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

HETEROARYL COMPOUNDS FOR THE TREATMENT OF PAINCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 592,371, filed October 23, 2023, and U.S. Provisional Application No. 63 / 592,715, filed October 24, 2023, each of which is incorporated by reference herein in its 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 tw o 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 nene injury indications include post-amputation pain, post-surgical nene 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 chaimel genes, preclinical work in animal models, and the clinical pharmacology of known sodium chamrel 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 Navi .8 Sodium Channels. Mol. Interv.. 2007. 7(4): p. 192-5); England. S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin. Investig. Drugs 17 (12), p. 1849-64 (2008); Krafte. D. S. and Bannon. A. W., Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8 (1), p. 50-56 (2008)). Because of the role Navs play in the initiation and propagation of neuronal signals, antagonists that reduce Nav currents can prevent or reduce neural signaling and Nav channels havebeen 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 Nav channels. The local anesthetic drugs such as lidocaine block pain by inhibiting Nav channels, 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 NavL l - Navi.9. The tissue localizations of the nine isoforms vary. Navl.4 is the primary sodium channel of skeletal muscle, and Navi.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 voltagedependent 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. Navi.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). Navi.8 is involved in spontaneous firing in damaged neurons, like those that drive neuropathic pain (Roza, C., et al., The tetrodotoxin-resistant Na+charnel Navi.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 Navi.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 Nav 1.8 in inflammatory' and neuropathic, but not post-operative, pain states. Pain, 2006. 123(1-2): pp. 75-82; Lai. J., et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, Navi.8. Pain, 2002. 95(1-2): p. 143-52; Dong, X.W.. et al., Small interfering RNA-mediated selective knockdown of Navi.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 andlocal 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. FEBSLett., 2000. 467(2-3): p. 249-52; Ruangsri, S., et al.. Relationship of axonal voltage-gated sodium channel 1.8 (Navi.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 Navi.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). Navl.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 Navl.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 Navl.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, Navl.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., ct al., Changes in the expression of Nav1.7, Navl.8 and Navi.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 Navl.8 and Navi.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 of Nav isoform selectivity, low potency, and / or other reasons). Accordingly, there remains a need to develop selective voltage-gated sodium channel inhibitors, such as selective Navl.8 inhibitors.SUMMARY

[0008] In one aspect, the invention relates to a compound described herein, 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- A):or a pharmaceutically acceptable salt thereof, wherein:X1is C-R1or N;X2is C-R2or N;X' is C-R' or N;X' is C-R' or N:R1is H, OH, halo, CN, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cg alkoxy, Ci-Ce haloalkoxy, -(CH2)mO„(CH2)oOCH3, -(CH2)mR“, -C(O)(CH2)mRa, -CCOjOR*. -CCOjR*, -C(O)NR6RC, -NR''’R\ CR"R‘R'. -CRiRcNRgC(O)CR / !R'R / , -NRZ’C(O)CR‘R«R', C3-C6cycloalkyl, 5-6 membered heteroaryl, or 4-10 membered hctcrocyclyl, wherein said CL-G, cycloalkyl, 5-6 membered hctcroaryl, or 4-10 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents independently selected from halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, and Ci-Ce haloalkoxy;R2and R3are defined as follows:(i) R2is H, OH, halo, CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, – (CH2)mRa, –C(O)ORb, –C(O)Rb, –C(O)NRbRc, –NRbRc, –CRdReRf, –CRbRcNRgC(O)CRhRiRj, –O(CH2)mRa, –CRbRcORg, –CRbRc(CH2)mO(CH2)oC(O)ORg, –CRbRc(CH2)mO(CH2)oCRgRhRa, –CRbRc(CH2)mO(CH2)oC(O)NRgRh, –CRbRc(CH2)mO(CH2)oRd, –CRbRcC(Rd)(Re)(Rf),–CRbRcNRgRh, –CH2C(O)NRbRc, –C(O)On(CH2)mRa, –NRb(CH2)mORc, –NRb(CH2)mRn, –(CH2)mNRbC(O)Rn, –NRbCRcRgRh, –(CH2)mNRbC(O)Rc, –SRb, –S(=O)2Rl, –N=S(=O)(Rl)(Rm), –S(=O)(=NRb)(Rl), 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 OH, CN, halo, oxo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy,–CH2OH –C(O)ORb, –NRbRc, and –C(O)NRbRc; and R3is H, OH, halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, –(CH2)mOCH3, or –(CH2)mRa; (ii) R2and R3, together with the carbon atoms to which they are attached, form a ring of formula: ; (iii) R2and R3, together with the car s to which they are attached, form a ring offormula: ; (iv) R2and R3, together with the carto which they are attached, form a ring of formula: ; (v) R2and R3, together with the caro which they are attached, form a ring of formula: ; Y is O or NRo;R4and R5are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy;R6and R7are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy, or R6and R7, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; R8is H or CH3; Rsand Rtare each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, –NRbRc, –NO2, –SO3H, –(CH2)mRa, or –O(CH2)mOCH3, or Rsand Rt, together with the atoms to which they are attached, form a ring of formula: ; Y is O or CH2; Ru, Rv, and Rware eacndependent y H, OH, a o, C1-C6a kyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, –NRbRc, –NO2, –SO3H, –(CH2)mRa, or –O(CH2)mOCH3; each Rxis independently H, halo, C1-C6alkyl, or C1-C6haloalkyl; Rais OH, halo, C1-C6alkoxy, or –NRbRc; Rb, Rc, Rg, Rh, Ri, and Rkare 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+; Rland Rmare each independently C1-C6alkyl; Rnis C3-C6cycloalkyl or 4-6 membered heterocyclyl wherein said C3-C6cycloalkyl or 4-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents selected from C1-C6alkyl and halo; Rois H, C1-C6 alkyl, or –C(O)O(C1-C6 alkyl); Rpis H, C1-C6alkyl, –C(O)NRbRc, or oxo; Rqis H or C1-C6alkyl; m and o are each independently 0, 1, 2, or 3; n is 0 or 1; and p is 0 or 1.

[0013] In another aspect, the invention relates to a compound of formula (I-A): ; or a pharmaceutically acceptable salt 11X is C-R or N; X2is C-R2or N; Xsis C-Rsor N; Xtis C-Rtor N; R1is 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; R2and R3are defined as follows: (i) R2is H, OH, halo, CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, – (CH2)mRa, –C(O)ORb, –C(O)Rb, –C(O)NRbRc, –NRbRc, –CRdReRf, –CRbRcNRgC(O)CRhRiRj, –O(CH2)mRa, –CRbRcORg, –CRbRc(CH2)mO(CH2)oC(O)ORg, –CRbRc(CH2)mO(CH2)oCRgRhRa, –CRbRc(CH2)mO(CH2)oC(O)NRgRh, –CRbRc(CH2)mO(CH2)oRd, –CRbRcC(Rd)(Re)(Rf),–CRbRcNRgRh, –CH2C(O)NRbRc, –C(O)On(CH2)mRa, –NRb(CH2)mORc, –NRb(CH2)mRn, –(CH2)mNRbC(O)Rn, –NRbCRcRgRh, –(CH2)mNRbC(O)Rc, –SRb, –S(=O)2Rl, –N=S(=O)(Rl)(Rm), –S(=O)(=NRb)(Rl), 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 OH, CN, halo, oxo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy,–CH2OH –C(O)ORb, –NRbRc, and –C(O)NRbRc; and R3is H, OH, halo, CN, C1-C6alkyl, C1-C6haloalkyl, –(CH2)mOCH3, or –(CH2)mRa; (ii) R2and R3, together with the carbon atoms to which they are attached, form a ring of formula:; (iii) R2and R3, together with the car s to which they are attached, form a ring of formula:; (iv) R2and R3, together with the car to which they are attached, form a ring of formula:; (v) R2and R3, together with the car o which they are attached, form a ring of formula:; Y is O or NRo; 4R and R5are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R6and R7are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6 alkoxy, or R6and R7, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; R8is H or CH3; Rsand Rtare each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, –NRbRc, –NO2, –SO3H, –(CH2)mRa, or –O(CH2)mOCH3, or Rsand Rt, together with the atoms to which they are attached, form a ring of formula: ; Z is O or CH2;Ru, Rv, and Rware each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, –NRbRc, –NO2, –SO3H, –(CH2)mRa, or –O(CH2)mOCH3; each Rxis independently H, halo, C1-C6alkyl, or C1-C6haloalkyl;Rais OH, halo, C1-C6alkoxy, or –NRbRc; Rb, Rc, Rg, Rh, Ri, and Rkare 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+; Rland Rmare each independently C1-C6alkyl; Rnis C3-C6cycloalkyl or 4-6 membered heterocyclyl wherein said C3-C6cycloalkyl or 4-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents selected from C1-C6alkyl and halo; Rois H, C1-C6alkyl, or –C(O)O(C1-C6alkyl); Rpis H, C1-C6 alkyl, –C(O)NRbRc, or oxo; Rqis H or C1-C6alkyl; m and o are each independently 0, 1, 2, or 3; n is 0 or 1; and p is 0 or 1.

[0014] 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.

[0015] As used herein, the term “compounds of the invention” refers to the compounds of formula (I-A) and all of the embodiments thereof (e.g., formulas (I-A-1), (I-A-2), etc.), as described herein, and to the compounds identified in Table A and Table B.

[0016] As described herein, the compounds of the invention comprise multiple variable groups (e.g., X1, R1, R4, Ru, etc.). As one of ordinary skill in the art will recognize, combinations of groups envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds. The term “stable,” in this context, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

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

[0018] As used herein, the term “alkyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having thespecified 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.

[0019] 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.

[0020] As used herein, the term “alkoxy” refers to a radical of the formula -ORawhere Rais an alkyl group having the specified number of carbon atoms. For example, a “C1-C6alkoxy” group is a radical of the formula -ORawhere Rais an alkyl group having the between one and six carbon atoms.

[0021] 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.

[0022] 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.

[0023] 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).

[0024] 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 heteroatoms independently 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”.

[0025] As used herein, labels such as “*s” and “*t”, such as those shown in the following structures, designate the carbon atoms to which the corresponding R groups (in this case, the Rsand Rtgroups, respectively) are attached: .

[0026] Similarly, l n the following structures, designate the carbon atop g g p case, the R2and R3groups, respectively) are attached: .

[0027] Unless oth hether 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.

[0028] 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 ofThe compound may have any configuration, or a mixture of configurations, at the stereocenter.

[0029] As used herein, in any chemical structure or formula, a bold or hashed straight bond attached to a stereocenter of a compound, such as indenotes the relative stereochemistry of the stereocenter, relative to other stereocenter(s) to which bold or hashed straight bonds are attached.

[0030] 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 stereochemi as the relative stereochemistry of thestereocenter, relative to other stereocenter(s) to which bold or hashed wedge bonds are attached.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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).

[0037] As used herein in the specification and claims, “H” refers to hydrogen and includes any stable isotope of hydrogen, namely1H and D. In the Examples, where an atom is designated as “H,” no effort was made to enrich that atom in a particular isotope of hydrogen, and therefore a person ofordinary skill in the art would understand that such hydrogen atom likely was present at approximately the natural abundance isotopic composition of hydrogen.

[0038] 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.

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

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

[0041] 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.

[0042] 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.

[0043] The deuterium (2H)-labeled compounds and salts can manipulate the rate of oxidative metabolism of the compound by way of the primary kinetic isotope effect. The primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies of the covalent bonds involved in the reaction. Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially. For example, if deuterium is bonded to a carbon atom at a non-exchangeable position, rate differences of kH / kD= 2-7 are typical. For a further discussion, see S. L. Harbeson and R. D. Tung, Deuterium In Drug Discovery andDevelopment, Ann. Rep. Med. Chem.2011, 46, 403-417, incorporated in its entirety herein by reference.

[0044] 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.

[0045] 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).

[0046] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein: Xsis C-Rs; Xtis C-Rt; R6and R7are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R8is H; and Rsand Rtare each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, –NRbRc, –NO2, –SO3H, –(CH2)mRa, or –O(CH2)mOCH3, or Rsand Rt, together with the atoms to which they are attached, form a ring of formula: .

[0047] In some embodiments, the invention relates to a compound of formula (I-A-1): ; or a pharmaceutically acceptable salt iable groups are defined as they aredefined for the compound of formula (I-A).

[0048] In some embodiments, the invention relates to a compound of formula (I-A) or (I-A-1), or a pharmaceutically acceptable salt thereof, wherein p is 0.

[0049] In some embodiments, the invention relates to a compound of formula (I-A) or (I-A-1), or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0050] In some embodiments, the invention relates to a compound of formula (I-A) or (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X1is N. In other embodiments, X1is C-R1and R1is H, halo, CN, C1-C6alkyl, 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, –(CH2)mNRbC(O)Rn, 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. In other embodiments, X1is C-R1, and R1is H, Br, Cl, F, CN, –CH3, –CH2OH, –OCH3, –OCHF2, –CH(CH3)2, –CH2OCH3, –N(CH3)2, C O OH C O CH C O OCH C O CH CH CH OH C O CH C O H CH 1 is, ,, X1, ora pharmaceutically acceptable salt thereof, wherein X2is C-R2and R2is H, halo, CN, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, –CRdReRf, , –CRbRcORg, –(CH2)mRa, –C(O)Rb, –NRbRc, –O(CH2)mRa, –C(O)NRbRc, –C(O)ORb, –C(O)On(CH2)mRa, –CH2C(O)NRbRc, –CRbRcNRgRh, –NRb(CH2)mORc, –NRbCRcRgRh, –(CH2)mNRbC(O)Rc, – (CH2)mNRbC(O)Rn, –CRbRc(CH2)mO(CH2)oCRgRhRa, –CRbRc(CH2)mO(CH2)oC(O)NRgRh, –CRbRc(CH2)mO(CH2)oC(O)ORg, –CRbRc(CH2)mO(CH2)oRd, –CRbRcC(Rd)(Re)(Rf), –CRbRcNRgC(O)CRhRiRj, –N=S(=O)(Rl)(Rm), –SRb, –S(=O)(=NRb)(Rl) , –S(=O)2Rl, 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 OH, CN, halo, oxo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy,– CH2OH, –C(O)NRbRc. In other embodiments, X2is C-R2, and R2is H, –OH, –CN, –Br, –Cl, –F, –CH3, –OCH3, –OCHF2, –CH2CH3, –CH2OH, –CH2OCH3, –CH2CH(CH3)2, –CH2CH(CH3)OH, –CH2CH2OCH3, –CH2CH2OH, –CH2NH2, –CH(CH3)CH2OCH3, –CH(CH3)CH2OH, –CH(CH3)2, –CH(CH3)CH2OH, –CH(CH3)N(H)CH3, –CH(CH3)OCH3, –CH(OH)CH3, –CH2N(CH3)2, –OCH(CH3)2, –OCH2CH2OH, –C(OH)(CH3)2, –C(OCH3)(CH3)2, –C(O)CH3, –C(O)N(CH3)2, –C(O)N(H)CH3, –C(O)OCH2CH2N(CH3)2, –C(O)OCH2CH2OH, –C(O)OCH2CH3, –C(O)OCH3, –CH(CH3)CH2OCH2C(CH3)2OH, –CH(CH3)CH2OCH2C(O)NH2, –CH(CH3)CH2OCH2C(O)OCH2CH3, –CH(CH3)CH2OCH2CH2OH, –CH(CH3)N(H)C(O)CH(CH3)NH2, –CH2C(O)N(H)CH3, –CH2C(O)NH2, –CH2N(CH3)C(O)CH(CH3)N(CH3)2,–CH2N(CH3)C(O)CH(CH3)N(H)CH3, –CH2N(H)C(O)CH(CH3)2, –CH2N(H)C(O)CH(CH3)N(CH3)2, –CH2N(H)C(O)CH(CH3)NH2, –CH2N(H)C(O)CH3, –N(CD3)2, –N(CH3)2, –N(CH3)C(O)CH3, –N(CH3)C(O)-cyclopropyl, –N(CH3)CH2CH2OCH3, –N(CH3)CH2CH2OH, –N(C ) ( )C S( O)(C ) S(CH3), –S(O)(CH3)=NCH3,SO CH H SO CHnts,– (3)2 3, – (3)2, – (3)2, – (3) , – (3)N( )3, –CH(CH3)OCH3, –CH(OH)CH3, –CH2N(CH3)2, –OCH(CH3)2, –OCH2CH2OH, –C(OH)(CH3)2, –C(OCH3)(CH3)2, –C(O)CH3, –C(O)N(CH3)2, –C(O)N(H)CH3, –C(O)OCH2CH2N(CH3)2, –C(O)OCH2CH2OH, –C(O)OCH2CH3, –C(O)OCH3, –CH(CH3)CH2OCH2C(CH3)2OH, –CH(CH3)CH2OCH2C(O)NH2, –CH(CH3)CH2OCH2C(O)OCH2CH3, –CH(CH3)CH2OCH2CH2OH, –CH(CH3)N(H)C(O)CH(CH3)NH2, –CH2C(O)N(H)CH3, –CH2C(O)NH2, –CH2N(CH3)C(O)CH(CH3)N(CH3)2, –CH2N(CH3)C(O)CH(CH3)N(H)CH3, –CH2N(H)C(O)CH(CH3)2, –CH2N(H)C(O)CH(CH3)N(CH3)2, –CH2N(H)C(O)CH(CH3)NH2, –CH2N(H)C(O)CH3, –CH2N(H)C(O)-1-methylpyrrolidine, –N(CD3)2, –N(CH3)2, –N(CH3)C(O)CH3, –N(CH3)C(O)-cyclopropyl, –N(CH3)CH2CH2OCH3, –N(CH3)CH2CH2OH, –N(CH3)2, –N(H)CH3, –N=S(=O)(CH3)2, –S(CH3), –S(O)(CH3)NCH3, –S(=O)(=NH)(CH3), –S(=O)2CH(CH3)2, –S(=O)2CH3, O, ) or (I-A-1), ora parmaceu ca y accepa e sa ereo, w eren s ,1-6a y, or –(2)mH3. In other embodiments, R3is H, –CH3,or –(CH2)OCH3.

[0053] In some embodiments, the invention relates to a compound of formula (I-A) or (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X2is CR2, and R2and R3, together with the carbon atoms to which they are attached, form a ring of formula: . In other embodiments, they are attached, form aring of formula: .In other embodiments, R2and R3, together with the carbon atoms to which they are attached, form a ring of formula: ,

[0054] In some embodiments, the invention relates to a compound of formula (I-A) or (I-A-1), or a pharmaceutically acceptable salt thereof, wherein R4is H.

[0055] In some embodiments, the invention relates to a compound of formula (I-A) or (I-A-1), or a pharmaceutically acceptable salt thereof, wherein R5is H, C1-C6alkyl, or C1-C6alkoxy. In other embodiments, R5is H, –CH3,–OCH3.

[0056] In some embodiments, the invention relates to a compound of formula (I-A) or (I-A-1), or a pharmaceutically acceptable salt thereof, wherein R6and R7are each independently H, C1-C6alkyl, C1-C6haloalkyl, or C3-C6cycloalkyl, or R6and R7, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl. In other embodiments, R6is C1-C6haloalkyl. In other embodiments, R6is –CF3. In other embodiments, R7is H or C1-C6alkyl. In other embodiments, R7is H or –CH3.

[0057] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R8is H.

[0058] In some embodiments, the invention relates to a compound of formula (I-A) or (I-A-1), or a pharmaceutically acceptable salt thereof, wherein Xsis C-Rs, and Rsis C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, or –O(CH2)mOCH3. In other embodiments, Xsis C-Rs, and Rsis –CH3, –OCH3, –OCH(CH3)2, –OCH(F)2, –OCH2CH2OCH3, or –OCH2CH3.

[0059] In some embodiments, the invention relates to a compound of formula (I-A) or (I-A-1), or a pharmaceutically acceptable salt thereof, wherein Xtis N. In other embodiments, Xtis C-Rt, and Rtis H, halo, or C1-C6 haloalkyl. In other embodiments, Xtis C-Rt, and Rtis H, Cl, F, –CH3, or –CF3.

[0060] In some embodiments, the invention relates to a compound of formula (I-A) or (I-A-1), or a pharmaceutically acceptable salt thereof, wherein Xsis C-Rs, Xtis C-Rt, and Rsand Rt, together with the carbon atoms to which they are attached, form a ring of formula: . In other embodiments, Rsand Rt, togetherbon atoms to which they are attached, form a ring of formula: .

[0061] In some embodiments, the inves to a compound of formula (I-A) or (I-A-1), or a pharmaceutically acceptable salt thereof, wherein Ruis H, halo, C1-C6alkoxy, or C1-C6haloalkoxy. In other embodiments, Ruis H, F, –OCH2CH3, or –OCHF2.

[0062] In some embodiments, the invention relates to a compound of formula (I-A) or (I-A-1), or a pharmaceutically acceptable salt thereof, wherein Rvis H or –NRbRc. In other embodiments, Rvis H or –NH2.

[0063] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Rwis H.

[0064] In some embodiments, the invention relates to a compound of formula (I-A-2): ; or a pharmaceutically acceptable sa able groups are defined as they aredefined for the compound of formula (I-A).

[0065] In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), or (I-A-2), or a pharmaceutically acceptable salt thereof, wherein R1is H or 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-4 substituents independently selected from halo and C1-C6alkyl. In other embodiments, R1is H or .In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), or (I-A-2), or a pharmaceutically acceptable salt thereof, wherein R2is H, –CRbRcNRgRh, –S(=O)(=NRb)(Rl) , or 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-4 substituents independently selected from OH, CN, halo, oxo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, –CH2OH, and –C(O)NRbRc. In other embodiments, .mula (I-A), (I-A-1), or (I-A-2), or a pharmaceutically acceptable salt thereof, wherein R5is H, C1-C6alkyl, or C1-C6alkoxy. In other embodiments, R5is H, –CH3, or –OCH3.

[0068] In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), or (I-A-2), or a pharmaceutically acceptable salt thereof, wherein Rsis C1-C6alkyl or C1-C6alkoxy. In other embodiments, Rsis–CH3or –OCH3.

[0069] 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.

[0070] Table A. Compound Structures and Names.O N Br OO N O N -O NNO ne- - - ne3- 3-3- - - -4- - -- -O N N 5- 3- 3-- )- 2-epharmaceutically acceptable salt thereof. In other embodiments, the invention relates to a compound selected from Table B, i.e., the compound in non-salt form.

[0072] Table B. Compound Structures and Names. l- ne- - - - -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.

[0074] Table C. Compound Structures and Names. N OTable C, or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to a compound selected from Table A or Table C, i.e., the compound in non-salt form.

[0076] In some embodiments, the invention relates to a compound selected from Table B or Table C, or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to a compound selected from Table B or Table C, i.e., the compound in non-salt form. Salts, Compositions, Uses, Formulation, Administration and Additional Agents Pharmaceutically acceptable salts and compositions

[0077] 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., bunionectomypain, 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.

[0078] 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.

[0079] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compound of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic amm i t i d i e cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0080] 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 as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0081] 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.

[0082] 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

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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; nerveavulsion 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] In yet another aspect, the invention features a method of treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain wherein said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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).

[0104] 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.

[0105] 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.

[0106] 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 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, mastocytocytosis, 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.

[0107] 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; trigeminalneuralgia; 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, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0108] 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

[0109] 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.

[0110] 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.

[0111] 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 oftreating 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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).

[0125] 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.

[0126] 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 oftreating or lessening the severity in a subject of shoulder arthroplasty pain or shoulder arthroscopy pain.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] 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).

[0131] 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.

[0132] 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.

[0133] 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, Ehlers-Danlos syndrome, Fabry’s disease, mastocytocytosis, 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.

[0134] 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; acutepancreatitis; 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.

[0135] 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, 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. Manufacture of Medicaments

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] In yet another aspect, the invention provides a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of neuropathic pain. In some aspects, the neuropathic pain comprises post-herpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small-fiber neuropathy. In some aspects, the neuropathic pain comprises diabetic neuropathy (e.g., diabetic peripheral neuropathy).

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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 manufactureof a medicament for use in treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain.

[0147] In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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).

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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 manufactureof a medicament for use in treating or lessening the severity in a subject of visceral pain. In some aspects, the visceral pain comprises visceral pain from abdominoplasty.

[0157] 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).

[0158] 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.

[0159] 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, mastocytocytosis, 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 lateralsclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastro-intestinal motility.

[0160] 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.

[0161] 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 neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain or postamputation pain.Administration of Compounds, Pharmaceutically Acceptable Salts, and Compositions

[0162] 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.

[0163] 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.

[0164] The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the condition being treated. In certain embodiments, the compound, salts, and compositions of the invention may be administered orally or parenterally at dosage levels of about 0.001 mg / kg to about 1000 mg / kg, one or more times a day, effective to obtain the desired therapeutic effect.

[0165] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound or salt, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, 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.

[0166] 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.

[0167] 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.

[0168] In order to prolong the effect of the compounds of the invention, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0169] 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.

[0170] 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) binderssuch 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.

[0171] 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.

[0172] 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.

[0173] 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 areprepared 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.

[0174] 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.

[0175] 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

[0176] 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 used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” For example, exemplary additional therapeutic agents include, but are not limited to: 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 asPhenylbutazone); 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.

