.

[0061] In some embodiments, the compounds of the invention, and pharmaceutically acceptable salts thereof, include each constituent atom at approximately the natural abundance isotopic composition of the specified element.

[0062] In some embodiments, the compounds of the invention, and pharmaceutically acceptable salts thereof, include one or more atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the most abundant isotope of the specified element (“isotope-labeled” compounds and salts). Examples of stable isotopes which are commercially available and suitable for the invention include without limitation isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, for example2H,13C,15N,18O,17O, and31P, respectively.

[0063] The isotope-labeled compounds and salts can be used in a number of beneficial ways, including as medicaments. In some embodiments, the isotope-labeled compounds and salts are deuterium (2H)- labeled. Deuterium (2H)-labeled compounds and salts are therapeutically useful with potential therapeutic advantages over the non-2H-labelled compounds. In general, deuterium (2H)-labeled compounds and salts can have higher metabolic stability as compared to those that are not isotope-labeled owing to the kinetic isotope effect described below. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which under most circumstances would represent a preferred embodiment of the present invention. The isotope-labeled compounds and salts can usually be prepared by carrying out the procedures disclosed in the synthesis schemes, the examples and the related description, replacing a non-isotope-labeled reactant by a readily available isotope-labeled reactant.

[0064] The deuterium (2H)-labeled compounds and salts can manipulate the rate of oxidative metabolism of the compound by way of the primary kinetic isotope effect. The primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies of the covalent bonds involved in the reaction. Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially. For example, if deuterium is bonded to a carbon atom at a non- exchangeable position, rate differences of kH / kD= 2-7 are typical. For a further discussion, see S. L. Harbeson and R. D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem.2011, 46, 403-417, incorporated in its entirety herein by reference.

[0065] The concentration of an isotope (e.g., deuterium) incorporated at a given position of an isotope- labeled compound of the invention, or a pharmaceutically acceptable salt thereof, may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor,” as used herein, means the ratio between the abundance of an isotope at a given position in an isotope-labeled compound (or salt) and the natural abundance of the isotope.

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

[0067] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently H or CH3. In other embodiments, N(R)2is NHCH3.

[0068] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X2ais N. In other embodiments, X2ais C-R2a. In some embodiments, R2ais H, D, halo, or C1-C6alkyl. In other embodiments, R2ais H, D, F, or CH3. In some embodiments, X2ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo. In other embodiments, X2ais N, C-H, C-D, C-CH3, or C-F.

[0069] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X2ais C-R2a; and R2ais H.

[0070] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X4ais N. In other embodiments, X4ais N+-O-. In other embodiments, X4ais C-R4a. In some embodiments, R4ais halo. In other embodiments, R4ais H or halo. In other embodiments, R4ais H or F. In other embodiments, X4ais C-F. In some embodiments, X4ais N, N+-O-, C-H, or C-halo. In other embodiments, X4ais N, N+-O-, C-H, or C-F.

[0071] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X4ais C-R4a; and R4ais halo.

[0072] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X5ais N. In other embodiments, X5ais C-R5a. In some embodiments, R5ais H, D, halo, or C1-C6alkyl. In other embodiments, R5ais H, D, F, or CH3. In some embodiments, X5ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo. In other embodiments, X5ais N, C-H, C-D, C-CH3, or C-F.

[0073] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X5ais C-R5a; and R5ais H.

[0074] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X6ais N. In other embodiments, X6ais C-R6a. In some embodiments, R6ais H, D, halo, or C1-C6alkyl. In other embodiments, R6ais H, D, F, or CH3. In some embodiments, X6ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo. In other embodiments, X6ais N, C-H, C-D, C-CH3, or C-F.

[0075] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X6ais C-R6a; and R6ais H.

[0076] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R4b1and R4b2are each independently H or C1-C6alkyl. In other embodiments, R4b1and R4b2are each independently H, C1-C6alkyl, or C3-C6cycloalkyl. In other embodiments, R4b1and R4b2are each independently H or CH3. In other embodiments, R4b1and R4b2are each independently H, CH3, CH2CH3, or cyclopropyl. In other embodiments, R4b1is C1-C6alkyl, and R4b2is H. In other embodiments, R4b1is H, and R4b2is C1-C6alkyl. In other embodiments, R4b1is CH3, and R4b2is H. In other embodiments, R4b1is H, and R4b2is CH3.

[0077] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5b1and R5b2are each independently C1-C6alkyl or C1-C6haloalkyl. In other embodiments, R5b1and R5b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl. In other embodiments, R5b1and R5b2are each independently H, CH3, or CF3. In other embodiments, R5b1and R5b2are each independently H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CHF2, CF2CH3, CH2CF3, or CF3. In other embodiments, R5b1is C1-C6alkyl, and R5b2is C1-C6haloalkyl. In other embodiments, R5b1is C1-C6haloalkyl, and R5b2is C1-C6alkyl. In other embodiments, R5b1is CH3, and R5b2is CF3. In other embodiments, R5b1is CF3, and R5b2is CH3.

[0078] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy. In other embodiments, R2cis OH, halo, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, or –L1-L2-(C3- C6cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R2cis H. In other embodiments, R2cis C1-C6alkoxy. In other embodiments, R2cis C1-C6haloalkoxy. In other embodiments, R2cis -L1-L2-(C3-C6cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R2cis OH, OCH3, OCD3, OCH2CH3, or OCHF2. In other embodiments, R2cis H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCHF2,. In other embodiments, R2cis OH. In other embodiments, R2cis OCH3. In other embodiments, R2cis OCD3. In other embodiments, R2cis OCH2CH3. In other embodiments, R2cis OCHF2.

[0079] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X3cis N. In other embodiments, X3cis C-R3c. In other embodiments, R3cis H, halo, C1-C6alkyl, or C1-C6haloalkyl. In other embodiments, R3cis H, CH3, CH2CH3, CHF2, CF3, F, or Cl. In some embodiments, X3cis N, C-H, C-CH3, C-CH2CH3, C-CHF2, C-CF3, C-F, or C-Cl.

[0080] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X3cis C-R3c; and R3cis H, halo, or C1-C6alkyl. In other embodiments, R3cis halo. In other embodiments, R3cis C1-C6alkyl. In other embodiments, R3cis H, F, Cl, or CH3. In other embodiments, R3cis H. In other embodiments, R3cis F. In other embodiments, R3cis Cl. In other embodiments, R3cis CH3.

[0081] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X4cis N. In other embodiments, X4cis C-R4c. In other embodiments, R4cis H, halo, or C1-C6haloalkyl. In other embodiments, R4cis H, CHF2, CF3, or F. In some embodiments, X4cis N, C-H, C-CHF2, C-CF3, or C-F.

[0082] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X4cis C-R4c; and R4cis halo. In other embodiments, R4cis F.

[0083] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X5cis N. In other embodiments, X5cis C-R5c. In other embodiments, R5cis H or halo. In other embodiments, R5cis H, D, or Cl. In some embodiments, X5cis N, C-H, C-D, or C- Cl.

[0084] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X5cis C-R5c; and R5cis H.

[0085] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X6cis N. In other embodiments, X6cis C-R6c. In other embodiments, R6cis H or halo. In other embodiments, R6cis H or F. In some embodiments, X6cis N, C-H, or C-F.

[0086] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R6cis H.

[0087] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X2ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo; X4ais N, N+-O-, C-H, or C-halo; X5ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo; X6ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo; each R is H or CH3; R4b1and R4b2are each independently H, C1-C6alkyl, or C3-C6cycloalkyl; R5b1and R5b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl; R2cis OH, halo, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, or –L1-L2-(C3-C6cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo; X3cis C-R3c; R3cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; X4cis C-R4c; R4cis H, halo, or C1-C6haloalkyl; X5cis C-R5c; R5cis H or halo; X6cis C-R6c; and R6cis H or halo.

[0088] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C-R5a; R5ais H; X6ais C-R6a; R6ais H; R4b1and R4b2are each independently H or C1-C6alkyl; R5b1and R5b2are each independently C1-C6alkyl or C1-C6haloalkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0089] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X2ais N, C-H, C-D, C-CH3, or C-F; X4ais N, N+-O-, C-H, or C-F; X5ais N, C-H, C-D, C-CH3, or C-F; X6ais N, C-H, C-D, C-CH3, or C-F; each R is H or CH3; R4b1and R4b2are each independently H, CH3, CH2CH3, or cyclopropyl; R5b1and R5b2are each independently H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CHF2, CF2CH3, CH2CF3, or CF3; R2cis H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCHF2, ; X3cis N, C-H, C-CH , C-3CH2CH3, C-CHF2, C-CF3, C-F, or C-Cl; X4cis N, C-H, C-CHF2, C-CF3, or C-F; X5cis N, C-H, C-D, or C- Cl; and X6cis N, C-H, or C-F.

[0090] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C-R5a; R5ais H; X6ais C-R6a; R6ais H; R4b1and R4b2are each independently H or CH3; R5b1and R5b2are each independently H, CH3, or CF3; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0091] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C-R5a; R5ais H; X6ais C-R6a; R6ais H; R4b1is C1-C6alkyl; R4b2is H; R5b1is C1-C6alkyl; R5b2is C1-C6haloalkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0092] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C-R5a; R5ais H; X6ais C-R6a; R6ais H; R4b1is H; R4b2is C1-C6alkyl; R5b1is C1-C6alkyl; R5b2is C1-C6haloalkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0093] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C-R5a; R5ais H; X6ais C-R6a; R6ais H; R4b1is C1-C6alkyl; R4b2is H; R5b1is C1-C6haloalkyl; R5b2is C1-C6alkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0094] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C-R5a; R5ais H; X6ais C-R6a; R6ais H; R5b1is C1-C6haloalkyl; R5b2is C1-C6alkyl; R4b1is H; R4b2is C1-C6alkyl; R2cis C1-C6alkoxy or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C- R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0095] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C-R5a; R5ais H; X6ais C-R6a; R6ais H; R5b1is CH3; R5b2is CF3; R4b1is CH3; R4b2is H; R2cis C1-C6alkoxy or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0096] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C-R5a; R5ais H; X6ais C-R6a; R6ais H; R5b1is CH3; R5b2is CF3; R4b1is H; R4b2is CH3; R2cis C1-C6alkoxy or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0097] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C-R5a; R5ais H; X6ais C-R6a; R6ais H; R5b1is CF3; R5b2is CH3; R4b1is CH3; R4b2is H; R2cis C1-C6alkoxy or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0098] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C-R5a; R5ais H; X6ais C-R6a; R6ais H; R5b1is CF3; R5b2is CH3; R4b1is H, and R4b2is CH3; R2cis C1-C6alkoxy or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0099] In some embodiments, the invention relates to a compound of formula (I) (including any of the foregoing embodiments thereof), i.e., the compound in non-salt form.

[0100] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein: X2ais N, N+-O-, or C-R2a; X4ais N, N+-O-, or C-R4a; X5ais N, N+-O-, or C-R5a; X6ais N, N+-O-, or C-R6a; each R is independently H or C1-C6alkyl; R2a, R4a, R5a, and R6aare each independently H, halo, C1-C6alkyl, or C1-C6haloalkyl; R4b1and R4b2are each independently H, C1-C6alkyl, C3-C6cycloalkyl, or C1-C6haloalkyl; R5b1and R5b2are each independently H, C1-C6alkyl, C3-C6cycloalkyl, or C1-C6haloalkyl; X3cis N or C-R3c; X4cis N or C-R4c; X5cis N or C-R5c; X6cis N or C-R6c; R2cis H, OH, halo, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, or –L1-L2-(C3-C6cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo; L1is a bond or O; L2is a bond or C1-C6alkylene; R3cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; R4cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; R5cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; andR6cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; provided that no more than two of X2a, X4a, X5a, and X6aare N or N+-O-; and provided that no more than one of X3c, X4c, X5c, and X6care N.

[0101] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X2ais C-R2a; X5ais C-R5a; X6ais C-R6a; R4b1and R4b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl; R5b1and R5b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl; X3cis C-R3c; X4cis C-R4c; X5cis C-R5c; X6cis C-R6c; and R2cis H, OH, halo, C1- C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0102] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently H or CH3. In other embodiments, N(R)2is NHCH3.

[0103] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X2ais N. In other embodiments, X2ais C-R2a. In some embodiments, R2ais H, D, halo, or C1-C6alkyl. In other embodiments, R2ais H, D, F, or CH3. In some embodiments, X2ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo. In other embodiments, X2ais N, C-H, C-D, C-CH3, or C-F.

[0104] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X2ais C-R2a; and R2ais H.

[0105] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X4ais N. In other embodiments, X4ais N+-O-. In other embodiments, X4ais C-R4a. In some embodiments, R4ais halo. In other embodiments, R4ais H or halo. In other embodiments, R4ais H or F. In other embodiments, X4ais C-F. In some embodiments, X4ais N, N+-O-, C-H, or C-halo. In other embodiments, X4ais N, N+-O-, C-H, or C-F.

[0106] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X4ais C-R4a; and R4ais halo.

[0107] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X5ais N. In other embodiments, X5ais C-R5a. In some embodiments, R5ais H, D, halo, or C1-C6alkyl. In other embodiments, R5ais H, D, F, or CH3. In some embodiments, X5ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo. In other embodiments, X5ais N, C-H, C-D, C-CH3, or C-F.

[0108] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X5ais C-R5a; and R5ais H.

[0109] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X6ais N. In other embodiments, X6ais C-R6a. In some embodiments, R6ais H, D, halo, or C1-C6alkyl. In other embodiments, R6ais H, D, F, or CH3. In some embodiments, X6ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo. In other embodiments, X6ais N, C-H, C-D, C-CH3, or C-F.

[0110] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X6ais C-R6a; and R6ais H.

[0111] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R4b1and R4b2are each independently H or C1-C6alkyl. In other embodiments, R4b1and R4b2are each independently H, C1-C6alkyl, or C3-C6cycloalkyl. In other embodiments, R4b1and R4b2are each independently H or CH3. In other embodiments, R4b1and R4b2are each independently H, CH3, CH2CH3, or cyclopropyl. In other embodiments, R4b1is C1-C6alkyl, and R4b2is H. In other embodiments, R4b1is H, and R4b2is C1-C6alkyl. In other embodiments, R4b1is CH3, and R4b2is H. In other embodiments, R4b1is H, and R4b2is CH3.

[0112] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R5b1and R5b2are each independently C1-C6alkyl or C1- C6haloalkyl. In other embodiments, R5b1and R5b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl. In other embodiments, R5b1and R5b2are each independently H, CH3, or CF3. In other embodiments, R5b1and R5b2are each independently H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CHF2, CF2CH3, CH2CF3, or CF3. In other embodiments, R5b1is C1-C6alkyl, and R5b2is C1-C6haloalkyl. In other embodiments, R5b1is C1-C6haloalkyl, and R5b2is C1-C6alkyl. In other embodiments, R5b1is CH3, and R5b2is CF3. In other embodiments, R5b1is CF3, and R5b2is CH3.

[0113] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy. In other embodiments, R2cis OH, halo, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, or –L1-L2-(C3-C6cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R2cis H. In other embodiments, R2cis C1-C6alkoxy. In other embodiments, R2cis C1-C6haloalkoxy. In other embodiments, R2cis -L1-L2-(C3-C6cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R2cis OH, OCH3, OCD3, OCH2CH3, orOCHF2. In other embodiments, R2cis H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2, . In other embodiments, R2cis OH. In other embodime2cnts, R is OCH3. In other embodiments, R2cis OCD3. In other embodiments, R2cis OCH2CH3. In other embodiments, R2cis OCHF2.

[0114] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X3cis N. In other embodiments, X3cis C-R3c. In other embodiments, R3cis H, halo, C1-C6alkyl, or C1-C6haloalkyl. In other embodiments, R3cis H, CH3, CH2CH3, CHF2, CF3, F, or Cl. In some embodiments, X3cis N, C-H, C-CH3, C-CH2CH3, C-CHF2, C-CF3, C-F, or C-Cl.

[0115] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X3cis C-R3c; and R3cis H, halo, or C1-C6alkyl. In other embodiments, R3cis halo. In other embodiments, R3cis C1-C6alkyl. In other embodiments, R3cis H, F, Cl, or CH3. In other embodiments, R3cis H. In other embodiments, R3cis F. In other embodiments, R3cis Cl. In other embodiments, R3cis CH3.

[0116] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X4cis N. In other embodiments, X4cis C-R4c. In other embodiments, R4cis H, halo, or C1-C6haloalkyl. In other embodiments, R4cis H, CHF2, CF3, or F. In some embodiments, X4cis N, C-H, C-CHF2, C-CF3, or C-F.

[0117] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X4cis C-R4c; and R4cis halo. In other embodiments, R4cis F.

[0118] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X5cis N. In other embodiments, X5cis C-R5c. In other embodiments, R5cis H or halo. In other embodiments, R5cis H, D, or Cl. In some embodiments, X5cis N, C-H, C-D, or C-Cl.

[0119] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X5cis C-R5c; and R5cis H.

[0120] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X6cis N. In other embodiments, X6cis C-R6c. In otherembodiments, R6cis H or halo. In other embodiments, R6cis H or F. In some embodiments, X6cis N, C- H, or C-F.

[0121] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R6cis H.

[0122] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X2ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo; X4ais N, N+-O-, C-H, or C-halo; X5ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo; X6ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo; each R is H or CH3; R4b1and R4b2are each independently H, C1-C6alkyl, or C3-C6cycloalkyl; R5b1and R5b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl; R2cis OH, halo, C1- C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, or –L1-L2-(C3-C6cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo; X3cis C-R3c; R3cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; X4cis C-R4c; R4cis H, halo, or C1-C6haloalkyl; X5cis C-R5c; R5cis H or halo; X6cis C- R6c; and R6cis H or halo.

[0123] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R4b1and R4b2are each independently H or C1-C6alkyl; R5b1and R5b2are each independently C1-C6alkyl or C1-C6haloalkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0124] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X2ais N, C-H, C-D, C-CH3, or C-F; X4ais N, N+-O-, C- H, or C-F; X5ais N, C-H, C-D, C-CH3, or C-F; X6ais N, C-H, C-D, C-CH3, or C-F; each R is H or CH3; R4b1and R4b2are each independently H, CH3, CH2CH3, or cyclopropyl; R5b1and R5b2are each independently H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CHF2, CF2CH3, CH2CF3, or CF3; R2cis H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCHF2,, ; X3cis N, C-H, C-CH3, C-CH2CH3, C-CHF2, C-CF3, C-F, or C-Cl; X4cis N, C-H, C-CHF2, C-CF3, or C-F; X5cis N, C-H, C-D, or C-Cl; and X6cis N, C-H, or C-F.

