Heteroaryl compounds for the treatment of pain

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

Attorney Docket No.67573-425864 (VPI / 24-007 WO) HETEROARYL COMPOUNDS FOR THE TREATMENT OF PAIN CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 665,695, filed June 28, 2024, and U.S. Provisional Application No.63 / 748,757, filed January 23, 2025, each of which are incorporated by reference herein in their entirety. BACKGROUND

[0002] Pain is a protective mechanism 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. Acute and chronic pain are two common pain states and can be distinguished by the duration of the pain. Acute pain can arise for many reasons (e.g., a hospital procedure) and treatment options are generally limited by poor efficacy and / or adverse events. Like acute pain, chronic pain can arise for many reasons and treatment options are limited by poor efficacy and / or adverse events.

[0003] 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.

[0004] 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, for example, neurons, skeletal myocytes, cardiac myocytes (Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). 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 andtherapeutic opportunities. Curr. Opin. Pharmacol.8 (1), p.50-56 (2008)). Because of the role NaVs play in the initiation and propagation of neuronal signals, antagonists that reduce NaVcurrents can prevent or reduce neural signaling 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)).

[0005] 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)).

[0006] 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 and neuropathic, but not post-operative, pain states. Pain, 2006.123(1-2): pp.75-82; Lai, J., et al., Inhibitionof 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, where NaV1.8 mediates large amplitude action potentials (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).

[0007] The inventors have discovered that some voltage-gated sodium channel inhibitors have limitations as therapeutic agents due to, for example, a poor therapeutic window (e.g., due to a lack ofNaVisoform selectivity, low potency, and / or other reasons). Accordingly, there remains a need to develop selective voltage-gated sodium channel inhibitors, such as selective NaV1.8 inhibitors. SUMMARY

[0008] In one aspect, the invention relates to a compound described herein (e.g., a compound of Formula (I), (II), (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III), (III-A-1), (III-A-2), or (III-A-3), or a compound of any one of Tables A, B, and C), or a pharmaceutically acceptable salt thereof.

[0009] 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.

[0010] 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.

[0011] 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. DETAILED DESCRIPTION

[0012] In one aspect, the invention relates to a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein: XA1is C-RA1, N, or N+-O-; XA2is C-RA2, N, or N+-O-;XA4is C-RA4, N, or N+-O-; XA5is C-RA5or N; XC1is C-RC1or N; XC2is C-RC2or N; RA1, RA2, RA3, and RA4are each independently H, OH, CN, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, –NHS(O)2(C1-C6alkyl), –C(O)ORb, –C(O)NRbRc, –(CH2)mO(CH2)oCH3, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents independently selected from C1-C6alkyl and –C(O)NRbRc; RA5is H, OH, halo, CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, –(CH2)mOn(CH2)oOCH3, –(CH2)mRa, –C(O)(CH2)mRa, –C(O)ORb, –C(O)Rb, –C(O)NRbRc, –NRbRc, –CRdReRf, –CRbRcNRgC(O)CRhRiRj, –NRbC(O)CRcRgRj, C3-C6cycloalkyl, 5-6 membered heteroaryl, or 4-10 membered heterocyclyl, wherein said C3-C6cycloalkyl, 5-6 membered heteroaryl, or 4-10 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents independently selected from halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; R1and R2are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R3and R4are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; p, Z, R5, R6, R7, and R8are defined as follows: (i) p is 0 or 1; Z is C(-R3)(-R4); R5and R6are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; and R7and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; or (ii) p is 0 or 1; Z is C(-R3)(-R4); R7and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; and R5and R6, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl optionally substituted with 1-6 Ry; or (iii) p is 0 or 1; Z is C(-R3)(-R4);R5and R7, together with the carbon atoms to which they are attached, form a fused C3-C6cycloalkyl optionally substituted with 1-6 Ry; and R6and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; or (iv) p is 0; Z is C(-R3)(-R4) or O; R5and R7, together with the carbon atoms to which they are attached, form a fused ring of formula, optionally substituted with 1-4 Ry; and R6and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R9is H or CH3; RC1and RC2are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, –[CH2]q-C3-C6cycloalkyl, –[CH2]q-O-C3-C6cycloalkyl, –[CH2]q-NRbRc, –(CH2)mORb, or –O(CH2)mORb, wherein said C1-C6alkyl and C1-C6alkoxy of RC1and RC2are each optionally substituted with an independently selected CN or 5-6 membered heteroaryl, or RC1and RC2, together with the carbon atoms to which they are attached, form a ring of formula:C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, –O-C3-C6cycloalkyl, –NRbRc, –(CH2)mORb, or –O(CH2)mOCH3; each Rxis independently H, halo, C1-C6alkyl, or C1-C6haloalkyl; each Ryis independently halo, OH, C1-C6alkyl, or C1-C6haloalkyl; Rais OH, halo, C1-C6alkoxy, or –NRbRc; Rb, Rc, Rg, Rh, and Riare each independently H or C1-C6alkyl, or Rband Rc, together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclyl; Rd, Re, and Rfare each independently H, OH, halo, C1-C6alkyl, or C1-C6alkoxy; Rjis H, C1-C6alkyl, –NRbRc, or –N(CH3)3+; m and o are each independently 0, 1, 2, or 3; q is 0 or 1; andn is 0 or 1.

[0013] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: p is 0 or 1; Z is C(-R3)(-R4); R5, R6, R7, and R8are defined as follows: (i) R5and R6are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; and R7and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; or (ii) R7and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; and R5and R6, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl optionally substituted with 1-6 Ry; or (iii) R5and R7, together with the carbon atoms to which they are attached, form a fused C3-C6cycloalkyl optionally substituted with 1-6 Ry; and R6and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy.

[0014] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: p is 0 or 1; Z is C(-R3)(-R4); R5, R6, R7, and R8are defined as follows: (i) R5and R6are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; and R7and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; or (ii) R7and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; and R5and R6, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl optionally substituted with 1-6 Ry; or (iii) R5and R7, together with the carbon atoms to which they are attached, form a fused C3-C6cycloalkyl optionally substituted with 1-6 Ry; andR6and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; and RC1and RC2are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, –[CH2]q-C3-C6cycloalkyl, –[CH2]q-O-C3-C6cycloalkyl, –[CH2]q-NRbRc, –(CH2)mORb, or –O(CH2)mOCH3, or RC1and RC2, together with the carbon atoms to which they are attached, form a ring of formula:

[0015] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein RC1and RC2are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, –[CH2]q-C3-C6cycloalkyl, –[CH2]q-O-C3-C6cycloalkyl, –[CH2]q-NRbRc, –(CH2)mORb, or –O(CH2)mOCH3, or RC1and RC2, together with the carbon atoms to which they are attached, form a ring of formula:

[0016] 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.

[0017] As used herein, the term “compounds of the invention” refers to the compounds of formula (I) and all of the embodiments thereof (e.g., Formula (II), (II-A), (II-B), (II-C), (II-D), (II-E), and (II-F)), as described herein, and to the compounds identified in Table A, Table B, and Table C.

[0018] As described herein, the compounds of the invention comprise multiple variable groups (e.g., XA1, RA3, R1, R6, XC1, RC3, 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 atemperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

[0019] As used herein, the term “halo” means F, Cl, Br or I.

[0020] As used herein, the term “alkyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having the specified number of carbon atoms, which is attached to the 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.

[0021] 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.

[0022] As used herein, the term “alkoxy” refers to a radical of the formula -OR where R is an alkyl group having the specified number of carbon atoms. For example, a “C1-C6alkoxy” group is a radical of the formula -OR where R is an alkyl group having the between one and six carbon atoms.

[0023] 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.

[0024] As used herein, the term “haloalkoxy” refers to an alkoxy group having the specified number of carbon atoms, wherein one or more of the hydrogen atoms of the of the alkyl group are replaced by halo groups.

[0025] As used herein, the term “heterocyclyl” refers to a stable, non-aromatic, mono-, bi-, or tricyclic (fused, bridged, or spiro) radical in which one or more ring atoms is a heteroatom (e.g., a heteroatom independently selected from N, O, P, and S), which has the specified number of ring atoms, and which is attached to the rest of the molecule by a single bond. Heterocyclic rings can be saturated, or can contain one or more double or triple bonds. In some embodiments, the “heterocyclyl” group has the indicated number of ring members, in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, and phosphorus, and each ring in the ring system contains 3 to 7 ring members. For example, a 6-membered heterocyclyl includes a total of 6 ring members, at least one of which is a heteroatom (e.g., a heteroatom independently selected from N, O, P, and S).

[0026] As used herein, the term “heteroaryl” refers to a stable mono-, bi-, or tricyclic ring radical having the specified number of ring atoms, wherein at least one ring in the system is aromatic, at least one aromatic ring in the system contains one or more heteroatoms (e.g., one or more heteroatomsindependently selected from N, O, P, and S). In some embodiments, each ring in the system contains 3 to 7 ring members. For example, a 6-membered heteroaryl includes a total of 6 ring members, at least one of which is a heteroatom selected from N, S, O, and P. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.

[0027] As used herein, labels such as “*C1” and “*C2”, such as those shown in the following structures, designate the carbon atoms to which the corresponding R groups (in this case, the RC1and RC2groups, respectively) are attached:

[0028] 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.

[0029] As used herein, in any chemical structure or formula, a non-bold, straight bond attached to a stereocenter of a compound, such as in, denotes that the configuration of the stereocenter is unspecified. The compound may have any configuration, or a mixture of configurations, at the stereocenter.

[0030] As used herein, in any chemical structure or formula, a bold or hashed straight bond 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. 0

[0031] As used herein, in any chemical structure or formula, a bold or hashed wedge bond 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.

[0032] 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.

[0033] As used herein, the prefix “dia-,” when used in connection with a chiral compound, refers to a mixture of two or more diastereomers of the compound. In a compound bearing the “dia-“ prefix, the (R)- and (S)- designators are assigned arbitrarily and do not necessarily reflect the absolute or relative configuration of the corresponding stereocenters in any component of the mixture. In some instances, all of the diastereomers in a mixture have a single absolute configuration at one or more stereocenters. In these instances, the stereochemical designators associated with the stereocenters having a single absolute configuration are marked with an asterisk (*), e.g., (R*)- and (S*)-. In some instances, all of the diastereomers in a mixture have the same relative stereochemistry at two or more stereocenters. In these instances, the stereochemical designators associated with such stereocenters are marked with a superscript number (n), e.g., (Rn)- and (Sn)-. The stereochemical designators marked with a superscript number reflect the relative stereochemistry of the corresponding stereocenters with respect to other stereocenters associated with stereochemical designators having the same superscript number, e.g., (R1)- and (S1)-, but they do not necessarily reflect the absolute configuration of such stereocenters. The stereochemical designators marked with an asterisk (*) do not necessarily reflect the relative stereochemistry of the corresponding stereocenters with respect to stereocenters associated with stereochemical designators marked with a superscript number (n) (and vice versa) or with respect to stereocenters associated with unmarked stereochemical designators. Likewise, the stereochemical designators marked with a superscript number (n) do not necessarily reflect the relative stereochemistry of the corresponding stereocenters with respect to stereocenters associated with stereochemical designators marked with a different superscript number (n) or with respect to stereocenters associated with unmarked stereochemical designators. 1

[0034] 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. In some instances, the absolute configuration of some stereocenters is known, while only the relative configuration of the other stereocenters is known. In these instances, the stereochemical designators associated with the stereocenters of known absolute configuration are marked with an asterisk (*), e.g., (R*)- and (S*)-, while the stereochemical designators associated with stereocenters of unknown absolute configuration are not so marked. The unmarked stereochemical designators associated with the stereocenters of unknown absolute configuration reflect the relative stereochemistry of those stereocenters with respect to other stereocenters of unknown absolute configuration, but do not necessarily reflect the relative stereochemistry with respect to the stereocenters of known absolute configuration. Where a compound contains two or more stereocenters of unknown absolute configuration, and the relative stereochemistry of such stereocenters with respect to each other is unknown, no stereochemical designator is provided for such stereocenters.

[0035] 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.

[0036] In the specification and claims, unless otherwise specified, any atom not specifically designated as a particular isotope in any compound of the invention is meant to represent any stable isotope of the specified element. In the Examples, where an atom is not specifically designated as a particular isotope in any compound of the invention, no effort 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.

[0037] As used herein, the term “stable,” when referring to an isotope, means that the isotope is not known to undergo spontaneous radioactive decay. Stable isotopes include, but are not limited to, the isotopes for which no decay mode is identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0038] As used herein in the specification and claims, “H” refers to hydrogen and includes any stable isotope of hydrogen, namely1H and D. In the Examples, where an atom is designated as “H,” no effort 2was 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 isotopic composition of hydrogen.

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

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

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

[0042] In some embodiments, the compounds of the invention, and pharmaceutically acceptable salts thereof, include 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.

[0043] 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-labeled 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.

[0044] The deuterium (2H)-labeled compounds and salts can manipulate the rate of oxidative metabolism of the compound by way of the primary kinetic isotope effect. The primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies of the covalent bonds involved in the reaction. Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially. For example, if deuterium is bonded to a carbon atom at a non- 3exchangeable position, rate differences of kH / kD= 2-7 are typical. For a further discussion, see S. L. Harbeson and R. D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem.2011, 46, 403-417, incorporated in its entirety herein by reference.

[0045] The concentration of an isotope (e.g., deuterium) incorporated at a given position of an isotope-labeled compound of the invention, or a pharmaceutically acceptable salt thereof, may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor,” as used herein, means the ratio between the abundance of an isotope at a given position in an isotope-labeled compound (or salt) and the natural abundance of the isotope.

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

[0047] In some embodiments, the invention relates to a compound of formula (II):or a pharmaceutically acceptable salt thereof, wherein: XA1is C-RA1, N, or N+-O-; XA2is C-RA2, N, or N+-O-; p is 0 or 1; XC1is C-RC1or N; XC2is C-RC2or N; RA1and RA2are each independently H, OH, CN, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, –NHS(O)2(C1-C6alkyl), –C(O)ORb, –C(O)NRbRc, –(CH2)mO(CH2)oCH3, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 5-6 membered heterocyclyl may be 4unsubstituted or may be substituted with 1-4 substituents independently selected from C1-C6alkyl and –C(O)NRbRc; R1and R2are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R3and R4are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R5, R6, R7, and R8are defined as follows: (i) R5and R6are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; and R7and R8are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; or (ii) R7and R8are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; and R5and R6, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl optionally substituted with 1-6 Ry; or (iii) R5and R7, together with the carbon atoms to which they are attached, form a fused C3-C6cycloalkyl optionally substituted with 1-6 Ry; and R6and R8are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R9is H or CH3; RC1, RC2, RC3, RC4, and RC5are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, –O-C3-C6cycloalkyl, –NRbRc, –(CH2)mORb, or –O(CH2)mOCH3; each Ryis independently halo, OH, C1-C6alkyl, or C1-C6haloalkyl; Rband Rcare each independently H or C1-C6alkyl, or Rband Rc, together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclyl; and m and o are each independently 0, 1, 2, or 3. 5

[0048] In some embodiments, the invention relates to a compound of formula (III):or a pharmaceutically acceptable salt thereof, wherein: XA1is C-RA1, N, or N+-O-; XA2is C-RA2, N, or N+-O-; Z is C(-R3)(-R4) or O; XC1is C-RC1or N; XC2is C-RC2or N; RA1and RA2are each independently H, OH, CN, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, –NHS(O)2(C1-C6alkyl), –C(O)ORb, –C(O)NRbRc, –(CH2)mO(CH2)oCH3, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents independently selected from C1-C6alkyl and –C(O)NRbRc; R3and R4are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R6and R8are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R9is H or CH3; RC1, RC2, RC3, RC4, and RC5are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, –O-C3-C6cycloalkyl, –NRbRc, –(CH2)mORb, or –O(CH2)mOCH3; each Ryis independently halo, OH, C1-C6alkyl, or C1-C6haloalkyl; Rband Rcare each independently H or C1-C6alkyl, or Rband Rc, together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclyl; m and o are each independently 0, 1, 2, or 3; and r is 0, 1, 2, 3, or 4.

[0049] In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein XA1is C-RA1. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein XA1is C-RA1, and RA1is –CN or –C(O)NRbRc. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein XA1is C-RA1, and RA1is –C(O)NRbRc. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein XA1is C-RA1, and RA1is –C(O)NH2. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein XA1is C-RA1, and RA1is –CN.

[0050] In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein XA2is N.

[0051] In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein XA1is C-RA1; RA1is –C(O)NH2; and XA2is N. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein XA1is C-RA1; RA1is –CN; and XA2is N.

[0052] In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein XA1is C-RA1; RA1is –C(O)NH2; XA2is N; RA3is H; XA4is C-RA4; RA4is H; XA5is C-RA5; and RA5is H. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein XA1is C-RA1; RA1is –CN; XA2is N; RA3is H; XA4is C-RA4; RA4is H; XA5is C-RA5; and RA5is H.

[0053] In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, and R3and R4are each H. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, and R1and R2are each H.

[0054] In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, and R3and R4are each H. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, and R3and R4are each F. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, and R3and R4are each independently H, C1-C3alkyl, or C1-C3haloalkyl. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, and R3is -CH3and R4is -CF3.

[0055] In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, and R5and R6are each independently H, 7C1-C3alkyl, or C1-C3haloalkyl. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, and R5and R6are each independently H, -CH3, or -CF3. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, and R5and R6are each H. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, and R5and R6are each -CH3. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, and R5is -CH3and R6is -CF3.

[0056] In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, and R5and R6are each independently H, C1-C4alkyl, or C1-C3haloalkyl. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, and R5and R6are each independently H, -CH3, -tBu, or -CF3. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, and R5is H and R6is -tBu. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, and R5and R6are each H. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, and R5and R6are each -CH3. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, and R5is -CH3and R6is -CF3.

[0057] In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, and R5and R6, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl optionally substituted with 1-6 Ry. In some embodiments, each Ryis independently halo. In other embodiments, each Ryis F. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, and R5and R6, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl optionally substituted with 1 or 2 Ry. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, and R5and R6, together with the carbon atom to which they are attached, form a C3cycloalkyl optionally substituted with 1 or 2 F. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, and R5and R6, together with the carbon atom to which they are attached, form a C4cycloalkyl optionally substituted with 1 or 2 F. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, and R5and R6, together with the carbon atom to which they are attached, form a C6cycloalkyl optionally substituted with 1 or 2 Ry.

[0058] In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, and R5and R7, together with the carbon atoms to which they are attached, form a fused C3-C6cycloalkyl optionally substituted with 1-6 Ry. In some embodiments, each Ryis independently halo. In other embodiments, each Ryis F. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, R5and R7, together with the carbon atoms to which they are attached, form a fused C3-C6cycloalkyl optionally substituted with 1 or 2 Ry. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, R5and R7, together with the carbon atoms to which they are attached, form a fused C5cycloalkyl optionally substituted with 1 or 2 Ry. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, R5and R7, together with the carbon atoms to which they are attached, form a fused C5cycloalkyl optionally substituted with 1 or 2 F. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, R5and R7, together with the carbon atoms to which they are attached, form a fused C6cycloalkyl optionally substituted with 1 or 2 Ry. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, R5and R7, together with the carbon atoms to which they are attached, form a fused C6cycloalkyl optionally substituted with 1 or 2 F.

[0059] In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, Z is C(-R3)(-R4), and R5and R7, together with the carbon atoms to which they are attached, form a fused C3-C6cycloalkyl optionally substituted with 1-6 Ry. In some embodiments, each Ryis independently halo. In other embodiments, each Ryis F. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, Z is C(-R3)(-R4), and R5and R7, together with the carbon atoms to which they are attached, form a fused C3-C6cycloalkyl optionally substituted with 1 or 2 Ry. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, Z is C(-R3)(-R4), and R5and R7, together with the carbon atoms to which they are attached, form a fused C5cycloalkyl optionally substituted with 1 or 2 Ry. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, Z is C(-R3)(-R4), and R5and R7, together with the carbon atoms to which they are attached, form a fused C5cycloalkyl optionally substituted with 1 or 2 F. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, Z is C(-R3)(-R4), and R5and R7, together with the carbon atoms to which they are attached, form a fused C6cycloalkyl optionally substituted with 1 or 2 Ry. In some embodiments, the invention relates to a 9compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, Z is C(-R3)(-R4), and R5and R7, together with the carbon atoms to which they are attached, form a fused C6cycloalkyl optionally substituted with 1 or 2 F.

[0060] In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, Z is C(-R3)(-R4), and R5and R7, together with the carbon atoms to which they are attached, form a fused C3-C6cycloalkyl optionally substituted with 1-6 Ry. In some embodiments, each Ryis independently halo. In other embodiments, each Ryis F. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, Z is C(-R3)(-R4), and R5and R7, together with the carbon atoms to which they are attached, form a fused C3-C6cycloalkyl optionally substituted with 1 or 2 Ry. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, Z is C(-R3)(-R4), and R5and R7, together with the carbon atoms to which they are attached, form a fused C5cycloalkyl optionally substituted with 1 or 2 Ry. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, Z is C(-R3)(-R4), and R5and R7, together with the carbon atoms to which they are attached, form a fused C5cycloalkyl optionally substituted with 1 or 2 F. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, Z is C(-R3)(-R4), and R5and R7, together with the carbon atoms to which they are attached, form a fused C6cycloalkyl optionally substituted with 1 or 2 Ry. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, Z is C(-R3)(-R4), and R5and R7, together with the carbon atoms to which they are attached, form a fused C6cycloalkyl optionally substituted with 1 or 2 F.

[0061] In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, Z is -CH2-, and R5and R7, together with the carbon atoms to which they are attached, form a fused C3-C6cycloalkyl optionally substituted with 1-6 Ry. In some embodiments, each Ryis independently halo. In other embodiments, each Ryis F. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, Z is -CH2-, and R5and R7, together with the carbon atoms to which they are attached, form a fused C3-C6cycloalkyl optionally substituted with 1 or 2 Ry. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, Z is -CH2-, and R5and R7, together with the carbon atoms to which they are attached, form a fused C5cycloalkyl optionally substituted with 1 or 2 Ry. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, Z is -CH2-, and R5and R7, together with the carbon atoms to which they are attached, form a fused C50cycloalkyl optionally substituted with 1 or 2 F. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, Z is -CH2-, and R5and R7, together with the carbon atoms to which they are attached, form a fused C6cycloalkyl optionally substituted with 1 or 2 Ry. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 0, Z is -CH2-, and R5and R7, together with the carbon atoms to which they are attached, form a fused C6cycloalkyl optionally substituted with 1 or 2 F.

[0062] In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, Z is -CH2-, and R5and R7, together with the carbon atoms to which they are attached, form a fused C3-Ccycloalkyl optionally substituted with 1-6 Ry. In some embodiments, each Ryis independently halo. In other embodiments, each Ryis F. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, Z is -CH2-, and R5and R7, together with the carbon atoms to which they are attached, form a fused C3-C6cycloalkyl optionally substituted with 1 or 2 Ry. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, Z is -CH2-, and R5and R7, together with the carbon atoms to which they are attached, form a fused C5cycloalkyl optionally substituted with 1 or 2 Ry. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, Z is -CH2-, and R5and R7, together with the carbon atoms to which they are attached, form a fused C5cycloalkyl optionally substituted with 1 or 2 F. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, Z is -CH2-, and R5and R7, together with the carbon atoms to which they are attached, form a fused C6cycloalkyl optionally substituted with 1 or 2 Ry. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p = 1, Z is -CH2-, and R5and R7, together with the carbon atoms to which they are attached, form a fused C6cycloalkyl optionally substituted with 1 or 2 F.

[0063] In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R7and R8are each independently H or C1-C3alkyl. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R7and R8are each independently H or -CH3. In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R7and R8are each H.

[0064] In some embodiments, the invention relates to a compound of formula (I) or (III), or a pharmaceutically acceptable salt thereof, wherein Z is O. 1

[0065] In some embodiments, the invention relates to a compound of formula (I) or (III), or a pharmaceutically acceptable salt thereof, wherein R6and R8are each H.

[0066] In some embodiments, the invention relates to a compound of formula (I) or (III), or a pharmaceutically acceptable salt thereof, wherein each Ryis independently halo, and r is 2. In some embodiments, the invention relates to a compound of formula (I) or (III), or a pharmaceutically acceptable salt thereof, wherein each Ryis F, and r is 2.

[0067] In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R9is H.

[0068] In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein XC1is C-RC1. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein XC2is C-RC2. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein XC2is N. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein XC1is C-RC1and XC2is C-RC2. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein XC1is C-RC1and XC2is N.

[0069] In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC1RC2, RC3, RC4, and RC5are each independently H, OH, halo, -C1-C3alkyl, -C3-C6cycloalkyl, or –(CH2)mORb. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC1, RC2, RC3, RC4, and RC5are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, -O-C3-C6cycloalkyl, or –CH2OH. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC1, RC2, RC3, RC4, and RC5are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, or –CH2OH. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC1RC2, RC3, RC4, and RC5are each independently H, OH, F, Cl, -CH3, -CH2CH3, -cyclopropyl, -OCH3, or -CH2OH. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC1, RC2, RC3, RC4, and RC5are each independently H, OH, F, Cl, -CH3, -CH2CH3, -OCH3, -CF3, C3cycloalkyl, -O-C3cycloalkyl, or –CH2OH. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC1, RC2, RC3, RC4, and RC5are each independently H, OH, F, Cl, -CH3, -CH2CH3, -OCH3, C3cycloalkyl, or –CH2OH.

[0070] In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC3is H, halo, or C1-C6alkyl. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC3is H. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC3is halo. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC3is C1-C6alkyl. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC3is H, F, or –CH3. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC3is F. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC3is –CH3.

