Heteroaryl compounds for pain treatment

Abstract

Compounds useful as inhibitors of sodium channels and pharmaceutically acceptable salts thereof are provided. Pharmaceutical compositions comprising the compound or a pharmaceutically acceptable salt thereof, as well as methods of using the compound, the pharmaceutically acceptable salt, and the pharmaceutical composition in the treatment of various disorders, including pain, are also provided. In another embodiment, the present invention relates to a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or vehicles.

Description

[Technical Field]

[0001] Cross-references to related applications This application claims the interests of U.S. Provisional Application No. 63 / 592,362 filed on 23 October 2023, U.S. Provisional Application No. 63 / 592,698 filed on 24 October 2023, and U.S. Provisional Application No. 63 / 644,192 filed on 8 May 2024, each of which is incorporated herein by reference in whole. [Background technology]

[0002] Pain is a protective mechanism that avoids tissue damage and prevents further damage to injured tissue. Nevertheless, there are many conditions in which pain persists beyond its usefulness, or in which the patient would benefit from pain suppression. Acute and chronic pain are two common pain conditions that can be distinguished by the duration of the pain. Acute pain can result from many reasons (e.g., hospital procedures), and treatment options are generally limited by insufficient efficacy and / or adverse events. Similar to acute pain, chronic pain can result from many reasons, and treatment options are limited by insufficient efficacy and / or adverse events.

[0003] Neuropathic pain is a form of chronic pain caused by damage to sensory nerves (Dieleman, JP, 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 systemic metabolic damage to nerves, and pain caused by discrete nerve damage. Metabolic neuropathy includes post-herpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Indications for discrete nerve damage include post-amputation pain, postoperative nerve injury pain, and nerve compression injuries such as neuropathic back pain.

[0004] Voltage-gated sodium channels (Na V ) is involved in pain signaling. V Sodium channels are biological mediators of electrical signaling, as they mediate the rapid increase in action potentials in many excitable cell types, such as neurons, skeletal muscle cells, and cardiomyocytes (Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). Evidence for the role of these channels in normal physiological function, pathological conditions arising from mutations in sodium channel genes, preclinical studies in animal models, and the clinical pharmacology of known sodium channel modulators all support the role of Na in pain sensation. V This suggests a central role (Rush, A.M. and TRCummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Na). V 1.8 Sodium Channels. Mol. Interv., 2007. 7(4): p.192-5), England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin. Investig. Drugs 17(12), p.1849-64 (2008), Krafte, DS and Bannon, AW, Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8(1), p.50-56 (2008). Na in the initiation and propagation of neuronal signals. V Due to the role that Na plays, V Antagonists that reduce current can prevent or reduce nerve signaling, Na VChannels have long been considered highly likely to reduce pain under conditions where high 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 are Na V have been identified as channel inhibitors. Local anesthetics such as lidocaine block pain by inhibiting Na V channels to block pain, and other compounds such as carbamazepine, lamotrigine, and tricyclic antidepressants, which have been proven effective in reducing pain, have also been suggested to act via 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] Na V form a subfamily of the voltage-gated ion channel superfamily, and include Na V 1.1 to Na V have 9 isoforms designated 1.9. The tissue localization of the 9 isoforms differs. Na V 1.4 is the primary sodium channel in skeletal muscle, and Na V 1.5 is the primary sodium channel in cardiomyocytes. Na V 1.7, 1.8, and 1.9 are mainly localized in the peripheral nervous system, and Na V1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the central and peripheral nervous systems. While the functional behavior of the nine isoforms is similar, they are distinct in the details of their voltage-gated and dynamic behavior (Catterall, WA, Goldin, AL, and Waxman, SG, International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57(4), p. 397 (2005)).

[0006] When they were discovered, Na V Channel 1.8 was identified as a likely target for analgesia (Akopian, AN, L. Sivilotti, and J.N. Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562): p.257-62). Subsequently, Na V 1.8 has been shown to be the carrier of sodium current that maintains action potential firing in small dorsal root ganglion (DRG) neurons in nociceptive sensory neurons (Blair, NT and BPBean, Roles of tetrodotoxin (TTX)-sensitive Na + current, TTX-resistant Na + current, and Ca 2+ current in the action potentials of nociceptive sensory neurons.J.Neurosci.,2002.22(23):p.10277-90). Na V1.8 is involved in spontaneous firing in damaged neurons, such as those that cause neuropathic pain (Roza, C., et al., The tetrodotoxin-resistant Na + channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice.J.Physiol.,2003.550(Pt 3):p.921-6, Jarvis,MF,et al.,A-803467,a potent and selective Na V 1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat.Proc.Natl.Acad.Sci.USA,2007.104(20):p.8520-5, Joshi,SK,et al.,Involvement of the TTX-resistant sodium channel Na V 1.8 in inflammatory and neuropathic,but not post-operative,pain states.Pain,2006.123(1-2):pp.75-82, Lai, J., et al.,Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel,Na V 1.8.Pain,2002.95(1-2):p.143-52, Dong,XW,et al.,Small interfering RNA-mediated selective knockdown of Na V1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. Neuroscience, 2007, 146(2): p.812-21, Huang, H.L., et al., Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves. Mol. Pain, 2008, 4: p.33, Black, J.A., et al., Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann. Neurol., 2008, 64(6): p.644-53, Coward, K., et al., Immunolocalization of SNS / PN3 and NaN / SNS2 sodium channels in human pain states. Pain, 2000, 85(1-2): p.41-50, Yiangou, Y., et al., SNS / PN3 and SNS2 / NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. FEBS Lett., 2000, 467(2-3): p.249-52, Ruangsri, S., et al., Relationship of axonal voltage-gated sodium channel 1.8 (Na V 1.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats. J. Biol. Chem. 286(46): p.39836-47). Na V The small DRG neurons that express 1.8 are Na V1.8 includes nociceptors involved in pain signaling that mediates large-amplitude action potentials (Blair, NT and BPBean, Roles of tetrodotoxin (TTX)-sensitive Na + current, TTX-resistant Na + current, and Ca 2+ current in the action potentials of nociceptive sensory neurons.J.Neurosci.,2002.22(23):p.10277-90). Na V 1.8 is necessary for rapid, repetitive action potentials in nociceptors and for spontaneous activity in damaged neurons. (Choi, JS and SG Waxman, Physiological interactions between Na V 1.7 and Na V 1.8 sodium channels: a computer simulation study.J.Neurophysiol.106(6):p.3173-84, Renganathan, M., TRCummins, and SGWaxman, Contribution of Na( V )1.8 sodium channels to action potential electrogenesis in DRG neurons.J.Neurophysiol.,2001.86(2):p.629-40, Roza,C.,et al.,The tetrodotoxin-resistant Na + channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550 (Pt 3): p. 921-6). In depolarized or damaged DRG neurons, Na V1.8 appears to be a driving factor for hyperexcitability (Rush, AM, et al., A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc. Natl. Acad. Sci. USA, 2006. 103(21): p. 8245-50). In some animal pain models, Na V 1.8 mRNA expression levels indicate an increase in DRG (Sun, W., et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats. Brain, 135 (Pt 2): p.359-75; Strickland, IT, et al., Changes in the expression of Na V 1.7,Na V 1.8 and Na V 1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain.Eur.J.Pain,2008.12(5):p.564-72, Qiu,F.,et al.,Increased expression of tetrodotoxin-resistant sodium channels Na V 1.8 and Na V 1.9 within dorsal root ganglia in a rat model of bone cancer pain.Neurosci.Lett.,512(2):p.61-6). The inventors of this invention believe that some voltage-gated sodium channel inhibitors may have an insufficient therapeutic window (e.g., Na VIt was discovered that it has limitations as a therapeutic agent due to a lack of isoform selectivity, low potency, and / or other reasons. Therefore, selective Na V The need to develop selective voltage-gated sodium channel inhibitors, such as 1.8 inhibitors, remains. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Dieleman,JP,et al.,Incidence rates and treatment of neuropathic pain conditions in the general population.Pain,2008.137(3):p.681-8 [Non-Patent Document 2] Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001) [Non-Patent Document 3] Rush, AMand TRCummins, Painful Research:Identification of a Small-Molecule Inhibitor that Selectively Targets NaV1.8 Sodium Channels.Mol.Interv.,2007.7(4):p.192-5) [Non-Patent Document 4] England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics.Expert Opin.Investig.Drugs 17(12), p.1849-64(2008) [Non-Patent Document 5] Krafte, DSand Bannon, AW, Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8(1), p. 50-56 (2008) [Non-Patent Document 6] Chahine, M., Chatelier, A., Babich, O., and Krupp, JJ, Voltage-gated sodium channels in neurological disorders.CNS Neurol.Disord.Drug Targets 7(2), p.144-58(2008) [Non-Patent Document 7] Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action.Eur.J.Pain 6 Suppl.A, p.3-9(2002) [Non-Patent Document 8] Wang, GK, Mitchell, J., and Wang, SY, Block of persistent late Na+ currents by antidepressant sertraline and paroxetine.J.Membr.Biol.222(2),p.79-90(2008) [Non-Patent Document 9] Catterall, WA, Goldin, AL, and Waxman, SG, International Union of Pharmacology.XLVII.Nomenclature and structure-function relationships of voltage-gated sodium channels.Pharmacol.Rev.57(4), p.397(2005) [Non-Patent Document 10] Akopian, 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 Non-Patent Document 11 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 Non-Patent Document 12 Roza, C., et al., The tetrodotoxin-resistant Na+ channel NaV1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550(Pt 3): p. 921-6 Non-Patent Document 13 Jarvis, M.F., et al., A-803467, a potent and selective NaV1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc. Natl. Acad. Sci. U S A, 2007. 104(20): p. 8520-5 Non-Patent Document 14 Joshi, S.K., et al., Involvement of the TTX-resistant sodium channel NaV1.8 in inflammatory and neuropathic, but not post-operative, pain states. Pain, 2006. 123(1-2): pp. 75-82 Non-Patent Document 15 Lai, J., et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8. Pain, 2002. 95(1-2): p. 143-52 Non-Patent Document 16 Dong, X.W., et al., Small interfering RNA-mediated selective knockdown of NaV1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. Neuroscience, 2007. 146(2): p. 812-21 Non-Patent Document 17 Huang, H.L., et al., Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves. Mol. Pain, 2008. 4: p. 33 Non-Patent Document 18 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 Non-Patent Document 19 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 Non-Patent Document 20 Yiangou, Y., et al., SNS / PN3 and SNS2 / NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. FEBS Lett., 2000. 467(2-3): p.249-52 Non-Patent Document 21 Ruangsri, S., et al., Relationship of axonal voltage-gated sodium channel 1.8 (NaV1.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats. J. Biol. Chem. 286(46): p.39836-47 Non-Patent Document 22 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 Non-Patent Document 23 Choi, J.S. and S.G. Waxman, Physiological interactions between NaV1.7 and NaV1.8 sodium channels: a computer simulation study. J. Neurophysiol. 106(6): p.3173-84 Non-Patent Document 24 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 Non-Patent Document 25 Roza, C., et al., The tetrodotoxin-resistant Na+ channel NaV1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003, 550(Pt 3): p. 921-6 Non-Patent Document 26 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 Non-Patent Document 27 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 Non-Patent Document 28 Strickland, IT, et al., Changes in the expression of NaV1.7,NaV1.8 and NaV1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain.Eur.J.Pain,2008.12(5):p.564-72 [Non-Patent Document 29] Qiu, F., et al., Increased expression of tetrodotoxin-resistant sodium channels NaV1.8 and NaV1.9 within dorsal root ganglia in a rat model of bone cancer pain.Neurosci.Lett.,512(2):p.61-6 [Overview of the project]

[0008] In one embodiment, the present invention relates to compounds described herein, or pharmaceutically acceptable salts thereof.

[0009] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

[0010] In yet another aspect, the present invention relates to a method for inhibiting voltage-gated sodium channels in a subject by administering a compound, a pharmaceutically acceptable salt, or a pharmaceutical composition to the subject.

[0011] In yet another aspect, the present invention relates to a method for treating or reducing the severity of various diseases, disorders, or conditions, including but not limited to chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., pain from aponeurosis resection, hernia repair, or abdominal wall reconstruction), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmias, by administering a compound, a pharmaceutically acceptable salt, or a pharmaceutical composition to a subject. [Modes for carrying out the invention]

[0012] In one embodiment, the present invention relates to a compound of formula (IA), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 1 However, CR 1 or N, X 2 However, CR 2 , N, or N + -O - And, X 3 However, CR 3 , N, or N + -O - And, X 5 However, CR 5 , N, or N + -O - And, p, X a , and X b The following applies: (i) p is 1, X a CR 11 R 12 X b Is it O? (ii) p is 1, X a O is X b CR 13 R 14 is, or (iii)p is 0, and X b is defined as O, X s is C-R s or N, X t is C-R t or N, R 1 is H, OH, halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -(CH2) m O n (CH2) o OCH3, -(CH2) m R a , -C(O)(CH2) m R a , -C(O)OR b , -C(O)R b , -C(O)NR b R c , -NR b R c , -CR d R e R f , -CR b R c NR g C(O)CR h R i R j , -NR b C(O)CR c R g R j , C3-C6 cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 10-membered heterocyclyl, wherein the C3-C6 cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 10-membered heterocyclyl may be unsubstituted, or may be substituted with 1 to 4 substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, R 2 , R 3 , R 4 , and R 5 are each independently H, OH, CN, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -NHS(O)2(C1-C6 alkyl), -C(O)ORb -C(O)NR b R c ,-(CH2) m O(CH2) o CH3, 5-6 membered heteroaryl, or 5-6 membered heterocycline, and even if the 5-6 membered heteroaryl or 5-6 membered heterocycline is not substituted, C1-C6 alkyl and -C(O)NR b R c It may also be substituted with 1 to 4 substituents selected independently of it. R 6 , R 7 , R 8 , and R 9 However, as follows, (i)R 6 and R 7 However, each is independently H, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. R 8 and R 9 However, each is independently H, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy, or (ii)R 6 and R 7 However, each is independently H, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. R 8 and R 9 They, together with the carbon atoms to which they are bonded, form a C3-C6 cycloalkyl group, or (iii)R 6 , R 7 , R 8 , and R 9 Together with the carbon atoms to which they are bonded, they form 1 to 3 R y The condensed C6-C was substituted as needed. 10 It is defined as forming an aryl, R 10 However, it is either H or CH3. R 11 and R 12However, each is independently H, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. R 13 and R 14 However, each is independently H, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. R s and R t However, each is independent of H, OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl, -NR b R c -NO2, -SO3H, -(CH2) m Ure b , or -O(CH2) m Is it OCH3, or R s and R t Together with the carbon atoms to which they are bonded, the formula [ka] Forming a ring, Y is either O or CH2. R u , R v , and R w However, each is independent of H, OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -NR b R c -NO2, -SO3H, -(CH2) m Ure b , or -O(CH2) m It is OCH3, Each R x However, independently, they are H, halo, C1-C6 alkyl, or C1-C6 haloalkyl. Each R y However, independently, these are H, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. R aHowever, OH, halo, C1-C6 alkoxy, or -NR b R c And, R b , R c , R g , R h , and R i However, each is independently either H or C1-C6 alkyl, or R b and R c These, together with the nitrogen atom to which they are bonded, form a 3-6 membered heterocycline. R d , R e , and R f However, each is independently H, OH, halo, C1-C6 alkyl, or C1-C6 alkoxy. R j However, H, C1-C6 alkyl, -NR b R c , or -N(CH3)3 + And, m and o are independently 0, 1, 2, or 3. This relates to compounds, or pharmaceutically acceptable salts thereof, where n is 0 or 1.

[0013] For the purposes of this invention, chemical elements are identified according to the 75th edition of the Handbook of Chemistry and Physics, CAS edition, and the Periodic Table of Elements. Furthermore, the general principles of organic chemistry are based on "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5 th This is described in Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, and its entire contents are incorporated herein by reference.

[0014] As used herein, the term “compounds of the present invention” means the compounds of formula (IA) described herein, and all of its embodiments (e.g., formulas (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), (IC-2), (ID-1), (ID-2), etc.), as well as the compounds specified in Tables A, B, C, D, and E.

[0015] As described herein, the compounds of the present invention have a plurality of variable groups (for example, X 1 , R 1 , R 6 , R u This includes, for example. As those skilled in the art will recognize, the combinations of groups envisioned by the present invention are combinations that result in the formation of stable or chemically viable compounds. In this context, the term “stable” means a compound that remains substantially unchanged when subjected to conditions that enable their generation, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable or chemically viable compound is a compound that remains substantially unchanged when held at a temperature of 40°C or less for at least one week in the absence of moisture or other chemically reactive conditions.

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

[0017] As used herein, the term "alkyl" refers to a linear or branched hydrocarbon radical group consisting only of carbon and hydrogen atoms, containing no unsaturation, and having a specified number of carbon atoms, which is bonded to the rest of the molecule by a single bond. For example, a "C1-C6 alkyl" group is an alkyl group having 1 to 6 carbon atoms.

[0018] As used herein, the term “cycloalkyl” refers to a stable, non-aromatic monocyclic or bicyclic (condensed, cross-linked, or spiro) saturated hydrocarbon radical consisting only of carbon and hydrogen atoms, having a specified number of carbon ring atoms, which are bonded to the rest of the molecule by single bonds. For example, a “C3-C8 cycloalkyl” group is a cycloalkyl group having 3 to 8 carbon atoms.

[0019] As used herein, the term "alkoxy" refers to the formula -OR a It refers to the radical of, in the formula, R a This is an alkyl group having a specified number of carbon atoms. For example, a "C1-C6 alkoxy" group is defined by the formula -OR a It is a radical of, and in the formula, R a It is an alkyl group having 1 to 6 carbon atoms.

[0020] As used herein, the term “haloalkyl” refers to an alkyl group having a specified number of carbon atoms, in which one or more of the hydrogen atoms of the alkyl group are replaced by a halo group. For example, a “C1-C6 haloalkyl” group is an alkyl group having 1 to 6 carbon atoms, in which one or more of the hydrogen atoms of the alkyl group are replaced by a halo group.

[0021] As used herein, the term "haloalkoxy" refers to an alkoxy group having a specified number of carbon atoms, wherein one or more hydrogen atoms of the alkyl group are replaced by a halo group.

[0022] As used herein, the term “heterocyclyl” refers to a stable, non-aromatic monocyclic, bicyclic, or tricyclic (condensed, bridging, or spiro) radical having one or more ring atoms that are heteroatoms (e.g., heteroatoms independently selected from N, O, P, and S), a specified number of ring atoms, and bonded to the rest of the molecule by single bonds. The heterocyclic rings may be saturated or may contain one or more double or triple bonds. In some embodiments, a “heterocyclyl” group has a specified number of ring members, with one or more ring members being heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, and silicon, and each ring in the system contains 3 to 7 ring members. For example, a 6-membered heterocyclyl contains 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).

[0023] As used herein, the term “heteroaryl” refers to a stable monocyclic, bicyclic, or tricyclic ring radical having a specified number of ring atoms, wherein at least one ring in the system is aromatic, and 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 contains 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 terms “heteroaryl ring” or “heteroaromatic.”

[0024] When used herein, labels such as "*s" and "*t" as shown in the following structures refer to the corresponding R groups (in this case, R, respectively). s Base and R t Specify the carbon atom to which the group is bonded: [ka]

[0025] Unless otherwise specified, the compounds of the present invention include all stereoisomers (e.g., enantiomers and diastereomers), double bond isomers (e.g., (Z) and (E)), structural isomers, and tautomers of the compounds specified herein by their chemical name and chemical structure, whether specified by their chemical name or chemical structure. Furthermore, monoisomers, double bond isomers, structural isomers, and tautomers, as well as mixtures of stereoisomers, double bond isomers, structural isomers, and tautomers, are within the scope of the present invention.

[0026] As used herein, in any chemical structure or formula, a straight bond that is not a thick line attached to the stereocenter of a compound, as in the following formula, is: [ka] This indicates that the stereochemistry of the stereocenter is unspecified. The compound may have any stereochemistry, or a mixture of stereochemistrys, at its stereocenter.

[0027] When used herein, in any chemical structure or formula, a straight bond between a stereocenter of a compound, represented by a thick or dashed line, as in the following formula, is: [ka] The relative stereochemistry of the chiral center with respect to other stereocenters to which it is attached by a thick or dashed linear bond is shown.

[0028] When used herein, in any chemical structure or formula, a wedge-shaped bond, indicated by a thick or dashed line, attached to the stereocenter of a compound, as in the following formula, [ka] The absolute stereochemistry of the chiral center, as well as the relative stereochemistry of the chiral center, are shown with respect to other chiral centers to which the wedge-shaped bond (indicated by a thick or dashed line) is attached.

[0029] As used herein, the prefix "rac-" refers to a racemic mixture of compounds when used in relation to chiral compounds. In compounds with the "rac-" prefix, the (R)- and (S)- designators in the chemical name reflect the relative stereochemistry of the compound.

[0030] As used herein, the prefix "dia-" refers to a mixture of two or more diastereomers of a compound, when used in relation to a chiral compound. In compounds with the "dia-" prefix, the (R)- and (S)- designations are assigned arbitrarily and do not necessarily reflect the absolute or relative stereochemistry of the corresponding stereocenters in any component of the mixture. In some examples, all diastereomers in a mixture have a single absolute stereochemistry at one or more stereocenters. In these examples, the stereochemical designators associated with a stereocenter having a single absolute stereochemistry are marked with an asterisk (*), e.g., (R*)- and (S*)-. In some examples, all diastereomers in a mixture have the same relative stereochemistry at two or more stereocenters. In these examples, the stereochemical designators associated with such stereocenters are marked with a superscript number ( n ), for example, (R n )- and (S n )- is used to mark stereochemical specifiers marked with a superscript number, for example, (R 1 )- and (S 1 A stereochemical specifier with an asterisk (*) reflects the relative stereochemistry of the corresponding stereocenter to other stereocenters associated with it, but does not necessarily reflect the absolute configuration of such stereocenters. Stereochemical specifiers marked with an asterisk (*) are indicated by a superscript number ( n With respect to stereocenters associated with stereochemical designators marked with ( ) (and vice versa), or with respect to stereocenters associated with unmarked stereochemical designators, the relative stereochemistry of the corresponding stereocenters is not necessarily reflected. Similarly, the superscript number ( n Stereochemical designators marked with ) are numbered with different superscript numbers ( nWith respect to stereocenters associated with stereochemical designators marked with ) or stereocenters associated with unmarked stereochemical designators, the relative stereochemistry of the corresponding stereocenters is not necessarily reflected.

[0031] As used herein, the prefix "rel-" refers to a single enantiomer of an unknown absolute configuration when used in relation to chiral compounds. In compounds with the "rel-" prefix, the (R)- and (S)- designators in the chemical name reflect the relative stereochemistry of the compound, but not necessarily the absolute stereochemistry of the compound. In some examples, the absolute configurations of some stereocenters are known, while only the relative configurations of other stereocenters are known. In these examples, stereochemical designators related to stereocenters with known absolute configurations are marked with an asterisk (*), e.g., (R*)- and (S*)-, while stereochemical designators related to stereocenters with unknown absolute configurations are not marked in this way. Unmarked stereochemical designators related to stereocenters with unknown absolute configurations reflect the relative stereochemistry of those stereocenters with respect to other stereocenters of the unknown absolute configuration, but not necessarily the relative stereochemistry with respect to stereocenters of known absolute configurations. If a compound contains two or more stereocenters with unknown absolute configurations, and the relative stereochemistry of such stereocenters relative to each other is unknown, no stereochemical specifier is provided for such stereocenters.

[0032] As used herein, the term “compound” refers to a collection of molecules having the same chemical structure, except that isotopic variations may exist between the constituent atoms of the molecules, when referring to the compounds of the present invention. The term “compound” includes such collections of molecules regardless of the purity of a given sample containing such collections of molecules. Accordingly, the term “compound” includes such collections of molecules in their pure form, in a mixture with one or more other substances (e.g., a solution, suspension, colloid, or pharmaceutical composition or dosage form), or in the form of hydrates, solvates, or cocrystals.

[0033] In this specification and in the claims, unless otherwise specified, any atom not specifically designated as a particular isotope of any compound of the present invention is intended to represent any stable isotope of the specified element. In the examples, if an atom is not specifically designated as a particular isotope of any compound of the present invention, no effort is made to enrich that atom in a particular isotope, and therefore, a person skilled in the art will understand that such an atom likely existed in the isotopic composition of the specified element at approximately its natural abundance.

[0034] As used herein, the term “stable” means, when referring to an isotope, that the isotope is not known to undergo spontaneous radioactive decay. Stable isotopes include, but are not limited to, those whose decay modes are not identified in V.S. Shirley & C. M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0035] As used herein and in the claims, "H" refers to hydrogen, any stable isotope of hydrogen, i.e. 1 This includes H and D. In the examples, when an atom is designated as "H", no attempt is made to concentrate that atom in a specific isotope of hydrogen, and therefore, those skilled in the art will understand that such hydrogen atoms likely existed in the approximately naturally occurring isotopic composition of hydrogen.

[0036] When used herein, 1 "H" refers to protium. When an atom in the compound of the present invention or a pharmaceutically acceptable salt thereof is designated as protium, protium is present at the designated position at least at the concentration of its natural abundance.

[0037] As used herein, "D", "d", and " 2"H" refers to deuterium.

[0038] In some embodiments, the compounds of the present invention and their pharmaceutically acceptable salts contain each constituent atom in an approximately naturally occurring isotopic composition of the specified elements.

[0039] In some embodiments, the compounds of the present invention and their pharmaceutically acceptable salts contain one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the most abundant isotope of the specified element ("isotope-labeled" compound and salt). Examples of commercially available stable isotopes suitable for the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, for example, respectively. 2 H, 13 C, 15 N, 18 O, 17 O, and 31 P is one example, but it is not limited to these.

[0040] Isotope-labeled compounds and salts can be used in several beneficial ways, such as for use as pharmaceuticals. In some embodiments, the isotope-labeled compounds and salts contain deuterium ( 2 H) Labeled. For example, deuterium ( 2 H) Labeled compounds and salts are therapeutically useful, non 2 It has potential therapeutic advantages over H-labeled compounds. Generally speaking, deuterium ( 2 H) Labeled compounds and salts may have higher metabolic stability compared to unlabeled compounds due to the kinetic isotope effect described below. This higher metabolic stability translates directly to an increased in vivo half-life or lower doses, which in most circumstances represents a preferred embodiment of the present invention. Isotopically labeled compounds and salts can typically be prepared by performing the procedures disclosed in the synthesis scheme, examples, and related descriptions, and by replacing unisotopically labeled reactants with readily available isotopely labeled reactants.

[0041] deuterium( 2H) Labeled compounds and salts can manipulate the oxidative metabolic rate of compounds through first-order kinetic isotope effects. First-order kinetic isotope effects are changes in the rate of chemical reactions resulting from the exchange of isotopic nuclei, which are then caused by changes in the ground state energy of the covalent bonds involved in the reaction. The exchange of heavier isotopes usually results in a decrease in the ground state energy of the chemical bond, and therefore a decrease in the rate-determining bond cleavage. If the bond cleavage occurs within or near the saddle point region along the coordination of a multi-product reaction, the product distribution ratio can change significantly. For example, when deuterium is bonded to a carbon atom in a non-exchangeable position, k H / k D A typical velocity difference is 2 to 7. For further consideration, see S.L. Harbeson and R.D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417, which is incorporated herein by reference in its entirety.

[0042] The concentration of an isotope (e.g., deuterium) incorporated at a given position in the isotope-labeled compound or a pharmaceutically acceptable salt thereof of the present invention may be defined by an isotope enrichment factor. As used herein, the term “isotope enrichment factor” means the ratio between the abundance of the isotope at a given position in the isotope-labeled compound (or salt) and the natural abundance of the isotope.

[0043] When the atom in the compound of the present 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 (approximately 45% deuterium incorporated). In some embodiments, the isotopic enrichment factors are at least 3500 (approximately 52.5% deuterium incorporated), at least 4000 (approximately 60% deuterium incorporated), at least 4500 (approximately 67.5% deuterium incorporated), at least 5000 (approximately 75% deuterium incorporated), at least 5500 (approximately 82.5% deuterium incorporated), at least 6000 (approximately 90% deuterium incorporated), at least 6333.3 (approximately 95% deuterium incorporated), at least 6466.7 (approximately 97% deuterium incorporated), at least 6600 (approximately 99% deuterium incorporated), or at least 6633.3 (approximately 99.5% deuterium incorporated).

[0044] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, X a However, it is CH2, X b However, it is O, R 6 and R 7 However, each is independently H, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. R 8 and R 9 However, each is independently H, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy, or R 8 and R 9 These, together with the carbon atoms to which they are bonded, form a C3-C6 cycloalkyl group. R s and R t However, each is independent of H, OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -NR b R c -NO2, -SO3H, -(CH2) m Ureb , or -O(CH2) m Is it OCH3, or R s and R t Together with the carbon atoms to which they are bonded, the formula [ka] Forming a ring, This relates to compounds, or pharmaceutically acceptable salts thereof, in which p is 0 or 1.