[0125] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C-R5a; R5ais H; X6ais C-R6a; R6ais H; R4b1and R4b2are each independently H or CH3; R5b1and R5b2are each independently H, CH3, or CF3; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0126] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R4b1is C1-C6alkyl; R4b2is H; R5b1is C1-C6alkyl; R5b2is C1-C6haloalkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0127] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R4b1is H; R4b2is C1-C6alkyl; R5b1is C1-C6alkyl; R5b2is C1-C6haloalkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0128] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R4b1is C1-C6alkyl; R4b2is H; R5b1is C1-C6haloalkyl; R5b2is C1-C6alkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C- R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0129] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R5b1is C1-C6haloalkyl; R5b2is C1-C6alkyl; R4b1is H; R4b2is C1-C6alkyl; R2cis C1-C6alkoxy or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0130] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R5b1is CH3; R5b2is CF3; R4b1is CH3; R4b2is H; R2cis C1-C6alkoxy or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0131] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R5b1is CH3; R5b2is CF3; R4b1is H; R4b2is CH3; R2cis C1-C6alkoxy orC1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0132] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R5b1is CF3; R5b2is CH3; R4b1is CH3; R4b2is H; R2cis C1-C6alkoxy or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0133] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R5b1is CF3; R5b2is CH3; R4b1is H, and R4b2is CH3; R2cis C1-C6alkoxy or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C- R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0134] In some embodiments, the invention relates to a compound of formula (I-A) (including any of the foregoing embodiments thereof), i.e., the compound in non-salt form.

[0135] In some embodiments, the invention relates to a compound of formula (I-A-1) ,or a pharmaceutically acceptable salt thereof, wherein: X4ais N, N+-O-, or C-R4a; each R is independently H or C1-C6alkyl; R4ais H, halo, C1-C6alkyl, or C1-C6haloalkyl; R4b1and R4b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl; R5b1and R5b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl; R2cis H, OH, halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; and R4cis H, halo, C1-C6alkyl, or C1-C6haloalkyl.

[0136] In some embodiments, the invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N. In other embodiments, X4ais N+-O-. In other embodiments, X4ais C-R4a. In other embodiments, X4ais C-F.

[0137] In some embodiments, the invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently H or CH3. In other embodiments, N(R)2is NHCH3.

[0138] In some embodiments, the invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein R4ais halo.

[0139] In some embodiments, the invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein R4b1and R4b2are each independently H or C1-C6alkyl. In other embodiments, R4b1and R4b2are each independently H or CH3. In other embodiments, R4b1is C1- C6alkyl, and R4b2is H. In other embodiments, R4b1is H, and R4b2is C1-C6alkyl. In other embodiments, R4b1is CH3, and R4b2is H. In other embodiments, R4b1is H, and R4b2is CH3.

[0140] In some embodiments, the invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein R5b1and R5b2are each independently C1-C6alkyl or C1- C6haloalkyl. In other embodiments, R5b1and R5b2are each independently H, CH3, or CF3. In other embodiments, R5b1is C1-C6alkyl, and R5b2is C1-C6haloalkyl. In other embodiments, R5b1is C1-C6haloalkyl, and R5b2is C1-C6alkyl. In other embodiments, R5b1is CH3, and R5b2is CF3. In other embodiments, R5b1is CF3, and R5b2is CH3.

[0141] In some embodiments, the invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy. In other embodiments, R2cis C1-C6alkoxy. In other embodiments, R2cis C1-C6haloalkoxy. In other embodiments, R2cis OH, OCH3, OCD3, OCH2CH3, or OCHF2. In other embodiments, R2cis OH. In other embodiments, R2cis OCH3. In other embodiments, R2cis OCD3. In other embodiments, R2cis OCH2CH3. In other embodiments, R2cis OCHF2.

[0142] In some embodiments, the invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein R3cis H, halo, or C1-C6alkyl. In other embodiments, R3cis halo. In other embodiments, R3cis C1-C6alkyl. In other embodiments, R3cis H, F, Cl, or CH3. In other embodiments, R3cis H. In other embodiments, R3cis F. In other embodiments, R3cis Cl. In other embodiments, R3cis CH3.

[0143] In some embodiments, the invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein R4cis halo. In other embodiments, R4cis F.

[0144] In some embodiments, the invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1and R4b2are each independently H or C1-C6alkyl; R5b1and R5b2are each independently C1-C6alkyl or C1-C6haloalkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0145] In some embodiments, the invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1and R4b2are each independently H or CH3; R5b1and R5b2are each independently H, CH3, or CF3; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0146] In some embodiments, the invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is C1-C6alkyl; R4b2is H; R5b1is C1-C6alkyl; R5b2is C1-C6haloalkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0147] In some embodiments, the invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is H; R4b2is C1-C6alkyl; R5b1is C1-C6alkyl; R5b2is C1-C6haloalkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0148] In some embodiments, the invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is C1-C6alkyl; R4b2is H; R5b1is C1-C6haloalkyl; R5b2is C1-C6alkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0149] In some embodiments, the invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is H; R4b2is C1-C6alkyl; R5b1is C1-C6haloalkyl; R5b2is C1-C6alkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0150] In some embodiments, the invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is CH3; R4b2is H; R5b1is CH3; R5b2is CF3; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0151] In some embodiments, the invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is H; R4b2is CH3; R5b1is CH3; R5b2is CF3; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0152] In some embodiments, the invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is CH3; R4b2is H; R5b1is CF3; R5b2is CH3; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0153] In some embodiments, the invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is H, and R4b2is CH3; R5b1is CF3; R5b2is CH3; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0154] In some embodiments, the invention relates to a compound of formula (I-A-1) (including any of the foregoing embodiments thereof), i.e., the compound in non-salt form.

[0155] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein: X2ais N, N+-O-, or C-R2a; X4ais N, N+-O-, or C-R4a; X5ais N, N+-O-, or C-R5a; X6ais N, N+-O-, or C-R6a; each R is independently H or C1-C6alkyl; R2a, R4a, R5a, and R6aare each independently H, halo, C1-C6alkyl, or C1-C6haloalkyl; R4b1and R4b2are each independently H, C1-C6alkyl, C3-C6cycloalkyl, or C1-C6haloalkyl; R5b1and R5b2are each independently H, C1-C6alkyl, C3-C6cycloalkyl, or C1-C6haloalkyl;X3cis N or C-R3c; X4cis N or C-R4c; X5cis N or C-R5c; X6cis N or C-R6c; R2cis H, OH, halo, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, or –L1-L2-(C3-C6cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo; L1is a bond or O; L2is a bond or C1-C6alkylene; R3cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; R4cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; R5cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; and R6cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; provided that no more than two of X2a, X4a, X5a, and X6aare N or N+-O-; and provided that no more than one of X3c, X4c, X5c, and X6care N.

[0156] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X2ais C-R2a; X5ais C-R5a; X6ais C-R6a; R4b1and R4b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl; R5b1and R5b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl; X3cis C-R3c; X4cis C-R4c; X5cis C-R5c; X6cis C-R6c; and R2cis H, OH, halo, C1- C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0157] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently H or CH3. In other embodiments, N(R)2is NHCH3.

[0158] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X2ais N. In other embodiments, X2ais C-R2a. In some embodiments, R2ais H, D, halo, or C1-C6alkyl. In other embodiments, R2ais H, D, F, or CH3. In some embodiments, X2ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo. In other embodiments, X2ais N, C-H, C-D, C-CH3, or C-F.

[0159] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X2ais C-R2a; and R2ais H.

[0160] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X4ais N. In other embodiments, X4ais N+-O-. In otherembodiments, X4ais C-R4a. In some embodiments, R4ais halo. In other embodiments, R4ais H or halo. In other embodiments, R4ais H or F. In other embodiments, X4ais C-F. In some embodiments, X4ais N, N+-O-, C-H, or C-halo. In other embodiments, X4ais N, N+-O-, C-H, or C-F.

[0161] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X4ais C-R4a; and R4ais halo.

[0162] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X5ais N. In other embodiments, X5ais C-R5a. In some embodiments, R5ais H, D, halo, or C1-C6alkyl. In other embodiments, R5ais H, D, F, or CH3. In some embodiments, X5ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo. In other embodiments, X5ais N, C-H, C-D, C-CH3, or C-F.

[0163] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X5ais C-R5a; and R5ais H.

[0164] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X6ais N. In other embodiments, X6ais C-R6a. In some embodiments, R6ais H, D, halo, or C1-C6alkyl. In other embodiments, R6ais H, D, F, or CH3. In some embodiments, X6ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo. In other embodiments, X6ais N, C-H, C-D, C-CH3, or C-F.

[0165] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X6ais C-R6a; and R6ais H.

[0166] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R4b1and R4b2are each independently H or C1-C6alkyl. In other embodiments, R4b1and R4b2are each independently H, C1-C6alkyl, or C3-C6cycloalkyl. In other embodiments, R4b1and R4b2are each independently H or CH3. In other embodiments, R4b1and R4b2are each independently H, CH3, CH2CH3, or cyclopropyl. In other embodiments, R4b1is C1-C6alkyl, and R4b2is H. In other embodiments, R4b1is H, and R4b2is C1-C6alkyl. In other embodiments, R4b1is CH3, and R4b2is H. In other embodiments, R4b1is H, and R4b2is CH3.

[0167] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R5b1and R5b2are each independently C1-C6alkyl or C1- C6haloalkyl. In other embodiments, R5b1and R5b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl. In other embodiments, R5b1and R5b2are each independently H, CH3, or CF3. In other embodiments, R5b1and R5b2are each independently H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CHF2,CF2CH3, CH2CF3, or CF3. In other embodiments, R5b1is C1-C6alkyl, and R5b2is C1-C6haloalkyl. In other embodiments, R5b1is C1-C6haloalkyl, and R5b2is C1-C6alkyl. In other embodiments, R5b1is CH3, and R5b2is CF3. In other embodiments, R5b1is CF3, and R5b2is CH3.

[0168] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy. In other embodiments, R2cis OH, halo, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, or –L1-L2-(C3-C6cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R2cis H. In other embodiments, R2cis C1-C6alkoxy. In other embodiments, R2cis C1-C6haloalkoxy. In other embodiments, R2cis -L1-L2-(C3-C6cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R2cis OH, OCH3, OCD3, OCH2CH3, or OCHF2. In other embodiments, R2cis H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2,. In other embodiments, R2cis OH. In other embodiments, R2cis OCH3. In other embodiments, R2cis OCD3. In other embodiments, R2cis OCH2CH3. In other embodiments, R2cis OCHF2.

[0169] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X3cis N. In other embodiments, X3cis C-R3c. In other embodiments, R3cis H, halo, C1-C6alkyl, or C1-C6haloalkyl. In other embodiments, R3cis H, CH3, CH2CH3, CHF2, CF3, F, or Cl. In some embodiments, X3cis N, C-H, C-CH3, C-CH2CH3, C-CHF2, C-CF3, C-F, or C-Cl.

[0170] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X3cis C-R3c; and R3cis H, halo, or C1-C6alkyl. In other embodiments, R3cis halo. In other embodiments, R3cis C1-C6alkyl. In other embodiments, R3cis H, F, Cl, or CH3. In other embodiments, R3cis H. In other embodiments, R3cis F. In other embodiments, R3cis Cl. In other embodiments, R3cis CH3.

[0171] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X4cis N. In other embodiments, X4cis C-R4c. In other embodiments, R4cis H, halo, or C1-C6haloalkyl. In other embodiments, R4cis H, CHF2, CF3, or F. In some embodiments, X4cis N, C-H, C-CHF2, C-CF3, or C-F.

[0172] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X4cis C-R4c; and R4cis halo. In other embodiments, R4cis F.

[0173] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X5cis N. In other embodiments, X5cis C-R5c. In other embodiments, R5cis H or halo. In other embodiments, R5cis H, D, or Cl. In some embodiments, X5cis N, C-H, C-D, or C-Cl.

[0174] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X5cis C-R5c; and R5cis H.

[0175] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X6cis N. In other embodiments, X6cis C-R6c. In other embodiments, R6cis H or halo. In other embodiments, R6cis H or F. In some embodiments, X6cis N, C- H, or C-F.

[0176] In some embodiments, the invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein R6cis H.

[0177] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X2ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo; X4ais N, N+-O-, C-H, or C-halo; X5ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo; X6ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo; each R is H or CH3; R4b1and R4b2are each independently H, C1-C6alkyl, or C3-C6cycloalkyl; R5b1and R5b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl; R2cis OH, halo, C1- C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, or –L1-L2-(C3-C6cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo; X3cis C-R3c; R3cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; X4cis C-R4c; R4cis H, halo, or C1-C6haloalkyl; X5cis C-R5c; R5cis H or halo; X6cis C- R6c; and R6cis H or halo.

[0178] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R4b1and R4b2are each independently H or C1-C6alkyl; R5b1and R5b2are each independently C1-C6alkyl or C1-C6haloalkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0179] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X2ais N, C-H, C-D, C-CH3, or C-F; X4ais N, N+-O-, C- H, or C-F; X5ais N, C-H, C-D, C-CH3, or C-F; X6ais N, C-H, C-D, C-CH3, or C-F; each R is H or CH3; R4b1and R4b2are each independently H, CH3, CH2CH3, or cyclopropyl; R5b1and R5b2are each independently H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CHF2, CF2CH3, CH2CF3, or CF3; R2cis H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCHF2, ; X3cis 3 H2CH3, C-CHF2, C-CF3, C-F, or C-Cl; X4N, C-H, C-CH , C-Ccis N, C-H, C-CHF2, C-CF3, or C-F; X5cis N, C-H, C-D, or C-Cl; and X6cis N, C-H, or C-F.

[0180] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R4b1and R4b2are each independently H or CH3; R5b1and R5b2are each independently H, CH3, or CF3; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0181] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R4b1is C1-C6alkyl; R4b2is H; R5b1is C1-C6alkyl; R5b2is C1-C6haloalkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0182] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R4b1is H; R4b2is C1-C6alkyl; R5b1is C1-C6alkyl; R5b2is C1-C6haloalkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0183] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R4b1is C1-C6alkyl; R4b2is H; R5b1is C1-C6haloalkyl; R5b2is C1-C6alkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C- R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0184] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R5b1is C1-C6haloalkyl; R5b2is C1-C6alkyl; R4b1is H; R4b2is C1-C6alkyl; R2cis C1-C6alkoxy or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0185] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R5b1is CH3; R5b2is CF3; R4b1is CH3; R4b2is H; R2cis C1-C6alkoxy or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0186] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R5b1is CH3; R5b2is CF3; R4b1is H; R4b2is CH3; R2cis C1-C6alkoxy or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0187] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R5b1is CF3; R5b2is CH3; R4b1is CH3; R4b2is H; R2cis C1-C6alkoxy or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0188] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R5b1is CF3; R5b2is CH3; R4b1is H, and R4b2is CH3; R2cis C1-C6alkoxy or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C- R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0189] In some embodiments, the invention relates to a compound of formula (I-B) (including any of the foregoing embodiments thereof), i.e., the compound in non-salt form.

[0190] In some embodiments, the invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein: X4ais N, N+-O-, or C-R4a; each R is independently H or C1-C6alkyl; R4ais H, halo, C1-C6alkyl, or C1-C6haloalkyl; R4b1and R4b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl; R5b1and R5b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl; R2cis H, OH, halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; and R4cis H, halo, C1-C6alkyl, or C1-C6haloalkyl.

[0191] In some embodiments, the invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N. In other embodiments, X4ais N+-O-. In other embodiments, X4ais C-R4a. In some embodiments, R4ais halo. In other embodiments, X4ais C-F.

[0192] In some embodiments, the invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently H or CH3. In other embodiments, N(R)2is NHCH3.

[0193] In some embodiments, the invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein R4ais halo.

[0194] In some embodiments, the invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein R4b1and R4b2are each independently H or C1-C6alkyl. In other embodiments, R4b1and R4b2are each independently H or CH3. In other embodiments, R4b1is C1- C6alkyl, and R4b2is H. In other embodiments, R4b1is H, and R4b2is C1-C6alkyl. In other embodiments, R4b1is CH3, and R4b2is H. In other embodiments, R4b1is H, and R4b2is CH3.

[0195] In some embodiments, the invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein R5b1and R5b2are each independently C1-C6alkyl or C1-C6haloalkyl. In other embodiments, R5b1and R5b2are each independently H, CH3, or CF3. In other embodiments, R5b1is C1-C6alkyl, and R5b2is C1-C6haloalkyl. In other embodiments, R5b1is C1-C6haloalkyl, and R5b2is C1-C6alkyl. In other embodiments, R5b1is CH3, and R5b2is CF3. In other embodiments, R5b1is CF3, and R5b2is CH3.

[0196] In some embodiments, the invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy. In other embodiments, R2cis C1-C6alkoxy. In other embodiments, R2cis C1-C6haloalkoxy. In other embodiments, R2cis OH, OCH3, OCD3, OCH2CH3, or OCHF2. In other embodiments, R2cis OH. In other embodiments, R2cis OCH3. In other embodiments, R2cis OCD3. In other embodiments, R2cis OCH2CH3. In other embodiments, R2cis OCHF2.

[0197] In some embodiments, the invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein R3cis H, halo, or C1-C6alkyl. In other embodiments, R3cis halo. In other embodiments, R3cis C1-C6alkyl. In other embodiments, R3cis H, F, Cl, or CH3. In other embodiments, R3cis H. In other embodiments, R3cis F. In other embodiments, R3cis Cl. In other embodiments, R3cis CH3.

[0198] In some embodiments, the invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein R4cis halo. In other embodiments, R4cis F.

[0199] In some embodiments, the invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1and R4b2are each independently H or C1-C6alkyl; R5b1and R5b2are each independently C1-C6alkyl or C1-C6haloalkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0200] In some embodiments, the invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1and R4b2are each independently H or CH3; R5b1and R5b2are each independently H, CH3, or CF3; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0201] In some embodiments, the invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is C1-C6alkyl; R4b2is H; R5b1is C1-C6alkyl; R5b2is C1-C6haloalkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0202] In some embodiments, the invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is H; R4b2is C1-C6alkyl; R5b1is C1-C6alkyl; R5b2is C1-C6haloalkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0203] In some embodiments, the invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is C1-C6alkyl; R4b2is H; R5b1is C1-C6haloalkyl; R5b2is C1-C6alkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0204] In some embodiments, the invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is H; R4b2is C1-C6alkyl; R5b1is C1-C6haloalkyl; R5b2is C1-C6alkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0205] In some embodiments, the invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is CH3; R4b2is H; R5b1is CH3; R5b2is CF3; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0206] In some embodiments, the invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is H; R4b2is CH3; R5b1is CH3; R5b2is CF3; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0207] In some embodiments, the invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is CH3; R4b2is H; R5b1is CF3; R5b2is CH3; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0208] In some embodiments, the invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is H, and R4b2is CH3; R5b1is CF3; R5b2is CH3; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0209] In some embodiments, the invention relates to a compound of formula (I-B-1) (including any of the foregoing embodiments thereof), i.e., the compound in non-salt form.