[0177] In another embodiment, additional appropriate therapeutic agents are selected from the following:

[0178] (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;

[0179] (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;

[0180] (3) a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal or thiopental;

[0181] (4) a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;

[0182] (5) a histamine (H1) antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;

[0183] (6) a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;

[0184] (7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine;

[0185] (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;

[0186] (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;

[0187] (10) a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline;

[0188] (11) an anticonvulsant, e.g. carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®) or valproate;

[0189] (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);

[0190] (13) a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

[0191] (14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

[0192] (15) a coal-tar analgesic, in particular paracetamol;

[0193] (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;

[0194] (17) a vanilloid receptor agonist (e.g. resinferatoxin or civamide) or antagonist (e.g. capsazepine, GRC-15300);

[0195] (18) a beta-adrenergic such as propranolol;

[0196] (19) a local anesthetic such as mexiletine;

[0197] (20) a corticosteroid such as dexamethasone;

[0198] (21) a 5-HT receptor agonist or antagonist, particularly a 5-HT1B / 1Dagonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

[0199] (22) a 5-HT2Areceptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-l-[2-(4- fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);

[0200] (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;

[0201] (24) Tramadol®, Tramadol ER (Ultram ER®), IV Tramadol, Tapentadol ER (Nucynta®);

[0202] (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;

[0203] (26) an alpha-2-delta ligand such as gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methyl gabapentin, (l[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3- aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino- 5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline, [(lR,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(l-aminomethyl- cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]- methylamine, (3S,4S)-(l-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3- aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-5- methyl-octanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and (3R,4R,5R)-3-amino- 4,5-dimethyl-octanoic acid;

[0204] (27) a cannabinoid such as KHK-6188;

[0205] (28) metabotropic glutamate subtype 1 receptor (mGluRl) antagonist;

[0206] (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;

[0207] (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;

[0208] (31) a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran and imipramine;

[0209] (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;

[0210] (33) an acetylcholinesterase inhibitor such as donepezil;

[0211] (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;

[0212] (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;

[0213] (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);

[0214] (37) a sodium channel blocker, such as lidocaine, lidocaine plus tetracaine cream (ZRS- 201) or eslicarbazepine acetate;

[0215] (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;

[0216] (38a) a NaV1.7 blocker such as (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-1'-yl)-(4-isopropoxy-3-methyl-phenyl)methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2- (trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-piperidine]-1'-yl]-(4-isobutoxy-3-methoxy-phenyl)methanone, 1-(4- benzhydrylpiperazin-1-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy]propan-2-ol, (4-butoxy-3-methoxy- phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'- yl]methanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-1'-yl]-(5-isopropoxy-6-methyl-2-pyridyl)methanone, (4-isopropoxy-3-methyl-phenyl)-[2- methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'- yl]methanone, 5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-piperidine]-1'-carbonyl]phenyl]pyridine-2-carbonitrile, (4-isopropoxy-3-methyl- phenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'- yl]methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2-methyl- spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 2,2,2-trifluoro-1-[1'-(5- isopropoxy-6-methyl-pyridine-2-carbonyl)-3,3-dimethyl-spiro[2,4-dihydropyrrolo[1,2-a]pyrazine- 1,4'-piperidine]-6-yl]ethanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2-methyl- spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, (4-isopropoxy-3-methoxy- phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'- yl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 1-[(3S)-2,3-dimethyl-1'-[4-(3,3,3- trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]-2,2,2- trifluoro-ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine- 1,4'-piperidine]-1'-yl]-[3-methoxy-4-[(1R)-1-methylpropoxy]phenyl]methanone, 2,2,2-trifluoro-1-[1'- (5-isopropoxy-6-methyl-pyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine- 1,4'-piperidine]-6-yl]ethanone, 1-[1'-[4-methoxy-3-(trifluoromethyl)benzoyl]-2-methyl-spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]-2,2-dimethyl-propan-1-one, (4-isopropoxy-3- methyl-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-1'-yl]methanone, [2-methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]-[4-(3,3,3- trifluoropropoxymethyl)phenyl]methanone, 4-bromo-N-(4-bromophenyl)-3-[(1-methyl-2-oxo-4- piperidyl)sulfamoyl]benzamide or (3-chloro-4-isopropoxy-phenyl)-[2-methyl-6-(1,1,2,2,2- pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone.

[0217] (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, CN112390745, CN111808019, CN112225695, CN112457294, CN112300051, CN112300069, CN112441969, and CN114591293, the entire contents of each application hereby incorporated by reference;

[0218] (39a) a NaV1.8 blocker such as 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo- 1,2-dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4- yl)-4-(perfluoroethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4- yl)benzamide, 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4- yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5- (trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4- (trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4- (perfluoroethyl)benzamide, 5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4- yl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5- (trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5- (trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5- (trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4- yl)benzamide, 4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-((5-fluoro-2- hydroxybenzyl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2- dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide, 2-(2,4-difluorophenoxy)-N-(2- oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2- (trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2- dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H- pyridin-4-yl)-4-(trifluoromethyl)benzamide, [4-[[2-(4-fluoro-2-methyl-phenoxy)-4- (trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate, 2-(4-fluoro-2- (methyl-d3)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, (4-(2-(4- fluoro-2-(methyl-d3)phenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate, 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2- carboxamide, 3-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(2- chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(4-chloro-2- methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 4-(3-(4- (trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinic acid, 2-(2,4-difluorophenoxy)-N-(3- sulfamoylphenyl)quinoline-3-carboxamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3- sulfamoylphenyl)quinoline-3-carboxamide, 3-(2,4-difluorophenoxy)-N-(3- sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoline-3-carboxamide, N-(3-sulfamoylphenyl)-3-(4- (trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide, 3-(4-chloro-2-methylphenoxy)-N-(3- sulfamoylphenyl)quinoxaline-2-carboxamide, 5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2- carboxamido)picolinic acid, 3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)quinoxaline-2-carboxamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4- yl)quinoxaline-2-carboxamide, 3-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2- carboxamide, N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, N-(4- carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 4-(3-(4- (trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)benzoic acid, N-(4-cyanophenyl)-3-(4-fluoro- 2-methoxyphenoxy)quinoxaline-2-carboxamide, 5-(4,5-dichloro-2-(4-fluoro-2- methoxyphenoxy)benzamido)picolinic acid, 5-(2-(2,4-dimethoxyphenoxy)-4,6- bis(trifluoromethyl)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2- methoxyphenoxy)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4,6- bis(trifluoromethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methoxyphenoxy)-4- (perfluoroethyl)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4- (perfluoroethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4- (trifluoromethyl)benzamido)benzoic acid, 5-(4,5-dichloro-2-(4-fluoro-2- methoxyphenoxy)benzamido)picolinic acid, 4-(2-(2-chloro-4-fluorophenoxy)-4- (perfluoroethyl)benzamido)benzoic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4- (perfluoroethyl)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4-chloro-2- methylphenoxy)benzamido)benzoic acid, 5-(4-(tert-butyl)-2-(4-fluoro-2- methoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2- methylphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4- dimethoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(2-chloro-4- fluorophenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-fluoro-2- methylphenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-chloro-2- methoxyphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4- difluorophenoxy)benzamido)picolinic acid, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5- (trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5- (trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6- (trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3- sulfamoylphenyl)benzamide, 2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5- (trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3- sulfamoylphenyl)benzamide, 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3- sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3- sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6- bis(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6- bis(trifluoromethyl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4- (trifluoromethoxy)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2- (4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 5-fluoro-2-(4- fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-4-cyano- N-(3-sulfamoylphenyl)benzamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4- (trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2- fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl- 4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethoxy)benzamide, 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, 4-[[3-chloro-2-fluoro-6-[2-methoxy-4- (trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, 4-[[2-fluoro-6-[2- (trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2- carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4- (trifluoromethoxy)phenoxy]benzamide, 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide, N-(3- carbamoyl-4-fluoro-phenyl)-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3- (trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methyl-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2,3,4- trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, N-(2-carbamoyl-4-pyridyl)-3- fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide, 4- [[6-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenoxy]-2-fluoro-3- (trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-6-[3- chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4- fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(4- carbamoyl-3-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzamide, 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4- (trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro- phenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-pentafluoroethyl)benzamide, 4-[[4- (difluoromethoxy)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2- carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-fluoro-4-(trifluoromethoxy)phenoxy]- 3-(trifluoromethyl)benzamide, 4-[[4-cyclopropyl-2-fluoro-6-[2-methoxy-4- (trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro- phenyl)-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide, 5-[[2- fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro- 6-(4-fluorophenoxy)-3-(trifluoromethyl)benzamide, or 4-[[2-fluoro-6-[3-fluoro-2-methoxy-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide;

[0219] (40) a combined NaV1.7 and NaV1.8 blocker, such as DSP-2230, Lohocla201 or BL-1021;

[0220] (41) a 5-HT3 antagonist, such as ondansetron;

[0221] (42) a TPRV 1 receptor agonist, such as capsaicin (NeurogesX®, Qutenza®); and the pharmaceutically acceptable salts and solvates thereof;

[0222] (43) a nicotinic receptor antagonist, such as varenicline;

[0223] (44) an N-type calcium channel antagonist, such as Z-160;

[0224] (45) a nerve growth factor antagonist, such as tanezumab;

[0225] (46) an endopeptidase stimulant, such as senrebotase;

[0226] (47) an angiotensin II antagonist, such as EMA-401;

[0227] (48) acetaminophen (including without limitation intravenous acetaminophen (e.g., Ofirmev®));

[0228] (49) bupivacaine (including without limitation bupivacaine liposome injectable suspension (e.g., Exparel®) bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll) and transdermal bupivacaine (Eladur®)); and

[0229] (50) bupivacaine and meloxicam combination (e.g., HTX-011).

[0230] 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.

[0231] 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.

[0232] 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.

[0233] In another embodiment, the additional therapeutic agent is oliceridine or ropivacaine (TLC590).

[0234] 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, WO2018 / 183782, WO2020 / 072835, and / or WO2022 / 036297 the entire contents of each application hereby incorporated by reference.

[0235] 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.

[0236] 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.

[0237] 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.

[0238] 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.

[0239] 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.

[0240] 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 carriersuitable for coating said implantable device. In still another aspect, the invention includes an implantable device coated with a composition comprising a compound or salt of the invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

[0241] 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.

[0242] 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

[0243] 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

[0244] 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.

[0245] As used herein, the term “radioisotope” refers to an isotope of an element that is known to undergo spontaneous radioactive decay. Examples of radioisotopes include3H,14C,32P,35S,18F,36Cl, and the like, as well as the isotopes for which a decay mode is identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0246] 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.

[0247] 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.

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] 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

[0253] Further embodiments of the disclosure are set out in the following numbered clauses: 1. A compound of formula (I-A):; or a pharmaceutically acceptable saltX1is C-R1or N; X2is C-R2or N; Xsis C-Rsor N; Xtis C-Rtor N; R1is 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; R2and R3are defined as follows: (i) R2is H, OH, halo, CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, – (CH2)mRa, –C(O)ORb, –C(O)Rb, –C(O)NRbRc, –NRbRc, –CRdReRf, –CRbRcNRgC(O)CRhRiRj, –O(CH2)mRa, –CRbRcORg, –CRbRc(CH2)mO(CH2)oC(O)ORg, –CRbRc(CH2)mO(CH2)oCRgRhRa, –CRbRc(CH2)mO(CH2)oC(O)NRgRh, –CRbRc(CH2)mO(CH2)oRd, –CRbRcC(Rd)(Re)(Rf), –CRbRcNRgRh, –CH2C(O)NRbRc, –C(O)On(CH2)mRa, –NRb(CH2)mORc, –NRb(CH2)mRn, –(CH2)mNRbC(O)Rn, –NRbCRcRgRh, –(CH2)mNRbC(O)Rc, –SRb, –S(=O)2Rl, –N=S(=O)(Rl)(Rm), –S(=O)(=NRb)(Rl), 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 OH, CN, halo, oxo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy,–CH2OH –C(O)ORb, –NRbRc, and –C(O)NRbRc; and R3is H, OH, halo, CN, C1-C6alkyl, C1-C6haloalkyl, –(CH2)mOCH3, or –(CH2)mRa; (ii) R2and R3, together with the carbon atoms to which they are attached, form a ring of formula: ;(iii) R2and R3, together with the carbon atoms to which they are attached, form a ring of formula: ; (iv) R2and R3, together with the carbon atoms ey are attached, form a ring of formula:; (v) R2and R3, together with the carbon atoms to ey are attached, form a ring offormula: ; Y is O or NRo; 45R and R are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R6and R7are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy, or R6and R7, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; R8is H or CH3; Rsand Rtare each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, –NRbRc, –NO2, –SO3H, –(CH2)mRa, or –O(CH2)mOCH3, or Rsand Rt, together with the atoms to which they are attached, form a ring of formula: ; Y is O or CH2;Ru, Rv, and Rware each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, –NRbRc, –NO2, –SO3H, –(CH2)mRa, or –O(CH2)mOCH3; each Rxis independently H, halo, C1-C6alkyl, or C1-C6haloalkyl; Rais OH, halo, C1-C6alkoxy, or –NRbRc; Rb, Rc, Rg, Rh, Ri, and Rkare 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+; Rland Rmare each independently C1-C6alkyl; Rnis C3-C6cycloalkyl or 4-6 membered heterocyclyl wherein said C3-C6cycloalkyl or 4-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents selected from C1-C6alkyl and halo; Rois H, C1-C6alkyl, or –C(O)O(C1-C6alkyl); Rpis H, C1-C6alkyl, –C(O)NRbRc, or oxo; Rqis H or C1-C6alkyl; m and o are each independently 0, 1, 2, or 3; n is 0 or 1; and p is 0 or 1. 2. The compound of clause 1, or a pharmaceutically acceptable salt thereof, wherein: Xsis C-Rs; Xtis C-Rt; R6and R7are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R8is H; and Rsand Rtare each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, –NRbRc, –NO2, –SO3H, –(CH2)mRa, or –O(CH2)mOCH3, or Rsand Rt, together with the atoms to which they are attached, form a ring of formula: .3. The compound of clause 1 or 2, or pharmaceutically acceptable salt thereof, wherein p is 0. 4. The compound of clause 1 or 2, or pharmaceutically acceptable salt thereof, wherein p is 1. 5. The compound of any one of clauses 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the compound has a formula (I-A-1):. 6. The compound of any one of, rmaceutically acceptable salt thereof, wherein X1is N. 7. The compound of any one of clauses 1 to 5, or a pharmaceutically acceptable salt thereof, wherein X1is C-R1and R1is H, halo, CN, C1-C6alkyl, 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, , –(CH2)mNRbC(O)Rn, 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. 8. The compound of clause 7, or a pharmaceutically acceptable salt thereof, wherein R1is H, Br, Cl, F, CN, –CH3, –CH2OH, –OCH3, –OCHF2, –CH(CH3)2, –CH2OCH3, –N(CH3)2, –C(O)OH, –C(O)CH3, –C(O)OCH3, –C(O)CH2CH2CH2OH, –C(O)N(CH3)2, –C(O)N(H)CH3,–C(O)OCH2CH3, ,9. The compound of any one of clauses 1 to 8, or a pharmaceutically acceptable salt thereof, wherein X2is C-R2and R2is H, halo, CN, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, –CRdReRf, , –CRbRcORg, –(CH2)mRa, –C(O)Rb, –NRbRc, –O(CH2)mRa, –C(O)NRbRc, –C(O)ORb, –C(O)On(CH2)mRa, –CH2C(O)NRbRc, –CRbRcNRgRh, –NRb(CH2)mORc, –NRbCRcRgRh, –(CH2)mNRbC(O)Rc, – (CH2)mNRbC(O)Rn, –CRbRc(CH2)mO(CH2)oCRgRhRa, –CRbRc(CH2)mO(CH2)oC(O)NRgRh, –CRbRc(CH2)mO(CH2)oC(O)ORg, –CRbRc(CH2)mO(CH2)oRd, –CRbRcC(Rd)(Re)(Rf), –CRbRcNRgC(O)CRhRiRj, –N=S(=O)(Rl)(Rm), –SRb, –S(=O)(=NRb)(Rl) ,–S(=O)2Rl, 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 OH, CN, halo, oxo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy,– CH2OH, –C(O)NRbRc. 10. The compound of clause 9, or a pharmaceutically acceptable salt thereof, wherein R2is H, –OH, –CN, –Br, –Cl, –F, –CH3, –OCH3, –OCHF2, –CH2CH3, –CH2OH, –CH2OCH3, –CH2CH(CH3)2, –CH2CH(CH3)OH, –CH2CH2OCH3, –CH2CH2OH, –CH2NH2, –CH(CH3)CH2OCH3, –CH(CH3)CH2OH, –CH(CH3)2, –CH(CH3)CH2OH, –CH(CH3)N(H)CH3, –CH(CH3)OCH3, –CH(OH)CH3, –CH2N(CH3)2, –OCH(CH3)2, –OCH2CH2OH, –C(OH)(CH3)2, –C(OCH3)(CH3)2, –C(O)CH3, –C(O)N(CH3)2, –C(O)N(H)CH3, –C(O)OCH2CH2N(CH3)2, –C(O)OCH2CH2OH, –C(O)OCH2CH3, –C(O)OCH3, –CH(CH3)CH2OCH2C(CH3)2OH, –CH(CH3)CH2OCH2C(O)NH2, –CH(CH3)CH2OCH2C(O)OCH2CH3, –CH(CH3)CH2OCH2CH2OH, –CH(CH3)N(H)C(O)CH(CH3)NH2, –CH2C(O)N(H)CH3, –CH2C(O)NH2, –CH2N(CH3)C(O)CH(CH3)N(CH3)2,–CH2N(CH3)C(O)CH(CH3)N(H)CH3, –CH2N(H)C(O)CH(CH3)2, –CH2N(H)C(O)CH(CH3)N(CH3)2, –CH2N(H)C(O)CH(CH3)NH2, –CH2N(H)C(O)CH3, –N(CD3)2, –N(CH3)2, –N(CH3)C(O)CH3, –N(CH3)C(O)-cyclopropyl, –N(CH3)CH2CH2OCH3, –N(CH3)CH2CH2OH, –N(CH3)2, –N(H)CH3, –N=S(=O)(CH3)2, –S(CH3), –S(O)(CH3)=NCH3, ,11. The compound of any of clauses 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R3is H, C1-C6alkyl, or –(CH2)mOCH3. 12. The compound of clause 11, or a pharmaceutically acceptable salt thereof, wherein R3is H, –CH3,or –(CH2)OCH3. 13. The compound of any one of clauses 1 to 8, or a pharmaceutically acceptable salt thereof, wherein X2is CR2, and R2and R3, together with the carbon atoms to which they are attached, form a ring of formula: .14. The compound of clause 13, or a pharmaceutically acceptable salt thereof, wherein R2and R3, together with the carbon atoms to which they are attached, form a ring of formula: . 15. The compoutically acceptable salt thereof, wherein R4is H. 16. The compound of any one of clauses 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R5is H, C1-C6alkyl, or C1-C6alkoxy. 17. The compound of clause 16, or a pharmaceutically acceptable salt thereof, wherein R5is H, –CH3,–OCH3. 18. The compound of any one of clause 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R6and R7are each independently H, C1-C6alkyl, C1-C6haloalkyl, or C3-C6cycloalkyl, or R6and R7, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl. 19. The compound of any one of clauses 1 to 4 and 6 to 18, or a pharmaceutically acceptable salt thereof, wherein R6is –CF3. 20. The compound of any one of clauses 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R7is H or C1-C6alkyl. 21. The compound of clause 20, or a pharmaceutically acceptable salt thereof, wherein R7is H or –CH3. 22. The compound of any one of clauses 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R8is H. 23. The compound of any one of clauses 1 to 22, or a pharmaceutically acceptable salt thereof, wherein Xsis C-Rs, and Rsis C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, or –O(CH2)mOCH3. 24. The compound of clause 23, or a pharmaceutically acceptable salt thereof, wherein Rsis –CH3, –OCH3, –OCH(CH3)2, –OCH(F)2, –OCH2CH2OCH3, or –OCH2CH3. 25. The compound of any one of clauses 1 to 24, or a pharmaceutically acceptable salt thereof, wherein Xtis C-Rt, and Rtis H, halo, or C1-C6haloalkyl.26. The compound of clause 25, or a pharmaceutically acceptable salt thereof, wherein Rtis H, Cl, F, –CH3, or –CF3. 27. The compound of any one of clauses 1 to 22, or a pharmaceutically acceptable salt thereof, wherein Xsis C-Rs, Xtis C-Rt, and Rsand Rt, together with the carbon atoms to which they are attached, form a ring of formula: . 28. The compound of clause 27, or a pally acceptable salt thereof, wherein Rsand Rt, together with the carbon atoms to which they are attached, form a ring of formula: . 29. The compound of any one of clauses o , or a pharmaceutically acceptable salt thereof, wherein Ruis H, halo, C1-C6alkoxy, or C1-C6haloalkoxy. 30. The compound of clause 29, or a pharmaceutically acceptable salt thereof, wherein Ruis H, F, –OCH2CH3, or –OCHF2. 31. The compound of any one of clauses 1 to 30, or a pharmaceutically acceptable salt thereof, wherein Rvis H or –NRbRc. 32. The compound of clause 31, or a pharmaceutically acceptable salt thereof, wherein Rvis H or –NH2. 33. The compound of any one of clauses 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the compound has a formula (I-A-2):.34. The compound of any one of clauses 1 to 4 and 33, or a pharmaceutically acceptable salt thereof, wherein R1is H or 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-4 substituents independently selected from halo and C1-C6alkyl. 35. The compound of clause 34, or a pharmaceutically acceptable salt thereof, wherein R1is H or .The compound of any one of clauses 1 to 4 and 33 to 35, or a pharmaceutically acceptable salt thereof, wherein R2is H, –CRbRcNRgRh, –S(=O)(=NRb)(Rl) , or 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-4 substituents independently selected from OH, CN, halo, oxo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, –CH2OH, and –C(O)NRbRc. 37. The compound of clause 36, or a pharmaceutically acceptable salt thereof, wherein R2is H, .. , pharmaceutically acceptable salt thereof, wherein R5is H, C1-C6alkyl, or C1-C6alkoxy. 39. The compound of clause 38, or a pharmaceutically acceptable salt thereof, wherein R5is H, –CH3, or –OCH3. 40 The compound of any one of clauses 1 to 4 and 33 to 39, or a pharmaceutically acceptable salt thereof, wherein Rsis C1-C6alkyl or C1-C6alkoxy. 41. The compound of clause 40, or a pharmaceutically acceptable salt thereof, wherein Rsis–CH3or –OCH3. 42. A compound selected from Table A, or a pharmaceutically acceptable salt thereof. 43. A compound selected from Table B, or a pharmaceutically acceptable salt thereof. 44. The compound of any one of clauses 1 to 43 in non-salt form.45. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of clauses 1 to 43, or a pharmaceutically acceptable salt thereof, or the compound of clause 44, and one or more pharmaceutically acceptable carriers or vehicles. 46. A pharmaceutical composition comprising the compound of any one of clauses 1 to 43, or a pharmaceutically acceptable salt thereof, or the compound of clause 44, and one or more pharmaceutically acceptable carriers or vehicles. 47. 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 43, or a pharmaceutically acceptable salt thereof, the compound of clause 44, or the pharmaceutical composition of clause 45 or 46. 48. The method of clause 47, wherein the voltage-gated sodium channel is NaV1.8. 49. 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 43, or a pharmaceutically acceptable salt thereof, the compound of clause 44, or the pharmaceutical composition of clause 45 or 46. 50. The method of clause 49, where the method comprises treating or lessening the severity in the subject of neuropathic pain. 51. The method of clause 50, wherein the neuropathic pain comprises post-herpetic neuralgia. 52. The method of clause 50, wherein the neuropathic pain comprises small-fiber neuropathy. 53. The method of clause 50, wherein the neuropathic pain comprises idiopathic small-fiber neuropathy. 54. The method of clause 50, wherein the neuropathic pain comprises diabetic neuropathy. 55. The method of clause 54, wherein the diabetic neuropathy comprises diabetic peripheral neuropathy. 56. The method of clause 49, wherein the method comprises treating or lessening the severity in the subject of musculoskeletal pain. 57. The method of clause 56, wherein the musculoskeletal pain comprises osteoarthritis pain.58. The method of clause 49, wherein the method comprises treating or lessening the severity in the subject of acute pain. 59. The method of clause 58, wherein the acute pain comprises acute post-operative pain. 60. The method of clause 49, wherein the method comprises treating or lessening the severity in the subject of postsurgical pain. 61. The method of clause 60, wherein the postsurgical pain comprises bunionectomy pain. 62. The method of clause 60, wherein the postsurgical pain comprises abdominoplasty pain. 63. The method of clause 60, wherein the postsurgical pain comprises herniorrhaphy pain. 64. The method of clause 49, wherein the method comprises treating or lessening the severity in the subject of visceral pain. 65. The method of any one of clauses 47 to 64, 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. 66. Use of the compound of any one of clauses 1 to 43, or a pharmaceutically acceptable salt thereof, the compound of clause 44, or the pharmaceutical composition of clause 45 or 46, as a medicament. EXAMPLES

[0254] General methods.1H NMR spectra were obtained as solutions in an appropriate deuterated solvent such as dimethyl sulfoxide-d6(DMSO-d6).