[0045] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, R 1 However, H, OH, halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -C(O)OR b And, R 10 However, H is, R s and R t However, each is independent of H, OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -NR b R c -NO2, -SO3H, -(CH2) m Ure a , or -O(CH2) m Is it OCH3, or R s and R t These, together with the atoms to which they are bonded, form the formula [ka] This relates to compounds that form a ring, or pharmaceutically acceptable salts thereof.

[0046] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein p is 1 and X a However, CR 11 R 12 X bThis relates to compounds, or pharmaceutically acceptable salts thereof, where O is present.

[0047] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, where R 11 This relates to compounds, or pharmaceutically acceptable salts thereof, in which H is present.

[0048] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, where R 12 This relates to compounds, or pharmaceutically acceptable salts thereof, in which H is present.

[0049] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein p is 1 and X a However, O and X b However, CR 13 R 14 This relates to a compound, or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, where R 13 However, the present invention relates to a compound that is C1-C6 alkyl or C1-C6 haloalkyl, or a pharmaceutically acceptable salt thereof. In other embodiments, R 13 is a C1-C6 alkyl group. In other embodiments, R 13 is a C1-C6 haloalkyl. In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, where R 13 However, the present invention relates to a compound that is -CH3 or -CF3, or a pharmaceutically acceptable salt thereof. In other embodiments, R 13 In other embodiments, R 13 It is -CF3.

[0051] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, where R 14However, the present invention relates to a compound that is C1-C6 alkyl or C1-C6 haloalkyl, or a pharmaceutically acceptable salt thereof. In other embodiments, R 14 is a C1-C6 alkyl group. In other embodiments, R 14 is a C1-C6 haloalkyl. In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, where R 14 However, the present invention relates to a compound that is -CH3 or -CF3, or a pharmaceutically acceptable salt thereof. In other embodiments, R 14 In other embodiments, R 14 It is -CF3.

[0052] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, where R 6 , R 7 , R 8 , and R 9 These, together with the carbon atoms to which they are bonded, form 1 to 3 R atoms as needed. y Substituted with, condensed C6-C 10 The present invention relates to compounds that form aryls, or pharmaceutically acceptable salts thereof. In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein R 6 , R 7 , R 8 , and R 9 This relates to compounds, or pharmaceutically acceptable salts thereof, that, together with the carbon atoms to which they are bonded, form condensed phenyls.

[0053] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, where R 10 The present invention relates to a compound of formula (IA) or a pharmaceutically acceptable salt thereof, wherein R 10 However, this relates to compounds that are CH3, or pharmaceutically acceptable salts thereof.

[0054] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, where R w This relates to compounds, or pharmaceutically acceptable salts thereof, in which H is present.

[0055] In some embodiments, the present invention relates to a compound of formula (IA-1), [ka] The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, wherein all variable groups are defined as defined for the compound of formula (IA).

[0056] In some embodiments, the present invention relates to a compound of formula (IB-1), [ka] The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, wherein all variable groups are defined as defined for the compound of formula (IA).

[0057] In some embodiments, the present invention relates to a compound of formula (IC-1), [ka] The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, wherein all variable groups are defined as defined for the compound of formula (IA).

[0058] In some embodiments, the present invention relates to a compound of formula (ID-1), [ka] The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, wherein all variable groups are defined as defined for the compound of formula (IA).

[0059] In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), or (IB-1), or pharmaceutically acceptable salts thereof, wherein p is 0, or to pharmaceutically acceptable salts thereof.

[0060] In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), or (IB-1), or pharmaceutically acceptable salts thereof, wherein p is 1, or pharmaceutically acceptable salts thereof.

[0061] In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, wherein X 1 The present invention relates to a compound or a pharmaceutically acceptable salt thereof in which N is present. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, wherein X 1 However, CR 1 And R 1 However, H, CN, C1-C6 alkyl, C1-C6 alkoxy, or -C(O)OR b The present invention relates to a compound, or a pharmaceutically acceptable salt thereof. In other embodiments, X 1 CR 1 And R 1 In other embodiments, X 1 CR 1 And R 1 In other embodiments, X 1 CR 1 And R 1 is a C1-C6 alkyl group. In other embodiments, X 1 CR 1 And R 1 In other embodiments, X 1 CR 1 And R 1 is -C(O)OR bIn some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, wherein X 1 However, CR 1 And R 1 The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is H, CN, -CH3, -OCH3, -C(O)OCH3, or -C(O)OCH2CH3. In other embodiments, X 1 CR 1 And R 1 In other embodiments, X 1 CR 1 And R 1 In other embodiments, X 1 CR 1 And R 1 In other embodiments, X 1 CR 1 And R 1 In other embodiments, X 1 CR 1 And R 1 This is -C(O)OCH2CH3.

[0062] In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, wherein X 2 The present invention relates to a compound of formula (IA) or (IA-1), or a pharmaceutically acceptable salt thereof, wherein X 2 However, CR 2 And R 2 However, H, OH, CN, halo, C1-C6 alkyl, C1-C6 alkoxy, -NHS(O)2(C1-C6 alkyl), -C(O)OR b -C(O)NR b R c, 5-6 membered heteroaryl, or 5-6 membered heterocycline, and even if the 5-6 membered heteroaryl or 5-6 membered heterocycline is not substituted, C1-C6 alkyl and -C(O)NR b R c The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, which may be substituted with 1 to 4 substituents independently selected from X. In other embodiments, X 2 CR 2 And R 2 In other embodiments, X 2 CR 2 And R 2 In other embodiments, X 2 CR 2 And R 2 In other embodiments, X 2 CR 2 And R 2 In other embodiments, X 2 CR 2 And R 2 is a C1-C6 alkyl group. In other embodiments, X 2 CR 2 And R 2 In other embodiments, X 2 CR 2 And R 2 In other embodiments, X 2 CR 2 And R 2 is -C(O)OR b In other embodiments, X 2 CR 2 And R 2 is -C(O)NR b R c In other embodiments, X 2 CR 2 And R 2 These are 5-6 member heteroaryl compounds, and these 5-6 member heteroaryl compounds, even when unsubstituted, are C1-C6 alkyl and -C(O)NR compounds. b Rc It may also be substituted with 1 to 4 substituents independently selected from X. In other embodiments, X 2 CR 2 And R 2 These are 5-6 member heterocyclines, and even when unsubstituted, these 5-6 member heterocyclines are C1-C6 alkyl and -C(O)NR b R c They may also be substituted with 1 to 4 substituents independently selected from. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, wherein X 2 However, CR 2 And R 2 However, H, Cl, F, OH, CN, -CH3, -OCH3, -C(O)OH, -C(O)NH2, -C(O)N(H)CH3, -N(H)S(O)2(CH3), [ka] The present invention relates to a compound or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, wherein X 2 However, CR 2 And R 2 is H, Cl, F, OH, CN, -CH3, -OCH3, -C(O)OH, -C(O)NH2, -C(O)N(H)CH3, -N(H)S(O)2(CH3), [ka] The present invention relates to a compound, or a pharmaceutically acceptable salt thereof. In other embodiments, X 2 CR 2 And R 2 In other embodiments, X 2 CR 2 And R 2 In other embodiments, X 2 CR2 And R 2 In other embodiments, X 2 CR 2 And R 2 In other embodiments, X 2 CR 2 And R 2 In other embodiments, X 2 CR 2 And R 2 In other embodiments, X 2 CR 2 And R 2 In other embodiments, X 2 CR 2 And R 2 In other embodiments, X 2 CR 2 And R 2 In other embodiments, X 2 CR 2 And R 2 In other embodiments, X 2 CR 2 And R 2 teeth, [ka] In other embodiments, X 2 CR 2 And R 2 teeth, [ka] In other embodiments, X 2 CR 2 And R 2 teeth, [ka] In other embodiments, X 2 CR 2 And R 2teeth, [ka] In other embodiments, X 2 CR 2 And R 2 teeth, [ka] In other embodiments, X 2 CR 2 And R 2 teeth, [ka] That is the case.

[0063] In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, wherein X 3 The present invention relates to a compound or a pharmaceutically acceptable salt thereof in which N is present. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, wherein X 3 However, CR 3 And R 3 However, H, CN, halo, C1-C6 alkoxy, -C(O)OR b , or -C(O)NR b R c The present invention relates to a compound, or a pharmaceutically acceptable salt thereof. In other embodiments, X 3 CR 3 And R 3 In other embodiments, X 3 CR 3 And R 3 In other embodiments, X 3 CR 3 And R 3 In other embodiments, X 3 CR 3 And R3 In other embodiments, X 3 CR 3 And R 3 is -C(O)OR b In other embodiments, X 3 CR 3 And R 3 is -C(O)NR b R c In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, wherein X 3 However, CR 3 And R 3 The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is H, Cl, F, CN, -OCH3, -C(O)OCH3, or -C(O)N(CH3)2. In other embodiments, X 3 CR 3 And R 3 In other embodiments, X 3 CR 3 And R 3 In other embodiments, X 3 CR 3 And R 3 In other embodiments, X 3 CR 3 And R 3 In other embodiments, X 3 CR 3 And R 3 In other embodiments, X 3 CR 3 And R 3 It is -C(O)N(CH3)2.

[0064] In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, where R 4 However, H, halo, C1-C6 alkyl, -C(O)ORb , or -C(O)NR b R c The present invention relates to a compound, or a pharmaceutically acceptable salt thereof. In other embodiments, R 4 In other embodiments, R 4 In other embodiments, R 4 is a C1-C6 alkyl group. In other embodiments, R 4 is -C(O)OR b In other embodiments, R 4 is -C(O)NR b R c In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, wherein R 4 The present invention relates to compounds, or pharmaceutically acceptable salts thereof, wherein the compound is H, Cl, F, -CH3, -C(O)OCH2CH3, or -C(O)NH2. In other embodiments, R 4 In other embodiments, R 4 In other embodiments, R 4 In other embodiments, R 4 In other embodiments, R 4 It is -C(O)NH2.

[0065] In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, wherein X 5 The present invention relates to a compound or a pharmaceutically acceptable salt thereof in which N is present. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, wherein X 5 However, CR 5 And R 5 However, H, halo, or -C(O)NR b R c The present invention relates to a compound, or a pharmaceutically acceptable salt thereof. In other embodiments, X5 CR 5 And R 5 In other embodiments, X 5 CR 5 And R 5 In other embodiments, X 5 CR 5 And R 5 is -C(O)NR b R c In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, wherein X 5 However, CR 5 And R 5 The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, which is H, F, or -C(O)NH2. In other embodiments, X 5 CR 5 And R 5 In other embodiments, X 5 CR 5 And R 5 It is -C(O)NH2.

[0066] In some embodiments, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt thereof, where R 6 This relates to compounds, or pharmaceutically acceptable salts thereof, in which H is present.

[0067] In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, where R 7が The present invention relates to compounds, or pharmaceutically acceptable salts thereof, which are H, OH, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. In other embodiments, R 7 In other embodiments, R 7 In other embodiments, R 7 is a C1-C6 alkyl group. In other embodiments, R 7is a C3-C6 cycloalkyl group. In other embodiments, R 7 is a C1-C6 alkoxy. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, where R 7 The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, which is H, OH, -OCH3, -CH3, or cyclopropyl. In other embodiments, R 7 In other embodiments, R 7 In other embodiments, R 7 It is cyclopropyl.

[0068] In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, where R 8 and R 9 However, each is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl, or R 8 and R 9 This relates to compounds, or pharmaceutically acceptable salts thereof, that, together with the carbon atoms to which they are bonded, form a C3-C6 cycloalkyl group. In other embodiments, R 8 and R 9 At least one of them is H. In other embodiments, R 8 and R 9 At least one of them is a C1-C6 alkyl group. In other embodiments, R 8 and R 9 At least one of them is a C1-C6 haloalkyl. In other embodiments, R 8 and R 9 At least one of them is a C3-C6 cycloalkyl. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, where R 8The present invention relates to a compound that is H or C1-C6 alkyl, or a pharmaceutically acceptable salt thereof. In other embodiments, R 8 In other embodiments, R 8 is a C1-C6 alkyl group. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, where R 8 The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, which is H, -CH3, or -CH2CH3. In other embodiments, R 8 In other embodiments, R 8 is -CH2CH3. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, where R 9 The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, which is H, C1-C6 alkyl, or C1-C6 haloalkyl. In other embodiments, R 9 In other embodiments, R 9 is a C1-C6 alkyl group. In other embodiments, R 9 is a C1-C6 haloalkyl. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, where R 9 The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, which is H, -CH3, or -CF3. In other embodiments, R 9 In other embodiments, R 9 is -CF3. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, where R 8 and R 9This invention relates to compounds, or pharmaceutically acceptable salts thereof, that, together with the carbon atoms to which they are bonded, form a C3-C6 cycloalkyl group. In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or pharmaceutically acceptable salts thereof, wherein R 8 and R 9 This relates to compounds, or pharmaceutically acceptable salts thereof, that, together with the carbon atoms to which they are bonded, form cyclobutane.

[0069] In some embodiments, the present invention relates to a compound of formula (IC-1) or (ID-1), or a pharmaceutically acceptable salt thereof, where R 11 However, H is R 12 This relates to compounds, or pharmaceutically acceptable salts thereof, in which H is present.

[0070] In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, wherein X s The present invention relates to a compound or a pharmaceutically acceptable salt thereof in which N is present. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, wherein X s However, CR s And R s However, H, OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl, -(CH2) m Ure b , or -O(CH2) m The present invention relates to compounds of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or pharmaceutically acceptable salts thereof, wherein X s However, CR s And R sHowever, H, OH, halo, C1-C6 alkyl, C1-C6 alkoxy, -(CH2) m Ure b , or -O(CH2) m The present invention relates to a compound that is OCH3, or a pharmaceutically acceptable salt thereof. In other embodiments, X s CR s And R s In other embodiments, X s CR s And R s In other embodiments, X s CR s And R s In other embodiments, X s CR s And R s is a C1-C6 alkyl group. In other embodiments, X s CR s And R s In other embodiments, X s CR s And R s is a C3-C6 cycloalkyl group. In other embodiments, X s CR s And R s is a -O-C3-C6 cycloalkyl group. In other embodiments, X s CR s And R s is, -(CH2) m Ure b In other embodiments, X s CR s And R s is -O(CH2) m OCH3. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, wherein X s However, CR s And R sThe present invention relates to compounds, or pharmaceutically acceptable salts thereof, wherein the compound is H, F, Cl, OH, -CH3, -CH2OH, -CH2OCH3, -OCH3, cyclopropyl, -O-cyclopropyl, -OCH(CH3)2, or -OCH2CH2OCH3. In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or pharmaceutically acceptable salts thereof, wherein X s However, CR s And R s The present invention relates to compounds, or pharmaceutically acceptable salts thereof, wherein the compound is H, F, Cl, OH, -CH3, -CH2OH, -CH2OCH3, -OCH3, cyclopropyl, -OCH(CH3)2, or -OCH2CH2OCH3. In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or pharmaceutically acceptable salts thereof, wherein X s However, CR s And R s The present invention relates to compounds, or pharmaceutically acceptable salts thereof, wherein the compound is H, F, OH, -CH3, -CH2OH, -OCH3, -OCH(CH3)2, or -OCH2CH2OCH3. In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or pharmaceutically acceptable salts thereof, wherein X s However, CR s And R s The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is H, Cl, F, OH, -CH3, -CH2OH, -OCH3, -OCH2CH3, -OCH(CH3)2, or -OCH2CH2OCH3. In other embodiments, X s CR s And R s In other embodiments, X s CR s And R s In other embodiments, X s CR s And R s In other embodiments, Xs CR s And R s In other embodiments, X s CR s And R s is -CH2OCH3. In other embodiments, X s CR s And R s In other embodiments, X s CR s And R s In other embodiments, X s CR s And R s In other embodiments, X s CR s And R s In other embodiments, X s CR s And R s This is -OCH2CH2OCH3.

[0071] In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, wherein X t The present invention relates to a compound or a pharmaceutically acceptable salt thereof in which N is present. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, wherein X t However, CR t And R t The present invention relates to compounds, or pharmaceutically acceptable salts thereof, wherein H is a halo, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl. In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or pharmaceutically acceptable salts thereof, wherein X t However, CR t And Rt The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, which is H, halo, C1-C6 alkyl, or C1-C6 alkoxy. In other embodiments, X t CR t And R t In other embodiments, X t CR t And R t In other embodiments, X t CR t And R t is a C1-C6 alkyl group. In other embodiments, X t CR t And R t In other embodiments, X t CR t And R t is a C3-C6 cycloalkyl. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, wherein X t However, CR t And R t The present invention relates to compounds, or pharmaceutically acceptable salts thereof, wherein the compound is H, Cl, F, -CH3, -OCH3, or cyclopropyl. In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or pharmaceutically acceptable salts thereof, wherein X t However, CR t And R t The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, which is H, Cl, F, -CH3, or -OCH3. In other embodiments, X t CR t And R t In other embodiments, X t CR t And R t In other embodiments, X t CR t And R tIn other embodiments, X t CR t And R t In other embodiments, X t CR t And R t It is cyclopropyl.

[0072] In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, wherein X s However, CR s X t However, CR t And R s and R t Together with the carbon atoms to which they are bonded, the formula [ka] The present invention relates to compounds that form a ring of X, or pharmaceutically acceptable salts thereof. In other embodiments, X s CR s X t CR t And R s and R t Together with the carbon atoms to which they are bonded, the formula [ka] It forms a ring. In other embodiments, X s CR s X t CR t And R s and R t Together with the carbon atoms to which they are bonded, the formula [ka] Forms a ring. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, wherein X s However, CR s X t However, CR t And R s and R t Together with the carbon atoms to which they are bonded, the formula [ka] The present invention relates to compounds that form a ring of X, or pharmaceutically acceptable salts thereof. In other embodiments, X s CR s X t CR t And R s and R t Together with the carbon atoms to which they are bonded, the formula [ka] It forms a ring. In other embodiments, X s CR s X t CR t And R s and R t Together with the carbon atoms to which they are bonded, the formula [ka] It forms a ring. In other embodiments, X s CR s X t CR t And R s and R t Together with the carbon atoms to which they are bonded, the formula [ka] It forms a ring.

[0073] In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, where R u The present invention relates to compounds, or pharmaceutically acceptable salts thereof, wherein H is a halo, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl. In other embodiments, R u In other embodiments, R u In other embodiments, R u is a C1-C6 alkyl group. In other embodiments, R u is a C1-C6 alkoxy. In other embodiments, R u is a C1-C6 haloalkyl. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, where R u The present invention relates to compounds, or pharmaceutically acceptable salts thereof, wherein the compound is H, F, or -CH3. In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or pharmaceutically acceptable salts thereof, wherein R u The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, which is H, Cl, F, -CH3, or -OCH3. In other embodiments, R u In other embodiments, R u In other embodiments, R u In other embodiments, R u It is -OCH3.

[0074] In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, where R vThe present invention relates to compounds, or pharmaceutically acceptable salts thereof, wherein H, halo, or C1-C6 alkyl is present. In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or pharmaceutically acceptable salts thereof, wherein R v The present invention relates to a compound that is H or C1-C6 alkyl, or a pharmaceutically acceptable salt thereof. In other embodiments, R v In other embodiments, R v In other embodiments, R v is a C1-C6 alkyl group. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or a pharmaceutically acceptable salt thereof, where R v The present invention relates to compounds, or pharmaceutically acceptable salts thereof, wherein the compound is H, F, or -CH3. In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), (IB-1), (IC-1), or (ID-1), or pharmaceutically acceptable salts thereof, wherein R v The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, which is H or -CH3. In other embodiments, R v In other embodiments, R v is either or -CH3.

[0075] In some embodiments, the present invention relates to a compound of formula (IA-2), [ka] The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, wherein all variable groups are defined as defined for the compound of formula (IA).

[0076] In some embodiments, the present invention relates to a compound of formula (IB-2), [ka] The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, wherein all variable groups are defined as defined for the compound of formula (IA).

[0077] In some embodiments, the present invention relates to a compound of formula (IC-2), [ka] The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, wherein all variable groups are defined as defined for the compound of formula (IA).

[0078] In some embodiments, the present invention relates to a compound of formula (ID-2), [ka] The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, wherein all variable groups are defined as defined for the compound of formula (IA).

[0079] In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), (IB-1), (IA-2), or (IB-2), or pharmaceutically acceptable salts thereof, wherein p is 0.

[0080] In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), (IB-1), (IA-2), or (IB-2), or pharmaceutically acceptable salts thereof, wherein p is 1.

[0081] In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), (IC-2), (ID-1), or (ID-2), or pharmaceutically acceptable salts thereof, wherein R 7The present invention relates to compounds, or pharmaceutically acceptable salts thereof, wherein H, C1-C6 alkyl, or C1-C6 alkoxy. In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), (IC-2), (ID-1), or (ID-2), or pharmaceutically acceptable salts thereof, wherein R 7 The present invention relates to a compound that is H or a C1-C6 alkoxy, or a pharmaceutically acceptable salt thereof. In other embodiments, R 7 In other embodiments, R 7 is a C1-C6 alkyl group. In other embodiments, R 7 is a C1-C6 alkoxy. In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), (IC-2), (ID-1), or (ID-2), or pharmaceutically acceptable salts thereof, wherein R 7 The present invention relates to compounds of formula (IA), (IA-1), or (IA-2), or pharmaceutically acceptable salts thereof, wherein R 7 The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, which is H or -OCH3. In other embodiments, R 7 In other embodiments, R 7 It is -OCH3.

[0082] In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), (IC-2), (ID-1), or (ID-2), or pharmaceutically acceptable salts thereof, wherein R s However, H, OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl, -(CH2) m Ure b , or -O(CH2) mThe present invention relates to compounds of formula (IA), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), (IC-2), (ID-1), or (ID-2), or to pharmaceutically acceptable salts thereof, wherein R s However, H, halo, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or -(CH2) m Ure b The present invention relates to compounds of formula (IA), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), (IC-2), (ID-1), or (ID-2), or to pharmaceutically acceptable salts thereof, wherein R s However, the present invention relates to a compound that is C1-C6 alkyl or C1-C6 alkoxy, or a pharmaceutically acceptable salt thereof. In other embodiments, R s In other embodiments, R s In other embodiments, R s is a C1-C6 alkyl group. In other embodiments, R s is a C1-C6 alkoxy. In other embodiments, R s is a C3-C6 cycloalkyl group. In other embodiments, R s is a -O-C3-C6 cycloalkyl group. In other embodiments, R s is, -(CH2) m Ure b In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), (IC-2), (ID-1), or (ID-2), or pharmaceutically acceptable salts thereof, wherein R sThe present invention relates to compounds, or pharmaceutically acceptable salts thereof, wherein the compound is H, F, Cl, OH, -CH3, -CH2OH, -CH2OCH3, -OCH3, cyclopropyl, -O-cyclopropyl, -OCH(CH3)2, or -OCH2CH2OCH3. In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), (IC-2), (ID-1), or (ID-2), or pharmaceutically acceptable salts thereof, wherein R s The present invention relates to compounds, or pharmaceutically acceptable salts thereof, wherein the compound is H, F, Cl, -CH3, -OCH3, cyclopropyl, or -CH2OCH3. In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), (IC-2), (ID-1), or (ID-2), or pharmaceutically acceptable salts thereof, wherein R s However, the present invention relates to a compound that is -CH3 or -OCH3, or a pharmaceutically acceptable salt thereof. In other embodiments, R s In other embodiments, R s In other embodiments, R s In other embodiments, R s In other embodiments, R s In other embodiments, R s In other embodiments, R s is -O-cyclopropyl. In other embodiments, R s It is CH2OCH3.

[0083] In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), (IC-2), (ID-1), or (ID-2), or pharmaceutically acceptable salts thereof, wherein R tThe present invention relates to compounds, or pharmaceutically acceptable salts thereof, wherein H is a halo, a C1-C6 alkyl, or a C3-C6 cycloalkyl. In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), (IC-2), (ID-1), or (ID-2), or pharmaceutically acceptable salts thereof, wherein R t The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, which is H or a halo. In other embodiments, R t In other embodiments, R t In other embodiments, R t is a C1-C6 alkyl group. In other embodiments, R t is a C3-C6 cycloalkyl. In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), (IC-2), (ID-1), or (ID-2), or pharmaceutically acceptable salts thereof, where R t The present invention relates to compounds, or pharmaceutically acceptable salts thereof, wherein the compound is H, F, Cl, -CH3, or cyclopropyl. In some embodiments, the present invention relates to compounds of formula (IA), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), (IC-2), (ID-1), or (ID-2), or pharmaceutically acceptable salts thereof, wherein R t The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, which is H or F. In other embodiments, R t In other embodiments, R t In other embodiments, R t teeth, -CH3 is another embodiment, R t It is cyclopropyl.

[0084] In some embodiments, the present invention relates to compounds selected from Table A, or pharmaceutically acceptable salts thereof. In other embodiments, the present invention relates to compounds selected from Table A, i.e., compounds in non-salt forms. Table A-1 Table A-2 Table A-3 Table A-4 Table A-5 Table A-6 Table A-7 Table A-8 Table A-9 Table A-10 Table A-11 Table A-12 Table A-13 Table A-14 Table A-15 Table A-16 Table A-17 [Table A-18]

[0085] In some embodiments, the present invention relates to compounds selected from Table B, or pharmaceutically acceptable salts thereof. In other embodiments, the present invention relates to compounds selected from Table B, i.e., compounds in non-salt forms. [Table B-1] [Table B-2] [Table B-3]

[0086] In some embodiments, the present invention relates to compounds selected from Table C, or pharmaceutically acceptable salts thereof. In other embodiments, the present invention relates to compounds selected from Table C, i.e., compounds in non-salt forms. [Table C-1] [Table C-2] [Table C-3] [Table C-4] [Table C-5]

[0087] In some embodiments, the present invention relates to compounds selected from Table D, or pharmaceutically acceptable salts thereof. In other embodiments, the present invention relates to compounds selected from Table D, i.e., compounds in non-salt forms. [Table D-1] [Table D-2] [Table D-3]

[0088] In some embodiments, the present invention relates to compounds selected from Table D, or pharmaceutically acceptable salts thereof. In other embodiments, the present invention relates to compounds selected from Table E, i.e., unsalted forms of the compounds. [Table E-1] [Table E-2]

[0089] Salts, compositions, uses, formulations, administration, and additional agents pharmaceutically acceptable salts and compositions As discussed herein, the present invention provides compounds and pharmaceutically acceptable salts thereof that are inhibitors of voltage-gated sodium channels, and thus the compounds and pharmaceutically acceptable salts thereof are useful in treating diseases, disorders and conditions including, but not limited to, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., pain from aponeurosis resection, hernia repair, or abdominal wall reconstruction), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmias. Accordingly, in another aspect of the present invention, pharmaceutical compositions are provided, which comprise the compounds described herein or pharmaceutically acceptable salts 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.

[0090] As used herein, the term “pharmaceutically acceptable” means a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and that is commensurate with a reasonable benefit / risk ratio. A “pharmaceutically acceptable salt” of a compound of the present invention includes any non-toxic salt that can be used to provide the compound of the present disclosure or an inhibitory metabolite or residue thereof, either directly or indirectly, at the time of administration to a recipient. The salt may be in pure form, in mixture with one or more other substances (e.g., in solution, suspension, or colloid), or in the form of a hydrate, solvate, or cocrystal. As used herein, the term “inhibitory metabolite or residue thereof” means that the metabolite or residue thereof is also an inhibitor of voltage-gated sodium channels.

[0091] Pharmacopoeia-acceptable salts are well known in the art. For example, SMBerge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmacopoeia-acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or 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 adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethane. Examples include sulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, and valersates. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1-4Examples include alkyl)4 salts. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons, where appropriate.

[0092] As used herein, the pharmaceutically acceptable compositions of the present invention also include, as used herein, any pharmaceutically acceptable carrier, adjuvant, or vehicle suitable for the desired specific dosage form, including all solvents, diluents, or other liquid vehicles, dispersing or suspension aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc. Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in the formulation of pharmaceutically acceptable compositions and known techniques for their preparation. Unless any conventional carrier medium is incompatible with the compounds of the present invention, for example, by producing any undesirable biological effect or otherwise interacting in a detrimental manner with any other component of the pharmaceutically acceptable composition, its use is intended to be within the scope of this disclosure.Some examples of materials that can serve as pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose). Examples of ingredients include, but are not limited to, colorants, release agents, coating agents, sweeteners, flavoring agents, and fragrances. Preservatives and antioxidants may also be present in the composition at the discretion of the compounder.

[0093] In another embodiment, the present invention is characterized by a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0094] In another embodiment, the present 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.

[0095] Use of compounds and pharmaceutically acceptable salts and compositions In another embodiment, the present invention is characterized by a method for inhibiting voltage-gated sodium channels in a subject, comprising administering the compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to the subject. In another embodiment, voltage-gated sodium channels are Na V It is 1.8.

[0096] In yet another aspect, the present invention is characterized by a method for treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., pain from aponeurosis resection, pain from hernia repair, or pain from abdoplasty), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia, comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0097] In yet another aspect, the present invention is characterized by a method for treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, hernia repair pain, aponeurosis resection pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia, comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0098] In yet another aspect, the present invention relates to a method for treating or reducing the severity of intestinal pain in a subject, wherein the intestinal pain includes pain from inflammatory bowel disease, pain from Crohn's disease, irritable bowel syndrome, endometriosis, polycystic ovary disease, salpingitis, cervicitis, or interstitial cystitis, and the method comprises administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0099] In yet another embodiment, the present invention features a method for treating neuropathic pain or reducing its severity in a subject, comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, neuropathic pain includes postherpetic neuralgia, small-diameter fiber neuropathy, diabetic neuropathy, or idiopathic small-diameter fiber neuropathy. In some embodiments, neuropathic pain includes diabetic neuropathy (e.g., diabetic peripheral neuropathy). As used herein, the term "idiopathic small-diameter fiber neuropathy" shall be understood to include any small-diameter fiber neuropathy.