[0210] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein: X2ais N, N+-O-, or C-R2a; X4ais N, N+-O-, or C-R4a; X5ais N, N+-O-, or C-R5a; X6ais N, N+-O-, or C-R6a; each R is independently H or C1-C6alkyl; R2a, R4a, R5a, and R6aare each independently H, halo, C1-C6alkyl, or C1-C6haloalkyl; R4b1and R4b2are each independently H, C1-C6alkyl, C3-C6cycloalkyl, or C1-C6haloalkyl; R5b1and R5b2are each independently H, C1-C6alkyl, C3-C6cycloalkyl, or C1-C6haloalkyl; X3cis N or C-R3c; X4cis N or C-R4c; X5cis N or C-R5c; X6cis N or C-R6c; R2cis H, OH, halo, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, or –L1-L2-(C3-C6cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo; L1is a bond or O; L2is a bond or C1-C6alkylene; R3cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; R4cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; R5cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; and R6cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; provided that no more than two of X2a, X4a, X5a, and X6aare N or N+-O-; and provided that no more than one of X3c, X4c, X5c, and X6care N.

[0211] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X2ais C-R2a; X5ais C-R5a; X6ais C-R6a; R4b1and R4b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl; R5b1and R5b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl; X3cis C-R3c; X4cis C-R4c; X5cis C-R5c; X6cis C-R6c; and R2cis H, OH, halo, C1- C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0212] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently H or CH3. In other embodiments, N(R)2is NHCH3.

[0213] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X2ais N. In other embodiments, X2ais C-R2a. In some embodiments, R2ais H, D, halo, or C1-C6alkyl. In other embodiments, R2ais H, D, F, or CH3. In some embodiments, X2ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo. In other embodiments, X2ais N, C-H, C-D, C-CH3, or C-F.

[0214] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X2ais C-R2a; and R2ais H.

[0215] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X4ais N. In other embodiments, X4ais N+-O-. In other embodiments, X4ais C-R4a. In some embodiments, R4ais halo. In other embodiments, R4ais H or halo. In other embodiments, R4ais H or F. In other embodiments, X4ais C-F. In some embodiments, X4ais N, N+-O-, C-H, or C-halo. In other embodiments, X4ais N, N+-O-, C-H, or C-F.

[0216] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X4ais C-R4a; and R4ais halo.

[0217] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X5ais N. In other embodiments, X5ais C-R5a. In some embodiments, R5ais H, D, halo, or C1-C6alkyl. In other embodiments, R5ais H, D, F, or CH3. In some embodiments, X5ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo. In other embodiments, X5ais N, C-H, C-D, C-CH3, or C-F.

[0218] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X5ais C-R5a; and R5ais H.

[0219] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X6ais N. In other embodiments, X6ais C-R6a. In some embodiments, R6ais H, D, halo, or C1-C6alkyl. In other embodiments, R6ais H, D, F, or CH3. In someembodiments, X6ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo. In other embodiments, X6ais N, C-H, C-D, C-CH3, or C-F.

[0220] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X6ais C-R6a; and R6ais H.

[0221] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R4b1and R4b2are each independently H or C1-C6alkyl. In other embodiments, R4b1and R4b2are each independently H, C1-C6alkyl, or C3-C6cycloalkyl. In other embodiments, R4b1and R4b2are each independently H or CH3. In other embodiments, R4b1and R4b2are each independently H, CH3, CH2CH3, or cyclopropyl. In other embodiments, R4b1is C1-C6alkyl, and R4b2is H. In other embodiments, R4b1is H, and R4b2is C1-C6alkyl. In other embodiments, R4b1is CH3, and R4b2is H. In other embodiments, R4b1is H, and R4b2is CH3.

[0222] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R5b1and R5b2are each independently C1-C6alkyl or C1- C6haloalkyl. In other embodiments, R5b1and R5b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl. In other embodiments, R5b1and R5b2are each independently H, CH3, or CF3. In other embodiments, R5b1and R5b2are each independently H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CHF2, CF2CH3, CH2CF3, or CF3. In other embodiments, R5b1is C1-C6alkyl, and R5b2is C1-C6haloalkyl. In other embodiments, R5b1is C1-C6haloalkyl, and R5b2is C1-C6alkyl. In other embodiments, R5b1is CH3, and R5b2is CF3. In other embodiments, R5b1is CF3, and R5b2is CH3.

[0223] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy. In other embodiments, R2cis OH, halo, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, or –L1-L2-(C3-C6cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R2cis H. In other embodiments, R2cis C1-C6alkoxy. In other embodiments, R2cis C1-C6haloalkoxy. In other embodiments, R2cis -L1-L2-(C3-C6cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R2cis OH, OCH3, OCD3, OCH2CH3, or OCHF2. In other embodiments, R2cis H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCHF2,. In other embodiments, R2cis OH. In other embodiments, R2cis OCH3. In other embodiments, R2cis OCD3. In other embodiments, R2cis OCH2CH3. In other embodiments, R2cis OCHF2.

[0224] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X3cis N. In other embodiments, X3cis C-R3c. In other embodiments, R3cis H, halo, C1-C6alkyl, or C1-C6haloalkyl. In other embodiments, R3cis H, CH3, CH2CH3, CHF2, CF3, F, or Cl. In some embodiments, X3cis N, C-H, C-CH3, C-CH2CH3, C-CHF2, C-CF3, C-F, or C-Cl.

[0225] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X3cis C-R3c; and R3cis H, halo, or C1-C6alkyl. In other embodiments, R3cis halo. In other embodiments, R3cis C1-C6alkyl. In other embodiments, R3cis H, F, Cl, or CH3. In other embodiments, R3cis H. In other embodiments, R3cis F. In other embodiments, R3cis Cl. In other embodiments, R3cis CH3.

[0226] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X4cis N. In other embodiments, X4cis C-R4c. In other embodiments, R4cis H, halo, or C1-C6haloalkyl. In other embodiments, R4cis H, CHF2, CF3, or F. In some embodiments, X4cis N, C-H, C-CHF2, C-CF3, or C-F.

[0227] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X4cis C-R4c; and R4cis halo. In other embodiments, R4cis F.

[0228] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X5cis N. In other embodiments, X5cis C-R5c. In other embodiments, R5cis H or halo. In other embodiments, R5cis H, D, or Cl. In some embodiments, X5cis N, C-H, C-D, or C-Cl.

[0229] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X5cis C-R5c; and R5cis H.

[0230] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X6cis N. In other embodiments, X6cis C-R6c. In other embodiments, R6cis H or halo. In other embodiments, R6cis H or F. In some embodiments, X6cis N, C- H, or C-F.

[0231] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R6cis H.

[0232] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X2ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo; X4ais N, N+-O-, C-H, or C-halo; X5ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo; X6ais N, C-H, C-D, C-(C1-C6alkyl), or C-halo; each R is H or CH3; R4b1and R4b2are each independently H, C1-C6alkyl, or C3-C6cycloalkyl; R5b1and R5b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl; R2cis OH, halo, C1- C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, or –L1-L2-(C3-C6cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo; X3cis C-R3c; R3cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; X4cis C-R4c; R4cis H, halo, or C1-C6haloalkyl; X5cis C-R5c; R5cis H or halo; X6cis C- R6c; and R6cis H or halo.

[0233] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R4b1and R4b2are each independently H or C1-C6alkyl; R5b1and R5b2are each independently C1-C6alkyl or C1-C6haloalkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0234] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X2ais N, C-H, C-D, C-CH3, or C-F; X4ais N, N+-O-, C- H, or C-F; X5ais N, C-H, C-D, C-CH3, or C-F; X6ais N, C-H, C-D, C-CH3, or C-F; each R is H or CH3; R4b1and R4b2are each independently H, CH3, CH2CH3, or cyclopropyl; R5b1and R5b2are each independently H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CHF2, CF2CH3, CH2CF3, or CF3; R2cis H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCHF2,, o ; X3cis N, C-H, C-CH3, C-CH2CH3, C-CHF2, C-CF3, C-F, or C-Cl; X4cis N, C-H, C-CHF2, C-CF3, or C-F; X5cis N, C-H, C-D, or C-Cl; and X6cis N, C-H, or C-F.

[0235] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R4b1and R4b2are each independently H or CH3; R5b1and R5b2are each independently H, CH3, or CF3; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0236] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R4b1is C1-C6alkyl; R4b2is H; R5b1is C1-C6alkyl; R5b2is C1-C6haloalkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0237] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R4b1is H; R4b2is C1-C6alkyl; R5b1is C1-C6alkyl; R5b2is C1-C6haloalkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0238] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R4b1is C1-C6alkyl; R4b2is H; R5b1is C1-C6haloalkyl; R5b2is C1-C6alkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C- R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0239] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R5b1is C1-C6haloalkyl; R5b2is C1-C6alkyl; R4b1is H; R4b2is C1-C6alkyl; R2cis C1-C6alkoxy or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0240] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R5b1is CH3; R5b2is CF3; R4b1is CH3; R4b2is H; R2cis C1-C6alkoxy or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0241] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R5b1is CH3; R5b2is CF3; R4b1is H; R4b2is CH3; R2cis C1-C6alkoxy or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0242] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R5b1is CF3; R5b2is CH3; R4b1is CH3; R4b2is H; R2cis C1-C6alkoxy or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C-R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0243] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; X2ais C-R2a; R2ais H; X5ais C- R5a; R5ais H; X6ais C-R6a; R6ais H; R5b1is CF3; R5b2is CH3; R4b1is H, and R4b2is CH3; R2cis C1-C6alkoxy or C1-C6haloalkoxy; X3cis C-R3c; R3cis H, halo, or C1-C6alkyl; X4cis C-R4c; R4cis halo; X5cis C- R5c; R5cis H; X6cis C-R6c; and R6cis H.

[0244] In some embodiments, the invention relates to a compound of formula (I-C) (including any of the foregoing embodiments thereof), i.e., the compound in non-salt form.

[0245] In some embodiments, the invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein: X4ais N, N+-O-, or C-R4a; each R is independently H or C1-C6alkyl; R4ais H, halo, C1-C6alkyl, or C1-C6haloalkyl; R4b1and R4b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl; R5b1and R5b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl; R2cis H, OH, halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; and R4cis H, halo, C1-C6alkyl, or C1-C6haloalkyl.

[0246] In some embodiments, the invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N. In other embodiments, X4ais N+-O-. In other embodiments, X4ais C-R4a. In some embodiments, R4ais halo. In other embodiments, X4ais C-F.

[0247] In some embodiments, the invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently H or CH3. In other embodiments, N(R)2is NHCH3.

[0248] In some embodiments, the invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein R4ais halo.

[0249] In some embodiments, the invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein R4b1and R4b2are each independently H or C1-C6alkyl. In other embodiments, R4b1and R4b2are each independently H or CH3. In other embodiments, R4b1is C1- C6alkyl, and R4b2is H. In other embodiments, R4b1is H, and R4b2is C1-C6alkyl. In other embodiments, R4b1is CH3, and R4b2is H. In other embodiments, R4b1is H, and R4b2is CH3.

[0250] In some embodiments, the invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein R5b1and R5b2are each independently C1-C6alkyl or C1- C6haloalkyl. In other embodiments, R5b1and R5b2are each independently H, CH3, or CF3. In other embodiments, R5b1is C1-C6alkyl, and R5b2is C1-C6haloalkyl. In other embodiments, R5b1is C1-C6haloalkyl, and R5b2is C1-C6alkyl. In other embodiments, R5b1is CH3, and R5b2is CF3. In other embodiments, R5b1is CF3, and R5b2is CH3.

[0251] In some embodiments, the invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy. In other embodiments, R2cis C1-C6alkoxy. In other embodiments, R2cis C1-C6haloalkoxy. In other embodiments, R2cis OH, OCH3, OCD3, OCH2CH3, or OCHF2. In other embodiments, R2cis OH. In other embodiments, R2cis OCH3. In other embodiments, R2cis OCD3. In other embodiments, R2cis OCH2CH3. In other embodiments, R2cis OCHF2.

[0252] In some embodiments, the invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein R3cis H, halo, or C1-C6alkyl. In other embodiments, R3cis halo. In other embodiments, R3cis C1-C6alkyl. In other embodiments, R3cis H, F, Cl, or CH3. In other embodiments, R3cis H. In other embodiments, R3cis F. In other embodiments, R3cis Cl. In other embodiments, R3cis CH3.

[0253] In some embodiments, the invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein R4cis halo. In other embodiments, R4cis F.

[0254] In some embodiments, the invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1and R4b2are each independently H or C1-C6alkyl; R5b1and R5b2are each independently C1-C6alkyl or C1-C6haloalkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0255] In some embodiments, the invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1and R4b2are each independently H or CH3; R5b1and R5b2are each independently H, CH3, or CF3; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0256] In some embodiments, the invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is C1-C6alkyl; R4b2is H; R5b1is C1-C6alkyl; R5b2is C1-C6haloalkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0257] In some embodiments, the invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is H; R4b2is C1-C6alkyl; R5b1is C1-C6alkyl; R5b2is C1-C6haloalkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0258] In some embodiments, the invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is C1-C6alkyl; R4b2is H; R5b1is C1-C6haloalkyl; R5b2is C1-C6alkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0259] In some embodiments, the invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is H; R4b2is C1-C6alkyl; R5b1is C1-C6haloalkyl; R5b2is C1-C6alkyl; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0260] In some embodiments, the invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is CH3; R4b2is H; R5b1is CH3; R5b2is CF3; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0261] In some embodiments, the invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is H; R4b2is CH3; R5b1is CH3; R5b2is CF3; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0262] In some embodiments, the invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is CH3; R4b2is H; R5b1is CF3; R5b2is CH3; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0263] In some embodiments, the invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein X4ais N; each R is H; R4b1is H, and R4b2is CH3; R5b1is CF3; R5b2is CH3; R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy; R3cis H, halo, or C1-C6alkyl; and R4cis halo.

[0264] In some embodiments, the invention relates to a compound of formula (I-C-1) (including any of the foregoing embodiments thereof), i.e., the compound in non-salt form.

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

[0266] Table A. Compound Structures and Names.4

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

[0268] Table B. Compound Structures and Names.4-( 5-4

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

[0270] Table C. Compound Names.

[0271] In some embodiments, the invention relates to a compound of formula, 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 compound is considered to be a “compound of the invention,” as that term is used herein.

[0272] In some embodiments, the invention relates to a compound of formula, 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 1, Step 6. Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0273] In some embodiments, the invention relates to a compound of formula, 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 (Chiralpak AS-H column). Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0274] In some embodiments, the invention relates to a compound of formula, 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 1 (Chiralpak AS-H column). Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0275] In some embodiments, the invention relates to a compound of formula, 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 compound is considered to be a “compound of the invention,” as that term is used herein.

[0276] In some embodiments, the invention relates to a compound of formula, 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 2, Step 10. Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0277] In some embodiments, the invention relates to a compound of formula, 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, Step 13. Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0278] In some embodiments, the invention relates to a compound of formula, 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, Step 13. Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0279] In some embodiments, the invention relates to a compound of formula, or a pharmaceutically acceptable salt thereof. Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0280] In some embodiments, the invention relates to a compound of formula, or a pharmaceutically acceptable salt thereof. Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0281] In some embodiments, the invention relates to a compound of formula, 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 compound is considered to be a “compound of the invention,” as that term is used herein.

[0282] In some embodiments, the invention relates to a compound of formula, 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 compound is considered to be a “compound of the invention,” as that term is used herein.

[0283] In some embodiments, the invention relates to a compound of formula, or a pharmaceutically acceptable salt thereof. Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0284] In some embodiments, the invention relates to a compound of formula, or a pharmaceutically acceptable salt thereof. Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0285] In some embodiments, the invention relates to a compound of formula, or a pharmaceutically acceptable salt thereof. Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0286] In some embodiments, the invention relates to a compound of formula, or a pharmaceutically acceptable salt thereof. Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0287] In some embodiments, the invention relates to a compound of formula, or a pharmaceutically acceptable salt thereof. Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0288] In some embodiments, the invention relates to a compound of formula, 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 (Chiralpak AS-H column). Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0289] In some embodiments, the invention relates to a compound of formula, 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 1 (Chiralpak AS-H column). Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0290] In some embodiments, the invention relates to a compound of formula, 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 inExample 4, Step 4. Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0291] In some embodiments, the invention relates to a compound of formula, 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 4, Step 4. Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0292] In some embodiments, the invention relates to a compound of formula, 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 (Chiralpak AS-H column). Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0293] In some embodiments, the invention relates to a compound of formula,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 4, Step 4 (Chiralpak AS-H column). Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0294] In some embodiments, the invention relates to a compound of formula, or a pharmaceutically acceptable salt thereof. Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0295] In some embodiments, the invention relates to a compound of formula, or a pharmaceutically acceptable salt thereof. Such compound is considered to be a “compound of the invention,” as that term is used herein.

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

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

[0298] In some embodiments, the invention relates to a compound of formula, or a pharmaceutically acceptable salt thereof. Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0299] In some embodiments, the invention relates to a compound of formula, or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry of the third eluting isomer when a mixture of racemic diastereomers (epimeric at the 5-position) is separated by SFC as described in Example 6, Step 7. Such compound is considered to be a “compound of the invention,” as that term is used herein.

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

[0301] In some embodiments, the invention relates to a compound of formula, or a pharmaceutically acceptable salt thereof. Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0302] In some embodiments, the invention relates to a compound of formula, 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 7, Step 11. Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0303] In some embodiments, the invention relates to a compound of formula, 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 7, Step 11. Such compound is considered to be a “compound of the invention,” as that term is used herein.