[0071] In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC4is halo. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC4is F or Cl. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC4is -CH3.

[0072] In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC5is halo. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC5is F or Cl. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC5is -C1-C3alkyl. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC5is -CH3or -CH2CH3. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC5is -C3-C6cycloalkyl. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC5is cyclopropyl. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC5is -OCH3or -CH2OH. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC5is -OCH3. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC5is -CH2OH. In some embodiments, the invention relates to a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein RC5is H.

[0073] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein p = 0:

[0074] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein p = 1:

[0075] In some embodiments, the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein p = 0:

[0076] In some embodiments, the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein p = 1:

[0077] In some embodiments, the invention relates to a compound of formula (II-A):or a pharmaceutically acceptable salt thereof, wherein: XA1is C-RA1, N, or N+-O-; XA2is C-RA2, N, or N+-O-; XC1is C-RC1or N; XC2is C-RC2or N; RA1and RA2are each independently H, OH, CN, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, –NHS(O)2(C1-C6alkyl), –C(O)ORb, –C(O)NRbRc, –(CH2)mO(CH2)oCH3, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents independently selected from C1-C6alkyl and –C(O)NRbRc; RC1, RC2, RC3, RC4, and RC5are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, –O-C3-C6cycloalkyl, –NRbRc, –(CH2)mORb, or –O(CH2)mOCH3; Rband Rcare each independently H or C1-C6alkyl, or Rband Rc, together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclyl; andm and o are each independently 0, 1, 2, or 3.

[0078] In some embodiments, the invention relates to a compound of formula (II-B):or a pharmaceutically acceptable salt thereof, wherein: XA1is C-RA1, N, or N+-O-; XA2is C-RA2, N, or N+-O-; XC1is C-RC1or N; XC2is C-RC2or N; RA1and RA2are each independently H, OH, CN, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, –NHS(O)2(C1-C6alkyl), –C(O)ORb, –C(O)NRbRc, –(CH2)mO(CH2)oCH3, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents independently selected from C1-C6alkyl and –C(O)NRbRc;halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, –O-C3-C6cycloalkyl, –NRbRc, –(CH2)mORb, or –O(CH2)mOCH3; Rband Rcare each independently H or C1-C6alkyl, or Rband Rc, together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclyl; and m and o are each independently 0, 1, 2, or 3. 6

[0079] In some embodiments, the invention relates to a compound of formula (II-B-1):or a pharmaceutically acceptable salt thereof, wherein: XA1is C-RA1, N, or N+-O-; XA2is C-RA2, N, or N+-O-; XC1is C-RC1or N; XC2is C-RC2or N; RA1and RA2are each independently H, OH, CN, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, –NHS(O)2(C1-C6alkyl), –C(O)ORb, –C(O)NRbRc, –(CH2)mO(CH2)oCH3, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents independently selected from C1-C6alkyl and –C(O)NRbRc;halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, –O-C3-C6cycloalkyl, –NRbRc, –(CH2)mORb, or –O(CH2)mOCH3; Rband Rcare each independently H or C1-C6alkyl, or Rband Rc, together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclyl; and m and o are each independently 0, 1, 2, or 3.

[0080] In some embodiments, the invention relates to a compound of formula (II-B-2):or a pharmaceutically acceptable salt thereof, wherein: XA1is C-RA1, N, or N+-O-; XA2is C-RA2, N, or N+-O-; XC1is C-RC1or N; XC2is C-RC2or N; RA1and RA2are each independently H, OH, CN, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, –NHS(O)2(C1-C6alkyl), –C(O)ORb, –C(O)NRbRc, –(CH2)mO(CH2)oCH3, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents independently selected from C1-C6alkyl and –C(O)NRbRc;ach independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, –O-C3-C6cycloalkyl, –NRbRc, –(CH2)mORb, or –O(CH2)mOCH3; Rband Rcare each independently H or C1-C6alkyl, or Rband Rc, together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclyl; and m and o are each independently 0, 1, 2, or 3.

[0081] In some embodiments, the invention relates to a compound of formula (II-C):or a pharmaceutically acceptable salt thereof, wherein: XA1is C-RA1, N, or N+-O-; XA2is C-RA2, N, or N+-O-; XC1is C-RC1or N; XC2is C-RC2or N; RA1and RA2are each independently H, OH, CN, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, –NHS(O)2(C1-C6alkyl), –C(O)ORb, –C(O)NRbRc, –(CH2)mO(CH2)oCH3, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 5-6 membered heterocyclyl may beunsubstituted or may be substituted with 1-4 substituents independently selected from C1-C6alkyl and –C(O)NRbRc; RC1, RC2, RC3, RC4, and RC5are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, –O-C3-C6cycloalkyl, –NRbRc, –(CH2)mORb, or –O(CH2)mOCH3; Rband Rcare each independently H or C1-C6alkyl, or Rband Rc, together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclyl; and m and o are each independently 0, 1, 2, or 3.

[0082] In some embodiments, the invention relates to a compound of formula (II-D):or a pharmaceutically acceptable salt thereof, wherein: XA1is C-RA1, N, or N+-O-; XA2is C-RA2, N, or N+-O-; XC1is C-RC1or N; XC2is C-RC2or N; RA1and RA2are each independently H, OH, CN, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, –NHS(O)2(C1-C6alkyl), –C(O)ORb, –C(O)NRbRc, –(CH2)mO(CH2)oCH3, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents independently selected from C1-C6alkyl and –C(O)NRbRc;independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, –O-C3-C6cycloalkyl, –NRbRc, –(CH2)mORb, or –O(CH2)mOCH3; Rband Rcare each independently H or C1-C6alkyl, or Rband Rc, together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclyl; and m and o are each independently 0, 1, 2, or 3.

[0083] In some embodiments, the invention relates to a compound of formula (II-E):or a pharmaceutically acceptable salt thereof, wherein: XA1is C-RA1, N, or N+-O-; XA2is C-RA2, N, or N+-O-; XC1is C-RC1or N; XC2is C-RC2or N; RA1and RA2are each independently H, OH, CN, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, –NHS(O)2(C1-C6alkyl), –C(O)ORb, –C(O)NRbRc, –(CH2)mO(CH2)oCH3, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents independently selected from C1-C6alkyl and –C(O)NRbRc;and RC5are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, –O-C3-C6cycloalkyl, –NRbRc, –(CH2)mORb, or –O(CH2)mOCH3; Rband Rcare each independently H or C1-C6alkyl, or Rband Rc, together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclyl; and m and o are each independently 0, 1, 2, or 3.

[0084] In some embodiments, the invention relates to a compound of formula (II-F):or a pharmaceutically acceptable salt thereof, wherein: XA1is C-RA1, N, or N+-O-; XA2is C-RA2, N, or N+-O-; XC1is C-RC1or N; XC2is C-RC2or N; RA1and RA2are each independently H, OH, CN, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, –NHS(O)2(C1-C6alkyl), –C(O)ORb, –C(O)NRbRc, –(CH2)mO(CH2)oCH3, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents independently selected from C1-C6alkyl and –C(O)NRbRc;ach independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, –O-C3-C6cycloalkyl, –NRbRc, –(CH2)mORb, or –O(CH2)mOCH3; Rband Rcare each independently H or C1-C6alkyl, or Rband Rc, together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclyl; and m and o are each independently 0, 1, 2, or 3.

[0085] In some embodiments, the invention relates to a compound of formula (III-A):or a pharmaceutically acceptable salt thereof, wherein: XA1is C-RA1, N, or N+-O-; XA2is C-RA2, N, or N+-O-; XC1is C-RC1or N; XC2is C-RC2or N; RA1and RA2are each independently H, OH, CN, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, –NHS(O)2(C1-C6alkyl), –C(O)ORb, –C(O)NRbRc, –(CH2)mO(CH2)oCH3, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 5-6 membered heterocyclyl may beunsubstituted or may be substituted with 1-4 substituents independently selected from C1-C6alkyl and –C(O)NRbRc;and RC5are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, –O-C3-C6cycloalkyl, –NRbRc, –(CH2)mORb, or –O(CH2)mOCH3; Rband Rcare each independently H or C1-C6alkyl, or Rband Rc, together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclyl; and m and o are each independently 0, 1, 2, or 3.

[0086] In some embodiments, the invention relates to a compound of formula (III-A-1):; or a pharmaceutically acceptable salt thereof, wherein: XA1is C-RA1, N, or N+-O-; XA2is C-RA2, N, or N+-O-; XC1is C-RC1or N; XC2is C-RC2or N; RA1and RA2are each independently H, OH, CN, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, –NHS(O)2(C1-C6alkyl), –C(O)ORb, –C(O)NRbRc, –(CH2)mO(CH2)oCH3, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents independently selected from C1-C6alkyl and –C(O)NRbRc; RC3, RC4, and RC5are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, –O-C3-C6cycloalkyl, –NRbRc, –(CH2)mORb, or –O(CH2)mOCH3; Rband Rcare each independently H or C1-C6alkyl, or Rband Rc, together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclyl; and m and o are each independently 0, 1, 2, or 3.

[0087] In some embodiments, the invention relates to a compound of formula (III-A-2):or a pharmaceutically acceptable salt thereof, wherein: XA1is C-RA1, N, or N+-O-; XA2is C-RA2, N, or N+-O-; XC1is C-RC1or N; XC2is C-RC2or N; RA1and RA2are each independently H, OH, CN, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, –NHS(O)2(C1-C6alkyl), –C(O)ORb, –C(O)NRbRc, –(CH2)mO(CH2)oCH3, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents independently selected from C1-C6alkyl and –C(O)NRbRc; RC1, RC2, RC3, RC4, and RC5are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, –O-C3-C6cycloalkyl, –NRbRc, –(CH2)mORb, or –O(CH2)mOCH3; Rband Rcare each independently H or C1-C6alkyl, or Rband Rc, together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclyl; and m and o are each independently 0, 1, 2, or 3.

[0088] In some embodiments, the invention relates to a compound of formula (III-A-3):or a pharmaceutically acceptable salt thereof, wherein: XA1is C-RA1, N, or N+-O-; XA2is C-RA2, N, or N+-O-; XC1is C-RC1or N; XC2is C-RC2or N; RA1and RA2are each independently H, OH, CN, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, –NHS(O)2(C1-C6alkyl), –C(O)ORb, –C(O)NRbRc, –(CH2)mO(CH2)oCH3, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents independently selected from C1-C6alkyl and –C(O)NRbRc;ach independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, –O-C3-C6cycloalkyl, –NRbRc, –(CH2)mORb, or –O(CH2)mOCH3; Rband Rcare each independently H or C1-C6alkyl, or Rband Rc, together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclyl; and m and o are each independently 0, 1, 2, or 3.

[0089] In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein XA1is C-RA1. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein XA1is C-RA1, and RA1is –CN or –C(O)NRbRc. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein XA1is C-RA1, and RA1is –C(O)NRbRc. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein XA1is C-RA1, and RA1is –C(O)NH2. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein XA1is C-RA1, and RA1is –CN.

[0090] In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein XA2is N.

[0091] In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein XA1is C-RA1; and XA2is N. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein XA1is C-RA1, and RA1is –C(O)NRbRc; and XA2is N. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein XA1is C-RA1; RA1is –C(O)NH2; and XA2is N.

[0092] In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein XC1is N. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein XC1is C-RC1. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein XC2is N. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein XC2is C-RC2. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein XC1is C-RC1and XC2is C-RC2. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein XC1is N and XC2is C-RC2. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein XC1is C-RC1and XC2is N.

[0093] In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC1RC2, RC3, RC4, and RC5are each independently H, OH, halo, -C1-C3alkyl, -C3-C6cycloalkyl, or –(CH2)mORb. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC1RC2, RC3, RC4, and RC5are each independently H, OH, F, Cl, -CH3, -CH2CH3, -cyclopropyl, -OCH3, or -CH2OH.

[0094] In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically 5acceptable salt thereof, wherein RC1is H, -C1-C3alkyl, or -C1-C6alkoxy. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC1is H, -CH3, -CH2CH3, or -OCH3. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC1is H. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC1is -C1-C3alkyl. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC1is -CH3, or -CH2CH3. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC1is -CH3. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC1is -CH2CH3. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC1is -C1-C6alkoxy. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC1is -OCH3.

[0095] In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC2is halo or C1-C6alkyl. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC2is halo. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC2is F or Cl. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC2is F. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC2is Cl. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt 6thereof, wherein RC2is C1-C6alkyl. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC2is –CH3.

[0096] In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC3is H, halo, or C1-C6alkyl. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC3is H. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC3is halo. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC3is F. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC3is C1-C6alkyl. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC3is –CH3.

[0097] In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC4is H. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC4is halo. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC4is F or Cl. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC4is -CH3.

[0098] In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC5is halo. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC5is F or Cl. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), 7(II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC5is -C1-C3alkyl. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC5is -CH3or -CH2CH3. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC5is -C3-C6cycloalkyl. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC5is cyclopropyl. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC5is -OCH3or -CH2OH. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC5is -OCH3. In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC5is -CH2OH. In some embodiments, the invention relates to a compound of (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein RC5is H.

[0099] In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein XC1is C-RC1, XC2is C-RC2, RC1is -CH3, RC2is F, RC3is F, RC4is H, and RC5is H.

[0100] In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein XC1is C-RC1, XC2is C-RC2, RC1is -OCH3, RC2is F, RC3is F, RC4is H, and RC5is H.

[0101] In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein XC1is C-RC1, XC2is C-RC2, RC1is -OCH3, RC2is Cl, RC3is F, RC4is H, and RC5is H.

[0102] In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically 8acceptable salt thereof, wherein XC1is C-RC1, XC2is C-RC2, RC1is -CH3, RC2is Cl, RC3is F, RC4is H, and RC5is H.

[0103] In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein XC1is C-RC1, XC2is C-RC2, RC1is -CH2CH3, RC2is F, RC3is F, RC4is H, and RC5is H.

[0104] In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein XC1is N, XC2is C-RC2, RC2is –CH3, RC3is F, RC4is H, and RC5is H.

[0105] In some embodiments, the invention relates to a compound of formula (II-A), (II-B), (II-B-1), (II-B-2), (II-C), (II-D), (II-E), (II-F), (III-A), (III-A-1), (III-A-2), or (III-A-3), or a pharmaceutically acceptable salt thereof, wherein XC1is C-RC1, XC2is N, RC1is -OCH3, RC3is –CH3, RC4is H, and RC5is H.

[0106] In some embodiments, the invention relates to a compound selected from Table A, or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to a compound selected from Table A, i.e., the compound in non-salt form.

[0107] Table A. Compound Structures and Names.9

[0108] 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, i.e., the compound in non-salt form.

[0109] Table B. Compound Structures and Names.2

[0110] 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, i.e., the compound in non-salt form.

[0111] Table C. Compound Structures and Names.

[0112] In some embodiments, the invention relates to a compound selected from Table D, or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to a compound selected from Table D, i.e., the compound in non-salt form.

[0113] Table D. Compound Structures and Names.6Salts, Compositions, Uses, Formulation, Administration and Additional Agents Pharmaceutically acceptable salts and compositions

[0114] 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.

[0115] 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.

[0116] 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, 7camphorate, 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.

[0117] 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, aluminum stearate, 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 asmagnesium 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.

[0118] 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.

[0119] 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

[0120] 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.

[0121] 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.

[0122] 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, herniorrhaphy pain, bunionectomy 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.

[0123] 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, irritable bowel syndrome, endometriosis, polycystic ovarian disease, salpingitis, cervicitis 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. 9

[0124] In yet another aspect, the invention features a method of treating or lessening the severity in a subject of neuropathic pain comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some aspects, the neuropathic pain comprises post-herpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small-fiber neuropathy. In some aspects, the neuropathic pain comprises diabetic neuropathy (e.g., diabetic peripheral neuropathy). As used herein, the phrase “idiopathic small- fiber neuropathy” shall be understood to include any small fiber neuropathy.

[0125] 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, HIV-induced neuropathy; post spinal cord injury pain, spinal stenosis 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.

[0126] 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.

[0127] 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.

[0128] 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, ankylosing spondylitis 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.

[0129] In yet another aspect, the invention features a method of treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain wherein 0said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0130] In yet another aspect, the invention features a method of treating or lessening the severity 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.

[0131] In yet another aspect, the invention features a method of treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises reflex sympathetic dystrophy pain, wherein said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0132] In yet another aspect, the invention features a method of treating or lessening the severity in a subject of pathological cough wherein said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0133] In yet another aspect, the invention features a method of treating or lessening the severity in a subject of acute pain comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some aspects, the acute pain comprises acute post-operative pain.

[0134] In yet another aspect, the invention features a method of treating or lessening the severity in a subject of postsurgical pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, hemorrhoidectomy pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain) comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0135] In yet another aspect, the invention features a method of treating or lessening the severity in a subject of bunionectomy pain comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0136] In yet another aspect, the invention features a method of treating or lessening the severity in a subject of shoulder arthroplasty pain or shoulder arthroscopy pain comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0137] In yet another aspect, the invention features a method of treating 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. 1

[0138] 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.

[0139] 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.

[0140] 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).

[0141] 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.

[0142] 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.

[0143] In another aspect, the invention features a method of treating or lessening the severity in a subject of acute pain, sub-acute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, nociplastic pain, arthritis, migraine, cluster headaches, tension headaches, and all other forms of headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain of multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, unspecific chronic back pain, head pain, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain (e.g., joint replacement pain, soft tissue surgery pain, post- thoracotomy pain, post-mastectomy pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain), cancer pain including chronic cancer pain and breakthrough cancer pain, stroke (e.g., post stroke central neuropathic pain), whiplash associated disorders, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud’s Disease, scleroderma, systemic lupus erythematosus, Epidermolysis 2bullosa, gout, juvenile idiopathic arthritis, melorheostosis, polymyalgia reumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperostosis, disc degeneration / herniation pain, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget’s disease pain, spinal canal stenosis, spondylodyscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry’s disease, mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy induced oral mucositis, Charcot neuropathic osteoarhropathy, temporo-mandibular joint disorder, painful joint arthroplasties, non-cardiac chest pain, pudendal neuralgia, renal colic, biliary tract diseases, vascular leg ulcers, pain in Parkinson’s disease, pain in Alzheimer’s disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, 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.

[0144] 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; persistent / chronic post-surgical pain (e.g., post amputation, post-thoracotomy, post- cardiac surgery), post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; phantom pain (e.g., following removal of lower extremity, upper extremity, breast); intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury pain; exercise pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, burn pain, trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; 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 3angina-induced pain, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0145] In another aspect, the invention features a method of treating or lessening the severity in a subject of trigeminal neuralgia, migraines treated with botox, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, iliolingual neuralgia, pudendal neuralgia, femoral neuropathy, meralgia paresthetica, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain or postamputation pain, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. Compounds, Pharmaceutically Acceptable Salts, and Compositions for Use

[0146] 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.

[0147] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting a voltage-gated sodium channel in a subject. In another aspect, the voltage-gated sodium channel is NaV1.8.

[0148] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., herniorrhaphy pain, bunionectomy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia.

[0149] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia.

[0150] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of gut pain, wherein gut pain comprises inflammatory bowel disease pain, Crohn’s disease pain, irritable bowel syndrome, endometriosis, polycystic ovarian disease, salpingitis, cervicitis or interstitial cystitis pain. 4

[0151] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of neuropathic pain. In some aspects, the neuropathic pain comprises post-herpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small-fiber neuropathy. In some aspects, the neuropathic pain comprises diabetic neuropathy (e.g., diabetic peripheral neuropathy). As used herein, the phrase “idiopathic small-fiber neuropathy” shall be understood to include any small fiber neuropathy.

[0152] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of 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, HIV- induced neuropathy; post spinal cord injury pain, spinal stenosis pain, small fiber neuropathy, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia.

[0153] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of musculoskeletal pain. In some aspects, the musculoskeletal pain comprises osteoarthritis pain.

[0154] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain.

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

[0156] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain. 5

[0157] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.

[0158] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises reflex sympathetic dystrophy pain.

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

[0160] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of acute pain. In some aspects, the acute pain comprises acute post-operative pain.

[0161] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of postsurgical pain (e.g., joint replacement pain, soft tissue surgery pain, post- thoracotomy pain, post-mastectomy pain, hemorrhoidectomy pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain).

[0162] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of bunionectomy pain.

[0163] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of shoulder arthroplasty pain or shoulder arthroscopy pain.

[0164] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of herniorrhaphy pain.

[0165] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of abdominoplasty pain.

[0166] 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. 6

[0167] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of a neurodegenerative disease. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt Hopkins Syndrome (PTHS).

[0168] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method 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.

[0169] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of 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.

[0170] 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, sub-acute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, nociplastic pain, arthritis, migraine, cluster headaches, tension headaches, and all other forms of headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain of multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, unspecific chronic back pain, head pain, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain), cancer pain including chronic cancer pain and breakthrough cancer pain, stroke (e.g., post stroke central neuropathic pain), whiplash associated disorders, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud’s Disease, scleroderma, systemic lupus erythematosus, Epidermolysis bullosa, gout, juvenile idiopathic arthritis, melorheostosis, polymyalgia reumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperostosis, disc degeneration / herniation pain, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget’s disease pain, spinal canal stenosis, spondylodyscitis, transverse myelitis, 7Ehlers-Danlos syndrome, Fabry’s disease, mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy induced oral mucositis, Charcot neuropathic osteoarhropathy, temporo-mandibular joint disorder, painful joint arthroplasties, non-cardiac chest pain, pudendal neuralgia, renal colic, biliary tract diseases, vascular leg ulcers, pain in Parkinson’s disease, pain in Alzheimer’s disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastro-intestinal motility.

[0171] 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; persistent / chronic post-surgical pain (e.g., post amputation, post-thoracotomy, post-cardiac surgery), post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; phantom pain (e.g., following removal of lower extremity, upper extremity, breast); intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury pain; exercise pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, burn pain, trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; 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.

[0172] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of trigeminal neuralgia, migraines treated with botox, cervical radiculopathy, 8occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, iliolingual neuralgia, pudendal neuralgia, femoral neuropathy, meralgia paresthetica, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain or postamputation pain. Manufacture of Medicaments

[0173] 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.

[0174] 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.

[0175] In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for 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., herniorrhaphy pain, bunionectomy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia.

[0176] 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, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia.

[0177] 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, irritable bowel syndrome, endometriosis, polycystic ovarian disease, salpingitis, cervicitis or interstitial cystitis pain.

[0178] 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 foruse in treating or lessening the severity in a subject of neuropathic pain. In some aspects, the neuropathic pain comprises post-herpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small- fiber neuropathy. In some aspects, the neuropathic pain comprises diabetic neuropathy (e.g., diabetic peripheral neuropathy).

[0179] 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, HIV-induced neuropathy; post spinal cord injury pain, spinal stenosis pain, small fiber neuropathy, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic neuropathy.

[0180] 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.

[0181] 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, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain.

[0182] 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, ankylosing spondylitis or vulvodynia.

[0183] 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.

[0184] 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 idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.

[0185] 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 reflex sympathetic dystrophy pain.

[0186] 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.

[0187] 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.

[0188] 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., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, hemorrhoidectomy pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain).

[0189] In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of herniorrhaphy pain.

[0190] 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.

[0191] 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 shoulder arthroplasty pain or shoulder arthroscopy pain.

[0192] 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.

[0193] 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 visceral pain. In some aspects, the visceral pain comprises visceral pain from abdominoplasty.

[0194] 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).

[0195] 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.

[0196] 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, sub-acute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, nociplastic pain, arthritis, migraine, cluster headaches, tension headaches, and all other forms of headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain of multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, unspecific chronic back pain, head pain, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain), cancer pain including chronic cancer pain and breakthrough cancer pain, stroke (e.g., post stroke central neuropathic pain), whiplash associated disorders, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud’s Disease, scleroderma, systemic lupus erythematosus, Epidermolysis bullosa, gout, juvenile idiopathic arthritis, melorheostosis, polymyalgia reumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperostosis, disc degeneration / herniation pain, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget’s disease pain, spinal canal stenosis, spondylodyscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry’s disease, mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy induced oral mucositis, Charcot neuropathic osteoarhropathy, temporo-mandibular joint disorder, painfuljoint arthroplasties, non-cardiac chest pain, pudendal neuralgia, renal colic, biliary tract diseases, vascular leg ulcers, pain in Parkinson’s disease, pain in Alzheimer’s disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastro-intestinal motility.

[0197] 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 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; persistent / chronic post-surgical pain (e.g., post amputation, post-thoracotomy, post-cardiac surgery), post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; phantom pain (e.g., following removal of lower extremity, upper extremity, breast); intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury pain; exercise pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, burn pain, trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; 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.

[0198] 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 trigeminal neuralgia, migraines treated with botox, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, iliolingual neuralgia, pudendal neuralgia, femoral neuropathy, meralgia paresthetica, saphenous 3neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain or postamputation pain. Administration of Compounds, Pharmaceutically Acceptable Salts, and Compositions

[0199] 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.

[0200] 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.

[0201] 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), buccally, as an oral or nasal spray, or the like, depending on the severity of the condition being treated. In certain embodiments, the compound, salts, and compositions of the invention may be administered orally or parenterally at dosage levels of about 0.001 mg / kg to about 1000 mg / kg, one or more times a day, effective to obtain the desired therapeutic effect.

[0202] 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, 4isopropyl 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.

[0203] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable 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.

[0204] 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 that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0205] 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 microencapsulated 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.

[0206] 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.

[0207] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound or salt is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, 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.