[0255] Compound purity, retention time, and electrospray mass spectrometry (ESI-MS) data were determined by LC / MS analysis.

[0256] LC / MS Method: The compounds were analysed by LC / MS according to one of the following methods, as shown in Table 1 Table 1. Description of LC / MS Methods LC / MS MhMethod DescriptionLC / MS MethodMethod DescriptionKinetex®EVO C182.6 µm 2.1 x 50 mm 2 to 98% MeCN in H2O (10 mM Ammonium % H 40 40 c e 40 % % MLC / MS MethodMethod DescriptionWatersTMAcquity BEH C81.7 µm 2.1 x 50 mm 50 to 95% MeCN in H2O (0.1% NH3) ic ic

[0257] 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 UPLC Ultra performance liquid chromatography HPLC / MS / MS High performance liquid chromatography / tandem mass spectrometry IS Internal standard HPLC High performance liquid chromatography SFC Supercritical fluid chromatography ESI Electrospray ionization cm centimeters g grams mg milligrams L Liter(s) mL Milliliters μL Microliters nL nanoliters mmol millimoles hr, h hours min Minutes ms millisecond mm Millimeters μm Micrometers nm nanometer MHz Megahertz Hz Hertz N Normal (concentration) M Molar (concentration) mM Millimolar (concentration) μM Micromolar (concentration) μW Microwave ppm Parts per million % w / v Weight-volume concentration % w / w Weight-weight concentration AcOH Acetic acid B2Pin2Bis(pinacolato)diboron tBuOH tert-butyl alcohol CPME Cyclopentyl methyl ether DCM Dichloromethane DCE Dichloroethane DIC N, N'-DiisopropylcarbodiimideAbbreviation Meaning DIEA, DIPEA N, N-Diisopropyl ethyl amine DIPA Diisopropylamine DMA N,N-Dimethylacetamide DMAP 4-(Dimethylamino)pyridine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DRG Dorsal root ganglia EtOH Ethanol EtOAc ethyl acetate IMS Industrial methylated spirit HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide TFA Trifluoroacetic acid T3P Propylphosphonic anhydride, i.e., 2,4,6-tripropyl-1,3,5,2,4,6- trioxatriphosphinane 2,4,6-trioxide Ru(BPY)3.6H2O Tris(2,2’-bipyridyl)dichlororuthenium(II) hexahydrate LiHMDS Lithium hexamethyldisilazane MeOH Methanol MeCN, ACN Acetonitrile mCPBA 3-chloroperbenzoic acid 2-MeTHF 2-Methyltetrahydrofuran MTBE Methyl tert-butyl ether NMP N-Methylpyrrolidone Proton-sponge®1,8-Bis(dimethylamino)naphthalene STAB Sodium triacetoxyborohydride TBAF Tetrabutylammonium fluoride TEA Triethylamine THF Tetrahydrofuran TBME Methyl tert-butyl ether or tert-Butyl methyl ether RB Round bottom (flask) RT Ambient temperature r.t. Retention time LED Light Emitting Diode 4CzIPN 1,2,3,5-Tetrakis(carbazol-9-yl)-4,6-dicyanobenzene ca. Circa (approximately) E-VIPR Electrical stimulation voltage ion probe reader HEK Human embryonic kidney KIR2.1 Inward-rectifier potassium ion channel 2.1 DMEM Dulbecco's Modified Eagle's Medium FBS Fetal bovine serum NEAA Non-essential amino acids HEPES 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid DiSBAC6(3) Bis-(1,3-dihexyl-thiobarbituric acid) trimethine oxonol CC2-DMPE Chlorocoumarin-2-dimyristoyl phosphatidylethanolamine VABSC-1 Voltage Assay Background Suppression Compound HS Human serum BSA Bovine Serum Albumin[025

[0259] A 8-mL dram vial, equipped with a stir bar, was charged with (2R,3S,4S,5R)-3-(3,4- difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Int-1, 100 mg, 0.282 mmol), 4-(benzyloxy)-6-bromo-3-(difluoromethoxy)-2-methylpyridine (98 mg, 0.285 mmol), K2CO3(59 mg, 0.43 mmol), (Ir[dF(CF3)ppy]2(dtbpy))PF6(32 mg, 0.029 mmol), NiCl2:(CH3OCH2)2(10 mg, 0.046 mmol) and 4,4'-dimethoxy-2,2'-bipyridine (10 mg, 0.046 mmol). DMF (5.0 mL) was injected into the tube via syringe under a nitrogen atmosphere. The mixture was degassed for 15 min by bubbling nitrogen through, then sealed with parafilm. The solution was stirred at 30 °C under the irradiation of a blue LED (450 nm) using a Penn OC Photoreactor M1 for 15 h. Upon reaction completion, the mixture was poured over a saturated NaHCO3solution (10 mL) and extracted with MTBE (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried (MgSO4) filtered and concentrated in vacuo. Purification by flash chromatography (24 g SiO2, 0 to 100% EtOAc in heptane) gave 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)- 4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-(difluoromethoxy)-2-methylpyridine (106 mg, 65%) as a colourless oil. ESI-MS m / z calc.573.175, found 574.6 (M+1)+; Retention time: 4.33 minutes using LC / MS method A. GENERAL METHOD B:

[0261] In a reaction vessel, a mixture of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Int-1, 1.618 g, 4.567 mmol) and 2-hydroxyisoindoline-1,3-dione (920 mg, 5.640 mmol) were dissolved in DCM (25 mL). DMAP (687 mg, 5.62 mmol) was added and the reaction mixture was stirred for 10 min at ambient temperature. DIC (760 µL, 4.85 mmol) was added and the mixture was stirred at ambient temperature for 1 h. On reaction completion, the mixture was treated with 2 M HCl (40 mL). The aqueous layer was separated and extracted with DCM (2 x 40 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. After adding DCM to the residue, a white precipitate formed. The solid was filtered, and the filtrate was concentrated in vacuo. Purification by flash chromatography (40 g SiO2, 0 to 40% EtOAc in heptane) gave 1,3-dioxoisoindolin-2-yl (2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (2.06 g, 90%).1H NMR (400 MHz, Chloroform-d) δ 7.88 (dd, J = 5.5, 3.1 Hz, 2H), 7.81 (dd, J = 5.5, 3.1 Hz, 2H), 7.07 - 6.98 (m, 1H), 6.92 (td, J = 9.2, 7.3 Hz, 1H), 5.33 (d, J = 0.8 Hz, 1H), 4.46 (t, J = 8.9 Hz, 1H), 4.10 (d, J = 2.4 Hz, 3H), 2.81 (q, J = 7.7 Hz, 1H), 1.69 (q, J = 1.2 Hz, 3H), 0.89 - 0.82 (m, 3H) ppm.19F NMR (376 MHz, Chloroform-d) δ -74.46, -136.60, -153.83 ppm. ESI-MS m / z calc.499.105, found 500.0 (M+1)+; Retention time: 1.12 minutes using LC / MS method M.

[0262] Step 2

[0263] A 5-mL microwave vial, equipped with a teflon cap and a stir bar, was charged with 1,3- dioxoisoindolin-2-yl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylate (51 mg, 0.102 mmol), DMSO (650 µL), TFA (13 µL, 0.17 mmol), 4-chloro-2-methylnicotinonitrile (13 mg, 0.085 mmol) and 4CzIPN (0.8 mg, 0.001 mmol). Nitrogen gas was vigorously bubbled through the solution for 5 min. The vial was sealed, and placed in a Hepatochem photoreactor (450 nM, 30W). The reaction was stirred and irradiated with blue light for 1 h at ambient temperature. Purification by flash chromatography (SiO2, 1 to 100% EtOAc in hexanes) gave 4-chloro-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl- 5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylnicotinonitrile (22 mg, 56%) as a clear oil.1H NMR (400 MHz, Chloroform-d) δ 7.51 (s, 1H), 7.19 - 7.07 (m, 1H), 6.95 - 6.75 (m, 1H), 5.47 (d, J = 11.0 Hz, 1H), 4.04 - 3.97 (m, 1H), 3.94 (d, J = 2.7 Hz, 3H), 2.87 - 2.73 (m, 1H), 2.66 (s, 3H), 1.74 (s, 3H), 0.84 (d, J = 7.7, 2.3 Hz, 3H) ppm. ESI-MS m / z calc.460.098, found 461.1 (M+1)+; Retention time: 2.26 minutes using LC / MS method D.GENERAL METHOD C: (E.G., 1) [0264

[0265] sout on o -( enzy oxy)- -(( , , ,5 )- -( , - uoro- -met oxyp eny )-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-(difluoromethoxy)-2-methylpyridine (Product of Example 1, Step 1, 106 mg, 0.185 mmol) in EtOH (2.0 mL) was added to a 20-mL vial containing Pd / C (10 wt % loading, wet, Degussa, 5 mg, 0.005 mmol). The reaction mixture was degassed with nitrogen for 5 min and stirred under a hydrogen atmosphere (balloon) for 5 min. The mixture was stirred under a hydrogen atmosphere for a further 10 min. Upon reaction completion, the mixture was sparged with nitrogen for 5 min and filtered through a 0.45 micron syringe filter. The filtrate was concentrated in vacuo. Purification by flash chromatography (12 g SiO2, 0 to 100% EtOAc in heptane) gave 6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-3-(difluoromethoxy)-2-methylpyridin-4(1H)-one (1, 92 mg, 100%) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 6.41 - 6.36 (m, 1H), 6.34 - 6.26 (m, 1H), 6.21 (t, J = 76.6 Hz, 1H), 5.79 (s, 1H), 4.69 (d, J = 11.1 Hz, 1H), 3.50 (dd, J = 11.1, 8.3 Hz, 1H), 2.67 - 2.62 (m, 3H), 2.18 (dq, J = 8.3, 7.9 Hz, 1H), 1.74 (s, 3H), 1.00 (s, 3H), 0.23 - 0.17 (m, 3H) ppm; NH pyridone not observed.19F NMR (376 MHz, Methanol-d4) δ -75.41, -84.37, -139.52, -156.35 ppm. ESI-MS m / z calc.483.128, found 484.5 (M+1)+; 482.40 (M-1)–; Retention time: 3.17 minutes using LC / MS method A. GENERAL METHOD D: (E.G., 141)

[0266]

[0267] To a suspension of rel-(R)-(4-(benzyloxy)-6-((2R*,3S*,4S*,5R*)-3-(3-chloro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridin-3- yl)(imino)(methyl)-λ6-sulfanone (Product of Step 4 in the synthesis of 141, 5 mg, 0.007 mmol) inwater (0.5 mL) was added HCl (50 µL, 4 M solution in 1,4-dioxane, 0.2 mmol). The reaction mixture was heated to reflux for 4 h. Upon reaction completion, the mixture was concentrated in vacuo. Purification by preparative reverse phase HPLC (C18X-bridge column, 38 to 53% MeCN in H2O containing 1% NH4OH) gave rel-6-((2R*,3S*,4S*,5R*)-3-(3-chloro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-3-((R)-S-methylsulfonimidoyl)pyridin-4(1H)-one (141, 2.5 mg, 71%) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 7.36 (dd, J = 8.0, 1.5 Hz, 1H), 7.27 (dd, J = 7.9, 1.6 Hz, 1H), 7.10 (t, J = 7.9 Hz, 1H), 6.52 (s, 1H), 5.35 (d, J = 11.2 Hz, 1H), 4.31 - 4.22 (m, 1H), 3.84 (s, 3H), 3.30 (s, 3H), 2.88 (p, J = 7.8 Hz, 1H), 2.73 (s, 3H), 1.68 (d, J = 1.1 Hz, 3H), 0.88 (dq, J = 7.5, 2.3 Hz, 3H) ppm; NH pyridone and sulfoximine not observed.19F NMR (376 MHz, Methanol-d4) δ -75.44 ppm. ESI-MS m / z calc.492.110, found 493.2 (M+1)+; 491.2 (M-1)- ; Retention time: 2.83 minutes using LC / MS method A. GENERAL METHOD E: (E.G., 85) Cl 1)Phosphazene BaseO CNP2-Et, tBuBrettPhosO O CN

[0268] Step 1:

[0269] A stirred mixture of 4-chloro-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylnicotinonitrile (Product of Step 1 of Example 4, 10 mg, 0.022 mmol) andtBuBrettPhos Pd G3 (2 mg, 0.002 mmol) in THF (500 µL) and water (6 µL) was degassed with nitrogen for 5 min. Phosphazene Base P2-Et (22 µL, 0.066 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 h. Upon reaction completion, the mixture was diluted with DMSO (500 μL) and filtered. Purification by reverse phase preparative chromatography (C18column, 1 to 99% MeCN in H2O containing 5 mM HCl) gave 6- ((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- yl)-2-methyl-4-oxo-1,4-dihydropyridine-3-carbonitrile (85, 4 mg, 41%) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 7.15 - 7.03 (m, 1H), 7.03 - 6.92 (m, 1H), 6.47 (d, J = 17.3 Hz, 1H), 5.54 - 5.32 (m, 1H), 4.18 (t, J = 11.2, 8.4 Hz, 1H), 3.99 (d, J = 2.6 Hz, 3H), 2.93 - 2.79 (m, 1H), 2.63 (s, 3H), 1.66 (s, 3H), 0.86 (d, 3H) ppm. ESI-MS m / z calc.442.132, found 443.1 (M+1)+; Retention time: 1.58 minutes using LC / MS method D.

[0271] 2( a)3( mg, . mmol), SPhos (3 mg, 0.007 mmo) an3 4( mg, 0.28 mmol) were successively added to a degassed and stirred solution of 4-(benzyloxy)-3-chloro-6- ((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- yl)-2-methylpyridine (Product of Step 2, Example 6, 50 mg, 0.092 mmol) in toluene (2 mL) and water (200 µL). Vinylboronic acid pinacol ester (25 mg, 0.16 mmol) was added and the reaction mixture was heated to 100 ºC for 2 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. Purification by flash chromatography (4 g SiO2, 0 to 100% EtOAc in heptane) gave 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-3-vinylpyridine, which was used without further purification in the next step. ESI-MS m / z calc.533.199, found 534.6 (M+1)+; Retention time: 1.28 minutes using LC / MS method C. GENERAL METHOD G: [0272A vial containing a mixture of 4-(benzyloxy)-3-bromo-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridine (Product of Step 3, Example 11, 150 mg, 0.253 mmol), 2-cyanopyridine-5-boronic acid pinacol ester (88 mg, 0.383 mmol), SPhos Pd G3 (24 mg, 0.031 mmol) and K3PO4(322 mg, 1.517 mmol) in toluene (1.5 mL) and water (150 µL) was sealed and nitrogen was flushed through the solution for 10 min. The reaction mixture was stirred and heated at 100 °C for 1 h. The mixture was diluted with DMSO (500 μL) and filtered. Purification by reverse phase preparative chromatography (C18column, 1 to 99%MeCN in H2O containing 5 mM HCl) gave 4'-(benzyloxy)-6'-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2'-methyl-[3,3'-bipyridine]-6- carbonitrile (88 mg, 57%), which was used without further purification in the next step. ESI-MS m / z calc.609.590, found 610.1 (M+1)+; Retention time: 1.91 minutes using LC / MS method D. GENERAL METHOD H:

[0273]

[0274] Ammonium carbamate (25 mg, 0.320 mmol) was added to a solution of 4-(benzyloxy)-6- ((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- yl)-2-methyl-3-(methylthio)pyridine (Product of Step 2, Example 9, 70 mg, 0.116 mmol) in MeOH (2 mL) and DCM (2 mL). PhI(OAc)2(110 mg, 0.342 mmol) was added and the reaction mixture was heated for 2 h at 40 °C. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was diluted with DCM, filtered and the filtrates were concentrated in vacuo. Purification by flash chromatography (12 g SiO2, 0 to 100 % EtOAc in heptane) gave rac-(4-(benzyloxy)-6- ((2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridin-3-yl)(imino)(methyl)-λ6-sulfanone (45 mg, 54%). ESI-MS m / z calc.584.177, found 585.5 (M+1)+; Retention time: 3.75 minutes using LC / MS method A. GENERAL METHOD I:

[0275]

[0276] 2-((2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridin-4(1H)-one (2, 1 g, 2.4 mmol) was suspended in DCM (25 mL), cooled in an ice bath and treated with NBS (940 mg, 5.28 mmol). The mixture wasstirred in the ice bath for 5 min and at ambient temperature for 1 h to give a pale-yellow clear solution. The solution was treated with water (50 mL) and a sodium thiosulfate solution (380 mg, 2.40 mmol), and stirred at ambient temperature for 0.5 h to give a 3 phases mixture. The DCM was removed in vacuo and the suspension was stirred at ambient temperature for 1 h, after which it was filtered, washing the solid with copious amounts of water. The solid was dried overnight to give 3,5- dibromo-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridin-4(1H)-one (1.33 g, 97%) as a colourless solid.1H NMR (400 MHz, Methanol-d4) δ 7.11 (t, J = 6.9 Hz, 1H), 6.97 (td, J = 9.4, 7.6 Hz, 1H), 5.87 (d, J = 10.9 Hz, 1H), 4.47 (t, J = 10.5 Hz, 1H), 3.90 (d, J = 2.4 Hz, 3H), 3.03 - 2.90 (m, 1H), 2.59 (s, 3H), 1.70 (s, 3H), 0.85 (dt, J = 7.9, 2.2 Hz, 3H) ppm; NH pyridone not observed.19F NMR (376 MHz, Methanol-d4) δ -74.70, -139.38, -156.46 (d, J = 18.9 Hz) ppm. ESI-MS m / z calc.572.957, found 576.0 (M+1)+; Retention time: 2.53 minutes using LC / MS method Q. GENERAL METHOD J: Br O Br OBn F3CO 1)BnBr, K2CO3, F COB3ºBr

[0277]

[0278] K2CO3(270 mg, 1.954 mmol), followed by benzyl bromide (170 µL, 1.429 mmol) were added to a solution of 3,5-dibromo-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl- 5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridin-4(1H)-one (Product of Step 2, Example 11, 750 mg, 1.304 mmol) in DMF (7.5 mL) and the mixture was heated at 45 °C for 6.5 h. Another portion of benzyl bromide (31 µL, 0.26 mmol) was added at 45 °C, after which the reaction mixture was cooled to ambient temperature and left stirring for 14 h. The suspension was concentrated in vacuo and the residue was partitioned between MTBE (20 mL) and water (20 mL). The organic phase was separated, washed with 1 M K2CO3(20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (24 g SiO2, 0 to 50% EtOAc in hexane) gave 4-(benzyloxy)-3,5-dibromo-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridine (658 mg, 76%) as a colourless solid.1H NMR (400 MHz, Methanol-d4) δ 7.59 - 7.49 (m, 2H), 7.45 - 7.30 (m, 3H), 6.95 - 6.83 (m, 2H), 6.00 (d, J = 10.8 Hz, 1H), 5.09 (s, 2H), 4.83 - 4.76 (m, 1H), 3.98 (d, J = 2.0 Hz, 3H), 2.85 (p, J = 7.6 Hz, 1H), 2.60 (s, 3H), 1.61 (s, 3H), 0.88 (dq, J = 7.2, 2.4 Hz, 3H) ppm.19F NMR (376 MHz, Methanol-d4) δ -75.76, -140.40 (d, J = 18.8 Hz), -156.73 (d, J = 18.8 Hz) ppm. ESI-MS m / z calc.663.004, found 666.0 (M+1)+; Retention time: 3.84 minutes using LC / MS method Q.GENERAL METHOD K:

[0279]

[0280] Benzy brom de ( 90 µL, .597 mmo) was added to a st rr ng suspens on of methyl 2- ((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- yl)-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (Product of Step 1 Example 12, 750 mg, 1.58 mmol) and Cs2CO3(515 mg, 1.58 mmol) in MeCN (3.8 mL). The reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with DMSO (500 μL) and filtered. Purification by reverse phase preparative chromatography (C18column, 1 to 99% MeCN in H2O containing 5 mM HCl) gave methyl 4-(benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methylnicotinate (460 mg, 51%) as a white semi-solid.1H NMR (400 MHz, Methanol-d4) δ 7.41 - 7.27 (m, 5H), 7.11 - 7.00 (m, 1H), 6.95 (s, 1H), 6.94 - 6.86 (m, 1H), 5.57 - 5.41 (m, 1H), 5.17 (s, 2H), 4.66 (dd, J = 10.7, 8.5 Hz, 1H), 3.91 (d, J = 1.9 Hz, 3H), 3.87 (s, 3H), 2.79 (p, J = 7.8 Hz, 1H), 2.40 (s, 3H), 1.57 (s, 3H), 0.90 - 0.73 (m, 3H) ppm. ESI-MS m / z calc.565.189, found 566.3 (M+1)+; Retention time: 2.14 minutes using LC / MS method D. GENERAL METHOD L:

[0281]

[0282] A 4-mL screw-top vial containing 4-(benzyloxy)-3-chloro-6-((2R,3S,4S,5R)-3-(3,4- difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridine (Product of Step 2 Example 6, 65 mg, 0.120 mmol), Pd(OAc)2(2.7 mg, 0.012 mmol), XPhos (5.7 mg, 0.012 mmol) and CsF (64 mg, 0.42 mmol) was purged with nitrogen. Nitrogen flushed 1,4- dioxane (1 mL) and tributyl(1-ethoxyvinyl)tin (65 µL, 0.192 mmol) were added and nitrogen was passed through the mixture for a further 2 min. The vial was sealed and the mixture was heated at 105°C for 2 h. The mixture was cooled to ambient temperature and filtered through a Celite®pad, washing with EtOAc. The filtrate was concentrated in vacuo to give a yellow oil (120 mg). Purification by flash chromatography gave 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-(1-ethoxyvinyl)-2- methylpyridine (47 mg, 68%) as a colourless gum.1H NMR (400 MHz, Methanol-d4) δ 7.44 - 7.29 (m, 5H), 7.12 (td, J = 6.0, 2.8 Hz, 1H), 7.04 (s, 1H), 6.88 (td, J = 9.5, 9.1, 7.6 Hz, 1H), 5.40 (d, J = 11.1 Hz, 1H), 5.24 (s, 2H), 4.52 (d, J = 2.3 Hz, 1H), 4.14 (d, J = 2.2 Hz, 1H), 4.10 (dd, J = 11.1, 7.8 Hz, 1H), 3.90 (d, J = 7.0 Hz, 2H), 3.86 (d, J = 2.2 Hz, 3H), 2.80 (p, J = 7.5 Hz, 1H), 2.41 (s, 3H), 1.66 (d, J = 1.2 Hz, 3H), 1.31 (t, J = 7.0 Hz, 3H), 0.88 - 0.81 (m, 3H) ppm. ESI-MS m / z calc.577.225, found 578.7 (M+1)+; Retention time: 1.28 minutes using LC / MS method C.

[0283] Step 2:

[0284] A mixture of hydrogen chloride (0.5 mL, 4 M solution in 1,4-dioxane, 2 mmol) and water (10 µL, 0.56 mmol) (one drop) was added to 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-(1-ethoxyvinyl)-2- methylpyridine (45 mg) and the resulting mixture was stirred at ambient temperature for 25 min. The mixture was quenched by addition of a saturated NaHCO3solution (4 mL). The mixture was diluted with water (6 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with a saturated brine solution, dried (MgSO4), filtered and concentrated in vacuo to give 1- (4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridin-3-yl)ethan-1-one (39 mg, 59%) as a light yellow oil.1H NMR (400 MHz, Methanol-d4) δ 7.45 - 7.34 (m, 5H), 7.19 - 7.13 (m, 2H), 6.90 (ddd, J = 10.0, 8.9, 7.6 Hz, 1H), 5.44 (d, J = 11.0 Hz, 1H), 5.30 (s, 2H), 4.19 - 4.10 (m, 1H), 3.89 (d, J = 2.2 Hz, 3H), 2.81 (p, J = 7.6 Hz, 1H), 2.48 (s, 3H), 2.33 (s, 3H), 1.66 (d, J = 1.2 Hz, 3H), 0.89 - 0.82 (m, 3H) ppm. ESI-MS m / z calc.549.194, found 550.6 (M+1)+; Retention time: 1.20 minutes using LC / MS method C. GENERAL METHOD M: (E.G., 202) [02

[0286] 2-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-6-methyl-4-oxo-1,4-dihydropyrimidin-5-yl)acetic acid (49 mg,0.094 mmol) was dissolved in DMF (1 mL). NH4Cl (15 mg, 0.28 mmol), HATU (72 mg, 0.19 mmol) and DIPEA (61 mg, 82 μL, 0.47 mmol) were successively added and the mixture was stirred at ambient temperature overnight. The mixture was partitioned between EtOAc and an aqueous NaHCO3solution, and the aqueous phase was separated and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by reverse phase chromatography (4 g C18column, 10 to 80% MeCN in H2O containing 0.1% NH4OH) followed by reverse phase HPLC (XBridge C18column, 10 to 60% MeCN in H2O containing 0.1% NH4OH) gave 2-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-6-methyl-4-oxo-1,4-dihydropyrimidin-5-yl)acetamide (202, 2.8 mg, 6%) as a colourless solid.1H NMR (400 MHz, Chloroform-d) δ 7.15 - 7.11 (m, 1H), 6.86 (td, J = 9.2, 7.5 Hz, 1H), 6.51 (br s, 1H), 5.27 (d, J = 10.5 Hz, 1H), 5.13 (br s, 1H), 3.99 - 3.94 (m, 4H), 3.41 (s, 2H), 2.81 - 2.73 (m, 1H), 2.27 (s, 3H), 1.65 (s, 3H), 0.81 - 0.78 (m, 3H) ppm; NH pyrimidone not observed. ESI-MS m / z calc.475.153, found 476.1 (M+1)+; Retention time: 1.33 minutes using LC / MS method J. Example 1 6-((2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-yl)-3-(difluoromethoxy)-2-methylpyridin-4(1H)-one (1)

[0288] (2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Int-1, 100 mg, 0.282 mmol) and 4-benzyloxy-6- bromo-3-(difluoromethoxy)-2-methylpyridine (Int-21, 98 mg, 0.285 mmol) were treated via the method described in General Method A to give 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-(difluoromethoxy)-2- methylpyridine (106 mg, 65%) as a colourless oil. ESI-MS m / z calc.573.175, found 574.6 (M+1)+; Retention time: 4.33 minutes using LC / MS Method A.