[0304] In some embodiments, the invention relates to a compound of formula, or a pharmaceutically acceptable salt thereof. Such compound is considered to be a “compound of the invention,” as that term is used herein. Solid Forms of Compounds of the Invention

[0305] In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, in solid form. In some embodiments, the compound of the invention, or pharmaceutically acceptable salt thereof, is in crystalline solid form. Solid Forms of Compound 7

[0306] In some embodiments, the invention relates to a compound of formula,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, Step 13, wherein the compound is in 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 having diffractions at angles (degrees 2 theta ± 0.2) of 9.9, 13.9, 15.7, and 19.0. In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, or at least three diffractions at angles (degrees 2 theta ± 0.2) of 9.9, 13.9, 15.7, and 19.0. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) of 7.3, 9.9, 13.9, 15.7, 19.0, 20.1, 20.3, and 25.4. 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 (degrees 2 theta ± 0.2) of 7.3, 9.9, 13.9, 15.7, 19.0, 20.1, 20.3, and 25.4. In other embodiments, Form A is characterized by an XRPD pattern substantially similar to Figure 1.

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

[0310] In some embodiments, Form A is obtainable 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 having diffractions at angles (degrees 2 theta ± 0.2) of 12.8, 14.1, 15.2, 18.5, and 20.3. In other embodiments, Form B is characterized by an XRPD pattern having at least one, at least two, at least three, or at least four diffractions at angles (degrees 2 theta ± 0.2) of 12.8, 14.1, 15.2, 18.5, and 20.3. In other embodiments, Form B is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) of 12.0, 12.8, 14.1, 15.2, 16.9, 18.4, 18.5, 18.7, 19.3, and 20.3. 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 (degrees 2 theta ± 0.2) of 12.0, 12.8, 14.1, 15.2, 16.9, 18.4, 18.5, 18.7, 19.3, and 20.3. In other embodiments, Form B is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) 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 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, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, atleast seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty- two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, or at least twenty- seven diffractions at angles (degrees 2 theta ± 0.2) 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 is characterized by an XRPD pattern substantially similar to Figure 4.

[0313] In some embodiments, Form B is characterized by a solid state13C NMR spectrum 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. In some embodiments, Form B is characterized by a solid state13C NMR spectrum substantially similar to Figure 5.

[0314] In some embodiments, Form B is characterized by a solid state19F NMR spectrum having peaks at chemical shifts of -137.1 and -152.8 ppm. In some embodiments, Form B is characterized by a solid state19F NMR spectrum substantially similar to Figure 6.

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

[0316] In some embodiments, Form B is characterized by an IR spectrum having peaks at 3501, 3356, 1684, 1565, 1505, and 1122 cm-1. In some embodiments, Form B is characterized by an IR spectrum substantially similar to Figure 9.

[0317] In some embodiments, Form B is characterized by an orthorhombic crystal system, as determined by single-crystal X-ray analysis. In other embodiments, Form B is characterized by a P212121space group, as determined by single-crystal X-ray analysis. In other embodiments, Form B is characterized by a unit cell, as determined by single-crystal X-ray analysis, of the following dimensions: 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 is obtainable by dissolving the compound in ethyl acetate and then crystallizing the compound by adding n-heptane as an antisolvent. In other embodiments, Form B is obtainable by the procedure described in Example 3.

[0319] In some embodiments, the invention relates to a compound of formula, wherein the compound is in 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 having diffractions at angles (degrees 2 theta ± 0.2) of 9.9, 13.9, 15.7, and 19.0. In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, or at least three diffractions at angles (degrees 2 theta ± 0.2) of 9.9, 13.9, 15.7, and 19.0. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) of 7.3, 9.9, 13.9, 15.7, 19.0, 20.1, 20.3, and 25.4. 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 (degrees 2 theta ± 0.2) of 7.3, 9.9, 13.9, 15.7, 19.0, 20.1, 20.3, and 25.4. In other embodiments, Form A is characterized by an XRPD pattern substantially similar to Figure 1.

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

[0323] In some embodiments, Form A is obtainable 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 having diffractions at angles (degrees 2 theta ± 0.2) of 12.8, 14.1, 15.2, 18.5, and 20.3. In other embodiments, Form B is characterized by an XRPD pattern having at least one, at least two, at least three, or at least four diffractions at angles (degrees 2 theta ± 0.2) of 12.8, 14.1, 15.2, 18.5, and 20.3. In other embodiments, Form B is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) of 12.0, 12.8, 14.1, 15.2, 16.9, 18.4, 18.5, 18.7, 19.3, and 20.3. 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 (degrees 2 theta ± 0.2) of 12.0, 12.8, 14.1, 15.2, 16.9, 18.4, 18.5, 18.7, 19.3, and 20.3. In other embodiments, Form B is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) 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 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, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty- two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, or at least twenty- seven diffractions at angles (degrees 2 theta ± 0.2) 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 is characterized by an XRPD pattern substantially similar to Figure 4.

[0326] In some embodiments, Form B is characterized by a solid state13C NMR spectrum 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. In other embodiments, Form B is characterized by a solid state13C NMR spectrum substantially similar to Figure 5.

[0327] In some embodiments, Form B is characterized by a solid state19F NMR spectrum having peaks at chemical shifts of -137.1 and -152.8 ppm. In other embodiments, Form B is characterized by a solid state19F NMR spectrum substantially similar to Figure 6.

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

[0329] In some embodiments, Form B is characterized by an IR spectrum having peaks at 3501, 3356, 1684, 1565, 1505, and 1122 cm-1. In other embodiments, Form B is characterized by an IR spectrum substantially similar to Figure 9.

[0330] In some embodiments, Form B is characterized by an orthorhombic crystal system, as determined by single-crystal X-ray analysis. In other embodiments, Form B is characterized by a P212121space group, as determined by single-crystal X-ray analysis. In other embodiments, Form B is characterized by a unit cell, as determined by single-crystal X-ray analysis, of the following dimensions: 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 is obtainable by dissolving the compound in ethyl acetate and then crystallizing the compound by adding n-heptane as an antisolvent. In other embodiments, Form B is obtainable by the procedure described in Example 3. Solid Forms of Compound 9

[0332] In some embodiments, the invention relates to a compound of formula, wherein the compound is in 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 crystal system, as determined by single-crystal X-ray analysis. In other embodiments, Form A is characterized by an I222 space group, as determined by single-crystal X-ray analysis. In other embodiments, Form A is characterized by a unit cell, as determined by single-crystal X-ray analysis, of the following dimensions: 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 is obtainable by dissolving the compound in a 10 / 90 dichloromethane / dichloroethane solution, followed by vapor diffusion of pentane. In some embodiments, Form A is obtainable by the procedure described in Example 3. Solid Forms of Compound 11

[0336] In some embodiments, the invention relates to a compound of formula, wherein the compound is in 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 having diffractions at angles (degrees 2 theta ± 0.2) of 10.1, 13.7, 14.1, 16.3, and 20.0. In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, or at least fourdiffractions at angles (degrees 2 theta ± 0.2) of 10.1, 13.7, 14.1, 16.3, and 20.0. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) 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 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 (degrees 2 theta ± 0.2) 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 (degrees 2 theta ± 0.2) 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 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 eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, or at least sixteen diffractions at angles (degrees 2 theta ± 0.2) 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 substantially similar to Figure 12.

[0339] In some embodiments, Form A is obtainable by suspending the compound in water. In other embodiments, Form A is obtainable 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 having diffractions at angles (degrees 2 theta ± 0.2) of 6.8, 13.2, 16.1, 20.6, and 21.3. In other embodiments, Form B is characterized by an XRPD pattern having at least one, at least two, at least three, or at least four diffractions at angles (degrees 2 theta ± 0.2) of 6.8, 13.2, 16.1, 20.6, and 21.3. In other embodiments, Form B is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) 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 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 (degrees 2 theta ± 0.2) 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 (degrees 2 theta ± 0.2) 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 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 eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, or at least seventeen diffractions at angles (degrees 2 theta ± 0.2) 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 substantially similar to Figure 13.

[0342] In some embodiments, Form A is characterized by a monoclinic crystal system, as determined by single-crystal X-ray analysis. In other embodiments, Form A is characterized by a P21space group, as determined by single-crystal X-ray analysis. In other embodiments, Form A is characterized by a unit cell, as determined by single-crystal X-ray analysis, of the following dimensions: 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 is obtainable by recrystallization from acetonitrile. In other embodiments, Form B is obtainable by the procedure described in Example 4. Solid Form of Compound 19

[0344] In some embodiments, the invention relates to a compound of formula, wherein the compound is in 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 (degrees 2 theta ± 0.2) of 13.7, 15.2, and 18.2. In other embodiments, Form A is characterized by an XRPD pattern having at least one or at least two diffractions at angles (degrees 2 theta ± 0.2) of 13.7, 15.2, and 18.2. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) of 13.7, 15.2, 18.2, 18.3, 20.8, and 23.8. 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 (degrees 2 theta ± 0.2) of 13.7, 15.2, 18.2, 18.3, 20.8, and 23.8. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) of 13.7, 14.3, 15.2, 18.2, 18.3, 20.8, 22.5, 23.8, and 25.8. 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, or at least eight diffractions at angles (degrees 2 theta ± 0.2) of 13.7, 14.3, 15.2, 18.2, 18.3, 20.8, 22.5, 23.8, and 25.8. In other embodiments, Form A ischaracterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) 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. 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, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, or at least fifteen diffractions at angles (degrees 2 theta ± 0.2) 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. In other embodiments, Form A is characterized by an XRPD pattern substantially similar to Figure 15.

[0347] In some embodiments, Form A is characterized by a solid state13C NMR spectrum having peaks at chemical shifts of 171.4, 141.6, 118.0, 112.2, 23.0, and 11.6 ppm. In other embodiments, Form A is characterized by a solid state13C 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. In other embodiments, Form A is characterized by a solid state13C NMR spectrum substantially similar to Figure 16.

[0348] In some embodiments, Form A is characterized by a solid state19F NMR spectrum having peaks at chemical shifts of -74.6, -141.5, and -154.6 ppm. In other embodiments, Form A is characterized by a solid state19F NMR spectrum substantially similar to Figure 17.

[0349] In some embodiments, Form A is characterized by a monoclinic crystal system, as determined by single-crystal X-ray analysis. In other embodiments, Form A is characterized by a P21space group, as determined by single-crystal X-ray analysis. In other embodiments, Form A is characterized by a unit cell, as determined by single-crystal X-ray analysis, of the following dimensions: 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 is obtainable by precipitation from methanol via addition of heptane antisolvent. In other embodiments, Form A is obtainable from a suspension of the compound in ethanol, acetonitrile, and water by lyophilization. In other embodiments, Form A is obtainable by dissolving the compound in methanol and allowing slow diffusion of heptane antisolvent. In other embodiments, Form A is obtainable by the procedure described in Example 5. Solid Form of Compound 22

[0351] In some embodiments, the invention relates to a compound of formula, wherein the compound has the absolute stereochemistry of the third eluting isomer when a mixture of racemic diastereomers (epimeric at the 5-position) is separated by SFC as described in Example 6, Step 7, wherein the compound is in 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 (degrees 2 theta ± 0.2) of 9.2, 10.4, and 15.7. In other embodiments, Form A is characterized by an XRPD pattern having at least one or at least two diffractions at angles (degrees 2 theta ± 0.2) of 9.2, 10.4, and 15.7. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) of 7.7, 9.2, 10.4, 12.9, 15.7, and 18.4. 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 (degrees 2 theta ± 0.2) of 7.7, 9.2, 10.4, 12.9, 15.7, and 18.4. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) 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 having 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 (degrees 2 theta ± 0.2) 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 having diffractions at angles (degrees 2 theta ± 0.2) 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 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, at least nine, at least ten, at least eleven, or at least twelve diffractions at angles (degrees 2 theta ± 0.2) 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 Figure 19.

[0354] In some embodiments, Form A is characterized by a solid state13C NMR spectrum having peaks at chemical shifts of 167.7, 126.0, 115.9, 43.5, and 20.3 ppm. In other embodiments, Form A is characterized by a solid state13C 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. In other embodiments, Form A is characterized by a solid state13C NMR spectrum substantially similar to Figure 20.

[0355] In some embodiments, Form A is characterized by a solid state19F NMR spectrum having peaks at chemical shifts of -82.2, -83.1, -111.7, and -114.4 ppm. In other embodiments, Form A is characterized by a solid state19F NMR spectrum substantially similar to Figure 21.

[0356] In some embodiments, Form A is obtainable by slow evaporation of a 1:12- methyltetrahydrofuran / heptane solution. In other embodiments, Form A is obtainable by the procedure described in Example 6. Solid Form of Compound 23

[0357] In some embodiments, the invention relates to a compound of formula, wherein the compound is in 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 (degrees 2 theta ± 0.2) of 17.2, 19.3, and 22.3. In other embodiments, Form A is characterized by an XRPD pattern having at least one or at least two diffractions at angles (degrees 2 theta ± 0.2) of 17.2, 19.3, and 22.3. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) of 14.2, 15.8, 17.2, 19.3, 22.3, and 30.6. 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 (degrees 2 theta ± 0.2) of 14.2, 15.8, 17.2, 19.3, 22.3, and 30.6. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) of 12.2, 14.2, 15.8, 17.2, 19.3, 22.3, 25.0, 25.1, and 30.6. 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, or at least eight diffractions at angles (degrees 2 theta± 0.2) of 12.2, 14.2, 15.8, 17.2, 19.3, 22.3, 25.0, 25.1, and 30.6. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) 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. 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, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, or at least twenty-one diffractions at angles (degrees 2 theta ± 0.2) 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. In other embodiments, Form A is characterized by an XRPD pattern substantially similar to Figure 22.

[0360] In some embodiments, Form A is characterized by a solid state13C NMR spectrum having peaks at chemical shifts of 171.1, 149.3, 123.3, 41.6, and 20.0 ppm. In other embodiments, Form A is characterized by a solid state13C 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. In other embodiments, Form A is characterized by a solid state13C NMR spectrum substantially similar to Figure 23.

[0361] In some embodiments, Form A is characterized by a solid state19F NMR spectrum having peaks at chemical shifts of -78.2, -113.5, and -115.1 ppm. In other embodiments, Form A is characterized by a solid state19F NMR spectrum substantially similar to Figure 24.

[0362] In some embodiments, Form A is characterized by a monoclinic crystal system, as determined by single-crystal X-ray analysis. In other embodiments, Form A is characterized by a P21space group, as determined by single-crystal X-ray analysis. In other embodiments, Form A is characterized by a unit cell, as determined by single-crystal X-ray analysis, of the following dimensions: 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 is obtainable by slow evaporation of a 1:12- methyltetrahydrofuran / heptane solution. In other embodiments, Form A is obtainable by dissolving the compound in methanol and allowing slow diffusion of heptane vapor. In other embodiments, Form A is obtainable by the procedure described in Example 6. Solid Form of Compound 25

[0364] In some embodiments, the invention relates to a compound of formula, 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 7, Step 11, wherein the compound is in 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 (degrees 2 theta ± 0.2) of 6.8, 7.9, and 13.8. In other embodiments, Form A is characterized by an XRPD pattern having at least one or at least two diffractions at angles (degrees 2 theta ± 0.2) of 6.8, 7.9, and 13.8. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) of 6.8, 7.9, 11.0, 13.7, 13.8, and 27.4. 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 (degrees 2 theta ± 0.2) of 6.8, 7.9, 11.0, 13.7, 13.8, and 27.4. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) of 6.8, 7.9, 11.0, 13.7, 13.8, 15.9, 16.3, 23.2, and 27.4. 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, or at least eight diffractions at angles (degrees 2 theta ± 0.2) of 6.8, 7.9, 11.0, 13.7, 13.8, 15.9, 16.3, 23.2, and 27.4. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) 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. 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, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, or at least twenty diffractions at angles (degrees 2 theta ± 0.2) 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. In other embodiments, Form A is characterized by an XRPD pattern substantially similar to Figure 26.

[0367] In some embodiments, Form A is obtainable by slow evaporation of a 1:12- methyltetrahydrofuran / heptane solution. In other embodiments, Form A is obtainable by the procedure described in Example 7. Salts, Compositions, Uses, Formulation, Administration and Additional Agents Pharmaceutically acceptable salts and compositions

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

[0369] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. A “pharmaceutically acceptable salt” of a compound of this invention includes any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. The salt may be in pure form, in a mixture (e.g., solution, suspension, or colloid) with one or more other substances, or in the form of a hydrate, solvate, or co-crystal. As used herein, the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of a voltage- gated sodium channel.

[0370] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19,incorporated herein by reference. Pharmaceutically acceptable salts of the compound of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0371] As described herein, the pharmaceutically acceptable compositions of the invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington’s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0372] In another aspect, the invention features a pharmaceutical composition comprising 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 comprising a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles. Uses of Compounds and Pharmaceutically Acceptable Salts and Compositions

[0374] In another aspect, the invention features a method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject a compound of the invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In another aspect, the voltage-gated sodium channel is NaV1.8.

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

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

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

[0378] In yet another aspect, the invention features a method of treating or lessening the severity in a subject of neuropathic pain comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some aspects, the neuropathic pain comprises post-herpetic neuralgia, small fiber neuropathy or idiopathic small-fiber neuropathy. As used herein, the phrase “idiopathic small-fiber neuropathy” shall be understood to include any small fiber neuropathy. In some aspects, the neuropathic pain comprises diabetic neuropathy.

[0379] In yet another aspect, the invention features a method of treating or lessening the severity in a subject of neuropathic pain, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton’s neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia; post spinal cord injury pain, small fiber neuropathy, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia wherein said method comprises administering an effective amount of a compound of the invention, 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 in a subject of musculoskeletal pain comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some aspects, the musculoskeletal pain comprises osteoarthritis pain.

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

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

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

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

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

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

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

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

[0390] In yet another aspect, the invention features a method of treating or lessening the severity in a subject of abdominoplasty pain comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

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

[0392] In yet another aspect, the invention features a method of treating or lessening the severity in a subject of a neurodegenerative disease comprising administering an effective amount of a compound of the invention, a 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 wherein the subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with an effective amount of the compound, pharmaceutically acceptable salt or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0394] In another aspect, the invention features a method of inhibiting a voltage-gated sodium channel in a biological sample comprising contacting the biological sample with an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In another aspect, the voltage-gated sodium channel is NaV1.8.

[0395] In another aspect, the invention features a method of treating or lessening the severity in a subject of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions,neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head pain, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical 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 gastro- intestinal motility, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0396] In another aspect, the invention features a method of treating or lessening the severity in a subject of femur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headaches; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy induced neuropathic pain; radiotherapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom pain; intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury pain; exercise pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, burn pain, trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogenital disease; urinary incontinence, pathological cough; hyperactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS), type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal extreme pain, pruritus, tinnitus, or angina-induced pain, comprisingadministering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. Compounds, Pharmaceutically Acceptable Salts, and Compositions for Use

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

[0398] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting a voltage-gated sodium channel in a subject. In another aspect, the voltage-gated sodium channel is NaV1.8.