[0100] In yet another aspect, the present invention relates to a method for treating neuropathic pain or reducing its severity in a subject, wherein the neuropathic pain includes postherpetic neuralgia, diabetic neuropathy, painful HIV-related sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom limb pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radiculopathy, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, HIV-induced neuropathy; pain after spinal cord injury, pain of spinal stenosis, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal-autonomic headache, wherein the method comprises administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0101] In yet another embodiment, the present invention features a method for treating musculoskeletal pain or reducing its severity in a subject, comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, musculoskeletal pain includes osteoarthritis pain.

[0102] In yet another aspect, the present invention is characterized by a method for treating or reducing the severity of musculoskeletal pain in a subject, wherein the musculoskeletal pain includes osteoarthritis pain, back pain, cold pain, burn pain, or toothache, and the method comprises administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0103] In yet another aspect, the present invention is characterized by a method for treating inflammatory pain or reducing its severity in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain, ankylosing spondylitis, or vulvodynia, and the method comprises administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0104] In yet another aspect, the present invention is characterized by a method for treating inflammatory pain or reducing its severity in a subject, wherein the inflammatory pain includes pain of rheumatoid arthritis, and the method comprises administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0105] In yet another aspect, the present invention is characterized by a method for treating idiopathic pain or reducing its severity in a subject, wherein the idiopathic pain includes pain of fibromyalgia, and the method comprises administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0106] In yet another aspect, the present invention is characterized by a method for treating idiopathic pain or reducing its severity in a subject, wherein the idiopathic pain includes pain of reflex sympathetic dystrophy, and the method comprises administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0107] In yet another aspect, the present invention relates to a method for treating a pathological cough or reducing its severity in a subject, wherein the method comprises administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0108] In yet another embodiment, the present invention features a method for treating acute pain or reducing its severity in a subject, comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, acute pain includes acute postoperative pain.

[0109] In yet another aspect, the present invention is characterized by a method for treating or reducing the severity of postoperative pain (for example, pain from joint replacement, pain from soft tissue surgery, pain after thoracotomy, pain after mastectomy, pain from hemorrhoidectomy, pain from hernia repair, pain from aponeurosis resection, or pain from abdominal wall reconstruction), comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0110] In yet another aspect, the present invention is characterized by a method for treating pain associated with aponeurosis resection or reducing its severity in a subject, comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0111] In yet another aspect, the present invention is characterized by a method for treating or reducing the severity of pain during shoulder arthroplasty or shoulder arthroscopy, comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0112] In yet another aspect, the present invention is characterized by a method for treating pain associated with hernia repair or reducing its severity in a subject, comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0113] In yet another aspect, the present invention is characterized by a method for treating or reducing the severity of pain associated with abdominoplasty, comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0114] In yet another embodiment, the present invention features a method for treating visceral pain or reducing its severity in a subject, comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, visceral pain includes visceral pain resulting from abdominoplasty.

[0115] In yet another embodiment, the present invention features a method for treating a neurodegenerative disease or reducing its severity in a subject, comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the neurodegenerative disease includes multiple sclerosis. In some embodiments, the neurodegenerative disease includes Pitt-Hopkins syndrome (PTHS).

[0116] In yet another embodiment, the present invention is characterized by a method in which a subject is treated simultaneously with one or more additional therapeutic agents administered before or after treatment with an effective amount of a compound, a pharmaceutically acceptable salt, or a pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0117] In another embodiment, the present invention is characterized by a method for inhibiting voltage-gated sodium channels in a biological sample, comprising contacting the biological sample with an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another embodiment, voltage-gated sodium channels are Na V It is 1.8.

[0118] In another aspect, the present invention relates to acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, dysalgesic pain, arthritis, migraine, cluster headache, tension headache, all other forms of headache, trigeminal neuralgia, herpes zoster neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, motor disorders, neuroendocrine disorders, ataxia, central neuropathic pain in multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, Diabetic neuropathy, radiculopathy, sciatica, back pain, unspecified chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (e.g., pain from joint replacement, pain from soft tissue surgery, pain after thoracotomy, pain after mastectomy, pain from hernia repair, pain from aponeurosis resection, or pain from abdominal wall reconstruction), cancer pain including chronic cancer pain and cancer breakthrough pain, stroke (e.g., central neuropathic pain after stroke), traumatic cervical syndrome, fragility fracture, vertebral fracture, ankylosing spondylitis, pemphigus, ray No's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, venous osteopathy, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic osteoproliferative disorder, intervertebral disc degeneration / hernia pain, nerve root compression, facet joint syndrome, spinal surgery failure syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylolisthesis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmic neuropathy, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy induction A method for treating or reducing the severity of conditions such as induced oral mucositis, Charcot arthritis, temporomandibular joint disorder, painful total knee replacement, noncardiac chest pain, pudendal neuralgia, renal colic, biliary tract disease, vascular lower extremity 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 gastrointestinal motility, comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0119] In another aspect, the present invention relates to pain from femoral cancer; 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; splenic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, postherpetic neuralgia; diabetic neuropathy; HIV-related neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve Transcutaneous injury; painful neuroma; ectopic proximal and distal discharge; radiculopathy; chemotherapy-induced neuropathic pain; radiation-induced neuropathic pain; persistent / chronic postoperative 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 limb pain (e.g., post-lower limb, upper limb, or mastectomy); intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; arthralgia; mechanical low back pain; neck pain; tenosynovitis; injury pain; movement pain; acute visceral pain; renal pelvis Inflammation; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pains; cesarean section pain; acute inflammatory pain, burn pain, traumatic pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; toothache; multiple sclerosis (MS) pain; depression pain; leprosy pain; Behçet's disease pain; painful steatosis; phlebitis pain; Guillain-Barré syndrome pain; painful leg and mobile toes; Haglund's syndrome; The present invention provides a method for treating or reducing the severity of widespread pain, paroxysmal pain, pruritus, tinnitus, or angina-induced pain in a patient, comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0120] In another embodiment, the present invention is characterized by a method for treating or reducing the severity of trigeminal neuralgia, Botox-treated migraine, cervical spondylotic radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexus disorder, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioinguinal neuralgia, pudendal neuralgia, femoral neuropathy, paresthesia of femoral pain, saphenous neuropathy, sciatic neuropathy, fibular neuropathy, tibial neuropathy, lumbosacral plexus disorder, stump pain of traumatic neuroma, or pain after amputation surgery, comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0121] Compounds for use, pharmaceutically acceptable salts, and compositions In another embodiment, the present invention is characterized by the compound of the present invention for use as a pharmaceutical agent, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0122] In another aspect, the present invention is characterized by a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of inhibiting voltage-gated sodium channels in a subject. In another aspect, voltage-gated sodium channels are Na V It is 1.8.

[0123] In another aspect, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in a method of treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., pain from hernia repair, pain from aponeurosis resection, or pain from abdoplasty), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmias.

[0124] In another aspect, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in a method of treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, hernia repair pain, aponeurosis resection pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmias.

[0125] In another embodiment, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in treating or reducing the severity of intestinal pain in subjects, wherein the intestinal pain includes pain of inflammatory bowel disease, pain of Crohn's disease, irritable bowel syndrome, endometriosis, polycystic ovary disease, salpingitis, cervicitis, or interstitial cystitis.

[0126] In other embodiments, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in a manner of treating neuropathic pain or reducing its severity in a subject. In some embodiments, neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some embodiments, neuropathic pain includes diabetic neuropathy (e.g., diabetic peripheral neuropathy). As used herein, the term "idiopathic small fiber neuropathy" shall be understood to include any small fiber neuropathy.

[0127] In another aspect, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in treating neuropathic pain or reducing its severity in subjects, wherein neuropathic pain includes postherpetic neuralgia, diabetic neuropathy, painful HIV-related sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom limb pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radiculopathy, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, HIV-induced neuropathy; pain after spinal cord injury, pain of spinal stenosis, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal-autonomic headache.

[0128] In another embodiment, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in a method of treating musculoskeletal pain or reducing its severity in a subject. In some embodiments, musculoskeletal pain includes osteoarthritis pain.

[0129] In another aspect, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in treating musculoskeletal pain or reducing its severity in subjects, wherein musculoskeletal pain includes osteoarthritis pain, back pain, cold pain, burn pain, or toothache.

[0130] In another aspect, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in treating inflammatory pain or reducing its severity in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain, ankylosing spondylitis, or vulvodynia.

[0131] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating inflammatory pain or reducing its severity in a subject, wherein the inflammatory pain includes pain of rheumatoid arthritis.

[0132] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in treating idiopathic pain or reducing its severity in a subject, wherein idiopathic pain includes pain of fibromyalgia.

[0133] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in treating idiopathic pain or reducing its severity in a subject, wherein the idiopathic pain includes pain of reflex sympathetic dystrophy.

[0134] In another embodiment, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in treating pathological cough or reducing its severity in a subject.

[0135] In another embodiment, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in a method of treating acute pain or reducing its severity in a subject. In some embodiments, acute pain includes acute postoperative pain.

[0136] In another embodiment, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in treating or reducing the severity of postoperative pain (e.g., pain from joint replacement surgery, pain from soft tissue surgery, pain after thoracotomy, pain after mastectomy, pain from hemorrhoidectomy, pain from hernia repair, pain from aponeurosis resection, or pain from abdominal wall reconstruction).

[0137] In another embodiment, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in treating pain associated with aponeurosis resection or reducing its severity in a subject.

[0138] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in treating or reducing the severity of pain associated with shoulder arthroplasty or shoulder arthroscopy in a subject.

[0139] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in treating pain associated with hernia repair or reducing its severity in a subject.

[0140] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in treating pain during abdominal wall reconstruction surgery or reducing its severity in a subject.

[0141] In another embodiment, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in treating visceral pain or reducing its severity in a subject. In some embodiments, visceral pain includes visceral pain resulting from abdominoplasty.

[0142] In other embodiments, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in treating neurodegenerative diseases or reducing their severity in subjects. In some embodiments, neurodegenerative diseases include multiple sclerosis. In some embodiments, neurodegenerative diseases include Pitt-Hopkins syndrome (PTHS).

[0143] In another embodiment, the present invention features a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof for use in a manner in which the subject is treated simultaneously with treatment by an effective amount of the compound, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, or with one or more additional therapeutic agents administered before or after such treatment. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0144] In another embodiment, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of inhibiting voltage-gated sodium channels in a biological sample, the method comprising contacting the biological sample with an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another embodiment, voltage-gated sodium channels are Na V It is 1.8.

[0145] In another aspect, the present invention relates to acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, dysalgesic pain, arthritis, migraine, cluster headache, tension headache, all other forms of headache, trigeminal neuralgia, herpes zoster neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, motor disorders, neuroendocrine disorders, ataxia, central neuropathic pain in multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic nerve pain Menstrual pain, diabetic neuropathy, radiculopathy, sciatica, back pain, unspecified chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (e.g., pain from joint replacement, pain from soft tissue surgery, pain after thoracotomy, pain after mastectomy, pain from hernia repair, pain from aponeurosis resection, or pain from abdominal wall reconstruction), cancer pain including chronic cancer pain and cancer breakthrough pain, stroke (e.g., central neuropathic pain after stroke), traumatic cervical syndrome, fragility fracture, vertebral fracture, ankylosing spondylitis, Pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, venous osteopathy, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic hyperostosis, intervertebral disc degeneration / hernia pain, nerve root compression, facet joint syndrome, spinal surgery failure syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylodiscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmic neuropathy, sarcoidosis, spondylolysis, spinal stenosis The present invention is characterized by a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, for use in a method of treating or reducing the severity of the following conditions: seriosis, chemotherapy-induced oral mucositis, Charcot arthritis, temporomandibular joint disorder, painful total knee replacement, noncardiac chest pain, pudendal neuralgia, renal colic, biliary tract disease, vascular lower extremity 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 gastrointestinal motility.

[0146] In another aspect, the present invention relates to pain from femoral cancer; 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; splenic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, postherpetic neuralgia; diabetic neuropathy; HIV-related neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; Peripheral nerve injury; painful neuroma; ectopic proximal and distal discharge; radiculopathy; chemotherapy-induced neuropathic pain; radiation-induced neuropathic pain; persistent / chronic postoperative 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 limb pain (e.g., post-lower limb, upper limb, or mastectomy); intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; arthralgia; mechanical low back pain; neck pain; tenosynovitis; injury pain; movement pain; acute internal Visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pains; cesarean section pain; acute inflammatory pain, burn pain, traumatic pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; toothache; multiple sclerosis (MS) pain; depression pain; leprosy pain; Behçet's disease pain; painful steatosis; phlebitis pain; Guillain-Barré syndrome pain; painful leg and mobile toes; The present invention features compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in treating or reducing the severity of widespread pain, paroxysmal pain, pruritus, tinnitus, or angina-induced pain in patients with Haglund's syndrome; erythromelalgia; Fabry disease; bladder and genitourinary disorders; urinary incontinence, pathological cough; overactive bladder; bladder pain syndrome; interstitial cystitis (IC); prostatitis; regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II; and widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain.

[0147] In another aspect, the present invention features compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in a method of treating or reducing the severity of trigeminal neuralgia, Botox-treated migraine, cervical spondylotic radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexus disorder, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioinguinal neuralgia, pudendal neuralgia, femoral neuropathy, paresthesia of femoral pain, saphenous neuropathy, sciatic neuropathy, fibular neuropathy, tibial neuropathy, lumbosacral plexus disorder, stump pain of traumatic neuroma, or pain after amputation surgery.

[0148] Pharmaceutical manufacturing In another embodiment, the present invention provides the use of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for the manufacture of pharmaceuticals.

[0149] In another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in the inhibition of voltage-gated sodium channels. In another aspect, voltage-gated sodium channels are Na V It is 1.8.

[0150] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., pain from hernia repair, pain from aponeurosis resection, or pain from abdoplasty), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmias.

[0151] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents to be used for treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, hernia repair pain, aponeurosis resection pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmias.

[0152] In yet another aspect, the present invention provides the use of the compounds, pharmaceutically acceptable salts, or pharmaceutical compositions described herein for the manufacture of agents for use in treating or reducing the severity of intestinal pain in subjects, the intestinal pain including pain of inflammatory bowel disease, pain of Crohn's disease, irritable bowel syndrome, endometriosis, polycystic ovary disease, salpingitis, cervicitis, or interstitial cystitis.

[0153] In yet another embodiment, the present invention provides compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for use in the manufacture of agents for use in treating neuropathic pain or reducing its severity in subjects. In some embodiments, neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some embodiments, neuropathic pain includes diabetic neuropathy (e.g., diabetic peripheral neuropathy).

[0154] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in treating neuropathic pain or reducing its severity in subjects, wherein neuropathic pain includes postherpetic neuralgia, diabetic neuropathy, painful HIV-related sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom limb pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radiculopathy, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, HIV-induced neuropathy; pain after spinal cord injury, pain of spinal stenosis, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic neuropathy.

[0155] In yet another embodiment, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in treating musculoskeletal pain or reducing its severity in subjects. In some embodiments, musculoskeletal pain includes osteoarthritis pain.

[0156] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in treating musculoskeletal pain or reducing its severity in subjects, wherein musculoskeletal pain includes osteoarthritis pain, back pain, cold pain, burn pain, or toothache.

[0157] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in treating inflammatory pain or reducing its severity in subjects, wherein the inflammatory pain includes rheumatoid arthritis pain, ankylosing spondylitis, or vulvodynia.

[0158] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in treating inflammatory pain or reducing its severity in subjects, wherein inflammatory pain includes pain of rheumatoid arthritis.

[0159] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in treating idiopathic pain or reducing its severity in subjects, wherein idiopathic pain includes pain of fibromyalgia.

[0160] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in treating idiopathic pain or reducing its severity in subjects, wherein idiopathic pain includes pain of reflex sympathetic dystrophy.

[0161] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in treating pathological cough or reducing its severity in subjects.

[0162] In yet another embodiment, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in treating acute pain or reducing its severity in a subject. In some embodiments, acute pain includes acute postoperative pain.

[0163] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents to be used for treating or reducing the severity of postoperative pain (e.g., pain from joint replacement surgery, pain from soft tissue surgery, pain after thoracotomy, pain after mastectomy, pain from hemorrhoidectomy, pain from hernia repair, pain from aponeurosis resection, or pain from abdominal wall reconstruction).

[0164] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents to be used for treating pain in hernia repair or for reducing its severity in a subject.

[0165] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents to be used for treating pain associated with aponeurosis resection or to reduce its severity in a subject.

[0166] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents to be used for treating or reducing the severity thereof in patients with pain during shoulder arthroplasty or shoulder arthroscopy.

[0167] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents to be used for treating pain during abdominal wall reconstruction or to reduce its severity in subjects.

[0168] In yet another embodiment, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in treating visceral pain or reducing its severity in a subject. In some embodiments, visceral pain includes visceral pain resulting from abdominoplasty.

[0169] In other embodiments, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in the manufacture of agents for use in treating neurodegenerative diseases or reducing their severity in subjects. In some embodiments, neurodegenerative diseases include multiple sclerosis. In some embodiments, neurodegenerative diseases include Pitt-Hopkins syndrome (PTHS).

[0170] In yet another embodiment, the present invention provides the use of the compound, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof for the manufacture of a drug to be used in combination with one or more additional therapeutic agents administered before or after treatment with the compound or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0171] In another aspect, the present invention relates to acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, dysalgesic pain, arthritis, migraine, cluster headache, tension headache, all other forms of headache, trigeminal neuralgia, herpes zoster neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, motor disorders, neuroendocrine disorders, ataxia, central neuropathic pain in multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia Pain, diabetic neuropathy, radiculopathy, sciatica, back pain, unspecified chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (e.g., pain from joint replacement, pain from soft tissue surgery, pain after thoracotomy, pain after mastectomy, pain from hernia repair, pain from aponeurosis resection, or pain from abdominal wall reconstruction), cancer pain including chronic cancer pain and cancer breakthrough pain, stroke (e.g., central neuropathic pain after stroke), traumatic cervical syndrome, fragility fracture, vertebral fracture, ankylosing spondylitis, pectoris Acne, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, venous osteopathy, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic hyperostosis, intervertebral disc degeneration / hernia pain, nerve root compression, facet joint syndrome, spinal surgery failure syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylolisthesis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmic neuropathy, sarcoidosis, spondylolysis, spondylolisthesis The present invention provides for the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents used to treat or alleviate the severity of conditions such as: angina pectoris, chemotherapy-induced oral mucositis, Charcot arthritis, temporomandibular joint disorder, painful total knee replacement, noncardiac chest pain, pudendal neuralgia, renal colic, biliary tract disease, vascular lower extremity ulcers, pain in Parkinson's disease, pain in Alzheimer's disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina pectoris, exercise-induced angina pectoris, palpitations, hypertension, or abnormal gastrointestinal motility.

[0172] In another aspect, the present invention relates to pain from femoral cancer; 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; splenic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, postherpetic neuralgia; diabetic neuropathy; HIV-related neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy. Peripheral nerve injury; painful neuroma; ectopic proximal and distal discharge; radiculopathy; chemotherapy-induced neuropathic pain; radiation-induced neuropathic pain; persistent / chronic postoperative 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 limb pain (e.g., post-lower limb, upper limb, or mastectomy); intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; arthralgia; mechanical low back pain; neck pain; tenosynovitis; injury pain; movement pain; acute internal Visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pains; cesarean section pain; acute inflammatory pain, burn pain, traumatic pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; toothache; multiple sclerosis (MS) pain; depression pain; leprosy pain; Behçet's disease pain; painful steatosis; phlebitis pain; Guillain-Barré syndrome pain; painful leg and mobile toes The present invention provides for the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents used for the treatment or reduction of the severity of widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain.

[0173] In another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents used for the treatment or reduction of the severity of trigeminal neuralgia, Botox-treated migraine, cervical spondylotic radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexus disorder, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioinguinal neuralgia, pudendal neuralgia, femoral neuropathy, paresthesia of femoral pain, saphenous neuropathy, sciatic neuropathy, fibular neuropathy, tibial neuropathy, lumbosacral plexus disorder, stump pain of traumatic neuroma, or pain after amputation surgery.

[0174] Administration of compounds, pharmaceutically acceptable salts, and compositions In certain embodiments of the present invention, an "effective amount" of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is an amount effective in treating or reducing the severity of one or more of the conditions listed above.

[0175] The compounds, salts, and compositions produced by the methods of the present invention may be administered in any amount and via any route of administration that is effective in treating or alleviating the severity of one or more of the painful or non-painful conditions listed herein. The exact amount required will vary among subjects, depending on the species, age, and general condition of the subject, the severity of the condition, the specific drug, and its mode of administration. The compounds, salts, and compositions of the present invention are preferably formulated in unit dosage forms for ease of administration and uniformity of dosage. As used herein, the term "unit dosage form" refers to a physically distinct drug unit that is appropriate for the subject being treated. However, it will be understood that the total daily dose of the compounds, salts, and compositions of the present invention should be determined by the attending physician within the bounds of sound medical judgment. The specific effective dose level for any particular subject or organism will depend on a variety of factors, including the disorder being treated and its severity; the activity of the specific compound or salt used; the specific composition used; the subject's age, weight, general health, sex, and diet; the timing, route of administration, and rate of excretion of the specific compound or salt used; the duration of treatment; the agents used in combination with or concurrently with the specific compound or salt used; and similar factors well known in the medical technology. As used herein, the terms “subject” or “patient” mean an animal, preferably a mammal, and most preferably a human.

[0176] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisional, vaginally, intraperitoneally, topically (as powder, ointment, or droplets), orally or as a nasal spray to the cheek, etc., depending on the severity of the condition being treated. In certain embodiments, the compounds, salts, and compositions of the present invention may be administered orally or parenterally once daily or more at dose levels of about 0.001 mg / kg to about 1000 mg / kg, which are effective in obtaining the desired therapeutic effect.

[0177] 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 form may include, for example, inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, as well as mixtures thereof. In addition to inert diluents, the oral composition may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0178] Preparations for injection, such as sterile aqueous or oily suspensions for injection, can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile preparations for injection may also be sterile solutions, suspensions, or emulsions for injection in non-toxic, parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution (United States Pharmacopeia), and isotonic sodium chloride solution. Furthermore, sterile fixatives have traditionally been used as solvents or suspension media. For this purpose, any non-irritating fixative, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids such as oleic acid are used in the preparation of injections.

[0179] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0180] To extend the effects of the compounds of the present invention, it is often desirable to delay the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. The absorption rate of the compound then depends on its dissolution rate, which in turn may depend on the crystal size and crystalline form. Alternatively, delaying the absorption of parenterally administered compound forms is achieved by dissolving or suspending the compound in an oil vehicle. Depot formulations for injection are prepared by forming a microencapsulation matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. The compound release rate can be controlled depending on the compound-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydrous). Depot injection formulations are also prepared by encapsulating the compound in liposomes or microemulsions compatible with body tissues.

[0181] A composition for rectal or vaginal administration is preferably a suppository that can be prepared by mixing the compound or salt of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active compound.

[0182] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound or salt is at least one inert, pharmaceutically acceptable excipient or carrier, e.g., sodium citrate or dicalcium phosphate, and / or a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, e.g., glycerol; d) disintegrants, e.g., agar, carbonate It is mixed with calcium, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders, e.g., paraffin; f) absorption enhancers, e.g., quaternary ammonium compounds; g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; h) absorbents, e.g., kaolin and bentonite clay; i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffers.

[0183] Similar types of solid compositions can also be used as fillers in soft and rigid gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in pharmaceutical formulation technology. They may optionally contain opacifying agents and may optionally be compositions that release the active ingredient in a delayed manner, only in or preferentially in a specific part of the intestinal tract. Examples of embedding compositions that can be used include polymer substances and waxes. Similar types of solid compositions can also be used as fillers in soft and rigid gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0184] The active compound or salt may also be in the form of microcapsules containing one or more of the excipients described above. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, controlled-release coatings, and other coatings well known in pharmaceutical formulation technology. In such solid dosage forms, the active compound or salt may be mixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also contain additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose, as is common practice. In the case of capsules, tablets, and pills, the dosage forms may also contain buffers. These may optionally contain opacifiers and may optionally be compositions that release the active ingredient in a delayed manner, only in or preferentially in a specific part of the intestinal tract. Examples of embedding compositions that may be used include polymeric substances and waxes.

[0185] Dosage forms for topical or transdermal administration of the compounds or salts of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and, if necessary, any required preservatives or buffers. Ophthalmic formulations, ear drops, and eye drops are also intended to be within the scope of the present invention. Furthermore, the present invention intends to utilize transdermal patches, which have the additional advantage of providing controlled delivery of the compound into the body. Such dosage forms are prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flow of the compound across the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0186] Generally as described above, the compounds of the present invention are useful as inhibitors of voltage-gated sodium channels. In one embodiment, the compound is Na V1.8 is an inhibitor, and therefore does not wish to be bound by any particular theory, but the compound, salt, and composition are Na V 1.8 is particularly useful for treating or reducing the severity of diseases, conditions, or disorders in which activation or hyperactivity is involved. V 1.8 If the activation or hyperactivity of Na is involved in a particular disease, condition, or disorder, then the disease, condition, or disorder may also be Na V 1.8 A disease, condition, or disorder may be referred to as a mediated disease. Therefore, in another embodiment, the present invention is Na V 1.8 The present invention provides a method for treating or reducing the severity of a disease, condition, or disorder in which activation or hyperactivity of the substance is involved in the disease state.

[0187] Na V The activity of the compounds used in the present invention as inhibitors of 1.8 may be assayed in accordance with methods generally described in International Publication No. 2014 / 120808 A9 and U.S. Publication No. 2014 / 0213616 A1 (both of which are incorporated in their entirety by reference), the methods described herein, and other methods known and available to those skilled in the art.

[0188] Additional medications The compounds, salts, and pharmaceutically acceptable compositions of the present invention can be used in combination therapy, and it will also be understood that the compounds, salts, and pharmaceutically acceptable compositions can be administered simultaneously with, before, or after one or more other desired treatments or medical procedures. The specific combination of therapies (treatments or procedures) used in a combination regimen will take into account the suitability of the desired therapeutic agent and / or procedure, as well as the desired therapeutic effect to be achieved. Naturally, the therapies used may achieve the desired effect for the same disorder (for example, the compounds of the present invention may be administered simultaneously with another agent used to treat the same disorder) or they may achieve a different effect (for example, control of any adverse effect). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease or condition are known to be "appropriate for the disease or condition being treated." For example, exemplary additional therapeutic agents include non-opioid analgesics (indoles, e.g., etodolac, indomethac, sulindac, tolmetine; naphthyl alkanones, e.g., nabumetone; oxicam, e.g., piroxicam; para-aminophenol derivatives, e.g., acetaminophen; propionic acid, e.g., fenoprofen, fluviprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, oxaprozine; salicylates, e.g., aspirin) Examples include, but are not limited to, magnesium choline trisalicylate, diflunisal; fenamet (e.g., meclofenamic acid, mefenamic acid; and pyrazoles (e.g., phenylbutazone)); or opioid (anesthetic) agonists (e.g., codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyfen, buprenorphine, butorphanol, dezosin, nalbufine, and pentazocine). Furthermore, non-pharmacological analgesic approaches may be used in conjunction with the administration of one or more compounds of the present invention.For example, anesthetics (spinal injection, nerve block), neurosurgical procedures (neurolysis of CNS pathways), nerve stimulation (percutaneous electroneurotherapy, dorsal column stimulation), physical therapy (physiotherapy, orthotic devices, diathermy), or psychiatric approaches (cognitive methods - pulmonary function, biofeedback, or behavioral methods) may also be used. Additional appropriate therapeutic agents or approaches are generally described in The Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp & Dohme Corp. (a subsidiary of Merck & Co., Inc.), 2011, and on the website of the Food and Drug Administration (www.fda.gov), the entire contents of which are incorporated herein by reference.