[0208] 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.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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

[0213] 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 the same disorder (for example, an inventive compound may be administered concurrently with another agent 7used 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: non-opioid analgesics (indoles such as Etodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such as Nabumetone; oxicams such as Piroxicam; para-aminophenol derivatives, such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylates such as Aspirin, Choline magnesium trisalicylate, Diflunisal; fenamates such as meclofenamic acid, Mefenamic acid; and pyrazoles such as Phenylbutazone); or opioid (narcotic) agonists (such as Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine). Additionally, 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.

[0214] In another embodiment, additional appropriate therapeutic agents are selected from the following:

[0215] (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;

[0216] (2) a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen (including without limitation intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketorolac (including without limitation ketorolac tromethamine (e.g., Toradol®)), meclofenamic acid, mefenamic acid, meloxicam, IV meloxicam (e.g., Anjeso®), nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac; 8

[0217] (3) a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal or thiopental;

[0218] (4) a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;

[0219] (5) a histamine (H1) antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;

[0220] (6) a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;

[0221] (7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine;

[0222] (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;

[0223] (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;

[0224] (10) a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline;

[0225] (11) an anticonvulsant, e.g. carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®) or valproate;

[0226] (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);

[0227] (13) a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

[0228] (14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

[0229] (15) a coal-tar analgesic, in particular paracetamol; 9

[0230] (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;

[0231] (17) a vanilloid receptor agonist (e.g. resinferatoxin or civamide) or antagonist (e.g. capsazepine, GRC-15300);

[0232] (18) a beta-adrenergic such as propranolol;

[0233] (19) a local anesthetic such as mexiletine;

[0234] (20) a corticosteroid such as dexamethasone;

[0235] (21) a 5-HT receptor agonist or antagonist, particularly a 5-HT1B / 1Dagonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

[0236] (22) a 5-HT2Areceptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-l-[2-(4- fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);

[0237] (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;

[0238] (24) Tramadol®, Tramadol ER (Ultram ER®), IV Tramadol, Tapentadol ER (Nucynta®);

[0239] (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;

[0240] (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, 0[(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;

[0241] (27) a cannabinoid such as KHK-6188;

[0242] (28) metabotropic glutamate subtype 1 receptor (mGluRl) antagonist;

[0243] (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;

[0244] (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;

[0245] (31) a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran and imipramine;

[0246] (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;

[0247] (33) an acetylcholinesterase inhibitor such as donepezil;

[0248] (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;

[0249] (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; 1

[0250] (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);

[0251] (37) a sodium channel blocker, such as lidocaine, lidocaine plus tetracaine cream (ZRS-201) or eslicarbazepine acetate;

[0252] (38) a NaV1.7 blocker, such as XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893 BIIB-074 (Vixotrigine), BIIB-095, ASP-1807, DSP-3905, OLP-1002, RQ- 00432979, FX-301, DWP-1706, DWP-17061, IMB-110, IMB-111, IMB-112 and such as those disclosed in WO2011 / 140425 (US2011 / 306607); WO2012 / 106499 (US2012196869); WO2012 / 112743 (US2012245136); WO2012 / 125613 (US2012264749), WO2012 / 116440 (US2014187533), WO2011026240 (US2012220605), US8883840, US8466188, WO2013 / 109521 (US2015005304), CN111217776, WO2020 / 117626, WO2021 / 252822, WO2021 / 252818, WO2021 / 252820, WO2014 / 201173, WO2012 / 125973, WO2013 / 086229, WO2013 / 134518, WO2014 / 201206, or WO2016 / 141035 the entire contents of each application hereby incorporated by reference;

[0253] (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]- 26-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.

[0254] (39) a NaV1.8 blocker, such as PF-04531083, PF-06372865 and such as those disclosed in WO2008 / 135826 (US2009048306), WO2006 / 011050 (US2008312235), WO2013 / 061205 (US2014296313), US20130303535, WO2013131018, US8466188, WO2013114250 (US2013274243), WO2014 / 120808 (US2014213616), WO2014 / 120815 (US2014228371) WO2014 / 120820 (US2014221435), WO2015 / 010065 (US20160152561), WO2015 / 089361 (US20150166589), WO2019 / 014352 (US20190016671), WO2018 / 213426, WO2020 / 146682, WO2020 / 146612, WO2020 / 014243, WO2020 / 014246, WO2020 / 092187, WO2020 / 092667 (US2020140411), WO2020 / 144375, WO2020 / 261114, WO2020 / 140959, WO2020 / 151728, WO2021 / 032074, WO2021 / 047622 (CN112479996), WO2021 / 257490, WO2021 / 257420, WO2021 / 257418, WO2022 / 263498, WO2022 / 235558, WO2022 / 235859, WO2023 / 138599, WO2024 / 041613, WO2024 / 046253, WO2024 / 046409, CN112390745, CN111808019, CN112225695, CN112457294, CN112300051, CN112300069, CN112441969, and CN114591293, the entire contents of each application hereby incorporated by reference;

[0255] (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- 3(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- 5sulfamoylphenyl)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;

[0256] (40) a combined NaV1.7 and NaV1.8 blocker, such as DSP-2230, Lohocla201 or BL-1021;

[0257] (41) a 5-HT3 antagonist, such as ondansetron;

[0258] (42) a TPRV 1 receptor agonist, such as capsaicin (NeurogesX®, Qutenza®); and the pharmaceutically acceptable salts and solvates thereof;

[0259] (43) a nicotinic receptor antagonist, such as varenicline;

[0260] (44) an N-type calcium channel antagonist, such as Z-160;

[0261] (45) a nerve growth factor antagonist, such as tanezumab;

[0262] (46) an endopeptidase stimulant, such as senrebotase;

[0263] (47) an angiotensin II antagonist, such as EMA-401;

[0264] (48) acetaminophen (including without limitation intravenous acetaminophen (e.g., Ofirmev®));

[0265] (49) bupivacaine (including without limitation bupivacaine liposome injectable suspension (e.g., Exparel®) bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll) and transdermal bupivacaine (Eladur®)); and

[0266] (50) bupivacaine and meloxicam combination (e.g., HTX-011).

[0267] 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.

[0268] 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.

[0269] 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.

[0270] In another embodiment, the additional therapeutic agent is oliceridine or ropivacaine (TLC590).

[0271] In another embodiment, the additional therapeutic agent is a NaV1.7 blocker such as ST-2427, ST-2578 and those disclosed in WO2010 / 129864, WO2015 / 157559, WO2017 / 059385, WO2018 / 183781, 7WO2018 / 183782, WO2020 / 072835, and / or WO2022 / 036297 the entire contents of each application hereby incorporated by reference.

[0272] In another embodiment, the additional therapeutic agent is selected from 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, and XT-150.

[0273] In another embodiment, the additional therapeutic agent is selected from Olinvyk, Zynrelef, Seglentis, Neumentum, Nevakar, HTX-034, CPL-01, ACP-044, HRS-4800, Tarlige, BAY2395840, LY3526318, Eliapixant, TRV045, RTA901, NRD1355-E1, MT-8554, LY3556050, AP-325, tetrodotoxin, Otenaproxesul, CFTX-1554, Funapide, iN1011-N17, JMKX000623 / ODM-111, ETX-801, OLP-1002, ANP-230 / DSP-2230, iN1011-N17, DSP-3905 and ACD440.

[0274] In another embodiment, the additional therapeutic agent is selected from HRS4800, ODM- 111 / JMKX000623, LX9211, LY3556050, LY3857210, CFTX01554 / CFTX-1554, MEDI7352, MEDI0618, BAY3178275, BAY2395840, GSK3858279, STC-004, HALNEURON, OLP-1002, ATX01, ANP230, CC-8464, iN1011-N17, ST-2427, MSD199, FZ008, VYNAV-01, BL-017881, Profervia (Cilnidipine), LS-04, vixotrigine, FX301 / PCRX-301, PF-04531083, PF-01247324, and DSP-3905.

[0275] 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.

[0276] 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.

[0277] 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 8hydrogel 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.

[0278] 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.

[0279] 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

[0280] The compounds of the invention can be prepared from known materials by the methods described in the Examples, other similar methods, and other methods known to one skilled in the art. As one skilled in the art would appreciate, the functional groups of the intermediate compounds in the methods described below may need to be protected by suitable protecting groups. Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art. The use of protecting groups is described in detail in T.G.M. Wuts et al., Greene’s Protective Groups in Organic Synthesis (4th ed.2006). Radiolabeled Analogs of the Compounds of the Invention

[0281] 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.

[0282] 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, 9Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0283] 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.

[0284] 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.

[0285] 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.

[0286] 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.

[0287] 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.

[0288] 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.

[0289] In another aspect, the radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, can be employed in combination therapies, in accordance with any of the embodiments described herein in connection with the compounds of the invention. ENUMERATED EMBODIMENTS

[0290] Additional embodiments, features, and advantages of the disclosure will be apparent from the following detailed description and through practice of the disclosure. The compounds and methods of the present disclosure can be described as embodiments in any of the following enumerated clauses. It will beunderstood that any of the embodiments described herein can be used in connection with any other embodiments described herein to the extent that the embodiments do not contradict one another. 1. A compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein: XA1is C-RA1, N, or N+-O-; XA2is C-RA2, N, or N+-O-; XA4is C-RA4, N, or N+-O-; XA5is C-RA5or N; XC1is C-RC1or N; XC2is C-RC2or N; RA1, RA2, RA3, and RA4are each independently H, OH, CN, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, –NHS(O)2(C1-C6alkyl), –C(O)ORb, –C(O)NRbRc, –(CH2)mO(CH2)oCH3, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents independently selected from C1-C6alkyl and –C(O)NRbRc; RA5is H, OH, halo, CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, –(CH2)mOn(CH2)oOCH3, –(CH2)mRa, –C(O)(CH2)mRa, –C(O)ORb, –C(O)Rb, –C(O)NRbRc, –NRbRc, –CRdReRf, –CRbRcNRgC(O)CRhRiRj, –NRbC(O)CRcRgRj, C3-C6cycloalkyl, 5-6 membered heteroaryl, or 4-10 membered heterocyclyl, wherein said C3-C6cycloalkyl, 5-6 membered heteroaryl, or 4-10 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents independently selected from halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; R1and R2are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R3and R4are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; 1p, Z, R5, R6, R7, and R8are defined as follows: (i) p is 0 or 1; Z is C(-R3)(-R4); R5and R6are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; and R7and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; or (ii) p is 0 or 1; Z is C(-R3)(-R4); R7and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; and R5and R6, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl optionally substituted with 1-6 Ry; or (iii) p is 0 or 1; Z is C(-R3)(-R4); R5and R7, together with the carbon atoms to which they are attached, form a fused C3-C6cycloalkyl optionally substituted with 1-6 Ry; and R6and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; or (iv) p is 0; Z is C(-R3)(-R4) or O; R5and R7, together with the carbon atoms to which they are attached, form a fused ring of formula, optionally substituted with 1-4 Ry; and R6and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R9is H or CH3; RC1and RC2are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, –[CH2]q-C3-C6cycloalkyl, –[CH2]q-O-C3-C6cycloalkyl, –[CH2]q-NRbRc, –(CH2)mORb, or –O(CH2)mOCH3, or RC1and RC2, together with the carbon atoms to which they are attached, form a ring of formula: 2Y is O or CH2; RC3, RC4, and RC5are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, –O-C3-C6cycloalkyl, –NRbRc, –(CH2)mORb, or –O(CH2)mOCH3; each Rxis independently H, halo, C1-C6alkyl, or C1-C6haloalkyl; each Ryis independently halo, OH, C1-C6alkyl, or C1-C6haloalkyl; Rais OH, halo, C1-C6alkoxy, or –NRbRc; Rb, Rc, Rg, Rh, and Riare each independently H or C1-C6alkyl, or Rband Rc, together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclyl; Rd, Re, and Rfare each independently H, OH, halo, C1-C6alkyl, or C1-C6alkoxy; Rjis H, C1-C6alkyl, –NRbRc, or –N(CH3)3+; m and o are each independently 0, 1, 2, or 3; q is 0 or 1; and n is 0 or 1. 2. The compound of clause 1, or a pharmaceutically acceptable salt thereof, wherein: p is 0 or 1; Z is C(-R3)(-R4); R5, R6, R7, and R8are defined as follows: (i) R5and R6are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; and R7and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; or (ii) R7and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; and R5and R6, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl optionally substituted with 1-6 Ry; or (iii) R5and R7, together with the carbon atoms to which they are attached, form a fused C3-C6cycloalkyl optionally substituted with 1-6 Ry; and R6and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy.3. The compound of clause 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II):wherein: XA1is C-RA1, N, or N+-O-; XA2is C-RA2, N, or N+-O-; p is 0 or 1; XC1is C-RC1or N; XC2is C-RC2or N; RA1and RA2are each independently H, OH, CN, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, –NHS(O)2(C1-C6alkyl), –C(O)ORb, –C(O)NRbRc, –(CH2)mO(CH2)oCH3, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents independently selected from C1-C6alkyl and –C(O)NRbRc; R1and R2are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R3and R4are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R5, R6, R7, and R8are defined as follows: (i) R5and R6are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; and R7and R8are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; or (ii) R7and R8are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; and R5and R6, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl optionally substituted with 1-6 Ry; or(iii) R5and R7, together with the carbon atoms to which they are attached, form a fused C3-C6cycloalkyl optionally substituted with 1-6 Ry; and R6and R8are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R9is H or CH3; RC1, RC2, RC3, RC4, and RC5are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, –O-C3-C6cycloalkyl, –NRbRc, –(CH2)mORb, or –O(CH2)mOCH3; each Ryis independently halo, OH, C1-C6alkyl, or C1-C6haloalkyl; Rband Rcare each independently H or C1-C6alkyl, or Rband Rc, together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclyl; and m and o are each independently 0, 1, 2, or 3. 4. The compound of clause 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (III):wherein: XA1is C-RA1, N, or N+-O-; XA2is C-RA2, N, or N+-O-; Z is C(-R3)(-R4) or O; XC1is C-RC1or N; XC2is C-RC2or N; RA1and RA2are each independently H, OH, CN, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, –NHS(O)2(C1-C6alkyl), –C(O)ORb, –C(O)NRbRc, –(CH2)mO(CH2)oCH3, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents independently selected from C1-C6alkyl and –C(O)NRbRc;R3and R4are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R6and R8are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R9is H or CH3; RC1, RC2, RC3, RC4, and RC5are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, –O-C3-C6cycloalkyl, –NRbRc, –(CH2)mORb, or –O(CH2)mOCH3; each Ryis independently halo, OH, C1-C6alkyl, or C1-C6haloalkyl; Rband Rcare each independently H or C1-C6alkyl, or Rband Rc, together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclyl; m and o are each independently 0, 1, 2, or 3; and r is 0, 1, 2, 3, or 4. 5. The compound of any one of clauses 1 to 4, or a pharmaceutically acceptable salt thereof, wherein XA1is C-RA1. 6. The compound of any one of clauses 1 to 5, or a pharmaceutically acceptable salt thereof, wherein RA1is –C(O)NRbRc, and Rband Rcare each independently H or C1-C6alkyl. 7. The compound of any one of clauses 1 to 6, or a pharmaceutically acceptable salt thereof, wherein XA2is N. 8. The compound of any one of clauses 1 to 7, or a pharmaceutically acceptable salt thereof, wherein: XA1is C-RA1; RA1is –C(O)NRbRc; Rband Rcare each H; and XA2is N. 9. The compound of any one of clauses 1 to 3 and 5 to 8, or a pharmaceutically acceptable salt thereof, wherein p is 0. 10. The compound of any one of clauses 1 to 3 and 5 to 8, or a pharmaceutically acceptable salt thereof, wherein p is 1.11. The compound of any one of clauses 1 to 3, 5 to 8 and 10, or a pharmaceutically acceptable salt thereof, wherein R1and R2are each H. 12. The compound of any one of clauses 1 to 3 and 5 to 11, or a pharmaceutically acceptable salt thereof, wherein R3and R4are each independently H or C1-C2haloalkyl. 13. The compound of any one of clauses 1 to 3 and 5 to 12, or a pharmaceutically acceptable salt thereof, wherein R3and R4are each independently H or CF3. 14. The compound of any one of clauses 1 to 3 and 5 to 13, or a pharmaceutically acceptable salt thereof, wherein R3and R4are each H. 15. The compound of any one of clauses 1 to 3 and 5 to 14, or a pharmaceutically acceptable salt thereof, wherein R5and R6are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy or, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl optionally substituted with 1-6 Ry, where each Ryis independently halo or C1haloalkyl. 16. The compound of any one of clauses 1 to 3 and 5 to 15, or a pharmaceutically acceptable salt thereof, wherein R5and R6are each independently H, C1-C4alkyl, or C1haloalkyl. 17. The compound of any one of clauses 1 to 3 and 5 to 16, or a pharmaceutically acceptable salt thereof, wherein R5and R6are each independently H, -CH3, -C(CH3)3or -CF3. 18. The compound of any one of clauses 1 to 3 and 5 to 15, or a pharmaceutically acceptable salt thereof, wherein R5and R6, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl optionally substituted with 1-3 Ry, where each Ryis independently halo or C1haloalkyl. 19. The compound of any one of clauses 1 to 3, 5 to 15, and 18, or a pharmaceutically acceptable salt thereof, wherein R5and R6, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl optionally substituted with 2 Ry, where each Ryis independently F. 20. The compound of any one of clauses 1 to 3 and 5 to 19, or a pharmaceutically acceptable salt thereof, wherein R7and R8are each independently H, OH, C1-C3alkyl, C1-C3haloalkyl, or C1-C3alkoxy. 21. The compound of any one of clauses 1 to 3 and 5 to 20, or a pharmaceutically acceptable salt thereof, wherein R7and R8are each independently H, OH, -CH3, -CF3, or -O-CH3. 722. The compound of any one of clauses 1 to 3 and 5to 14, or a pharmaceutically acceptable salt thereof, wherein: R5and R7, together with the carbon atoms to which they are attached, form a fused C3-C6cycloalkyl optionally substituted with 1-3 Ry; R6and R8are each H; and each Ryis independently halo. 23. The compound of any one of clauses 1 to 3, 5 to 14, and 22, or a pharmaceutically acceptable salt thereof, wherein: R5and R7, together with the carbon atoms to which they are attached, form a fused C5or C6cycloalkyl optionally substituted with 2 F; and R6and R8are each H. 24. The compound of any one of clauses 1 and 4 to 8, or a pharmaceutically acceptable salt thereof, wherein Z is O. 25. The compound of any one of clauses 1, 4 to 8, and 24, or a pharmaceutically acceptable salt thereof, wherein R6and R8are each H. 26. The compound of any one of clauses 1, 4 to 8, 24, and 25, or a pharmaceutically acceptable salt thereof, wherein each Ryis independently halo, and r is 2. 27. The compound of any one of clauses 1, 4 to 8, and 24 to 26, or a pharmaceutically acceptable salt thereof, wherein each Ryis F, and r is 2. 28. The compound of any one of clauses 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R9is H. 29. The compound of any one of clauses 1 to 28, or a pharmaceutically acceptable salt thereof, wherein: XC1is C-RC1; and XC2is C-RC2. 30. The compound of any one of clauses 1 to 28, or a pharmaceutically acceptable salt thereof, wherein: XC1is C-RC1; and XC2is N. 831. The compound of any one of clauses 1 to 30, or a pharmaceutically acceptable salt thereof, wherein RC1, RC2, RC3, RC4, and RC5are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, -O-C3-C6cycloalkyl, or –CH2OH. 32. The compound of any one of clauses 1 to 31, or a pharmaceutically acceptable salt thereof, wherein RC1, RC2, RC3, RC4, and RC5are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, or –CH2OH. 33. The compound of any one of clauses 1 to 32, or a pharmaceutically acceptable salt thereof, wherein RC1, RC2, RC3, RC4, and RC5are each independently H, OH, F, Cl, -CH3, -CH2CH3, -OCH3, -CF3, C3cycloalkyl, -O-C3cycloalkyl, or –CH2OH. 34. The compound of any one of clauses 1 to 33, or a pharmaceutically acceptable salt thereof, wherein RC1, RC2, RC3, RC4, and RC5are each independently H, OH, F, Cl, -CH3, -CH2CH3, -OCH3, C3cycloalkyl, or –CH2OH. 35. The compound of any one of clauses 1 to 34, or a pharmaceutically acceptable salt thereof, wherein RC1is -CH3, RC2is F, RC3is F, RC4is H, and RC5is H. 36. The compound of any one of clauses 1 to 34, or a pharmaceutically acceptable salt thereof, wherein RC1is -OCH3, RC2is F, RC3is F, RC4is H, and RC5is H. 37. The compound of any one of clauses 1 to 34, or a pharmaceutically acceptable salt thereof, wherein RC1is -OCH3, RC2is Cl, RC3is F, RC4is H, and RC5is H. 38. The compound of any one of clauses 1 to 34, or a pharmaceutically acceptable salt thereof, wherein RC1is -CH3, RC2is Cl, RC3is F, RC4is H, and RC5is H. 39. The compound of any one of clauses 1 to 34, or a pharmaceutically acceptable salt thereof, wherein RC1is -CH2CH3, RC2is F, RC3is F, RC4is H, and RC5is H. 40. A compound selected from Table A, or a pharmaceutically acceptable salt thereof. 41. A compound selected from Table B, or a pharmaceutically acceptable salt thereof. 42. A compound selected from Table C, or a pharmaceutically acceptable salt thereof. 43. The compound of any one of clauses 1 to 42 in non-salt form.44. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of clauses 1 to 42, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the compound of clause 43, and one or more pharmaceutically acceptable carriers or vehicles. 45. A pharmaceutical composition comprising the compound of any one of clauses 1 to 42, or a pharmaceutically acceptable salt thereof, or the compound of clause 43, and one or more pharmaceutically acceptable carriers or vehicles. 46. A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject the compound of any one of clauses 1 to 42, or a pharmaceutically acceptable salt thereof, the compound of clause 43, or the pharmaceutical composition of clause 44 or 45. 47. The method of clause 46, wherein the voltage-gated sodium channel is NaV1.8. 48. 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 clauses 1 to 42, or a pharmaceutically acceptable salt thereof, the compound of clause 43, or the pharmaceutical composition of clause 44 or 45. 49. The method of clause 48, where the method comprises treating or lessening the severity in the subject of neuropathic pain. 50. The method of clause 49, wherein the neuropathic pain comprises post-herpetic neuralgia. 51. The method of clause 49, wherein the neuropathic pain comprises small-fiber neuropathy. 52. The method of clause 49, wherein the neuropathic pain comprises idiopathic small-fiber neuropathy. 53. The method of clause 49, wherein the neuropathic pain comprises diabetic neuropathy. 54. The method of clause 53, wherein the diabetic neuropathy comprises diabetic peripheral neuropathy. 55. The method of clause 48, wherein the method comprises treating or lessening the severity in the subject of chronic pain. 0056. The method of clause 55, wherein the chronic pain is lumbosacral radiculopathy. 57. The method of clause 48, wherein the method comprises treating or lessening the severity in the subject of musculoskeletal pain. 58. The method of clause 57, wherein the musculoskeletal pain comprises osteoarthritis pain. 59. The method of clause 48, wherein the method comprises treating or lessening the severity in the subject of acute pain. 60. The method of clause 59, wherein the acute pain comprises acute post-operative pain. 61. The method of clause 48, wherein the method comprises treating or lessening the severity in the subject of postsurgical pain. 62. The method of clause 61, wherein the postsurgical pain comprises bunionectomy pain. 63. The method of clause 61, wherein the postsurgical pain comprises abdominoplasty pain. 64. The method of clause 61, wherein the postsurgical pain comprises herniorrhaphy pain. 65. The method of clause 48, wherein the method comprises treating or lessening the severity in the subject of visceral pain. 66. The method of any one of clauses 46 to 65, 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. 67. Use of the compound of any one of clauses 1 to 42, or a pharmaceutically acceptable salt thereof, the compound of clause 43, or the pharmaceutical composition of clause 44 or 45, as a medicament. EXAMPLES

[0291] General methods.1H NMR spectra were obtained as solutions in an appropriate deuterated solvent such as dimethyl sulfoxide-d6(DMSO-d6).