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

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

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

[0402] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of neuropathic pain. In some aspects, the neuropathic pain comprises post-herpetic neuralgia, small fiber neuropathy or idiopathic small-fiber neuropathy. As used herein, thephrase “idiopathic small-fiber neuropathy” shall be understood to include any small fiber neuropathy. In some aspects, the neuropathic pain comprises diabetic neuropathy.

[0403] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of neuropathic pain, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton’s neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia; post spinal cord injury pain, small fiber neuropathy, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia.

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

[0405] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of musculoskeletal pain, wherein musculoskeletal pain comprises 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 or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain or vulvodynia.

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

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

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

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

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

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

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

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

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

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

[0417] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method wherein the subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with an effective amount of the compound, pharmaceutically acceptable salt or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0418] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting a voltage-gated sodium channel in a biological sample comprising contacting the biological sample with an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In another aspect, the voltage-gated sodium channel is NaV1.8.

[0419] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head pain, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical 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 gastro-intestinal motility.

[0420] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of femur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headaches; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury;painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy induced neuropathic pain; radiotherapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom pain; intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury pain; exercise pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, burn pain, trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogenital disease; urinary incontinence, pathological cough; hyperactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS), type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal extreme pain, pruritus, tinnitus, or angina-induced pain. Manufacture of Medicaments

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

[0422] In another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in inhibiting a voltage-gated sodium channel. In another aspect, the voltage-gated sodium channel is NaV1.8.

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

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

[0425] In yet another aspect, the invention provides the use of the compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity in a subject of gut pain, wherein gut pain comprises inflammatory bowel disease pain, Crohn’s disease pain or interstitial cystitis pain.

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

[0427] In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in a treating or lessening the severity in a subject of neuropathic pain, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton’s neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti- retroviral therapy induced neuralgia; post spinal cord injury pain, small fiber neuropathy, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic neuropathy.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0442] In another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head pain, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical 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 gastro-intestinal motility.

[0443] In another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture ofa medicament for use in treating or lessening the severity of femur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headaches; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy induced neuropathic pain; radiotherapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom pain; intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury pain; exercise pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory, burn pain, trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogenital disease; urinary incontinence; pathological cough; hyperactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS) type I; complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal extreme pain, pruritus, tinnitus, or angina-induced pain. Administration of Pharmaceutically acceptable salts and compositions.

[0444] In certain embodiments of the invention an “effective amount” of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is that amount effective for treating or lessening the severity of one or more of the conditions recited above.

[0445] The compounds, salts, and compositions, according to the method of the invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the pain or non-pain diseases recited herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition, the particular agent, its mode of administration, and the like. The compounds,salts, and compositions of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compounds, salts, and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound or salt employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound or salt employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound or salt employed, and like factors well known in the medical arts. 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 this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the condition being treated. In certain embodiments, the compound, salts, and compositions of the invention may be administered orally or parenterally at dosage levels of about 0.001 mg / kg to about 100 mg / kg, or about 0.01 mg / kg to about 50 mg / kg, of subject body weight per day, one or more times a 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, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0448] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

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

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

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

[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 suchas, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, 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 may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0454] The active compound or salt can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound or salt may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

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

[0456] As described generally above, the compounds of the invention are useful as inhibitors of voltage-gated sodium channels. In one embodiment, the compounds are inhibitors of NaV1.8 and thus, without wishing to be bound by any particular theory, the compounds, salts, and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of NaV1.8 is implicated in the disease, condition, or disorder. When activation or hyperactivity of NaV1.8 is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as a “NaV1.8 -mediated disease, condition or disorder.” Accordingly, in another aspect, the invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of NaV1.8 is implicated in the disease state.

[0457] The activity of a compound utilized in this invention as an inhibitor of NaV1.8 may be assayed according to methods described generally in International Publication No. WO 2014 / 120808 A9 and U.S. Publication No.2014 / 0213616 A1, both of which are incorporated by reference in their entirety, methods described herein, and other methods known and available to one of ordinary skill in the art. Additional Therapeutic Agents

[0458] It will also be appreciated that the compounds, salts, and pharmaceutically acceptable compositions of the invention can be employed in combination therapies, that is, the compounds, salts, and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and / or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for thesame disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” For example, exemplary additional therapeutic agents include, but are not limited to: nonopioid 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, nondrug analgesic approaches may be utilized in conjunction with administration of one or more compounds of the invention. For example, anesthesiologic (intraspinal infusion, neural blockade), neurosurgical (neurolysis of CNS pathways), neurostimulatory (transcutaneous electrical nerve stimulation, dorsal column stimulation), physiatric (physical therapy, orthotic devices, diathermy), or psychologic (cognitive methods-hypnosis, biofeedback, or behavioral methods) approaches may also be utilized. Additional appropriate therapeutic agents or approaches are described generally in The Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp &Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and the Food and Drug Administration website, www.fda.gov, the entire contents of which are hereby incorporated by reference.

[0459] In another embodiment, additional appropriate therapeutic agents are selected from the following:

[0460] (1) an opioid analgesic, e.g. 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) a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen (including without limitation intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketorolac (including without limitation ketorolac tromethamine (e.g., Toradol®)), meclofenamic acid, mefenamic acid, meloxicam, IVmeloxicam (e.g., Anjeso®), nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

[0462] (3) a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal or thiopental;

[0463] (4) a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;

[0464] (5) a histamine (H1) antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;

[0465] (6) a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;

[0466] (7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine;

[0467] (8) an NMDA receptor antagonist, e.g. dextromethorphan ((+)-3-hydroxy-N- methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2- piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g. ifenprodil, traxoprodil or (-)-(R)-6-{2-[4- (3-fluorophenyl)-4-hydroxy-l- piperidinyl]-l-hydroxyethyl-3,4-dihydro-2(lH)-quinolinone;

[0468] (9) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-l, 2,3,4- tetrahydroisoquinolin-2-yl)-5-(2-pyridyl) quinazoline;

[0469] (10) a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline;

[0470] (11) an anticonvulsant, e.g. carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®) or valproate;

[0471] (12) a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g. (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11 -tetrahydro-9-methyl-5-(4- methylphenyl)-7H- [l,4]diazocino[2,l-g][l,7]-naphthyridine-6-13-dione (TAK-637), 5- [[(2R,3S)-2-[(lR)-l-[3,5- bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-l,2-dihydro-3H-l,2,4- triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]- methylamino]-2-phenylpiperidine (2S,3S);

[0472] (13) a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

[0473] (14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

[0474] (15) a coal-tar analgesic, in particular paracetamol;

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

[0476] (17) a vanilloid receptor agonist (e.g. resinferatoxin or civamide) or antagonist (e.g. capsazepine, GRC-15300);

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

[0478] (19) a local anesthetic such as mexiletine;

[0479] (20) a corticosteroid such as dexamethasone;

[0480] (21) a 5-HT receptor agonist or antagonist, particularly a 5-HT1B / 1Dagonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

[0481] (22) a 5-HT2Areceptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-l-[2-(4- fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);

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

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

[0484] (25) a PDE5 inhibitor, such as 5-[2-ethoxy-5-(4-methyl-l-piperazinyl-sulphonyl)phenyl]- l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)- 2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',l':6,l]-pyrido[3,4-b]indole- l,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-l-yl-l-sulphonyl)-phenyl]-5-methyl-7- propyl-3H-imidazo[5,l-f][l,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(l- ethyl-3-azetidinyl)-2,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)- 3-ethyl-2-(l-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-l-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H- pyrazolo[4,3- d]pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-l-yl]-N- (pyrimidin-2-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) an alpha-2-delta ligand such as gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methyl gabapentin, (l[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3- aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5- methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline, [(lR,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(l-aminomethyl-cyclohexylmethyl)- 4H-[1,2,4]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) a cannabinoid such as KHK-6188;

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

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

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

[0490] (31) a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran and imipramine;

[0491] (32) an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(l- iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(l-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2- [(l-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,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-carboxamidine, NXN-462, or guanidinoethyldisulfide;

[0492] (33) an acetylcholinesterase inhibitor such as donepezil;

[0493] (34) a prostaglandin E2 subtype 4 (EP4) antagonist 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) a leukotriene B4 antagonist; such as l-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman- 7-yl)-cyclopentanecarboxylic acid (CP- 105696), 5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E- hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870;

[0495] (36) a 5-lipoxygenase inhibitor, 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) a sodium channel blocker, such as lidocaine, lidocaine plus tetracaine cream (ZRS- 201) or eslicarbazepine acetate;

[0497] (38) a NaV1.7 blocker, such as XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893, BIIB-074 (Vixotrigine), BIIB-095, ASP-1807, DSP-3905, OLP- 1002, RQ-00432979, FX-301, DWP-17061, IMB-110, IMB-111, IMB-112 and such as those disclosed in WO2011 / 140425 (US2011 / 306607); WO2012 / 106499 (US2012196869); WO2012 / 112743 (US2012245136); WO2012 / 125613 (US2012264749), WO2012 / 116440 (US2014187533), WO2011026240 (US2012220605), US8883840, US8466188, or WO2013 / 109521 (US2015005304), the entire contents of each application hereby incorporated by reference.

[0498] (38a) a NaV1.7 blocker 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'- piperidine]-6-yl]ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-piperidine]-1'-yl]-(4-isobutoxy-3-methoxy-phenyl)methanone, 1-(4-benzhydrylpiperazin- 1-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy]propan-2-ol, (4-butoxy-3-methoxy-phenyl)-[2-methyl-6- (trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]-(5-isopropoxy- 6-methyl-2-pyridyl)methanone, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(1,1,2,2,2- pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 5-[2-methyl- 4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'- carbonyl]phenyl]pyridine-2-carbonitrile, (4-isopropoxy-3-methyl-phenyl)-[6-(trifluoromethyl)spiro[3,4- dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4'-piperidine]-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'-piperidine]- 6-yl]ethanone, 2,2,2-trifluoro-1-[1'-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-3,3-dimethyl-spiro[2,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 2,2,2-trifluoro-1-[1'-(5- isopentyloxypyridine-2-carbonyl)-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6- yl]ethanone, (4-isopropoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]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'-piperidine]-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'-piperidine]-6-yl]ethanone, 1-[1'-[4-methoxy-3- (trifluoromethyl)benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]-2,2- dimethyl-propan-1-one, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, [2-methyl-6-(1- methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]-[4-(3,3,3- 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'-piperidine]-1'-yl]methanone.

[0499] (39) a NaV1.8 blocker, such as PF-04531083, PF-06372865 and such as those disclosed in WO2008 / 135826 (US2009048306), WO2006 / 011050 (US2008312235), WO2013 / 061205 (US2014296313), US20130303535, WO2013131018, US8466188, WO2013114250 (US2013274243), WO2014 / 120808 (US2014213616), WO2014 / 120815 (US2014228371) WO2014 / 120820 (US2014221435), WO2015 / 010065 (US20160152561), WO2015 / 089361 (US20150166589), WO2019014352 (US20190016671), WO2018 / 213426, WO2020 / 146682, WO2020 / 146612,WO2020 / 014243, WO2020 / 014246, WO2020 / 092187, and WO2020 / 092667 (US2020140411), the entire contents of each application hereby incorporated by reference.

[0500] (39a) a NaV1.8 blocker 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, 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)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H- pyridin-4-yl)-4-(trifluoromethyl)benzamide, [4-[[2-(4-fluoro-2-methyl-phenoxy)-4- (trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate, 2-(4-fluoro-2-(methyl- d3)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-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- carboxamido)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- carboxamido)picolinic acid, 3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)quinoxaline-2-carboxamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4- yl)quinoxaline-2-carboxamide, 3-(4-fluorophenoxy)-N-(3-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-carboxamido)benzoic acid, N-(4-cyanophenyl)-3-(4-fluoro-2- methoxyphenoxy)quinoxaline-2-carboxamide, 5-(4,5-dichloro-2-(4-fluoro-2- methoxyphenoxy)benzamido)picolinic acid, 5-(2-(2,4-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-dichloro-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)-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-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2- methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2- methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 4,5-dichloro-2-(4-fluoro-2-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-fluoro- phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethoxy)benzamide, 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, 4-[[3-chloro-2-fluoro-6-[2-methoxy-4- (trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, 4-[[2-fluoro-6-[2- (trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2- carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-3-(difluoromethyl)-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) a combined NaV1.7 and NaV1.8 blocker, such as DSP-2230, Lohocla201 or BL- 1021;

[0502] (41) a 5-HT3 antagonist, such as ondansetron;

[0503] (42) a TPRV 1 receptor agonist, such as capsaicin (NeurogesX®, Qutenza®); and the pharmaceutically acceptable salts and solvates thereof;

[0504] (43) a nicotinic receptor antagonist, such as varenicline;

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

[0506] (45) a nerve growth factor antagonist, such as tanezumab;

[0507] (46) an endopeptidase stimulant, such as senrebotase;

[0508] (47) an angiotensin II antagonist, such as EMA-401;

[0509] (48) acetaminophen (including without limitation intravenous acetaminophen (e.g., Ofirmev®));

[0510] (49) bupivacaine (including without limitation bupivacaine liposome injectable suspension (e.g., Exparel®), bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll) and transdermal bupivacaine (Eladur®)); and

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

[0512] In one embodiment, the additional appropriate therapeutic agents are selected from V- 116517, Pregabalin, controlled release Pregabalin, Ezogabine (Potiga®). Ketamine / amitriptyline topical cream (Amiket®), AVP-923, Perampanel (E-2007), Ralfinamide, transdermal bupivacaine (Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561 or ARC-4558.

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

[0514] In another embodiment, the additional therapeutic agent is selected from a GlyT2 / 5HT2 inhibitor, such as Operanserin (VVZ149), a TRPV modulator such as CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101, MDR16523, or MDR652, a EGR1 inhibitor such as Brivoglide (AYX1), an NGF inhibitor such as Tanezumab, Fasinumab, ASP6294, MEDI7352, a Mu opioid agonist such as Cebranopadol, NKTR181 (oxycodegol), a CB-1 agonist such as NEO1940 (AZN1940), an imidazoline 12 agonist such as CR4056 or a p75NTR-Fc modulator such as LEVI-04.

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

[0516] In another embodiment, the additional therapeutic agent is a NaV1.7 blocker such as ST- 2427 and those disclosed in WO2010129864, WO2015157559, WO2017059385, WO2018183781, WO2018183782, and WO2020072835 the entire contents of each application hereby incorporated 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, Opiranserin (UnafraTM), brivoligide, SR419, NRD.E1, LX9211, LY3016859, ISC-17536, NFX-88, LAT-8881, AP-235, NYX 2925, CNTX-6016, S-600918, S-637880, RQ-00434739, KLS-2031, MEDI 7352, or XT-150.

[0518] In another embodiment, the additional therapeutic agent is a sodium channel inhibitor (also known as a sodium channel blocker), such as the NaV1.7 and NaV1.8 blockers identified above.

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

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

[0521] Another aspect of the invention relates to inhibiting NaV1.8 activity in a biological sample or a subject, which method comprises administering to the subject, or contacting said biological sample with a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. The term “biological sample,” as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0522] Inhibition of NaV1.8 activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, the study of sodium channels in biological and pathological phenomena; and the comparative evaluation of new sodium channel inhibitors. Synthesis of the Compounds of the Invention

[0523] The compounds of the invention can be prepared from known materials by the methods described in the Examples, other similar methods, and other methods known to one skilled in the art. As one skilled in the art would appreciate, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art. The use of protecting groups is described in detail in T.G.M. Wuts et al., Greene’s Protective Groups in Organic Synthesis (4th ed. 2006). Radiolabeled Analogs of the Compounds of the Invention

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

[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 include3H,14C,32P,35S,18F,36Cl, and the like, as well as the isotopes for which a decay mode is identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

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

[0527] In another aspect, the invention relates to pharmaceutically acceptable salts of the radiolabeled analogs, in accordance with any of the embodiments described herein in connection with the compounds of the invention.

[0528] In another aspect, the invention relates to pharmaceutical compositions comprising the radiolabeled analogs, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle, in accordance with any of the embodiments described herein in connection with the compounds of the invention.

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

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

[0531] In another aspect, the invention relates to the use of the radiolabeled analogs, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments, in accordance with any of the embodiments described herein in connection with the compounds of the invention.

[0532] In another aspect, the radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, can be employed in combination therapies, in accordance with any of the embodiments described herein in connection with the compounds of the invention. EXAMPLES

[0533] General methods.1H NMR (400 MHz) spectra were obtained as solutions in an appropriate deuterated solvent such as dimethyl sulfoxide-d6(DMSO-d6).

[0534] Analytical supercritical fluid chromatography (SFC) separation of various isomeric mixtures was accomplished using a Waters UPC2-SFC instrument comprising a convergence manager, a sample manager, a binary solvent manager, a column manager-30S, a PDA detector, an isocratic solvent manager and a QDa detector. Columns used include those by manufactured by Regis Technologies (e.g., R’R Whelk 0-1, 3.5µm particle size, 5.0 cm x 3.0 mm size) with a mobile phase of Solvent A: liquid CO2(58-60 bar / 40 °C) Solvent B: methanol HPLC grade with 20mM NH3at a flow rate of 2ml / min and an injection volume of 2µl. Gradient: at 0 min (95:5) A:B, at 3.5 min (50:50) A:B, at 3.55 min (40:60) A:B, at 3.95 min (40:60) A:B and at 4.0min (95:5) A:B. Samples for analytical SFC were dissolved in methanol at approximately 0.5mg / ml concentration.