[0189] In another embodiment, additional suitable therapeutic agents are selected from the following: (1) Opioid analgesics, such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, levorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyfen, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butafanol, nalbufine, pentazocine, or diferikephalin. (2) Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flurbiprofen, ibuprofen (intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketrolac (ketrolactromethamine (e.g., Toradol®), but not limited to these), meclofenamic acid, mefenamic acid, meloxicam, IV meloxicam (e.g., Anjeso®), nabumetone, naproxen, nimeslide, nitroflubiprofen, orsalazine, oxaprozine, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetine, or zomepirac, (3) Barbiturate sedatives, such as amobarbital, aprobarbital, butabarbital, butarbital, mefobarbital, metharbital, methexital, pentobarbital, phenobarbital, (4) Benzodiazepines having a sedative effect, for example, chlordiazepoxide, chlorazepatinate, diazepam, flazepam, lorazepam, oxazepam, temazepam, or triazolam. (5) Histamine (H1) antagonists having a sedative effect, for example, diphenhydramine, pyriramine, promethazine, chlorpheniramine, or chlorcyclidine. (6) Sedatives, for example, glutethimid, meprobamate, methaqualone, or dichlorphenazone, (7) Skeletal muscle relaxants, for example, baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphenadrine, (8) NMDA receptor antagonists, e.g., dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextromethorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline kinin, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), combination preparations of morphine and dextromethorphan), topiramate, neramexane or persinfotel containing 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, (9) Alpha-adrenaline, for example, doxazosin, tamsulosin, clonidine, guanfacine, dexemmetomidine, modafinyl, or 4-amino-6,7-dimethoxy-2-(5-methanesulfonamide-l,2,3,4-tetrahydroisoquinoline-2-yl)-5-(2-pyridyl)quinazoline (10) Tricyclic antidepressants, for example, desipramine, imipramine, amitriptyline, or nortriptyline, (11) Anticonvulsants, for example, carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®), or valproic acid, (12) Tachykikinin (NK) antagonists, especially NK-3, NK-2, or NK-1 antagonists, for example, (alpha-R,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[l,4]diazosino[2,1g][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), precipitant, ranepitant, dapitant, or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S), (13) Muscarinic antagonists, for example oxybutynin, tolterodine, propiverine, tropsium chloride, dalifenacin, solifenacin, temiverine, and ipratropium, (14) COX-2 selective inhibitors, e.g., celecoxib, rofecoxib, parecoxib, valdecoxib, delacoxib, etoricoxib, or lumiracoxib, (15) Coal tar analgesics, especially paracetamol, (16) Neuroleptics, for example, droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesolidazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, certindol, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, lacloprid, zotepine, bifepurnox, asenapine, lurasidone, amisulpride, paraperidone, palindore, eprivanserin, osanetant, limonabant, meclinertan, Miraxion®, or sarizotan. (17) Vanilloid receptor agonists (e.g., resinferatoxin or ciboamide) or antagonists (e.g., capsazepine, GRC-15300), (18) Beta-adrenaline, for example, propranolol, (19) Local anesthetics, for example, mexiletine, (20) Corticosteroids, for example, dexamethasone, (21) 5-HT receptor agonists or antagonists, in particular 5-HT receptor agonists such as eletriptan, sumatriptan, naratriptan, zolitriptan, or rizatriptan. 1B / 1D Agonist, (22)5-HT 2A Receptor antagonists, for example, R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907), (23) Cholinergic (nicotinic) analgesics, for example, isopronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinyl methoxy)-2-chloropyridine (ABT-594), or nicotine, (24) Tramadol (registered trademark), Tramadol ER (Ultram ER (registered trademark)), IV Tramadol, Tapentazole ER (Nucynta (registered trademark)), (25) PDE5 inhibitors, e.g., 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulfonyl)phenyl]-1-methyl-3-n-propyl-l, 6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-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-1-yl-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,lf][l,2,4]triazine-4-one (waldenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(l-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4, 3-d]pyrimidine-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(l-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-one, 5-[2-ethoxy-5-(4-ethylpiperazine-1-ylsulfonyl)pyridine-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine- 7-ONE, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidine-1-yl]-N-(pyrimidine-2-ylmethyl)pyrimidine-5-carboxamide, 3-(l-methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo[4,3-d]pyrimidine-5-yl)-N-[2-(l-methylpyrrolidine-2-yl)ethyl]-4-propoxybenzenesulfonamide, (26) Alpha-2-delta ligands, e.g., gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methylgabapentin, (l[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hepta-3-yl)-acetic acid, (3S,5R)-3-aminomethyl-5-methylheptanoic acid, (3S,5R)-3-amino-5-methylheptanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)- Proline, [(lR,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hepta-6-yl]acetic acid, 3-(l-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazole-5-one, C-[1-(1H-tetrazole-5-ylmethyl)-cycloheptile]-methylamine, (3S,4S)-(l-aminomethyl-3,4-dimethylcyclopentyl)acetic acid, (3S,5R)-3-aminomethyl-5-methyloctanoic acid, (3S,5R)-3-amino-5-methylnonanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (3R,4R,5R)-3-amino-4,5-dimethylheptanoic acid, and (3R,4R,5R)-3-amino-4,5-dimethyloctanoic acid, (27) Cannabinoids, e.g., KHK-6188, (28) Metabolic glutamate subtype 1 receptor (mGluRl) antagonists, (29) Serotonin reuptake inhibitors, for example, sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, esitalopram, d,l-fenfluramine, femoxetine, ioxetine, cyanodothiopine, ritoxetine, dapoxetine, nefazodone, sericlamine, and trazodone. (30) Norepinephrine reuptake inhibitors, e.g., maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion, nomifensin, and biloxazine (Vivalan®), in particular selective norepinephrine reuptake inhibitors, e.g., reboxetine, in particular (S,S)-reboxetine, (31) Dual serotonin-norepinephrine reuptake inhibitors, e.g., venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran, and imipramine. (32) Inducible nitric oxide synthase (iNOS) inhibitors, e.g., 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-pyridinecarbonitride; 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-pyridinecarbonitride, 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 guanidinoethyl disulfide, (33) Acetylcholinesterase inhibitors, for example, donepezil, (34) Prostaglandin E2 subtype 4 (EP4) antagonists, for example, N-[({2-[4-(2-ethyl-4,6-dimethyl-lH-imidazo[4,5-c]pyridine-l-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[(15)-l-({[5-chloro-2-(3-fluorophenoxy)pyridine-3-yl]carbonyl}amino)ethyl]benzoic acid, (35) Leukotriene B4 antagonists, e.g., l-(3-biphenyl-4-ylmethyl-4-hydroxychroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]valeric acid (ONO-4057) or DPC-11870, (36) 5-lipoxygenase inhibitors, e.g., dileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxymethyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504), (37) Sodium channel blockers, e.g., lidocaine, lidocaine + tetracaine cream (ZRS-201), or eslicarbazepine acetate, (38) Na V1.7 Blockers, e.g., XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893, BIIB-074 (bixotrigine), BIIB-095, ASP-1807, DSP-3905, OLP-1002, RQ-00432979, FX-301, DWP-1706, DWP-17061, IMB-110, IMB-111, IMB-112, and WO2011 / 140425 (US2011 / 306607); WO2012 / 106499 (US2012 196869);WO2012 / 112743(US2012245136);WO2012 / 125613(US2012264749), WO2012 / 116440(US201 4187533), WO2011026240(US2012220605), US8883840, US8466188, WO2013 / 109521(US2015005304), As disclosed in 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 are incorporated herein by reference), (38a)Na V1.7 Blockers, e.g., (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl)-(4-isopropoxy-3-methylphenyl)methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydro Ropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]-(4-isobutoxy-3-methoxyphenyl)methanone, 1-(4-benzhydrylpiperazine-1-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy]propan-2-ol, (4-butoxy-3-methoxyphenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-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-methylphenyl)-[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-carbonilicate, (4-isopropoxy-3-methylphenyl)-[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-methylpyridine-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-methoxyphenyl)-[2-methyl-6-(trifluoromethyl (L)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- [Iyl]-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-methylpyridine-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-methylphenyl)-[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, (39) Na V1.8 Blockers, e.g., PF-04531083, PF-06372865, and e.g., WO2008 / 135826 (US2009048306), WO2006 / 011050 (US2008312235), WO2013 / 061205 (US2014296313), US20130303535, WO2013131018, US8466188, WO2013114250 (US2013274243), WO2014 / 120808 (US2014 213616), WO2014 / 120815(US2014228371)WO2014 / 120820(US2014221435), WO2015 / 010065(US20160152561), WO2015 / 089361 (US20150166589), WO2019 / 014352(US20190016671), WO2018 / 213426, WO2020 / 146682, WO2020 / 146612, WO2020 / 014243, WO202 0 / 014246, WO2020 / 092187, WO2020 / 092667(US2020140411), WO2020 / 144375, WO2020 / 261114, WO2020 / 140959, WO2020 / 15172 8, WO2021 / 032074, WO2021 / 047622(CN112479996), WO2021 / 257490, WO2021 / 257420, WO2021 / 257418, WO2022 / 263498, WO2022 Disclosed in / 235558, WO2022 / 235859, WO2023 / 138599, WO2024 / 041613, WO2024 / 046253, WO2024 / 046409, CN112390745, CN111808019, CN112225695, CN112457294, CN112300051, CN112300069, CN112441969, and CN114591293 (the entire contents of each application are incorporated herein by reference), (39a)Na V1.8 Blockers, e.g., 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)-4-(perfluoroethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)benzamide, 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2- Xo-1,2-dihydropyridine-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)-5-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridine-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)-4-(perfluoroethyl)benzamide, 5-chloro-2-(4 -Fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)benzamide, N-(2-oxo-1,2-dihydropyridine-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)-5-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)- 5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)benzamide, 4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)benzamide, 2-((5-fluoro-2-hydroxybenzyl)oxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridine-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide, 2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridine-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluoro Phenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1H-pyridine-4-yl)-4-(trifluoromethyl)benzamide, [4-[[2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate, 2-(4-fluoro-2-(methyl-d3)phenoxy)-N-(2-oxo-1,2-dihydropyridine-4- (Iyl)-4-(trifluoromethyl)benzamide, (4-(2-(4-fluoro-2-(methyl-d3)phenoxy)-4-(trifluoromethyl)benzamide)-2-oxopyridine-1(2H)-yl)methyldihydrogen phosphate, 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-methoxyphenoxy)-N-( 3-Sulfamoylphenyl)Quinoxaline-2-Carboxamide, 3-(4-Chloro-2-Methoxyphenoxy)-N-(3-Sulfamoylphenyl)Quinoxaline-2-Carboxamide, 4-(3-(4-(Trifluoromethoxy)phenoxy)Quinoxaline-2-Carboxamide)Picolinic Acid, 2-(2,4-Difluorophenoxy)-N-(3-Sulfamoylphenyl)Quinoline-3-Carboxamide, 2-(4-Fluoro-2-Methoxyphenoxy)-N-(3-Sulfamoylphenyl)Quinoline-3-Carboxamide, 3-(2,4-Difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoline-3-carboxamide, N-(3-sulfamoylphenyl)-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide, 3-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)quinoxaline- 2-Carboxamide, 5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide)picolinic acid, 3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)quinoxaline-2-carboxamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridine-4-yl)quinoxaline-2-carboxamide, 3-(4-fluorophenoxy)-N- (3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, N-(4-carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide)benzoic acid, N-(4-cyanophenyl)-3-(4 -Fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamide)picolinic acid, 5-(2-(2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamide)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamide)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4,6-Bis(trifluoromethyl)benzamide) picolinic acid, 4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamide) benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamide) picolinic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide) benzoic acid, 5-(4,5-Dichloromethyl 4-(4-fluoro-2-methoxyphenoxy)benzamide) picolinic acid, 4-(2-(2-chloro-4-fluorophenoxy)-4-(perfluoroethyl)benzamide) benzoic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(perfluoroethyl)benzamide) benzoic acid, 4-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamide) benzoic acid, 4-(4, 5-Dichloro-2-(4-chloro-2-methylphenoxy)benzamide)benzoic acid, 5-(4-(tert-butyl)-2-(4-fluoro-2-methoxyphenoxy)benzamide) picolinic acid, 5-(4,5-Dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamide) picolinic acid, 4-(4,5-Dichloro-2-(4-fluoro-2-methylphenoxy)benzamide)benzoic acid, 5-(4,5- Dichloro-2-(2,4-dimethoxyphenoxy)benzamide) picolinic acid, 5-(4,5-dichloro-2-(2-chloro-4-fluorophenoxy)benzamide) picolinic acid, 5-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamide) picolinic acid, 4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamide) benzoic acid, 5-(4,5-dichloro-2-(2,4-Difluorophenoxy)benzamide)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- Luorofenoxy)-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 Mido, 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-(triduteriomethoxy)-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-pheni, N-(3-carbamoyl-4-fluorophenyl)-3 -(difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, 4-[[2-fluoro-6-[2-(triduteriomethoxy)-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-fluorophenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[2-fluoro-6-[2-(triduteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluorophenyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluorophenyl)-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-(triduteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluorophenyl)-2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzamide, or 4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, (40)Na V 1.7 and Na V 1.8 Combinations of blockers, e.g., DSP-2230, Lohocla201 or BL-1021, (41) 5-HT3 antagonists, e.g., ondansetron, (42) TPRV1 receptor agonists, such as capsaicin (NeurogesX®, Qutenza®), and pharmaceutically acceptable salts and solvates thereof. (43) Nicotinic receptor antagonists, e.g., varenicline, (44) N-type calcium channel antagonists, e.g., Z-160, (45) Nerve growth factor antagonists, e.g., tanezumab, (46) Endopeptidase stimulants, e.g., senlevotase, (47) Angiotensin II antagonists, e.g., EMA-401, (48) Acetaminophen (including, but not limited to, intravenous acetaminophen (e.g., Ofrmev®)), (49) Bupivacaine (including, but not limited to, bupivacaine liposome injection suspension (e.g., Exparel®), bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll), and transdermal bupivacaine (Eladur®)), and (50) A combination of bupivacaine and meloxicam (e.g., HTX-011).

[0190] In one embodiment, additional suitable therapeutic agents are selected from V-116517, pregabalin, sustained-release pregabalin, ezogabine (Potiga®), ketamine / amitriptyline topical cream (Amiket®), AVP-923, Perampanel (E-2007), rufinamide, transdermal bupivacaine (Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561, or ARC-4558.

[0191] In another embodiment, additional suitable therapeutic agents are selected from N-(6-amino-5-(2,3,5-trichlorophenyl)pyridine-2-yl)acetamide, N-(6-amino-5-(2-chloro-5-methoxyphenyl)pyridine-2-yl)-1-methyl-1H-pyrazole-5-carboxamide, or 3-((4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)methyl)oxetane-3-amine.

[0192] In another embodiment, additional therapeutic agents are selected from GlyT2 / 5HT2 inhibitors, e.g., Operanserin (VVZ149), TRPV modulators, e.g., CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101, MDR16523, or MDR652, EGR1 inhibitors, e.g., Brivoglide (AYX1), NGF inhibitors, e.g., tanezumab, facinumab, ASP6294, MEDI7352, Mu opioid agonists, e.g., cebranopadol, NKTR181 (oxycodegol), CB-1 agonists, e.g., NEO1940 (AZN1940), imidazoline 12 agonists, e.g., CR4056, or p75NTR-Fc modulators, e.g., LEVI-04.

[0193] In another embodiment, the additional therapeutic agent is oryceridine or ropivacaine (TLC590).

[0194] In another embodiment, the additional therapeutic agent is Na V 1.7 Blockers, e.g., ST-2427 or ST-2578, as disclosed in WO2010 / 129864, WO2015 / 157559, WO2017 / 059385, WO2018 / 183781, WO2018 / 183782, WO2020 / 072835, and / or WO2022 / 036297 (the entire contents of each application are incorporated herein by reference).

[0195] In another embodiment, additional therapeutic agents include ASP18071, CC-8464, ANP-230, ANP-231, NOC-100, NTX-1175, ASN008, NW3509, AM-6120, AM-8145, AM-0422, BL-017881, NTM-006, Opiranserin (Unafra®), Brivolizide, 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 Selected from 7352 and XT-150.

[0196] In another embodiment, additional therapeutic agents are 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.

[0197] In another embodiment, additional therapeutic agents include HRS4800, ODM-111 / JMKX000623, LX9211, LY3556050, LY3857210, CFTX01554 / CFTX-1554, MEDI7352, MEDI0618, BAY3178275, BAY2395840, GSK3858279, STC-004, HALNEURON, and OLP-1. Select from 002, ATX01, ANP230, CC-8464, iN1011-N17, ST-2427, MSD199, FZ008, VYNAV-01, BL-017881, Profervia (silnidipine), LS-04, bixotrigine, FX301 / PCRX-301, PF-04531083, PF-01247324, and DSP-3905.

[0198] In another embodiment, the additional therapeutic agent is the Na identified above. V 1.7 and Na V 1.8 These are sodium channel inhibitors (also known as sodium channel blockers), such as 1.8-blockers.

[0199] The amount of additional therapeutic agents present in the composition of the present invention may be less than or equal to the amount typically administered in a composition containing the therapeutic agent as the sole active agent. The amount of additional therapeutic agents in the composition of this disclosure may range from about 10% to 100% of the amount typically present in a composition containing the agent as the sole therapeutic active agent.

[0200] The compounds and salts of the present invention, or pharmaceutically acceptable compositions thereof, may also be incorporated into compositions for coating implantable medical devices such as prostheses, prosthetic valves, vascular grafts, stents, and catheters. Therefore, in another embodiment, the present invention includes compositions for coating implantable devices, generally comprising the compounds or salts of the present invention described above, as well as the classes and subclasses herein, and carriers suitable for coating such implantable devices. In yet another embodiment, the present invention includes implantable devices coated with compositions comprising the compounds or salts of the present invention described above, as well as the classes and subclasses herein, and carriers suitable for coating such implantable devices. General preparations of suitable coatings and coated implantable devices are described in U.S. Patents 6,099,562, 5,886,026, and 5,304,121. The coatings are typically biocompatible polymer materials such as hydrogel polymers, polymethyldisiloxanes, polycaprolactones, polyethylene glycols, polylactic acid, ethylene vinyl acetates, and mixtures thereof. The coating may be further covered with a suitable top coating of fluorosilicone, polysaccharide, polyethylene glycol, phospholipid, or a combination thereof, as needed, to impart sustained-release properties to the composition.

[0201] Another aspect of the present invention is Na in a biological sample or subject. V 1.8 With regard to inhibiting activity, the method includes administering to a subject or contacting the biological sample with the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. As used herein, the term “biological sample” includes, but is not limited to, cell cultures or extracts thereof, biopsy materials obtained from mammals or extracts thereof, and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[0202] Na in biological samples V1.8 Inhibition of activity is useful for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, the study of sodium channels in biological and pathological phenomena, and the comparative evaluation of novel sodium channel inhibitors.

[0203] Synthesis of the Compound of the Present Invention The compounds of the present invention can be prepared from known materials by the methods described in the examples, other similar methods, and other methods known to those skilled in the art. As will be understood by those skilled in the art, the functional groups of the intermediate compounds in the following methods may need to be protected by suitable protecting groups. Protecting groups may be added or removed according to standard techniques well known to those skilled in the art. The use of protecting groups is described in detail in TGMWuts et al., Greene's Protective Groups in Organic Synthesis (4th ed. 2006).

[0204] Radially labeled compound of the compound of the present invention In another aspect, the present invention relates to radiolabeled analogues of the compounds of the present invention. As used herein, the term “radiolabeled analogue of the compounds of the present invention” means a compound that is identical to the compounds of the present invention described herein, except that one or more atoms are replaced with radioisotopes of atoms present in the compounds of the present invention, including all embodiments thereof.

[0205] As used herein, the term “radioisotope” refers to an isotope of an element known to undergo spontaneous radioactive decay. Examples of radioisotopes include: 3 H, 14 C, 32 P, 35 S, 18 F, 36Examples include Cl, as well as isotopes whose decay modes have been identified in V.S. Shirley & CMLederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0206] Radiolabeled analogs can be used in many beneficial ways, including various types of assays such as substrate tissue distribution assays. For example, tritium ( 3 H) Labeling and / or carbon-14 ( 14 C) Labeled compounds are particularly useful in various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detection capabilities.

[0207] In another aspect, the present invention relates to pharmaceutically acceptable salts of radiolabeled analogs according to any of the embodiments described herein relating to the compounds of the present invention.

[0208] In another aspect, the present invention relates to a pharmaceutical composition comprising a radiolabeled analog or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle, according to any embodiment described herein in relation to the compound of the present invention.

[0209] In another aspect, the present invention relates to a method for inhibiting voltage-gated sodium channels, and a method for treating or reducing the severity of various diseases and disorders, including pain, in a subject, comprising administering an effective amount of a radiolabeled analog, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof, as described herein in relation to the compounds of the present invention.

[0210] In another aspect, the present invention relates to radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof for use in accordance with any of the embodiments described herein relating to the compounds of the present invention.

[0211] In another aspect, the present invention relates to the use of radiolabeled analogs or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of pharmaceuticals, according to any of the embodiments described herein relating to the compounds of the present invention.

[0212] In another embodiment, radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof may be used in combination therapy according to any of the embodiments described herein relating to the compounds of the present invention.