[0292] Compound purity, retention time, and electrospray mass spectrometry (ESI-MS) data were determined by LC / MS analysis. LC / MS methods employed in the following examples are described in Table E. 01

[0293] Table E. LC / MS Methods.02Abbreviations

[0294] 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 spectrometry HPLC High performance liquid chromatography SFC Supercritical fluid chromatography ESI Electrospray ionization cm Centimeters g Grams mg Milligrams L Liter(s) mL Milliliter(s) μL Microliter(s) mmol Millimole(s) h Hour(s) min Minute(s) mm Millimeter(s) μm Micrometer(s) MHz Megahertz Hz Hertz N Normal (concentration) M Molar (concentration) mM Millimolar (concentration) ppm Parts per million % w / v Weight-volume concentration % w / w Weight-weight concentration p-ABSA 4-Acetamidobenzenesulfonyl azide AcCl Acetyl chloride AcOH Acetic acid Bn Benzyl B2pin2Bis(pinacolato)diboron tBu tert-Butyl m-CPBA 3-Chloroperbenzoic acid DAST (Diethylamino)sulfur trifluoride DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE Dichloroethane DCM Dichloromethane DEA Diethylamine Dess Martin periodinane 1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one DIAD Diisopropyl azodicarboxylate DIBAL Diisobutylaluminium hydride DIPEA N,N-Diisopropylethylamine DMAP 4-(Dimethylamino)pyridine DMF Dimethylformamide 0304Example 1 rel-2-((1R,2R,3aR,6aS)-1-(3,4-Difluoro-2-methoxyphenyl)-4,4-difluorooctahydropentalen-2-yl)-4-oxo- 1,4-dihydro-1,6-naphthyridine-5-carboxamide (1) and rel-2-((1S,2S,3aS,6aR)-1-(3,4-difluoro-2- methoxyphenyl)-4,4-difluorooctahydropentalen-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5- carboxamide (2)Step 1:

[0295] Oxalyl chloride (436.5 mg, 0.3 mL, 3.439 mmol) was added to a solution of rac- (1R,2R,3aR,6aS)-1-(3,4-difluoro-2-methoxyphenyl)-4,4-difluorooctahydropentalene-2-carboxylic acid (C - 8b, 1 g, 3.006 mmol) and DMF (12 μL, 0.155 mmol) in DCM (8 mL) at ambient temperature and the reaction mixture was stirred at ambient temperature for 2 h.1-(4-Aminopyridin-3-yl)ethan-1-one hydrochloride (575 mg, 3.331 mmol) and Et3N (1.089 g, 1.5 mL, 10.762 mmol) were successively added and the reaction mixture was stirred for 65 h at ambient temperature. The mixture was quenched by addition of water (100 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, 10 to 100 % EtOAc in heptane) gave rac-(1R,2R,3aR,6aS)-N-(3-acetylpyridin-4-yl)-1-(3,4-difluoro-2- methoxyphenyl)-4,4-difluorooctahydropentalene-2-carboxamide (1.08 g, 80%) as an off-white solid.1H NMR (400 MHz, Chloroform-d) δ 12.03 (s, 1H), 9.09 (s, 1H), 8.64 - 8.48 (m, 2H), 6.94 - 6.85 (m, 1H), 6.84 - 6.72 (m, 1H), 4.00 (d, J = 2.4 Hz, 3H), 3.82 (dd, J = 12.2, 8.3 Hz, 1H), 3.22 (quin, J = 8.8 Hz, 1H), 3.10 (td, J = 12.1, 6.6 Hz, 1H), 3.00 - 2.83 (m, 1H), 2.73 (s, 3H), 2.50 (dd, J = 13.3, 6.7 Hz, 1H), 2.12 -1.83 (m, 3H), 1.40 - 1.29 (m, 1H), 1.22 - 1.08 (m, 1H) ppm. ESI-MS m / z calc.450.157, found 451.2 (M+1)+. Step 2:

[0296] Et3N (450.12 mg, 0.62 mL, 4.448 mmol) and TMSOTf (2.44 g, 2 mL, 10.978 mmol) were successively added to a solution of rac-(1R,2R,3aR,6aS)-N-(3-acetylpyridin-4-yl)-1-(3,4-difluoro-2- methoxyphenyl)-4,4-difluorooctahydropentalene-2-carboxamide (1 g, 2.218 mmol) in toluene (10 mL) and the reaction mixture was stirred at 90 °C for 4 h. The reaction was cooled to ambient temperature, diluted with 2-MeTHF (30 mL) and washed with a saturated aqueous NaHCO3solution (20 mL). The aqueous layer was extracted with 2-MeTHF (3 x 30 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in 2-MeTHF (30 mL), washed with a saturated aqueous NH4Cl solution (20 mL), water (20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by trituration from 2-MeTHF (2 mL) and MTBE (10 mL) gave rac-2-((1R,2R,3aR,6aS)-1-(3,4-difluoro-2-methoxyphenyl)-4,4-difluorooctahydropentalen-2-yl)-1,6- naphthyridin-4(1H)-one (820 mg, 85%) as a tan solid.1H NMR (400 MHz, Methanol-d4) δ 9.24 (s, 1H), 8.56 (d, J = 6.0 Hz, 1H), 7.52 (d, J = 6.0 Hz, 1H), 6.99 - 6.94 (m, 1H), 6.90 - 6.81 (m, 1H), 6.28 (s, 1H), 4.04 (d, J = 2.2 Hz, 3H), 3.93 (dd, J = 12.8, 8.1 Hz, 1H), 3.47 (td, J = 12.4, 6.8 Hz, 1H), 3.39 - 3.32 (m, 1H, overlapped with solvent), 3.08 - 2.95 (m, 1H), 2.62 (dd, J = 13.4, 6.7 Hz, 1H), 2.10 - 1.96 (m, 3H), 1.44 - 1.21 (m, 2H) ppm; exchangeable H not observed. ESI-MS m / z calc.432.146, found 433.2 (M+1)+. Step 3:

[0297] m-CPBA (206 mg, 0.919 mmol) was added to a solution of rac-2-((1R,2R,3aR,6aS)-1-(3,4- difluoro-2-methoxyphenyl)-4,4-difluorooctahydropentalen-2-yl)-1,6-naphthyridin-4(1H)-one (215 mg, 0.455 mmol) in DCM (9 mL) and the reaction mixture was stirred at ambient temperature for 6 h. The reaction was diluted with EtOAc (30 mL) and extracted with a saturated aqueous NaHCO3solution (3 x 30 mL). The combined organic layers were washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo to give rac-2-((1R,2R,3aR,6aS)-1-(3,4-difluoro-2-methoxyphenyl)-4,4- difluorooctahydropentalen-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine 6-oxide (170 mg, 79%) as a yellow solid, which was used without further purification in the next step.1H NMR (400 MHz, Methanol-d4) δ 8.86 (d, J = 1.8 Hz, 1H), 8.35 (dd, J = 7.3, 1.9 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.00 - 6.91 (m, 1H), 6.90 - 6.81 (m, 1H), 6.29 (s, 1H), 4.03 (d, J = 2.2 Hz, 3H), 3.93 (dd, J = 12.7, 8.1 Hz, 1H), 3.47 (td, J = 12.3, 7.0 Hz, 1H), 3.40 - 3.33 (m, 1H), 3.08 - 2.93 (m, 1H), 2.66 - 2.55 (m, 1H), 2.11 - 1.93 (m, 3H), 1.46 - 1.34 (m, 1H), 1.32 - 1.21 (m, 1H) ppm; exchangeable H not observed. ESI-MS m / z calc.448.141, found 449.2 (M+1)+.Step 4:

[0298] Under a nitrogen atmosphere, TMSCN (146.71 mg, 0.185 mL, 1.479 mmol) and AcCl (110.4 mg, 0.1 mL, 1.406 mmol) were successively added to a solution of rac-2-((1R,2R,3aR,6aS)-1-(3,4- difluoro-2-methoxyphenyl)-4,4-difluorooctahydropentalen-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine 6- oxide (165 mg, 0.347 mmol) in DCM (2 mL) and the reaction mixture was stirred at ambient temperature for 19 h. The reaction was carefully quenched by pouring the mixture into a stirred saturated aqueous NaHCO3solution (10 mL). The aqueous phase was separated and extracted with DCM (15 mL). The combined organic layers were washed with a saturated aqueous NaHCO3solution (10 mL) and water (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by reverse phase chromatography (5 to 80% MeCN in water with 0.1% formic acid) gave rac-2-((1R,2R,3aR,6aS)-1-(3,4-difluoro-2- methoxyphenyl)-4,4-difluorooctahydropentalen-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile (38 mg, 24%) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 8.65 (d, J = 5.9 Hz, 1H), 7.70 (d, J = 5.9 Hz, 1H), 6.99 - 6.92 (m, 1H), 6.91 - 6.81 (m, 1H), 6.29 (s, 1H), 4.04 (d, J = 2.2 Hz, 3H), 3.93 (dd, J = 12.9, 8.0 Hz, 1H), 3.51 - 3.41 (m, 1H), 3.40 - 3.27 (m, 1H, overlapped with solvent), 3.09 - 2.93 (m, 1H), 2.61 (dd, J = 13.4, 6.5 Hz, 1H), 2.11 - 1.93 (m, 3H), 1.46 - 1.33 (m, 1H), 1.32 - 1.21 (m, 1H) ppm; exchangeable H not observed. ESI-MS m / z calc.457.141, found 458.2 (M+1)+. Step 5:

[0299] In a sealed vial, a solution of rac-2-((1R,2R,3aR,6aS)-1-(3,4-difluoro-2-methoxyphenyl)-4,4- difluorooctahydropentalen-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile (100 mg, 0.167 mmol) and TFA (2.22 g, 1.5 mL, 19.470 mmol) in toluene (2.5 mL) was stirred at 70 °C for 48 h. The reaction mixture was concentrated in vacuo. Purification by reverse phase chromatography (C18column, 5% to 100% MeCN in water with 0.1% formic acid) gave rac-2-((1R,2R,3aR,6aS)-1-(3,4-difluoro-2- methoxyphenyl)-4,4-difluorooctahydropentalen-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5- carboxamide (80 mg, 97%) as a tan solid.1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 8.43 (d, J = 5.9 Hz, 1H), 7.43 (d, J = 5.9 Hz, 1H), 7.39 (br s, 1H), 7.20 (br s, 1H), 7.16 - 7.00 (m, 2H), 6.12 (br s, 1H), 3.94 (d, J = 1.7 Hz, 3H), 3.87 (dd, J = 13.0, 7.8 Hz, 1H), 3.47 - 3.36 (m, 1H), 3.25 - 3.15 (m, 1H), 3.04 - 2.90 (m, 1H), 2.38 (dd, J = 13.1, 6.7 Hz, 1H), 2.11 - 1.95 (m, 3H), 1.38 - 1.27 (m, 1H), 1.18 - 1.06 (m, 1H) ppm. ESI-MS m / z calc.475.152, found 476.2 (M+1)+. Step 6:

[0300] The enantiomers of rac-2-((1R,2R,3aR,6aS)-1-(3,4-difluoro-2-methoxyphenyl)-4,4- difluorooctahydropentalen-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (56 mg, 0.117 mmol) were separated by chiral SFC using a Lux®i-Cellulose-5 column, 5 μm particle size, 25 cm x 21.2 mm from Phenomenex (Mobile phase: 30% MeOH, 70% CO2; Flow rate 75 mL / min) to give: 07

[0301] First Eluting Isomer: rel-2-((1R,2R,3aR,6aS)-1-(3,4-difluoro-2-methoxyphenyl)-4,4- difluorooctahydropentalen-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (Compound 1, 24 mg, 43%).1H NMR (400 MHz, Methanol-d4) δ 8.48 (d, J = 6.0 Hz, 1H), 7.53 (d, J = 6.1 Hz, 1H), 7.00 - 6.92 (m, 1H), 6.90 - 6.80 (m, 1H), 6.24 (br s, 1H), 4.02 (d, J = 2.1 Hz, 3H), 3.92 (dd, J = 12.8, 8.1 Hz, 1H), 3.51 - 3.39 (m, 1H), 3.36 - 3.27 (m, 1H, overlapped with solvent), 3.09 - 2.94 (m, 1H), 2.60 (dd, J = 13.0, 6.8 Hz, 1H), 2.10 - 1.94 (m, 3H), 1.44 - 1.21 (m, 2H) ppm, exchangeable H not observed. ESI-MS m / z calc.475.152, found 476.2 (M+1)+.

[0302] Second Eluting Isomer: rel-2-((1S,2S,3aS,6aR)-1-(3,4-difluoro-2-methoxyphenyl)-4,4- difluorooctahydropentalen-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (Compound 2, 25 mg, 45%).1H NMR (400 MHz, Methanol-d4) δ 8.48 (d, J = 5.9 Hz, 1H), 7.53 (d, J = 5.7 Hz, 1H), 7.02 - 6.92 (m, 1H), 6.90 - 6.79 (m, 1H), 6.24 (br s, 1H), 4.02 (d, J = 2.0 Hz, 3H), 3.92 (dd, J = 13.0, 7.9 Hz, 1H), 3.50 - 3.40 (m, 1H), 3.38 - 3.27 (m, 1H, overlapped with solvent), 3.09 - 2.93 (m, 1H), 2.60 (dd, J = 13.0, 6.5 Hz, 1H), 2.13 - 1.92 (m, 3H), 1.44 - 1.23 (m, 2H) ppm, exchangeable H not observed. ESI-MS m / z calc.475.152, found 476.2 (M+1)+. Example 2 rel-2-((1S,2S)-2-(3,4-Difluoro-2-methoxyphenyl)-4,4-dimethylcyclohexyl)-4-oxo-1,4-dihydro-1,6- naphthyridine-5-carboxamide (3) and rel-2-((1R,2R)-2-(3,4-difluoro-2-methoxyphenyl)-4,4- dimethylcyclohexyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (4)Step 1:

[0303] T3P®(3.4 mL, 50 % w / v solution in EtOAc, 5.343 mmol) was added to a solution of rac- (1R,2R)-2-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylcyclohexane-1-carboxylic acid (C - 11a, 618 mg,1.693 mmol), 1-(4-aminopyridin-3-yl)ethan-1-one hydrochloride (470 mg, 2.723 mmol) and Et3N (1.089 g, 1.5 mL, 10.762 mmol) in EtOAc (7 mL) and reaction mixture was stirred at ambient temperature overnight. The reaction was quenched by addition of a saturated aqueous NaHCO3solution (20 mL) and extracted with EtOAc (3 x30 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by reverse phase chromatography (C18column, 5 to 95% MeCN in water with 0.1% formic acid) gave rac-(1R,2R)-N-(3-acetylpyridin-4-yl)-2-(3,4-difluoro-2- methoxyphenyl)-4,4-dimethylcyclohexane-1-carboxamide (193 mg, 24%) as a yellow glassy solid.1H NMR (400 MHz, Chloroform-d) δ 11.71 (br s, 1H), 9.06 (s, 1H), 8.57 - 8.47 (m, 2H), 6.97 - 6.87 (m, 1H), 6.84 - 6.71 (m, 1H), 3.97 (d, J = 1.7 Hz, 3H), 3.55 (t, J = 11.1 Hz, 1H), 2.71 (s, 3H), 2.68 - 2.56 (m, 1H), 2.02 - 1.92 (m, 2H), 1.66 - 1.50 (m, 3H), 1.46 - 1.34 (m, 1H), 1.16 (s, 3H), 1.00 (s, 3H) ppm. ESI-MS m / z calc.416.191, found 417.2 (M+1)+. Step 2:

[0304] In a sealed tube, KOtBu (100 mg, 0.891 mmol) was added to a solution of rac-(1R,2R)-N-(3- acetylpyridin-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylcyclohexane-1-carboxamide (193 mg, 0.402 mmol) in 1,4-dioxane (4 mL). The tube was sealed and the solution was placed under a nitrogen atmosphere. The reaction was heated at 50 °C for 1 h, at 90 °C for 2 h and at 100 °C for 20 h. The mixture was cooled to ambient temperature, diluted with a saturated aqueous NH4Cl solution (10 mL) and extracted with DCM (3 x 15 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by reverse phase chromatography (C18column, 5 to 95% of MeCN in water with 0.1% formic acid) gave rac-2-((1R,2R)-2-(3,4-difluoro-2-methoxyphenyl)-4,4- dimethylcyclohexyl)-1,6-naphthyridin-4(1H)-one (55 mg, 34%) as a beige solid.1H NMR (400 MHz, Chloroform-d) δ 9.41 (s, 1H), 8.59 (d, J = 5.6 Hz, 1H), 8.16 (br s, 1H), 7.14 (d, J = 5.4 Hz, 1H), 6.98 - 6.74 (m, 2H), 6.20 (s, 1H), 4.02 (br s, 3H), 3.67 - 3.43 (m, 1H), 2.83 - 2.66 (m, 1H), 2.04 - 1.80 (m, 2H), 1.71 - 1.39 (m, 4H), 1.14 (s, 3H), 1.05 (s, 3H) ppm. ESI-MS m / z calc.398.181, found 399.2 (M+1)+. Step 3:

[0305] m-CPBA (57 mg, 0.254 mmol) was added to a solution of rac-2-((1R,2R)-2-(3,4-difluoro-2- methoxyphenyl)-4,4-dimethylcyclohexyl)-1,6-naphthyridin-4(1H)-one (50 mg, 0.126 mmol) in DCM (2 mL) and reaction mixture was stirred at ambient temperature for 4 h. The reaction was diluted with EtOAc (20 mL) and washed with a saturated aqueous NaHCO3solution (3 x 30 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give rac-2-((1R,2R)-2-(3,4-difluoro-2- methoxyphenyl)-4,4-dimethylcyclohexyl)-4-oxo-1,4-dihydro-1,6-naphthyridine 6-oxide (40 mg, 71%) as an orange solid, which was used without further purification in the next step. ESI-MS m / z calc.414.176, found 415.2 (M+1)+. 09Step 4:

[0306] In a sealed tube, TMSCN (95.160 mg, 0.12 mL, 0.959 mmol) and Et3N (130.68 mg, 0.18 mL, 1.291 mmol) were successively added to a solution of rac-2-((1R,2R)-2-(3,4-difluoro-2-methoxyphenyl)- 4,4-dimethylcyclohexyl)-4-oxo-1,4-dihydro-1,6-naphthyridine 6-oxide (40 mg, 0.090 mmol) in DCM (2 mL) under a nitrogen atmosphere. The tube was sealed and the reaction mixture was stirred at ambient temperature overnight. The mixture was diluted with a saturated NaHCO3solution (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to give rac-2-((1R,2R)-2-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylcyclohexyl)-4-oxo-1,4- dihydro-1,6-naphthyridine-5-carbonitrile (35 mg, 86%) as a beige solid, which was used without further purification in the next step.1H NMR (400 MHz, Methanol-d4) δ 8.62 (d, J = 5.9 Hz, 1H), 7.66 (d, J = 5.9 Hz, 1H), 7.12 - 6.97 (m, 1H), 6.94 - 6.77 (m, 1H), 6.21 (s, 1H), 3.90 (s, 3H), 3.78 - 3.58 (m, 1H), 3.00 - 2.78 (m, 1H), 2.07 - 1.90 (m, 2H), 1.71 - 1.45 (m, 4H), 1.22 (s, 3H), 1.04 (s, 3H) ppm; exchangeable H not observed. ESI-MS m / z calc.423.176, found 424.2 (M+1)+. Step 5:

[0307] In a sealed tube, TFA (740 mg, 0.5 mL, 6.490 mmol) and a drop of water were successively added to a solution of rac-2-((1R,2R)-2-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylcyclohexyl)-4-oxo- 1,4-dihydro-1,6-naphthyridine-5-carbonitrile (35 mg, 0.077 mmol) in toluene (2 mL). The tube was sealed and the reaction mixture was stirred at 70 °C overnight. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was diluted with EtOAc (30 mL), washed with a saturated aqueous NaHCO3solution (2 x 10 mL), dried (Na2SO4) and concentrated in vacuo. Purification by reverse phase chromatography (C18column, 5 to 95% of MeCN in water with 0.1% formic acid) gave rac-2-((1R,2R)-2-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylcyclohexyl)-4-oxo-1,4-dihydro-1,6- naphthyridine-5-carboxamide. Step 6:

[0308] The enantiomers of rac-2-((1R,2R)-2-(3,4-difluoro-2-methoxyphenyl)-4,4- dimethylcyclohexyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (56 mg, 0.117 mmol) were separated by chiral SFC using a Lux®Cellulose-4 column, 5 μm particle size, 15 cm x 21.2 mm from Phenomenex (Mobile phase: 30% MeOH, 70% CO2; Flow rate 75 mL / min) to give:

[0309] First Eluting Isomer: rel-2-((1S,2S)-2-(3,4-difluoro-2-methoxyphenyl)-4,4- dimethylcyclohexyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (Compound 3, 7.8 mg, 22% over 2 steps) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 15.11 (s, 1H), 8.90 (br s, 1H), 8.53 (d, J = 5.6 Hz, 1H), 7.95 (d, J = 5.6 Hz, 1H), 6.98 - 6.85 (m, 2H), 6.75 - 6.57 (m, 1H), 6.03 (br s, 1H), 3.94 (s, 3H), 3.88 - 3.72 (m, 1H), 3.20 - 3.06 (m, 1H), 1.99 - 1.88 (m, 2H), 1.69 - 1.45 (m, 4H, overlapped with water), 1.21 (s, 3H), 1.02 (s, 3H) ppm. ESI-MS m / z calc.441.186, found 442.2 (M+1)+. 10

[0310] Second Eluting Isomer: rel-2-((1R,2R)-2-(3,4-difluoro-2-methoxyphenyl)-4,4- dimethylcyclohexyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (Compound 4, 10 mg, 28% over 2 steps) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 15.10 (s, 1H), 8.89 (br s, 1H), 8.51 (d, J = 5.9 Hz, 1H), 7.93 (d, J = 5.6 Hz, 1H), 6.96 - 6.85 (m, 2H), 6.74 - 6.56 (m, 1H), 6.02 (br s, 1H), 3.92 (s, 3H), 3.85 - 3.72 (m, 1H), 3.18 - 3.03 (m, 1H), 1.97 - 1.87 (m, 2H), 1.66 - 1.45 (m, 4H, overlapped with water), 1.20 (s, 3H), 1.01 (s, 3H) ppm. ESI-MS m / z calc.441.186, found 442.2 (M+1)+. Example 3 rel-2-((1R,2R,3aR,6aS)-1-(3,4-Difluoro-2-methylphenyl)-4,4-difluorooctahydropentalen-2-yl)-4-oxo-1,4- dihydro-1,6-naphthyridine-5-carboxamide (5) and rel-2-((1S,2S,3aS,6aR)-1-(3,4-difluoro-2- methylphenyl)-4,4-difluorooctahydropentalen-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (6)Step 1:

[0311] DIPEA (3.33 g, 4.5 mL, 25.765 mmol) was added to a stirred solution of rac- (1R,2R,3aR,6aS)-1-(3,4-difluoro-2-methylphenyl)-4,4-difluorooctahydropentalene-2-carboxylic acid (C - 8a, 536 mg, 1.620 mmol) and 1-(4-aminopyridin-3-yl)ethan-1-one hydrochloride (342 mg, 1.981 mmol) in DMF (13 mL) and the reaction mixture was stirred at ambient temperature for 30 min. HATU (936 mg, 2.461 mmol) was added and the reaction was stirred at 40 °C for 2 h. The mixture was cooled to ambient temperature and diluted with EtOAc (50 mL) and water (50 mL). The aqueous phase was separated and extracted with EtOAc (3 x 50 mL). The combined organic phases were concentrated in vacuo and the residue was dissolved in MTBE (60 mL). The solution was washed with water (4 x 30 mL), dried 11(Na2SO4), filtered and concentrated in vacuo to give rac-(1R,2R,3aR,6aS)-N-(3-acetylpyridin-4-yl)-1-(3,4- difluoro-2-methylphenyl)-4,4-difluorooctahydropentalene-2-carboxamide (656 mg, 88%) as a yellow solid, which was used without further purification in the next step.1H NMR (400 MHz, Chloroform-d) δ 12.06 (s, 1H), 9.08 (s, 1H), 8.62 - 8.50 (m, 2H), 7.00 - 6.86 (m, 2H), 3.75 - 3.65 (m, 1H), 3.23 - 3.07 (m, 2H), 3.01 - 2.86 (m, 1H), 2.76 - 2.68 (m, 3H), 2.55 - 2.46 (m, 1H), 2.31 (d, J = 2.5 Hz, 3H), 2.13 - 1.85 (m, 3H), 1.34 - 1.15 (m, 2H) ppm. ESI-MS m / z calc.434.162, found 435.2 (M+1)+. Step 2:

[0312] In a sealed tube, KOtBu (365 mg, 3.253 mmol) was added to a solution of rac- (1R,2R,3aR,6aS)-N-(3-acetylpyridin-4-yl)-1-(3,4-difluoro-2-methylphenyl)-4,4- difluorooctahydropentalene-2-carboxamide (656 mg, 1.421 mmol) in 1,4-dioxane (15 mL). The solution was placed under a nitrogen atmosphere and the tube was sealed. The reaction mixture was heated at 100 °C for 22 h. The reaction was cooled to ambient temperature, diluted with a saturated aqueous NH4Cl solution (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to give rac-2-((1R,2R,3aR,6aS)-1-(3,4-difluoro-2- methylphenyl)-4,4-difluorooctahydropentalen-2-yl)-1,6-naphthyridin-4(1H)-one (463 mg, 73%) as a beige solid, which was used without further purification in the next step.1H NMR (400 MHz, Methanol- d4) δ 9.23 (s, 1H), 8.56 (d, J = 5.9 Hz, 1H), 7.51 (d, J = 5.9 Hz, 1H), 7.03 - 6.90 (m, 2H), 6.26 (s, 1H), 3.88 - 3.79 (m, 1H), 3.60 - 3.49 (m, 1H), 3.09 - 2.95 (m, 1H), 2.68 - 2.58 (m, 1H), 2.38 (d, J = 2.5 Hz, 3H), 2.11 - 1.93 (m, 3H), 1.37 - 1.21 (m, 3H) ppm; exchangeable H not observed. ESI-MS m / z calc. 416.151, found 417.2 (M+1)+. Step 3:

[0313] m-CPBA (472 mg, 2.106 mmol) was added to a solution of rac-2-((1R,2R,3aR,6aS)-1-(3,4- difluoro-2-methylphenyl)-4,4-difluorooctahydropentalen-2-yl)-1,6-naphthyridin-4(1H)-one (463 mg, 1.043 mmol) in DCM (20 mL) and the reaction mixture was stirred at ambient temperature for 2.5 h. The mixture was concentrated in vacuo and the residue was solubilised in EtOAc (30 mL). The mixture was washed with a saturated aqueous NaHCO3solution (2 x 30 mL) and brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo to give rac-2-((1R,2R,3aR,6aS)-1-(3,4-difluoro-2-methylphenyl)-4,4- difluorooctahydropentalen-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine 6-oxide (452 mg, 71%) as a yellow solid, which was used in the next step without further purification..1H NMR (400 MHz, Methanol-d4) δ 8.84 (s, 1H), 8.35 (d, J = 6.4 Hz, 1H), 7.68 (d, J = 6.9 Hz, 1H), 7.02 - 6.90 (m, 2H), 6.26 (s, 1H), 3.88 - 3.77 (m, 1H), 3.60 - 3.48 (m, 1H), 3.06 - 2.93 (m, 1H), 2.67 - 2.55 (m, 1H), 2.37 (d, J = 2.1 Hz, 3H), 2.10 - 1.90 (m, 3H), 1.36 - 1.20 (m, 3H) ppm; exchangeable H not observed. ESI-MS m / z calc.432.146, found 433.2 (M+1)+.Step 4:

[0314] Under a nitrogen atmosphere, TMSCN (317.2 mg, 0.4 mL, 3.197 mmol) and AcCl (220.8 mg, 0.2 mL, 2.813 mmol) were successively added to a solution of rac-2-((1R,2R,3aR,6aS)-1-(3,4- difluoro-2-methylphenyl)-4,4-difluorooctahydropentalen-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine 6- oxide (452 mg, 0.739 mmol) in DCM (10 mL) and the reaction mixture was stirred at ambient temperature for 2 h. The reaction was carefully quenched, by pouring the mixture into a stirred saturated aqueous NaHCO3solution (20 mL), and diluted with DCM (20 mL). The organic layer was separated, washed with a saturated NaHCO3aqueous solution (2 x 20 mL) and water (20 mL), dried (Na2SO4), filtered and concentrated in vacuo to give rac-2-((1R,2R,3aR,6aS)-1-(3,4-difluoro-2-methylphenyl)-4,4- difluorooctahydropentalen-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile (450 mg, 100%) as a tan solid, which was used without further purification in the next step.1H NMR (400 MHz, DMSO-d6) δ 12.11 (br s, 1H), 8.66 (d, J = 5.6 Hz, 1H), 7.72 (d, J = 5.6 Hz, 1H), 7.20 - 7.03 (m, 2H), 6.28 (s, 1H), 3.88 (dd, J = 12.6, 7.7 Hz, 1H), 3.50 (td, J = 12.3, 7.0 Hz, 1H), 3.23 (quin, J = 8.4 Hz, 1H), 3.04 - 2.89 (m, 1H), 2.41 (dd, J = 13.2, 6.6 Hz, 1H), 2.32 (d, J = 2.2 Hz, 3H), 2.13 - 1.92 (m, 3H), 1.32 - 1.20 (m, 1H), 1.16 - 1.02 (m, 1H) ppm. ESI-MS m / z calc.441.146, found 442.2 (M+1)+. Step 5:

[0315] A solution of rac-2-((1R,2R,3aR,6aS)-1-(3,4-difluoro-2-methylphenyl)-4,4- difluorooctahydropentalen-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile (455 mg, 0.808 mmol) and TFA (8.88 g, 6 mL, 77.879 mmol) in a mixture of toluene (10 mL) and water (0.2 mL) was stirred at 70 °C for 24 h and at ambient temperature for 3 days. The reaction mixture was concentrated in vacuo. The residue was solubilized in EtOAc (50 mL), washed with a saturated NaHCO3aqueous solution (3 x 50 mL) and brine (50 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Purification by reverse phase chromatography (C18column, 2.5 to 60 % MeCN in water with 0.1% formic acid) gave rac-2-((1R,2R,3aR,6aS)-1-(3,4-difluoro-2-methylphenyl)-4,4- difluorooctahydropentalen-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (136 mg, 37%).1H NMR (400 MHz, Methanol-d4) δ 8.48 (br s, 1H), 7.59 - 7.48 (m, 1H), 7.02 - 6.91 (m, 2H), 6.23 (s, 1H), 3.86 - 3.75 (m, 1H), 3.57 - 3.45 (m, 1H), 3.10 - 2.93 (m, 1H), 2.67 - 2.55 (m, 1H), 2.36 (d, J = 2.2 Hz, 3H), 2.10 - 1.93 (m, 3H), 1.42 - 1.20 (m, 3H) ppm; exchangeable H not observed. ESI-MS m / z calc. 459.157, found 460.2 (M+1)+. Step 6:

[0316] The enantiomers of rac-2-((1R,2R,3aR,6aS)-1-(3,4-difluoro-2-methylphenyl)-4,4- difluorooctahydropentalen-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide were separated by chiral SFC using a Lux®i-Cellulose-5 column, 5 μm particle size, 25 cm x 30 mm from Phenomenex (Mobile phase: 30% MeOH (supplemented with 0.1% DEA), 70% CO2; Flow rate 100 mL / min) to give:

[0317] First Eluting Isomer: rel-2-((1R,2R,3aR,6aS)-1-(3,4-difluoro-2-methylphenyl)-4,4- difluorooctahydropentalen-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (Compound 5, 60 mg, 16%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.43 (d, J = 5.7 Hz, 1H), 7.48 - 7.31 (m, 2H), 7.27 - 7.03 (m, 3H), 6.12 (s, 1H), 3.85 (b dd, J = 12.4, 7.9 Hz, 1H), 3.46 (td, J = 12.1, 6.8 Hz, 1H), 3.27 - 3.18 (m, 1H), 3.05 - 2.89 (m, 1H), 2.40 (br dd, J = 13.1, 6.5 Hz, 1H), 2.32 (d, J = 1.7 Hz, 3H), 2.09 - 1.94 (m, 3H), 1.31 - 1.22 (m, 1H), 1.15 - 1.04 (m, 1H) ppm. ESI-MS m / z calc.459.157, found 460.2 (M+1)+.

[0318] Second Eluting Isomer: rel-2-((1S,2S,3aS,6aR)-1-(3,4-difluoro-2-methylphenyl)-4,4- difluorooctahydropentalen-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (Compound 6, 62 mg, 16%) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 8.47 (d, J = 5.9 Hz, 1H), 7.53 (d, J = 5.9 Hz, 1H), 7.07 - 6.87 (m, 2H), 6.23 (s, 1H), 3.82 (dd, J = 12.7, 8.1 Hz, 1H), 3.58 - 3.44 (m, 1H), 3.10 - 2.90 (m, 1H), 2.61 (dd, J = 13.3, 6.7 Hz, 1H), 2.37 (d, J = 2.4 Hz, 3H), 2.13 - 1.91 (m, 3H), 1.35 - 1.23 (m, 3H) ppm; exchangeable H not observed. ESI-MS m / z calc.459.157, found 460.2 (M+1)+. Example 4 rel-2-((1R,2R,4S)-2-(3,4-Difluoro-2-methoxyphenyl)-4-methyl-4-(trifluoromethyl)cyclopentyl)-4-oxo- 1,4-dihydro-1,6-naphthyridine-5-carboxamide (7)Step 1:

[0319] DIPEA (3.6260 g, 4.9 mL, 28.056 mmol) was added to a stirred solution of dia- (1R1,2R1,4S2)-2-(3,4-difluoro-2-methoxyphenyl)-4-methyl-4-(trifluoromethyl)cyclopentane-1-carboxylic acid (C - 9c, 1.23 g, 2.764 mmol) and 1-(4-aminopyridin-3-yl)ethan-1-one hydrochloride (575 mg, 3.331 mmol) in DMF (10 mL) and the reaction mixture was stirred at ambient temperature for 30 min. HATU (1.58 g, 4.155 mmol) was added and the reaction was stirred at 40 °C for 1 h. The mixture was cooled to ambient temperature. Purification by reverse phase chromatography (C18column, 5 to 100% MeCN in water with 0.1% formic acid) gave dia-(1R1,2R1,4S2)-N-(3-acetylpyridin-4-yl)-2-(3,4-difluoro-2- methoxyphenyl)-4-methyl-4-(trifluoromethyl)cyclopentane-1-carboxamide (1.21 g, 81%) as a light yellow solid.1H NMR (400 MHz, Methanol-d4) δ 9.06 (s, 1H), 8.57 (d, J = 6.2 Hz, 1H), 8.54 - 8.49 (m, 1H), 7.18 - 7.10 (m, 1H), 7.01 - 6.90 (m, 1H), 3.93 (d, J = 2.2 Hz, 1.5H), 3.91 (d, J = 2.2 Hz, 1.5H), 3.80 - 3.63 (m, 1H), 3.39 - 3.33 (m, 0.5H), 3.27 - 3.21 (m, 0.5H), 2.64 (s, 1.5H), 2.63 (s, 1.5H), 2.56 - 2.47 (m,1.5H), 2.38 - 2.30 (m, 0.5H), 2.11 - 1.92 (m, 1.5H), 1.84 - 1.75 (m, 0.5H), 1.43 (s, 3H) ppm; exchangeable H not observed. ESI-MS m / z calc.456.147, found 457.2 (M+1)+. Step 2:

[0320] The isomers of dia-(1R1,2R1,4S2)-N-(3-acetylpyridin-4-yl)-2-(3,4-difluoro-2- methoxyphenyl)-4-methyl-4-(trifluoromethyl)cyclopentane-1-carboxamide (1.21 g, 2.246 mmol) were separated by chiral SFC using a Lux®Cellulose-2 column, 5 μm particle size, 25 cm x 30 mm from Phenomenex (Mobile phase: 3% EtOH, 97% CO2; Flow rate 100 mL / min) to give:

[0321] First Eluting Isomer: rel-(1S,2S,4R)-N-(3-acetylpyridin-4-yl)-2-(3,4-difluoro-2- methoxyphenyl)-4-methyl-4-(trifluoromethyl)cyclopentane-1-carboxamide (160.1 mg, 15%) as an off- white solid.1H NMR (400 MHz, Chloroform-d) δ 11.57 (br s, 1H), 9.06 (br s, 1H), 8.59 (br s, 2H), 7.00 (t, J = 6.4 Hz, 1H), 6.92 - 6.78 (m, 1H), 3.97 - 3.92 (m, 3H), 3.78 (td, J = 11.7, 7.6 Hz, 1H), 3.22 - 3.07 (m, 1H), 2.64 (s, 3H), 2.53 (br dd, J = 14.1, 8.4 Hz, 1H), 2.28 (br t, J = 12.9 Hz, 1H), 2.09 - 1.92 (m, 2H), 1.43 (s, 3H) ppm. ESI-MS m / z calc.456.147, found 457.2 (M+1)+.

[0322] Second Eluting Isomer: rel-(1R,2R,4S)-N-(3-acetylpyridin-4-yl)-2-(3,4-difluoro-2- methoxyphenyl)-4-methyl-4-(trifluoromethyl)cyclopentane-1-carboxamide (263.5 mg, 23%) as an off- white solid.1H NMR (400 MHz, Chloroform-d) δ 11.58 (br s, 1H), 9.05 (br s, 1H), 8.58 (br s, 2H), 7.00 (ddd, J = 8.5, 5.9, 2.2 Hz, 1H), 6.89 - 6.78 (m, 1H), 3.95 - 3.87 (m, 3H), 3.78 (td, J = 11.9, 7.3 Hz, 1H), 3.22 - 3.07 (m, 1H), 2.67 - 2.62 (m, 3H), 2.53 (dd, J = 14.1, 8.4 Hz, 1H), 2.36 - 2.19 (m, 1H), 2.07 - 1.93 (m, 2H), 1.46 - 1.40 (m, 3H) ppm. ESI-MS m / z calc.456.147, found 457.1 (M+1)+.

[0323] Third Eluting Isomer: rel-(1S,2S,4S)-N-(3-acetylpyridin-4-yl)-2-(3,4-difluoro-2- methoxyphenyl)-4-methyl-4-(trifluoromethyl)cyclopentane-1-carboxamide (179.9 mg, 17%) as a colorless sticky solid.1H NMR (400 MHz, Chloroform-d) δ 11.64 (br s, 1H), 9.06 (br s, 1H), 8.59 (br s, 2H), 6.93 (ddd, J = 8.5, 6.0, 2.1 Hz, 1H), 6.81 (td, J = 9.1, 7.3 Hz, 1H), 3.99 (d, J = 2.7 Hz, 3H), 3.70 (td, J = 11.5, 8.9 Hz, 1H), 3.22 (td, J = 11.7, 6.9 Hz, 1H), 2.66 (s, 3H), 2.65 (br s, 1H), 2.62 - 2.50 (m, 2H), 2.01 (dd, J = 13.3, 6.9 Hz, 1H), 1.41 (s, 3H) ppm. ESI-MS m / z calc.456.147, found 457.2 (M+1)+.

[0324] Fourth Eluting Isomer: rel-(1R,2R,4R)-N-(3-acetylpyridin-4-yl)-2-(3,4-difluoro-2- methoxyphenyl)-4-methyl-4-(trifluoromethyl)cyclopentane-1-carboxamide (184.5 mg, 17%) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 11.64 (br s, 1H), 9.06 (br s, 1H), 8.60 (br s, 2H), 6.96 - 6.89 (m, 1H), 6.86 - 6.76 (m, 1H), 3.99 (d, J = 2.6 Hz, 3H), 3.77 - 3.65 (m, 1H), 3.22 (td, J = 11.7, 7.0 Hz, 1H), 2.66 (s, 3H), 2.62 - 2.50 (m, 2H), 2.01 (dd, J = 13.3, 6.9 Hz, 1H), 1.70 (m, 1H), 1.41 (s, 3H) ppm. ESI-MS m / z calc.456.147, found 457.2 (M+1)+. Step 3:

[0325] Et3N (68.97 mg, 95 μL, 0.682 mmol) and TMSOTf (305 mg, 0.25 mL, 1.372 mmol) were successively added to a stirred solution of rel-(1R,2R,4S)-N-(3-acetylpyridin-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-4-methyl-4-(trifluoromethyl)cyclopentane-1-carboxamide (102 mg, 0.223 mmol) in DCE (2 mL) and the reaction mixture was stirred at 80 °C for 5 h. The mixture was cooled to ambient temperature. Additional amounts of Et3N (29.04 mg, 40 μL, 0.287 mmol) and TMSOTf (122 mg, 0.1 mL, 0.549 mmol) were added and the reaction was stirred at 80 °C for 18 h. The mixture was cooled to ambient temperature, diluted with a 0.5 M aqueous NaOH solution (20 mL) and extracted with a 9:1 mixture of DCM:EtOH (3 x 20 mL) and 2-MeTHF (3 x 20 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by reverse phase chromatography (C18column, 5 to 95% MeCN in water with 0.1% formic acid) gave rel-2-((1R,2R,4S)-2-(3,4-difluoro-2- methoxyphenyl)-4-methyl-4-(trifluoromethyl)cyclopentyl)-1,6-naphthyridin-4(1H)-one (102 mg, 99%) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 9.24 (s, 1H), 8.55 (d, J = 6.0 Hz, 1H), 7.48 (d, J = 6.1 Hz, 1H), 7.15 - 7.04 (m, 1H), 7.01 - 6.86 (m, 1H), 6.31 (s, 1H), 4.01 - 3.93 (m, 1H), 3.90 (d, J = 2.3 Hz, 3H), 3.49 (td, J = 12.0, 7.7 Hz, 1H), 2.77 (dd, J = 14.0, 7.8 Hz, 1H), 2.31 - 2.21 (m, 1H), 2.17 - 2.07 (m, 1H), 1.91 (t, J = 13.0 Hz, 1H), 1.49 (s, 3H) ppm; exchangeable H not observed. ESI-MS m / z calc. 438.137, found 439.1 (M+1)+. Step 4:

[0326] m-CPBA (104 mg, 0.464 mmol) was added to a solution of rel-2-((1R,2R,4S)-2-(3,4-difluoro- 2-methoxyphenyl)-4-methyl-4-(trifluoromethyl)cyclopentyl)-1,6-naphthyridin-4(1H)-one (101 mg, 0.218 mmol) in DCM (4 mL) and the reaction mixture was stirred at ambient temperature for 16 h. The reaction was concentrated in vacuo, diluted with EtOAc (50 mL) and washed with a saturated aqueous NaHCO3solution (3 x 50 mL) and brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to give rel-2- ((1R,2R,4S)-2-(3,4-difluoro-2-methoxyphenyl)-4-methyl-4-(trifluoromethyl)cyclopentyl)-4-oxo-1,4- dihydro-1,6-naphthyridine 6-oxide (90 mg, 79%) as an orange solid, which was used without further purification in the next step.1H NMR (400 MHz, Methanol-d4) δ 8.86 (d, J = 2.0 Hz, 1H), 8.34 (dd, J = 7.3, 1.9 Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.15 - 7.04 (m, 1H), 6.98 - 6.86 (m, 1H), 6.32 (s, 1H), 4.01 - 3.94 (m, 1H), 3.92 (d, J = 2.2 Hz, 3H), 3.55 - 3.44 (m, 1H), 2.76 (dd, J = 14.1, 7.6 Hz, 1H), 2.31 - 2.20 (m, 1H), 2.16 - 2.07 (m, 1H), 1.90 (br t, J = 12.8 Hz, 1H), 1.48 (s, 3H) ppm; exchangeable H not observed. ESI-MS m / z calc.454.132, found 455.1 (M+1)+. Step 5:

[0327] In a sealed tube, TMSCN (39.65 mg, 50 μL, 0.400 mmol) and Et3N (54.450 mg, 75 μL, 0.538 mmol) were added to a stirred solution of rel-2-((1R,2R,4S)-2-(3,4-difluoro-2-methoxyphenyl)-4-methyl- 4-(trifluoromethyl)cyclopentyl)-4-oxo-1,4-dihydro-1,6-naphthyridine 6-oxide (90 mg, 0.172 mmol) in DCM (1 mL) under a nitrogen atmosphere. The tube was sealed and the reaction mixture was stirred at ambient temperature for 18 h. Additional TMSCN (19.825 mg, 25 μL, 0.200 mmol) and Et3N (27.588 mg, 38 μL, 0.273 mmol) were added and the reaction was stirred at ambient temperature for 2 h. The mixturewas diluted with a saturated NaHCO3solution (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to give rel-2- ((1R,2R,4S)-2-(3,4-difluoro-2-methoxyphenyl)-4-methyl-4-(trifluoromethyl)cyclopentyl)-4-oxo-1,4- dihydro-1,6-naphthyridine-5-carbonitrile (88 mg, 100%) as a brown solid, which was used without further purification in the next step.1H NMR (400 MHz, Methanol-d4) δ 8.62 (d, J = 5.9 Hz, 1H), 7.66 (d, J = 5.9 Hz, 1H), 7.13 - 7.07 (m, 1H), 6.97 - 6.88 (m, 1H), 6.35 (s, 1H), 4.01 - 3.94 (m, 1H), 3.92 (d, J = 2.2 Hz, 3H), 3.54 - 3.43 (m, 1H), 2.80 - 2.70 (m, 1H), 2.29 - 2.20 (m, 1H), 2.11 (dd, J = 13.5, 7.4 Hz, 1H), 1.90 (br t, J = 12.8 Hz, 1H), 1.48 (s, 3H) ppm; exchangeable H not observed. ESI-MS m / z calc.463.132, found 464.1 (M+1)+. Step 6:

[0328] A solution of rel-2-((1R,2R,4S)-2-(3,4-difluoro-2-methoxyphenyl)-4-methyl-4- (trifluoromethyl)cyclopentyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile (88 mg, 0.171 mmol) and TFA (1.924 g, 1.3 mL, 16.874 mmol) in a mixture of toluene (2 mL) and water (40 μL) was stirred at 70 °C for 4 h. Additional TFA (296 mg, 0.2 mL, 2.596 mmol) was added and the mixture was stirred at 70 °C for a further 15 h. The reaction was cooled to ambient temperature and concentrated in vacuo. The residue was solubilised in EtOAc (10 mL), washed with a saturated aqueous NaHCO3solution (3 x 10 mL) and brine (10 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Purification by reverse phase chromatography (C18column, 2.5 % to 70 % MeCN in water with 0.1% formic acid) followed by flash chromatography (SiO2, 0 to 100 % EtOAc in heptane) gave rel-2- ((1R,2R,4S)-2-(3,4-difluoro-2-methoxyphenyl)-4-methyl-4-(trifluoromethyl)cyclopentyl)-4-oxo-1,4- dihydro-1,6-naphthyridine-5-carboxamide (7, 31 mg, 37%) as a white solid.1H NMR (400 MHz, DMSO- d6) δ 11.62 (s, 1H), 8.43 (d, J = 5.9 Hz, 1H), 7.42 - 7.36 (m, 2H), 7.23 - 7.06 (m, 3H), 6.14 (s, 1H), 3.94 (td, J = 11.8, 7.6 Hz, 1H), 3.86 (d, J = 1.5 Hz, 3H), 3.43 (td, J = 12.0, 7.7 Hz, 1H), 2.64 (dd, J = 13.8, 7.7 Hz, 1H), 2.12 - 1.98 (m, 2H), 1.85 (br t, J = 12.9 Hz, 1H), 1.43 (s, 3H) ppm. ESI-MS m / z calc.481.142, found 482.2 (M+1)+.Example 5 rel-2-((1S,2S)-2-(3,4-Difluoro-2-methoxyphenyl)-5,5-difluorocyclohexyl)-4-oxo-1,4-dihydro-1,6- naphthyridine-5-carboxamide (8) and rel-2-((1R,2R)-2-(3,4-difluoro-2-methoxyphenyl)-5,5- difluorocyclohexyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (9)Step 1:

[0329] SOCl2(500 µL, 6.855 mmol) was added to a stirred solution of rac-(1R,2R)-2-(3,4-difluoro- 2-methoxyphenyl)-5,5-difluorocyclohexane-1-carboxylic acid (C - 17, 217 mg, 0.709 mmol) and DMF (10 µL, 0.129 mmol) in DCM (4 mL) and the reaction mixture was stirred at ambient temperature for 20 min. The mixture was concentrated in vacuo, coevaporated with toluene (2 x 3 mL) and the residue was redissolved in DCM (4 mL).1-(4-Aminopyridin-3-yl)ethan-1-one (97 mg, 0.712 mmol) and DIPEA (500 µL, 2.870 mmol) were successively added and the mixture was stirred at ambient temperature for 20 min. The reaction was concentrated in vacuo. Purification by flash chromatography (12 g SiO2, 0 to 70% EtOAc in hexanes) gave rac-(1R,2R)-N-(3-acetylpyridin-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-5,5- difluorocyclohexane-1-carboxamide (205 mg, 68%).1H NMR (400 MHz, Chloroform-d) δ 11.60 (s, 1H), 9.03 (s, 1H), 8.53 (d, J = 5.9 Hz, 1H), 8.46 (d, J = 5.8 Hz, 1H), 6.95 - 6.89 (m, 1H), 6.77 (q, J = 8.6 Hz, 1H), 3.97 (d, J = 2.4 Hz, 3H), 3.37 - 3.23 (m, 1H), 3.19 - 2.93 (m, 1H), 2.67 (s, 3H), 2.44 - 2.35 (m, 1H), 2.35 - 2.14 (m, 2H), 2.03 - 1.85 (m, 3H) ppm. ESI-MS m / z calc.486.158, found 487.4 (M+1)+. Step 2:

[0330] Et3N (200 µL, 1.435 mmol) and TMSOTf (550 µL, 3.044 mmol) were successively added to a solution of rac-(1R,2R)-N-(3-acetylpyridin-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-5,5- difluorocyclohexane-1-carboxamide (205 mg, 0.483 mmol) in DCE (4 mL) and the reaction mixture washeated at 95 °C for 2.5 h. The mixture was cooled to ambient temperature and partitioned between DCM and a saturated aqueous NaHCO3solution. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, 0 to 10% MeOH in DCM) gave rac- 2-((1R,2R)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexyl)-1,6-naphthyridin-4(1H)-one (100 mg, 51%).1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 9.03 (s, 1H), 8.53 (d, J = 5.8 Hz, 1H), 7.36 (d, J = 5.9 Hz, 1H), 7.14 (s, 1H), 7.08 - 6.96 (m, 1H), 6.12 (d, J = 1.4 Hz, 1H), 3.81 (s, 3H), 3.65 - 3.52 (m, 1H), 3.30 - 3.21 (m, 1H), 2.48 - 2.36 (m, 2H), 2.27 - 2.01 (m, 2H), 1.94 - 1.87 (m, 1H), 1.72 (br s, 1H) ppm. ESI-MS m / z calc.406.130, found 407.4 (M+1)+. Step 3 and 4:

[0331] m-CPBA (141 mg, 0.629 mmol) was added to a suspension of rac-2-((1R,2R)-2-(3,4- difluoro-2-methoxyphenyl)-5,5-difluorocyclohexyl)-1,6-naphthyridin-4(1H)-one (99 mg, 0.244 mmol) in DCM (5 mL) and the mixture was stirred at ambient temperature for 1 h. Et3N (1.0 mL, 7.175 mmol) and TMSCN (500 µL, 3.750 mmol) were successively added and the resulting solution was stirred at ambient temperature for 1 h. Additional TMSCN (500 µL, 3.750 mmol) was added and the mixture was stirred for a further 2 h. The mixture was concentrated in vacuo. Purification by flash chromatography (12 g SiO2, 0 to 6% MeOH in DCM) gave rac-2-((1R,2R)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexyl)- 4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile, which was used without further purification in the next step. ESI-MS m / z calc.431.126, found 432.3 (M+1)+. Step 5:

[0332] TFA (3 mL, 38.94 mmol) was added to the residue of rac-2-((1R,2R)-2-(3,4-difluoro-2- methoxyphenyl)-5,5-difluorocyclohexyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile in toluene (3 mL) and the reaction mixture was stirred at 70 ºC for 16 h. The mixture was concentrated in vacuo and partitioned between EtOAc and a saturated aqueous NaHCO3solution. The organic phase was separated, dried (Na2SO4), filtered and concentrated in vacuo. Purification by reverse phase HPLC (C18column, 10 to 99% MeCN in water) gave rac-2-((1R,2R)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexyl)- 4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (83 mg, 76% over 3 steps). ESI-MS m / z calc. 449.136, found 450.5 (M+1)+. Step 6:

[0333] The enantiomers of rac-2-((1R,2R)-2-(3,4-difluoro-2-methoxyphenyl)-5,5- difluorocyclohexyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (55 mg, 0.122 mmol) were separated by chiral SFC using a Chiralpak®IC column, 5 μm particle size, 25 cm x 22.1 mm from Daicel Corporation (Mobile phase: 30% MeOH (supplemented with 20 mM ammonia), 70% CO2; Flow rate 60 mL / min) to give: 19

[0334] First Eluting Isomer: rel-2-((1S,2S)-2-(3,4-difluoro-2-methoxyphenyl)-5,5- difluorocyclohexyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (8, 25.0 mg, 45%).1H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 8.41 (d, J = 5.8 Hz, 1H), 7.40 (s, 1H), 7.35 (d, J = 5.8 Hz, 1H), 7.25 - 7.10 (m, 2H), 7.09 - 7.01 (m, 1H), 6.08 (s, 1H), 3.83 (s, 3H), 3.60 (br s, 1H), 2.45 - 2.24 (m, 2H), 2.28 - 1.99 (m, 3H), 1.94 - 1.86 (m, 1H), 1.69 (br s, 1H) ppm. ESI-MS m / z calc.449.136, found 450.3 (M+1)+.