[0289] Step 2:

[0290] 4-(Benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-3-(difluoromethoxy)-2-methylpyridine (106 mg, 0.185 mmol)was treated via the method described in General Method C to give 6-((2R,3S,4S,5R)-3-(3,4-difluoro- 2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-(difluoromethoxy)-2- methylpyridin-4(1H)-one (1) (92 mg, 100%) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 6.41 - 6.36 (m, 1H), 6.34 - 6.26 (m, 1H), 6.21 (t, J = 76.6 Hz, 1H), 5.79 (s, 1H), 4.69 (d, J = 11.1 Hz, 1H), 3.50 (dd, J = 11.1, 8.3 Hz, 1H), 2.67 - 2.62 (m, 3H), 2.18 (dq, J = 8.3, 7.9 Hz, 1H), 1.74 (s, 3H), 1.00 (s, 3H), 0.23 - 0.17 (m, 3H) ppm; NH pyridone not observed. ESI-MS m / z calc.483.128, found 484.5 (M+1)+; 482.4 (M-1)-; Retention time: 3.17 minutes using LC / MS Method A.

[0291] The following compounds were made using the methods described in Example 1 except that different halide coupling partners were used in Step 1 in place of 4-(benzyloxy)-6-bromo-3- (difluoromethoxy)-2-methylpyridine Int-21. In the case of 25, EtOAc was used as the solvent in place of EtOH in Step 2: Cmpd Compound LC / MS Found MS r LC / MS No. Name (m / z calc.) M+1 etentionMethodNMR (shifts in ppm), , J d, =Cmpd Compound LC / MS Found MS No. Name (m / z calc.) M+1 retention LC / MS MNMR (shifts in ppm)timeethodm, J z, z, .8 J 8 J 3 , eCmpd Compound LC / MS Found MS No. Name (m / z calc.) M+1 retention LC / MSNMR (shifts in ppm)timeMethodJ 5 ), J H - ) J 3 dCmpd Compound LC / MS Found MS No. Name (m / z calc.) M+1 retention LC / MS MetNMR (shifts in ppm)timehod2 , .3 J = 2 , , . J 2 4 4, , .0Cmpd Compound LC / MS Found MS No. Name (m / z calc.) M+1 retention LC / MSNMR (shifts in ppm)timeMethod4 ), s, 3 J 1 , 1Cmpd Compound LC / MS Found MS No. Name (m / z calc.) M+1 retention LC / MSNMR (shifts in ppm)timeMethod.6 d, 5 , . J 8 , ot - ,Cmpd Compound LC / MS Found MS No. Name (m / z calc.) M+1 retention LC / MS MetNMR (shifts in ppm)timehodJ 7 ), .3 = 2 , J = ), d, .2 eCmpd Compound LC / MS Found MS No. Name (m / z calc.) M+1 retention LC / MS MetNMR (shifts in ppm)timehodJ = , e ), 1 , 7 , d, = .0 J 1 ,Cmpd Compound LC / MS Found MS +1 retenti LC / MS No. Name (m / z calc.) M onNMR (shifts in ppm)timeMethod), s, ,in Step 1, rac-(2R,3S,4S,5R)-3-(2-methoxy-3-(trifluoromethyl)phenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used as the starting material in place of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxylic acid Int-1. Between Step 1 and Step 2, a step was introduced to separate the enantiomers by chiral SFC using a Chirapak®IA column, 5 μm particle size, 25 cm x 20 mm from Daicel Corporation: Cmpd Compound LC / MS Found MS LC / l M+1 retention / MS MhNMR (shifts in ppm),Cmpd Compound LC / MS Found MS Name M+1 rete LC / MS No. (m / z calc.) ntionNMR (shifts in ppm)timeMethod), s, s, 5in Step 1, different halide coupling partners were used in place of 4-benzyloxy-6-bromo-3- (difluoromethoxy)-2-methylpyridine Int-21 and (2R,3S,4S,5R)-3-(4-fluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used as the starting material in place of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid Int-1: Cmpd Compound LC / MS Found MS LC / MS / l 1 retentionNMR (shifts in ppm)= J J ),Cmpd Compound LC / MS Found MS No. Name (m / z calc.) M+1 retention LC / MSNMR (shifts in ppm)timeMethod= J eStep 1, (2R,3S,4S,5R)-3-(2-ethoxy-3,4-difluorophenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used as the starting material in place of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxylic acid Int-1: Cmpd Compound LC / MS Found MS No Name (m / z calc) M+1 retention LC / MS MethodNMR (shifts in ppm)= , ), - = ), = Hn Step 1, (2R,3S,4S,5R)-3-(3,4-difluoro-2-isopropoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used as the starting material in place of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxylic acid Int-1:Cmpd Compound LC / MS Found MS LC / No. Name (m / z calc.) M+1 retention MSNMR (shifts in ppm)timeMethod8 z, .1Step 1, (2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used as the starting material in place of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxylic acid Int-1: Cmpd Compound LC / MS Found MS No Name (m / z calc) M+1 retention LC / MS MethodNMR (shifts in ppm)7 z, ), z,in Step 1, rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid Int-4 was used as the starting material in place of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxylic acid Int-1. The enantiomers of Step 1 were further separated by chiral SFC using a Chiralcel®OJ-H column, 5 μm particle size, 25 cm x 10 mm from Daicel Corporation: Cmpd LC / MS Found MS LC / MS)rel-2-((2R,3S,4S,5R)-1H NMR (400 MHz, 3-(3,4-Difluoro-2- Methanol-d4) δ 7.03 - methylphenyl)-4,5- 6.94 (m, 2H), 6.21 (s, 8 7 2 1 , , z, , z, )in Step 1, rac-(2R,3S,4S,5R)-4,5-dimethyl-3-(2-methyl-3-(trifluoromethyl)phenyl)-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used as the starting material in place of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxylic acid Int-1. Between Step 1 and Step 2, a step was introduced to separate the enantiomers by chiral SFC using a Chiralpak®IA column, 5 μm particle size, 25 cm x 10 mm from Daicel Corporation:Cmpd Compound LC / MS Found MS e M+1 retentio LC / MS NMR (shifts in No. Nam (m / z calc.) n time Method ppm) , , , , 0 = , , .0 , 2at, in Step 1, rac-(2R,3S,4S,5R)-3-(4-fluoro-2-methoxy-3-methylphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid Int-11 was used as the starting material in place of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxylic acid Int-1. Between Step 1 and Step 2, a step was introduced to separate the enantiomers by chiral SFC using a Chiralpak®IG column, 5 μm particle size, 25 cm x 10 mm from Daicel Corporation:Cmpd Compound LC / MS Found MS Name M+1 rete LC / MS No. (m / z calc.) ntionNMR (shifts in ppm)timeMethodJ 3 8 ), H , 9 3 s, 3in Step 1, rac-(2R,3S,4S,5R)-3-(7-ethoxy-2,2-difluorobenzo[d][1,3]dioxol-4-yl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid Int-14 was used as the starting material in place of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxylic acid Int-1. Between Step 1 and Step 2, a step was introduced to separate the enantiomers by chiral SFC using a Chiralpak®IA column, 5 μm particle size, 25 cm x 10 mm from Daicel Corporation:Cmpd Compound LC / MS Found MS LC / MS NMR (sh No. Name z calc.) M+1 ret ifts in (m / ention time Method ppm)at, in Step 1, rac-(2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)tetrahydrofuran-2- carboxylic acid Int-15 was used as the starting material in place of (2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid Int-1. Between Step 1 and Step 2, a step was introduced to separate the enantiomers by chiral SFC using a Chiralpak®IA, 5 μm particle size, 25 cm x 10 mm from Daicel Corporation or Chiralpak®IC column, 5 μm particle size, 25 cm x 20 mm from Daicel Corporation respectively:Cmpd Compound LC / MS Found MS No. Name z calc.) M+1 reten LC / MS NMR (shifts in (m / tion time Method ppm) , .3 , 4 = .7 = , .3 = , , 5 = .6 = ,Cmpd Compound LC / MS Found MS No. Name z calc.) M+1 reten LC / MS NMR (shifts in (m / tion time Method ppm) , .3 .4 = , .6 = , inStep 1, (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid Int-16 was used as the starting material in place of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxylic acid Int-1: Cmpd Compound LC / MS Found MS / l M+1 retention LC / MS MhNMR (shifts in ppm)0 p,, Step 1, (2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid Int-2 and 4-(benzyloxy)-2-bromo-6- methylpyridine were respectively used as starting materials in place of (2R,3S,4S,5R)-3-(3,4-difluoro- 2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid Int-1 and 4- (benzyloxy)-6-bromo-3-(difluoromethoxy)-2-methylpyridine Int-21:Cmpd Compound LC / MS Found MS No. Name M+1 ret LC / MS (m / z calc.) entionNMR (shifts in ppm)timeMethodd, , s, nStep 1, (2R,3R,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4-methoxy-5-methyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid and 4-(benzyloxy)-2-bromo-6-methylpyridine were respectively used as starting materials in place of (2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid Int-1 and 4- (benzyloxy)-6-bromo-3-(difluoromethoxy)-2-methylpyridine Int-21: Cmpd Compound LC / MS Found MS LC N N m ( / z l ) M+1 retention / MS Mth dNMR (shifts in ppm)d, , = = s, d, Jn Step 1, (2R,3S,4S,5R)-3-(4-(difluoromethoxy)-3-fluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid Int-10 and 4-(benzyloxy)-2-bromo-6- methylpyridine were respectively used as starting materials in place of (2R,3S,4S,5R)-3-(3,4-difluoro- 2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid Int-1 and 4- (benzyloxy)-6-bromo-3-(difluoromethoxy)-2-methylpyridine Int-21. In Step 2, EtOAc was used as the solvent in place of EtOH:Cmpd Compound LC / MS Found MS o. Name M+1 ret LC / MS N (m / z calc.) entionNMR (shifts in ppm)timeMethods, z, ), nStep 1, (2R,3S,4S,5R)-3-(3-chloro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid Int-9 and 4-(benzyloxy)-2-bromo-6- methylpyridine were respectively used as starting materials in place of (2R,3S,4S,5R)-3-(3,4-difluoro- 2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid Int-1 and 4- (benzyloxy)-6-bromo-3-(difluoromethoxy)-2-methylpyridine Int-21. The debenzylation Step 2 was carried out using the conditions described in General Method D: Cmpd Compound LC / MS Found MS LC / M N N ( / z l ) M+1 retention S Mth dNMR (shifts in ppm), - ,, in Step 1, rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic Int-3 and 4-(benzyloxy)-2-bromo-6-methylpyridine were respectively used as starting materials in place of (2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid Int-1 and 4- (benzyloxy)-6-bromo-3-(difluoromethoxy)-2-methylpyridine Int-21. Between Step 1 and Step 2, astep was introduced to separate the enantiomers by chiral SFC using a Chiralpak®IG column, 5 μm particle size, 25 cm x 20 mm from Daicel Corporation: Cmpd Compound LC / MS Found MS z calc.) M+1 ret LC / MS No. Name (m / entionNMR (shifts in ppm)timeMethod- (benzyloxy)-6-chloro-N,2-dimethylnicotinamide was used as the coupling partner in Step 1. The product of Step 2 (18) was chlorinated, as outlined below:

[0309] Chlorination reaction: NCS (5.1 mg, 0.038 mmol) was added to a stirred solution of 6- ((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- yl)-N,2-dimethyl-4-oxo-1,4-dihydropyridine-3-carboxamide (18, 15 mg, 0.031 mmol) in DCM (500 µL) and MeOH (100 µL). The mixture was stirred at ambient temperature for 70 min. The mixture was diluted with EtOAc, washed with a 10% aqueous Na2S2O3solution, water, and brine. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. Purification by reverse phase preparative chromatography (C18column, 1 to 99% MeCN in water containing 5 mM HCl modifier over 15 min) gave 5-chloro-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-N,2-dimethyl-4-oxo-1,4-dihydropyridine-3-carboxamide (54, 2 mg, 12%) as an off-white solid.1H NMR (400 MHz, Methanol-d4) δ 7.10 (t, J = 6.8 Hz, 1H), 6.98 (q, J = 8.9 Hz, 1H), 5.83 (d, J = 11.0 Hz, 1H), 4.47 (t, J = 10.5 Hz, 1H), 3.91 (s, 3H), 3.00 - 2.94 (m, 1H), 2.85 (s, 3H), 2.55 (s, 3H), 1.71 (s, 3H), 0.88 - 0.84 (m, 3H) ppm; NH pyridone and amide not observed. ESI-MS m / z calc.508.118, found 509.1 (M+1)+; Retention time: 2.26 minutes using LC / MS method Q.

[0310] The following compound was made using methods described in Example 1, except that ethyl 4-(benzyloxy)-2-chloro-6-methylnicotinate Int-18a was used as the coupling partner in Step 1. The product of Step 2 (4) was brominated, as outlined below:

[0311] Bromination reaction: To a solution of ethyl 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methyl-4-oxo-1,4- dihydropyridine-3-carboxylate (4, 63 mg, 0.13 mmol) in DCM (1 mL) and acetic acid (500 µL) was added NBS (27.5 mg, 0.155 mmol) in a single portion. The mixture was stirred at ambient temperature for 16 h and concentrated in vacuo. The residue was dissolved in EtOAc and washed with a 10% aqueous Na2S2O3solution and a saturated NaHCO3solution. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. Purification by reverse phase preparative chromatography (C18column, 30 to 99% MeCN in water containing 5 mM HCl modifier) gave ethyl 5-bromo-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (55, 58.8 mg, 80%) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 7.06 - 6.94 (m, 2H), 5.39 (dd, J = 10.9, 6.2 Hz, 1H), 4.55 - 4.45 (m, 1H), 4.36 (dq, J = 10.8, 7.1 Hz, 1H), 4.21 (dq, J = 10.8, 7.1 Hz, 1H), 3.90 (s, 3H), 2.95 - 2.85 (m, 1H), 2.54 (d, J = 13.6 Hz, 3H), 1.64 (s, 3H), 1.32 (td, J = 7.1, 1.5 Hz, 3H), 0.81 (dq, J = 7.6, 2.3 Hz, 3H) ppm; NH pyridone not observed. ESI-MS m / z calc.567.068, found 569.9 (M+1)+; Retention time: 2.54 minutes using LC / MS method Q.

[0312] The following compound was made using methods described in Example 1, except that ethyl 4-(benzyloxy)-2-chloro-6-methylnicotinate Int-18a was used as the coupling partner in Step 1. The product of Step 2 (4) was chlorinated, as outlined below:

[0313] Chlorination reaction: Ethyl 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (4, 20 mg, 0.035 mmol) was dissolved in DCM (1 mL) and MeOH (300 µL). NCS (10 mg, 0.075 mmol) was added in one portion and the reaction mixture was stirred at ambient temperature for 24 h. The mixture was quenched by addition of a saturated aqueous Na2S2O3solution (1 mL) and poured onto water (10 mL). The mixture was extracted with DCM (3 x 10 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (4 g SiO2, 0 to 100 % EtOAc in heptane) gave ethyl 5-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methyl-4-oxo-1,4- dihydropyridine-3-carboxylate (56, 8.3 mg, 43%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 12.19 (s, 1H), 6.80 - 6.69 (m, 1H), 6.64 (t, J = 7.0 Hz, 1H), 6.21 (d, J = 10.4 Hz, 1H), 4.88 (t, J = 9.3 Hz, 1H), 4.54 (t, J = 7.4 Hz, 2H), 4.02 (d, J = 2.0 Hz, 3H), 2.79 (p, J = 7.7 Hz, 1H), 2.50 (s, 3H), 1.56 (s, 3H), 1.47 (t, J = 7.1 Hz, 3H), 0.92 - 0.82 (m, 3H) ppm. ESI-MS m / z calc.523.118, found 524.1 (M+1)+; 522.1 (M-1)-; Retention time: 2.85 minutes using LC / MS method A.

[0314] The following compound was made using methods described in Example 1, except that ethyl 4-(benzyloxy)-2-chloro-6-methylnicotinate Int-18a was used as the coupling partner in Step 1. The product of Step 2 (4) was saponified, as outlined below:

[0315] Ester hydrolysis: A solution of ethyl 5-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methyl-4-oxo-1,4- dihydropyridine-3-carboxylate (4, 2.9 mg, 0.005 mmol) in EtOH (250 µL) was treated with NaOH (20 µL, 2 M solution in water, 0.04 mmol) and heated at 50 °C for 1 h. Additional NaOH (20 µL, 2 M solution in water, 0.04 mmol) was added and the mixture was heated at 100 °C for 1 h. Purification by reverse phase HPLC (C18X-bridge column, 31% to 45% MeCN in H2O containing 0.1% NH4OH) gave 5-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (Ammonium salt) (57, 1.61 mg, 58%).1H NMR (500 MHz, Methanol-d4) δ 7.22 (ddd, J = 8.4, 5.6, 2.3 Hz, 1H), 7.07 (s, 1H), 6.92 (q, J = 8.9 Hz, 1H), 4.44 (s, 1H), 3.92 (d, J = 2.2 Hz, 3H), 2.91 (t, J = 8.4 Hz, 1H), 2.62 (s, 3H), 1.72 (s, 3H), 0.86 (dq, J = 7.4, 2.2 Hz, 3H) ppm; NH pyridone and OH acid not observed. ESI-MS m / z calc.495.087, found 496.1 (M+1)+; Retention time: 2.79 minutes using LC / MS method A.

[0316] The following compound was made using methods described in Example 1, except that ethyl 4-(benzyloxy)-2-bromonicotinate was used as the coupling partner in Step 1. The product of Step 2 (17) was brominated, as outlined below:

[0317] Bromination reaction: To a solution of ethyl 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydropyridine-3- carboxylate (17, 50 mg, 0.103 mmol) in DCM (780 µL) and acetic acid (390 µL) was added NBS (22 mg, 0.123 mmol) in a single portion. The reaction mixture was stirred at ambient temperature for 2 h. Purification by reverse phase preparative chromatography (C18column, 1 to 99% MeCN in water containing 5 mM HCl modifier) gave ethyl 5-bromo-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydropyridine-3- carboxylate (58, 41 mg, 70%) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 8.16 (s, 1H), 7.09 - 6.91 (m, 2H), 5.42 (d, J = 10.7 Hz, 1H), 4.37 - 4.23 (m, 2H), 4.19 - 4.05 (m, 1H), 3.89 (d, J = 2.4 Hz, 3H), 3.01 - 2.74 (m, 1H), 1.66 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H), 0.81 (dd, J = 8.1, 2.2 Hz, 3H) ppm; NH pyridone not observed. ESI-MS m / z calc.553.052, found 553.9 (M+1)+; Retention time: 1.73 minutes using LC / MS method D.

[0318] The following compound was made using methods described in Example 1, except that 4- (benzyloxy)-2-bromo-6-methylpyridine was used as the coupling partner in Step 1. The product of Step 2 (2) was sulfonylated, as outlined below:

[0319] Sulfonylation reaction: A 20 mL scintillation vial, charged with 2-((2R,3S,4S,5R)-3-(3,4- difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridin- 4(1H)-one (2, 542 mg, 1.286 mmol), was cooled down in an ice / brine bath. Concentrated H2SO4, cooled in an ice / brine bath, was added to the solid and the mixture was stirred at 0 °C for 35 min. The ice / brine bath was removed. The mixture was warmed to ambient temperature and stirred overnight. The reaction mixture was added to a flask containing water (30 mL) cooled at -2 °C, at such a rate to keep the internal temperature below 5 °C. A tan precipitate formed. The mixture was stirred for 15 min, filtered, and the solid was rinsed with water (3 x 8 mL). The solid was air-dried under suction for 30 min then in a vacuum oven at 42 °C. Purification by flash column chromatography (40g SiO2, 0 to 10 % MeOH in MeCN) gave 5-((2R,3S,4S,5R)-4,5-dimethyl-2-(6-methyl-4-oxo-1,4-dihydropyridin-2- yl)-5-(trifluoromethyl)tetrahydrofuran-3-yl)-2,3-difluoro-4-methoxybenzenesulfonic acid (59, 472 mg, 73%).1H NMR (400 MHz, DMSO-d6) δ 14.30 (s, 1H), 7.37 - 7.22 (m, 2H), 7.07 (d, J = 2.3 Hz, 1H), 5.61 (d, J = 11.0 Hz, 1H), 4.31 (dd, J = 11.0, 8.2 Hz, 2H), 3.93 (d, J = 2.4 Hz, 3H), 2.96 (p, J = 7.7 Hz, 1H), 2.61 (s, 3H), 1.66 (s, 3H), 0.81 (dd, 3H) ppm. ESI-MS m / z calc.497.093, found 498.2 (M+1)+; Retention time: 1.41 minutes using LC / MS method Q.

[0320] The following compound was made using methods described in Example 1, except that 4- (benzyloxy)-2-bromo-6-methylpyridine was used as the coupling partner in Step 1. The product of Step 2 (2) was nitrated, as outlined below:

[0321] Nitration: 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridin-4(1H)-one (2, 1 g, 2.4 mmol) was slowly added to HNO3(5 mL, 65 % w / w solution in water, 72 mmol) under stirring at ambient temperature. Another portion of HNO3(5 mL, 65 % w / w solution in water, 72 mmol) was added and the mixture was stirred at ambient temperature for 0.5 h. The resulting solution was slowly added to cold H2SO4(5 mL, 94 mmol), causing a strong exotherm. The internal temperature was kept between -5 and -20 °C by cooling in a dry-ice / acetone bath. At the end of addition, the mixture was warmed to ambient temperature and stirred for 1 h. The yellow solution was slowly added to ice / water (250 mL) and stirred for 1 h. The solid was collected by filtration, washed with water and dried in vacuo. The solid was dissolved in EtOAc, dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography (24g SiO2, 0 to 100 % EtOAc in heptane) gave 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxy-5-nitrophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridin- 4(1H)-one (60, 671 mg, 59%).1H NMR (400 MHz, Methanol-d4) δ 7.90 (dd, J = 7.6, 2.2 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 5.57 (d, J = 10.9 Hz, 1H), 4.25 (dd, J = 10.9, 8.5 Hz, 1H), 4.20 (d, J = 4.6 Hz, 3H), 2.97 (p, J = 7.8 Hz, 1H), 2.50 (s, 3H), 1.68 (d, J = 1.2 Hz, 3H), 0.91(dq, J = 7.4, 2.3 Hz, 3H) ppm; NH pyridone not observed. ESI-MS m / z calc.462.121, found 463.0 (M+1)+; Retention time: 1.81 minutes using LC / MS method Q.

[0322] 2-((2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxy-5-nitrophenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridin-4(1H)-one (60, 100 mg, 0.216 mmol) was reduced using the method described in General Method C to give 2-((2R,3S,4S,5R)-3-(5-amino-3,4- difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridin- 4(1H)-one (Hydrochloride salt) (61, 60 mg, 58%).1H NMR (400 MHz, Methanol-d4) δ 7.05 - 6.98 (m, 2H), 6.74 (dd, J = 8.6, 2.3 Hz, 1H), 5.58 (d, J = 11.2 Hz, 1H), 4.22 (dd, J = 11.2, 8.5 Hz, 1H), 3.84 (d, J = 1.5 Hz, 3H), 2.89 (p, J = 7.8 Hz, 1H), 2.67 (s, 3H), 1.69 (s, 3H), 0.94 (dq, J = 7.4, 2.4 Hz, 3H) ppm; NH pyridone and NH2amine not observed. ESI-MS m / z calc.432.147, found 433.0 (M+1)+; Retention time: 1.62 minutes using LC / MS method Q.