[0213] List of embodiments Further embodiments of this disclosure are described in the following numbered clauses. 1. Compound of formula (IA), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 1 However, CR 1 or N, X 2 However, CR 2 , N, or N + -O - And, X 3 However, CR 3 , N, or N + -O - And, X 5 However, CR 5 , N, or N + -O - And, p, X a , and X b The following applies: (i) p is 1, X a CR 11 R 12 X b Is it O? (ii) p is 1, X a O is X b CR 13 R 14 is, or (iii) p is 0, Xb It is defined that O, X s However, CR s or N, X t However, CR t or N, R 1 However, H, OH, halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -(CH2) m O n (CH2) o OCH3, -(CH2) m R a -C(O)(CH2) m R a , -C(O)OR b , -C(O)R b -C(O)NR b R c , -NR b R c ,-CR d R e R f ,-CR b R c NR g C(O)CR h R i R j , -NR b C(O)CR c R g R j The C3-C6 cycloalkyl, 5-6 member heteroaryl, or 4-10 member heterocyclil may be unsubstituted, or it may be substituted with 1-4 substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. R 2 , R 3 , R 4 , and R 5 However, each is independent of H, OH, CN, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -NHS(O)2(C1-C6 alkyl), -C(O)OR b, -C(O)NR b R c , -(CH2) m O(CH2) o CH3, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl, wherein the 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl may be unsubstituted, or may be substituted with 1 to 4 substituents independently selected from C1-C6 alkyl and -C(O)NR b R c , R 6 , R 7 , R 8 , and R 9 are defined as follows: (i) R 6 and R 7 are each independently H, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy, R 8 and R 9 are each independently H, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy, or (ii) R 6 and R 7 are each independently H, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy, R 8 and R 9 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl, or (iii) R 6 , R 7 , R 8 , and R 9 together with the carbon atom to which they are attached form a fused C6-C y aryl optionally substituted with 1 to 3 R 10 , R 10 is H or CH3, R 11 and R 12However, each is independently H, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. R 13 and R 14 However, each is independently H, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. R s and R t However, each is independent of H, OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl, -NR b R c -NO2, -SO3H, -(CH2) m Ure b , or -O(CH2) m Is it OCH3, or R s and R t Together with the carbon atoms to which they are bonded, the formula [ka] Forming a ring, Y is either O or CH2. R u , R v , and R w However, each is independent of H, OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -NR b R c -NO2, -SO3H, -(CH2) m Ure b , or -O(CH2) m It is OCH3, Each R x However, independently, they are H, halo, C1-C6 alkyl, or C1-C6 haloalkyl. Each R y However, independently, these are H, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. R aHowever, OH, halo, C1-C6 alkoxy, or -NR b R c And, R b , R c , R g , R h , and R i However, each is independently either H or C1-C6 alkyl, or R b and R c These, together with the nitrogen atom to which they are bonded, form a 3-6 member heterocycline. R d , R e , and R f However, each is independently H, OH, halo, C1-C6 alkyl, or C1-C6 alkoxy. R j However, H, C1-C6 alkyl, -NR b R c , or -N(CH3)3 + And, m and o are independently 0, 1, 2, or 3. A compound, or a pharmaceutically acceptable salt thereof, in which n is 0 or 1. 2.X a However, it is CH2, X b However, it is O, R 6 and R 7 However, each is independently H, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. R 8 and R 9 However, each is independently H, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy, or R 8 and R 9 These, together with the carbon atoms to which they are bonded, form a C3-C6 cycloalkyl group. R s and R t However, each is independent of H, OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -NRb R c , -NO2, -SO3H, -(CH2) m OR b , or -O(CH2) m OCH3, or R s and R t together with the carbon atom to which they are attached, form the ring of the formula [Chemical Formula] , p is 0 or 1, the compound according to clause 1, or a pharmaceutically acceptable salt thereof. 3. R 1 is H, OH, halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -C(O)OR b , R 10 is H, R s and R t are each independently H, OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -NR b R c , -NO2, -SO3H, -(CH2) m OR a , or -O(CH2) m OCH3, or R s and R t together with the carbon atom to which they are attached, form the ring of the formula [Chemical Formula] , the compound according to clause 1 or 2, or a pharmaceutically acceptable salt thereof. 4. The compound according to any one of clauses 1 to 3, wherein p is 0, or a pharmaceutically acceptable salt thereof. 5. The compound according to any one of clauses 1 to 3, wherein p is 1, or a pharmaceutically acceptable salt thereof. 6. p is 1, and X a is CR 11 R 12 , and X bA compound described in any one of clauses 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound is O. 7.R 11 However, the compound described in Clause 6, or a pharmaceutically acceptable salt thereof, is H. 8.R 12 A compound described in Clause 6 or 7, or a pharmaceutically acceptable salt thereof, wherein H is present. 9. p is 1, X a However, O and X b However, CR 13 R 14 The compound described in any one of clauses 1 to 3, or a pharmaceutically acceptable salt thereof. 10.R 13 The compounds described in Clause 9, or pharmaceutically acceptable salts thereof, which are C1-C6 alkyl or C1-C6 haloalkyl. 11.R 13 The compounds described in Clause 10, or pharmaceutically acceptable salts thereof, which are -CH3 or -CF3. 12.R 14 The compound described in any one of clauses 9 to 11, which is a C1-C6 alkyl or C1-C6 haloalkyl, or a pharmaceutically acceptable salt thereof. 13.R 14 However, the compounds described in Clause 12, or pharmaceutically acceptable salts thereof, which are -CH3 or -CF3. 14. The compound is a compound described in any one of clauses 1 to 5 having formula (IA-1), or a pharmaceutically acceptable salt thereof. [ka] 15.X 1 However, the compound described in any one of clauses 1 to 14, or a pharmaceutically acceptable salt thereof, is N. 16.X 1 However, CR 1 And R 1 However, H, CN, C1-C6 alkyl, C1-C6 alkoxy, or -C(O)OR b The compound described in any one of clauses 1 to 15, or a pharmaceutically acceptable salt thereof. 17.R1 The compounds described in Clause 16, or pharmaceutically acceptable salts thereof, wherein the compound is H, CN, -CH3, -OCH3, -C(O)OCH3, or -C(O)OCH2CH3. 18.X 2 However, the compound described in any one of clauses 1 to 17, or a pharmaceutically acceptable salt thereof, is N. 19.X 2 However, CR 2 And R 2 However, H, OH, CN, halo, C1-C6 alkyl, C1-C6 alkoxy, -NHS(O)2(C1-C6 alkyl), -C(O)OR b -C(O)NR b R c , 5-6 member heteroaryl, or 5-6 member heterocyclil, Even if a 5-6 membered heteroaryl or 5-6 membered heterocyclyl is not substituted, C1-C6 alkyl and -C(O)NR b R c A compound described in any one of clauses 1 to 17, or a pharmaceutically acceptable salt thereof, which may also be substituted with 1 to 4 substituents independently selected from the compound. 20.R 2 is H, Cl, F, OH, CN, -CH3, -OCH3, -C(O)OH, -C(O)NH2, -C(O)N(H)CH3, -N(H)S(O)2(CH3), [ka] The compounds described in Article 19, or their pharmaceutically acceptable salts. 21.X 3 However, the compound described in any one of clauses 1 to 20, or a pharmaceutically acceptable salt thereof, is N. 22.X 3 However, CR 3 And R 3 However, H, CN, halo, C1-C6 alkoxy, -C(O)OR b , or -C(O)NR b R c The compound described in any one of clauses 1 to 20, or a pharmaceutically acceptable salt thereof. 23.R 3 The compounds described in Clause 22, or pharmaceutically acceptable salts thereof, wherein the compound is H, Cl, F, CN, -OCH3, -C(O)OCH3, or -C(O)N(CH3)2. 24.R 4 However, H, halo, C1-C6 alkyl, -C(O)OR b , or -C(O)NR b R c The compound described in any one of clauses 1 to 23, or a pharmaceutically acceptable salt thereof. 25.R 4 The compounds described in Clause 24, or pharmaceutically acceptable salts thereof, wherein the compound is H, Cl, F, -CH3, -C(O)OCH2CH3, or -C(O)NH2. 26.X 5 However, the compound described in any one of clauses 1 to 25, or a pharmaceutically acceptable salt thereof, is N. 27.X 5 However, CR 5 And R 5 However, H, halo, or -C(O)NR b R c The compound described in any one of clauses 1 to 25, or a pharmaceutically acceptable salt thereof. 28.R 5 The compound described in Clause 27, or a pharmaceutically acceptable salt thereof, wherein the compound is H, F, or -C(O)NH2. 29.R 7 A compound described in any one of Clauses 1 to 28, or a pharmaceutically acceptable salt thereof, wherein the compound is H, OH, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. 30.R 7 The compound described in Clause 29, or a pharmaceutically acceptable salt thereof, wherein the compound is H, OH, -OCH3, -CH3, or cyclopropyl. 31.R 8 and R 9 However, each is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl, or R 8 and R 9The compounds described in any one of Clauses 1 to 30, or pharmaceutically acceptable salts thereof, which together with the carbon atoms to which they are bonded, form a C3-C6 cycloalkyl group. 32.R 8 A compound described in any one of clauses 1 to 31, which is H or C1-C6 alkyl, or a pharmaceutically acceptable salt thereof. 33.R 8 The compound described in Clause 32, or a pharmaceutically acceptable salt thereof, wherein the compound is H, -CH3, or -CH2CH3. 34.R 9 A compound described in any one of clauses 1 to 33, which is H, C1-C6 alkyl, or C1-C6 haloalkyl, or a pharmaceutically acceptable salt thereof. 35.R 9 The compound described in Clause 34, or a pharmaceutically acceptable salt thereof, wherein the compound is H, -CH3, or -CF3. 36.R 8 and R 9 The compounds described in any one of Clauses 1 to 31, or pharmaceutically acceptable salts thereof, which together with the carbon atoms to which they are bonded, form a C3-C6 cycloalkyl group. 37.R 8 and R 9 The compounds described in Clause 36, or pharmaceutically acceptable salts thereof, which, together with the carbon atoms to which they are bonded, form cyclobutane. 38.R 6 , R 7 , R 8 , and R 9 These, together with the carbon atoms to which they are bonded, form 1 to 3 R atoms as needed. y Substituted with, condensed C6-C 10 Compounds described in any one of the clauses 1-13 or 15-28 that form an aryl group, or pharmaceutically acceptable salts thereof. 39.R 6 , R 7 , R 8 , and R 9 The compounds described in Clause 38, or pharmaceutically acceptable salts thereof, which, together with the carbon atoms to which they are bonded, form a condensed phenyl. 40.R 10 A compound described in any one of clauses 1 to 39, or a pharmaceutically acceptable salt thereof, wherein H is present. 41.X s However, the compound described in any one of clauses 1 to 40, or a pharmaceutically acceptable salt thereof, is N. 42.X s However, CR s And R s However, H, OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -(CH2) m Ure b , or -O(CH2) m A compound that is OCH3, as described in any one of clauses 1 to 40, or a pharmaceutically acceptable salt thereof. 43.X s However, CR s And R s The compounds described in Clause 42, or pharmaceutically acceptable salts thereof, wherein the compound is H, F, Cl, OH, -CH3, -CH2OH, -CH2OCH3, -OCH3, cyclopropyl, -OCH(CH3)2, or -OCH2CH2OCH3. 44.X s However, CR s And R s However, H, OH, halo, C1-C6 alkyl, C1-C6 alkoxy, -(CH2) m Ure b , or -O(CH2) m A compound that is OCH3, as described in any one of clauses 1 to 40, or a pharmaceutically acceptable salt thereof. 45.R s The compounds described in Clause 44, or pharmaceutically acceptable salts thereof, wherein the compound is H, F, OH, -CH3, -CH2OH, -OCH3, -OCH(CH3)2, or -OCH2CH2OCH3. 46.X t However, the compound described in any one of clauses 1 to 45, or a pharmaceutically acceptable salt thereof, is N. 47.X t However, CR t And R tA compound according to any one of clauses 1 to 45, wherein the compound is H, halo, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl. 48.X t However, CR t And R t The compound according to Clause 47, wherein the compound is H, Cl, F, -CH3, -OCH3, or cyclopropyl. 49.X t However, CR t And R t A compound according to any one of clauses 1 to 45, wherein the compound is H, halo, C1-C6 alkyl, or C1-C6 alkoxy. 50.R t The compound described in Clause 49, wherein the compound is H, Cl, F, -CH3, or -OCH3. 51.R s and R t Together with the carbon atoms to which they are bonded, the formula [ka] A compound described in any one of clauses 1 to 40, or a pharmaceutically acceptable salt thereof, which forms a ring. 52.R s and R t Together with the carbon atoms to which they are bonded, the formula [ka] A compound described in Clause 51, or a pharmaceutically acceptable salt thereof, that forms a ring. 53.R u A compound described in any one of clauses 1 to 52, wherein the compound is H, halo, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl, or a pharmaceutically acceptable salt thereof. 54.R u The compound described in Clause 53, or a pharmaceutically acceptable salt thereof, wherein the compound is H, F, or -CH3. 55.R v A compound described in any one of clauses 1 to 54, or a pharmaceutically acceptable salt thereof, wherein the compound is H, halo, or C1-C6 alkyl. 56.R v The compound described in Clause 55, or a pharmaceutically acceptable salt thereof, which is H, F, or -CH3. 57.R v A compound described in any one of clauses 1 to 54, which is H or C1-C6 alkyl, or a pharmaceutically acceptable salt thereof. 58.R v The compound described in Clause 57, or a pharmaceutically acceptable salt thereof, wherein the compound is H or -CH3. 59.R w A compound described in any one of clauses 1 to 58, or a pharmaceutically acceptable salt thereof, wherein H is present. 60. The compound is a compound described in any one of clauses 1 to 5 having formula (IA-2), or a pharmaceutically acceptable salt thereof. [ka] 61.R 7 A compound described in any one of clauses 1 to 5 and 60, which is H, C1-C6 alkyl, or C1-C6 alkoxy, or a pharmaceutically acceptable salt thereof. 62.R 7 The compound described in Clause 60, or a pharmaceutically acceptable salt thereof, wherein the compound is H, -CH3, or -OCH3. 63.R 7 A compound described in any one of clauses 1 to 5 and 60, which is H or a C1-C6 alkoxy, or a pharmaceutically acceptable salt thereof. 64.R 7 The compound described in Clause 63, or a pharmaceutically acceptable salt thereof, wherein the compound is H or -OCH3. 65.R s However, H, halo, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or -(CH2) m Ure b The compounds described in any one of clauses 1-5 and 60-64, or pharmaceutically acceptable salts thereof. 66.R sThe compound described in Clause 65, or a pharmaceutically acceptable salt thereof, wherein the compound is H, F, Cl, -CH3, -OCH3, cyclopropyl, or -CH2OCH3. 67.R s The compound described in any one of clauses 1-5 and 60-64, which is a C1-C6 alkyl or C1-C6 alkoxy, or a pharmaceutically acceptable salt thereof. 68.R s However, the compounds described in Clause 67, or pharmaceutically acceptable salts thereof, which are -CH3 or -OCH3. 69.R t A compound described in any one of clauses 1-5 and 60-68, or a pharmaceutically acceptable salt thereof, wherein the compound is H, halo, C1-C6 alkyl, or C3-C6 cycloalkyl. 70.R t The compounds described in Clause 69, or pharmaceutically acceptable salts thereof, wherein the compound is H, F, Cl, -CH3, or cyclopropyl. 71.R t A compound described in any one of clauses 1-5 and 60-68, or a pharmaceutically acceptable salt thereof, wherein H is or a halo. 72.R t However, the compounds described in Clause 71, or pharmaceutically acceptable salts thereof, which are H or F. 73. A compound selected from Table A, or a pharmaceutically acceptable salt thereof. 74. A compound selected from Table B, or a pharmaceutically acceptable salt thereof. 75. A compound selected from Table C, or a pharmaceutically acceptable salt thereof. 76. A compound selected from Table D, or a pharmaceutically acceptable salt thereof. 77. A compound described in any one of the clauses 1 to 76, which is in a non-salt form. 78. A pharmaceutical composition comprising a therapeutically effective amount of a compound described in any one of clauses 1 to 76 or a pharmaceutically acceptable salt thereof, or a compound described in clause 77, and one or more pharmaceutically acceptable carriers or vehicles. 79. A pharmaceutical composition comprising a compound described in any one of clauses 1 to 76 or a pharmaceutically acceptable salt thereof, or a compound described in clause 77, and one or more pharmaceutically acceptable carriers or vehicles. 80. A method for inhibiting voltage-gated sodium channels in a subject, comprising administering to the subject a compound described in any one of Clauses 1 to 76 or a pharmaceutically acceptable salt thereof, a compound described in Clause 77, or a pharmaceutical composition described in Clause 78 or 79. 81. Voltage-gated sodium channels, Na V 1.8 The method described in Article 80. 82. A method for treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of clauses 1 to 76, a compound described in clause 77, or a pharmaceutical composition described in clause 78 or 79. 83. The method according to Clause 82, wherein the method includes treating neuropathic pain or reducing its severity in a subject. 84. The method according to Clause 83, wherein neuropathic pain includes postherpetic neuralgia. 85. The method according to Clause 83, wherein neuropathic pain includes small fiber neuropathy. 86. The method according to Clause 83, wherein neuropathic pain includes idiopathic small fiber neuropathy. 87. The method according to Clause 83, wherein neuropathic pain includes diabetic neuropathy. 88. The method according to Clause 87, wherein diabetic neuropathy includes diabetic peripheral neuropathy. 89. The method of Article 82, wherein the method includes treating musculoskeletal pain or reducing its severity in a subject. 90. The method according to Clause 89, wherein musculoskeletal pain includes osteoarthritis pain. 91. The method of Article 82, wherein the method includes treating acute pain or reducing its severity in a subject. 92. The method according to Clause 91, wherein acute pain includes acute postoperative pain. 93. The method of Article 82, wherein the method includes treating postoperative pain or reducing its severity in a subject. 94. Postoperative pain, including pain from a banyon excision, as described in Clause 93. 95. Postoperative pain, including abdominal wall reconstruction pain, as described in Clause 93. 96. Postoperative pain, including pain from hernia repair surgery, as described in Clause 93. 97. The method of Article 82, wherein the method includes treating visceral pain or reducing its severity in a subject. 98. The method according to any one of the clauses 80 to 97, wherein the subject is treated simultaneously with, or before, treatment with, one or more additional therapeutic agents administered concurrently with, treatment with a compound, a pharmaceutically acceptable salt, or a pharmaceutical composition. 99. Use as a drug of any compound described in any one of Clauses 1 to 76 or a pharmaceutically acceptable salt thereof, a compound described in Clause 77, or a pharmaceutical composition described in Clause 78 or 79. [Examples]

[0214] Basic method. 1 The 1H NMR spectrum was obtained as a solution in a suitable deuterated solvent such as dimethyl sulfoxide-d6 (DMSO-d6).

[0215] Compound purity, retention time, and electrospray mass spectrometry (ESI-MS) data were determined by LC / MS analysis.

[0216] LC / MS method: [Table 6-1] [Table 6-2]

[0217] Abbreviation Unless otherwise stated, or as the context indicates, the following abbreviations should be understood to have the following meanings: [Table 7-1] [Table 7-2]

[0218] Example 1 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthyridine-4(1H)-one(1) [ka] Step 1: (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (intermediate A, 96 mg, 0.27 mmol), 4-benzyloxy-2-chloro-1,6-naphthyridine (intermediate K, 100 mg, 0.369 mmol), K2CO3 (75 mg, 0.543 mmol), 4-methoxy-2-(4-methoxy-2-pyridyl)pyridine (6 mg, 0.028 mmol), nickel(II) chloride dimethoxyethane adduct (6 mg, 0.027 mmol), and (Ir[dF(CF3)ppy]2(dtbpy))PF6 (6 mg, 0.005 mmol) were added to a 20 mL vial equipped with a stirring rod, which had been dried with a heat gun. DMF (5.3 mL) was injected into a tube by syringe under a nitrogen atmosphere. The mixture was degassed for 15 minutes by bubbling with nitrogen and then sealed with Parafilm. The solution was then stirred at 30°C for 17 hours under blue LED (450 nm) irradiation using a Penn OC Photoreactor M2. The mixture was diluted with water (10 mL) and brine (100 mL), and the organic layer was extracted with toluene (3 × 50 mL). The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under vacuum. Preparative reverse-phase HPLC (C) was performed. 18 Purification by column chromatography over 30 minutes using 30-99% ACN in water containing 5 mM HCl modifier yielded 4-(benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthirizine (61.2 mg, 41%) as a pale yellow solid. ESI-MS m / z calculated value: 544.179, measured value: 545.3 (M+1). + ;Retention time: 2.62 minutes, using LC / MS method Q.

[0219] Step 2: A solution of 4-(benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthiridine (61.2 mg) in ethyl acetate (2.7 mL) was added to a 20 mL vial containing Pd / C (10 wt% packed, wet, Degussa, 15 mg, 0.014 mmol). The reaction mixture was degassed under nitrogen for 5 minutes and stirred under a hydrogen atmosphere for 5 minutes. The mixture was heated to 40°C for 15 minutes under a hydrogen atmosphere. The reaction mixture was filtered through a Celite® pad and washed with ethyl acetate. The filtrate was concentrated under vacuum to obtain a yellow solid. Preparative reverse-phase HPLC (C 18 Purification by column chromatography over 30 minutes with 1-99% ACN in water containing 5 mM HCl modifier yielded 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthyrizine-4(1H)-one (1, 9.4 mg, 8%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 12.53(s,1H),9.27(s,1H),8.69(s,1H),8.09(s,1H),7.30(ddd,J=8.3,5.8,2.0Hz,1H),7.21-7.09(m,1H),6.57(s,1H),5.55(d,J= ESI-MS m / z calculated value 454.132, actual value 455.3(M+1) + ;Retention time: 1.81 min, using LC / MS method Q.

[0220] The following compounds were prepared using the same method as described in Example 1, except that a different coupling partner was used in Step 1. In Step 2, EtOH or MeOH was used as the solvent instead of ethyl acetate, and the reaction was carried out at ambient temperature. [Table 8-1] [Table 8-2]

[0221] The following compounds were prepared using the method described in Example 1, except that a different coupling partner was used in Step 1. Step 2 was not necessary. [Table 9]

[0222] The following compounds were prepared using the method described in Example 1, except that a different coupling partner was used in Step 1 and debenzylation Step 2 was performed using TFA, similar to Step 3 of Example 3. [Table 10]

[0223] The following compounds were prepared using the method described in Example 1, except that Step 1 was performed using the conditions outlined below.

[0224] Nickel photochemistry: In a 20 mL vial equipped with a stirring rod and dried in an oven, (R)-1-phenylethane-1-aminium(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (intermediate A) (100 mg, 0.2 mmol), 4-(benzyloxy)-2-chloroquinoline (110 mg, 0.408 mmol), K2CO3 (55 mg, 0.40 mmol), 2,2'-bipyridine (4 mg, 0.026 mmol), nickel(II) bromide (5 mg, 0.023 mmol), and 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (8 mg, 0.01 mmol) in DMF (13 mL) were added under a nitrogen atmosphere. The mixture was degassed for 15 minutes by bubbling with nitrogen, and then sealed with Parafilm. The solution was stirred at ambient temperature for 17 hours under blue LED (450 nm) irradiation using a Penn OC Photoreactor M1. After the reaction was complete, the mixture was quenched by adding water (30 mL) and extracted with RINKAN (3 × 10 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under vacuum. Preparative reverse-phase HPLC (C) was performed. 18 Purification by column chromatography over 15 minutes using 1-99% ACN in water containing an HCl modifier yielded 4-(benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)quinoline (54 mg, 44%) as a white solid. ESI-MS m / z calculated value: 543.183, measured value: 544.6 (M+1). + ;Retention time: 2.74 min, using LC / MS method Q. [Table 11]

[0225] The following compounds were prepared using the method described in Example 1, except that a different coupling partner was used in Step 1. Step 2 was unnecessary. The final nitrile hydrolysis step was introduced using the method described in Step 5 of Example 15. [Table 12]

[0226] Example 2 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-8-fluoroquinoline-4(1H)-one(10) [ka] Step 1: N,N'-diisopropylmethandiimine (190 μL, 1.21 mmol) was added under nitrogen to a stirred mixture in DCM (7.8 mL) containing (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (intermediate A, 390 mg, 1.04 mmol), 2-hydroxyisoindoline-1,3-dione (215 mg, 1.32 mmol), and DMAP (135 mg, 1.105 mmol). The reaction mixture was stirred under nitrogen at ambient temperature for 19 hours. Upon completion of the reaction, the mixture was concentrated under vacuum and purified by flash column chromatography (SiO2, 1-100% ethyl hexane) to obtain 1,3-dioxoisoindolin-2-yl(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (240 mg, 46%) as a clear oil. 1H NMR(400MHz,chloroform-d)δ 7.85(dd,J=5.5,3.1Hz,2H),7.78(dd,J=5.5,3.1Hz,2H),7.06-6.97(m,1H),6.95-6.84(m,1H),5.29(d,J=9.2Hz ,1H),4.44(t,J=8.9Hz,1H),4.07(s,3H),2.91-2.68(m,1H),1.67(s,3H),0.83(dq,J=7.3,2.3Hz,3H)ppm.ESI-MS m / z calculated value 499.105, actual value 500.0 (M+1) + ; Retention time: 2.11 min, using LC / MS method D.

[0227] Step 2: 4-chloro-8-fluoroquinoline (15 mg, 0.083 mmol) and 2,4,5,6-tetra(carbazol-9-yl)benzene-1,3-dicarbonitrile (1 mg, 0.001 mmol) were continuously added to a stirred solution of 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, 0.10 mmol) in a mixture of DMSO (900 μL) and TFA (13 μL, 0.17 mmol). Nitrogen gas was passed through the solution vigorously for 5 minutes. The solution was sealed and placed in a Hepatochem photoreactor (450 nm, 30 W). The reaction mixture was stirred and irradiated with blue light at ambient temperature for 3 hours. Purification by flash column chromatography (SiO2, 1-100% ethyl hexane) yielded 4-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-8-fluoroquinoline, which was used in the next step without further purification.

[0228] Step 3: In the reaction vial, add 4-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-8-fluoroquinoline and a mixture of water (22 μL, 1.2 mmol) and THF (750 μL) t BuBrettPhos Pd G3 (7 mg, 0.008 mmol) was packed into the container. The mixture was degassed for 5 minutes by bubbling nitrogen through the mixture. Phosphazene base P2-Et (82 μL, 0.25 mmol) was added, and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with DMSO (5 mL) and filtered. Reverse-phase preparative HPLC (C) was performed. 18 Purification by column chromatography and water containing 5 mM HCl (1-99% MeCN) yielded 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-8-fluoroquinoline-4(1H)-one (10, 3.1 mg, 8% over two steps) as a pale yellow solid. 1 H NMR(400MHz, methanol-d4)δ 8.04(d,J=8.2,1.3Hz,1H),7.74-7.57(m,1H),7.56-7.43(m,1H),7.3 1-7.14(m,1H),7.09-6.92(m,1H),6.72-6.58(m,1H),5.72(d,J=11.3H z,1H),4.29(dd,J=11.2,8.1Hz,1H),3.94(d,J=2.5Hz,3H),2.97-2.81(m,1H),1.73(d,J=1.4Hz,3H),0.92(d,J=7.6,2.5Hz,3H)ppm.ESI-MS Calculated value (m / z): 471.127, Measured value: 472.1 (M+1) + ;Retention time: 1.80 minutes, using LC / MS method D.

[0229] The following compounds were prepared using the same method as described in Example 2, except that different coupling partners were used in Step 2. [Table 13-1] [Table 13-2]

[0230] The following compounds were prepared using the same method as in Example 2, except that (Ir[dF(CF3)ppy]2(dtbpy))PF6 was used as a catalyst in step 2 instead of 2,4,5,6-tetra(carbazol-9-yl)benzene-1,3-dicarbonitrile. A different coupling partner was used in step 2 of compound 19, and DMA was used as the solvent instead of DMSO. [Table 14]

[0231] The following compounds were prepared using the method described in Example 2, except that rac-(2R,3S,4S,5R)-4-cyclopropyl-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used as the starting material in Step 1. In Step 2, (Ir[dF(CF3)ppy]2(dtbpy))PF6 was used as the catalyst instead of 2,4,5,6-tetra(carbazol-9-yl)benzene-1,3-dicarbonitrile. The product from Step 3 was further purified by chiral SFC using a Regis Technologies (R,R)-Whelk-O® 1 column, particle size 5 μm, 5.0 cm × 3.0 mm to obtain the first eluting isomer 20 (rt=2.74 min) and the second eluting isomer 21 (rt=8.29 min). [Table 15]

[0232] The following compounds were prepared using the method described in Example 2, except that methyl 5-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate and 4-benzyloxy-5-chloroquinoline were used as coupling partners in Step 2, respectively. Step 3 was not necessary. [Table 16]

[0233] The following compounds were prepared using the method described in Example 2, except that 4-benzyloxy-6-chloroquinoline and 4-benzyloxy-5,7-dimethyl-1,6-naphthiridine were used as coupling partners in Step 2, respectively. Step 3 was omitted. The final hydrogenation-deprotection step was carried out at ambient temperature using Pd / C in EtOH. [Table 17]

[0234] The following compounds were prepared using the method described in Example 2, except that in Step 2, 8-benzyloxy-2-methoxy-1,5-naphthyridine was used as the coupling partner, and (Ir[dF(CF3)ppy]2(dtbpy))PF6 was used instead of 2,4,5,6-tetra(carbazol-9-yl)benzene-1,3-dicarbonitrile. Step 3 was omitted. HCl was added, and the final hydrogenation step was carried out in 1,4-dioxane under conditions similar to those described in Step 2 of Example 1. [Table 18]

[0235] The following compounds were prepared using the method described in Example 2, except that 4-chloroquinoline-5-carbonitrile was used as the coupling partner in Step 2. Step 3 was omitted and replaced with the SNAr step, which was carried out with benzyl alcohol under the same conditions as described in Step 1 for intermediate K. The final benzyl deprotection step was carried out under the same conditions as described in Step 2 of Example 1. [Table 19]

[0236] The following compounds were prepared using the same method as in Example 2, except that 4-benzyloxy-5-chloro-8-fluoro-1,6-naphthyridine was used as the coupling partner in Step 2, and (Ir[dF(CF3)ppy]2(dtbpy))PF6 was used instead of 2,4,5,6-tetra(carbazol-9-yl)benzene-1,3-dicarbonitrile. The products from Step 2 were subjected to the conditions outlined below. The final benzyl deprotection step was carried out using the same conditions as in Step 2 of Example 1.

[0237] Negishi reaction: 4-(benzyloxy)-5-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-8-fluoro-1,6-naphthyridine (26 mg, 0.044 mmol) and Ni(dppp)Cl2 (5 mg, 0.009 mmol) were dissolved in THF (500 μL) under a nitrogen atmosphere and cooled to 0°C. MeMgBr (22 μL, 3 M solution in Et2O, 0.07 mmol) was added dropwise at 0°C. The reaction mixture was warmed to ambient temperature and stirred overnight. THF (500 μL), Ni(dppp)Cl2 (5 mg, 0.009 mmol), and MeMgBr (22 μL, 3 M solution in Et2O, 0.07 mmol) were added to the reaction mixture and stirred for 24 hours. The mixture was quenched with 1 M HCl (2 mL) and poured into water (10 mL). The mixture was extracted with ELISA (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried, and concentrated under vacuum in (MgSO4). Purification by flash column chromatography (12 g of SiO2, 0-50% ethyl phosphate in heptane) yielded 4-(benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-difluoromethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-8-fluoro-5-methyl-1,6-naphthyridine (7.6 mg, 30%) as a colorless oil. [Table 20]

[0238] The following compounds were prepared using the method described in Example 2, except that methyl 4-chloroquinoline-6-carboxylate was used as the coupling partner in Step 2. As outlined below, the product from Step 2 was hydrolyzed and subjected to amidation conditions, after which Step 3 was carried out.

[0239] Hydrolysis: Methyl 4-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)quinoline-6-carboxylate was dissolved in a mixture of MeOH (1 mL), THF (5 mL), and 1N aqueous LiOH, and stirred overnight at ambient temperature. The mixture was concentrated under vacuum. 1N HCl (1 mL) was added, and the product was extracted by DCM. The organic phase was separated and concentrated under vacuum to obtain 4-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)quinoline-6-carboxylic acid (36.2 mg, 70%) as a light brown solid. ESI-MS m / z calculated value: 515.092, measured value: 516.0 (M+1) + ; Retention time: 3.03 min, using LC / MS method Q.

[0240] Amidation: 4-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)quinoline-6-carboxylic acid (10 mg, 0.019 mmol), dimethylamine hydrochloride (7.9 mg, 8.4 μL, 0.096 mmol), and DIEA (20 mg, 27 μL, 0.16 mmol) were combined in THF (1 mL) and stirred for 5 minutes. HATU (22 mg, 0.058 mmol) was added, and the mixture was stirred at ambient temperature for 2 hours, then concentrated under vacuum. Reverse-phase preparative HPLC (C) was performed. 18 Purification by column chromatography (using 1-99% acetonitrile in water) yielded 4-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-N,N-dimethylquinoline-6-carboxamide as a colorless, transparent solid. ESI-MS m / z calculated value: 542.140, measured value: 543.0 (M+1). + ;Retention time: 1.75 minutes, using LC / MS method D. [Table 21]

[0241] Example 3 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide(30) [ka] Step 1: To a 10 mL solution of 4-(benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthiridine (1.0 g, 1.84 mmol) at 0°C in DCM (10 mL), mCPBA (453 mg, 1.84 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 hours. The mixture was diluted with DCM (200 mL) and washed with saturated NaHCO3 aqueous solution (100 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated under vacuum. Purification by flash column chromatography (SiO2, 1-10% MeOH in DCM) yielded 4-(benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthiridine 6-oxide (980 mg, 95%) as an off-white solid. ESI-MS m / z calculation value: 560.173, measured value: 561.1 (M+1). + ; Retention time: 1.93 minutes, using LC / MS method D.

[0242] Step 2: To a 20 mL solution of DCM containing 4-(benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthirizine 6-oxide (980 mg, 1.75 mmol), trimethylsilyl cyanide (285 μL, 2.28 mmol) and Et3N (490 μL, 3.52 mmol) were successively added. The reaction mixture was stirred at ambient temperature for 19 hours and then concentrated under vacuum. Purification by flash chromatography (SiO2, 1-100% ELISA in hexane) yielded 4-(benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthyrizine-5-carbonitrile (740 mg, 74%) as a white solid. 1 H NMR(400MHz, methanol-d4)δ 8.74(d,J=5.8Hz,1H),7.97(d,J=5.8Hz,1H),7.71-7.55(m,2H),7.48-7.32(m,4H),7.33-7.19(m,1H),7.01-6.82(m,1H),5.6 6-5.59(m,3H),4.18-4.11(m,1H),3.83(d,J=2.3Hz,3H),2.94-2.75(m,1H),1.74-1.61(m,3H),0.94-0.78(m,3H)ppm.ESI-MS m / z calculated value 569.174, actual value 570.2 (M+1) + ; Retention time: 2.23 minutes, using LC / MS method D.

[0243] Step 3: A solution of 4-(benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthyridine-5-carbonitrile (100 mg, 0.176 mmol) and trifluoroacetic acid (1.1 mL, 14 mmol) in toluene (1 mL) was heated under nitrogen at 70°C for 2 hours. The reaction mixture was concentrated under vacuum, diluted with DMSO (500 μL), filtered, and analyzed by reverse-phase preparative chromatography (C). 18 Purification with water containing 5 mM hydrochloric acid (1-99% acetonitrile) yielded 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyrizine-5-carboxamide (30 mg, 30 mg, 33%) as a white solid. 1 ¹H NMR (400MHz, methanol-d4) δ 8.82 (d, J=6.3Hz, 1H), 8.25 (d, J=6.3Hz, 1H), 7.32-7.16 (m, 1H), 7.12-6.89 (m, 1H), 6.76 (s, 1H), 5.70 (d, J=11.2Hz, 1H), 4.34 (dd, J=11.2, 8.6Hz, 1H), 3.97 (d, J=2.6Hz, 3H), 3.02-2.80 (m, 1H), 1.75 (s, 3H), 1.03-0.81 (m, 3H) ppm. ESI-MS m / z calculated value 497.137, measured value 498.1 (M+1) + ; Retention time: 1.42 minutes, using LC / MS method D.

[0244] By HPLC purification, 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile (31 mg, 14 mg, 16%) was also obtained as a white solid. 1¹H NMR (400MHz, methanol-d4): δ 8.69 (d, J=5.9Hz, 1H), 7.90 (d, J=5.9Hz, 1H), 7.27-7.12 (m, 1H), 7.08-6.89 (m, 1H), 6.31 (s, 1H), 5.52 (d, J=11.2Hz, 1H), 4.25 (dd, J=11.2, 8.5Hz, 1H), 3.95 (d, J=2.6Hz, 3H), 2.96-2.81 (m, 1H), 1.72 (s, 3H), 0.98-0.78 (m, 3H) ppm; NH pyridone was not observed. ESI-MS m / z calculated value 479.127, measured value 480.1 (M+1). + ; Retention time: 1.63 minutes, using LC / MS method D.