[0335] Second Eluting Isomer: rel-2-((1R,2R)-2-(3,4-difluoro-2-methoxyphenyl)-5,5- difluorocyclohexyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (9, 6.5 mg, 12%).1H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 8.41 (d, J = 5.8 Hz, 1H), 7.40 (s, 1H), 7.35 (d, J = 5.8 Hz, 1H), 7.27 - 7.10 (m, 2H), 7.10 - 6.97 (m, 1H), 6.08 (s, 1H), 3.83 (s, 3H), 3.69 - 3.53 (m, 1H), 3.30 - 3.22 (m, 1H), 2.45 - 2.33 (m, 2H), 2.26 - 2.04 (m, 2H), 1.90 (d, J = 12.8 Hz, 1H), 1.69 (br s, 1H) ppm. ESI-MS m / z calc.449.136, found 450.4 (M+1)+. Example 6 rel-2-((1S,2S,4R)-2-(4-Fluoro-2-methoxy-3-methylphenyl)-4-(trifluoromethyl)cyclopentyl)-4-oxo-1,4- dihydro-1,6-naphthyridine-5-carboxamide (10) and rel-2-((1R,2R,4S)-2-(4-fluoro-2-methoxy-3- methylphenyl)-4-(trifluoromethyl)cyclopentyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (11)Step 1:

[0336] HATU (776.4 mg, 2.042 mmol) was added to a stirred solution of dia-(1R1,2R1,4S2)-2-(4- fluoro-2-methoxy-3-methylphenyl)-4-(trifluoromethyl)cyclopentane-1-carboxylic acid (C - 3a, 590 mg, 1.842 mmol), 1-(4-aminopyridin-3-yl)ethan-1-one (278.2 mg, 2.043 mmol) and DIPEA (1 mL, 5.741 mmol) in DCM (3 mL) and the reaction mixture was stirred at ambient temperature for 20 h. The mixture was diluted with EtOAc, washed with water (2 x 40 mL) and brine (40 mL), dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography (SiO2, 0% to 100% EtOAc in DCM) gave dia-(1R1,2R1,4S2)-N-(3-acetylpyridin-4-yl)-2-(4-fluoro-2-methoxy-3-methylphenyl)-4-(trifluoromethyl)cyclopentane-1-carboxamide (1.1 g, 100%) as a yellow foam. ESI-MS m / z calc.438.157, found 439.4 (M+1)+. Step 2:

[0337] Et3N (770 µL, 5.524 mmol) and TMSOTf (2 mL, 11.07 mmol) were successively added to a stirred solution of dia-(1R1,2R1,4S2)-N-(3-acetylpyridin-4-yl)-2-(4-fluoro-2-methoxy-3-methylphenyl)-4- (trifluoromethyl)cyclopentane-1-carboxamide (808 mg, 1.751 mmol) in toluene (9 mL) and the reaction mixture was heated at 95 °C for 4 h under nitrogen. The reaction was cooled to ambient temperature, washed with 2 N aqueous K2CO3and the aqueous phase was extracted with DCM (x 2). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, 0 to 50% of MeOH in DCM) gave dia-2-((1R1,2R1,4S2)-2-(4-fluoro-2-methoxy-3- methylphenyl)-4-(trifluoromethyl)cyclopentyl)-1,6-naphthyridin-4(1H)-one (576 mg, 74%) as a tan solid. ESI-MS m / z calc.420.146, found 421.5 (M+1)+. Step 3:

[0338] m-CPBA (446.6 mg, 1.993 mmol) was added to a suspension of dia-2-((1R1,2R1,4S2)-2-(4- fluoro-2-methoxy-3-methylphenyl)-4-(trifluoromethyl)cyclopentyl)-1,6-naphthyridin-4(1H)-one (576 mg, 1.302 mmol) in DCM (9 mL) and the reaction mixture was stirred at ambient temperature for 4 h to give a solution of dia-2-((1R1,2R1,4S2)-2-(4-fluoro-2-methoxy-3-methylphenyl)-4-(trifluoromethyl)cyclopentyl)- 4-oxo-1,4-dihydro-1,6-naphthyridine 6-oxide, which was used without further purification in the next step. ESI-MS m / z calc.436.141, found 437.4 (M+1)+. Step 4:

[0339] Et3N (4 mL, 28.7 mmol) and TMSCN (1.6 mL, 12.79 mmol) were successively added to the DCM solution of dia-2-((1R1,2R1,4S2)-2-(4-fluoro-2-methoxy-3-methylphenyl)-4- (trifluoromethyl)cyclopentyl)-4-oxo-1,4-dihydro-1,6-naphthyridine 6-oxide and the reaction mixture was stirred at ambient temperature for 1 h. The reaction was partitioned between a saturated aqueous NaHCO3solution (75 mL) and EtOAc (30 mL). The aqueous layer was separated and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, 0 to 10% of MeOH in DCM) gave dia-2-((1R1,2R1,4S2)-2-(4-fluoro-2-methoxy-3-methylphenyl)-4- (trifluoromethyl)cyclopentyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile (344 mg, 59% over 2 steps) as an off-white solid. ESI-MS m / z calc.445.141, found 446.4 (M+1)+. Step 5:

[0340] TFA (3 mL, 38.94 mmol) was added to a suspension of dia-2-((1R1,2R1,4S2)-2-(4-fluoro-2- methoxy-3-methylphenyl)-4-(trifluoromethyl)cyclopentyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5- carbonitrile (344 mg, 0.772 mmol) in toluene (5 mL) and the reaction mixture was stirred at 70 °C for 3 h.The reaction was cooled to ambient temperature and concentrated in vacuo. Purification by reverse phase HPLC (C18column, 0 to 40% MeCN with 5 mM HCl) gave:

[0341] First Eluting Isomers: rac-2-((1R,2R,4R)-2-(4-fluoro-2-methoxy-3-methylphenyl)-4- (trifluoromethyl)cyclopentyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (130 mg, 36%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 8.43 (d, J = 5.8 Hz, 1H), 7.44 (d, J = 5.8 Hz, 1H), 7.38 (br s, 1H), 7.36 - 7.30 (m, 1H), 7.20 (br s, 1H), 6.96 (t, J = 8.8 Hz, 1H), 5.95 (s, 1H), 3.85 - 3.72 (m, 1H), 3.60 (s, 3H), 3.43 - 3.32 (m, 2H), 2.56 - 2.51 (m, 1H), 2.38 - 2.26 (m, 1H), 2.08 (d, J = 1.6 Hz, 3H), 2.11 - 2.01 (m, 1H), 1.98 - 1.88 (m, 1H) ppm. ESI-MS m / z calc.463.152, found 464.5 (M+1)+.

[0342] Second Eluting Isomers: rac-2-((1R,2R,4S)-2-(4-fluoro-2-methoxy-3-methylphenyl)-4- (trifluoromethyl)cyclopentyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (64 mg, 18%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 8.43 (d, J = 5.8 Hz, 1H), 7.42 - 7.36 (m, 2H), 7.28 (dd, J = 8.6, 6.7 Hz, 1H), 7.19 (br s, 1H), 6.94 (t, J = 8.8 Hz, 1H), 6.05 (d, J = 1.5 Hz, 1H), 3.88 - 3.75 (m, 1H), 3.62 (s, 3H), 3.46 - 3.33 (m, 1H), 3.32 - 3.25 (m, 1H), 2.48 - 2.39 (m, 2H), 2.31 - 2.18 (m, 1H), 2.08 (d, J = 1.8 Hz, 3H), 1.76 - 1.63 (m, 1H) ppm. ESI-MS m / z calc.463.152, found 464.4 (M+1)+. Step 6:

[0343] The enantiomers of rac-2-((1R,2R,4S)-2-(4-fluoro-2-methoxy-3-methylphenyl)-4- (trifluoromethyl)cyclopentyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (60 mg, 0.130 mmol) were separated by chiral SFC using a Lux®Cellulose-4 column, 5 μm particle size, 25 cm x 21.2 mm from Phenomenex (Mobile phase: 42% MeOH (supplemented with 20 mM ammonia), 58% CO2; Flow rate 65 mL / min) to give:

[0344] First Eluting Isomer: rel-2-((1S,2S,4R)-2-(4-fluoro-2-methoxy-3-methylphenyl)-4- (trifluoromethyl)cyclopentyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (10, 20 mg, 33%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 11.62 (br s, 1H), 8.42 (d, J = 5.7 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.28 (dd, J = 8.6, 6.7 Hz, 1H), 7.19 (s, 1H), 6.94 (t, J = 8.8 Hz, 1H), 6.05 (s, 1H), 3.88 - 3.76 (m, 1H), 3.61 (s, 3H), 3.43 - 3.23 (m, 2H), 2.48 - 2.37 (m, 2H), 2.31 - 2.18 (m, 1H), 2.08 (d, J = 1.6 Hz, 3H), 1.75 - 1.62 (m, 1H) ppm. ESI-MS m / z calc.463.152, found 464.5 (M+1)+.

[0345] Second Eluting Isomer: rel-2-((1R,2R,4S)-2-(4-fluoro-2-methoxy-3-methylphenyl)-4- (trifluoromethyl)cyclopentyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (11, 20 mg, 33%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 11.63 (br s, 1H), 8.42 (d, J = 5.7 Hz, 1H), 7.42 - 7.36 (m, 2H), 7.32 - 7.24 (m, 1H), 7.19 (br s, 1H), 6.94 (t, J = 8.8 Hz, 1H), 6.05 (s, 1H), 3.88 - 3.76 (m, 1H), 3.61 (s, 3H), 3.45 - 3.23 (m, 2H), 2.49 - 2.39 (m, 2H), 2.31 - 2.18 (m, 1H), 2.08 (d, J = 1.6 Hz, 3H), 1.75 - 1.62 (m, 1H) ppm. ESI-MS m / z calc.463.152, found 464.6 (M+1)+.Example 7 dia-2-((1R1,2R1,4R2)-4-(tert-Butyl)-2-(3,4-difluoro-2-methoxyphenyl)cyclohexyl)-4-oxo-1,4-dihydro-1,6- naphthyridine-5-carboxamide (12)Step 1:

[0346] T3P®(2.339 mL, 50 wt% solution in EtOAc, 3.676 mmol) was added to a stirred solution of dia-(1R1,2R1,4R2)-4-(tert-butyl)-2-(3,4-difluoro-2-methoxyphenyl)cyclohexane-1-carboxylic acid (C - 18, 600 mg, 1.838 mmol), 1-(4-aminopyridin-3-yl)ethan-1-one (500.5 mg, 3.676 mmol) and DIPEA (475.1 mg, 640.3 µL, 3.676 mmol) in THF (10 mL) and the reaction mixture was stirred at ambient temperature for 20 h. The reaction was concentrated in vacuo. Purification by high pressure reverse phase chromatography (SunFire C18column, 1 to 100% MeCN in water with 5 mM HCl) gave dia- (1R1,2R1,4R2)-N-(3-acetylpyridin-4-yl)-4-(tert-butyl)-2-(3,4-difluoro-2-methoxyphenyl)cyclohexane-1- carboxamide (432 mg, 53%) as a light yellow oil. ESI-MS m / z calc.444.222, found 445.7 (M+1)+. Step 2:

[0347] Under a nitrogen atmosphere, Et3N (1 mL, 7.175 mmol) and TMSOTf (2.5 mL, 13.84 mmol) were successively added to a solution of dia-(1R1,2R1,4R2)-N-(3-acetylpyridin-4-yl)-4-(tert-butyl)-2-(3,4- difluoro-2-methoxyphenyl)cyclohexane-1-carboxamide (900 mg, 2.025 mmol) in DCE (10.80 mL) and the reaction mixture was heated at 90 °C for 8 h. The reaction was cooled to ambient temperature and washed with a 2 N aqueous K2CO3solution (10 mL). The aqueous phase was extracted with DCM (2 x 20 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. Purification by high pressure reverse phase chromatography (SunFire C18column, 1 to 100% MeCN in water with 5 mM HCl) gave dia-2-((1R1,2R1,4R2)-4-(tert-butyl)-2-(3,4-difluoro-2-methoxyphenyl)cyclohexyl)-1,6- naphthyridin-4(1H)-one (800 mg, 75%) as a white solid. ESI-MS m / z calc.426.212, found 427.5 (M+1)+. Step 3 and 4:

[0348] m-CPBA (31.53 mg, 0.141 mmol) was added to a suspension of dia-2-((1R1,2R1,4R2)-4-(tert- butyl)-2-(3,4-difluoro-2-methoxyphenyl)cyclohexyl)-1,6-naphthyridin-4(1H)-one (30 mg, 0.070 mmol) in DCM (1.263 mL) and the reaction mixture was stirred at ambient temperature for 4 h. Et3N (163.3 mg, 224.9 µL, 1.614 mmol) and TMSCN (93.02 mg, 125 µL, 0.938 mmol) were successively added and the reaction was stirred at ambient temperature for 2.5 h. The reaction was concentrated in vacuo. Purification by high pressure reverse phase chromatography (Luna C18column, 1 to 100% MeCN in water with 5 mM 23HCl) gave dia-2-((1R1,2R1,4R2)-4-(tert-butyl)-2-(3,4-difluoro-2-methoxyphenyl)cyclohexyl)-4-oxo-1,4- dihydro-1,6-naphthyridine-5-carbonitrile (27.8 mg, 88% over 2 steps) as a white solid. ESI-MS m / z calc. 451.207, found 452.5 (M+1)+. Step 5:

[0349] A mixture of dia-2-((1R1,2R1,4R2)-4-(tert-butyl)-2-(3,4-difluoro-2- methoxyphenyl)cyclohexyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile (30 mg, 0.066 mmol), K2CO3(30 mg, 0.217 mmol) and H2O2(100 µL, 35 wt% solution in water, 1.029 mmol) in DMSO (750 µL) was stirred at ambient temperature for 24 h. Purification by reverse phase chromatography (Luna C18column, 1 to 100% MeCN in water) gave dia-2-((1R1,2R1,4R2)-4-(tert-butyl)-2-(3,4-difluoro-2- methoxyphenyl)cyclohexyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (12, 2 mg, 6%) as a colourless solid.1H NMR (400 MHz, Methanol-d4) δ 8.74 (d, J = 6.0 Hz, 1H), 7.88 - 7.83 (m, 1H), 7.07 (dd, J = 7.6, 5.0 Hz, 1H), 6.87 (q, J = 8.8 Hz, 1H), 6.74 (d, J = 12.9 Hz, 1H), 3.97 - 3.89 (m, 3H), 2.23 (d, J = 12.9 Hz, 1H), 2.15 - 1.93 (m, 4H), 1.90 - 1.70 (m, 2H), 1.51 - 1.34 (m, 2H), 1.04 (s, 4H), 0.95 (s, 5H) ppm; exchangeable H not observed. ESI-MS m / z calc.469.218, found 470.5 (M+1)+. Example 8 rel-2-((4R,6S,7S)-7-(3,4-Difluoro-2-methoxyphenyl)-1,1-difluorospiro[3.4]octan-6-yl)-4-oxo-1,4- dihydro-1,6-naphthyridine-5-carboxamide (13) and rel-2-((4S,6R,7R)-7-(3,4-difluoro-2-methoxyphenyl)- 1,1-difluorospiro[3.4]octan-6-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (14)Step 1:

[0350] HATU (230 mg, 0.605 mmol) was added to a solution of rac-(4S,6R,7R)-7-(3,4-difluoro-2- methoxyphenyl)-1,1-difluorospiro[3.4]octane-6-carboxylic acid (C - 19, 183 mg, 0.452 mmol), 1-(4- aminopyridin-3-yl)ethan-1-one (76 mg, 0.558 mmol) and DIPEA (178.32 mg, 0.24 mL, 1.380 mmol) inDMF (4 mL) and the reaction mixture was stirred at ambient temperature for 2 h. Purification by reverse phase chromatography (5 to 80% MeCN in water with 0.1% formic acid) gave rac-(4S,6R,7R)-N-(3- acetylpyridin-4-yl)-7-(3,4-difluoro-2-methoxyphenyl)-1,1-difluorospiro[3.4]octane-6-carboxamide (167 mg, 76%) as a yellow solid.1H NMR (400 MHz, Chloroform-d) δ 11.98 (s, 1H), 9.26 (s, 1H), 9.15 (d, J = 6.8 Hz, 1H), 8.58 (d, J = 6.8 Hz, 1H), 7.13 - 7.07 (m, 1H), 6.97 - 6.89 (m,1H), 3.90 (d, J = 2.3 Hz, 3H), 3.85 - 3.76 (m, 1H), 3.39 (td, J = 11.0, 7.0 Hz, 1H), 2.77 - 2.62 (m, 4H), 2.56 - 2.38 (m, 2H), 2.32 - 2.16 (m, 1H), 1.24 - 1.12 (m, 2H), 0.99 - 0.89 (m, 2H) ppm. ESI-MS m / z calc.450.157, found 451.2 (M+1)+. Step 2:

[0351] KOtBu (78 mg, 0.695 mmol) was added to a solution of rac-(4S,6R,7R)-N-(3-acetylpyridin-4- yl)-7-(3,4-difluoro-2-methoxyphenyl)-1,1-difluorospiro[3.4]octane-6-carboxamide (135 mg, 0.278 mmol) in a mixture of 2-MeTHF (3 mL) and NMP (0.15 mL) and the reaction mixture was stirred at 60 °C for 16 h. The reaction was cooled to ambient temperature and partitioned between a saturated aqueous NH4Cl solution (10 mL) and EtOAc (20 mL). The aqueous layer was separated and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by reverse phase chromatography (C18column, 5 to 50% MeCN in water with 0.1% formic acid) gave rac-2-((4S,6R,7R)-7-(3,4-difluoro-2-methoxyphenyl)-1,1- difluorospiro[3.4]octan-6-yl)-1,6-naphthyridin-4(1H)-one (108.5 mg, 87%) as a tan solid.1H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 9.08 (br s, 1H), 8.55 (br s, 1H), 7.44 (d, J = 5.6 Hz, 1H), 7.36 - 7.29 (m, 1H), 7.19 - 7.08 (m, 1H), 6.08 (s, 1H), 4.04 (td, J = 12.0, 6.4 Hz, 1H), 3.78 (d, J = 1.3 Hz, 3H), 3.45 - 3.35 (m, 1H), 2.73 - 2.57 (m, 1H), 2.45 - 2.18 (m, 2H), 2.14 - 1.98 (m, 1H, overlapped with MeCN), 1.26 - 1.03 (m, 4H) ppm. ESI-MS m / z calc.432.146, found 433.2 (M+1)+. Step 3 and 4:

[0352] m-CPBA (116 mg, 0.518 mmol) was added to a solution of rac-2-((4S,6R,7R)-7-(3,4- difluoro-2-methoxyphenyl)-1,1-difluorospiro[3.4]octan-6-yl)-1,6-naphthyridin-4(1H)-one (100 mg, 0.223 mmol) in DCM (6 mL) and the reaction mixture was stirred at ambient temperature for 3.5 h. Et3N (333.96 mg, 0.46 mL, 3.300 mmol) and TMSCN (222.04 mg, 0.28 mL, 2.238 mmol) were successively added and the reaction mixture was stirred at ambient temperature for 16 h. The reaction was quenched by addition of a saturated aqueous NaHCO3solution (20 mL) and diluted with DCM (20 mL). The aqueous layer was separated and extracted with DCM (30 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. Purification by reverse phase chromatography (C18column, 5 to 70% MeCN in water with 0.1% formic acid) gave rac-2-((4S,6R,7R)-7-(3,4-difluoro-2- methoxyphenyl)-1,1-difluorospiro[3.4]octan-6-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile (70 mg, 65% over 2 steps) as a brown solid.1H NMR (400 MHz, Methanol-d4) δ 8.65 (d, J = 4.2 Hz, 1H), 7.67 (br s, 1H), 7.23 - 7.14 (m, 1H), 7.03 - 6.92 (m, 1H), 6.35 (s, 1H), 4.00 - 3.90 (m, 1H), 3.80 (d, J = 252.0 Hz, 3H), 3.67 - 3.57 (m, 1H), 2.81 - 2.54 (m, 2H), 2.47 - 2.29 (m, 1H), 2.25 - 2.08 (m, 1H), 1.20 - 1.09 (m, 2H), 1.05 - 0.97 (m, 2H) ppm; exchangeable H not observed. ESI-MS m / z calc.457.141, found 458.2 (M+1)+. Step 5:

[0353] NaOH (20 mg, 0.5 mmol) and a solution of H2O2(44 μL, 35 wt% solution in water, 0.453 mmol) were successively added to a solution of rac-2-((4S,6R,7R)-7-(3,4-difluoro-2-methoxyphenyl)-1,1- difluorospiro[3.4]octan-6-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile (40 mg, 0.082 mmol) in a mixture of DMSO (1.5 mL) and water (0.5 mL) and the reaction mixture was stirred at ambient temperature for 2 h. Additional amounts of NaOH (20 mg, 0.5 mmol) and H2O2(40 μL, 35 wt% solution in water, 0.412 mmol) were added and the mixture was further stirred at ambient temperature for 1.5 h. Purification by reverse phase chromatography (C18column, 5 to 60% MeCN in water with 0.1% formic acid) gave rac-2-((4S,6R,7R)-7-(3,4-difluoro-2-methoxyphenyl)-1,1-difluorospiro[3.4]octan-6-yl)-4-oxo- 1,4-dihydro-1,6-naphthyridine-5-carboxamide (31 mg, 79%). Step 6:

[0354] The enantiomers of rac-2-((4S,6R,7R)-7-(3,4-difluoro-2-methoxyphenyl)-1,1- difluorospiro[3.4]octan-6-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide were separated by chiral SFC using a Lux®Cellulose-4 column, 5 μm particle size, 250 cm x 30 mm from Phenomenex (Mobile phase: 50% MeOH (supplemented with 0.1% mM ammonia), 50% CO2; Flow rate 80 mL / min) to give:

[0355] First Eluting Isomer: rel-2-((4R,6S,7S)-7-(3,4-difluoro-2-methoxyphenyl)-1,1- difluorospiro[3.4]octan-6-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (13, 5.9 mg, 19%) as a white solid, after subsequent purification by reverse phase chromatography (C18column, 5 to 60% MeCN in water with 0.1% formic acid) followed by SFC separation using a Lux®Cellulose 3 column, 5 μm particle size, 250 cm x 30 mm from Phenomenex (Mobile phase: 20% MeOH, 80% CO2, flow rate 100 mL / min).1H NMR (400 MHz, DMSO-d6) δ 11.63 (br s, 1H), 8.44 (d, J = 5.7 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.25 - 7.13 (m, 3H), 6.15 (s, 1H), 3.94 - 3.86 (m, 1H), 3.74 (d, J = 1.1 Hz, 3H), 3.57 (td, J = 12.0, 5.7 Hz, 1H), 2.65 - 2.55 (m, 1H, overlapped with solvent), 2.54 - 2.44 (m, 1H, overlapped with solvent), 2.31 - 2.14 (m, 1H), 2.07 - 1.91 (m, 1H), 1.23 - 1.03 (m, 4H) ppm. ESI-MS m / z calc.475.152, found 476.2 (M+1)+.