[0323] The following compound was made by transesterification of ethyl 2-((2R,3S,4S,5R)-3- (3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-methoxy-6- methyl-4-oxo-1,4-dihydropyridine-3-carboxylate 21 as outlined below:

[0324] Transesterification: To a solution of ethyl 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-methoxy-6-methyl-4-oxo- 1,4-dihydropyridine-3-carboxylate (6 mg, 0.006 mmol) in MeOH (1 mL) was added NH3(200 µL, 7 M solution in MeOH, 1.4 mmol). The mixture was heated at 60 °C for 16 h. The mixture was concentrated in vacuo then re-suspended in MeOH and filtered. The filtrate was concentrated in vacuo. After purification by reverse phase HPLC (C18X-bridge column, 38% to 53% MeCN in H2O containing 0.1% NH4OH), the residue was partitioned between EtOAc (5 mL) and a saturated NaHCO3solution (10 mL). The organic phase was separated and washed with a saturated NaHCO3solution (2 x 10 mL), dried (MgSO4), filtered, concentrated in vacuo and lyophilized to give methyl 2- ((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- yl)-5-methoxy-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (62, 1.2 mg, 40%) as a white solid.1H NMR (500 MHz, Methanol-d4) δ 7.05 - 6.99 (m, 2H), 5.37 (s, 1H), 4.50 (s, 1H), 3.91 (d, J = 2.1 Hz, 3H), 3.83 (s, 3H), 3.78 (s, 3H), 2.88 (p, J = 8.0 Hz, 1H), 2.36 (s, 3H), 1.65 (s, 3H), 0.82 (dt, J = 7.5, 2.3 Hz, 3H) ppm; NH pyridone not observed. ESI-MS m / z calc.505.152, found 506.5 (M+1)+; 504.4 (M-1)-; Retention time: 2.98 minutes using LC / MS method A.

[0325] The following compound was made using the method described in Example 1, except that 4-(benzyloxy)-2-bromo-3-methoxy-6-methylpyridine Int-19 was used as the coupling partner in Step 1. The product of Step 2 (8) was chlorinated using two different methods, as outlined below:

[0326] Chlorination method 1: To a solution of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-methoxy-6-methylpyridin- 4(1H)-one (8) (280 mg, 0.626 mmol) in MeOH (3 mL) at 40 ºC, DMSO (10 µL, 0.141 mmol) and NCS (200 mg, 1.498 mmol) were added and the mixture was stirred at 40 ºC. When reasonable conversion to the main product was observed, the reaction was stopped. Purification by flashchromatography (24 g SiO2, 0 to 100 % EtOAc in heptane) gave 3-chloro-6-((2R,3S,4S,5R)-3-(3,4- difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-methoxy-2- methylpyridin-4(1H)-one (63, 10.6 mg, 3%).1H NMR (500 MHz, DMSO-d6) δ 7.17 - 7.08 (m, 1H), 6.96 (ddd, J = 8.6, 5.6, 2.0 Hz, 1H), 5.59 (d, J = 11.4 Hz, 1H), 4.59 - 4.48 (m, 1H), 3.92 (d, J = 2.1 Hz, 3H), 3.73 (s, 3H), 2.86 (p, J = 7.8 Hz, 1H), 2.40 (s, 3H), 1.64 (s, 3H), 0.75 (dd, J = 7.7, 2.2 Hz, 3H) ppm; NH pyridone not observed. ESI-MS m / z calc.481.107, found 482.5 (M+1)+; 480.4 (M-1)-; Retention time: 3.06 minutes using LC / MS method A.

[0327] Chlorination method 2: To a solution of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-methoxy-6-methylpyridin- 4(1H)-one (8) (100 mg, 0.07 mmol) in CHCl3(342 µL) at 35 ºC, DMSO (1 mg, 1 µL, 0.014 mmol) and NCS (11 mg, 0.084 mmol) were added and the mixture was stirred at 35 ºC under air until full conversion (about 30 min). The reaction mixture was concentrated in vacuo. Purification by flash column chromatography gave 6-(chloromethyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)- 4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-methoxypyridin-4(1H)-one (64, 2.2 mg, 6%).1H NMR (500 MHz, Chloroform-d) δ 6.86 (td, J = 9.2, 7.3 Hz, 1H), 6.80 - 6.73 (m, 1H), 6.55 (s, 1H), 4.69 (ddd, J = 11.2, 6.3, 3.2 Hz, 1H), 3.97 (d, J = 2.8 Hz, 3H), 3.82 (s, 3H), 3.53 (dd, J = 11.3, 8.1 Hz, 1H), 3.03 (dd, J = 15.3, 3.2 Hz, 1H), 2.83 - 2.73 (m, 1H), 2.58 (p, J = 7.8 Hz, 1H), 1.52 (d, J = 1.1 Hz, 3H), 0.74 (dq, J = 7.5, 2.3 Hz, 3H) ppm; NH pyridone not observed. ESI-MS m / z calc.481.108, found 482.5 (M+1)+; 480.4 (M-1)-; Retention time: 3.42 minutes using LC / MS method A.

[0328] The following compound was made using the method described in Example 1, except that ethyl 4-(benzyloxy)-6-chloro-2-methylnicotinate was used as the coupling partner in Step 1. Between Step 1 and Step 2, a step was introduced to reduce the ester group, as outlined below:

[0329] Ester reduction: A reaction vial, equipped with a stir bar and containing a solution of ethyl 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methylnicotinate (335 mg, 0.57 mmol) in THF (8 mL), was cooled to -40 °C. LiAlH4(600 µL, 2 M solution in THF, 1.2 mmol) was added dropwise and the reaction mixture was stirred at -40 °C for 1 h. The mixture was warmed up to 0 °C for 30 min, and then stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0 °C, quenched by addition of water (300 μL), 4 M NaOH (300 μL) and water (900 μL) and allowed to stir at ambient temperature for 15 min. The mixture was filtered through a pad of Celite®, washing with EtOAc. The mother liquors were concentrated in vacuo. Purification by flash chromatography (24 g SiO2, 0 to 40 % EtOAc in heptane) gave (4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridin-3-yl)methanol (170 mg, 55%) as a colourless solid. ESI-MS m / z calc.537.193, found 538.1 (M+1)+; Retention time: 1.23 minutes using LC / MS method D.Cmpd Compound LC / MS Found MS retention LC / MS No. Name (m / z calc.) M+1MetNMR (shifts in ppm)timehodd, , d, , ), .in Step 1, different halide coupling partners were used. General method D was used instead of General Method C to carry out the debenzylation in Step 2: Cmpd Compound LC / MS Found MS No Name (m / z calc) M+1 retention LC / MS MethodNMR (shifts in ppm), ), , , ), )) , , ,Cmpd Compound LC / MS Found MS No. Name (m / z calc.) M+1 retention LC / MSNMR (shifts in ppm)timeMethod, ), , ),in Step 1, (3S,4R,6R)-4-(3,4-difluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H- pyran-3-carboxylic acid Int-34 was used as the starting material in place of (2R,3S,4S,5R)-3-(3,4- difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid Int-1. Different halide coupling partners were used in Step 1 in place of 4-(benzyloxy)-6-bromo-3- (difluoromethoxy)-2-methylpyridine Int-21. The halide coupling partner for compound 75 was Int-39 (SFC Peak 1) and the halide coupling partner for 76 was Int-40 (SFC peak 2). In the case of 71, 72, 74, and 73, MeOH was used as the solvent in place of EtOH in Step 2: Cmpd Compound LC / MS Found MS LC / MS NMR (shifts in ppm) No. Name (m / z calc.) M+1 retention Method , z, , 2 z, , ),Cmpd Compound LC / MS Found MS LC / MS NMR (shifts in ppm) No. Name (m / z calc.) M+1 retention Method time s, , , ), , br , , ), br - br s, , )Cmpd Compound LC / MS Found MS LC / MS NMR (shifts in ppm) No. Name (m / z calc.) M+1 retention Method time , , , , , z, ,Example 2 Ethyl 6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (77), ethyl 5-bromo-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (78) and ethyl 5-cyano-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (79)

[0333] (2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Int-1, 400 mg, 1.13 mmol) and ethyl 4- (benzyloxy)-6-chloro-2-methylnicotinate (345 mg, 1.13 mmol) were treated via the method described in General Method A to give ethyl 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylnicotinate (550 mg, 84%). ESI-MS m / z calc.579.200, found 580.4 (M+1)+; Retention time: 2.22 minutes using LC / MS Method D.

[0334] Step 2:

[0335] Ethyl 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methylnicotinate (550 mg, 0.95 mmol) was treated via the method described in General Method C to give ethyl 6-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-4-oxo-1,4- dihydropyridine-3-carboxylate (77, 302 mg, 55%).1H NMR (400 MHz, Methanol-d4) δ 7.12 - 7.01 (m, 1H), 7.02 - 6.88 (m, 1H), 6.47 (s, 1H), 5.38 (d, J = 11.2 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 4.18(dd, J = 11.2, 8.3 Hz, 1H), 3.97 (d, J = 2.5 Hz, 3H), 3.01 - 2.75 (m, 1H), 2.43 (s, 3H), 1.66 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H), 0.86 (d, J = 7.5, 2.3 Hz, 3H) ppm; NH pyridone not observed. ESI-MS m / z calc.489.157, found 490.1 (M+1)+; Retention time: 1.67 minutes using LC / MS Method Q.

[0336] Step 3:

[0337] Ethyl 6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (77, 240 mg, 0.490 mmol) was treated via the method described in General Method I to give ethyl 5-bromo-6- ((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- yl)-2-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (78, 140 mg, 49%).1H NMR (400 MHz, Methanol-d4) δ 7.22 - 7.07 (m, 1H), 7.06 - 6.92 (m, 1H), 5.87 (d, J = 10.9 Hz, 1H), 4.54 - 4.38 (m, 1H), 4.32 (q, J = 7.2 Hz, 2H), 3.91 (s, 3H), 3.07 - 2.89 (m, 1H), 2.41 (s, 3H), 1.71 (s, 3H), 1.32 (t, J = 6.7 Hz, 3H), 0.86 (d, J = 7.6, 2.4 Hz, 3H) ppm; NH pyridone not observed. ESI-MS m / z calc.567.068, found 570.0 (M+1)+; Retention time: 1.91 minutes using LC / MS Method D.

[0338] Step 4:

[0339] Ethyl 5-bromo-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (78, 140 mg, 0.241 mmol) was treated via the method described General Method K to give ethyl 4- (benzyloxy)-5-bromo-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methylnicotinate (153 mg, 96%). ESI-MS m / z calc.657.115, found 659.9 (M+1)+; Retention time: 2.17 minutes using LC / MS Method D.

[0340] Step 5:

[0341] A microwave vessel, loaded with ethyl 4-(benzyloxy)-5-bromo-6-((2R,3S,4S,5R)-3-(3,4- difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylnicotinate (120 mg, 0.182 mmol), zinc cyanide (32 mg, 0.27 mmol), and Pd(PPh3)4(42 mg, 0.036 mmol) was capped and purged with nitrogen. DMF (1.9 mL) was added via syringe to the reaction vessel and the reaction was sparged by bubbling nitrogen through the solution for 10 min. The reaction mixture was heated at 90 °C for 1 h, cooled to ambient temperature, filtered, and concentrated in vacuo. Purification by reverse phase preparative chromatography (C18column, 1 to 99% MeCN in water containing 5 mM HCl modifier) gave ethyl 5-cyano-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-4-oxo-1,4- dihydropyridine-3-carboxylate (79, 2 mg, 2%) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 7.15 - 7.06 (m, 1H), 7.07 - 6.95 (m, 1H), 5.47 (d, J = 11.1 Hz, 1H), 4.57 (t, J = 10.4 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 3.95 (d, J = 2.4 Hz, 3H), 3.05 - 2.85 (m, 1H), 2.40 (s, 3H), 1.73 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H), 0.87 (dd, J = 7.7, 2.3 Hz, 3H) ppm; NH pyridone not observed. ESI-MS m / z calc. 514.150, found 515.1 (M+1)+; Retention time: 1.73 minutes using LC / MS Method D.

[0342] The following compound was made using the method described in Example 2 except that, Steps 3, 4 and 5 were omitted. The product of Step 2 (77) was chlorinated using the conditionsdescribed for the synthesis of ethyl 5-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (56): Cmpd Compound LC / MS Found MS No. Name (m / z calc.) M+1 retention LC / MS MethodNMR (shifts in ppm)time d, , z, , , ,that, in Step 1, ethyl 4-(benzyloxy)-2-bromonicotinate was used as the halide coupling partner in place of ethyl 4-(benzyloxy)-6-chloro-2-methylnicotinate: Cmpd Compound LC / MS Found MS retent LC / MS N N / l M+1 ionM th dNMR (shifts in ppm)), , ), 1 6 ,, Steps 2,3, 4 and 5 were omitted. In Step 1, (6-chloro-4-methoxypyridin-3-yl)methanol was used as the halide coupling partner in place of ethyl 4-(benzyloxy)-6-chloro-2-methylnicotinate. The product of Step 1 was demethylated in the presence of BBr3, as outlined below:

[0345] Demethylation: A reaction vial, containing a solution of (6-((2R,3S,4S,5R)-3-(3,4- difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-methoxypyridin- 3-yl)methanol (25.1 mg, 0.056 mmol) in DCM (1 mL), was degassed under an atmosphere of N2for 5min. The vial was sealed and cooled to 0 °C. BBr3(170 µL, 1 M solution in DCM, 0.170 mmol) was added slowly, the reaction mixture was warmed to ambient temperature and stirred for 6 h. The mixture was poured into ice-water and extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification by reverse phase preparative chromatography (C18column, 10 to 99% MeCN in water containing 5 mM HCl modifier) gave 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-5-(hydroxymethyl)pyridin-4(1H)-one (82, 13.4 mg, 55%) as a solid.1H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 7.32 (s, 1H), 7.19 (ddd, J = 8.2, 5.6, 2.2 Hz, 1H), 6.87 - 6.75 (m, 1H), 5.92 (d, J = 11.3 Hz, 1H), 4.66 (d, J = 1.1 Hz, 2H), 4.22 (dd, J = 11.4, 8.2 Hz, 1H), 4.00 (s, 3H), 2.96 (p, J = 7.7 Hz, 1H), 2.66 (s, 1H), 1.81 - 1.71 (m, 3H), 0.95 (dq, J = 7.5, 2.3 Hz, 3H) ppm; NH pyridone not observed. ESI-MS m / z calc.433.131, found 434.4 (M+1)+; Retention time: 1.52 minutes using LC / MS method Q. Example 3 N-((2-((2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-6-methyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)isobutyramide (83) and N-((6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)isobutyramide (84)

[0347] In a sealed vial, a solution of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridin-4(1H)-one (2, 398 mg, 0.954 mmol) and methyl isobutyrylglycinate (465 mg, 2.92 mmol) in toluene (6 mL) was heated at 115 °C for 20 h. The reaction mixture was concentrated in vacuo. Purification by flash chromatography (40 g SiO2, 0 to 10% MeOH in DCM) gave N-((2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methyl-4-oxo-1,4-dihydropyridin-3- yl)methyl)isobutyramide (83, 148 mg, 30%).1H NMR (400 MHz, Methanol-d4) δ 7.21 (s, 1H), 6.98 (d, J = 10.1 Hz, 1H), 6.23 (s, 1H), 5.75 (d, J = 11.0 Hz, 1H), 4.34 (s, 1H), 4.27 (dd, J = 14.1, 5.5 Hz, 1H), 4.06 (d, J = 14.5 Hz, 1H), 3.85 (s, 3H), 3.07 - 2.78 (m, 1H), 2.41 (p, J = 7.1 Hz, 1H), 2.35 (s,3H), 1.70 (s, 3H), 1.10 (dd, J = 6.9, 2.6 Hz, 6H), 0.87 (dd, J = 7.4, 2.3 Hz, 3H) ppm; NH pyridone and NH amide not observed. ESI-MS m / z calc.516.205, found 517.5 (M+1)+; Retention time: 2.26 minutes using LC / MS method V.

[0348] Also obtained N-((6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)isobutyramide (84, 52 mg, 10%).1H NMR (400 MHz, Methanol-d4) δ 7.04 (dt, J = 8.0, 5.5, 1.9 Hz, 1H), 6.95 (ddd, J = 9.4, 7.4 Hz, 1H), 6.34 (s, 1H), 5.32 (d, J = 11.3 Hz, 1H), 4.21 (s, 2H), 4.17 (dd, J = 11.3, 8.3 Hz, 1H), 3.96 (d, J = 2.4 Hz, 3H), 2.83 (p, J = 7.7 Hz, 1H), 2.48 (s, 3H), 2.42 - 2.29 (m, 1H), 1.65 (s, 3H), 1.04 (d, J = 6.9 Hz, 6H), 0.86 (dq, J = 7.3, 2.3 Hz, 3H) ppm; NH pyridone and NH amide not observed. ESI-MS m / z calc.516.205, found 517.4 (M+1)+; Retention time: 2.20 minutes using LC / MS method V. Example 4 6-((2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-yl)-2-methyl-4-oxo-1,4-dihydropyridine-3-carbonitrile (85)

[0350] 1,3-Dioxoisoindolin-2-yl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl- 5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (Product from Step 1 of General Method B, 13 mg, 0.085 mmol) and 4-chloro-2-methylnicotinonitrile (13 mg, 0.085 mmol) were treated via the method described in General Method B Step 2 to give 4-chloro-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylnicotinonitrile (22 mg, 56%).1H NMR (400 MHz, Chloroform-d) δ 7.51 (s, 1H), 7.19 - 7.07 (m, 1H), 6.95 - 6.75 (m, 1H), 5.47 (d, J = 11.0 Hz, 1H), 4.04 - 3.97 (m, 1H), 3.94 (d, J = 2.7 Hz, 3H), 2.87 - 2.73 (m, 1H), 2.66 (s, 3H), 1.74 (s, 3H), 0.84 (d, J = 7.7, 2.3 Hz, 3H) ppm. ESI-MS m / z calc.460.098, found 461.1 (M+1)+; Retention time: 2.26 minutes using LC / MS method D.

[0351] Step 2:

[0352] 4-Chloro-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methylnicotinonitrile (10 mg, 0.022 mmol) was treated via the method described in General Method E to give 6-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-4-oxo-1,4-dihydropyridine-3-carbonitrile (85, 4 mg, 41%).1H NMR (400 MHz, Methanol-d4) δ 7.15 - 7.03 (m, 1H), 7.03 - 6.92 (m, 1H), 6.47 (d, J = 17.3 Hz, 1H), 5.54 - 5.32 (m, 1H), 4.18 (t, J = 11.2, 8.4 Hz, 1H), 3.99 (d, J = 2.6 Hz, 3H), 2.93 - 2.79 (m, 1H), 2.63 (s, 3H), 1.66 (s, 3H), 0.86 (d, 3H) ppm; NH pyridone not observed. ESI-MS m / z calc.442.132, found 443.1 (M+1)+; Retention time: 1.58 minutes using LC / MS method D.

[0353] The following compounds were made using methods described in Example 4 using different coupling partners in Step 1: Cmpd Compound LC / MS Found MS No. Name (m / z calc.) M+1 retention LC / MSNMR (shifts in ppm)tiMethodd, , .4 ), z, , ), , z, , - d, H 4 d, J 4Cmpd Compound LC / MS Found MS No. Name (m / z calc.) M+1 retention LC / MSNMR (shifts in ppm)timeMethod-chloro-3-fluoro-2-methylpyridine was used as the coupling partner in Step 1. The product of Step 2 was further brominated using the conditions described for compound 58: Cmpd Compound LC / MS Found MS LC / No. Name (m / z calc.) M+1 retention MS MethodNMR (shifts in ppm)01 z, ), 9 -c o o- - uo o- - e y py e was use as e coup g pa e ep . e p o uc o ep was further brominated using the conditions described for compound 58. A final carbonylation step was carried out as outlined below:

[0356] Carbonylation reaction: A suspension of 3-bromo-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-6-methylpyridin- 4(1H)-one (90, 25 mg, 0.048 mmol), Et3N (25 µL, 0.179 mmol) and PdCl2(dppf)·DCM (5.9 mg, 0.007 mmol) in MeOH (500 µL) was sparged with carbon monoxide for 15 min at ambient temperature. The reaction mixture was stirred under a carbon monoxide atmosphere (balloon) at 65 °C over the weekend. The solution was filtered and purified by preparative reverse phase HPLC (C18column, 1 to 99% MeCN in water containing 5 mM HCl modifier over 20 min) to give methyl 2- ((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- yl)-5-fluoro-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (91, 12.1 mg, 44%) as a brown solid. 1H NMR (400 MHz, Methanol-d4) δ 7.05 - 6.96 (m, 2H), 5.44 (d, J = 10.8 Hz, 1H), 4.52 (t, J = 10.3 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 2.94 - 2.82 (m, 1H), 2.42 (s, 3H), 1.62 (s, 3H), 0.85 - 0.78 (m, 3H)ppm; NH pyridone not observed. ESI-MS m / z calc.493.132, found 494.1 (M+1)+; Retention time: 2.29 minutes using LC / MS method Q.

[0357] The following compounds were made using methods described in Example 4 except that different coupling partners were used in Step 1. Step 2 was omitted. A final benzyl deprotection step was introduced using the conditions described in General Method C: Cmpd Compound LC / MS Found MS No. Name (m / z calc.) M+1 retention LC / MSNMR (shifts in ppm)timeMethod7 , ne J , 5 net different coupling partners were used in Step 1. Step 2 was omitted. A final benzyl deprotection step was carried out at 80 °C, using a 4 M HCl solution in 1,4-dioxane:Cmpd Compound LC / MS Found MS No. Name (m / z calc.) M+1 retention LC / MSNMR (shifts in ppm)timeMethodd, ), , s, 06 d, ), ,6-((2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-yl)-3-isopropoxy-2-methylpyridin-4(1H)-one (96) [0359

[0360] 4-(Benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methylnicotinonitrile (Product of Step 2 in Example 6, 35 mg, 0.064 mmol) was treated via the method described in General Method E to give 4-(benzyloxy)-6- ((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- yl)-2-methylpyridin-3-ol (13 mg, 38%) as a light yellow oil.1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 7.52 - 7.45 (m, 2H), 7.42 - 7.29 (m, 3H), 7.11 (s, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.05 - 6.97(m, 1H), 5.33 (d, J = 11.1 Hz, 1H), 5.24 (s, 2H), 4.24 (dd, J = 11.1, 7.3 Hz, 1H), 3.87 (d, J = 2.0 Hz, 3H), 2.73 (t, J = 7.5 Hz, 1H), 2.25 (s, 3H), 1.58 (s, 3H), 0.74 (d, J = 7.5 Hz, 3H) ppm.

[0361] Step 2:

[0362] Sodium hydride (1.7 mg, 60% dispersion in mineral oil, 0.042 mmol) was added to a solution of 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridin-3-ol (12 mg, 0.022 mmol) in NMP (0.5 mL) at 0 °C and the reaction mixture was stirred for 5 min.2-Iodopropane (4.6 µL, 0.046 mmol) was added, the mixture was warmed to ambient temperature and then heated at 50 °C overnight. The mixture was cooled to ambient temperature and allowed to stand for 1.5 days. The mixture was partitioned between EtOAc (5 mL), a half-saturated brine solution (3 mL), water (2 mL) and a saturated brine solution (2 mL). The organic layer was dried (MgSO4), filtered concentrated in vacuo to give 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-3-isopropoxy-2-methylpyridine (16 mg, 100%) as a yellow oil. ESI-MS m / z calc.565.225, found 566.6 (M+1)+; Retention time: 1.28 minutes using LC / MS method C.

[0363] Step 3:

[0364] 4-(Benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-3-isopropoxy-2-methylpyridine (16 mg, 0.028 mmol) was treated via the method described in General Method C to give 6-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-isopropoxy-2- methylpyridin-4(1H)-one (96, 9 mg, 66%) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 7.05 (ddd, J = 7.8, 5.6, 2.0 Hz, 1H), 7.02 - 6.94 (m, 1H), 6.41 (s, 1H), 5.35 (d, J = 11.3 Hz, 1H), 4.69 (p, J = 6.1 Hz, 1H), 4.18 (dd, J = 11, 8.3 Hz, 1H), 3.98 (d, J = 2.5 Hz, 3H), 2.86 (p, J = 7.6 Hz, 1H), 2.36 (s, 3H), 1.68 (d, J = 1.1 Hz, 3H), 1.23 (dd, J = 6.2, 1.6 Hz, 6H), 0.91 - 0.84 (m, 3H) ppm; NH pyridone not observed. ESI-MS m / z calc.475.178, found 476.5 (M+1)+; Retention time: 3.18 minutes using LC / MS method A.

[0365] The following compound was made using methods described in Example 5 except that, in Step 1, 4-(benzyloxy)-3-bromo-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridine was used as the starting material in place of 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methylnicotinonitrile andtBuXPhos Pd G3 was used as the catalyst in place oftBuBrettPhos Pd G3. Step 2 was omitted:Cmpd Compound LC / MS Found MS LC / No. Name (m / z calc.) M+1 retention MSNMR (shifts in ppm)timeMethodd, , 1 ), ), H6-((2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-yl)-3-isopropyl-2-methylpyridin-4(1H)-one (98)

[0366]

[0367] DMAP (6.86 g, 56.2 mmol) was added to a solution of (2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Int-1, 1.618 g, 4.567 mmol) and 2-hydroxyisoindoline-1,3-dione (920 mg, 5.64 mmol) in DCM (25 mL) and the reaction mixture was stirred for 10 min at ambient temperature. DIPEA (760 µL, 4.85 mmol) was added and the mixture was stirred at ambient temperature for 1 h. The mixture was treated with 2M HCl (40 mL) and extracted with DCM (2 x 40 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The oil was diluted with DCM and a white precipitate formed. The solid was filtered and the mother liquors were concentrated in vacuo. Purification byflash chromatography (SiO2, 0 to 40% EtOAc in heptane) gave 1,3-dioxoisoindolin-2-yl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxylate (2.06 g, 90%).1H NMR (400 MHz, Chloroform-d) δ 7.88 (dd, J = 5.5, 3.1 Hz, 2H), 7.81 (dd, J = 5.5, 3.1 Hz, 2H), 7.07 - 6.98 (m, 1H), 6.92 (td, J = 9.2, 7.3 Hz, 1H), 5.33 (d, J = 0.8 Hz, 1H), 4.46 (t, J = 8.9 Hz, 1H), 4.10 (d, J = 2.4 Hz, 3H), 2.81 (q, J = 7.7 Hz, 1H), 1.69 (q, J = 1.2 Hz, 3H), 0.89 - 0.82 (m, 3H) ppm.