[0245] The following compounds were prepared using the method described in Step 1 of Example 1, followed by the method described in Example 3, except that for compounds 32 and 33, (2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used as the starting material. Compound 33 was isolated as a trace product in Step 3. For compounds 34 and 35, rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (intermediate C) was used as the starting material. Final SFC purification was performed using a Chiralpak IG (250×20mm) column (250×20mm) manufactured by Daicel Corporation, with a particle size of 5μm, yielding the first eluted isomer (rt=1.90 min)34 and the second eluted isomer (rt=3.60 min)35. [Table 22-1] [Table 22-2]

[0246] Example 4 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide(36) [ka] Step 1: To a 10 mL solution of (2R,3R,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (intermediate B, 1.1 g, 2.9 mmol) in DCM, DMF (11 μL, 0.14 mmol), followed by oxalyl chloride (3 mL, 2.0 M solution in DCM, 6 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred for 1 hour and concentrated under vacuum. The residue was dissolved in DCM and concentrated under vacuum to remove residual oxalyl chloride (×3). The acid chloride was dissolved in 10 mL of DCM and added dropwise to a 10 mL solution of 1-(4-aminopyridine-3-yl)ethane-1-one (458 mg, 3.36 mmol) and Et3N (820 μL, 5.88 mmol) in DCM. The reaction mixture was stirred at ambient temperature for 1 hour. The mixture was quenched with water (20 mL) and washed with saturated NaHCO3 solution (20 mL) and 1 M citric acid (20 mL). The organic layer was dried with (MgSO4), filtered, and concentrated under vacuum to obtain (2R,3R,4S,5R)-N-(3-acetylpyridine-4-yl)-3-(3,4-difluoro-2-methylphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (1.31 g, 95%) as an off-white solid. 1H NMR(400MHz,chloroform-d)δ 12.90(s,1H),9.22(s,1H),8.90(d,J=6.5Hz,1H),8.58(d,J=6.5Hz,1H),7.36-7.32(m,1H),7.12(q,J=8.8Hz,1H),5.19(d,J=11.5H) ESI-MS m / z calculated value 472.142, actual value 473.0(M+1) + ;Retention time: 3.37 minutes, using LC / MS method A.

[0247] Step 2: Under a nitrogen atmosphere, NaO t Bu (20.32 g, 211.4 mmol) was added to a solution of (2R,3R,4S,5R)-N-(3-acetylpyridine-4-yl)-3-(3,4-difluoro-2-methylphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (51.21 g, 104.4 mmol) in 1,4-dioxane (500 mL), generating an exothermic reaction of 23°C to 27.5°C. The reaction mixture was heated at 56°C for 10 minutes, then cooled to ambient temperature and quenched by adding water (100 mL). The pH of the solution was adjusted to 5 by carefully adding 2 M HCl. The aqueous phase was extracted with ELISA (500 mL, then 2 × 100 mL). The combined organic phase was dried over (MgSO4), filtered, and concentrated under vacuum to obtain an orange solid. The solid (58.28 g) was pulverized with a 1:1 mixture of DCM (125 mL) and heptane (125 mL). The mixture was aged for 1 hour. The pale pink solid was collected by filtration and rinsed with a 1:1 mixture of DCM:heptane to obtain 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthyridine-4(1H)-one (37.022 g, 78%) as an off-white solid. 1¹H NMR (400MHz, chloroform-d) δ 9.38 (s, 1H), 8.52 (d, J=6.2Hz, 1H), 7.75 (d, J=6.2Hz, 1H), 7.25 (ddd, J=8.9, 4.9, 1.7Hz, 1H), 7.03 (p, J=8.7Hz, 1H), 6.08 (s, 1H), 5.53 (d, J=11.1Hz, 1H), 3.97 (dd, J=11.3, 4.9Hz, 1H), 3.86 (d, J=5.0Hz, 1H), 2.96 (s, 3H), 2.36-2.24 (m, 3H), 1.71 (s, 3H) ppm; NH pyridone was not observed. 19 F NMR (376 MHz, chloroform-d) δ -75.13, -137.68 (d, J=21.1 Hz), -138.56 (d, J=21.1 Hz) ppm. ESI-MS m / z calculated value 454.132, measured value 455.2 (M+1) + ;453.2(M-1) - ;Retention time: 0.76 minutes, using LC / MS method C.

[0248] Step 3: To a MeCN (50 mL) suspension of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthyridine-4(1H)-one (5 g, 11 mmol), formamide (9 mL, 226 mmol) was added and the mixture was stirred until completely dissolved. The reaction mixture was heated at 75°C. A solution of (NH4)2S2O8 (5.58 g, 24.5 mmol) in water (7 mL) was added via an addition funnel over 6 minutes. The mixture was heated at 75°C until the starting materials had completely disappeared. An additional amount of (NH4)2S2O8 (1.26 g, 5.521 mmol) in water (1.5 mL) was added to the reaction mixture and the reactants were cooled to ambient temperature. The pH of the solution was adjusted to pH 8 by adding saturated NaHCO3 solution. The mixture was extracted with HCl (3 × 10 mL). The organic extract was concentrated under vacuum. Purification by flash chromatography (40 g SiO2, 0-60% HCl in heptane, followed by 100% HCl) yielded 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyrizine-5-carboxamide (36, 1.35 g, 24%). 1 ¹H NMR (400MHz, methanol-d4) δ 8.53 (d, J=6.0Hz, 1H), 7.67 (d, J=6.1Hz, 1H), 7.39 (ddd, J=9.0, 5.0, 1.7Hz, 1H), 7.17 (q, J=9.0Hz, 1H), 6.22 (s, 1H), 5.53 (d, J=11.2Hz, 1H), 4.16 (d, J=5.0Hz, 1H), 3.93 (dd, J=11.2, 4.9Hz, 1H), 2.99 (s, 3H), 2.32 (d, J=2.4Hz, 3H), 1.74 (d, J=1.3Hz, 3H) ppm; NH pyridone and NH2 amide were not observed. ESI-MS m / z calculated value: 497.137, measured value: 498.2 (M+1) + ;Retention time: 2.50 minutes, using LC / MS method A.

[0249] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyrizine-7,8-dicarboxamide (37, 765 mg, 2.41%) was also isolated. ESI-MS m / z calculated value 540.439, measured value 541.1 (M+1) + ;Retention time: 2.71 minutes, using LC / MS method H.

[0250] Example 5 7-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)pyrido[2,3-d]pyrimidine-5(8H)-one (38) and 7-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-4-carboxamide (39) [ka] Step 1: To a solution of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (intermediate A, 500 mg, 1.41 mmol) in DCM (5 mL), DMF (6 μL, 0.08 mmol) and oxalyl chloride (250 μL, 2.87 mmol) were added, and the resulting mixture was stirred at ambient temperature for 20 minutes. The mixture was concentrated under vacuum and azeotropically mixed with DCM (2 × 5 mL) to obtain (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl chloride, which was used without further purification.

[0251] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl chloride was dissolved in DCM (5 mL) and added dropwise to a DCM (5 mL) solution of Et3N (400 μL, 2.87 mmol) and 1-(4-aminopyrimidine-5-yl)ethane-1-one (213 mg, 1.55 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, and then the reaction mixture was carried over to the next step.

[0252] Step 2: Et3N (1.38 mL, 9.901 mmol) and TMSOTf (1.53 mL, 8.467 mmol) were added to the reaction mixture from step 1 above, and the mixture was heated at 45°C for 16 hours. The mixture was cooled to ambient temperature, poured into saturated NaHCO3 aqueous solution (50 mL), and diluted with DCM (50 mL). The aqueous layer was separated and extracted with DCM (50 mL). The combined organic extracts were washed with brine (50 mL), dried, filtered, and concentrated under vacuum. Purification by flash chromatography (40 g SiO2, 0-100% ethyl phosphate in heptane) yielded 7-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)pyrido[2,3-d]pyrimidine-5(8H)-one (38, 268 mg, 42% over two steps) as an off-white solid. 1 H NMR(500MHz,DMSO-d6)δ 12.55(s,1H),9.25(s,1H),9.15(s,1H),7.27-7.23(m,1H),7.18-7.12(m,1H),6.55(s,1H),5.45(d,J=11.3Hz,1H), 4.38(dd,J=11.3,8.3Hz,1H),3.90(d,J=1.9Hz,3H),2.85(dq,J=7.8Hz,1H),1.71(s,3H),0.76(d,J=5.3Hz,3H)ppm. 19F NMR (471 MHz, DMSO-d6): δ -73.15, -137.96, -154.82 ppm. ESI-MS m / z: Calculated value 455.127, Measured value 456.3 (M+1) + ;454.2(M-1) - ;Retention time: 2.52 minutes, using LC / MS method A.

[0253] Step 3: 7-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)pyrido[2,3-d]pyrimidine-5(8H)-one (100 mg, 0.220 mmol) and K2S2O8 (131 mg, 0.485 mmol) were suspended in MeCN (200 μL) and water (40 μL). The mixture was heated to 75°C and formamide (350 μL, 8.78 mmol) was added. The resulting mixture was stirred at 75°C for 2 hours. The reaction mixture was quenched by adding saturated NaHCO3 aqueous solution (2 mL), poured into saturated NaHCO3 aqueous solution (10 mL), and diluted with ELISA (10 mL). The aqueous layer was separated and extracted with ELISA (2 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried (MgSO4), and concentrated under vacuum. Reverse-phase HPLC (C) 18 Purification using an X-bridge column and 15.8-30.5% MeCN in H2O containing 0.1% ammonium hydroxide yielded 7-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-4-carboxamide (39 mg, 12.9 mg, 12%). 1H NMR(500MHz,DMSO-d6)δ 12.56(s,1H),9.08(s,1H),7.64(s,1H),7.53(s,1H),7.27-7.23(m,1H),7.18-7.11(m,1H),6.53(s,1H),5.44(d,J=11.3H) z,1H),4.37(dd,J=11.3,8.3Hz,1H),3.90(d,J=1.9Hz,3H),2.85(p,J=7.7Hz,1H),1.71(s,3H),0.76(d,J=7.4Hz,3H)ppm. 19 F NMR (471 MHz, DMSO-d6): δ -73.13, -137.86, -154.75 ppm. ESI-MS m / z: Calculated value 498.133, Measured value 499.4 (M+1) + ;497.2(M-1) - ;Retention time: 2.39 minutes, using LC / MS method A.

[0254] The following compounds were prepared using the method described in Example 5, except that the conditions used in Step 1 were the same as those used in Step 1 of Example 6, and (2R,3S,4S,5R)-3-(3-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (intermediate H) was used instead of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (intermediate A). [Table 23]

[0255] The following compounds were prepared using the method described in Example 5, except that in Step 1, rac-(2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used as the starting material and 1-(4-aminopyridine-3-yl)ethane-1-one was used as the coupling partner. In Step 2, DIPEA was used as the base instead of triethylamine. The product from Step 3 was further purified by chiral SFC using a Daicel Corporation Chiralpak IB column (250 × 20 mm), particle size 5 μm, to obtain the first eluting isomer 41 (rt=2.99 min) and the second eluting isomer 42 (rt=4.49 min). [Table 24]

[0256] Example 6 2-((2R,3R,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4-hydroxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide(43) [ka] Step 1: (2R,3R,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4-(methoxymethoxy)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (intermediate I, 460 mg, 1.20 mmol) was dissolved in 15 mL of ethyl acetate. 1-(4-aminopyridine-3-yl)ethane-1-one (500 mg, 3.67 mmol) and Et3N (1.2 mL, 8.6 mmol) were added at ambient temperature. T3P (3.5 mL, 50% w / w solution in ethyl acetate, 5.9 mmol) was added dropwise, and the reaction mixture was stirred at ambient temperature for 2 hours. The mixture was quenched by adding saturated NaHCO3 solution (20 mL). The mixture was extracted with ethyl acetate (2 × 15 mL), the combined organic extract was dried in (MgSO4), filtered, and concentrated under vacuum. Purification by flash chromatography (24 g SiO2, 0-100% ethyl phosphate in heptane) yielded (2R,3R,4S,5R)-N-(3-acetylpyridine-4-yl)-3-(3,4-difluoro-2-methylphenyl)-4-hydroxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (270 mg, 45%). ESI-MS m / z calculated value: 502.153, measured value: 503.2 (M+1). + ;501.1(M-1) - ;Retention time: 0.97 minutes, using LC / MS method C.

[0257] Step 2: Potassium tert-butoxide (130 mg, 1.16 mmol) was added at ambient temperature to a stirred solution of (2R,3R,4S,5R)-N-(3-acetylpyridine-4-yl)-3-(3,4-difluoro-2-methylphenyl)-4-hydroxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (270 mg, 0.537 mmol) in 1,4-dioxane (5 mL), and the reaction mixture was heated at 50°C for 1 hour. The mixture was quenched by adding saturated NH4Cl solution (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated under vacuum to obtain 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4-(methoxymethoxy)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthirizine-4(1H)-one (260 mg, 100%), which was used in the next step without further purification. ESI-MS m / z calculated value: 484.142, measured value: 485.2 (M+1) + ;483.2(M-1) - ;Retention time: 0.74 min, using LC / MS method C.

[0258] Steps 3 and 4: Potassium persulfate (100 mg, 0.370 mmol) was added to a solution of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4-(methoxymethoxy)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthyridine-4(1H)-one (160 mg, 0.330 mmol) and formamide (600 μL, 15.05 mmol) in a mixture of MeCN (2 mL) and water (0.5 mL), and the mixture was heated at 75°C for 1 hour. The reaction mixture was quenched by adding water and diluted with ethyl acetate. The aqueous phase was separated and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under vacuum to obtain 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4-(methoxymethoxy)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide, which was used in the next step without further purification. ESI-MS m / z calculated value 527.148, measured value 528.2 (M+1) + ;526.2(M-1) - ;Retention time: 0.67 minutes, using LC / MS method C.

[0259] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4-(methoxymethoxy)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide was dissolved in a mixture of toluene (1 mL) and TFA (1 mL) and heated at 75°C for 1 hour. The reaction mixture was neutralized by adding saturated NaHCO3 solution and extracted with ELISA (3 × 10 mL). The combined organic extract was dried (MgSO4), filtered, and concentrated under vacuum. Purification by flash chromatography (12 g SiO2, 0-100% 3:1 HCl:EtOH in heptane) yielded 2-((2R,3R,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4-hydroxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyrizine-5-carboxamide (43, 24 mg, 15% over two steps). 1 ¹H NMR (500MHz, methanol-d4) δ 8.52 (d, J=6.0Hz, 1H), 7.66 (d, J=6.0Hz, 1H), 7.33 (ddd, J=9.1, 4.9, 1.7Hz, 1H), 7.11 (q, J=8.9Hz, 1H), 6.23 (s, 1H), 5.56 (d, J=11.2Hz, 1H), 4.46 (d, J=4.8Hz, 1H), 3.89 (dd, J=11.2, 4.8Hz, 1H), 2.26 (d, J=2.3Hz, 3H), 1.70 (s, 3H) ppm; NH pyridone, NH2 amide, and OH alcohol were not observed. 19 F NMR (471 MHz, methanol-d4): δ -76.03, -142.02--142.30 (m), -142.74--143.01 (m) ppm. ESI-MS m / z: Calculated value 483.122, Measured value 484.1 (M+1) + ;482.2(M-1) - ;Retention time: 1.79 minutes, using LC / MS method A.

[0260] The following compounds were prepared using the method described in Example 6, except that in Step 1, (2R,3R,4S,5R)-3-(3,4-difluoro-2-((methoxymethoxy)methyl)phenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (intermediate J) was used as the starting material. [Table 25]

[0261] The following compounds were prepared using the same method as described in Example 6, except that in Step 1, (2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-(methoxymethoxy)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used as the starting material. Steps 3 and 4 were omitted. After Step 2, the formamide portion of the compound was introduced according to the procedure from Example 3. [Table 26]

[0262] Example 7 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)pyrido[4,3-d]pyrimidine-4(1H)-one(46) [ka] Step 1: (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (intermediate A, 400 mg, 1.13 mmol) was dissolved in a mixture of DCM (10 mL) and DMF (10 μL, 0.13 mmol) cooled to 0°C. Then, oxalyl chloride (990 μL, 11.4 mmol) was added dropwise over 2 minutes, and the mixture was stirred for 1 hour. The reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (10 mL) and added dropwise to an ice-cold solution of methyl 4-aminonicotinate (172 mg, 1.13 mmol), DMAP (3 mg, 0.024 mmol), and DIPEA (200 μL, 1.15 mmol) in DCM (10 mL). The mixture was stirred for 90 minutes and slowly warmed to ambient temperature. The mixture was quenched with a saturated aqueous solution of NaHCO3 (50 mL). The aqueous layer was separated and extracted with DCM (50 mL). The combined organic extract was dried (MgSO4), filtered, and concentrated under vacuum to obtain 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)methyl nicotinate (530 mg, 96%) as a brown waxy solid. 1 1H NMR (400MHz, DMSO-d6)δ 11.72(s,1H),9.07(s,1H),8.62(d,J=5.9Hz,1H),8.44(d,J=5.8Hz,1H),7.3 7(ddd,J=8.5,5.9,2.1Hz,1H),7.18(ddd,J=10.1,8.9,7.7Hz,1H),5.30(d,J= 11.0Hz,1H),4.19(dd,J=11.0,7.5Hz,1H),4.08(s,1H),3.92(d,J=2.1Hz,3H ),1.71(s,3H),0.95(d,J=6.6Hz,3H),0.73(dd,J=7.5,2.5Hz,3H)ppm.ESI-MS m / z calculated value: 488.137, measured value: 489.1 (M+1) + ;487.2(M-1) - ;Retention time: 1.05 minutes, using LC / MS method C.

[0263] Step 2: 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)methyl nicotinate (530 mg, 1.085 mmol) was dissolved in ammonia (10 mL, 7 M solution in MeOH, 70 mmol) and stirred overnight at ambient temperature. The reaction mixture was concentrated under vacuum. The residue was dissolved in ethyl acetate and washed with saturated line solution. The organic layer was separated, dried (MgSO4), filtered, and concentrated under vacuum. Flash chromatography (24 g SiO2, 20-100% ethyl acetate in heptane), followed by preparative reverse-phase HPLC (Waters C4). 18 Purification by X-bridge column and 47-95% MeCN in H2O containing 1% ammonium hydroxide yielded 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)pyrido[4,3-d]pyrimidine-4(1H)-one (46, 180 mg, 35%) as a white solid. 1 H NMR(400MHz,chloroform-d)δ 10.06(s,1H),9.40(s,1H),8.73(d,J=5.6Hz,1H),7.30(d,J=5.6Hz,1H),7.12(ddd,J=8.3,5.5,2.2Hz,1H),6.83(td,J=9.1,7.3Hz,1H),5.33(d ,J=10.9Hz,1H),4.11(dd,J=10.9,8.5Hz,1H),3.90(d,J=2.9Hz,3H),2.78(p,J=7.8Hz,1H),1.66(s,3H),0.78(dq,J=7.6,2.3Hz,3H)ppm.ESI-MS m / z calculated value: 455.127, measured value: 456.1 (M+1) + ;454.1(M-1) - ;Retention time: 0.78 min, using LC / MS method C.

[0264] Example 8 2-((2R,3S,4S,5R)-3-(3-chloro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide(47) [ka] Step 1: The starting material, 2-((2R,3S,4S,5R)-3-(3-chloro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-((4-methoxybenzyl)oxy)-1,6-naphthiridine-5-carbonitrile, was prepared using the same method as described in Step 1 of Example 1, followed by Steps 1 and 2 of Example 3. However, in Step 1 of Example 1, (2R,3S,4S,5R)-3-(3-chloro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (intermediate G) was used as the acid starting material, and 2-chloro-4-((4-methoxybenzyl)oxy)-1,6-naphthiridine was used as the coupling partner.

[0265] The crude residue of 2-((2R,3S,4S,5R)-3-(3-chloro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-((4-methoxybenzyl)oxy)-1,6-naphthyridine-5-carbonitrile was dissolved in DMSO (2 mL). NaOH (285 μL, 6 M aqueous solution, 1.7 mmol) and hydrogen peroxide (350 μL, 30% w / w solution in water, 3.43 mmol) were added, and the mixture was stirred at ambient temperature for 2 hours. The mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried (MgSO4), filtered, and concentrated under vacuum to obtain 2-((2R,3S,4S,5R)-3-(3-chloro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-((4-methoxybenzyl)oxy)-1,6-naphthyridine-5-carboxamide.

[0266] Step 2: To a solution of 2-((2R,3S,4S,5R)-3-(3-chloro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-((4-methoxybenzyl)oxy)-1,6-naphthyrizine-5-carboxamide in DCM (2 mL), TFA (1 mL, 13 mmol) was added, and the mixture was stirred at ambient temperature for 30 minutes. Preparative reverse-phase HPLC (Waters C 18 Purification using a Sunfire column and 38-53% MeCN in H2O containing 0.1% trifluoroacetic acid yielded 2-((2R,3S,4S,5R)-3-(3-chloro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyrizine-5-carboxamide (47 mg, 12.2 mg, 4% over two steps) as a pale yellow solid. 1 1H NMR (400MHz, DMSO-d6) δ 11.47 (s,1H), 8.49 (d,J=5.8Hz,1H), 7.56 (d,J=5.9Hz,1H), 7.42 (s,1H), 7.22 (q,J=4.3,2.8Hz,3H), 6.40 (s,1H), 5.52 (d,J=11.1Hz,1H), 4.22 (dd,J=11.1,7.8Hz,1H), 2.94 (p,J=7.5Hz,1H), 2.28 (d,J=2.3Hz,3H), 1.73 (s,3H), 0.77-0.70 (m,3H) ppm; NH pyridone was not observed. ESI-MS m / z calculated value 481.143, measured value 482.1 (M+1) + ;480.1(M-1) - ;Retention time: 2.71 minutes, using LC / MS method A.

[0267] The following compounds were prepared using the same method as described in Example 8, except that 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-((4-methoxybenzyl)oxy)-1,6-naphthyridine was used as the starting material. [Table 27]

[0268] The following compounds were prepared using the same method as described in Example 8, except that in Step 1, 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)pyrido[4,3-d]pyrimidine-4(1H)-one (46) was used as the starting material. Step 2 was unnecessary. [Table 28]

[0269] Example 9 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-N-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide 2,2,2-trifluoroacetate(50) [ka] Steps 1 and 2: An ice-cold mixture of hydrogen peroxide (180 μL, 5.87 mmol) and ethyl 2-oxopropanoate (295 μL, 2.66 mmol) was added to an ice-cold, vigorously stirred suspension of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthyrizine-4(1H)-one (1,80 mg, 0.18 mmol), FeSO4.7H2O (490 mg, 1.76 mmol), and sulfuric acid (325 μL, 6.10 mmol) in a mixture of DCM (15 mL) and water (1.5 mL). After the reaction was complete, the mixture was diluted with ice water (100 mL) and extracted with ethyl phosphate (50 mL x 2). The combined organic extract was concentrated under vacuum. The residue was dissolved in methylamine (5 mL, 33% w / w solution in ethanol) and stirred overnight at ambient temperature. The mixture was concentrated under vacuum. Preparative reverse-phase HPLC (Waters C4) was used. 18 Purification using a Sunfire column and 38-53% MeCN in H2O containing 0.1% trifluoroacetic acid yielded 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-N-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide 2,2,2-trifluoroacetate (50 mg, 9.0 mg, 8% over two steps). 1 H NMR(400MHz,chloroform-d)δ 9.23(s,1H),8.72(s,2H),7.20(s,1H),7.07(s,1H),6.81(q,J=8.9,8.3Hz,1H),5.76(d,J=10.4Hz,1H),4.20(t,J=9.4Hz,1 H),3.90(s,1H),3.85(d,J=2.7Hz,3H),3.42(s,3H),3.13(d,J=3.3Hz,3H),2.84-2.74(m,1H),0.89-0.77(m,3H)ppm.ESI-MS m / z calculated value 511.153, actual value 512.2 (M+1) + ;510.2(M-1) - ;Retention time: 2.77 minutes, using LC / MS method B.

[0270] Example 10 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-methoxy-1,6-naphthyridine-4(1H)-one(51) [ka] Step 1: Recrystallized NBS (37 mg, 0.21 mmol) was added at 0°C to a solution of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthyridine-4(1H)-one (1,100 mg, 0.198 mmol) in a mixture of DCM (0.8 mL) and acetic acid (0.4 mL). The reaction mixture was warmed to ambient temperature. After 20 minutes, the mixture was diluted with DCM (10 mL) and washed with semi-saturated NaHCO3 solution (10 mL). The aqueous layer was extracted with DCM (10 mL). The combined organic extracts were washed with saturated Na2S2O3 solution, dried, filtered, and concentrated under vacuum. Purification by flash chromatography (12 g SiO2, 0-20% 3:1 siRNA:EtOH in heptane) yielded 3-bromo-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthyrizine-4(1H)-one (72 mg, 68%) as a bright yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 11.79(s,1H),9.21(s,1H),8.68(s,1H),7.67(s,1H),7.19(d,J=9.0Hz,1H),7.09(s,1H),5.93(d,J =10.9Hz,1H),4.58(s,1H),3.87(s,3H),3.04(s,1H),1.75(s,3H),0.80(d,J=7.6Hz,3H)ppm.ESI-MS m / z calculated value 532.042, actual value 535.1 (M+1) + ;Retention time: 0.77 min, using LC / MS method C.

[0271] Step 2: 3-Bromo-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthyrizine-4(1H)-one (218 mg, 0.409 mmol) and CuI (85 mg, 0.45 mmol) were suspended in CPME (1.7 mL), and the mixture was purged with nitrogen. NaOMe (0.28 mL, 25% w / w solution in MeOH) was added, and the reaction mixture was heated at 70°C for 64 hours. The mixture was cooled to ambient temperature, diluted with ethyl acetate, filtered through a Celite® plug, and concentrated under vacuum. Reverse-phase chromatography (C) was performed. 18 Purification by column chromatography using 25-50% MeCN in water containing 0.1% NH3OH yielded 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-methoxy-1,6-naphthyrizine-4(1H)-one (51, 98 mg, 49%) as a yellow solid. 1 ¹H NMR (400MHz, methanol-d4) δ 9.37(s,1H), 8.58(s,1H), 7.69(s,1H), 7.15(ddd,J=8.2,5.6,2.2Hz,1H), 6.98(ddd,J=10.0,8.9,7.6Hz,1H), 5.89(d,J=11.2Hz,1H), 4.42(dd,J=11.2,9.4Hz,1H), 3.93(d,J=2.5Hz,3H), 3.82(s,3H), 3.07-2.90(m,1H), 1.78(d,J=1.3Hz,3H), 0.89(dt,J=7.6,2.3Hz,3H) ppm; NH pyridone was not observed. ESI-MS m / z calculated value: 484.142, measured value: 485.3 (M+1) + ;483.3(M-1) - ;Retention time: 0.85 minutes, using LC / MS method A.

[0272] The following compounds were prepared by subjecting 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-methoxy-1,6-naphthyridine-4(1H)-one (51) to a benzyl protection step, followed by subjecting it to the conditions described in Example 3. [Table 29]

[0273] Example 11 6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-8-oxo-5,8-dihydro-1,5-naphthyridine 1-oxide(53) [ka] Step 1: 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,5-naphthyridine-4(1H)-one (6.7 mg, 0.015 mmol) in DCM (1 mL) was treated with m CPBA (5.2 mg, 0.030 mmol) and stirred under nitrogen at ambient temperature. The mixture was stirred for 16 hours and then concentrated under vacuum. Preparative reverse-phase HPLC (C) was performed. 18 Purification by X-bridge column and 47%-95% MeCN in H2O containing 0.1% ammonium hydroxide yielded 6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-8-oxo-5,8-dihydro-1,5-naphthyridine 1-oxide (53 mg, 3.1 mg, 43%). 11H NMR (400MHz, DMSO-d6)δ 16.74(s,1H),8.61(d,J=6.0Hz,1H),8.07-7.95(m,1H),7.72(dd,J=8.9,6.1H z,1H),7.31(ddd,J=8.5,5.9,2.1Hz,1H),7.23(s,1H),7.11(ddd,J=10.1,8.9 ,7.7Hz,1H),5.60(d,J=11.0Hz,1H),4.34(dd,J=11.1,7.5Hz,1H),3.90(d,J= 2.1Hz,3H),2.84(p,J=7.5Hz,1H),1.69(s,3H),0.83-0.75(m,3H)ppm.ESI-MS m / z calculated value: 470.127, measured value: 471.6 (M+1) + ;Retention time: 3.75 minutes, using LC / MS method A.

[0274] The following compounds were prepared using the same method as described in Example 11, except that 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (30) was used as the starting material. [Table 30]

[0275] Example 12 N-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-yl)methanesulfonamide(55) [ka] Step 1: 4-(benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthyridine 6-oxide (154 mg, 0.275 mmol) was dissolved in POCl3 (1.0 mL, 10.7 mmol), and the resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated under vacuum and diluted with DCM (20 mL). The mixture was poured into saturated NaHCO3 aqueous solution (20 mL) and stirred for 10 minutes. The aqueous layer was separated and extracted with DCM (2 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried, filtered, and concentrated under vacuum. Purification by flash chromatography (12 g SiO2, 0-100% ethyl phosphate in heptane) yielded 4-(benzyloxy)-5-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthirizine (91.7 mg, 58%) as a turbid oil. 1 H NMR(400MHz,chloroform-d)δ 8.36(d,J=5.7Hz,1H),7.58(d,J=5.7Hz,1H),7.56-7.52(m,2H),7.45-7. 36(m,3H),7.25-7.20(m,1H),7.18(s,1H),6.86-6.78(m,1H),5.56(d,J=1 0.8Hz,1H),5.45-5.35(m,2H),4.02(dd,J=10.8,7.8Hz,1H),3.86(d,J=2. 6Hz,3H),2.78(dq,J=7.8,7.5Hz,1H),1.66(s,3H),0.88-0.84(m,3H)ppm. 19 F NMR (376 MHz, chloroform-d) δ -74.50, -137.58, -154.81 ppm. ESI-MS m / z calculated value 578.140, measured value 579.6 (M+1) + ; Retention time: 4.24 minutes, using LC / MS A method.