[0356] Second Eluting Isomer: rel-2-((4S,6R,7R)-7-(3,4-difluoro-2-methoxyphenyl)-1,1- difluorospiro[3.4]octan-6-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (14, 8.5 mg, 27%) as a white solid, after subsequent purification by SFC separation using a Lux®Cellulose 3 column, 5 μm particle size, 250 cm x 30 mm from Phenomenex (Mobile phase: 20% MeOH, 80% CO2, flow rate 100 mL / min).1H NMR (400 MHz, DMSO-d6) δ 11.63 (br s, 1H), 8.44 (d, J = 5.9 Hz, 1H), 7.46 - 7.34 (m,2H), 7.27 - 7.12 (m, 3H), 6.15 (s, 1H), 3.94 - 3.85 (m, 1H), 3.74 (d, J = 1.5 Hz, 3H), 3.57 (td, J = 12.0, 5.8 Hz, 1H), 2.66 - 2.54 (m, 1H, overlapped with solvent), 2.54 - 2.44 (m, 1H, overlapped with solvent), 2.32 - 2.12 (m, 1H), 2.08 - 1.90 (m, 1H), 1.23 - 1.03 (m, 4H) ppm. ESI-MS m / z calc.475.152, found 476.2 (M+1)+. Example 9 rel-2-((1R,2R,3aR,6aS)-1-(3,4-Difluoro-2-hydroxyphenyl)-4,4-difluorooctahydropentalen-2-yl)-4-oxo- 1,4-dihydro-1,6-naphthyridine-5-carboxamide (15)Step 1:

[0357] A vial containing a mixture of rel-2-((1R,2R,3aR,6aS)-1-(3,4-difluoro-2-methoxyphenyl)-4,4- difluorooctahydropentalen-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (1, 45 mg, 0.095 mmol), NaI (22 mg, 0.147 mmol) and HBr (450 µL, 30 % w / v solution in AcOH, 1.668 mmol) was heated at 70 °C for 4 h. The reaction was quenched by addition of water and extracted with DCM (3 x). The organic layer was separated, washed with a saturated aqueous Na2SO3solution and a saturated aqueous NaHCO3solution, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, 0 to 80% EtOAc in DCM) followed by reverse phase chromatography (C18column, 0 to 40% MeCN in water with HCl) gave rel-2-((1R,2R,3aR,6aS)-1-(3,4-difluoro-2- hydroxyphenyl)-4,4-difluorooctahydropentalen-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5- carboxamide (15, 10.2 mg, 23%).1H NMR (400 MHz, Methanol-d4) δ 8.84 (d, J = 6.0 Hz, 1H), 8.06 (d, J = 6.0 Hz, 1H), 6.96 (s, 1H), 6.93 - 6.86 (m, 1H), 6.59 (td, J = 9.4, 7.5 Hz, 1H), 4.14 - 4.03 (m, 1H), 3.84 - 3.67 (m, 1H), 3.48 (p, J = 8.7 Hz, 1H), 3.16 - 2.95 (m, 1H), 2.71 - 2.59 (m, 1H), 2.15 - 2.05 (m, 2H), 1.47 - 1.25 (m, 3H) ppm; exchangeable H not observed. ESI-MS m / z calc.461.136, found 462.5 (M+1)+.Example 10 rel-2-((7S,8S)-7-(3,4-Difluoro-2-methoxyphenyl)spiro[4.5]decan-8-yl)-1,6-naphthyridin-4(1H)-one (16) and rel-2-((7R,8R)-7-(3,4-difluoro-2-methoxyphenyl)spiro[4.5]decan-8-yl)-1,6-naphthyridin-4(1H)-oneStep 1:

[0358] A stirred suspension of rac-(7R,8R)-7-(3,4-difluoro-2-methoxyphenyl)spiro[4.5]decane-8- carboxylic acid (C - 15, 597 mg, 1.841 mmol) and DMF (15 µL, 0.194 mmol) in a mixture of SOCl2(2 mL, 27.42 mmol) and DCM (7 mL) was heated at 60 °C for 1 h. The reaction was cooled to ambient temperature, diluted with toluene (3 mL) and concentrated in vacuo. Pyridine (450 µL, 5.564 mmol) was added to a solution of the residue and 1-(4-amino-3-pyridyl)ethanone (280 mg, 2.057 mmol) in DCM (7 mL) and the reaction mixture was stirred at ambient temperature for 16 h. The mixture was filtered to remove insoluble solids and concentrated in vacuo. Purification by flash chromatography (SiO2, 0 to 30% EtOAc in hexanes) gave rac-(7R,8R)-N-(3-acetylpyridin-4-yl)-7-(3,4-difluoro-2- methoxyphenyl)spiro[4.5]decane-8-carboxamide (433.3 mg, 53%).1H NMR (400 MHz, Chloroform-d) δ 11.68 (s, 1H), 9.03 (s, 1H), 8.52 - 8.46 (m, 2H), 6.95 - 6.87 (m, 1H), 6.82 - 6.69 (m, 1H), 3.94 (d, J = 1.8 Hz, 3H), 3.53 - 3.37 (m, 1H), 2.69 (s, 3H), 2.66 - 2.58 (m, 1H), 2.06 - 1.94 (m, 1H), 1.93 - 1.80 (m, 1H), 1.72 - 1.56 (m, 8H), 1.50 - 1.37 (m, 4H) ppm. ESI-MS m / z calc.442.207, found 443.2 (M+1)+. Step 2:

[0359] TMSOTf (700 µL, 3.874 mmol) was added to a stirred solution of rac-(7R,8R)-N-(3- acetylpyridin-4-yl)-7-(3,4-difluoro-2-methoxyphenyl)spiro[4.5]decane-8-carboxamide (433 mg, 0.979 mmol) and Et3N (275 µL, 1.973 mmol) in DCE (4.5 mL) and the reaction mixture was heated at 100 °C for 16 h and at 110 °C for 24 h. The reaction was cooled to ambient temperature and partitioned between EtOAc and a saturated aqueous NaHCO3solution. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. Purification by reverse phase chromatography (C18column, 20 to 75% MeCN in water with 5 mM HCl) gave rac-2-((7R,8R)-7-(3,4-difluoro-2-methoxyphenyl)spiro[4.5]decan- 8-yl)-1,6-naphthyridin-4(1H)-one as a white solid. ESI-MS m / z calc.424.196, found 425.2 (M+1)+.Step 3:

[0360] The enantiomers of rac-2-((7R,8R)-7-(3,4-difluoro-2-methoxyphenyl)spiro[4.5]decan-8-yl)- 1,6-naphthyridin-4(1H)-one were separated by chiral SFC using a Chiralpak®IC column, 5 μm particle size, 25 cm x 21.2 mm from Daicel Corporation (Mobile phase: 28% MeOH (supplemented with 20 mM ammonia), 72% CO2; Flow rate 70 mL / min) to give:

[0361] First Eluting Isomer: rel-2-((7S,8S)-7-(3,4-difluoro-2-methoxyphenyl)spiro[4.5]decan-8- yl)-1,6-naphthyridin-4(1H)-one (16, 7 mg, 2% over 2 steps).1H NMR (400 MHz, Chloroform-d) δ 9.39 (s, 1H), 8.89 (s, 1H), 8.55 (d, J = 5.8 Hz, 1H), 7.12 (s, 1H), 6.94 - 6.64 (m, 2H), 6.14 (s, 1H), 4.00 (s, 3H), 3.43 (s, 1H), 2.74 (s, 1H), 2.06 - 1.95 (m, 1H), 1.83 - 1.71 (m, 2H), 1.67 - 1.59 (m, 9H), 1.51 - 1.41 (m, 2H) ppm. ESI-MS m / z calc.424.196, found 425.2 (M+1)+.

[0362] Second Eluting Isomer: rel- 2-((7R,8R)-7-(3,4-difluoro-2-methoxyphenyl)spiro[4.5]decan- 8-yl)-1,6-naphthyridin-4(1H)-one (17, 7.6 mg, 2% over 2 steps).1H NMR (400 MHz, Chloroform-d) δ 9.40 (s, 1H), 8.71 (s, 1H), 8.56 (d, J = 5.8 Hz, 1H), 7.08 (d, J = 5.9 Hz, 1H), 6.81 (s, 2H), 6.13 (s, 1H), 4.01 (s, 3H), 3.41 (s, 1H), 2.72 (s, 1H), 2.05 - 1.94 (m, 1H), 1.79 - 1.69 (m, 2H), 1.67 - 1.56 (m, 9H), 1.49 - 1.42 (m, 2H) ppm. ESI-MS m / z calc.424.196, found 425.2 (M+1)+. Example 11Step 1:

[0363] Under a nitrogen atmosphere, DMF (1.8 mL) was added to a stirred mixture of (2R,3R,3aS,6aR)-3-(3,4-difluoro-2-methylphenyl)-6,6-difluorohexahydrofuro[3,2-b]furan-2-carboxylic acid (C - 20, 50 mg, 0.156 mmol), 4-benzyloxy-2-chloro-1,6-naphthyridine (Int-5, 43 mg, 0.159 mmol), K2CO3(64 mg, 0.463 mmol), 4-methoxy-2-(4-methoxy-2-pyridyl)pyridine (4 mg, 0.019 mmol), NiCl2glyme (4 mg, 0.018 mmol), and (Ir[dF(CF3)ppy]2(dtbpy))PF6(9 mg, 0.008 mmol), and the reaction was degassed for 15 min by passing nitrogen gas through the mixture. The solution was stirred at 30 °C for 19h under irradiation of a blue LED (450 nm) using a Hepatochem photoreactor equipped with a cooling fan. Purification by preparative reverse phase HPLC (C18column, 1 to 99 % ACN in water with 5 mM HCl) gave rac-4-(benzyloxy)-2-((2R,3S,3aS,6aR)-3-(3,4-difluoro-2-methylphenyl)-6,6- difluorohexahydrofuro[3,2-b]furan-2-yl)-1,6-naphthyridine (39 mg) which was used without further purification in the next step. Step 2:

[0364] TFA (400 µL, 5.192 mmol) was added to a solution of rac-4-(benzyloxy)-2- ((2R,3S,3aS,6aR)-3-(3,4-difluoro-2-methylphenyl)-6,6-difluorohexahydrofuro[3,2-b]furan-2-yl)-1,6- naphthyridine (39 mg) in toluene (500 µL). The reaction mixture was heated at 70 °C for 1 h and concentrated in vacuo. Purification by preparative reverse phase HPLC (C18column, 1 to 99 % ACN in water with 5 mM HCl) gave rac-2-((2R,3S,3aS,6aR)-3-(3,4-difluoro-2-methylphenyl)-6,6- difluorohexahydrofuro[3,2-b]furan-2-yl)-1,6-naphthyridin-4(1H)-one hydrochloride (18, 11 mg, 15%) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 9.35 (s, 1H), 8.69 (dd, J = 6.9, 1.1 Hz, 1H), 8.13 (d, J = 6.9 Hz, 1H), 7.54 - 7.33 (m, 1H), 7.14 (q, J = 9.0 Hz, 1H), 6.21 (s, 1H), 5.53 (d, J = 11.0 Hz, 1H), 5.14 - 5.00 (m, 2H), 4.37 - 4.16 (m, 1H), 4.05 (dt, J = 13.0, 10.4 Hz, 1H), 3.83 (dd, J = 11.0, 4.2 Hz, 1H), 2.17 (s, 3H) ppm; exchangeable H not observed. ESI-MS m / z calc.420.110, found 421.0 (M+1)⁺. Example 12130Step 1:

[0365] DIPEA (1.187 g, 1.6 mL, 9.186 mmol) was added to a stirred solution of dia-(1R1,2R1,4S2)-2- (3,4-difluoro-2-methyphenyl)-4-(trifluoromethyl)cyclopentane-1-carboxylic acid (C - 3c, 950 mg, 2.974 mmol), 1-(4-aminopyridin-3-yl)ethan-1-one (515 mg, 3.783 mmol) and HATU (1.5 g, 3.945 mmol) in DMF (20 mL) and the reaction mixture was stirred at ambient temperature for 20 h. The reaction was diluted with EtOAc (200 mL), washed with a 1:1 mixture of water and a saturated aqueous brine solution (2 x 50 mL), and brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, 10 to 100% EtOAc in heptane) gave:

[0366] First Eluting Isomers: rac-(1R,2R,4S)-N-(3-acetylpyridin-4-yl)-2-(3,4-difluoro-2- methylphenyl)-4-(trifluoromethyl)cyclopentane-1-carboxamide (353 mg, 27%) as a light yellow oil.1H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 9.07 (s, 1H), 8.59 (d, J = 5.6 Hz, 1H), 8.25 (d, J = 5.6 Hz, 1H), 7.38 - 7.19 (m, 2H), 3.60 (td, J = 11.5, 6.8 Hz, 1H), 3.29 - 3.11 (m, 2H), 2.62 - 2.56 (m, 3H), 2.42 - 2.33 (m, 1H), 2.28 (t, J = 8.6 Hz, 2H), 2.18 (d, J = 1.7 Hz, 3H), 1.71 (td, J = 12.3, 9.9 Hz, 1H) ppm. ESI- MS m / z calc.426.137, found 427.2 (M+1)+.

[0367] Secon Eluting Isomers: rac-(1R,2R,4R)-N-(3-acetylpyridin-4-yl)-2-(3,4-difluoro-2- methylphenyl)-4-(trifluoromethyl)cyclopentane-1-carboxamide (638 mg, 46%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 9.10 (s, 1H), 8.59 (d, J = 5.9 Hz, 1H), 8.29 (d, J = 5.6 Hz, 1H), 7.40 - 7.21 (m, 2H), 3.62 - 3.50 (m, 1H), 3.31 - 3.21 (m, 2H), 2.61 (s, 3H), 2.47 - 2.40 (m, 1H), 2.31 - 2.20 (m, 1H), 2.16 (d, J = 1.2 Hz, 3H), 2.06 - 1.92 (m, 2H, overlapped with solvent) ppm. ESI-MS m / z calc.426.137, found 427.1 (M+1)+. Step 2:

[0368] Et3N (290.4 mg, 0.4 mL, 2.870 mmol) and TMSOTf (1.228 g, 1 mL, 5.525 mmol) were successively added to a solution of rac-(1R,2R,4S)-N-(3-acetylpyridin-4-yl)-2-(3,4-difluoro-2- methylphenyl)-4-(trifluoromethyl)cyclopentane-1-carboxamide (350 mg, 0.788 mmol) in toluene (8 mL) and the reaction mixture was stirred at 90 °C for 19 h. The reaction was cooled to ambient temperature and diluted with 2-MeTHF (150 mL). The mixture was washed with a saturated aqueous NaHCO3solution (50 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by reverse phase chromatography (C18column, 5 to 95% MeCN in water with 0.1% formic acid) gave, after trituration from MTBE and heptane (3:1, 20 mL), rac-2-((1R,2R,4S)-2-(3,4-difluoro-2-methylphenyl)-4- (trifluoromethyl)cyclopentyl)-1,6-naphthyridin-4(1H)-one (111 mg, 33%) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 9.07 (s, 1H), 8.55 (br d, J = 5.9 Hz, 1H), 7.40 (d, J = 5.9 Hz, 1H), 7.27 - 7.16 (m, 2H), 6.08 (s, 1H), 3.76 (td, J = 11.7, 6.7 Hz, 1H), 3.51 - 3.36 (m, 1H), 3.31 - 3.19 (m, 1H), 2.58 - 2.39 (m, 2H, overlapped with solvent), 2.31 - 2.14 (m, 4H), 1.60 (td, J = 12.2, 9.5 Hz, 1H) ppm. ESI- MS m / z calc.408.126, found 409.2 (M+1)+. The filtrates were concentrated in vacuo to give a secondcrop of rac-2-((1R,2R,4S)-2-(3,4-difluoro-2-methylphenyl)-4-(trifluoromethyl)cyclopentyl)-1,6- naphthyridin-4(1H)-one (55 mg, 13%, 75% chemical purity) as a yellow oil. ESI-MS m / z calc.408.126, found 409.2 (M+1)+. Steps 3 and 4:

[0369] m-CPBA (110 mg, 0.491 mmol) was added to a stirred solution of rac-2-((1R,2R,4S)-2-(3,4- difluoro-2-methylphenyl)-4-(trifluoromethyl)cyclopentyl)-1,6-naphthyridin-4(1H)-one (106 mg, 0.245 mmol) in DCM (5 mL) and the reaction mixture was stirred at ambient temperature for 21 h. TMSCN (198.25 mg, 0.25 mL, 1.998 mmol) and Et3N (254.1 mg, 0.35 mL, 2.511 mmol) were successively added and the reaction mixture was stirred at ambient temperature for 25 h. Additional amounts of TMSCN (198.25 mg, 0.25 mL, 1.998 mmol) and Et3N (254.1 mg, 0.35 mL, 2.511 mmol) were added and the reaction mixture was stirred at ambient temperature for 4.5 h. The reaction was concentrated in vacuo and the residue was diluted with EtOAc (80 mL). The organic layer was separated, washed with a saturated aqueous NaHCO3solution (3 x 10 mL) and brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by reverse phase chromatography (C18column, 5 to 95% MeCN in water with 0.1% formic acid) gave rac-2-((1R,2R,4S)-2-(3,4-difluoro-2-methylphenyl)-4-(trifluoromethyl)cyclopentyl)-4- oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile. Step 5:

[0370] The enantiomers of rac-2-((1R,2R,4S)-2-(3,4-difluoro-2-methylphenyl)-4- (trifluoromethyl)cyclopentyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile were separated by chiral SFC using a Lux®Cellulose-2 column, 5 μm particle size, 25 cm x 30 mm from Phenomenex (Mobile phase: 35% ethanol, 65% CO2; Flow rate 100 mL / min) to give:

[0371] First Eluting Isomer: rel-2-((1S,2S,4R)-2-(3,4-difluoro-2-methylphenyl)-4- (trifluoromethyl)cyclopentyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile (27 mg, 24% over 3 steps) as an off-white solid.1H NMR (400 MHz, Methanol-d4) δ 8.63 (d, J = 5.9 Hz, 1H), 7.63 (d, J = 5.9 Hz, 1H), 7.17 (ddd, J = 8.7, 4.8, 1.6 Hz, 1H), 7.12 - 7.01 (m, 1H), 6.30 (s, 1H), 3.76 (td, J = 11.8, 7.0 Hz, 1H), 3.45 (td, J = 11.2, 8.7 Hz, 1H), 3.28 - 3.17 (m, 1H), 2.65 - 2.50 (m, 2H), 2.37 - 2.22 (m, 4H), 1.81 (td, J = 12.5, 9.2 Hz, 1H) ppm; exchangeable H not observed. ESI-MS m / z calc.433.121, found 434.1 (M+1)+.

[0372] Second Eluting Isomer: rel-2-((1R,2R,4S)-2-(3,4-difluoro-2-methylphenyl)-4- (trifluoromethyl)cyclopentyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile (24 mg, 23% over 3 steps) as an off-white solid.1H NMR (400 MHz, Methanol-d4) δ 8.63 (d, J = 5.9 Hz, 1H), 7.63 (d, J = 5.9 Hz, 1H), 7.22 - 7.13 (m, 1H), 7.12 - 7.03 (m, 1H), 6.30 (s, 1H), 3.76 (td, J = 11.8, 7.0 Hz, 1H), 3.45 (td, J = 11.1, 8.7 Hz, 1H), 3.28 - 3.17 (m, 1H), 2.64 - 2.50 (m, 2H), 2.37 - 2.20 (m, 4H), 1.81 (td, J = 12.5, 9.2 Hz, 1H) ppm; exchangeable H not observed. ESI-MS m / z calc.433.121, found 434.1 (M+1)+.Step 6:

[0373] A solution of rel-2-((1R,2R,4S)-2-(3,4-difluoro-2-methylphenyl)-4- (trifluoromethyl)cyclopentyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile (21 mg, 0.048 mmol) and TFA (1.036 g, 0.7 mL, 9.086 mmol) in a mixture of toluene (1 mL) and water (0.03 mL, 1.665 mmol) was stirred at 70 °C for 17 h. The reaction was concentrated in vacuo and the residue was diluted with EtOAc (70 mL). The organic layer was separated and washed with a saturated aqueous NaHCO3solution (10 mL) and brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by reverse phase chromatography (C18column, 5 to 95% MeCN in water with 0.1% formic acid) gave rel-2- ((1R,2R,4S)-2-(3,4-difluoro-2-methylphenyl)-4-(trifluoromethyl)cyclopentyl)-4-oxo-1,4-dihydro-1,6- naphthyridine-5-carboxamide (19, 15 mg, 69%) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 8.48 (br d, J = 5.9 Hz, 1H), 7.47 (br d, J = 4.9 Hz, 1H), 7.23 - 7.12 (m, 1H), 7.12 - 7.01 (m, 1H), 6.23 (br s, 1H), 3.74 (td, J = 11.8, 7.0 Hz, 1H), 3.49 - 3.36 (m, 1H), 3.29 - 3.16 (m, 1H), 2.62 - 2.49 (m, 2H), 2.38 - 2.24 (m, 1H), 2.21 (d, J = 2.2 Hz, 3H), 1.82 (td, J = 12.5, 9.3 Hz, 1H) ppm; exchangeable H not observed. ESI-MS m / z calc.451.132, found 452.1 (M+1)+.

[0374] The following compounds were made using methods analogous to those disclosed in the specification.

[0375] Table F. Compounds Prepared Using Analogous Methods.*SFC separation performed at the last step except if specified otherwise. Intermediate C - 1 rac-(1R,2R)-2-(3,4-Difluoro-2-methoxyphenyl)-4,4-dimethylcyclopentane-1-carboxylic acidStep 1:

[0376] Nitrogen gas was passed through a stirred solution of methyl 4,4-dimethyl-2- (((trifluoromethyl)sulfonyl)oxy)cyclopent-1-ene-1-carboxylate (13.35 g, 42.532 mmol) and (3,4-difluoro- 2-methoxyphenyl)boronic acid (9.6 g, 51.081 mmol) in a mixture of 2-MeTHF (200 mL) and a 2 M aqueous Na2CO3solution (53 mL, 106 mmol) for 30 min. Pd(PPh3)4(2.4 g, 2.077 mmol) was added and the reaction mixture was stirred at 80 °C for 3 h. The reaction was cooled to ambient temperature, diluted with water (200 mL) and EtOAc (200 mL). The aqueous layer was separated and extracted with EtOAc (100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, 0 to 10% EtOAc in heptane) gave methyl 2-(3,4-difluoro-2- 60methoxyphenyl)-4,4-dimethylcyclopent-1-ene-1-carboxylate (11.12 g, 88%) as a pale yellow oil.1H NMR (400 MHz, Chloroform-d) δ 6.89 - 6.74 (m, 2H), 3.87 (d, J = 1.7 Hz, 3H), 3.58 (s, 3H), 2.63 - 2.59 (m, 2H), 2.58 - 2.54 (m, 2H), 1.18 (s, 6H) ppm. ESI-MS m / z calc.296.122, found 297.2 (M+1)+. Step 2:

[0377] Under a nitrogen atmosphere, 5% Pd / C (3.84 g, 1.804 mmol) was added to a solution of methyl 2-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylcyclopent-1-ene-1-carboxylate (10.9 g, 36.749 mmol) in EtOAc (250 mL). Hydrogen gas was passed through the solution for 30 min and the reaction mixture was stirred under an atmospheric pressure of hydrogen gas for 16 h. Additional 5% Pd / C (1 g, 0.470 mmol) was added and the reaction mixture was stirred under an atmospheric pressure of hydrogen gas for a further 16 h. The mixture was filtered through a pad of Celite®, washing the filtered cake with EtOAc (150 mL). The filtrates were concentrated in vacuo to give methyl dia-(1R1,2R2)-2-(3,4-difluoro-2- methoxyphenyl)-4,4-dimethylcyclopentane-1-carboxylate (10.89 g, 99%) as a 66:34 mixture of cis and trans diastereomers and as a colourless oil.1H NMR (400 MHz, Chloroform-d) δ 6.94 - 6.87 (m, 0.34H), 6.87 - 6.71 (m, 1.66H), 4.02 (d, J = 2.2 Hz, 1.98H), 3.98 - 3.88 (m, 1.66H), 3.77 (td, J = 10.9, 8.2 Hz, 0.34H), 3.59 (s, 1.02H), 3.34 (ddd, J = 9.7, 8.4, 6.6 Hz, 0.66H), 3.19 (s, 1.98H), 3.10 - 3.00 (m, 0.34H), 2.06 - 1.89 (m, 2.02H), 1.86 - 1.79 (m, 0.34H), 1.75 (ddd, J = 13.3, 8.4, 1.6 Hz, 0.66H), 1.60 (ddd, J = 12.2, 6.4, 1.5 Hz, 0.66H), 1.55 - 1.48 (m, 0.34H), 1.24 (s, 1.98H), 1.15 (s, 1.02H), 1.12 (s, 1.02H), 1.10 (s, 1.98H) ppm. ESI-MS m / z calc.298.138, found 299.1 (M+1)+. Step 3:

[0378] NaOtBu (19 mg, 0.198 mmol) was added to a solution of a 66:34 mixture of cis and trans diastereomers of methyl dia-(1R1,2R2)-2-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylcyclopentane-1- carboxylate (40 mg, 0.113 mmol) in MeOH (1 mL) at ambient temperature and the reaction mixture was stirred at ambient temperature for 16 h. KOtBu (20 mg, 0.178 mmol) was added and the mixture was stirred at 50 °C for 4 h. The reaction was cooled to ambient temperature and partitioned between MTBE (20 mL) and a 0.25 N aqueous HCl solution (20 mL). The aqueous layer was separated and extracted with MTBE (20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give rac-(1R,2R)-2-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylcyclopentane-1-carboxylic acid (C - 1, 38 mg, 100%) as a colourless oil.1H NMR (400 MHz, Chloroform-d) δ 6.94 - 6.87 (m, 1H), 6.85 - 6.76 (m, 1H), 3.91 (d, J = 2.0 Hz, 3H), 3.76 (td, J = 10.9, 8.2 Hz, 1H), 3.10 - 3.01 (m, 1H), 1.95 (ddd, J = 19.1, 12.8, 8.4 Hz, 2H), 1.88 - 1.80 (m, 1H), 1.59 - 1.49 (m, 1H), 1.14 (s, 3H), 1.12 (s, 3H) ppm; exchangeable H not observed. ESI-MS m / z calc.284.122, found 285.2 (M+1)+.Intermediate C - 2 rac-(2R,3R)-3-(3,4-Difluoro-2-methoxyphenyl)spiro[4.5]decane-2-carboxylic acidStep 1:

[0379] Under a nitrogen atmosphere, Tf2O (1.5 mL, 8.916 mmol) was added dropwise to a stirred solution of methyl rac-3-oxospiro[4.5]decane-2-carboxylate (1.5 g, 7.134 mmol) and DIPEA (1.8 mL, 10.33 mmol) in DCM (16.5 mL) at -78 °C and the reaction mixture was stirred at -78 °C for 5 min and at ambient temperature for 1 h. The reaction was quenched by addition of a saturated NH4Cl solution. The aqueous phase was separated and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, 0 to 60% EtOAc in hexanes) gave methyl 3-(((trifluoromethyl)sulfonyl)oxy)spiro[4.5]dec-2-ene-2-carboxylate (1.69 g, 69%) as an orange oil.1H NMR (400 MHz, Chloroform-d) δ 3.79 (s, 3H), 2.56 (t, J = 2.6 Hz, 2H), 2.50 (t, J = 2.6 Hz, 2H), 1.56 - 1.37 (m, 10H) ppm. ESI-MS m / z calc.342.075, found 343.1 (M+1)+. Step 2:

[0380] In a vial, nitrogen gas was passed through a stirred mixture of methyl 3- (((trifluoromethyl)sulfonyl)oxy)spiro[4.5]dec-2-ene-2-carboxylate (1 g, 2.921 mmol), PdCl2(PPh3)2(164 mg, 0.234 mmol) and (3,4-difluoro-2-methoxyphenyl)boronic acid (600 mg, 3.193 mmol) in a mixture of 1,4-dioxane (6.6 mL) and a saturated aqueous NaHCO3solution (3.4 mL) for 5 min. The vial was sealed and the reaction mixture was stirred at 50 °C for 1.5 h. The mixture was cooled to ambient temperature and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, 1 to 60% EtOAc in hexanes) gave methyl 3-(3,4-difluoro-2-methoxyphenyl)spiro[4.5]dec-2-ene-2-carboxylate (945 mg, 96%) as a yellow oil.1H NMR (400 MHz, Chloroform-d) δ 6.95 - 6.72 (m, 2H), 3.86 (d, J = 1.8 Hz, 3H), 3.58 (s, 3H), 2.60 (dt, J = 17.3, 2.3 Hz, 4H), 1.59 - 1.40 (m, 10H) ppm. ESI-MS m / z calc.336.154, found 337.1 (M+1)+. Step 3:

[0381] Mg (315 mg, 11.97 mmol) was added to a solution of methyl 3-(3,4-difluoro-2- methoxyphenyl)spiro[4.5]dec-2-ene-2-carboxylate (500 mg, 1.486 mmol) in MeOH (15.5 mL) and thereaction mixture was vigorously stirred at ambient temperature for 2 h. The mixture was partitioned between 1 N aqueous HCl and EtOAc. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, 1 to 60% EtOAc in hexanes) gave methyl dia-(2R1,3R2)-3- (3,4-difluoro-2-methoxyphenyl)spiro[4.5]decane-2-carboxylate (370 mg, 74%) as an orange oil. ESI-MS m / z calc.338.169, found 339.2 (M+1)+. Step 4:

[0382] In a vial, LiOH.H2O (186 mg, 4.433 mmol) was added to a stirred solution of methyl dia- (2R1,3R2)-3-(3,4-difluoro-2-methoxyphenyl)spiro[4.5]decane-2-carboxylate (300 mg, 0.887 mmol) in a mixture of THF (5.1 mL), MeOH (2.6 mL) and water (2.6 mL). The vial was capped and placed in a pre- heated heating block set at 70 °C for 5 h. The reaction was cooled to ambient temperature and partitioned between 1 N aqueous HCl and EtOAc. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, 0 to 60% of EtOAc in hexanes) gave rac-(2R,3R)-3- (3,4-difluoro-2-methoxyphenyl)spiro[4.5]decane-2-carboxylic acid 2-(3,4-difluoro-2-methoxy- phenyl)spiro[4.5]decane-3-carboxylic acid (C - 2, 167 mg, 58%) as a yellow oil. ESI-MS m / z calc. 324.154, found 325.3 (M+1)+.