[0368] Step 2:

[0369] 1,3-Dioxoisoindolin-2-yl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl- 5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (2.00 g, 4.005 mmol) and 4-(benzyloxy)-3-chloro-2- methylpyridine (816 mg, 3.49 mmol) were treated via the method described in General Method B Step 2 to give 4-(benzyloxy)-3-chloro-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridine (634 mg, 29%).1H NMR (400 MHz, Chloroform-d) δ 7.49 - 7.30 (m, 5H), 7.09 (ddd, J = 8.4, 5.7, 2.3 Hz, 1H), 6.94 (s, 1H), 6.86 - 6.73 (m, 1H), 5.39 (d, J = 10.8 Hz, 1H), 5.25 (d, J = 5.5 Hz, 2H), 4.06 - 3.99 (m, 1H), 3.90 (d, J = 2.4 Hz, 3H), 2.76 (t, J = 7.6 Hz, 1H), 2.52 (d, J = 0.4 Hz, 3H), 1.64 (d, J = 1.3 Hz, 3H), 0.89 - 0.74 (m, 3H) ppm. ESI-MS m / z calc.541.144, found 542.1 (M+1)+; Retention time: 1.24 minutes using LC / MS method C.

[0370] Step 3:

[0371] 4-(Benzyloxy)-3-chloro-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridine (1.04 g, 1.77 mmol) was treated via the method described in General Method F to give 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4- difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-3-(prop- 1-en-2-yl)pyridine (728 mg, 72%).1H NMR (400 MHz, Methanol-d4) δ 7.41 - 7.26 (m, 5H), 7.14 - 7.06 (m, 1H), 7.01 (s, 1H), 6.91 - 6.81 (m, 1H), 5.38 (d, J = 11.1 Hz, 1H), 5.31 - 5.25 (m, 1H), 5.20 (s, 2H), 4.83 - 4.77 (m, 1H), 4.09 (dd, J = 11.1, 7.8 Hz, 1H), 3.85 (d, J = 2.2 Hz, 3H), 2.79 (p, J = 7.6 Hz, 1H), 2.37 (s, 3H), 1.96 (s, 3H), 1.64 (s, 3H), 0.89 - 0.76 (m, 3H) ppm. ESI-MS m / z calc.547.215, found 548.6 (M+1)+; Retention time: 2.48 minutes using LC / MS method Q.

[0372] Step 4:

[0373] 4-(Benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-3-(prop-1-en-2-yl)pyridine (7.4 g, 13.5 mmol) was treated via the method described in General Method C to give 6-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-isopropyl-2-methylpyridin- 4(1H)-one (98, 6.15 g, 98%) as an off-white solid.1H NMR (400 MHz, Methanol-d4) δ 7.02 (t, J = 7.3 Hz, 1H), 7.00 - 6.89 (m, 1H), 6.24 (s, 1H), 5.30 (d, J = 11.3 Hz, 1H), 4.16 (dd, J = 11.4, 8.2 Hz, 1H), 3.97 (d, J = 2.4 Hz, 3H), 3.16 (p, J = 7.0 Hz, 1H), 2.83 (p, J = 7.7 Hz, 1H), 2.39 (s, 3H), 1.67 - 1.62 (m, 3H), 1.26 (dd, J = 7.1, 2.4 Hz, 6H), 0.85 (dq, J = 7.6, 2.3 Hz, 3H) ppm; NH pyridone not observed.19F NMR (376 MHz, Methanol-d4) δ -75.46, -139.63 (d, J = 18.9 Hz), -156.37 (d, J = 18.8Hz) ppm. ESI-MS m / z calc.459.183, found 460.5 (M+1)+; Retention time: 1.97 minutes using LC / MS method Q.

[0374] The following compounds were made using methods described in Example 6 except that different Suzuki coupling partners were used in Step 3. In the case of 104, EtOAc was used as the solvent in Step 4 in place of EtOH. Step 4 was omitted for compounds 103 and 105. In the case of 106, 4-(benzyloxy)-3-bromo-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridine was used in place of 4-(benzyloxy)-3-chloro- 6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-yl)-2-methylpyridine, dichloro[1,1'-ferrocenylbis(diphenylphosphane)]palladium dichloromethane was used as the catalyst, K2CO3was used as the base, and dioxane as the solvent: Cmpd Compound LC / MS Found MS ret LC / MS No. Name (m / z calc.) M+1 entionMethodNMR (shifts in ppm)5 ), J 6Cmpd Compound LC / MS Found MS LC / MS No. Name (m / z calc.) M+1 retentionNMR (shifts in ppm)timeMethod02 , ), ), z, 6 ), = H J = ), ), z, 6 4, 5 ), z, 1Cmpd Compound LC / MS Found MS No. Name (m / z calc.) M+1 retention LC / MSNMR (shifts in ppm)timeMethodd, ), = 3 , , 4, J = ), z, , , 79 ), z, s, 4, in Step 1, rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic Int-3 was used as the starting material in place of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid Int-1. A final step was introduced to separate the enantiomers by chiral SFC using a Lux®Cellulose-5 column, 5 μm particle size, 25 cm x 10 mm from Phenomenex, Inc:

[0376] First Eluting Isomer (rt = 4.79 minutes): rel-6-((2S,3R,4R,5S)-3-(3,4-difluoro-2- methoxyphenyl)-4-methyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-isopropyl-2-methylpyridin- 4(1H)-one (107, 15 mg, 16%).1H NMR (500 MHz, Chloroform-d) δ 6.95 (t, J = 7.3 Hz, 1H), 6.86 - 6.75 (m, 1H), 6.23 (s, 1H), 5.38 (d, J = 10.8 Hz, 1H), 4.77 (p, J = 8.0, 7.3 Hz, 1H), 4.10 (dt, J = 7.9, 4.3 Hz, 1H), 3.94 (d, J = 2.6 Hz, 3H), 3.15 (p, J = 7.1 Hz, 1H), 2.95 (hept, J = 7.0 Hz, 1H), 2.39 (s, 3H), 1.32 (dd, J = 7.0, 2.2 Hz, 6H), 0.81 - 0.79 (m, 3H) ppm; NH pyridone not observed. ESI-MS m / z calc.445.168, found 446.2 (M+1)+; 444.2 (M-1)-; Retention time: 3.07 minutes using LC / MS Method A.

[0377] Second Eluting Isomer (rt = 5.46 minutes): rel-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4-methyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-isopropyl-2-methylpyridin- 4(1H)-one (108, 9 mg, 9%).1H NMR (500 MHz, Chloroform-d) δ 7.22 - 7.13 (m, 1H), 6.83 (td, J = 9.0, 7.2 Hz, 1H), 6.04 (s, 1H), 5.34 (d, J = 10.6 Hz, 1H), 4.69 (p, J = 7.2 Hz, 1H), 3.99 (d, J = 10.3 Hz, 1H), 3.96 (d, J = 2.8 Hz, 3H), 3.15 (p, J = 7.1 Hz, 1H), 2.95 (h, J = 7.1 Hz, 1H), 2.37 (s, 3H), 1.30 (dd, J = 7.1, 1.1 Hz, 6H), 0.88 - 0.78 (m, 3H) ppm; NH pyridone not observed. ESI-MS m / z calc. 445.167, found 446.3 (M+1)+; 444.2 (M-1)-; Retention time: 3.08 minutes using LC / MS Method A.

[0378] The following compound was made using methods described in Example 6 except that, in Step 1, (2R,3S,4S,5R)-3-(4-fluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-carboxylic acid was used as the starting material in place of (2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid Int-1: Cmpd Compound LC / MS Found MS retenti LC / MS l onNMR (shifts in ppm)8, 2 0 , d.

[0379] The following compound was made using methods described in Example 6 except that, in Step 1, (2R,3S,4S,5R)-3-(3-fluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used as the starting material in place of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxylic acid Int-1: Cmpd Compound LC / MS Found MS me (m / z calc.) M+1 rete LC / MS No. Na ntionNMR (shifts in ppm)timeMethod05 d, ), 1, = HEthyl dia-2-(2-(6-((2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-4-oxo-1,4-dihydropyridin-3-yl)propoxy)acetate (111) [0

[0381] To a solution of 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-3-(prop-1-en-2-yl)pyridine (Product ofStep 3 in Example 6, 700 mg, 1.28 mmol) in THF (14 mL) under a nitrogen atmosphere, was added 9-BBN (40 mL, 0.5 M solution in THF, 20 mmol). The reaction mixture was heated at 30 ºC for 2 days. The mixture was cooled to ambient temperature, quenched by addition of NaOH (14 mL, 1 M aqueous solution, 14 mmol) and stirred for 30 min. H2O2(5 mL, 30% aqueous solution, 163 mmol) was added and the mixture was stirred for a further 30 min. The reaction mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (24 g SiO2, 0 to 100% EtOAc in heptane) gave dia-2-(4- (benzyloxy)-6-((2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridin-3-yl)propan-1-ol (430 mg, 59%) as a mixture of epimers. ESI-MS m / z calc.565.225, found 566.7 (M+1)+; Retention time: 1.17 minutes using LC / MS Method C.

[0382] Step 2:

[0383] Ethyl diazoacetate (180 µL, 1.71 mmol) was added dropwise to a degassed solution of dia-2-(4-(benzyloxy)-6-((2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridin-3-yl)propan-1-ol (300 mg, 0.53 mmol) and rhodium(II) 2,2,2-trifluoroacetate (20 mg, 0.03 mmol) in toluene (5 mL) at 50 ºC. The reaction mixture was stirred for 10 min at 50 ºC and then concentrated in vacuo. Purification by flash chromatography (12 g SiO2, 0 to 100% EtOAc in heptane) gave ethyl dia-2-(2-(4-(benzyloxy)-6- ((2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridin-3-yl)propoxy)acetate (171 mg, 49%) as a mixture of epimers. ESI-MS m / z calc.651.262, found 652.5 (M+1)+; Retention time: 1.27 minutes using LC / MS Method C.

[0384] Step 3:

[0385] Ethyl dia-2-(2-(4-(benzyloxy)-6-((2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)- 4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridin-3-yl)propoxy)acetate (15 mg, 0.023 mmol) was treated via the method described in General Method C to give ethyl dia-2-(2-(6- ((2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-4-oxo-1,4-dihydropyridin-3-yl)propoxy)acetate (111, 5.6 mg, 37%) as a mixture of epimers.1H NMR (400 MHz, Chloroform-d) δ 6.90 (s, 1H), 6.83 (q, J = 8.6 Hz, 1H), 5.30 (dd, J = 11.0, 2.3 Hz, 1H), 4.27 - 4.20 (m, 3H), 4.17 (qd, J = 7.2, 0.8 Hz, 2H), 4.03 (d, J = 2.4 Hz, 2H), 3.95 (t, J = 2.5 Hz, 3H), 3.83 (ddd, J = 8.5, 5.8, 2.5 Hz, 1H), 3.12 (s, 1H), 2.72 (h, J = 7.9 Hz, 1H), 2.35 (d, J = 4.6 Hz, 3H), 1.64 - 1.60 (m, 3H), 1.32 - 1.22 (m, 6H), 0.80 (dd, J = 7.7, 2.4 Hz, 3H) ppm; NH pyridone not observed. ESI-MS m / z calc.561.214, found 563.3 (M+1)+; 560.2 (M-1)-; Retention time: 3.26 minutes using LC / MS Method A.

[0386] The following compound was made using methods described in Example 7 except that, an additional Grignard reaction step was introduced between Step 2 and Step 3, as outlined below:

[0387] Grignard reaction: MeMgBr (100 µL, 3 M in Et2O, 0.3 mmol) was added to a stirred solution of ethyl dia-2-(2-(4-(benzyloxy)-6-((2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridin-3-yl)propoxy)acetate (50 mg, 0.076 mmol) in THF (1 mL) at 0 ºC and the reaction mixture was warmed to ambient temperature. Upon reaction completion, the mixture was quenched by addition of a saturated NH4Cl solution (5 mL) and extracted with EtOAc (2 x 5 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (4 g SiO2, 0 to 100 % EtOAc in heptane) gave dia-1-(2-(4-(benzyloxy)-6-((2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridin-3-yl)propoxy)-2-methylpropan-2- ol (32 mg, 65%). ESI-MS m / z calc.637.282, found 638.2 (M+1)+; Retention time: 1.24 minutes using LC / MS Method C. Cmpd Compound LC / MS Found MS No. Name (m / z calc.) M-1 retention LC / MS MethodNMR (shifts in ppm)= J J t, - .5additional amidation step was introduced between Step 2 and Step 3 as outlined below:

[0389] Amidation: Ethyl dia-2-(2-(4-(benzyloxy)-6-((2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridin-3- yl)propoxy)acetate (35 mg, 0.053 mmol) was dissolved in NH3(3 mL, 7 M solution in MeOH, 21 mmol) under N2and stirred for 16 h. The solution was concentrated in vacuo. Purification by flash chromatography (4 g SiO2, 0 to 100 % EtOAc in heptane) gave dia-2-(2-(4-(benzyloxy)-6- ((2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridin-3-yl)propoxy)acetamide (22 mg, 66%). ESI- MS m / z calc.622.247, found 623.3 (M+1)+; Retention time: 1.11 minutes using LC / MS Method C.Cmpd Compound LC / MS Found MS No. Name M+1 ret LC / MS (m / z calc.) entionNMR (shifts in ppm)timeMethod, , , J ), , eadditional ester reduction step was introduced between Step 2 and Step 3 as outlined below:

[0391] Ester reduction: LiAlH4(100 µL of 1 M, 0.1 mmol) was added to a stirred solution of ethyl dia-2-(2-(4-(benzyloxy)-6-((2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridin-3-yl)propoxy)acetate (60 mg, 0.092 mmol) in THF (1.2 mL) at -78 ºC, and the mixture warmed to 0 ºC. Upon reaction completion, the reaction mixture was quenched by addition of a saturated NH4Cl solution (10 mL) and diluted with DCM (10 mL). The organic extract was dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (4 g SiO2, 0 to 100 % EtOAc in heptane) gave dia-2-(2-(4-(benzyloxy)-6- ((2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridin-3-yl)propoxy)ethan-1-ol (21 mg, 37%). ESI- MS m / z calc.609.251, found 610.3 (M+1)+; Retention time: 1.16 minutes using LC / MS Method C. Cmpd Compound LC / MS Found MS retention LC / MSNMR (shifts in ppm), .Example 8 6-((2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-yl)-3-((2-methoxyethyl)(methyl)amino)-2-methylpyridin-4(1H)-one (115) 1) 2-hydroxyisoindoline-1,3- OBnF3COO 3) 2-methoxyethan-1-amine, dione, N,N'- F COPhosphazene Base P2-Et,diisopropylmethanediimine,3CltOHBuXPhos Pd G3, THF,DMAP DCM 90%F3COF CONH34)NaH MeI NMP 0 °CN Me[0392

[0393] N,N'-Diisopropylmethanediimine (6.86 g, 56.2 mmol) was added to a mixture of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxylic acid (Int-1, 1.618 g, 4.567 mmol) and 2-hydroxyisoindoline-1,3-dione (920 mg, 5.64 mmol) in DCM (25 mL) and the reaction mixture was stirred for 10 min at ambient temperature. DIPEA (760 µL, 4.85 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 h. On reaction completion, the mixture was treated with 2 M HCl (40 mL) and extracted with DCM (2 x 40 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The oil was taken up in DCM and a white precipitate formed. The precipitate was filtered and the mother liquors were concentrated in vacuo. Purification by flash chromatography (SiO2, 0 to 40% EtOAc in heptane) gave 1,3-dioxoisoindolin-2-yl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)- 4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (2.06 g, 90%).1H NMR (400 MHz, Chloroform-d) δ 7.88 (dd, J = 5.5, 3.1 Hz, 2H), 7.81 (dd, J = 5.5, 3.1 Hz, 2H), 7.07 - 6.98 (m, 1H), 6.92 (td, J = 9.2, 7.3 Hz, 1H), 5.33 (d, J = 0.8 Hz, 1H), 4.46 (t, J = 8.9 Hz, 1H), 4.10 (d, J = 2.4 Hz, 3H), 2.81 (q, J = 7.7 Hz, 1H), 1.69 (q, J = 1.2 Hz, 3H), 0.89 - 0.82 (m, 3H) ppm.

[0394] Step 2:

[0395] 1,3-Dioxoisoindolin-2-yl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl- 5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (2 g, 4 mmol) and 4-(benzyloxy)-3-chloro-2- methylpyridine (1.47 g, 6.28 mmol) were treated via the method described in General Method B Step 2 to give 4-(benzyloxy)-3-chloro-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridine (634 mg, 29%).1H NMR (400 MHz,Chloroform-d) δ 7.49 - 7.30 (m, 5H), 7.09 (ddd, J = 8.4, 5.7, 2.3 Hz, 1H), 6.94 (s, 1H), 6.86 - 6.73 (m, 1H), 5.39 (d, J = 10.8 Hz, 1H), 5.25 (d, J = 5.5 Hz, 2H), 4.06 - 3.99 (m, 1H), 3.90 (d, J = 2.4 Hz, 3H), 2.76 (t, J = 7.6 Hz, 1H), 2.52 (d, J = 0.4 Hz, 3H), 1.64 (d, J = 1.3 Hz, 3H), 0.89 - 0.74 (m, 3H), 0.82 - 0.75 (m, 1H) ppm. Retention time: 1.24 minutes using LC / MS Method C.

[0396] Step 3:

[0397] 4-(Benzyloxy)-3-chloro-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridine (100 mg, 0.175 mmol), 2- methoxyethan-1-amine (31 µL, 0.36 mmol) andtBuXPhos Pd G3 (15 mg, 0.019 mmol) were added to a 4-mL screw-top vial and the vessel was purged with nitrogen. A nitrogen purged solution of phosphazene base P2-Et (175 µL, 0.526 mmol) in THF (0.85 mL) was added and the resulting mixture was purged with nitrogen for a further 3 min. The vial was sealed and the mixture was stirred and heated at 50 °C in a pre-heated heating block for 6 h. The mixture was cooled to ambient temperature and allowed to stand for a further 10 h. The reaction mixture was stirred at 50 °C for 6 h, then cooled to ambient temperature and allowed to stand for 1.5 days. The mixture was diluted with EtOAc (10 mL), washed with a half-saturated aqueous NH4Cl solution (7 mL) and a saturated aqueous brine solution, dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil. Purification by flash chromatography gave 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-N-(2-methoxyethyl)-2- methylpyridin-3-amine (65 mg, 64%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.50 - 7.44 (m, 2H), 7.40 (ddd, J = 7.7, 6.8, 1.0 Hz, 2H), 7.37 - 7.32 (m, 1H), 7.12 (d, J = 7.4 Hz, 2H), 7.08 - 7.00 (m, 1H), 5.36 (d, J = 11.1 Hz, 1H), 5.21 (d, J = 2.4 Hz, 2H), 4.32 (dd, J = 11.1, 7.4 Hz, 1H), 4.14 (t, J = 6.7 Hz, 1H), 3.90 (d, J = 2.0 Hz, 3H), 3.33 (t, J = 5.5 Hz, 2H), 3.18 (s, 5H), 2.76 (t, J = 7.4 Hz, 1H), 2.32 (s, 3H), 1.61 (s, 3H), 0.76 (d, J = 7.4 Hz, 3H) ppm. ESI-MS m / z calc.580.236, found 581.4 (M+1)+; Retention time: 1.19 minutes using LC / MS method C.

[0398] Step 4:

[0399] Sodium hydride (5.5 mg, 60 % w / w dispersion in mineral oil, 0.14 mmol) was added to a stirred solution of 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-N-(2-methoxyethyl)-2-methylpyridin-3-amine (64 mg, 0.11 mmol) in NMP (1 mL) at 0 °C and the mixture was stirred at 0 °C for 10 min. MeI (10 µL, 0.16 mmol) was added and the mixture was warmed to ambient temperature. After 16 h, the mixture was cooled to 0 °C and additional amounts of sodium hydride (2 x 5.5 mg, 60 % w / w dispersion in mineral oil, 0.14 mmol) and MeI (2 x 10 µL, 0.16 mmol) were added until reaction completion. The reaction was quenched by addition of a saturated aqueous NH4Cl solution (1 mL), diluted with EtOAc (10 mL) and washed with a half-saturated aqueous NH4Cl solution (5 mL), water (5 mL) and a saturated aqueous brine solution. Purification by flash chromatography gave 4-(benzyloxy)-6- ((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- yl)-N-(2-methoxyethyl)-N,2-dimethylpyridin-3-amine (49 mg, 75%) as a colourless oil.1H NMR (400MHz, DMSO-d6) δ 7.51 - 7.47 (m, 2H), 7.42 (ddd, J = 8.0, 7.0, 1.0 Hz, 2H), 7.38 - 7.33 (m, 1H), 7.19 (d, J = 5.8 Hz, 2H), 7.11 - 7.01 (m, 1H), 5.41 (d, J = 11.0 Hz, 1H), 5.27 - 5.18 (m, 2H), 4.33 (dd, J = 11.1, 7.3 Hz, 1H), 3.90 (d, J = 2.0 Hz, 3H), 3.26 (t, J = 6.0 Hz, 2H), 3.13 (s, 3H), 3.05 (t, J = 5.9 Hz, 2H), 2.78 (t, J = 7.4 Hz, 1H), 2.64 (s, 3H), 2.36 (s, 3H), 1.62 (s, 3H), 0.77 (d, J = 7.4 Hz, 3H) ppm.19F NMR (376 MHz, DMSO-d6) δ -73.47, -138.68, -155.30 ppm. ESI-MS m / z calc.594.252, found 595.4 (M+1)+; Retention time: 1.29 minutes using LC / MS method C.

[0400] Step 5:

[0401] Pd / C (35 mg, 5 % w / w, 0.016 mmol) was added to 4-(benzyloxy)-6-((2R,3S,4S,5R)-3- (3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-N-(2- methoxyethyl)-N,2-dimethylpyridin-3-amine (48 mg, 0.081 mmol) and the vessel was purged with nitrogen. EtOH (1.5 mL) was added and the suspension was flushed with nitrogen for 3 min. The atmosphere was replaced by a hydrogen atmosphere and the mixture stirred at ambient temperature for 8 min. The vessel was purged with nitrogen and the reaction mixture was filtered through a PTFE syringe filter (0.45 μm), washing with EtOAc. The filtrate was concentrated in vacuo to give a colourless oil. Purification by reverse phase preparative HPLC gave 6-((2R,3S,4S,5R)-3-(3,4-difluoro- 2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-((2- methoxyethyl)(methyl)amino)-2-methylpyridin-4(1H)-one (115, 38 mg, 92%) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 7.04 (d, J = 6.4 Hz, 1H), 7.02 - 6.94 (m, 1H), 6.32 (s, 1H), 5.33 (d, J = 11.3 Hz, 1H), 4.18 (dd, J = 11.3, 8.3 Hz, 1H), 3.99 (d, J = 2.5 Hz, 3H), 3.31 (s, 2H), 3.27 (s, 3H), 3.21 (d, J = 5.7 Hz, 2H), 2.85 (p, J = 7.7 Hz, 1H), 2.71 (s, 3H), 2.45 - 2.40 (m, 3H), 1.67 (d, J = 1.2 Hz, 3H), 0.93 - 0.83 (m, 3H) ppm; NH pyridone not observed.19F NMR (376 MHz, Methanol-d4) δ - 75.44, -139.66, -156.44 ppm. ESI-MS m / z calc.504.205, found 505.7 (M+1)+; Retention time: 3.26 minutes using LC / MS method A.