[0535] Preparative SFC used the same stationary and mobile phases as those described above for analytical SFC but the samples were purified using a different instrument and gradient method asfollows. Preparative SFC separation of various isomeric mixtures was accomplished using a Waters Prep-100 SFC instrument comprising a Back Pressure Regulator, a 2767 Sample Manager, a 2545 Quarternary Gradient Module, a Column Oven, a 2998 PDA detector, an Isocratic Solvent Manager, a P- 200 CO2 pump, SFC Flow Splitter-100, 3 Heat exchangers, a Series III LC pump and a QDa detector. Columns used include those manufactured by Regis Technologies (e.g., R’R Whelk 0-1, 5.0µm particle size, 25.0 cm x 21.1 mm size) with a mobile phase of Solvent A: liquid CO2(58-60 bar / 40 °C) Solvent B: methanol HPLC grade with 20mM NH3at a flow rate of 100ml / min and an injection volume of 500µl (50mg crude loading), 2:1 ratio of methanol to dichloroethane was used for solubilization and SFC injection of crude compound. For injection 500µl / 50mg loading the following method was used: Isocratic: at 0 min to 7.6min (80:20) A:B, Gradient: at 8.1min (75:25) A:B, Isocratic at 8.2 to 10.6min (75:25) (A:B), Gradient: at 10.7min (80:20) A:B and Isocratic: at 11min (80:20) (A:B). For injection 1500µl / 150mg loading the following method was used: Isocratic: at 0 min to 7.5min (80:20) A:B, Gradient: at 7.6min (75:25) A:B, Gradient: at 8.1min (60:40) A:B, Isocratic: at 8.7min to 10.6min (60:40) A:B, Gradient: at 10.7min (80:20) A:B and Isocratic: at 12min (80:20) A:B.

[0536] LC / MS Method: LC / MS analysis was conducted using an Acquity UPLC BEH C8column (50 × 2.1 mm, 1.7 μm particle) made by Waters (pn: 186002877) with a (2.1 × 5 mm, 1.7 μm particle) guard column (pn: 186003978), and a dual gradient run from 2-98% mobile phase B over 4.45 minutes. Mobile phase A = H2O (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 at room temperature in transmission mode 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 operated at a voltage of 45 kV and a current of 40 mA with copper radiation (1.54060 Å). The powder sample was placed on a 96 well sample holder with mylar film and loaded into the instrument. The sample was scanned over the range of about 3° to about 40°2θ with a step size of 0.0131303° and 49s per step.

[0538] Solid state NMR analysis was conducted on a Bruker-Biospin 400 MHz wide-bore spectrometer equipped with Bruker-Biospin 4mm HFX probe was used. Samples were packed into 4mm ZrO2rotors and spun under Magic Angle Spinning (MAS) condition with spinning speed typically set to 12.5 kHz. The proton relaxation time was measured using1H MAS T1saturation recovery relaxationexperiment in order to set up proper recycle delay of the13C cross-polarization (CP) MAS experiment. The fluorine relaxation time was measured using19F MAS T1saturation recovery relaxation experiment in order to set up proper recycle delay of the19F MAS experiment. The CP contact time of carbon CPMAS experiment was set to 2 ms. A CP proton pulse with linear ramp (from 50% to 100%) was employed. The carbon Hartmann-Hahn match was optimized on external reference sample (glycine). Both carbon and fluorine spectra were recorded with proton decoupling using TPPM15 decoupling sequence with the field strength of approximately 100 kHz.

[0539] Thermogravimetric analysis (TGA) data were collected on a TA Discovery Thermogravimetric Analyzer or equivalent instrumentation. A sample with weight of approximately 1-5 mg was scanned from 25 °C to 350 °C at a heating rate of 10 °C / min. Data were collected by Thermal Advantage Q SeriesTM software and analyzed by 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 instrumentation. A sample with a weight between 1 and 10 mg was weighed into an aluminum pan. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. The heating program was set to heat the sample at a heating rate of 10° C / min to a temperature of 300° C. When the run was completed, the data were analyzed by 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 acquired on a Bruker diffractometer equipped with Cu Kαradiation (λ=1.5478 Å) and a CCD detector. The structure was solved and refined using SHELX programs (Sheldrick, G.M., Acta Cryst., (2008) A64, 112-122). Abbreviations

[0543] Unless otherwise noted, or where the context dictates otherwise, the following abbreviations shall be understood to have the following meanings: Abbreviation Meaning NMR Nuclear magnetic resonance ESI-MS Electrospray mass spectrometry LC / MS Liquid chromatography-mass spectrometryUPLC Ultra 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 auto purification ESI Electrospray ionization LED Light-emitting diode g grams mg milligrams L Liter(s) mL Milliliters μL Microliters nL nanoliters mmol millimoles hr, h hours min Minutes ms millisecond mm Millimeters μm Micrometers nm nanometer MHz Megahertz Hz Hertz N Normal (concentration) M Molar (concentration) mM Millimolar (concentration) μM Micromolar (concentration) ppm Parts per million % w / v Weight-volume concentration ArBPin 2-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane t-BuOH tert-butyl alcohol DAST Diethylaminosulfur trifluoride DCM Dichloromethane DCE Dichloroethane DIEA, DIPEA N, N-Diisopropyl ethyl amine DMA N,N-Dimethylacetamide DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DRG Dorsal root ganglia EtOH Ethanol EtOAc Ethyl acetate HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide T3P Propylphosphonic anhydride, i.e., 2,4,6-tripropyl-1,3,5,2,4,6- trioxatriphosphinane 2,4,6-trioxideTCFH 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. Circa (approximately) E-VIPR Electrical stimulation voltage ion probe reader HEK Human embryonic kidney KIR2.1 Inward-rectifier potassium ion channel 2.1 DMEM Dulbecco's Modified Eagle's Medium FBS Fetal bovine serum NEAA Non-essential amino acids HEPES 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid DiSBAC6(3) Bis-(1,3-dihexyl-thiobarbituric acid) trimethine oxonol CC2-DMPE Chlorocoumarin-2-dimyristoyl phosphatidylethanolamine VABSC-1 Voltage Assay Background Suppression Compound HS Human serum BSA Bovine Serum AlbuminExample 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)

[0544] 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 (16 mL of 2 M, 32.00 mmol) in dioxane (60 mL) was heated at 100 °C for 1 hour. The solution was diluted in EtOAc and water, the layers separated and the organic layer washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (220 g SiO2, 0 to 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%).1H 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 calc.398.09528, found 399.0 (M+1)+.

[0546] Step 2:

[0547] Magnesium filings (3.5 g, 144.0 mmol) were ground 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 finished (30 mins). The reaction was then heated at 90 °C for 3 hours before being cooled to 0 °C and quenched and acidified by careful addition of 2 M HCl. The mixture was concentrated in vacuo and extracted with DCM (3 x 100 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo 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 at the position adjacent to the ester (stereochemical assignments tentative). ESI-MS m / z calc.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 KOt-Bu (4.25 g, 37.87 mmol). The reaction was stirred at ambient temperature overnight then quenched by addition of saturated aqueous NH4Cl solution and diluted with EtOAc. The aqueous layer was separated and extracted with EtOAc and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in EtOH (20 mL) and LiOH (15 mL of 2 M, 30.00 mmol) and the mixture stirred at 110 °C for 1 hour. The reaction was quenched by addition of saturated aqueous NH4Cl solution and diluted with EtOAc. The aqueous layer was separated and extracted with EtOAc and the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography (80 g SiO2, 0 to 100% EtOAc in heptanes) gave 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 at the position adjacent to the ester (stereochemical assignments tentative). ESI-MS m / z calc.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) stirring at 0 °C was added DMF (50 µL, 0.65 mmol) and oxalyl chloride (400 µL, 4.59 mmol). The reaction was warmed to ambient temperature over 30 mins then concentrated in vacuo. The residue was further dried on a high-vacuum apparatus for 5 mins 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 NEt3(800 µL, 5.74 mmol) in DCM (9 mL) with stirring at 0 °C. The reaction was warmed to ambient temperature over 4 hours, then quenched by addition of MeOH (2 mL) and concentrated in vacuo. Purification by flash chromatography (12 g SiO2, 0 to 70% EtOAc in heptane, loaded in DCM) gave 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 a 85:15 mixture of epimers at the position adjacent to the amide (stereochemical assignments tentative). ESI-MS m / z calc.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 (15 mL of 7 M, 105.0 mmol) was stirred in a sealed vessel at 100 °C for 16 hours. The solution was concentrated in vacuo 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 at the position adjacent to the amide (stereochemical assignments tentative). ESI-MS m / z calc.491.12796, found 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, 0.81mmol) by chiral SFC using a Chiralpak IC column, 5um particle size, 25 cm x 20 mm from Daicel gave:

[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 assignments 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 calc.491.12796, found 492.2 (M+1)+; 490.3 (M-1)-.

[0557] Second Eluting Isomer (rt = 4.28 min): The second eluting isomer was purified further by reverse phase preparative HPLC (basic eluent) to give 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 assignments 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 calc.491.12796, found 492.1 (M+1)+.

[0558] The following compound was made using a similar method to that described in Example 1, but no SFC separation step 6 was carried out at the end of the synthesis, and the compound was isolated as a racemate:

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

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

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

[0562] The following compounds were made 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 the addition of LiOH / EtOH in step 3. The purification in step 6 was conducted by SFC using a DEAP column, 5µm particle size, 25 cm x 21.2 mm from Princeton Chromatography Inc. on an SFC 100instrument from Waters Corp., followed by chiral SFC using a Chiralpak AS-H column, 5µm particle size, 25 cm x 10 mm from Daicel on a Minigram SFC instrument from Berger Instruments. Compound 3a was purified further by chiral SFC using a Chiralpak OD-H column, 5µm particle size, 25 cm x 10 mm from Daicel on a Minigram SFC instrument from Berger Instruments. Compounds 38 and 39 were separated by chiral SFC using a (R,R)-Whelk-O1 column, 5 µm particle size, 25 cm x 21.2 mm from Regis Technologies:

[0563] The following compounds were made 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 the addition of LiOH / EtOH in step 3. The purification in step 6 was conducted by SFC using a LuxCellulose-2 column, 5µm particle size, 25 cm x 10 mm from Phenomenex on an SFC 100 instrument from Waters Corp., on a Minigram SFC instrument from Berger Instruments:

[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 an activating agent rather than oxalyl chloride. The purification in step 6 was conducted by SFC using a Lux i-Cellulose-5 column, 5µm particle size, 25 cm x 10 mm from Phenomenex on an SFC 100 instrument from Waters Corp., on a Minigram SFC instrument from Berger Instruments:

[0565] The following compounds were made using a method similar to that described in Example 1, except that methylamine was used in place of ammonia in Step 5. In step 6, purification was performed by chiral SFC using a Chiralpak AS-H column, 5µm particle size, 25 cm x 10 mm from Daicel on a Minigram SFC instrument from Berger Instruments: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)

[0566] Step 1:

[0567] To a solution of ethyl 2-diazo-3-oxo-butanoate (5.0 g, 31.4 mmol) in DCM (50 mL) stirring at 0 °C was added triethylamine (8.05 g, 11.2 mL, 78.8 mmol). TBSOTf (9.24 g, 8.2 mL, 34.3 mmol) was added slowly and the reaction mixture was stirred for 30 mins at 0 °C. The reaction mixture was washed with 30% NaHCO3solution (200 mL). The organic layer was separated and washed with water (500 mL) then dried over MgSO4. 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 TiCl4(56.8 g, 33 mL, 299.2 mmol) was added dropwise. The reaction was kept at -78 °C for 10 min before 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 kept at -78 °C for 1 hour then a saturated solution of NaHCO3was added and the mixture diluted with DCM. The organic layer was dried over MgSO4, concentrated in vacuo and the residue purified by column chromatography (0 to 30% EtOAc in hexane) to give ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-5-methyl-3-oxo-hexanoate (39 g, 61%) as a pale yellow liquid.1H NMR (400 MHz, Chloroform-d) δ 4.92 (s, 1H), 4.32 (q, J = 7.1 Hz, 2H), 3.63 (d, J = 15.5 Hz, 1H), 2.84 (d, J = 15.5 Hz, 1H), 1.41 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H) ppm.

[0570] Step 3:

[0571] Rhodium (II) acetate (643 mg, 1.45 mmol) was charged into an oven dried two necked flask. Toluene (970 mL) was added and the solution was stirred at 100 °C for 10 mins. The solution was briefly lifted out of the oil bath whilst a solution of ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-5-methyl-3- oxo-hexanoate (39 g, 145.4 mmol) in a toluene (200 mL) was added dropwise, and the reaction was heated at reflux for 1 hr. The reaction mixture was filtered through filter paper and the filtrate was concentrated in vacuo to give ethyl 5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (30.89 g, 88%).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 and the reaction stirred for 2.5 hours before saturated aqueous NH4Cl (75 mL) was added. The mixture was warmed to ambient temperature, the layers separated, and the aqueous layer extracted with DCM (2 x 30 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give 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 K3PO4(13 mL of 2 M aq., 26.0 mmol). The mixture was degassed with N2for 20 mins before Pd(PPh3)4(466 mg, 0.40 mmol) was added and then heated to 100 °C for 1 h. The mixture was filtered by celite pad, the filtrate diluted with water (50 mL) and the aqueous layer extracted with EtOAc (50 x 2 mL). The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (SiO2, 0-2% EtOAc in hexane) to give ethyl 4-(3,4- difluoro-2-methoxy-phenyl)-2-methyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (2.5 g, 85%) as a light- yellow liquid.1H NMR (400 MHz, Chloroform-d) δ 6.87 (pd, J = 8.8, 6.2 Hz, 2H), 4.15 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.42 (d, J = 17.4 Hz, 1H), 2.93 (d, J = 17.4 Hz, 1H), 1.65 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H) ppm. ESI-MS m / z calc.366.089, found 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 H2for 96 hours. The catalyst was removed by filtration, the solids washed with EtOH (50 mL) and the filtrate concentrated in vacuo. A further 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 stirred under a balloon of H2at ambient temperature for 24 hours. The catalyst was removed by filtration, the solids washed with EtOH (50 mL) and the filtrate concentrated in vacuo. A further 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 stirred under a balloon of H2at ambient temperature for 4 days. The catalyst was removed by filtration, the solids washed with EtOH (50 mL) and the filtrate concentrated in vacuo 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.1H NMR (500 MHz, Chloroform-d) δ 6.89 - 6.86 (m, 1H), 6.82 - 6.77 (m, 1H), 4.93 (d, J = 8.9 Hz, 1H), 4.23 (dt, J = 13.0, 7.6 Hz, 1H), 4.08 (d, J = 2.9 Hz, 3H), 3.85 - 3.71 (m, 2H), 2.82 (t, J = 12.5 Hz, 1H), 2.04 (dd, J = 12.0, 6.7 Hz, 1H), 1.53 (s, 3H), 0.94 (t, J = 7.1 Hz, 3H) ppm;19F NMR (471 MHz, Chloroform-d) δ -80.15, -136.84 (d, J = 19.4 Hz), -154.77 (d, J = 19.6 Hz) ppm.

[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 stirred at 50 °C for 2 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between 1M HCl and MTBE. The layers were separated and the aqueous layer was extracted twice with MTBE. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give rac-(2R,3S,5R)-3-(3,4-difluoro-2- methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (5.11 g, 96%) as a colourless oil, as a single diastereomer.1H NMR (500 MHz, Chloroform-d) δ 6.99 - 6.96 (m, 1H), 6.92 - 6.87 (m, 1H), 4.68 (d, J = 10.5 Hz, 1H), 4.00 (d, J = 2.7 Hz, 3H), 3.90 (ddd, J = 12.0, 10.6, 8.2 Hz, 1H), 2.58 (t, J = 12.5 Hz, 1H), 2.31 (dd, J = 13.0, 8.2 Hz, 1H), 1.60 (s, 3H) ppm;19F NMR (471 MHz, Chloroform-d) δ -81.56, -136.40 (d, J = 19.6 Hz), -153.60 (d, J = 19.5 Hz) ppm. ESI-MS m / z calc. 340.0734, found 339.5 (M-1)-.

[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 hours, allowing it to warm to ambient temperature before further oxalyl chloride (300 µL, 3.55 mmol) was added. The reaction was stirred for a further hour before being concentrated in vacuo. The residue was dissolved in DCM (30 mL) and the solution 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 resultant mixture stirred for 30 mins before being quenched with MeOH and concentrated in vacuo. Purification by flash chromatography (40 g SiO2, 0 to 60% ethyl acetate in heptane, loaded in DCM) gave 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%).1H 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 calc.474.1214, found 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 methanolic ammonia (20 mL of 7 M, 140.0 mmol) and the reaction stirred at ambienttemperature overnight. Additional methanolic ammonia (5 mL of 7 M, 35.0 mmol) was added and reaction stirred at ambient temperature for a further 3 hrs before being concentrated in vacuo 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%).1H 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 calc.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 (R,R)-Whelk-O1 column, 5µm particle size, 25 cm x 21.2 mm from Regis Technologies 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 calc.459.12173, found 460.2 (M+1)+and 458.3 (M-1)-.1H 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 calc.459.12173, found 460.2 (M+1)+and 458.3 (M-1)-.1H 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 compounds were made using a method similar to that described Example 2, except that 5-amino-2-fluorobenzamide was used as coupling partner in step 8, and step 9 was omitted: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)

[0589] 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) with stirring at 0 °C under nitrogen. Trimethylsilyl trifluoromethanesulfonate (8.5 mL, 47.0 mmol) was added dropwise over 5 mins and the mixture was stirred for a further 30 mins at 0 °C. The reaction mixture was diluted with pentane (100 mL), the layers separated and the organic phase washed with dilute aqueous sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was dried (MgSO4), and concentrated in vacuo to give ethyl (Z)-2-diazo-3- trimethylsilyloxy-pent-3-enoate (9.4 g, 99%) as a red oil.1H NMR (500 MHz, Chloroform-d) δ 5.33 (q, J = 7.0 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 1.67 (d, J = 7.0 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 0.22 (s, 9H) ppm.

[0591] Step 2:

[0592] To a solution of 1,1,1-trifluoropropan-2-one (8 mL, 89.4 mmol) in DCM (80 mL) stirring at -78 ºC was added TiCl4(70 mL of 1 M in DCM, 70.00 mmol) via cannula. To the resulting solution, a solution of ethyl (Z)-2-diazo-3-trimethylsilyloxy-pent-3-enoate (36.1 g of 31.3 %w / w, 46.6 mmol) in 40 mL of DCM was added dropwise over 15 mins. After 100 mins the reaction was carefully quenched with water, allowing the temperature to rise slowly, and then extracted with DCM. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography (330 g SiO2, 0 to 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 solution in toluene.1H NMR (500 MHz, Chloroform-d) δ 4.33 (q, J = 7.1 Hz, 2H), 4.14 (q, J = 7.0 Hz, 1H), 3.98 (s, 1H), 1.43 (q, J = 1.2 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H), 1.31 (dq, J = 7.0, 1.4 Hz, 3H) ppm. ESI-MS m / z calc. 282.08273, found 283.1 (M+1)+; 281.0 (M-1)-.