[0276] Step 2: 4-(benzyloxy)-5-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthirizine (46 mg, 0.079 mmol), methanesulfonamide (12 mg, 0.13 mmol), Pd(OAc)2 (1 mg, 0.004 mmol), xanthophos (5 mg, 0.008 mmol), and Cs2CO3 (52 mg, 0.16 mmol) were suspended in 1,4-dioxane (500 μL) and heated at 100°C for 16 hours. The reaction mixture was cooled to ambient temperature. Purification by flash chromatography (12 g SiO2, 0-100% ethyl phosphate in heptane) yielded N-(4-(benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthyridine-5-yl)methanesulfonamide (32 mg, 63%) as a white solid. ESI-MS m / z calculated value: 637.167, measured value: 636.6 (M-1). - ;Retention time: 1.16 minutes, using LC / MS method C.

[0277] Step 3: N-(4-(benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthyridine-5-yl)methanesulfonamide was dissolved in ELISA (2 mL), and then Pd / C (5 mg, 10% w / w wet, Degussa, 0.005 mmol) was added. N2 and then hydrogen were flushed over the mixture for 5 minutes each. The mixture was stirred under a hydrogen atmosphere for 1.5 hours. N2 was flushed over the solution for 5 minutes, the mixture was filtered using a syringe filter, and rinsed with ELISA. The filtrate was concentrated under vacuum. Reverse-phase HPLC (C) 18Purification by X-bridge column (MeCN in H2O containing 0.1% ammonium hydroxide), followed by flash chromatography (12 g SiO2, 0-100% ethyl phosphate in heptane), yielded N-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-yl)methanesulfonamide (55 mg, 12.0 mg, 27%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 12.92(s,1H),11.95(s,1H),8.25(d,J=6.0Hz,1H),7.27-7.20(m,2H),7.19-7.11(m,1H),6.51(s,1H),5.48(d,J=11.3Hz,1H) ,4.26(dd,J=11.3,8.2Hz,1H),3.91(d,J=2.2Hz,3H),3.41(s,3H),2.91-2.82(m,1H),1.70(s,3H),0.78(d,J=6.5Hz,3H)ppm. 19 F NMR(376MHz,DMSO-d6)δ-73.11,-137.75,-154.68ppm.ESI-MS m / z calculated value 547.120, actual value 548.6(M+1) + ;546.5(M-1) - ;Retention time: 3.27 minutes, using LC / MS method A.

[0278] Using a similar procedure, the following compounds were isolated in addition to the above products.

[0279] 5-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthirizine-4(1H)-one hydrochloride (56 mg, 2%) was isolated as a white solid. 1¹H NMR (400MHz, methanol-d4) δ 8.24 (d, J=5.6Hz, 1H), 7.25 (d, J=5.6Hz, 1H), 6.91 (dd, J=9.5, 6.3Hz, 2H), 6.69 (s, 1H), 6.60 (d, J=10.7Hz, 1H), 4.26 (dd, J=10.7, 7.6Hz, 1H), 4.07 (d, J=2.6Hz, 3H), 2.89 (p, J=7.0Hz, 1H), 1.56 (s, 3H), 0.92 (dt, J=7.6, 2.5Hz, 3H) ppm; NH pyridone was not observed. ESI-MS m / z calculated value 488.093, measured value 489.0 (M+1) + ;Retention time: 2.49 minutes, using LC / MS method D.

[0280] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine 6-oxide hydrochloride (57 mg, 3.1 mg, 3%) was isolated as a colorless, transparent solid. 1 ¹H NMR (400MHz, methanol-d4) δ 9.05 (d, J=2.1Hz, 1H), 8.59 (dd, J=7.3, 2.1Hz, 1H), 7.55 (d, J=7.3Hz, 1H), 7.03-6.89 (m, 2H), 6.55 (d, J=1.0Hz, 1H), 5.90 (d, J=11.0Hz, 1H), 4.37 (dd, J=11.0, 8.0Hz, 1H), 4.08 (d, J=2.7Hz, 3H), 2.95 (p, J=7.7Hz, 1H), 1.60 (s, 3H), 0.94 (dt, J=7.6, 2.3Hz, 3H) ppm; NH pyridone was not observed. ESI-MS m / z calculated value: 470.127, measured value: 471.1 (M+1) + ;Retention time: 1.86 minutes, using LC / MS method D.

[0281] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-hydroxy-1,6-naphthyrizine-4(1H)-one (58, 2.1 mg). 1H NMR(400MHz,chloroform-d)δ 12.72(s,1H),9.00(s,1H),7.23(ddt,J=9.2,5.8,3.0Hz,1H),7.19(s,1H ),7.06(s,1H),6.90-6.79(m,1H),6.68(d,J=7.4Hz,1H),5.51(d,J=11.0 Hz,1H),4.11(dd,J=11.0,7.7Hz,1H),3.94(d,J=2.5Hz,3H),2.82(p,J=7.6Hz,1H),1.74(d,J=1.1Hz,3H),0.88(dt,J=7.4,2.4Hz,3H)ppm.ESI-MS m / z calculated value: 470.127, measured value: 471.1 (M+1) + ;469.2(M-1);Retention time: 3.38 minutes, using LC / MS method B.

[0282] Example 13 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide(59) [ka] Step 1: 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyrizine-5-carboxamide (50 mg, 0.098 mmol) was added to a 2 mL ice-cold solution of DCM with BBr3 (300 μL, 1 M solution in heptane, 0.3 mmol). The mixture was stirred under nitrogen and warmed to ambient temperature. After 19 hours, an additional 300 μL of BBr3 (1 M solution in heptane, 0.3 mmol) was added, and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was quenched with brine. The aqueous layer was separated and extracted with DCM. The combined organic extracts were dried in (MgSO4), filtered, and concentrated under vacuum. Purification by flash chromatography (4g SiO2, 0-44% 3:1 HCl:EtOH containing 2% NH4OH in heptane) yielded 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyrizine-5-carboxamide (59 mg, 24.4 mg, 49%). 1 ¹H NMR (500MHz, methanol-d4) δ 8.51 (d, J=6.0Hz, 1H), 7.71 (d, J=6.0Hz, 1H), 7.03 (ddd, J=8.4, 5.6, 2.2Hz, 1H), 6.71 (ddd, J=9.9, 8.8, 7.4Hz, 1H), 6.31 (s, 1H), 5.54 (d, J=11.3Hz, 1H), 4.27 (dd, J=11.3, 8.3Hz, 1H), 2.93 (p, J=7.7Hz, 1H), 1.71 (s, 3H), 0.90 (dt, J=7.8, 2.1Hz, 3H) ppm; NH pyridone and NH2 amide were not observed. ESI-MS m / z calculated value 483.122, measured value 484.6 (M+1) + ;Retention time: 2.15 minutes, using LC / MS method A.

[0283] The following compounds were prepared using the method described in Example 13, except that in Step 1, 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide was used as the starting material instead of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide. [Table 31]

[0284] Example 14 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxylic acid(61) [ka] Step 1: The starting material 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthiridine-5-carbonitrile was prepared using the method described in Example 3, except that in Step 1, compound 7 was used as the starting material instead of 4-(benzyloxy)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthiridine. Step 3 was omitted.

[0285] NaOH (85 mg, 2.1 mmol) was added all at once to a stirred solution of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyrizine-5-carbonitrile (50 mg, 0.104 mmol) in a mixture of EtOH (0.5 mL) and water (0.1 mL). The reaction mixture was heated to 100°C for 10 minutes in a sealed vial. The mixture was cooled to ambient temperature, quenched by adding water, and slowly acidified to pH 0 by adding 1 M HCl solution. The mixture was extracted with DCM (3 × 10 mL). The combined organic extracts were dried (MgSO4) and concentrated in a vacuum to obtain (2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxylic acid (61, 51 mg, 94%). 1 H NMR(500MHz,DMSO-d6)δ 13.07(s,1H),11.63(s,1H),8.52(d,J=5.9Hz,1H),7.60(d,J=5.9Hz,1H),7.38-7.14(m,2H),6.39(s,1H),5.50(d,J=11. 3Hz,1H),4.25(d,J=4.8Hz,1H),4.05(ddd,J=21.4,12.2,6.0Hz,1H),2.85(s,3H),2.35(d,J=2.3Hz,3H),1.70(s,3H)ppm. 19 F NMR(471MHz,DMSO-d6)δ-73.92,-139.86--140.13(m),-140.83(d,J=32.7Hz).ESI-MS m / z calculated value 498.121, measured value 499.0(M+1) + ;497.0(M-1) - ;Retention time: 2.14 minutes, using LC / MS method A.

[0286] Example 15 2-((3R,4R,6R)-4-(3,4-difluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide(62) [ka] Step 1: DMF (38 mg, 40 μL, 0.52 mmol) was added to a stirred solution of (3S,4R,6R)-4-(3,4-difluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxylic acid (C-20a, 1.925 g, 5.434 mmol) in SOCl2 (6.5 g, 4 mL, 55 mmol), and the reaction mixture was heated at 60 °C for 1 hour. The reaction mixture was cooled to ambient temperature, concentrated under vacuum, and the residue was azeotropically mixed with toluene (2 × 10 mL). The residue was dissolved in DCM (54 mL), and the mixture was cooled in an ice bath. 1-(4-aminopyridine-3-yl)ethane-1-one (890 mg, 6.54 mmol), followed by pyridine (1.8 g, 1.8 mL, 22 mmol), and the mixture was heated to ambient temperature and stirred for 4 hours. The reaction mixture was diluted with HCl (100 mL). The organic phase was separated, washed with saturated NH4Cl solution (40 mL), NaHCO3 solution (40 mL), and semi-saturated brine solution (40 mL), dried, filtered, and concentrated under vacuum to obtain (3S,4R,6R)-N-(3-acetylpyridine-4-yl)-4-(3,4-difluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxamide (2.917 g, 100%) as a colorless rubber. ESI-MS m / z calculated value: 472.142, measured value: 473.2 (M+1). + ;Retention time: 1.04 minutes, using LC / MS method P.

[0287] Step 2: Et3N (0.045 mL, 0.32 mmol) and TMSOTf (0.12 mL, 0.66 mmol) were successively added to a solution of (3S,4R,6R)-N-(3-acetylpyridine-4-yl)-4-(3,4-difluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxamide (50 mg, 0.106 mmol) in DCE (1 mL). The reaction mixture was sealed and heated at 95°C for 2.5 hours. The reaction mixture was cooled to ambient temperature and diluted with 2N K2CO3 (30 mL). The aqueous phase was separated and extracted by DCM. The combined organic phase was dried in (MgSO4), filtered, and concentrated under vacuum. Purification by flash chromatography (SiO2, 0-10% MeOH in DCM) yielded 2-((3R,4R,6R)-4-(3,4-difluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-1,6-naphthirizine-4(1H)-one (48 mg, 94%). ESI-MS m / z calculated value: 454.132, measured value: 455.1 (M+1). + ;Retention time: 1.61 min, using LC / MS method Q.

[0288] Step 3: mCPBA (140 mg, 0.625 mmol) was added to a solution of 2-((3R,4R,6R)-4-(3,4-difluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-1,6-naphthyrizine-4(1H)-one (147.2 mg, 0.324 mmol) in DCM (3.5 mL), and the reaction mixture was stirred at ambient temperature for 4 hours. The reaction product was partitioned between saturated KHCO3 aqueous solution (40 mL), brine (100 mL), and ethyl acetate (50 mL). The aqueous layer was separated and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under vacuum to obtain 2-((3R,4R,6R)-4-(3,4-difluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine 6-oxide (72 mg, 173.3 mg, 100%) as a brown solid, which was used in the next step without further purification. ESI-MS m / z calculated value: 470.127, measured value: 471.1 (M+1) + ;Retention time: 1.99 minutes, using LC / MS method S.

[0289] Step 4: TMSCN (13.0 mL, 97.5 mmol) and dimethylcarbamyl chloride (9.0 mL, 97.8 mmol) were continuously added to a stirred solution of 2-((3R,4R,6R)-4-(3,4-difluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine 6-oxide (72 (≤), 23 g, 48.9 mmol) in DCM (230 mL), and the turbid solution was stirred at ambient temperature for 14 hours. Additional dimethylcarbamyl chloride (2.25 mL, 24.4 mmol) was added, and the mixture was stirred at ambient temperature for a further 24 hours. KHCO3 (230 mL, 1 M aqueous solution, 230 mmol) was added, and the reaction mixture was stirred at ambient temperature for 15 minutes. Most of the DCM was removed under vacuum at 30°C, the suspension was filtered, and the solid was washed with water. The solid was suspended in a mixture of DCM (250 mL) and EtOH (250 mL) to obtain a yellow-orange solution. Most of the DCM was removed under vacuum at 70-80°C. The resulting suspension was stirred at ambient temperature for 30 minutes, filtered, washed with EtOH, dried in a vacuum oven at 40°C, and nitrogen-bled over the weekend to obtain 2-((3R,4R,6R)-4-(3,4-difluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile (70 (≤), 19.3 g, 82%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 12.02(s,1H),8.66(d,J=5.8Hz,1H),7.65(d,J=5.8Hz,1H),7.21(ddd,J=8.3,5.9,2.0Hz,1H),7.17-7.00(m,1H),6.38 (s,1H),4.10(dd,J=11.5,4.3Hz,1H),4.04-3.80(m,5H),3.39-3.33(m,1H),2.00-1.78(m,2H),1.68(s,3H)ppm.ESI-MS m / z calculated value 479.127, actual value 480.4 (M+1) + ; Retention time: 2.26 min, using LC / MS method Q.

[0290] Step 5: TFA (212 mL, 2.75 mol) was added to a stirred suspension of 2-((3R,4R,6R)-4-(3,4-difluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile (70 (≤), 21.2 g, 44.2 mmol) in toluene (212 mL), and the resulting solution was heated under reflux for 23 hours. The mixture was concentrated under vacuum and evaporated simultaneously with toluene (2×). The residue was partitioned between 2-MeTHF (250 mL) and saturated NaHCO3 solution (250 mL), and the mixture was stirred in a warm water bath for 3 hours. The organic phase was separated and washed with saturated NaHCO3 solution (200 mL) and brine (200 mL). The aqueous phase was back-extracted with 2-MeTHF (200 mL), and the combined organic phase was dried, filtered, and concentrated under vacuum. Purification by recrystallization from DCM and EtOH yielded 2-((3R,4R,6R)-4-(3,4-difluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyrizine-5-carboxamide (62, 22.48 g, 94%) as a colorless solid. 1 H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),8.43(d,J=5.8Hz,1H),7.51-7.28(m,2H),7.30-7.13(m,2H),7.08(q,J=9.1Hz,1H),6.21(s,1H), 4.07(dd,J=11.6,4.3Hz,1H),4.02-3.80(m,5H),3.31-3.19(m,1H),1.95-1.75(m,2H),1.68(s,3H)ppm.ESI-MS m / z calculated value 497.137, actual value 498.5(M+1) + ;Retention time: 1.91 minutes, using LC / MS method Q.

[0291] The following compounds were prepared using the same method as described in Example 15, except that a different coupling partner was used in Step 1. In Step 1, both activation and amide coupling were carried out at ambient temperature. Cyanation Step 4 was carried out under the same conditions as described in Step 4 of Example 17. In the case of 64, the product of Step 5 was further purified by chiral SFC using a Lux® Cellulose-4 column from Phenomenex Inc., particle size 5 μm, 25 cm × 21.2 mm (mobile phase: 40% MeOH (supplemented with 20 mM ammonia), 60% CO2, flow rate 75 mL / min) to obtain the second eluting isomer 64 (rt = 6.55 min). [Table 32]

[0292] The following compounds were prepared using the same method as described in Example 15, except that a different coupling partner was used in Step 1. In Step 1, both activation and amide coupling were carried out at ambient temperature. Cyclization Step 2 was carried out in toluene as the solvent. Cyanation Step 4 was carried out under the same conditions as described in Step 4 of Example 17. [Table 33]

[0293] The following compounds were prepared using the same method as described in Example 15, except that different amine coupling partners were used in Step 1 and the amide coupling was performed at ambient temperature. Cyanation Step 4 was carried out under the same conditions as described in Step 4 of Example 17. [Table 34]

[0294] The following compounds were prepared using the same method as described in Example 15, except that different amine coupling partners were used in Step 1 and the amide coupling was performed at ambient temperature. Cyclization Step 2 was carried out in toluene as the solvent. Cyanation Step 4 was carried out under the same conditions as described in Step 4 of Example 17. In the case of compound 68, the product of Step 5 was further purified by chiral SFC using a Lux® Cellulose-4 column from Phenomenex Inc., particle size 5 μm, 25 cm × 21.2 mm (mobile phase: 38% MeOH (supplemented with 20 mM ammonia), 62% CO2, flow rate 74 mL / min) to obtain the second eluted isomer 68 (rt = 7.53 min). [Table 35]

[0295] The following compounds were prepared using the same method as described in Example 15, except that step 5 was not required. [Table 36]

[0296] The following compounds were prepared using the same method as described in Example 15, except that steps 3-5 were not required. [Table 37]

[0297] The following compounds were prepared using the same method as described in Example 15, except that steps 4 and 5 were not required. [Table 38]

[0298] The following compounds were prepared using the same method as described in Example 15, except that different amine coupling partners were used in Step 1. In Step 1, both the activation step and the amide coupling step were carried out from 0°C to ambient temperature under the same conditions as described in Step 1 of Example 16. Step 3, N-oxide formation, was carried out from 0°C to ambient temperature. Step 4, cyanide formation, was carried out from 0°C to ambient temperature under the same conditions as described in Step 4 of Example 17. For compound 73, the product of Step 5 was further purified by chiral SFC using a Lux® Cellulose-4 column from Phenomenex Inc., particle size 5 μm, 25 cm × 21.2 mm (mobile phase: 40% MeOH (supplemented with 0.1% DEA), 60% CO2, flow rate 60 mL / min) to obtain the first eluted isomer 73 (rt = 6.40 min). In the case of compound 74, the product from step 5 was further purified using a chiral SFC (mobile phase: 45% MeOH (supplemented with 0.1% DEA), 55% CO2, flow rate 65 mL / min) with a Lux® Cellulose-4 column from Phenomenex Inc., particle size 5 μm, 25 cm × 21.2 mm, to obtain the first eluted isomer 74 (rt = 7.22 min). [Table 39]

[0299] Example 16 2-((3R,4R,6R)-4-(3,4-difluoro-2-methylphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide(75) [ka] Step 1: Oxalyl chloride (122 mL, 1.40 mol) was added over 45 minutes to a solution of (3S,4R,6R)-4-(3,4-difluoro-2-methylphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxylic acid (C-20b, 451.2 g, 1.334 mol) and DMF (5.2 mL, 67 mmol) in DCM (3.4 L), and the reaction mixture was stirred at ambient temperature for 3 hours. The mixture was cooled to 5°C and added at 5°C to a suspension of 1-(4-aminopyridine-3-yl)ethane-1-one (218.0 g, 1.601 mol) and Et3N (651 mL, 4.67 mol) in DCM (3.4 L) using a solvent pump at a rate that kept the temperature below 14°C. The resulting suspension was stirred overnight at ambient temperature. The mixture was poured into an aqueous solution of KHSO4 (5.87 L, 1 M aqueous solution, 5.87 mol). The organic phase was separated, washed with KHSO4 (4.0 L, 1 M aqueous solution, 4.0 mol) and K2CO3 (4.0 L, 1 M aqueous solution, 4.0 mol), dried to (MgSO4), filtered, and concentrated under vacuum. Purification by recrystallization from EtOH yielded (3S,4R,6R)-N-(3-acetylpyridine-4-yl)-4-(3,4-difluoro-2-methylphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxamide (565 g, 91%). 1 H NMR(400MHz,DMSO-d6)δ 11.39(s,1H),9.05(s,1H),8.55(d,J=5.8Hz,1H),8.08(d,J=5.7Hz,1H),7 .34(dd,J=8.8,3.0Hz,1H),7.20(q,J=9.0Hz,1H),4.21(dd,J=11.7,4.5Hz ,1H),3.86(t,J=11.2Hz,1H),3.65-3.49(m,1H),3.29(dd,J=11.0,4.6Hz, 1H),2.60(s,3H),2.30(s,3H),1.88-1.74(m,2H),1.57(s,3H)ppm.ESI-MS m / z calculated value: 456.147, measured value: 457.5 (M+1) + ;Retention time: 2.24 minutes, using LC / MS method Q.

[0300] Step 2: TMSOTf (2.38 mL, 13.2 mmol) was added at ambient temperature to a stirred solution of (3S,4R,6R)-N-(3-acetylpyridine-4-yl)-4-(3,4-difluoro-2-methylphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxamide (1 g, 2.2 mmol) and Et3N (932 μL, 6.69 mmol) in toluene (10 mL), and the exothermic reaction was brought to 30°C. The reaction mixture was heated at 110°C for 20 hours. The mixture was poured into K2CO3 (10 mL, 2 M aqueous solution, 20 mmol) and stirred at ambient temperature for 2 hours. The gelatinous mixture was filtered and washed with water and toluene. Reverse-phase chromatography (C) was performed. 18 Purification by column chromatography using 5-100% MeCN in water yielded 2-((3R,4R,6R)-4-(3,4-difluoro-2-methylphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-1,6-naphthirizine-4(1H)-one (757 mg, 77%) as a cream-colored solid. 1 H NMR(400MHz,DMSO-d6)δ 11.69(s,1H),9.04(s,1H),8.54(d,J=5.9Hz,1H),7.41-7.28(m,1H),7.2 8-7.09(m,2H),6.32(s,1H),4.11(dd,J=11.6,4.3Hz,1H),3.97(t,J=11. ESI-MS m / z calculated value: 438.137, measured value: 439.4 (M+1) + ;Retention time: 1.82 minutes, using LC / MS method Q.

[0301] Step 3: mCPBA (85.4 mg, 0.381 mmol) was added to a suspension of 2-((3R,4R,6R)-4-(3,4-difluoro-2-methylphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-1,6-naphthyrizine-4(1H)-one (84 mg, 0.191 mmol) in DCM (2 mL), and the reaction mixture was stirred at ambient temperature for 19.5 hours. The mixture was partitioned between saturated NaHCO3 aqueous solution (30 mL) and ethyl acetate (20 mL). The aqueous layer was separated and extracted with ethyl acetate (20 mL). The combined organic extracts were washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated under vacuum to obtain 2-((3R,4R,6R)-4-(3,4-difluoro-2-methylphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine 6-oxide (116 mg, 100%) as an amber-colored oil, which was used in the next step without further purification. ESI-MS m / z calculated value 454.132, measured value 455.2 (M+1) + ; Retention time: 1.97 minutes, using LC / MS method S.

[0302] Step 4: TMSCN (372 μL, 2.79 mmol) and dimethylcarbamyl chloride (257 μL, 2.79 mmol) were successively added to a suspension of 2-((3R,4R,6R)-4-(3,4-difluoro-2-methylphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine 6-oxide (610 mg, 1.27 mmol) in DCM (6 mL), and the reaction mixture was stirred at ambient temperature for 24 hours. The reaction mixture was quenched by adding 1 M KHCO3 aqueous solution (6 mL), and the mixture was stirred at ambient temperature for 5 minutes. DCM was removed by distillation under vacuum at 40°C. The suspension was stirred at ambient temperature for 20 minutes, filtered, washed with water, and dried to obtain 2-((3R,4R,6R)-4-(3,4-difluoro-2-methylphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile (70 (or more), 588 mg, 90%) as a cream-colored solid. ESI-MS m / z calculated value: 463.132, measured value: 464.4 (M+1). + ;Retention time: 2.28 min, using LC / MS method Q.

[0303] Step 5: TFA (105 mL, 1.36 mol) was added to a stirred solution of 2-((3R,4R,6R)-4-(3,4-difluoro-2-methylphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile (70 (or more), 10.5 g, 21.5 mmol) in toluene (105 mL), and the solution was heated under reflux for 19 hours. The reaction mixture was concentrated under vacuum and evaporated simultaneously with toluene (2×). The residue was partitioned between 2-MeTHF (100 mL) and saturated NaHCO3 solution (100 mL), and the emulsion was stirred at 40-45°C for 1.5 hours. The organic phase was separated and washed with saturated NaHCO3 solution (100 mL) and brine (100 mL). The combined aqueous phase was back-extracted with 2-MeTHF (200 mL). The combined organic phase was dried, filtered, and concentrated under vacuum. Recrystallization from EtOH, followed by purification by chiral SFC (mobile phase: 40% MeOH (supplemented with 0.1% ammonia), 60% CO2, flow rate 100 mL / min) using a Daicel Corporation Chiralpak® IC column, particle size 5 μm, 25 cm × 20 mm, yielded 2-((3R,4R,6R)-4-(3,4-difluoro-2-methylphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyrizine-5-carboxamide (75, 8.2 g, 79%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 11.63(s,1H),8.43(d,J=5.8Hz,1H),7.47-7.29(m,2H),7.18(dt,J=10.0,5.0Hz,3H),6.30(s,1H),4.16-4.03(m,1H),3.95(t,J =11.2Hz,1H),3.88-3.70(m,1H),3.39-3.33(m,1H),2.31(d,J=2.3Hz,3H),1.89(dd,J=13.0,3.5Hz,1H),1.71(s,4H)ppm.ESI-MS m / z calculated value 481.143, actual value 482.6 (M+1) + ;Retention time: 1.93 minutes, using LC / MS method Q.

[0304] The following compounds were prepared using the same method as described in Example 16, except that steps 4 and 5 were not required. [Table 40]

[0305] Example 17 2-((3R,4R,6R)-4-(4-fluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide(77) [ka] Step 1: HATU (1.8 g, 4.7 mmol) was added to a solution of (3S,4R,6R)-4-(4-fluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxylic acid (C-20e, 1.335 g, 3.970 mmol), 1-(4-aminopyridine-3-yl)ethane-1-one hydrochloride (822 mg, 4.76 mmol), and DIPEA (2.2 mL, 12.6 mmol) in DMF (36 mL), and the reaction mixture was stirred at ambient temperature for 75 minutes. The mixture was diluted with ELISA and washed with water and brine. The organic layer was dried with (Na2SO4), filtered, and concentrated under vacuum. Purification by flash chromatography (0-60% ethyl hexane) yielded (3S,4R,6R)-N-(3-acetylpyridine-4-yl)-4-(4-fluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxamide (1.80 g, 100%) as a sticky, pale yellow solid. 11H NMR (400 MHz, chloroform-d)δ 11.60(s,1H),9.01(s,1H),8.52(d,J=5.8Hz,1H),8.46(d,J=5.9Hz,1H),7.1 3(dd,J=8.5,6.5Hz,1H),6.62-6.45(m,2H),4.18-4.07(m,1H),4.00(t,J=11 .4Hz,1H),3.81(s,3H),3.68-3.57(m,1H),3.22-3.10(m,1H),2.64(s,3H),2 .24(t,J=13.2Hz,1H),1.73(dd,J=13.2,4.0Hz,1H),1.60(s,3H)ppm.ESI-MS m / z calculated value: 454.152, measured value: 455.3 (M+1) + ;Retention time: 1.94 minutes, using LC / MS method Q.

[0306] Step 2: KO t Bu (1.03 g, 9.18 mmol) was added to a stirred solution of (3S,4R,6R)-N-(3-acetylpyridine-4-yl)-4-(4-fluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxamide (1.8 g, 4.0 mmol) in 1,4-dioxane (35 mL), and the reaction mixture was stirred at 100°C under a nitrogen atmosphere for 17 hours. The reaction mixture was cooled to ambient temperature, and the mixture was partitioned between saturated NH4Cl aqueous solution and HCl. The aqueous layer was separated and extracted with HCl (2×). The combined organic extract was dried over (Na2SO4), filtered, and concentrated under vacuum. Purification by flash chromatography (SiO2, 0-10% MeOH in DCM) yielded 2-((3R,4R,6R)-4-(4-fluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-1,6-naphthirizine-4(1H)-one (90 mg, 620 mg, 36%) as a pale yellow solid. 11H NMR (400MHz, DMSO-d6)δ 11.64(s,1H),9.04(s,1H),8.55(d,J=5.8Hz,1H),7.37(d,J=5.9Hz,1H),7.3 0(dd,J=8.5,6.8Hz,1H),6.80(dd,J=11.4,2.6Hz,1H),6.66(td,J=8.5,2.5H z,1H),6.16(s,1H),4.13-4.03(m,1H),3.98-3.83(m,2H),3.77(s,3H),3.32 -3.28(m,1H),2.02-1.87(m,1H),1.86-1.75(m,1H),1.66(s,3H)ppm.ESI-MS m / z calculated value: 436.141, measured value: 437.3 (M+1) + ;Retention time: 1.14 minutes, using LC / MS method D.