[0402] The following compounds were made using methods described in Example 8 except that, in Step 3, different amines were used in place of 2-methoxyethan-1-amine. Step 4 was omitted in all cases. In the case of compound 123, tert-butyl 6,6-difluoro-1,4-diazepane-1-carboxylate was used as the amine in Step 3, and the Boc-protecting group was removed using HCl in 1,4-dioxane prior to Step 5:Cmpd Compound LC / MS Found MS No. Name (m / z calc.) M+1 retention LC / MS MeNMR (shifts in ppm)timethod9 1 .2 d. d, ne 3, J J , neCmpd Compound LC / MS Found MS No. Name (m / z calc.) M+1 retention LC / MS MetNMR (shifts in ppm)timehodr- J 9 J , s, 3, J d, 4 .2 d.Cmpd Compound LC / MS Found MS No. Name (m / z calc.) M+1 retention LC / MSNMR (shifts in ppm)timeMethodd, J t, J (t, 6Cmpd Compound LC / MS Found MS No. Name (m / z calc.) M+1 retention LC / MSNMR (shifts in ppm)timeMethodt, – 9 5 J H d.in Step 3, tert-butyl (3S,4S)-4-amino-3-fluoro-piperidine-1-carboxylate was used in place of 2- methoxyethan-1-amine and the Boc-protecting group was subsequently removed using HCl in 1,4- dioxane. Prior to Steps 4 and 5, an additional methylation step (via reductive amination) was introduced as outlined below:

[0404] Methylation: Formaldehyde (10 µL, 37 % w / w solution in water, 0.14 mmol) and acetic acid (7.75 µL, 0.1363 mmol) were added to a solution of 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4- difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-N-((3S,4S)-3- fluoropiperidin-4-yl)-2-methylpyridin-3-amine (34 mg, 0.055 mmol) in 2-MeTHF (1 mL) and the mixture was stirred at ambient temperature for 10 min. STAB (35 mg, 0.17 mmol) was added in a single portion and the resulting suspension stirred at ambient temperature for 140 min. Additional portions of formaldehyde (5 μL, 0.07 mmol), acetic acid (4 μL, 0.07 mmol) and STAB (17 mg, 0.08 mmol) were added and the mixture stirred for 16 h. The mixture was quenched with a saturated aqueous NH4Cl solution (0.5 mL), basified with a 50% saturated aqueous NaHCO3solution (5 mL) and extracted with EtOAc (2 x 7 mL). The combined extracts were washed with saturated brine, dried (MgSO4), filtered and concentrated in vacuo to afford 4-benzyloxy-6-((2R,3S,4S,5R)-3-(3,4-difluoro- 2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-N-((3S,4S)-3-fluoro-1- methylpiperidin-4-yl)-2-methylpyridin-3-amine (33 mg, 95%) as a yellow oil. ESI-MS m / z calc. 637.274, found 638.4 (M+1)+; Retention time: 1.18 minutes using LC / MS method C.Cmpd Compound LC / MS Found MS No. Name .) M+1 re LC / MS (m / z calc tentionNMR (shifts in ppm)timeMethod), ), 3 5 s, s,n Step 3, methylamine was used as the amine coupling partner in place of 2-methoxyethan-1-amine. Step 4 was replaced with an acylation step using cyclopropanecarbonyl chloride to provide intermediate N-(4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridin-3-yl)-N-methylcyclopropanecarboxamide: Cmpd Compound LC / MS Found MS r LC / MS l 1 etentionNMR (shifts in ppm), = t, ,

[0406] The following compounds were made using methods described in Example 8 except that, the starting material of Step 3 was prepared by treating ethyl 5-bromo-2-((2R,3S,4S,5R)-3-(3,4- difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methyl-4-oxo- 1,4-dihydropyridine-3-carboxylate (55) via the method described in General method K and dimethylamine was used in place of 2-methoxyethan-1-amine. Step 4 was omitted. Ethyl 2- ((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- yl)-5-hydroxy-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate 129 was also obtained as a side- product in the synthesis of ethyl 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-5-(dimethylamino)-6-methyl-4-oxo-1,4-dihydropyridine-3- carboxylate 128: Cmpd Compound LC / MS Found MS retention LC / MS NMR (shifts in No. Name (m / z calc.) M+1 Method ppm) , z, , 2 ), , , , - ), , , , nd

[0407] The following compounds were made using methods described in Example 8 except that, in Step 1, rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid Int-3 was used as the starting material in place of in place of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid Int-1. In Step 3, dimethylamine was used in place of 2-methoxyethan-1-amine. Step 4 was omitted. Before carrying out Step 5, an additional step was introduced to separate the enantiomers by chiral SFC using a Chiralart Amylose-SA column, 5 μm particle size, 25 cm x 20 mm from YMC Co., Ltd.: Cmpd Compound LC / MS Found MS . Name (m / z calc.) M+1 rete LC / MS NMR (shifts in No ntion ti Method ppm) , 6 ), , , , , , 6 , , , 4 ,

[0408] The following compound was made using methods described in Example 8 except that, in Step 1, (2R,3S,4S,5R)-3-(4-fluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-carboxylic acid was used as the starting material in place of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid Int-1. In Step 3, dimethylamine was used in place of 2-methoxyethan-1-amine. Step 4 was omitted: Cmpd Compound LC / MS Found MS No. Name (m / z calc.) M+1 retention LC / MSNMR (shifts in ppm)timeMethodJ , ), , HStep 1, (2R,3S,4S,5R)-3-(3-fluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used as the starting material in place of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxylic acid Int-1. In Step 3, dimethylamine was used in place of 2-methoxyethan-1-amine. Step 4 was omitted: Cmpd Compound LC / MS Found MS l 1 retention LC / MSNMR (shifts in ppm)5 , , z, , 3

[0410] The following compound was made using methods described in Example 8 using Steps 3 and 5, except that the starting material in Step 3 was 4-(benzyloxy)-3-bromo-6-((2R,3S,4S,5R)-3-(3,4- difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridine (prepared in Example 11, debromination). In Step 3, dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene] palladium(II) was used as the catalyst in place oftBuXPhos Pd G3, and NaOtBu used in place of phosphazene base P2-Et. Step 4 was omitted. Cmpd Compound LC / MS Found MS 1 retenti LC / MS No. Name (m / z calc.) M+ onNMR (shifts in ppm)timeMethod, s, , 3rel-6-((2R*,3S*,4S*,5R*)-3-(3,4-Difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-3-((R)-S-methylsulfonimidoyl)pyridin-4(1H)-one (135) and rel-6-((2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-3-((S)-S-methylsulfonimidoyl)pyridin-4(1H)-one (136)

[0411] Step 1:

[0412] (2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Int-1, 1.618 g, 4.567 mmol) and 2- hydroxyisoindoline-1,3-dione (920 mg, 5.640 mmol) were treated via the method described in General Method B Step 1, to give 1,3-dioxoisoindolin-2-yl (2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (2.06 g, 90%).1H NMR (400 MHz, Chloroform-d) δ 7.88 (dd, J = 5.5, 3.1 Hz, 2H), 7.81 (dd, J = 5.5, 3.1 Hz, 2H), 7.07 - 6.98 (m, 1H), 6.92 (td, J = 9.2, 7.3 Hz, 1H), 5.33 (d, J = 0.8 Hz, 1H), 4.46 (t, J = 8.9 Hz, 1H), 4.10 (d, J = 2.4 Hz, 3H), 2.81 (q, J = 7.7 Hz, 1H), 1.69 (q, J = 1.2 Hz, 3H), 0.89 - 0.82 (m, 3H) ppm.19F NMR (376 MHz, Chloroform-d) δ -74.46, -136.60, -153.83 ppm. ESI-MS m / z calc.499.105, found 500.0 (M+1)+; Retention time: 1.12 minutes using LC / MS method M.

[0413] Step 2:

[0414] 1,3-Dioxoisoindolin-2-yl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl- 5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.65 g, 2.81 mmol) and 4-(benzyloxy)-2-methyl-3- (methylthio)pyridine (620 mg, 2.53 mmol) were treated via the method described in General Method B Step 2, to give 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-3-(methylthio)pyridine (490 mg, 26%) as a colourless oil.1H NMR (500 MHz, DMSO-d6) δ 7.52 - 7.46 (m, 2H), 7.44 - 7.39 (m, 2H), 7.38 - 7.30 (m, 1H), 7.23 (s, 1H), 7.19 - 7.10 (m, 1H), 7.05 (td, J = 9.4, 7.7 Hz, 1H), 5.45 (d, J = 10.9 Hz, 1H), 5.40 - 5.21 (m, 2H), 4.30 (dd, J = 11.0, 7.4 Hz, 1H), 3.89 (d, J = 1.8 Hz, 3H), 2.77 (p, J = 7.4 Hz, 1H), 2.54 (s, 3H), 2.25 (s, 3H), 1.62 (s, 3H), 0.76 (dd, J = 7.5, 2.4 Hz, 3H) ppm.19F NMR (471 MHz, DMSO-d6) δ -73.34, -136.92 - -139.88 (m), -155.14 (d, J = 32.0 Hz) ppm. ESI-MS m / z calc.553.171, found 554.6 (M+1)+; Retention time: 1.31 minutes using LC / MS method C.

[0415] Step 3:

[0416] 4-(Benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-3-(methylthio)pyridine (1 g, 1.55 mmol) was treated via the method described in General Method H to give dia-(4-(benzyloxy)-6-((2R*,3S*,4S*,5R*)-3- (3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2- methylpyridin-3-yl)(imino)(methyl)-λ6-sulfanone (510 mg, 52%) as a mixture of diastereoisomers. ESI-MS m / z calc.584.177, found 586.3 (M+1)+; Retention time: 3.70 minutes using LC / MS method A.

[0417] Step 4:

[0418] The diastereomers of dia-(4-(benzyloxy)-6-((2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridin-3- yl)(imino)(methyl)-λ6-sulfanone were separated by chiral SFC using a Chiralpak®IC column, 5 μm particle size, 25 cm x 20 mm from Daicel Corporation to give:

[0419] First Eluting Isomer (rt = 4.59 minutes): rel-(R)-(4-(benzyloxy)-6-((2R*,3S*,4S*,5R*)-3- (3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2- methylpyridin-3-yl)(imino)(methyl)-λ6-sulfanone (157.6 mg, 32%). ESI-MS m / z calc.584.177, found 585.2 (M+1)+; Retention time: 3.68 minutes using LC / MS method A.

[0420] Second Eluting Isomer (rt = 6.14 minutes): rel-(S)-(4-(benzyloxy)-6- ((2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridin-3-yl)(imino)(methyl)-λ6-sulfanone (173.9 mg, 37%). ESI-MS m / z calc.584.177, found 585.2 (M+1)+; Retention time: 3.67 minutes using LC / MS method A.

[0421] Step 5:

[0422] rel-(R)-(4-(Benzyloxy)-6-((2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridin-3-yl)(imino)(methyl)-λ6-sulfanone (142.6 mg, 0.227 mmol) (First Eluting Isomer, rt = 4.59 minutes) was treated via the method described in General Method C to give rel-6-((2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)- 4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-3-((R)-S- methylsulfonimidoyl)pyridin-4(1H)-one (135, 113.9 mg, 67%).1H NMR (400 MHz, Methanol-d4) δ 7.06 (ddd, J = 8.2, 5.6, 2.1 Hz, 1H), 6.96 (ddd, J = 9.9, 8.9, 7.4 Hz, 1H), 6.51 (s, 1H), 5.36 (d, J = 11.2 Hz, 1H), 4.19 (dd, J = 11.2, 8.1 Hz, 1H), 3.99 (d, J = 2.5 Hz, 3H), 2.85 (p, J = 7.7 Hz, 1H), 2.74 (s, 3H), 1.66 (d, J = 1.2 Hz, 3H), 0.86 (dq, J = 7.3, 2.3 Hz, 3H) ppm; NH pyridone and sulfoximine not observed. ESI-MS m / z calc.494.130, found 496.0 (M+1)+; 493.1 (M-1)-; Retention time: 2.85 minutes using LC / MS method A.

[0423] rel-(S)-(4-(Benzyloxy)-6-((2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridin-3-yl)(imino)(methyl)-λ6-sulfanone (250 mg, 0.428 mmol) (Second Eluting Isomer (rt = 6.14 minutes) was treated via the method described in General Method C to give rel-6-((2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)- 4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-3-((S)-S- methylsulfonimidoyl)pyridin-4(1H)-one (136, 138.7 mg, 66%).1H NMR (400 MHz, Methanol-d4) δ 7.06 (dd, J = 8.3, 5.9 Hz, 1H), 6.96 (td, J = 9.3, 7.5 Hz, 1H), 6.51 (s, 1H), 5.35 (d, J = 11.2 Hz, 1H), 4.20 (dd, J = 11.3, 8.2 Hz, 1H), 3.99 (d, J = 2.5 Hz, 3H), 3.30 (d, J = 1.8 Hz, 3H), 2.85 (p, J = 7.8 Hz, 1H), 2.75 (s, 3H), 1.66 (d, J = 1.2 Hz, 3H), 0.86 (dq, J = 7.4, 2.3 Hz, 3H) ppm; NH pyridone and sulfoximine not observed.19F NMR (376 MHz, Methanol-d4) δ -75.47, -136.33 - -142.38 (m), -156.44 ppm. ESI-MS m / z calc.494.130, found 496.0 (M+1)+; 493.1 (M-1)-; Retention time: 2.85 minutes using LC / MS method A.

[0424] The following compound was made using the methods described in Example 9 except that Step 4 was omitted:Cmpd Compound LC / MS Found MS . Name M+1 rete LC / MS No (m / z calc.) ntionNMR (shifts in ppm)timeMethod35 ), z, = H eadditional methylation step was introduced after Step 3, as outlined below. Step 4 was omitted:

[0426] N-Methylation of sulfoximine: To a solution of dia-(4-(benzyloxy)-6-((2R*,3S*,4S*,5R*)-3- (3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2- methylpyridin-3-yl)(imino)(methyl)-λ6-sulfanone (18 mg, 0.024 mmol) in MeCN (1.5 mL) was added formaldehyde (25 µL, 37 % w / w solution in water, 0.33 mmol), triethylsilane (30 µL, 0.18 mmol) and TFA (15 µL, 0.19 mmol). The reaction mixture was stirred at ambient temperature for 18 h and then quenched by addition of a NaHCO3solution. The mixture was extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give dia-(4-(benzyloxy)-6- ((2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-2-methylpyridin-3-yl)(methyl)(methylimino)-λ6-sulfanone (25 mg, 35%) as a colourless oil and as a mixture of diastereoisomers. ESI-MS m / z calc.598.192, found 599.2 (M+1)+; Retention time: 1.12 minutes using LC / MS Method C.Cmpd Compound LC / MS Found MS No. Name calc.) M+1 retent LC / MS NMR (shifts in (m / z ion time Method ppm) , , .2 2 , 5 , at,in Step 1, (2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used as the starting material in place of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxylic acid Int-1: Cmpd Compound LC / MS Found MS / l M+1 retention LC / MS MhNMR (shifts in ppm)8 0 8 ), ,Cmpd Compound LC / MS Found MS No. Name ) M+1 re LC / MS (m / z calc. tentionNMR (shifts in ppm)timeMethod9 1 8 ), ,in Step 1, (2R,3S,4S,5R)-3-(3-chloro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid Int-9 was used as the starting material in place of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxylic acid Int-1. In Step 5, the debenzylation step was carried out using the method described in General Method D: Cmpd Compound LC / MS Found MS retention LC / MSNMR (shifts in ppm)J 30 68 .Cmpd Compound LC / MS Found MS No. Name M+1 ret LC / MS (m / z calc.) entionNMR (shifts in ppm)timeMethodJ ), , ), , ethe product of Step 2 was made using General Method A using (2R,3R,4S,5R)-3-(3,4-difluoro-2- methylphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid and 4- (benzyloxy)-6-chloro-2-methyl-3-(methylthio)pyridine Int-28 as the starting materials. In Step 4, the diastereomers were separated by chiral SFC using a Chiralpak®IB column, 5 μm particle size, 25 cm x 20 mm from Daicel Corporation. Step 5 was carried out in EtOAc in place of EtOH as the solvent:Cmpd Compound LC / MS Found MS +1 retenti LC / MS No. Name (m / z calc.) M onNMR (shifts in ppm)timeMethod4 , , , , . 3 , , , , .

[0430] The following compounds were made using methods described in Example 9 except that, in Step 1, (2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic Int-2 was used as the starting material in place of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxylic acid Int-1. In Step 4, the diastereomers were separated by chiral SFC using a Chiralcel®OJ-H column, 5 μm particle size, 25 cm x 20 mm from Daicel Corporation:Cmpd Compound LC / MS Found MS LC / M No. Name (m / z calc.) M+1 retention SNMR (shifts in ppm)timeMethod3 02 2 e 3 02 2

[0431] The following compound was made using methods described in Example 9 except that in Step 2, 4-chloro-2-methyl-3-(methylthio)pyridine Int-30 was used as the coupling partner in place of 4-(benzyloxy)-2-methyl-3-(methylthio)pyridine. Steps 3, 4 and 5 were omitted. The product of Step 2 was further hydroxylated using the conditions described in Example 4 Step 2. A final oxidation step was introduced, as outlined below:

[0432] Oxidation: To a solution of 6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-3-(methylthio)pyridin-4(1H)-one (25 mg, 0.052 mmol) in DCM (1 mL) was added mCPBA (20 mg, 0.11 mmol) in one portion and the mixture was stirred at -20 °C for 4 h. The mixture was quenched by addition of a NaHCO3solution (2 mL) and extracted with DCM (3 x 5 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (12 g SiO2, 0 to 100 % EtOAc in heptane) gave the crude product. The residue was diluted with EtOAc (10 mL) and washed with a saturated aqueous NaHCO3solution (3 x 10 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The product was lyophilized to give 6-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methyl-3- (methylsulfonyl)pyridin-4(1H)-one (147, 6.7 mg, 25%).1H NMR (500 MHz, Methanol-d4) δ 7.04 (ddd, J = 7.9, 5.6, 2.0 Hz, 1H), 6.97 (td, J = 9.4, 7.4 Hz, 1H), 6.42 (s, 1H), 5.35 (d, J = 11.2 Hz, 1H), 4.19 (dd, J = 11.2, 8.2 Hz, 1H), 4.00 (d, J = 2.5 Hz, 3H), 3.25 (s, 3H), 2.86 (p, J = 7.7 Hz, 1H), 2.73 (s, 3H), 1.65 (d, J = 1.2 Hz, 3H), 0.86 (dd, J = 7.6, 2.3 Hz, 3H) ppm; NH pyridone not observed. ESI- MS m / z calc.495.114, found 496.4 (M+1)+; 494.4 (M-1)-; Retention time: 2.74 minutes using LC / MS method A. Example 10 3-Bromo-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridin-4(1H)-one (148) and 2-((2R,3S,4S,5R)-3-(3,4- difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-isopropyl-6- methylpyridin-4(1H)-one (149) O Br O

[0433] Step 1:

[0434] 2-((2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridin-4(1H)-one (2, 6 g, 14.4 mmol) was treated via the method described in General Method I to give 3,5-dibromo-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridin-4(1H)-one (7.69 g, 92%).1H NMR (400 MHz, Chloroform-d) δ 7.09 (s, 1H), 6.84 (dd, J = 9.2, 7.4 Hz, 1H), 5.81 (d, J = 10.0 Hz, 1H), 4.53 (t, J = 9.9 Hz, 1H), 3.88 (d, J = 2.4 Hz, 3H), 2.82 (p, 1H), 2.53 (s, 3H), 1.66 (s, 3H), 0.82 (dd, J = 7.7, 2.4 Hz, 3H) ppm; NH pyridone not observed. ESI-MS m / z calc.572.957, found 575.9 (M+1)+; Retention time: 2.53 minutes using LC / MS method Q.

[0435] Step 2:

[0436] A suspension of 3,5-dibromo-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridin-4(1H)-one (2.5 g, 4.35 mmol) in acetic acid (38 mL) was heated with a heat gun to 100 °C. Only partial dissolution occurred. Additional acetic acid (26 mL) was added and the mixture was heated to 106 °C with a heat gun. Upon cooling to 45 °C, some cloudiness was observed. Additional acetic acid (10 mL) was added and the mixture was reheated to dissolve the suspension. The solution was maintained at 35 °C to ensure precipitation did not occur. Under N2atmosphere, palladium (371 mg, 5 % w / w, 0.174 mmol) was added and the nitrogen atmosphere was replaced with hydrogen using a balloon. The mixture was stirred at 45 °C for 2.5 h. The reaction mixture cooled to ambient temperature. A minor amount of precipitation was observed. The mixture was re-heated to 40 °C and then filtered through a pad of Celite®. The filtrate was concentrated in vacuo. The residue was slowly added to a solution of NaOAc (1g, ~ 3eq) in ice water (30 mL) to give a cream suspension. The suspension was stirred at ambient temperature for 1 h, filtered, washed with water and air dried under suction over weekend to give 3- bromo-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridin-4(1H)-one (148, 2.10 g, 94%) as a light purple solid.1H NMR (400 MHz, Methanol-d4) δ 7.11 (s, 1H), 7.02 - 6.87 (m, 1H), 6.31 (s, 1H), 5.91 (d, J = 10.9 Hz, 1H), 4.45 (s, 1H), 3.90 (d, J = 2.4 Hz, 3H), 3.05 - 2.86 (m, 1H), 2.37 (s, 3H), 1.70 (s, 3H), 0.86 (ddd, J = 7.9, 2.1 Hz, 3H) ppm; NH pyridone not observed. ESI-MS m / z calc.496.266, found 498.0 (M+1)+; Retention time: 2.34 minutes using LC / MS method Q.

[0437] Step 3:

[0438] 3-Bromo-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridin-4(1H)-one (148, 3 g, 5.9 mmol) was treated via the method described in General Method K to give 4-(benzyloxy)-3-bromo-2-((2R,3S,4S,5R)-3- (3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6- methylpyridine (3.350 g, 96%).1H NMR (400 MHz, Methanol-d4) δ 7.50 - 7.42 (m, 2H), 7.42 - 7.28 (m, 3H), 6.94 - 6.81 (m, 3H), 6.05 (d, J = 10.8 Hz, 1H), 5.21 (dd, J = 2.7 Hz, 2H), 4.81 (dd, J = 10.9, 8.0 Hz, 1H), 3.95 (d, J = 1.9 Hz, 3H), 2.84 (p, J = 7.6 Hz, 1H), 2.42 (s, 3H), 1.63 (s, 3H), 0.90 - 0.81(m, 3H) ppm. ESI-MS m / z calc.585.093, found 587.6 (M+1)+; Retention time: 2.45 minutes using LC / MS method D.

[0439] Step 4:

[0440] 4-(Benzyloxy)-3-bromo-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridine (17 mg, 0.029 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (7.6 mg, 0.045 mmol) were treated via the method described in General Method G to give 4-(benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methyl-3-(prop-1-en-2- yl)pyridine (10.7 mg, 67%). ESI-MS m / z calc.547.215, found 548.5 (M+1)+; Retention time: 1.82 minutes using LC / MS method Q.

[0441] Step 5:

[0442] 4-(Benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-6-methyl-3-(prop-1-en-2-yl)pyridine (10.7 mg) was treated via the method described in General Method C. Purification by reverse phase HPLC (10 to 100 % MeCN in H2O containing 5 mM HCl over 20 min) gave 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)- 4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-isopropyl-6-methylpyridin-4(1H)-one (149, 4.1 mg, 46%).1H NMR (400 MHz, Methanol-d4) δ 7.26 - 7.17 (m, 1H), 7.13 - 7.02 (m, 1H), 6.92 (s, 1H), 5.77 (d, J = 10.5 Hz, 1H), 4.37 (t, J = 10.9 Hz, 1H), 3.86 (d, J = 2.5 Hz, 3H), 3.24 - 3.12 (m, 1H), 3.11 - 2.98 (m, 1H), 2.63 (s, 3H), 1.75 (s, 3H), 1.33 (d, J = 7.0 Hz, 3H), 0.98 (d, J = 6.9 Hz, 3H), 0.89 (dd, J = 7.8, 2.3 Hz, 3H) ppm; NH pyridone not observed. ESI-MS m / z calc.459.183, found 460.3 (M+1)+; Retention time: 2.11 minutes using LC / MS method Q.