[0593] Step 3:

[0594] A solution of rhodium tetraacetate (245 mg, 0.55 mmol) in benzene (32 mL) was heated at reflux for 10 min before a solution of ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxo- hexanoate (10 g, 35.4 mmol) in benzene (13 mL) was added slowly via addition funnel while refluxing for 60 mins. The mixture was then concentrated in vacuo to give ethyl rac-(4R,5R)-4,5-dimethyl-3-oxo- 5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (9.0 g, 100%) as a green coloured residue containing residual catalyst, and as a mixture of epimers at the position next to the ester. This material was used without further purification.1H NMR (500 MHz, Chloroform-d) δ 4.83 - 4.57 (m, 1H), 4.38 - 4.16 (m, 2H), 2.60 (dddd, J = 9.3, 8.2, 5.6, 1.4 Hz, 1H), 1.73 - 1.63 (m, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.24 (ddq, J = 6.4, 4.1, 1.9 Hz, 3H) ppm.

[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) stirring at -78 °C was added DIPEA (29.680 g, 40 mL, 229.64 mmol). A solution of trifluoromethylsulfonyl trifluoromethanesulfonate (53.440 g, 32 mL, 189.41 mmol) in DCM (200 mL) was added to the reaction mixture at the same temperature over 1h. The reaction mixture was stirred for 30 mins at 0 °C before being quenched with 100 mL saturated aqueous NaHCO3solution. The organic layer was separated and aqueous layer extracted with DCM (160 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give ethyl rac-(4R,5R)-2,3-dimethyl-2-(trifluoromethyl)-4- (trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (71 g, 97%).1H NMR (400 MHz, Chloroform-d) δ 4.38-4.32 (m, 2H), 3.29-3.23 (m, 1H), 1.64 (s, 3H), 1.37-1.33 (m, 6H) ppm.

[0597] Step 5:

[0598] To stirred a solution of ethyl rac-(4R,5R)-2,3-dimethyl-2-(trifluoromethyl)-4- (trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (26 g, 67.311 mmol) in toluene (130.00 mL) was added (3,4-difluoro-2-methoxy-phenyl)boronic acid (14 g, 74.5 mmol) followed by K3PO4(100 mL of 2 M, 200.00 mmol) under an argon atmosphere. The reaction was degassed before tetrakis(triphenylphosphine)palladium(0) (4 g, 3.46 mmol) was added. After further degassing, the reaction was heated at 100 °C for 2 hours. The reaction was diluted in water and the aqueous layer extracted with EtOAc (2 x100 mL). The combined organic layers were concentrated in vacuo. Purification by flash chromatography (SiO2, 0 to 10% EtOAc in heptane) gave ethyl 4-(3,4-difluoro-2- methoxy-phenyl)-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (24.4 g, 93%) as a 6:1 diastereomeric mixture, with the major isomer believed to be ethyl rac-(4R,5R)-4-(3,4-difluoro-2- methoxy-phenyl)-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate. Major isomer:1H NMR (400 MHz, Chloroform-d) δ 6.88 - 6.79 (m, 2H), 4.17 - 4.09 (m, 2H), 3.90 (s, 3H), 3.46 (q, J = 7.4 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 isomer1H NMR (400 MHz, Chloroform-d) δ 6.88 - 6.79 (m, 2H), 4.17-4.09 (m, 2H), 3.88(s, 3H), 3.76-3.71(m, 1H), 1.51 (s, 3H), 1.12 (t, J = 7.4 Hz, 3H), 0.99 (dd, J = 5.4, 2.7 Hz, 3H) ppm. ESI-MS m / z calc.380.1047, found 381.02 (M+1)+.

[0599] Step 6:

[0600] To an ice-cooled 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 BBr3(370mL of 1 M, 370.0 mmol) dropwise. Upon completion the mixture was quenched by addition of water and aqueous sodium bicarbonate solution, the aqueous layer extracted with DCM and the combined organic layers dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (430 mL) at ambient temperature and TFA (40 mL, 519.2 mmol) was added, then the reaction was heated to 45 ºC. Upon completion, the mixture was quenched by addition of aqueous sodium bicarbonate solution and the aqueous layer extracted with DCM, dried (MgSO4) and concentrated in vacuo to give the desired product in a 5:1 mixture of diastereomers. Recrystallization was carried out by solubilizing the crude in the smallest possible amount of DCM and adding a layer of heptane on top of this solution (liquid-liquid diffusion). After approx.1 hour, 56.5 g (d.r.97:3 syn:anti) from the first and second crystallization was obtained, and a further 4.6 g (d.r.96:4 syn:anti) from the third crystallization was obtained. The first to third batches were combined to give 6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1H-furo[2,3- c]chromen-4-one (61 g, 78%), with the major isomer believed to be rac-(1S,2R)-6,7-difluoro-1,2- dimethyl-2-(trifluoromethyl)-1H-furo[2,3-c]chromen-4-one. ESI-MS m / z calc.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 of substrate) at ambient temperature for 4 hours and 30 minutes. The mixture was filtered through a pad of celite, washing with EtOAc. The filtrate was concentrated in vacuo to give a white solid. The white solid was suspended in MeOH (600 mL) and added to a suspension of Pd(OH)2(13.62 g of 20% w / w, 19.40 mmol) in MeOH (150 mL) in a 2.25 L Parr bottle. The resulting mixture was shaken in the Parr hydrogenator under a hydrogen pressure of 60 psi overnight. The suspension was filtered through celite under a nitrogen atmosphere, rinsed with MeOH and then with EtOAc, and the resulting filtrate was concentrated in vacuo 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%).1H 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 = 8.4, 6.0 Hz, 1H), 3.49 (s, 3H), 3.01 - 2.86 (m, 1H), 1.50 (q, J = 1.2 Hz, 3H), 0.89 (dq, J = 7.6, 1.9 Hz, 3H) ppm. ESI-MS m / z calc.354.08905, found 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 mins, keeping the internal temperature below 10 °C. The mixture was stirred at 0 °C for a further 5 min, and then the mixture was warmed slightly. When the temperature had reached 13 °C, the reaction was cooled down again with an ice bath before adding 2 M HCl (365 mL, to pH 1), keeping 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 in vacuo 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%).1H 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 calc.340.0734, found 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 K2CO3(82.6 g, 597.7 mmol) and MeI (37 mL, 594.3 mmol). The reaction was heated to 80 °C (internally temperature reached 61 °C) for 5 hours before being cooled to ambient temperature and diluted with DCM (350 mL). The mixture was filtered, washing the filter cake with more DCM (350 mL) and the filtrate was concentrated in vacuo to give methyl rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy- phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (64.7 g, 100%) as an orange oil containing some residual K2CO3. This material was used in the next step without further purification.1H NMR (400 MHz, Chloroform-d) δ 6.91 (ddd, J = 7.6, 5.7, 1.9 Hz, 1H), 6.85 (td, J = 9.1, 7.2 Hz, 1H), 4.91 (d, J = 10.2 Hz, 1H), 4.13 (dd, J = 10.2, 8.0 Hz, 1H), 4.00 (d, J = 2.7 Hz, 3H), 3.71 (s, 3H), 2.72 (p, J = 7.7 Hz, 1H), 1.62 (q, J = 1.2 Hz, 3H), 0.76 (dq, J = 7.5, 2.4 Hz, 3H) ppm.

[0607] Step 10:

[0608] Methyl rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylate (63.2 g, 171.6 mmol) was dissolved in MeOH (500 mL) and water (300 mL). LiOH.H2O (14.8882 g, 354.8 mmol) was added and the resultant mixture stirred at ambient temperature for 2 hours. The MeOH was removed in vacuo and the mixture was diluted in MTBE (320 mL). 2 M HCl (440 mL) was added to reach pH 1, the layers were separated and the aqueous layer extracted twice with MTBE (100 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to give rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (60.3 g, 99%) as an orange oil.1H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 7.40 - 6.82 (m, 2H), 4.96 (dd, J = 15.5, 10.5 Hz, 1H), 4.08 (dd, J = 10.4, 7.6 Hz, 1H), 3.93 (d, J = 2.2 Hz, 3H), 2.67 (p, J = 7.7 Hz, 1H), 1.59 - 1.49 (m, 3H), 0.77 - 0.63 (m, 3H) ppm. ESI-MS m / z calc.354.08905, found 353.1 (M-1)-.

[0609] Step 11:

[0610] To a solution of rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (158.6 g, 447.7 mmol) and DMF (135 µL, 1.74 mmol) in DCM (1.5 L) stirring at 0 °C under nitrogen was added oxalyl chloride (79 mL, 905.6 mmol) via dropping funnel, over 30 mins. Halfway through addition the ice bath was removed and the mixture allowed to warm ambient temperature over the remainder of the addition. The mixture was stirred at ambient temperature for a further 1 hour before being evaporated in vacuo. The residue was dissolved in DCM (700 mL) and added via dropping funnel to a solution of methyl 4-aminopyridine-2-carboxylate (81.5 g, 535.7 mmol), DMF (135 µL, 1.744 mmol) and Et3N (95 mL, 681.6 mmol) in DCM (780 mL) stirring at -10 °C. The rate of addition was controlled so as to keep internal temperature below 5 °C (~15 mins). Following addition, the mixture was diluted in water (600 mL), the layers were separated and the aqueous phase was further extracted with DCM (100 mL). Solid formed at the interface between the layers and was collected by filtration to provide filtered desired product (43.2g). The filtrate was washed further with water (600 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was suspended in MeOH (360 mL) and stirred rapidly for 20 mins. The mixture was filtered and the solid washed with MeOH and dried under vacuum for 30 mins. This material was combined with the previously obtained product to give methyl rac-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)- 4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (166.2 g, 76%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.57 (d, J = 5.4 Hz, 1H), 8.36 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 5.5, 2.2 Hz, 1H), 7.16 (qd, J = 9.2, 6.3 Hz, 2H), 5.11 (d, J = 10.1 Hz, 1H), 4.25 (dd, J = 10.2, 7.7 Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 3.87 (s, 3H), 2.77 (p, J = 7.6 Hz, 1H), 1.61 (s, 3H), 0.81 - 0.65 (m, 3H) ppm. ESI-MS m / z calc.488.13705, found 489.6 (M+1)+; 487.6 (M-1)-.

[0611] Step 12:

[0612] Methanolic ammonia (3 L of 7 M, 21.00 mol) was added to methyl rac-(2R,3S,4S,5R)-4- [[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carbonyl]amino]pyridine-2-carboxylate (166 g, 339.9 mmol) and the reaction stirred at ambient temperature overnight. The mixture was concentrated in vacuo to give rac-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine- 2-carboxamide (173 g) as an off-white solid, which was used in the next step without further purification. ESI-MS m / z calc.473.1374, found 474.6 (M+1)+; 472.6 (M-1)-.

[0613] Step 13:

[0614] rac-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (670 mg, 1.415 mmol) was purified by chiral SFC (using a (R’R) Whelk O-1 column, 3-5 µm particle size, 5.0 cm x 3.0 mm from Regis Technologies with Solvent A: liquid CO2[58-60 bar / 40 °C; Solvent B: methanol HPLC grade with 20 mM NH3on a UPC2-SFC instrument from Waters Corp.) to give:

[0615] First Eluting Isomer: (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, 198 mg):1H NMR (500 MHz, Methanol-d4) δ 8.52 (d, J = 5.5 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 7.94 (dd, J = 5.5, 2.2 Hz, 1H), 7.16 (ddd, J = 8.2, 5.6, 2.3 Hz, 1H), 7.02 (ddd, J = 9.9, 8.9, 7.5 Hz, 1H), 5.12 (d, J = 10.4 Hz, 1H), 4.37 (dd, J = 10.4, 8.0 Hz, 1H), 4.03 (d, J = 2.2 Hz, 3H), 2.84 (p, J = 7.6 Hz, 1H), 1.70 (d, J = 1.1 Hz, 3H), 0.86 (dq, J = 7.4, 2.4 Hz, 3H) ppm. ESI-MS m / z calc.473.1374, found 474.6 (M+1)+; 472.7 (M-1)-.

[0616] Second Eluting Isomer: (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, 195 mg):1H NMR (500 MHz, Methanol-d4) δ 8.39 (d, J = 5.5 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.80 (dd, J = 5.5, 2.0 Hz, 1H), 7.02 (ddd, J = 8.2, 5.7, 2.4 Hz, 1H), 6.88 (ddd, J = 9.9, 8.8, 7.5 Hz, 1H), 4.98 (d, J = 10.4 Hz, 1H), 4.23 (dd, J = 10.4, 7.9 Hz, 1H), 3.89 (d, J = 2.2 Hz, 3H), 2.70 (p, J = 7.6 Hz, 1H), 1.56 (d, J = 1.1 Hz, 3H), 0.72 (dq, J = 7.6, 2.4 Hz, 3H) ppm. ESI-MS m / z calc.473.1374, found 474.6 (M+1)+; 472.8 (M-1)-.

[0617] The absolute stereochemistry of 6 and 7 was determined by single-crystal X-ray crystallography of 7.

[0618] Compound 7 – Solid Form A

[0619] Crystallization of Compound 7 in methanol at 60 °C produced a crystalline form of Compound 7, which is referred to herein as Form A. Form A was characterized by XRPD, TGA, and DSC analysis.

[0620] The XRPD pattern of Form A is depicted in Figure 1, and the corresponding data are summarized in the following table:.

[0621] The TGA thermogram of Form A is depicted in Figure 2 and shows negligible weight loss from ambient temperature up until thermal degradation.

[0622] The DSC thermogram of Form A is depicted in Figure 3 and shows a melting onset of 186 °C with a peak at 187 °C.

[0623] Compound 7 – Solid Form B

[0624] Compound 7 was dissolved in ethyl acetate (6 volumes) at 68 °C. The mixture was cooled to 50 °C over 1 hour, and n-heptane (6 volumes) was added over 5 hours. The mixture was then cooled to 20 °C over a further 5 hours and held overnight. The resulting solid material was filtered, washed with heptane (3 volumes), and dried to produce a crystalline form of Compound 7, which is referred to herein as Form B. Form B was characterized by XRPD, solid state NMR (13C and19F), TGA, DSC, IR, and single-crystal X-ray analysis.

[0625] The XRPD pattern of Form B is depicted in Figure 4, and the corresponding data are summarized in the following table:

[0626] The solid state13C NMR spectrum of Form B is depicted in Figure 5, and the corresponding data are summarized in the following table:

[0627] The solid state19F NMR spectrum of Form B is depicted in Figure 6, and the corresponding data are summarized in the following table:

[0628] The TGA thermogram of Form B is depicted in Figure 7 and shows negligible weight loss from ambient temperature up until thermal degradation.

[0629] The DSC thermogram of Form B is depicted in Figure 8 and shows a melting onset of 182 °C with a peak at 183 °C.

[0630] The IR spectrum of Form B is depicted in Figure 9 and includes peaks at 3501, 3356, 1684, 1565, 1505, and 1122 cm-1.

[0631] Crystals having Form B were grown for single-crystal X-ray analysis by dissolving 1 mg of Compound 7 material in 500 μL of ethanol, which was allowed to evaporate slowly over several days. The thermal ellipsoid plot, at 50% probability, is depicted in Figure 10, and the unit cell parameters are reported in the following table:

[0632] The following compounds were made using a similar method to that of Example 3 and were separated by chiral SFC using a (R,R)-Whelk-O1 column, 5 µm particle size, 25 cm x 21.2 mm from Regis Technologies :Compound 9 – Solid Form A

[0633] A crystalline form of Compound 9, referred to herein as Form A, was obtained and was characterized by single-crystal X-ray analysis. Crystals having Form A were grown for single-crystal X- ray analysis by dissolving ~1 mg of Compound 9 material in 350 µL of 10 / 90 dichloromethane / dichloroethane solution, which was then vapor diffused with pentane over several days. The thermal ellipsoid plot, at 50% probability, is depicted in Figure 11, and the unit cell parameters are reported in the following table:

[0634] The following compound was made from (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy- phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid, which can be obtained by separating the enantiomers of the 6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1H-furo[2,3-c]chromen- 4-one obtained in Step 6 using the SFC conditions described in Step 1 of Example 23, and using the resulting optically pure material in steps 7 and 8 of Example 3, by a method similar to that described in Steps 9-12 of Example 3, using CD3I in place of MeI in Step 9:

[0635] The following compounds were prepared by methods similar to the methods described herein:Example 4 (2S,3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (10) and (2R,3S,4S,5R)-4- [[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carbonyl]amino]pyridine-2-carboxamide (11)

[0636] Step 1:

[0637] 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 (9.30 g, 27.33 mmol, prepared as described in Example 3, Step 8) in DCM (50 mL) stirring at 0 ºC was added a solution of KOH (18.4 g, 328.0 mmol) in H2O (50 mL) and the solution stirred vigorously. [Bromo(difluoro)methyl]-trimethyl-silane (22.5 g, 110.8 mmol) was added and stirring continued at this temperature. Upon complete consumption of starting material, the mixture was acidified by addition of 1 N HCl, extracted with DCM and concentrated in vacuo. The resultant oil was dissolved in tert-butanol (50 mL) at ambient temperature and KOt-Bu (7.5 g, 66.84 mmol) was added. After complete conversion the mixture was acidified with 1 N HCl, diluted with DCM, the layers separated and the aqueous layer extracted. The organic phase was washed with water concentrated in vacuo to give rac-(2R,3S,4S,5R)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]- 4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (10.10 g, 95%) which was used without further purification.

[0638] Step 2:

[0639] To an ice-cooled solution of rac-(2R,3S,4S,5R)-3-[2-(difluoromethoxy)-3,4-difluoro- phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (10.10 g, 25.88 mmol) in DCM (100 mL) stirring at 0 °C, DMF (400 µL, 5.17 mmol) and oxalyl chloride (4.85 mL, 55.60 mmol) were added. The mixture was warmed to ambient temperature over 30 min before being concentrated in vacuo. The solids were dissolved in DCM (80 mL) and DMF (400 µL, 5.17 mmol) and the solution added to an ice cooled solution of methyl 4-aminopyridine-2-carboxylate (4.05 g, 26.62 mmol) and NEt3(4.5 mL, 32.29 mmol) in DCM (80 mL). The reaction was warmed to ambient temperature over 2 hours then quenched by addition of water (1 drop) and MeOH (2 mL) and concentrated in vacuo. Purification by flash chromatography (4 g SiO2, 0 to 100% EtOAc in petroleum ether) gave methyl rac- (2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (5.4 g, 40%). ESI-MS m / z calc.524.1182, found 523.6 (M-1)-.