[0383] The following Intermediates were made using the method described in Intermediate C - 2, except that, in Step 1, different starting materials were used in place of methyl rac-3- oxospiro[4.5]decane-2-carboxylate. In Step 2, in some occurrences, different Suzuki coupling partners were used in place of (3,4-difluoro-2-methoxyphenyl)boronic acid. In the case of Intermediate C - 18, Steps 2, 3 and 4 were respectively carried out at 75, 50 and 50 °C:63

[0384] The following Intermediate was made using the method described in Intermediate C - 2, except that Step 1 was omitted. In Step 2, a different starting material was used in place of methyl rac-3- oxospiro[4.5]decane-2-carboxylate and the reaction was carried out at 75 °C. In Step 3, the reaction was carried out at reflux of the solvent:

[0385] The following Intermediates were made using the method described in Intermediate C - 2, except that, in Step 1, a different starting material was used in place of methyl rac-3-oxospiro[4.5]decane- 2-carboxylate. The reaction was carried out at 0 °C in the case of C - 3f and at -78 °C in the case of C - 3g and C - 3h. In Step 2, different Suzuki coupling partners were used in place of (3,4-difluoro-2- methoxyphenyl)boronic acid. Step 3 was carried out at 0 °C. The conditions used in Step 4 were those of Intermediate C - 16 Step 5: 64Intermediate C - 3d rac-(1R,2R,4S)-2-(2-Cyclopropoxy-3,4-difluorophenyl)-4-(trifluoromethyl)cyclopentane-1-carboxylic acid

[0386] Step 1:

[0387] Ethyl rac-(1R,2R,4S)-2-(3,4-difluoro-2-methoxyphenyl)-4-(trifluoromethyl)cyclopentane-1- carboxylate was prepared using the method described in Intermediate C - 8a except that Steps 1 to 6 were omitted. In Steps 7 and 8, ethyl rac-2-oxo-4-(trifluoromethyl)cyclopentane-1-carboxylate was used as the starting material in place of rac-(3aR,6aR)-4,4-difluorohexahydropentalen-1(2H)-one and the conditions were those of Intermediate C - 2 Steps 1 and 2. The hydrogenation Step 9 was carried out in EtOH at 60 psi and 60 °C and Pd(OH)2was used as the catalyst in place of Pd / C. Step 10 was omitted.

[0388] BBr3(264 mg, 0.1 mL, 1.054 mmol) was added to a stirred solution of ethyl rac-(1R,2R,4S)- 2-(3,4-difluoro-2-methoxyphenyl)-4-(trifluoromethyl)cyclopentane-1-carboxylate (210 mg, 0.537 mmol) in DCM (4 mL) at 0 °C and the reaction mixture was stirred at 0 °C for 2.5 h. The reaction was quenched by slowly pouring the mixture over a stirred mixture of a saturated aqueous NaHCO3solution(15 mL) and DCM (20 mL). The aqueous layer was separated and extracted with DCM (20 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, 0 to 30% EtOAc in heptane) gave ethyl rac-(1R,2R,4S)-2-(3,4-difluoro-2- hydroxyphenyl)-4-(trifluoromethyl)cyclopentane-1-carboxylate (180 mg, 90%) as a clear oil. ESI-MS m / z calc.338.094, found 339.1 (M+1)+.

[0389] Step 2:

[0390] Cs2CO3(320 mg, 0.982 mmol) was added to a solution of ethyl rac-(1R,2R,4S)-2-(3,4- difluoro-2-hydroxyphenyl)-4-(trifluoromethyl)cyclopentane-1-carboxylate (175 mg, 0.471 mmol) in DMF (3 mL) and the reaction mixture was stirred at ambient temperature for 30 min. A solution of CF3SO3cPr (312 mg, 1.477 mmol) in DMF (1 mL) was added and the mixture was stirred at 40 °C for 4 h. The reaction was cooled to ambient temperature and partitioned between water (50 mL) and MTBE (30 mL). The aqueous layer was separated and extracted with MTBE (2 x 30 mL). The combined organic layers were washed with water (4 x 40 mL) and brine (40 mL), dried (Na2SO4), filtered and concentrated in vacuo to give a crude mixture of ethyl rac-(1R,2R,4S)-2-(2-cyclopropoxy-3,4-difluorophenyl)-4- (trifluoromethyl)cyclopentane-1-carboxylate containing 13% of ethyl rac-(1R,2R,4S)-2-(2-(allyloxy)-3,4- difluorophenyl)-4-(trifluoromethyl)cyclopentane-1-carboxylate (200 mg) as a brown oil. ESI-MS m / z calc.378.125, found 379.1 (M+1)+.

[0391] Step 3:

[0392] NMO (21 mg, 0.179 mmol) and a solution of OsO4(12.2 mg, 2.5 % w / w intBuOH, 0.001 mmol) intBuOH (1 mL) were successively added to a solution of a crude mixture of ethyl rac- (1R,2R,4S)-2-(2-cyclopropoxy-3,4-difluorophenyl)-4-(trifluoromethyl)cyclopentane-1-carboxylate containing 13% of ethyl rac-(1R,2R,4S)-2-(2-(allyloxy)-3,4-difluorophenyl)-4- (trifluoromethyl)cyclopentane-1-carboxylate (200 mg) in a mixture oftBuOH (3 mL) and water (3 mL) at ambient temperature and the reaction mixture was stirred at ambient temperature for 16 h. The reaction was quenched by addition of a 10% aqueous Na2S2O3solution (10 mL) and extracted with MTBE (2 x 20 mL). The combined organic layers were washed with water (3 x 10 mL) and brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, 0 to 30% EtOAc in heptane) gave ethyl rac-(1R,2R,4S)-2-(2-cyclopropoxy-3,4-difluorophenyl)-4- (trifluoromethyl)cyclopentane-1-carboxylate (155 mg, 92% over 2 steps) as a clear oil.1H NMR (400 MHz, Chloroform-d) δ 6.95 - 6.80 (m, 2H), 4.29 - 4.23 (m, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.49 (td, J = 11.3, 7.3 Hz, 1H), 3.07 - 2.96 (m, 1H), 2.95 - 2.82 (m, 1H), 2.33 - 2.21 (m, 3H), 1.80 (td, J = 12.5, 9.8 Hz, 1H), 1.15 (t, J = 7.1 Hz, 3H), 0.87 - 0.80 (m, 2H, overlapped with grease), 0.71 - 0.62 (m, 2H) ppm. ESI-MS m / z calc.378.125, found 379.1 (M+1)+. Ethyl rac-(1R,2R,4S)-2-(2-(2,3-dihydroxypropoxy)-3,4- difluorophenyl)-4-(trifluoromethyl)cyclopentane-1-carboxylate was not isolated.

[0393] Step 4:

[0394] A solution of ethyl rac-(1R,2R,4S)-2-(2-cyclopropoxy-3,4-difluorophenyl)-4- (trifluoromethyl)cyclopentane-1-carboxylate (80 mg, 0.192 mmol) and LiOH.H2O (20 mg, 0.477 mmol) in a mixture of THF (1.6 mL), MeOH (1 mL) and water (1 mL) was stirred at ambient temperature for 48 h. The reaction was concentrated in vacuo to remove MeOH and THF. The aqueous solution was diluted with 1 N aqueous HCl solution (10 mL) and extracted with MTBE (2 x 20 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo to give rac- (1R,2R,4S)-2-(2-cyclopropoxy-3,4-difluorophenyl)-4-(trifluoromethyl)cyclopentane-1-carboxylic acid (C - 3d, 67 mg, 99%) as a pale yellow oil.1H NMR (400 MHz, Chloroform-d) δ 6.94 - 6.88 (m, 1H), 6.88 - 6.80 (m, 1H), 4.25 (td, J = 6.4, 3.4 Hz, 1H), 3.58 - 3.49 (m, 1H), 3.10 - 3.02 (m, 1H), 2.95 - 2.83 (m, 1H), 2.33 - 2.23 (m, 3H), 1.86 - 1.79 (m, 1H), 0.88 - 0.75 (m, 2H, overlapped with grease), 0.70 - 0.60 (m, 2H) ppm; exchangeable H not observed. ESI-MS m / z calc.350.094, found 349.0 (M-1)-. Intermediate C - 3e rac-(1R,2R,4S)-2-(2-Cyclopropyl-3,4-difluorophenyl)-4-(trifluoromethyl)cyclopentane-1-carboxylic acid

[0395] Step 1:

[0396] Tf2O (461.18 mg, 0.275 mL, 1.635 mmol) was added dropwise to a stirred solution of ethyl rac-(1R,2R,4S)-2-(3,4-difluoro-2-hydroxyphenyl)-4-(trifluoromethyl)cyclopentane-1-carboxylate (500 mg, 1.323 mmol) and DIPEA (333.9 mg, 0.45 mL, 2.584 mmol) in DCM (15 mL...

Claims

CLAIMS What is claimed is:

1. A compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein: XA1is C-RA1, N, or N+-O-; XA2is C-RA2, N, or N+-O-; XA4is C-RA4, N, or N+-O-; XA5is C-RA5or N; XC1is C-RC1or N; XC2is C-RC2or N; RA1, RA2, RA3, and RA4are each independently H, OH, CN, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, –NHS(O)2(C1-C6alkyl), –C(O)ORb, –C(O)NRbRc, –(CH2)mO(CH2)oCH3, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents independently selected from C1-C6alkyl and –C(O)NRbRc; RA5is H, OH, halo, CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, –(CH2)mOn(CH2)oOCH3, –(CH2)mRa, –C(O)(CH2)mRa, –C(O)ORb, –C(O)Rb, –C(O)NRbRc, –NRbRc, –CRdReRf, –CRbRcNRgC(O)CRhRiRj, –NRbC(O)CRcRgRj, C3-C6cycloalkyl, 5-6 membered heteroaryl, or 4-10 membered heterocyclyl, wherein said C3-C6cycloalkyl, 5-6 membered heteroaryl, or 4-10 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents independently selected from halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; R1and R2are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R3and R4are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; p, Z, R5, R6, R7, and R8are defined as follows:226(i) p is 0 or 1; Z is C(-R3)(-R4); R5and R6are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; and R7and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; or (ii) p is 0 or 1; Z is C(-R3)(-R4); R7and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; and R5and R6, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl optionally substituted with 1-6 Ry; or (iii) p is 0 or 1; Z is C(-R3)(-R4); R5and R7, together with the carbon atoms to which they are attached, form a fused C3-C6cycloalkyl optionally substituted with 1-6 Ry; and R6and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; or (iv) p is 0; Z is C(-R3)(-R4) or O; R5and R7, together with the carbon atoms to which they are attached, form a fused ring of formula, optionally substituted with 1-4 Ry; and R6and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R9is H or CH3; RC1and RC2are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, –[CH2]q-C3-C6cycloalkyl, –[CH2]q-O-C3-C6cycloalkyl, –[CH2]q-NRbRc, –(CH2)mORb, or –O(CH2)mORb, wherein said C1-C6alkyl and C1-C6alkoxy of RC1or RC2are each optionally substituted with an independently selected CN or 5-6 membered heteroaryl; or RC1and RC2, together with the carbon atoms to which they are attached, form a ring of formula:Y is O or CH2; RC3, RC4, and RC5are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, –O-C3-C6cycloalkyl, –NRbRc, –(CH2)mORb, or –O(CH2)mOCH3; each Rxis independently H, halo, C1-C6alkyl, or C1-C6haloalkyl; each Ryis independently halo, OH, C1-C6alkyl, or C1-C6haloalkyl; Rais OH, halo, C1-C6alkoxy, or –NRbRc; Rb, Rc, Rg, Rh, and Riare each independently H or C1-C6alkyl, or Rband Rc, together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclyl; Rd, Re, and Rfare each independently H, OH, halo, C1-C6alkyl, or C1-C6alkoxy; Rjis H, C1-C6alkyl, –NRbRc, or –N(CH3)3+; m and o are each independently 0, 1, 2, or 3; q is 0 or 1; and n is 0 or 1.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RC1and RC2are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, –[CH2]q-C3-C6cycloalkyl, –[CH2]q-O-C3-C6cycloalkyl, –[CH2]q-NRbRc, –(CH2)mORb, or –O(CH2)mOCH3, or RC1and RC2, together with the carbon atoms to which they are attached, form a ring of formula:

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: p is 0 or 1; Z is C(-R3)(-R4); R5, R6, R7, and R8are defined as follows: (i) R5and R6are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; andR7and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; or (ii) R7and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; and R5and R6, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl optionally substituted with 1-6 Ry; or (iii) R5and R7, together with the carbon atoms to which they are attached, form a fused C3-C6cycloalkyl optionally substituted with 1-6 Ry; and R6and R8are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II):wherein: XA1is C-RA1, N, or N+-O-; XA2is C-RA2, N, or N+-O-; p is 0 or 1; XC1is C-RC1or N; XC2is C-RC2or N; RA1and RA2are each independently H, OH, CN, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, –NHS(O)2(C1-C6alkyl), –C(O)ORb, –C(O)NRbRc, –(CH2)mO(CH2)oCH3, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents independently selected from C1-C6alkyl and –C(O)NRbRc; R1and R2are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; 29R3and R4are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R5, R6, R7, and R8are defined as follows: (i) R5and R6are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; and R7and R8are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; or (ii) R7and R8are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; and R5and R6, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl optionally substituted with 1-6 Ry; or (iii) R5and R7, together with the carbon atoms to which they are attached, form a fused C3-C6cycloalkyl optionally substituted with 1-6 Ry; and R6and R8are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R9is H or CH3;independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, –O-C3-C6cycloalkyl, –NRbRc, –(CH2)mORb, or –O(CH2)mOCH3; each Ryis independently halo, OH, C1-C6alkyl, or C1-C6haloalkyl; Rband Rcare each independently H or C1-C6alkyl, or Rband Rc, together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclyl; and m and o are each independently 0, 1, 2, or 3.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (III):wherein: XA1is C-RA1, N, or N+-O-; XA2is C-RA2, N, or N+-O-; Z is C(-R3)(-R4) or O; XC1is C-RC1or N; XC2is C-RC2or N; RA1and RA2are each independently H, OH, CN, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, –NHS(O)2(C1-C6alkyl), –C(O)ORb, –C(O)NRbRc, –(CH2)mO(CH2)oCH3, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents independently selected from C1-C6alkyl and –C(O)NRbRc; R3and R4are each independently H, halo, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R6and R8are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R9is H or CH3;independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, –O-C3-C6cycloalkyl, –NRbRc, –(CH2)mORb, or –O(CH2)mOCH3; each Ryis independently halo, OH, C1-C6alkyl, or C1-C6haloalkyl; Rband Rcare each independently H or C1-C6alkyl, or Rband Rc, together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclyl; m and o are each independently 0, 1, 2, or 3; and r is 0, 1, 2, 3, or 4.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein XA1is C-RA1.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein RA1is CN or –C(O)NRbRc, and Rband Rcare each independently H or C1-C6alkyl; optionally wherein RA1is –C(O)NRbRc, and Rband Rcare each independently H or C1-C6alkyl.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein XA2is N.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein: XA1is C-RA1; RA1is –C(O)NRbRc; Rband Rcare each H; and XA2is N.

10. The compound of any one of claims 1 to 4 and 6 to 9, or a pharmaceutically acceptable salt thereof, wherein p is 0.

11. The compound of any one of claims 1 to 4 and 6 to 9, or a pharmaceutically acceptable salt thereof, wherein p is 1.

12. The compound of any one of claims 1 to 4, 6 to 9, and 11, or a pharmaceutically acceptable salt thereof, wherein R1and R2are each H.

13. The compound of any one of claims 1 to 4 and 6 to 12, or a pharmaceutically acceptable salt thereof, wherein R3and R4are each independently H or C1-C2haloalkyl; optionally wherein: R3and R4are each independently H or CF3; or R3and R4are each H.

14. The compound of any one of claims 1 to 4 and 6 to 13, or a pharmaceutically acceptable salt thereof, wherein: (i) R5and R6are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy or, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl optionally substituted with 1-6 Ry, where each Ryis independently halo or C1haloalkyl; or (ii) R5and R6are each independently H, C1-C4alkyl, or C1haloalkyl, optionally wherein R5and R6are each independently H, -CH3, -C(CH3)3or -CF3; or (iii) R5and R6, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl optionally substituted with 1-3 Ry, where each Ryis independently halo or C1haloalkyl, optionally wherein R5and R6, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl optionally substituted with 2 Ry, where each Ryis independently F.

15. The compound of any one of claims 1 to 4 and 6 to 14, or a pharmaceutically acceptable salt thereof, wherein R7and R8are each independently H, OH, C1-C3alkyl, C1-C3haloalkyl, or C1-C3alkoxy;optionally wherein R7and R8are each independently H, OH, -CH3, -CF3, or -O-CH3.

16. The compound of any one of claims 1 to 4 and 6 to 13, or a pharmaceutically acceptable salt thereof, wherein: R5and R7, together with the carbon atoms to which they are attached, form a fused C3-C6cycloalkyl optionally substituted with 1-3 Ry; R6and R8are each H; and each Ryis independently halo; optionally wherein R5and R7, together with the carbon atoms to which they are attached, form a fused C5or C6cycloalkyl optionally substituted with 2 F; and R6and R8are each H.

17. The compound of any one of claims 1 and 5 to 9, or a pharmaceutically acceptable salt thereof, wherein Z is O.

18. The compound of any one of claims 1, 5 to 9, and 17, or a pharmaceutically acceptable salt thereof, wherein R6and R8are each H.

19. The compound of any one of claims 1, 5 to 9, 17, and 18, or a pharmaceutically acceptable salt thereof, wherein each Ryis independently halo, and r is 2.

20. The compound of any one of claims 1, 5 to 9, and 17 to 19, or a pharmaceutically acceptable salt thereof, wherein each Ryis F, and r is 2.

21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R9is H.

22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein: XC1is C-RC1; and XC2is C-RC2.

23. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein: XC1is C-RC1; and XC2is N. 3324. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein: XC1is N; and XC2is C-RC2.

25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein RC1, RC2, RC3, RC4, and RC5are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, -O-C3-C6cycloalkyl, or –CH2OH; optionally wherein: (i) RC1, RC2, RC3, RC4, and RC5are each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, or –CH2OH; or (ii) RC1, RC2, RC3, RC4, and RC5are each independently H, OH, F, Cl, -CH3, -CH2CH3, -OCH3, -CF3, C3cycloalkyl, -O-C3cycloalkyl, or –CH2OH; or (ii) RC1, RC2, RC3, RC4, and RC5are each independently H, OH, F, Cl, -CH3, -CH2CH3, -OCH3, C3cycloalkyl, or –CH2OH.

26. The compound of any one of claims 1 to 22 and 25, or a pharmaceutically acceptable salt thereof, wherein RC1is -CH3, RC2is F, RC3is F, RC4is H, and RC5is H.

27. The compound of any one of claims 1 to 22 and 25, or a pharmaceutically acceptable salt thereof, wherein RC1is -OCH3, RC2is F, RC3is F, RC4is H, and RC5is H.

28. The compound of any one of claims 1 to 22 and 25, or a pharmaceutically acceptable salt thereof, wherein RC1is -OCH3, RC2is Cl, RC3is F, RC4is H, and RC5is H.

29. The compound of any one of claims 1 to 22 and 25, or a pharmaceutically acceptable salt thereof, wherein RC1is -CH3, RC2is Cl, RC3is F, RC4is H, and RC5is H.

30. The compound of any one of claims 1 to 22 and 25, or a pharmaceutically acceptable salt thereof, wherein RC1is -CH2CH3, RC2is F, RC3is F, RC4is H, and RC5is H.

31. The compound of any one of claims 1 to 21, 23, and 25, or a pharmaceutically acceptable salt thereof, wherein XC1is C-RC1, XC2is N, RC1is -OCH3, RC3is –CH3, RC4is H, and RC5is H.

32. The compound of any one of claims 1 to 21, 24, and 25, or a pharmaceutically acceptable salt thereof, wherein XC1is N, XC2is C-RC2, RC2is –CH3, RC3is F, RC4is H, and RC5is H.

33. A compound selected from Table A, or a pharmaceutically acceptable salt thereof.

34. A compound selected from Table B, or a pharmaceutically acceptable salt thereof.

35. A compound selected from Table C, or a pharmaceutically acceptable salt thereof.

36. A compound selected from Table D, or a pharmaceutically acceptable salt thereof.

37. The compound of any one of claims 1 to 36 in non-salt form.

38. A pharmaceutical composition comprising the compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, or the compound of claim 37, and one or more pharmaceutically acceptable carriers or vehicles.

39. 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 to 36, or a pharmaceutically acceptable salt thereof, the compound of claim 37, or the pharmaceutical composition of claim 38; optionally wherein the voltage-gated sodium channel is NaV1.

8.

40. 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 to 36, or a pharmaceutically acceptable salt thereof, the compound of claim 37, or the pharmaceutical composition of claim 38.

41. The method of claim 40, wherein: (i) the method comprises treating or lessening the severity in the subject of neuropathic pain, optionally wherein: (a) the neuropathic pain comprises post-herpetic neuralgia; or (b) the neuropathic pain comprises small-fiber neuropathy; or (c) the neuropathic pain comprises idiopathic small-fiber neuropathy; or (d) the neuropathic pain comprises diabetic neuropathy, optionally wherein the diabetic neuropathy comprises diabetic peripheral neuropathy; or (ii) the method comprises treating or lessening the severity in the subject of chronic pain, optionally wherein the chronic pain is lumbosacral radiculopathy; or 35(iii) the method comprises treating or lessening the severity in the subject of musculoskeletal pain, optionally wherein the musculoskeletal pain comprises osteoarthritis pain; or (iv) the method comprises treating or lessening the severity in the subject of acute pain, optionally wherein the acute pain comprises acute post-operative pain; or (v) the method comprises treating or lessening the severity in the subject of postsurgical pain, optionally wherein: (a) the postsurgical pain comprises bunionectomy pain; or (b) the postsurgical pain comprises abdominoplasty pain; or (c) the postsurgical pain comprises herniorrhaphy pain; or (vi) the method comprises treating or lessening the severity in the subject of visceral pain.

42. The method of any one of claims 39 to 41, 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.

43. Use of the compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, the compound of claim 37, or the pharmaceutical composition of claim 38, as a medicament.

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