[0443] The following compounds were made using methods described in Example 10 except that different boronate coupling partners were used in Step 4. For compound 155, Pd(OH)2was used in place of Pd / C in Step 5. For compound 154, tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazole-1-carboxylate was used as the boronate coupling partner in Step 4, and Step 5 was replaced with acidic deprotection conditions (20 eq TFA in toluene, 70 ºC, 2 h) to afford the final compound 154.Cmpd Compound LC / MS Found MS LC / No. Name (m / z calc.) M+1 retention MSNMR (shifts in ppm)timeMethod4 , , J , ), , 9 , , J J 1 11 4 66 3 6, 6 - -Cmpd Compound LC / MS Found MS No. Name (m / z calc.) M+1 retention LC / MSNMR (shifts in ppm)timeMethod, 8 = ), 7 - 7 00

[0444] The following compound was made using methods described in Example 10 except that Step 4 was replaced by a Buchwald coupling step using the conditions outlined below:

[0445] Buchwald coupling: Me2NH (700 µL, 2 M solution in THF, 1.4 mmol) and LiHMDS (700 µL, 1.0 M solution in THF, 0.7 mmol) were successively added to a suspension of 4- (benzyloxy)-3-bromo-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridine (85 mg, 0.14 mmol) in THF (1 mL) and the reaction mixture was degassed for 5 min.tBuBrettPhos Pd G3 (15 mg, 0.018 mmol) was added and the mixture was stirred at ambient temperature for 30 min. The reaction mixture was quenched by addition of a NH4Cl solution and extracted with EtOAc. The organic extracts were dried andconcentrated in vacuo. Purification by reverse phase preparative chromatography (C18column, 1 to 99% MeCN in water containing 5 M HCl modifier over 20 min) gave 4-(benzyloxy)-2- ((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- yl)-N,N,6-trimethylpyridin-3-amine (20 mg, 16%) as a clear glassy solid. ESI-MS m / z calc.550.225, found 551.1 (M+1)+; Retention time: 0.65 minutes using LC / MS method T. Cmpd Compound LC / MS Found MS No. Name (m / z calc.) M+1 retention LC / MSNMR (shifts in ppm)timeMethod, , , J J 3 62 4Step 4 was replaced by a Negishi coupling step using the conditions outlined below. In the case of 157, the Negishi coupling step was carried out using cyclopropylzinc bromide in place of cyclobutylzinc bromide:

[0447] Negishi coupling: A vial containing 4-(benzyloxy)-3-bromo-2-((2R,3S,4S,5R)-3-(3,4- difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridine (26.4 mg, 0.045 mmol) and Pd(tBu3P)2(2.6 mg, 0.005 mmol) was purged with nitrogen. Cyclobutylzinc bromide (1 mL, 0.5 M solution in THF, 0.5 mmol) was added and the mixture was sparged with nitrogen for 1 min. The mixture was stirred at ambient temperature for 4 h, then diluted with MeOH (500 μL), filtered, and purified by reverse phase preparative chromatography (C18column, 1 to 99% MeCN in 5 mM HCl) to provide 4-(benzyloxy)-3-cyclobutyl-2-((2R,3S,4S,5R)-3- (3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6- methylpyridine. ESI-MS m / z calc.561.230, found 562.6 (M+1)+; Retention time: 2.01 minutes using LC / MS method D.Cmpd Compound LC / MS Found MS LC / MS NMR (shifts in ppm) No. Name (m / z calc.) M+1 retention Method time 2 , , - , 6 54 1 7 , ,[ ] e o ow g co pou s we e a e us g e o s esc e a p e e cep a Step 4 was replaced by a Stille coupling step using the conditions outlined below. In Step 5, (Pd(OH)2was used in place of Pd / C. In the case of compound 161, 2-(tributylstannyl)oxazole was used as the Stille coupling partner in place of tributyl(2,3-dihydrofuran-5-yl)stannane and Step 5 was replaced by a benzyl deprotection step carried out at 70 °C, using an excess of TFA in toluene.

[0449] Stille coupling: A solution of tributyl(2,3-dihydrofuran-5-yl)stannane (20 mg, 0.056 mmol), Pd(PPh3)4(3.1 mg, 0.003 mmol) and 4-(benzyloxy)-3-bromo-2-((2R,3S,4S,5R)-3-(3,4- difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridine (30 mg, 0.051 mmol) in toluene (1 mL) was sparged with nitrogen for 3 min. The reaction was stirred at 100 °C for 30 min and then concentrated in vacuo. Purification by flash chromatography (SiO2, 0 to 30% EtOAc in hexanes) gave 4-(benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-(4,5-dihydrofuran-2-yl)-6-methylpyridine.Cmpd Compound LC / MS Found MS LC / MS NMR (shifts in ppm) No. Name (m / z calc.) M+1 retention Method time 5 , , J J 0 , 78 7 , - 22 1 24 , , 9 8 ,Example 11 2-((2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-yl)-3,5-diisopropyl-6-methylpyridin-4(1H)-one (162)

[0451] 2-((2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridin-4(1H)-one (2, 6 g, 14.4 mmol) was treated via the method described in General Method J to give 3,5-dibromo-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridin-4(1H)-one (7.69 g, 92%).1H NMR (400 MHz, Chloroform-d) δ 7.09 (s, 1H), 6.84 (dd, J = 9.2, 7.4 Hz, 1H), 5.81 (d, J = 10.0 Hz, 1H), 4.53 (t, J = 9.9 Hz, 1H), 3.88 (d, J = 2.4 Hz, 3H), 2.82 (p, 1H), 2.53 (s, 3H), 1.66 (s, 3H), 0.82 (dd, J = 7.7, 2.4 Hz, 3H) ppm; NH pyridone not observed. ESI-MS m / z calc.572.957, found 575.9 (M+1)+; Retention time: 2.53 minutes using LC / MS method Q.

[0452] Step 2:

[0453] 3,5-Dibromo-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridin-4(1H)-one (750 mg, 1.304 mmol) was treated via the method described in General Method J to give 4-(benzyloxy)-3,5-dibromo-2-((2R,3S,4S,5R)-3- (3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6- methylpyridine (658 mg, 76%).1H NMR (400 MHz, Methanol-d4) δ 7.59 - 7.49 (m, 2H), 7.45 - 7.30 (m, 3H), 6.95 - 6.83 (m, 2H), 6.00 (d, J = 10.8 Hz, 1H), 5.09 (s, 2H), 4.83 - 4.76 (m, 1H), 3.98 (d, J = 2.0 Hz, 3H), 2.85 (p, J = 7.6 Hz, 1H), 2.60 (s, 3H), 1.61 (s, 3H), 0.88 (dq, J = 7.2, 2.4 Hz, 3H) ppm.19F NMR (376 MHz, Methanol-d4) δ -75.76, -140.40 (d, J = 18.8 Hz), -156.73 (d, J = 18.8 Hz) ppm. ESI-MS m / z calc.663.004, found 666.0 (M+1)+; Retention time: 3.84 minutes using LC / MS Method Q.

[0454] Step 3:

[0455] SPhos (7 mg, 0.017 mmol) was added to a stirring mixture of 4-(benzyloxy)-3,5-dibromo- 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-yl)-6-methylpyridine (132 mg, 0.198 mmol) and K3PO4(127 mg, 0.598 mmol) in toluene (2.64 mL) and water (264 µL) and the reaction mixture was flushed with nitrogen for 20 min.4,4,5,5-Tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (47 µL) and Pd(dba)2(4 mg, 0.007 mmol) were successively added to the mixture. The reaction mixture was flushed with nitrogen for 5 min and heated at 100 °C for 17 h. Additional amounts of 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2- dioxaborolane (0.11 mL) were added and the heating was continued for a further 90 min. The mixture was diluted with water and EtOAc. The organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (12 g SiO2, 0 to 10% MTBE in hexanes) gave 4-(benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-6-methyl-3,5-di(prop-1-en-2-yl)pyridine (83 mg, 71%), which was used without further purification in the next step.

[0456] Step 4:

[0457] A mixture of 4-(benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methyl-3,5-di(prop-1-en-2-yl)pyridine (83 mg, 0.14 mmol) and Pd(OH)2(21 mg, 20% w / w, 50% wet, 0.015 mmol) in ethanol (1.5 mL) was stirred under hydrogen for 19 h. The mixture was filtered and additional amounts of Pd(OH)2(30 mg, 20% w / w, 50% wet, 0.021 mmol) were added. The reaction mixture was stirred under hydrogen for 24 h. The mixture was filtered and purified by reverse phase HPLC (MeCN in H2O containing 5 mM HCl) to give 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-3,5-diisopropyl-6-methylpyridin-4(1H)-one (Hydrochloride salt) (162, 38 mg, 50%).1H NMR (400 MHz, Methanol-d4) δ 7.25 - 7.14 (m, 1H), 7.12 - 6.99 (m, 1H), 5.70 (d, J = 10.5 Hz, 1H), 4.39 (t, J = 10.8 Hz, 1H), 3.85 (d, J = 2.4 Hz, 3H), 3.42 - 3.32 (m, 1H), 3.23 - 3.09 (m, 1H), 3.09 - 2.96 (m, 1H), 2.64 (s, 3H), 1.72 (s, 3H), 1.37 - 1.29 (m, 9H), 1.03 (d, J = 6.9 Hz, 3H), 0.93 - 0.83 (m, 3H) ppm; NH pyridone not observed. ESI-MS m / z calc.501.230, found 502.6 (M+1)+; Retention time: 2.52 minutes using LC / MS method Q.

[0458] The following compound was made using methods described in Example 11 except that, an additional debromination step was introduced after Step 2, using the conditions outlined below. Step 3 was omitted:

[0459] Debromination: A solution of 4-(benzyloxy)-3,5-dibromo-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridine (5 g, 7.516 mmol) in THF (50 mL) was placed under a nitrogen atmosphere and cooled in a dry ice / acetone bath. When the internal temperature reached -71 °C, PhMgBr (5 mL, 3 M solution in Et2O, 15 mmol) was added via syringe. After stirring the mixture for 20 min,sBuLi (8.1 mL, 1.4 M in cyclohexane, 11 mmol) was slowly added via syringe. After stirring the mixture at -60 °C for 1 h, the reaction mixture was quenched by addition of a mixture of acetic acid (21 mL, 370 mmol) and water (5.25 mL). The mixture was warmed to ambient temperature and concentrated in vacuo (10 mBar, 35 °C) to remove most of the THF. The residue was partitioned between EtOAc (200 mL) and water (50 mL). The organic layer was separated, washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated in vacuo (10mBar, 45 °C). Purification by flash chromatography gave 4-(benzyloxy)-3-bromo-6-((2R,3S,4S,5R)-3- (3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2- methylpyridine (3.20 g, 72%) as a colourless oil.1H NMR (400 MHz, Methanol-d4) δ 7.50 - 7.25 (m, 5H), 7.10 (ddd, J = 8.4, 5.6, 2.3 Hz, 1H), 7.05 (s, 1H), 6.86 (ddd, J = 10.0, 8.9, 7.6 Hz, 1H), 5.39 (d, J = 11.0 Hz, 1H), 5.31 (s, 2H), 4.17 - 4.09 (m, 1H), 3.85 (d, J = 2.2 Hz, 3H), 2.78 (p, J = 7.6 Hz, 1H), 2.54 (s, 3H), 1.63 (d, J = 1.3 Hz, 3H), 0.83 (ddd, J = 7.5, 2.3 Hz, 3H) ppm. ESI-MS m / z calc.585.094, found 587.9 (M+1)+; Retention time: 2.66 minutes using LC / MS Method Q. Cmpd Compound LC / MS Found MS Name (m / z calc.) M+1 retenti LC / MS No. onNMR (shifts in ppm)tiMethod2 , ), ,2-((2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-yl)-N,6-dimethyl-4-oxo-1,4-dihydropyridine-3-carboxamide (164)

[0460] Step 1:

[0461] A suspension of 3-bromo-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridin-4(1H)-one (148, 500.2 mg, 0.988 mmol), Et3N (0.44 mL, 3.2 mmol), and Pd(dppf)Cl2·CH2Cl2(81 mg, 0.099 mmol) in MeOH (9.8 mL) was stirred under a carbon monoxide atmosphere at 18 bar in a steel bomb, in a 70 °C oil bath. Additional Pd(dppf)Cl2·CH2Cl2(41 mg, 0.05 mmol) was added and the mixture was sparged with CO for 15 min at ambient temperature, then stirred under a carbon monoxide atmosphere (balloon) at 65°C over the weekend. The reaction mixture was filtered through a disposable filter, washing through with MeOH. The filtrate was concentrated in vacuo. The residue was dissolved in DCM, washed with 1 M citric acid (20 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (40 g SiO2, 0 to 8% MeOH in DCM) gave methyl 2-((2R,3S,4S,5R)-3-(3,4-difluoro- 2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methyl-4-oxo-1,4- dihydropyridine-3-carboxylate (474 mg, 89%). ESI-MS m / z calc.475.142, found 476.3 (M+1)+; Retention time: 2.16 minutes using LC / MS Method Q.

[0462] Step 2:

[0463] Methyl 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (750 mg, 1.58 mmol) was treated via the method described in General Method K to give methyl 4-(benzyloxy)- 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-yl)-6-methylnicotinate (460 mg, 51%) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 7.41 - 7.27 (m, 5H), 7.11 - 7.00 (m, 1H), 6.95 (s, 1H), 6.94 - 6.86 (m, 1H), 5.57 - 5.41 (m, 1H), 5.17 (s, 2H), 4.66 (dd, J = 10.7, 8.5 Hz, 1H), 3.91 (d, J = 1.9 Hz, 3H), 3.87 (s, 3H), 2.79 (p, J = 7.8 Hz, 1H), 2.40 (s, 3H), 1.57 (s, 3H), 0.90 - 0.73 (m, 3H) ppm. ESI-MS m / z calc.565.189, found 566.3 (M+1)+; Retention time: 2.14 minutes using LC / MS Method D.

[0464] Step 3:

[0465] A mixture of methyl 4-(benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)- 4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methylnicotinate (450 mg, 0.796 mmol) and NaOH (160 mg, 4 mmol) in a mixture of MeOH (1.4 mL), water (1.4 mL) and THF (1.4 mL) was heated at 90 °C for 3 h. The reaction mixture was diluted with MeOH (500 μL), filtered, and purified by reverse phase preparative chromatography (C18column, 1 to 99% MeCN in water containing 5 mM HCl) to give 4-(benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-6-methylnicotinic acid (411 mg, 92%) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 7.46 - 7.39 (m, 2H), 7.39 - 7.24 (m, 3H), 7.21 - 7.06 (m, 1H), 6.98 (s, 1H), 6.95 - 6.81 (m, 1H), 5.57 (d, J = 10.8 Hz, 1H), 5.20 (s, 2H), 4.71 (dd, J = 10.9, 8.6 Hz, 1H), 3.89 (d, J = 1.9 Hz, 3H), 2.98 - 2.77 (m, 1H), 2.44 (s, 3H), 2.03 (s, 1H), 1.63 (s, 3H), 0.87 - 0.73 (m, 3H) ppm. ESI-MS m / z calc.551.173, found 552.3 (M+1)+; Retention time: 1.14 minutes using LC / MS Method D.

[0466] Step 4:

[0467] Methanamine (186 µL, 33 wt % solution in ethanol, 4.53 mmol) was added to a solution of 4-(benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-6-methylnicotinic acid (275 mg, 0.499 mmol), HATU (190 mg, 0.500 mmol) and DIPEA (261 µL, 1.50 mmol) in DMF (2.7 mL), under nitrogen and the reaction mixture was stirred at ambient temperature for 1 h. Purification by reverse phase preparative chromatography (C18column, 1 to 99% MeCN in water containing 5 mM HCl) gave 4-(benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- yl)-N,6-dimethylnicotinamide (210 mg, 73%).

[0468] Step 5:

[0469] 4-(Benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl)-N,6-dimethylnicotinamide (210 mg) was treated via the method described in General Method C to give 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)- 4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-N,6-dimethyl-4-oxo-1,4-dihydropyridine-3- carboxamide (164, 138 mg, 57%) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 7.16 - 6.91 (m, 2H), 6.72 (s, 1H), 5.80 (d, J = 10.9 Hz, 1H), 4.47 (t, J = 10.5 Hz, 1H), 3.92 (d, J = 2.4 Hz, 3H), 3.01 - 2.85 (m, 1H), 2.82 (s, 3H), 2.54 (s, 3H), 1.68 (s, 3H), 0.88 - 0.69 (m, 3H) ppm; NH pyridone and amide not observed. ESI-MS m / z calc.474.158, found 475.1 (M+1)+; Retention time: 1.38 minutes using LC / MS method D.

[0470] The following compounds were made using methods described in Example 12 except that, in Step 4, different amines were used as the amide coupling partner: Cmpd Compound LC / MS Found MS LC / MS NMR (shifts in ppm) No. Name (m / z calc.) M+1 retention Method 7 , 7Cmpd Compound LC / MS Found MS LC / MS NMR (shifts in ppm) No. Name (m / z calc.) M+1 retention Method time , ),final chlorination step was carried out as outlined below:

[0472] Chlorination: NCS (5.2 mg, 0.039 mmol) was added in a single portion to a solution of 2- ((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- yl)-N,6-dimethyl-4-oxo-1,4-dihydropyridine-3-carboxamide (15.4 mg, 0.032 mmol) in a mixture of DCM (0.5 mL) and AcOH (10 µL, 0.18 mmol). The reaction mixture was stirred at ambient temperature for 2 h. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc, washed with a 10% Na2S2O3solution and a saturated NaHCO3solution. The organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification by reverse phase HPLC (30 to 99% MeCN in water containing 5 mM HCl) gave 5-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-N,6-dimethyl-4-oxo-1,4- dihydropyridine-3-carboxamide (168, 9.9 mg, 60%) as a white solid.1H NMR (400 MHz, Methanol- d4) δ 7.05 (ddd, J = 8.0, 5.7, 2.0 Hz, 1H), 6.96 (td, J = 9.4, 7.4 Hz, 1H), 5.79 (d, J = 10.9 Hz, 1H), 4.44 (t, J = 10.4 Hz, 1H), 3.92 (s, 3H), 2.93 (dd, J = 9.8, 7.6 Hz, 1H), 2.82 (s, 3H), 2.60 (s, 3H), 1.67 (s, 3H), 0.79 (dq, J = 7.8, 2.2 Hz, 3H) ppm; NH pyridone and amide not observed. ESI-MS m / z calc. 508.119, found 509.1 (M+1)+; Retention time: 2.14 minutes using LC / MS method Q.

[0473] The following compound was made using methods described in Example 12 except that the product of Step 2 was made using the method described in Example 1 Step 1 by combining (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxylic acid (Int-1) and ethyl 4-(benzyloxy)-6-chloro-5-fluoronicotinate: Cmpd Compound LC / MS Found MS ( / z r t nti n LC / MSNMR hift i, 7 1Cmpd Compound LC / MS MS (m / z Found retent LC / MS No. Name ionNMR (shifts in ppm)calc.) M+1 timeMethod), m,2-((2R,3S,4S,5R)-3-(3,4-Difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-yl)-6-methylpyridin-4(1H)-one (170)

[0474] Ste

[0475] 2-((2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxyphenyl)-...

Claims

CLAIMS What is claimed is:

1. A compound of formula (I-A): ;X1is C-R1or N; X2is C-R2or N; Xsis C-Rsor N; Xtis C-Rtor N; R1is 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; R2and R3are defined as follows: (i) R2is H, OH, halo, CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, – (CH2)mRa, –C(O)ORb, –C(O)Rb, –C(O)NRbRc, –NRbRc, –CRdReRf, –CRbRcNRgC(O)CRhRiRj, –O(CH2)mRa, –CRbRcORg, –CRbRc(CH2)mO(CH2)oC(O)ORg, –CRbRc(CH2)mO(CH2)oCRgRhRa, –CRbRc(CH2)mO(CH2)oC(O)NRgRh, –CRbRc(CH2)mO(CH2)oRd, –CRbRcC(Rd)(Re)(Rf),–CRbRcNRgRh, –CH2C(O)NRbRc, –C(O)On(CH2)mRa, –NRb(CH2)mORc, –NRb(CH2)mRn, – (CH2)mNRbC(O)Rn, –NRbCRcRgRh, –(CH2)mNRbC(O)Rc, –SRb, –S(=O)2Rl, –N=S(=O)(Rl)(Rm), – S(=O)(=NRb)(Rl), 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 OH, CN, halo, oxo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy,–CH2OH –C(O)ORb, –NRbRc, and –C(O)NRbRc; and R3is H, OH, halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, –(CH2)mOCH3, or –(CH2)mRa; (ii) R2and R3, together with the carbon atoms to which they are attached, form a ring of formula:; (iii) R2and R3, together with the carbon atoms to ey are attached, form a ring of formula:; (iv) R2and R3, together with the carbon atoms t ey are attached, form a ring offormula: ; (v) R2and R3, together with the carbon atoms to ey are attached, form a ring offormula: ; Y is O or NRo; 45R and R are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R6and R7are each independently H, OH, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6 alkoxy, or R6and R7, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl; R8is H or CH3; Rsand Rtare each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1- C6haloalkoxy, –NRbRc, –NO2, –SO3H, –(CH2)mRa, or –O(CH2)mOCH3, or Rsand Rt, together with the atoms to which they are attached, form a ring of formula: ; Z is O or CH2;Ru, Rv, and Rware each independently H, OH, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, –NRbRc, –NO2, –SO3H, –(CH2)mRa, or –O(CH2)mOCH3; each Rxis independently H, halo, C1-C6alkyl, or C1-C6haloalkyl;Rais OH, halo, C1-C6alkoxy, or –NRbRc; Rb, Rc, Rg, Rh, Ri, and Rkare 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+; Rland Rmare each independently C1-C6alkyl; Rnis C3-C6cycloalkyl or 4-6 membered heterocyclyl wherein said C3-C6cycloalkyl or 4-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents selected from C1-C6alkyl and halo; Rois H, C1-C6alkyl, or –C(O)O(C1-C6alkyl); Rpis H, C1-C6 alkyl, –C(O)NRbRc, or oxo; Rqis H or C1-C6alkyl; m and o are each independently 0, 1, 2, or 3; n is 0 or 1; and p is 0 or 1.

2. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein p is 0.

3. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein p is 1.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound has a formula (I-A-1):.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X1is N.

6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X1is C-R1and R1is H, halo, CN, C1-C6alkyl, 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, , –(CH2)mNRbC(O)Rn, C3-C6cycloalkyl, 5-6 memberedheteroaryl, 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, optionally wherein R1is H, Br, Cl, F, CN, –CH3, –CH2OH, –OCH3, –OCHF2, –CH(CH3)2, –CH2OCH3, –N(CH3)2, –C(O)OH, –C(O)CH3, –C(O)OCH3, –C(O)CH2CH2CH2OH, –C(O)N(CH3)2, , ,. p y , p y p , wherein X2is C-R2and R2is H, halo, CN, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, –CRdReRf, –CRbRcORg, –(CH2)mRa, –C(O)Rb, –NRbRc, –O(CH2)mRa, –C(O)NRbRc, –C(O)ORb, –C(O)On(CH2)mRa, –CH2C(O)NRbRc, –CRbRcNRgRh, –NRb(CH2)mORc, –NRbCRcRgRh, –(CH2)mNRbC(O)Rc, – (CH2)mNRbC(O)Rn, –CRbRc(CH2)mO(CH2)oCRgRhRa, –CRbRc(CH2)mO(CH2)oC(O)NRgRh, –CRbRc(CH2)mO(CH2)oC(O)ORg, –CRbRc(CH2)mO(CH2)oRd, –CRbRcC(Rd)(Re)(Rf), –CRbRcNRgC(O)CRhRiRj, –N=S(=O)(Rl)(Rm), –SRb, –S(=O)(=NRb)(Rl) , –S(=O)2Rl, 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 OH, CN, halo, oxo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy,– CH2OH, –C(O)NRbRc.

8. The compound of any of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R3is H, C1-C6alkyl, or –(CH2)mOCH3.

9. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein X2is CR2, and R2and R3, together with the carbon atoms to which they are attached, form a ring of formula: .

10. The compoundceutically acceptable salt thereof, wherein R4is H and R8is H.

11. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R5is H, C1-C6alkyl, or C1-C6alkoxy.

12. The compound of any one of claim 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R6and R7are each independently H, C1-C6alkyl, C1-C6haloalkyl, or C3-C6cycloalkyl, or R6and R7, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl.

13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein Xsis C-Rs, and Rsis C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, or –O(CH2)mOCH3.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein Xtis C-Rt, and Rtis H, halo, or C1-C6haloalkyl.

15. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein Xsis C-Rs, Xtis C-Rt, and Rsand Rt, together with the carbon atoms to which they are attached, form a ring of formula: .

16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein Ruis H, halo, C1-C6alkoxy, or C1-C6haloalkoxy.

17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Rvis H or –NRbRc.

18. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound has a formula (I-A-2): .

19. The compound of any one of claims 1 tnd 18, or a pharmaceutically acceptable salt thereof, wherein R1is H or 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-4 substituents independently selected from halo and C1-C6alkyl.

20. The compound of any one of claims 1 to 3, 18, and 19, or a pharmaceutically acceptable salt thereof, wherein R2is H, –CRbRcNRgRh, –S(=O)(=NRb)(Rl) , or 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-4 substituents independently selected from OH, CN, halo, oxo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, –CH2OH, and –C(O)NRbRc.

21. The compound of any one of claims 1 to 3 and 18 to 20, or a pharmaceutically acceptable salt thereof, wherein R5is H, C1-C6alkyl, or C1-C6alkoxy.

22. The compound of any one of claims 1 to 3 and 18 to 21, or a pharmaceutically acceptable salt thereof, wherein Rsis C1-C6alkyl or C1-C6alkoxy.

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

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

25. The compound of any one of claims 1 to 24 in non-salt form.

26. A pharmaceutical composition comprising the compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or the compound of claim 25, and one or more pharmaceutically acceptable carriers or vehicles.

27. 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 24, or a pharmaceutically acceptable salt thereof, the compound of claim 25, or the pharmaceutical composition of claim 26, optionally wherein the voltage-gated sodium channel is NaV1.

8.

28. 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 24, or a pharmaceutically acceptable salt thereof, the compound of claim 25, or the pharmaceutical composition of claim 26, optionally wherein: (i) the method comprises treating or lessening the severity in the subject of neuropathic pain, optionally wherein the neuropathic pain comprises post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, or diabetic peripheral neuropathy; or (ii) the method comprises treating or lessening the severity in the subject of musculoskeletal pain, optionally wherein the musculoskeletal pain comprises osteoarthritis pain; or (iii) 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 (iv) the method comprises treating or lessening the severity in the subject of postsurgical pain, optionally wherein the postsurgical pain comprises bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain; or (v) the method comprises treating or lessening the severity in the subject of visceral pain.

29. The method of claim 27 or 28, 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.

30. Use of the compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, the compound of claim 25, or the pharmaceutical composition of claim 26, as a medicament.

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