[0640] Step 3:

[0641] Methyl rac-(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl- 5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (5.50 g, 10.49 mmol) was dissolved in MeOH (300 mL) and methanolic ammonia (300 mL of 3.37 M, 1.01 mol) and stirred at ambient temperature overnight before the reaction mixture was concentrated in vacuo to afford rac- (2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (115, 5.18 g, 97%).1H NMR (500 MHz, Methanol-d4) δ 8.38 (d, J = 5.6 Hz, 1H), 8.15 (d, J = 2.1 Hz, 1H), 7.79 (dd, J = 5.5, 2.2 Hz, 1H), 7.23 - 7.10 (m, 2H), 6.83 (td, J = 73.1, 1.0 Hz, 1H), 4.99 (d, J = 10.3 Hz, 1H), 4.27 (dd, J = 10.4, 8.1 Hz, 1H), 2.73 (p, J = 7.7 Hz, 1H), 1.56 (d, J = 1.2 Hz, 3H), 0.78 - 0.72 (m, 3H) ppm. ESI-MS m / z calc. 509.11856, found 510.5 (M+1)+; 508.6 (M-1)-.

[0642] Step 4:

[0643] Purification of rac-(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (82 mg, 0.1562 mmol) by chiral SFC [System: (R,R)-Whelk-O1 column, 5 µm particle size, 25 cm x 21.2 mm from Regis Technologies, MeOH, 20 mM NH3] gave:

[0644] First Eluting Isomer: (2S,3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]- 4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (10, 23 mg).1H NMR (500 MHz, Methanol-d4) δ 8.53 (d, J = 5.5 Hz, 1H), 8.30 (dd, J = 2.2, 0.6 Hz, 1H), 7.93 (dd, J = 5.5, 2.2 Hz, 1H), 7.40 - 7.23 (m, 2H), 6.97 (td, J = 73.1, 1.0 Hz, 1H), 5.14 (d, J = 10.4 Hz, 1H), 4.41 (dd, J = 10.3, 8.1 Hz, 1H), 2.87 (p, J = 7.7 Hz, 1H), 1.71 (d, J = 1.3 Hz, 3H), 0.94 - 0.81 (m, 3H) ppm. ESI-MS m / z calc.509.11856, found 510.4 (M+1)+; 508.4 (M-1)-.

[0645] Second Eluting Isomer: (2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro- phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (11, 28 mg, 70%).1H NMR (500 MHz, Methanol-d4) δ 8.53 (d, J = 5.5 Hz, 1H), 8.30 (dd, J = 2.2, 0.6 Hz, 1H), 7.93 (dd, J = 5.5, 2.2 Hz, 1H), 7.40 - 7.23 (m, 2H), 6.97 (td, J = 73.1, 1.0 Hz, 1H), 5.14 (d, J = 10.4 Hz, 1H), 4.41 (dd, J = 10.3, 8.1 Hz, 1H), 2.87 (p, J = 7.7 Hz, 1H), 1.71 (d, J = 1.3 Hz, 3H), 0.94 - 0.81 (m, 3H) ppm. ESI-MS m / z calc.509.11856, found 510.4 (M+1)+, 508.4 (M-1)-.

[0646] The absolute stereochemistry of 10 and 11 was determined by single-crystal X-ray crystallography of 11. Compound 11 – Solid Form A

[0647] Compound 11 was suspended in distilled water, the suspension was stirred at 37 °C for 24 hours, at which time the suspension was filter-centrifuged. The resulting solid was dried at 60 °C overnight in a vacuum oven to afford a crystalline form of Compound 11, which is referred to herein as Form A. Form A was characterized by XRPD analysis.

[0648] The XRPD pattern of Form A is depicted in Figure 12, and the corresponding data are summarized in the following table:Compound 11 – Solid Form B

[0649] Compound 11 was recrystallized from acetonitrile and dried overnight to produce a crystalline form of Compound 11, which is referred to herein as Form B. Form B was characterized by XRPD and single-crystal X-ray analysis.

[0650] The XRPD pattern of Form B is depicted in Figure 13, and the corresponding data are summarized in the following table:

[0651] Crystals having Form A were grown for single-crystal X-ray analysis by concentration of a toluene solution of Compound 11. The thermal ellipsoid plot, at 50% probability, is depicted in Figure 14, and the unit cell parameters are reported in the following table: Crystal System: Monoclinic

[0652] The following compounds were made using a method similar to that described in Example 4, except that 5-amino-2-fluorobenzamide was used in place of methyl 4-aminopyridine-2- carboxylate in Step 2, and Step 3 was omitted. In step 4, purification was performed by chiral SFC using a (R,R)-Whelk-O1 column, 5 µm particle size, 25 cm x 21.2 mm from Regis Technologies:

[0653] The following compounds were made using a method similar to that described in Example 4, except that 3-aminobenzamide was used in place of methyl 4-aminopyridine-2-carboxylate in Step 2, and Step 3 was omitted. In step 4, purification was performed by chiral SFC using a Lux Cellulose-2 column, 5 µm particle size, 25 cm x 10 mm from Phenomenex, Inc.:

[0654] The following compound was made using a method similar to that described in Example 4, except that rac-(2R,3S,4S,5R)-3-(2-(difluoromethoxy)-4-fluoro-3-methylphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used as the starting material for step 2. Rac- (2R,3S,4S,5R)-3-(2-(difluoromethoxy)-4-fluoro-3-methylphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid was prepared using methods analogous to those described for other intermediates of this application. The separation of the racemates at step 4 was not carried out and the compound was isolated as a racemate:

[0655] The following compounds were made by separating 53 by chiral SFC (Exampe 4, Step 4) using a Chiralpak AS-H column, 5 µm particle size, 25 cm x 10 mm from Daicel on a Minigram SFC instrument from Berger Instruments:Example 5 (2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide (18)

[0656] To a solution of (2R,3S,4S,5R)-4-[[...

Claims

CLAIMS What is claimed is:

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: X2ais N, N+-O-, or C-R2a; X4ais N, N+-O-, or C-R4a; X5ais N, N+-O-, or C-R5a; X6ais N, N+-O-, or C-R6a; each R is independently H or C1-C6alkyl; R2a, R4a, R5a, and R6aare each independently H, halo, C1-C6alkyl, or C1-C6haloalkyl; R4b1and R4b2are each independently H, C1-C6alkyl, C3-C6cycloalkyl, or C1-C6haloalkyl; R5b1and R5b2are each independently H, C1-C6alkyl, C3-C6cycloalkyl, or C1-C6haloalkyl; X3cis N or C-R3c; X4cis N or C-R4c; X5cis N or C-R5c; X6cis N or C-R6c; R2cis H, OH, halo, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, or –L1-L2-(C3-C6cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo; L1is a bond or O; L2is a bond or C1-C6alkylene; R3cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; R4cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; R5cis H, halo, C1-C6alkyl, or C1-C6haloalkyl; and R6cis H, halo, C1-C6alkyl, or C1-C6haloalkyl;provided that no more than two of X2a, X4a, X5a, and X6aare N or N+-O-; and provided that no more than one of X3c, X4c, X5c, and X6care N.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: X2ais C-R2a; X5ais C-R5a; X6ais C-R6a; R4b1and R4b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl; R5b1and R5b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl; X3cis C-R3c; X4cis C-R4c; X5cis C-R5c; X6cis C-R6c; and R2cis H, OH, halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

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

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

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein X4ais C-R4a; and R4ais H or halo.

6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein X4ais N.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein each R is H or CH3.

8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein each R is H.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein X2ais C-R2a; and R2ais H, halo, or C1-C6alkyl.

10. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein X2ais C-R2a; and R2ais H.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein X5ais C-R5a; and R5ais H, halo, or C1-C6alkyl.

12. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein X5ais C-R5a; and R5ais H.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein X6ais C-R6a; and R6ais H, halo, or C1-C6alkyl.

14. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein X6ais C-R6a; and R6ais H.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R4b1and R4b2are each independently H, C1-C6alkyl, or C3-C6cycloalkyl.

16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R4b1and R4b2are each independently H or C1-C6alkyl.

17. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R4b1and R4b2are each independently H or CH3.

18. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R4b1is C1-C6alkyl, and R4b2is H.

19. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R4b1is H, and R4b2is C1-C6alkyl.

20. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R4b1is CH3, and R4b2is H.

21. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R4b1is H, and R4b2is CH3.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R5b1and R5b2are each independently H, C1-C6alkyl, or C1-C6haloalkyl.

23. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R5b1and R5b2are each independently C1-C6alkyl or C1-C6haloalkyl.

24. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R5b1and R5b2are each independently H, CH3, or CF3.

25. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R5b1is C1-C6alkyl, and R5b2is C1-C6haloalkyl.

26. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R5b1is C1-C6haloalkyl, and R5b2is C1-C6alkyl.

27. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R5b1is CH3, and R5b2is CF3.

28. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R5b1is CF3, and R5b2is CH3.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R2cis OH, C1-C6alkoxy, or C1-C6haloalkoxy.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein X3cis C-R3c.

31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein R3cis H, halo, or C1-C6alkyl.

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein X4cis C-R4c; and R4cis H, halo, or C1-C6haloalkyl.

33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein R4cis halo.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein X5cis C-R5c; and R5cis H or halo.

35. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein R5cis H.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein X6cis C-R6c; and R6cis H or halo.

37. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein R6cis H.

38. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Table A.

39. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Table B or Table C.

40. The compound of any one of claims 1-39.

41. The compound of claim 40, wherein the compound is in crystalline solid form.

42. The compound of claim 40, wherein the compound has formula.

43. The compound of claim 42, wherein the compound is in crystalline solid form.

44. The compound of claim 43, wherein the crystalline solid form is Form A.

45. The compound of claim 44, wherein Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) of 9.9, 13.9, 15.7, and 19.

0.

46. The compound of claim 44 or 45, wherein Form A is characterized by a DSC thermogram having a melting onset of 186 °C with a peak at 187 °C.

47. The compound of claim 43, wherein the crystalline solid form is Form B.

48. The compound of claim 47, wherein Form B is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) of 12.8, 14.1, 15.2, 18.5, and 20.

3.

49. The compound of claim 47 or 48, wherein Form B is characterized by a solid state13C NMR spectrum 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 or a solid state19F NMR spectrum having peaks at chemical shifts of -137.1 and -152.8 ppm.

50. The compound of any one of claims 47-49, wherein Form B is characterized by a DSC thermogram having a melting onset of 182 °C with a peak at 183 °C.

51. The compound of any one of claims 47-50, wherein Form B is characterized by an IR spectrum having peaks at 3501, 3356, 1684, 1565, 1505, and 1122 cm-1.

52. The compound of any one of claims 47-51, wherein Form B is characterized by an orthorhombic crystal system, as determined by single-crystal X-ray analysis.

53. The compound of claim 52, wherein Form B is characterized by a P212121space group, as determined by single-crystal X-ray analysis.

54. The compound of claim 52 or 53, wherein Form B is characterized by a unit cell, as determined by single-crystal X-ray analysis, of the following dimensions: a=7.3929(2) Å; b=14.5827(4) Å; c=18.9312(6) Å; α=90°; β=90°; and γ=90°.

55. The compound of any one of claims 47-54, wherein Form B is obtainable by dissolving the compound in ethyl acetate and then crystallizing the compound by adding n-heptane as an antisolvent.

56. The compound of claim 40, wherein the compound has formula.

57. The compound of claim 56, wherein the compound is in crystalline solid form.

58. The compound of claim 57, wherein the crystalline solid form is Form A.

59. The compound of claim 58, wherein Form A is characterized by an orthorhombic crystal system, as determined by single-crystal X-ray analysis.

60. The compound of claim 58 or 59, wherein Form A is characterized by an I222 space group, as determined by single-crystal X-ray analysis.

61. The compound of any one of claims 58-60, wherein Form A is characterized by a unit cell, as determined by single-crystal X-ray analysis, of the following dimensions: a=12.0172(5) Å; b=15.6682(6) Å; c=24.1406(11) Å; α=90°; β=90°; and γ=90°.

62. The compound of claim 40, wherein the compound has formula.

63. The compound of claim 62, wherein the compound is in crystalline solid form.

64. The compound of claim 63, wherein the crystalline solid form is Form A.

65. The compound of claim 64, wherein Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) of 10.1, 13.7, 14.1, 16.3, and 20.

0.

66. The compound of claim 63, wherein the crystalline solid form is Form B.

67. The compound of claim 66, wherein Form B is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) of 6.8, 13.2, 16.1, 20.6, and 21.

3.

68. The compound of claim 64 or 65, wherein Form A is characterized by a monoclinic crystal system, as determined by single-crystal X-ray analysis.

69. The compound of any one of claims 64, 65, and 68, wherein Form A is characterized by a P21space group, as determined by single-crystal X-ray analysis.

70. The compound of any one of claims 64, 65, 68, and 69, wherein Form A is characterized by a unit cell, as determined by single-crystal X-ray analysis, of the following dimensions: a=12.0863(2) Å; b=7.48310(10) Å; c=23.9904(4) Å; α=90°; β=90.0130(10)°; and γ=90°.

71. The compound of claim 40, wherein the compound has formula72. The compound of claim 71, wherein the compound is in crystalline solid form.

73. The compound of claim 72, wherein the crystalline solid form is Form A.

74. The compound of claim 73, wherein Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) of 13.7, 15.2, and 18.

2.

75. The compound of claim 73 or 74, wherein Form A is characterized by a solid state13C NMR spectrum having peaks at chemical shifts of 171.4, 141.6, 118.0, 112.2, 23.0, and 11.6 ppm or a solid state19F NMR spectrum having peaks at chemical shifts of -74.6, -141.5, and -154.6 ppm.

76. The compound of any one of claims 73-75, wherein Form A is characterized by a monoclinic crystal system, as determined by single-crystal X-ray analysis.

77. The compound of any one of claims 73-76, wherein Form A is characterized by a P21space group, as determined by single-crystal X-ray analysis.

78. The compound of any one of claims 73-77, wherein Form A is characterized by a unit cell, as determined by single-crystal X-ray analysis, of the following dimensions: a=11.2266(3) Å; b=7.3948(2) Å; c=13.1432(4) Å; α=90°; β=100.3980(1)°; and γ=90°.

79. The compound of claim 40, wherein the compound has formula, wherein the compound has the absolute stereochemistry of the third eluting isomer when a mixture of racemic diastereomers (epimeric at the 5-position) is separated by SFC as described in Example 6, Step 7.

80. The compound of claim 79, wherein the compound is in crystalline solid form.

81. The compound of claim 80, wherein the crystalline solid form is Form A.

82. The compound of claim 81, wherein Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) of 9.2, 10.4, and 15.

7.

83. The compound of claim 81 or 82, wherein Form A is characterized by a solid state13C NMR spectrum having peaks at chemical shifts of 167.7, 126.0, 115.9, 43.5, and 20.3 ppm or a solid state19F NMR spectrum having peaks at chemical shifts of -82.2, -83.1, -111.7, and -114.4 ppm.

84. The compound of claim 40, wherein the compound has formula.

85. The compound of claim 84, wherein the compound is in crystalline solid form.

86. The compound of claim 85, wherien the crystalline solid form is Form A.

87. The compound of claim 86, wherein Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) of 17.2, 19.3, and 22.

3.

88. The compound of claim 86 or 87, wherein Form A is characterized by a solid state13C NMR spectrum having peaks at chemical shifts of 171.1, 149.3, 123.3, 41.6, and 20.0 ppm or a solid state19F NMR spectrum having peaks at chemical shifts of -78.2, -113.5, and -115.1 ppm.

89. The compound of any one of claims 86-88, wherein Form A is characterized by a monoclinic crystal system, as determined by single-crystal X-ray analysis.

90. The compound of any one of claims 86-89, wherein Form A is characterized by a P21space group, as determined by single-crystal X-ray analysis.

91. The compound of any one of claims 86-90, wherein Form A is characterized by a unit cell, as determined by single-crystal X-ray analysis, of the following dimensions: a=7.8661(3) Å; b=7.9167(3) Å; c=16.8777(7) Å; α=90°; β=98.487(2)°; and γ=90°.

92. The compound of claim 40, wherein the compound has formula, 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 7, Step 11.

93. The compound of claim 92, wherein the compound is in crystalline solid form.

94. The compound of claim 93, wherein the crystalline solid form is Form A.

95. The compound of claim 94, wherein Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) of 6.8, 7.9, and 13.

8.

96. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, or the compound of any one of claims 40-95 and one or more pharmaceutically acceptable carriers or vehicles.

97. A pharmaceutical composition comprising the compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, or the compound of any one of claims 40-95 and one or more pharmaceutically acceptable carriers or vehicles.

98. A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject the compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, the compound of any one of claims 40-95, or the pharmaceutical composition of claim 96 or 97.

99. The method of claim 98, wherein the voltage-gated sodium channel is NaV1.

8.

100. A method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia comprising administering to the subject an effective amount of the compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, the compound of any one of claims 40- 95, or the pharmaceutical composition of claim 96 or 97.

101. The method of claim 100, where the method comprises treating or lessening the severity in the subject of neuropathic pain.

102. The method of claim 101, wherein the neuropathic pain comprises post-herpetic neuralgia.

103. The method of claim 101, wherein the neuropathic pain comprises small fiber neuropathy or idiopathic small-fiber neuropathy.

104. The method of claim 101, wherein the neuropathic pain comprises diabetic neuropathy.

105. The method of claim 100, wherein the method comprises treating or lessening the severity in the subject of musculoskeletal pain.

106. The method of claim 105, wherein the musculoskeletal pain comprises osteoarthritis pain.

107. The method of claim 100, wherein the method comprises treating or lessening the severity in the subject of acute pain.

108. The method of claim 107, wherein the acute pain comprises acute post-operative pain.

109. The method of claim 100, wherein the method comprises treating or lessening the severity in the subject of postsurgical pain.

110. The method of claim 109, wherein the postsurgical pain comprises bunionectomy pain.

111. The method of claim 109, wherein the postsurgical pain comprises herniorrhaphy pain.

112. The method of claim 109, wherein the postsurgical pain comprises abdominoplasty pain.

113. The method of claim 100, wherein the method comprises treating or lessening the severity in the subject of visceral pain.

114. A method of treating or lessening the severity in a subject of pain comprising administering to the subject an effective amount of the compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, the compound of any one of claims 40-95, or the pharmaceutical composition of claim 96 or 97.

115. The method of any one of claims 97-114, wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound, pharmaceutically acceptable salt, or pharmaceutical composition.

116. Use of the compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, the compound of any one of claims 40-95, or the pharmaceutical composition of claim 96 or 97, as a medicament.