[0307] Step 3: mCPBA (466 mg, 2.70 mmol) was added to a 15 mL solution of 2-((3R,4R,6R)-4-(4-fluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-1,6-naphthyrizine-4(1H)-one (90 mg, 592 mg, 1.36 mmol), and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction product was partitioned between saturated KHCO3 aqueous solution, brine, and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (3×). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under vacuum to obtain 2-((3R,4R,6R)-4-(4-fluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine 6-oxide (612 mg, 100%) as a light brown solid. ESI-MS m / z calculated value: 452.136, measured value: 453.2 (M+1). + ;Retention time: 1.24 minutes, using LC / MS method D.

[0308] Step 4: Et3N (2.9 mL, 21 mmol) and TMSCN (1.8 mL, 13.5 mmol) were successively added to a stirred solution of 2-((3R,4R,6R)-4-(4-fluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine 6-oxide (612 mg) in DCM (20 mL), and the reaction mixture was stirred at ambient temperature for 18 hours. The mixture was partitioned between saturated NaHCO3 aqueous solution and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic extracts were washed with brine and water, dried in (Na2SO4), filtered, and concentrated under vacuum. Purification by flash chromatography (SiO2, hexane 0-100% ELISA) yielded 2-((3R,4R,6R)-4-(4-fluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)4-oxo-1,4-dihydro-1,6-naphthyrizine-5-carbonitrile (317 mg, 51%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 12.05(s,1H),8.64(d,J=5.8Hz,1H),7.65(d,J=5.8Hz,1H),7.29(dd,J=8 .6,6.7Hz,1H),6.80(dd,J=11.4,2.5Hz,1H),6.66(td,J=8.4,2.5Hz,1H), 6.28(s,1H),4.06(dd,J=11.5,4.4Hz,1H),3.96-3.86(m,2H),3.77(s,4H) ,1.96-1.86(m,1H),1.79(dd,J=12.9,3.7Hz,1H),1.65(s,3H)ppm.ESI-MS Calculated value (m / z): 461.136, Measured value: 462.3 (M+1) + ;Retention time: 1.45 minutes, using LC / MS method D.

[0309] Step 5: Water (20 μL, 1.1 mmol) and TFA (16 mL, 208 mmol) were successively added to a suspension of 2-((3R,4R,6R)-4-(4-fluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyrizine-5-carbonitrile (312 mg, 0.676 mmol) in toluene (18 mL), and the reaction mixture was stirred at 70 °C for 16 hours. The reaction mixture was cooled to ambient temperature and concentrated under vacuum. The residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with ethyl acetate (2×). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under vacuum. Reverse-phase chromatography (C) was performed. 18 Purification by column chromatography using 1-99% MeCN in 5 mM aqueous HCl yielded 2-((3R,4R,6R)-4-(4-fluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyrizine-5-carboxamide (77 mg, 265.5 mg, 80%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),8.43(d,J=5.8Hz,1H),7.47-7.33(m,2H),7.30(t,J=7.7Hz,1H),7.19(s,1H),6.85-6.77(m,1H),6.71-6.62(m,1H), 6.13(s,1H),4.09-4.00(m,2H),3.90(t,J=11.0Hz,2H),3.79(s,3H),1.96-1.88(m,1H),1.84-1.76(m,1H),1.65(s,3H)ppm.ESI-MS m / z calculated value 479.147, actual value 480.3 (M+1) + ;Retention time: 1.77 minutes, using LC / MS method Q.

[0310] The following compounds were prepared using the same method as described in Example 17, except that different coupling partners were used in Step 1. [Table 41]

[0311] The following compounds were prepared using the same method as described in Example 17, except that different coupling partners were used in Step 1. Step 5 was carried out in the absence of water. For compound 86, hydrolysis step 5 was carried out at 60°C. [Table 42-1] [Table 42-2] [Table 42-3]

[0312] The following compounds were prepared using the same method as described in Example 17, except that a different coupling partner was used in Step 1. Cyanation Step 4 was carried out using DIPEA instead of Et3N as the base. Step 5 was carried out in the absence of water. [Table 43]

[0313] The following compounds were prepared using the same method as described in Example 17, except that steps 3-5 were not required. For compound 89, a different coupling partner was used in step 1. [Table 44]

[0314] The following compounds were prepared using the same method as described in Example 17, except that a different coupling partner was used in Step 1. Step 5 was not necessary. [Table 45]

[0315] Step 1 was carried out using 1-(4-aminopyridine-3-yl)propane-1-one hydrochloride and DIPEA, respectively, as different coupling partners, instead of (3S,4R,6R)-4-(3,4-difluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxylic acid (C-20a), 1-(4-aminopyridine-3-yl)ethane-1-one hydrochloride and pyridine, under the same conditions as described in Step 1 of Example 15, and using the same method as described in Example 17, except that both activation and amide coupling were carried out at ambient temperature. Step 5 was carried out at 80°C in the absence of water. [Table 46]

[0316] The following compounds were prepared using the same method as described in Example 17, except that different coupling partners were used in Step 1. Cyclization Step 2 was carried out under the same conditions as described in Step 2 of Example 15. In the case of compound 93, the product from Step 5 was further purified by chiral SFC (mobile phase: 40% MeOH, 60% CO2, flow rate 100 mL / min) using a Lux® Cellulose-5 column from Phenomenex Inc., particle size 5 μm, 25 cm × 30 mm to obtain the second eluting isomer 93 (rt = 7.03 min). In the case of compound 95, a step was introduced between step 4 and step 5, and the diastereomers were separated by chiral SFC (mobile phase: 30% MeOH, 70% CO2, flow rate 100 mL / min) using a Lux(trademark) i-Cellulose-5 column from Phenomenex Inc., particle size 5 μm, 25 cm × 30 mm, to obtain the precursor of 95, which was the second isomer to elute (rt = 3.90 min). [Table 47]

[0317] The following compounds were prepared using the same method as described in Example 17, except that different coupling partners were used in Step 1. Cyclization Step 2 was carried out under the same conditions as described in Step 2 of Example 16, with the reaction performed at 90°C for 96 and 99, and at 95°C for 97 and 98, respectively. In the case of 96, the product from Step 5 was further purified by chiral SFC (mobile phase: 60% MeOH, 40% CO2, flow rate 100 mL / min) using a Lux® Cellulose-2 column from Phenomenex Inc., particle size 5 μm, 25 cm × 30 mm to obtain the second eluting isomer 96 (rt=2.12 min). [Table 48-1] [Table 48-2]

[0318] The following compounds were prepared using the same method as described in Example 17, except that different coupling partners were used in Step 1. Cyclization Step 2 was carried out under the same conditions as described in Step 2 of Example 16, and the reaction was carried out at 95°C. Step 5 was carried out in the absence of water. The product of Step 5 was further purified using a chiral SFC (mobile phase: 28% MeOH (supplemented with 20 mM ammonia), 72% CO2, flow rate 68 mL / min) with a Chiralpak® IC column from Daicel Corporation, particle size 5 μm, 25 cm × 21.2 mm to obtain the second eluting isomer 100 (rt=6.20 min) and the fourth eluting isomer 101 (rt=9.54 min). [Table 49]

[0319] The following compounds were prepared using the same method as described in Example 17, except that different coupling partners were used in Step 1 and the reaction was carried out in DCM instead of DMF as the solvent. Cyclization Step 2 was carried out under the same conditions as described in Step 2 of Example 16, and the reaction was carried out at 95°C. Step 5 was carried out in the absence of water. For 103 and 104, the products of Step 5 were further purified using a chiral SFC with a Daicel Corporation Chiralpak® AD column, particle size 5 μm, 25 cm × 21.2 mm (mobile phase: 24% MeOH (supplemented with 20 mM ammonia), 76% CO2, flow rates of 70 and 72 mL / min, respectively) to obtain the first eluting isomer 103 (rt=2.35 min) and the first eluting isomer 104 (rt=3.26 min). In the case of 105, the product from step 5 was further purified using a chiral SFC (mobile phase: 20% MeOH (supplemented with 20 mM ammonia), 80% CO2, flow rate 70 mL / min) with a Chiralpak® AD column from Daicel Corporation, particle size 5 μm, 25 cm × 21.2 mm, to obtain the first eluted isomer 105 (rt=2.95 min). In the case of 106, the product from step 5 was further purified using a chiral SFC (mobile phase: 22% MeOH (supplemented with 20 mM ammonia), 78% CO2, flow rate 70 mL / min) with a Chiralpak® AD column from Daicel Corporation, particle size 5 μm, 25 cm × 21.2 mm, to obtain the first eluted isomer 106 (rt=3.10 min). In the case of 107, the product from step 5 was further purified using a chiral SFC (mobile phase: 30% MeOH (supplemented with 20 mM ammonia), 70% CO2, flow rate 70 mL / min) with a Chiralpak® IG column from Daicel Corporation, particle size 5 μm, 25 cm × 21.2 mm, to obtain the first eluted isomer 107 (rt = 2.51 min). [Table 50-1] [Table 50-2]

[0320] The following compounds were prepared using the same method as described in Example 17, except that different coupling partners were used in Step 1 and the reaction was carried out in a mixture of DCM and DMF as the solvent. Cyclization Step 2 was carried out under the same conditions as described in Step 2 of Example 16, and the reaction was carried out at 95°C. Steps 3-5 were unnecessary. [Table 51]

[0321] The following compounds were prepared using the same method as described in Example 17, except that different coupling partners were used in Step 1 and the reaction was carried out in DCM instead of DMF as the solvent. Cyclization Step 2 was carried out under the same conditions as described in Step 2 of Example 16, and the reaction was carried out at 95°C. Hydrolysis Step 5 was carried out at 90°C. In the case of 109, the product of Step 5 was further purified using a chiral SFC with a Daicel Corporation Chiralpak® IG column, particle size 5 μm, 25 cm × 21.2 mm (mobile phase: 24% MeOH (supplemented with 20 mM ammonia), 76% CO2, flow rate 70 mL / min) to obtain the first eluted isomer 109 (rt=2.75 min). In the case of 110, the product from step 5 was further purified using a chiral SFC (mobile phase: 45% MeOH (supplemented with 0.1% DEA), 55% CO2, flow rate 70 mL / min) with a (R,R)-Whelk-O® column from Regis Technologies, Inc., particle size 5 μm, 25 cm × 21.1 mm, to obtain the second isomer to elute, 110 (rt = 5.54 min). [Table 52]

[0322] The following compounds were prepared using the same method as described in Example 17, except that different coupling partners were used in Step 1 and the reaction was carried out in DCM instead of DMF as the solvent. Cyclization Step 2 was carried out under the same conditions as described in Step 2 of Example 16, and the reaction was carried out at 100°C. Step 5 was carried out in the absence of water. The product of Step 5 was further purified using a chiral SFC with a (R,R)-Whelk-O® column from Regis Technologies, Inc., particle size 5 μm, 25 cm × 30 mm (mobile phase: 45% MeOH (supplemented with 0.1% DEA), 55% CO2, flow rate 70 mL / min) to obtain the second eluting isomer 111 (rt=3.39 min). [Table 53]

[0323] The following compounds were prepared using the same method as described in Example 17, except that different coupling partners were used in Step 1 and the reaction was carried out in a mixture of DCM and DMF as the solvent. Cyclization Step 2 was carried out under the same conditions as described in Step 2 of Example 16, and the reaction was carried out at 95°C. Hydrolysis Step 5 was carried out at 90°C. The product of Step 5 was further purified using a chiral SFC with a Daicel Corporation Chiralpak® AD-H column, particle size 5 μm, 25 cm × 30 mm (mobile phase: 20% MeOH (supplemented with 0.1% DEA), 80% CO2, flow rate 75 mL / min) to obtain the first eluted isomer 112 (room temperature = 2.95 min). [Table 54]

[0324] Example 18 2-((3R,4R,6R)-4-(3,4-difluoro-2-hydroxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide(113) [ka] Step 1: A solution of 2-((3R,4R,6R)-4-(3,4-difluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyrizine-5-carboxamide (62, 200 mg, 0.402 mmol) and NaI (95 mg, 0.63 mmol) in HBr (1.9 mL, 30% w / v in AcOH, 7.1 mmol) was stirred at 50°C for 7 hours. The reaction mixture was quenched by adding water and extracted with ethyl acetate (3×). The combined organic extract was washed with saturated aqueous NaHCO3 solution, dried, filtered, and concentrated under vacuum. Purification by reverse-phase chromatography (SiO2, 0-100% ethyl acetate in hexane), followed by reverse-phase chromatography (C 18 2-((3R,4R,6R)-4-(3,4-difluoro-2-hydroxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyrizine-5-carboxamide (113 mg, 67 mg, 34%) was obtained by column chromatography and aqueous solution (0-40% MeCN) containing HCl. 1 H NMR(400MHz,chloroform-d)δ 15.84(s,1H),10.46(s,1H),8.92(s,1H),8.70(d,J=5.7Hz,1H),8.19(d,J= 5.7Hz,1H),6.94-6.87(m,1H),6.86(s,1H),6.71-6.60(m,1H),6.19(s,1H) ,4.14-3.98(m,2H),3.68(t,J=11.5Hz,1H),3.29(td,J=11.2,4.7Hz,1H),2 .33(t,J=13.1Hz,1H),1.83(dd,J=13.3,3.7Hz,1H),1.60(s,3H)ppm.ESI-MS m / z calculated value: 483.122, measured value: 484.5 (M+1) + ;Retention time: 1.60 minutes, using LC / MS method Q.

[0325] Example 19 2-((3R,4R,6R)-4-(3,4-difluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-N-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide(114) [ka] Step 1: NaOH (50 mg, 1.25 mmol) was added to a stirred solution of 2-((3R,4R,6R)-4-(3,4-difluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile (70 mg, 50 mg, 0.10 mmol) in EtOH (1 mL), and the reaction mixture was heated under reflux for 30 minutes. The reaction mixture was cooled to ambient temperature, diluted with water (10 mL), and acidified to pH 5 by adding 1 N aqueous HCl. The mixture was extracted with ELISA (2 ×). The combined organic extracts were dried (MgSO4), filtered, and concentrated under vacuum to obtain 2-((3R,4R,6R)-4-(3,4-difluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxylic acid, which was used in the next step without further purification. ESI-MS m / z calculated value: 498.121, measured value: 499.1 (M+1) + ;Retention time: 0.60 minutes, using LC / MS method T.

[0326] Step 2: HATU (50 mg, 0.13 mmol), DIPEA (0.05 mL, 0.29 mmol), and methanamine hydrochloride (7 mg, 0.104 mmol) were successively added to a solution of 2-((3R,4R,6R)-4-(3,4-difluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxylic acid in DCM (1 mL), and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with water, and the phases were separated. The aqueous phase was extracted with ELISA. The combined organic layers were washed with brine, dried, filtered, and concentrated under vacuum. Purification by flash chromatography (SiO2, 0-10% MeOH in DCM) yielded 2-((3R,4R,6R)-4-(3,4-difluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-N-methyl-4-oxo-1,4-dihydro-1,6-naphthyrizine-5-carboxamide (114 mg, 13.3 mg, 24%). 1 H NMR(400MHz,DMSO-d6)δ 11.62(s,1H),8.43(d,J=5.8Hz,1H),7.80(d,J=5.5Hz,1H),7.36(d,J=5.8Hz,1H),7.28-7.17(m,1H),7.15-7.02(m,1H),6.17(s,1H), 4.08(dd,J=11.6,4.3Hz,1H),4.00-3.85(m,5H),3.31-3.26(m,1H),2.69(d,J=4.4Hz,3H),1.94-1.78(m,2H),1.68(s,3H)ppm.ESI-MS m / z calculated value 511.153, actual value 512.2 (M+1) + ;Retention time: 1.80 min, using LC / MS method Q.

[0327] Example 20 2-((3R,4R,6R)-4-(3,4-difluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-5-(1,5-dimethyl-1H-1,2,3-triazol-4-yl)-1,6-naphthyridine-4(1H)-one(115) [ka] Step 1: POCl3 (3.3 g, 2 mL, 21.5 mmol) was added to a solution of 2-((3R,4R,6R)-4-(3,4-difluoro-2-methoxyphenyl)-6-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine 6-oxide (72 g, 500 mg, 0.964 mmol) in DCM (20 mL), and the react...

Claims

1. Compound of formula (I-A), 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, X １ However, CR １ or N, X ２ However, CR ２ , N, or N ＋ -O － And, X ３ is C-R ３ , N, or N ＋ -O － ​ X ５ However, CR ５ , N, or N ＋ -O － And, p, X ａ , and X ｂ The following applies: (i) p is 1, X ａ CR １１ R １２ X ｂ Is it O? (ii) p is 1, X ａ O is X ｂ CR １３ R １４ is, or (iii) p is 0, X ｂ It is defined that O, X ｓ However, CR ｓ or N, X ｔ However, CR ｔ or N, R １ However, H, OH, Halo, CN, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, -(CH ２ ) ｍ O ｎ (CH ２ ) ｏ OCH ３ ,-(CH ２ ) ｍ R ａ , -C(O)(CH ２ ) ｍ R ａ , -C(O)OR ｂ , -C(O)R ｂ , -C(O)NR ｂ R ｃ , -NR ｂ R ｃ , -CR ｄ R ｅ R ｆ , -CR ｂ R ｃ NR ｇ C(O)CR ｈ R ｉ R ｊ , -NR ｂ C(O)CR ｃ R ｇ R ｊ , C ３ -C ６ The C is a cycloalkyl, a 5-6 membered heteroaryl, or a 4-10 membered heterocycline. ３ -C ６ Even if cycloalkyl, 5-6 membered heteroaryl, or 4-10 membered heterocyclyl is not substituted, halo, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, and C １ -C ６ They may also be substituted with 1 to 4 substituents independently selected from the haloalkoxy. R ２ , R ３ , R ４ , and R ５ are each independently H, OH, CN, halo, C １ -C ６ alkyl, C １ -C ６ alkoxy, C １ -C ６ haloalkyl, -NHS(O) ２ (C １ -C ６ alkyl), -C(O)OR ｂ , -C(O)NR ｂ R ｃ , -(CH ２ ) ｍ O(CH ２ ) ｏ CH ３ , 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl, and the 5- to 6-membered heteroaryl or the 5- to 6-membered heterocyclyl is unsubstituted, or may be substituted with 1 to 4 substituents each independently selected from C １ -C ６ alkyl and -C(O)NR ｂ R ｃ , R ６ , R ７ , R ８ , and R ９ However, as follows, (i) R ６ and R ７ However, each is independent of H, OH, and C. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ It is an alkoxy, R ８ and R ９ However, each is independent of H, OH, and C. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ It is an alkoxy, or (ii) R ６ and R ７ However, each is independent of H, OH, and C. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ It is an alkoxy, R ８ and R ９ Together with the carbon atoms to which they are bonded, C ３ -C ６ They form cycloalkyl groups, or (iii) R ６ , R ７ , R ８ , and R ９ These, together with the carbon atoms to which they are bonded, form 1 to 3 R ｙ The condensed C that was substituted as needed. ６ -C １０ It is defined as forming an aryl, R １０ However, H or CH ３ And, R １１ and R １２ However, each is independent of H, OH, and C. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ It is an alkoxy, R １３ and R １４ However, each is independent of H, OH, and C. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ It is an alkoxy, R ｓ and R ｔ However, each is independent of H, OH, halo, and C. １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, C ３ -C ６ Cycloalkyl, -O-C ３ -C ６ Cycloalkyl, -NR ｂ R ｃ , -NO ２ , -SO ３ H, -(CH ２ ) ｍ OR ｂ , or -O(CH ２ ) ｍ OCH ３ is or R ｓ and R ｔ Together with the carbon atoms to which they are bonded, the formula 【Chemistry 2】 Forming a ring, Y is O or CH ２ And, R ｕ , R ｖ , and R ｗ However, each is independent of H, OH, halo, and C. １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, -NR ｂ R ｃ , -NO ２ , -SO ３ H, -(CH ２ ) ｍ OR ｂ , or -O(CH ２ ) ｍ OCH ３ And, Each R ｘ However, they became independent: H, Halo, C １ -C ６ Alkyl, or C １ -C ６ It is a haloalkyl, Each R ｙ However, independently, H, OH, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ It is an alkoxy, R ａ But, OH, Halo, C １ -C ６ Alkoxy, or -NR ｂ R ｃ And, R ｂ , R ｃ , R ｇ , R ｈ , and R ｉ However, each independently, H or C １ -C ６ Alkyl or R ｂ and R ｃ These, together with the nitrogen atom to which they are bonded, form a 3-6 membered heterocycline. R ｄ , R ｅ , and R ｆ However, each is independent of H, OH, halo, and C. １ -C ６ Alkyl, or C １ -C ６ It is an alkoxy, R ｊ However, H, C １ -C ６ Alkyl, -NR ｂ R ｃ , or -N(CH ３ ) ３ ＋ And, m and o are independently 0, 1, 2, or 3. A compound, or a pharmaceutically acceptable salt thereof, in which n is 0 or 1.

2. X ａ However, CH ２ And, X ｂ However, it is O, R ６ and R ７ However, each is independent of H, OH, and C. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ It is an alkoxy, R ８ and R ９ However, each is independent of H, OH, and C. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ It is either an alkoxy or R ８ and R ９ Together with the carbon atoms to which they are bonded, C ３ -C ６ Forming a cycloalkyl group, R ｓ and R ｔ However, each is independent of H, OH, halo, and C. １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, -NR ｂ R ｃ , -NO ２ , -SO ３ H, -(CH ２ ) ｍ OR ｂ , or -O(CH ２ ) ｍ OCH ３ is or R ｓ and R ｔ Together with the carbon atoms to which they are bonded, the formula 【Transformation 3】 Forming a ring, The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1.

3. A compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, wherein p is 0.

4. p is 1, and if necessary, (i) p is 1, X ａ However, CR １１ R １２ X ｂ However, is it O, or (ii) p is 1, X ａ However, O and X ｂ However, CR １３ R １４ The compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof.

5. The compound is the compound according to any one of claims 1 to 4, having formula (I-A-1), or a pharmaceutically acceptable salt thereof. 【Chemistry 4】

6. X １ However, CR １ And R １ However, H, CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, or -C(O)OR ｂ And, if necessary, R １ is H, CN, -CH ３ , -OCH ３ , -C(O)OCH ３ , or -C(O)OCH ２ CH ３ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

7. X ２ However, CR ２ And R ２ However, H, OH, CN, Halo, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, -NHS(O) ２ (C １ -C ６ Alkyl), -C(O)OR ｂ , -C(O)NR ｂ R ｃ , a 5-6 member heteroaryl, or a 5-6 member heterocycline, and even if the 5-6 member heteroaryl or the 5-6 member heterocycline is not substituted, C １ -C ６ Alkyl and -C(O)NR ｂ R ｃ It may also be substituted with 1 to 4 substituents independently selected from R, as needed. ２ However, H, Cl, F, OH, CN, -CH ３ , -OCH ３ , -C(O)OH, -C(O)NH ２ , -C(O)N(H)CH ３ , -N(H)S(O) ２ (CH ３ ), 【Transformation 5】 The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

8. X ３ A compound according to any one of claims 1 to 7, wherein N is present, or a pharmaceutically acceptable salt thereof.

9. X ３ However, CR ３ And R ３ However, H, CN, Halo, C １ -C ６ Alkoxy, -C(O)OR ｂ , or -C(O)NR ｂ R ｃ And, if necessary, R ３ is H, Cl, F, CN, -OCH ３ , -C(O)OCH ３ , or -C(O)N(CH ３ ) ２ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

10. R ４ However, H, Haro, C １ -C ６ Alkyl, -C(O)OR ｂ , or -C(O)NR ｂ R ｃ And, if necessary, R ４ However, H, Cl, F, -CH ３ , -C(O)OCH ２ CH ３ , or -C(O)NH ２ The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. X ５ However, CR ５ And R ５ However, H, halo, or -C(O)NR ｂ R ｃ And, if necessary, R ５ However, H, F, or -C(O)NH ２ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. R ７ However, H, OH, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ It is an alkoxy, and R as needed. ７ is H, OH, -OCH ３ ien-CH ３ A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein the compound is cyclopropyl.

13. R ８ and R ９ However, H and C are independent of each other. １ -C ６ Alkyl, C １ -C ６ Haloalkyl or C ３ -C ６ It is either cycloalkyl or R ８ and R ９ Together with the carbon atoms to which they are bonded, C ３ -C ６ Form a cycloalkyl group, and if necessary, (i) R ８ However, H or C １ -C ６ It is alkyl, and R as needed. ８ However, H, -CH ３ , or -CH ２ CH ３ And, (ii) R ９ However, H, C １ -C ６ Alkyl, or C １ -C ６ It is a haloalkyl, and R is used as needed. ９ However, H, -CH ３ , or CF ３ is it, or (iii) R ８ and R ９ Together with the carbon atoms to which they are bonded, C ３ -C ６ Form a cycloalkyl group, and if necessary, R ８ and R ９ The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein the carbon atoms to which they are bonded together form cyclobutane.

14. R １０ A compound according to any one of claims 1 to 13, wherein H is present, or a pharmaceutically acceptable salt thereof.

15. R １０ However, CH ３ The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

16. X ｓ However, CR ｓ And R ｓ However, H, OH, halo, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, -O-C ３ -C ６ Cycloalkyl, -(CH ２ ) ｍ OR ｂ , or -O(CH ２ ) ｍ OCH ３ And, if necessary, X ｓ However, CR ｓ And R ｓ However, H, F, Cl, OH, -CH ３ ien-CH ２ OH, -CH ２ OCH ３ , -OCH ３ , cyclopropyl, -O-cyclopropyl, -OCH(CH ３ ) ２ , or -OCH ２ CH ２ OCH ３ The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.

17. X ｔ However, CR ｔ And R ｔ However, H, Haro, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, or C ３ -C ６ It is a cycloalkyl, and if necessary, X ｔ However, CR ｔ And R ｔ However, H, Cl, F, -CH ３ , -OCH ３ A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein the compound is cyclopropyl.

18. R ｓ and R ｔ Together with the carbon atoms to which they are bonded, the formula 【Transformation 6】 Forms a ring, and if necessary, R ｓ and R ｔ Together with the carbon atoms to which they are bonded, the formula 【Transformation 7】 A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, which forms a ring.

19. R ｕ However, H, Haro, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ It is a haloalkyl, and R is used as needed. ｕ However, H, F, or -CH ３ The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.

20. R ｖ However, H, halo, or C １ -C ６ It is alkyl, and R as needed. ｖ However, H, F, or -CH ３ The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof.

21. R ｗ A compound according to any one of claims 1 to 20, wherein H is present, or a pharmaceutically acceptable salt thereof.

22. The compound is the compound according to any one of claims 1 to 4, having formula (I-A-2), or a pharmaceutically acceptable salt thereof. 【Transformation 8】

23. R ７ However, H, C １ -C ６ Alkyl, or C １ -C ６ It is an alkoxy, and R as needed. ７ However, H, -CH ３ , or -OCH ３ A compound according to any one of claims 1 to 4 and 22, or a pharmaceutically acceptable salt thereof.

24. R ｓ However, H, Haro, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, or -(CH ２ ) ｍ OR ｂ And, if necessary, R ｓ However, H, F, Cl, -CH ３ , -OCH ３ , cyclopropyl, or -CH ２ OCH ３ The compound according to any one of claims 1 to 4 and 22 to 23, or a pharmaceutically acceptable salt thereof.

25. R ｔ However, H, Haro, C １ -C ６ Alkyl, or C ３ -C ６ It is a cycloalkyl, and R as needed. ｔ However, H, F, Cl, -CH ３ A compound according to any one of claims 1 to 4 and 22 to 24, or a pharmaceutically acceptable salt thereof, which is cyclopropyl.

26. A compound selected from Table A, which may optionally be a compound selected from Table B, or a pharmaceutically acceptable salt thereof.

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

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

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

30. The compound according to any one of claims 1 to 29, which is in a non-salt form.

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, or a compound according to claim 30, and one or more pharmaceutically acceptable carriers or vehicles.

32. A method for inhibiting voltage-gated sodium channels in a subject, the method comprising administering to the subject a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, the compound according to claim 30, or the pharmaceutical composition according to claim 31, wherein the voltage-gated sodium channels are, if necessary, Na Ｖ 1.8, method.

33. A method for treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia, wherein the method comprises administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of claims 1 to 29, the compound described in claim 30, or the pharmaceutical composition described in claim 31, and if necessary, (i) The method comprises treating neuropathic pain or reducing its severity in the subject, and, if necessary, the neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, idiopathic small fiber neuropathy, diabetic neuropathy, or diabetic peripheral neuropathy, or (ii) The method comprises treating musculoskeletal pain or reducing its severity in the subject, and if necessary, the musculoskeletal pain includes osteoarthritis pain, or (iii) The method includes treating acute pain or reducing its severity in the subject, and if necessary, the acute pain includes acute postoperative pain, or (iv) The method includes treating postoperative pain or reducing its severity in the subject, and if necessary, the postoperative pain includes bunion resection pain, abdominal wall repair pain, or hernia repair pain, (v) A method comprising treating visceral pain or reducing its severity in the subject.

34. The method according to any one of claims 32 to 33, wherein the subject is treated simultaneously with, or before, treatment with, one or more additional therapeutic agents administered before or after, treatment with the compound, the pharmaceutically acceptable salt, or the pharmaceutical composition.

35. Use as a pharmaceutical agent of the compound described in any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, the compound described in claim 30, or the pharmaceutical composition described in claim 31.

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