Substituted tetrahydrofuran analogs as modulators of sodium channels

Abstract

Compounds of formula I and pharma- ceutically acceptable salts thereof are provided that are useful as inhibitors of sodium channels.Also provided are pharmaceutical compositions comprising the compounds or pharma- ceutically acceptable salts, and methods of using the compounds, pharma- ceutically acceptable salts, and pharmaceutical compositions in the treatment of various disorders, including pain.In yet another aspect, the present invention relates to methods of inhibiting voltage-gated sodium channels in a subject by administering a compound, a pharma- ceutically acceptable salt, or a pharmaceutical composition to the subject. TIFF2024522293000280.tif4252

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 197,199, filed on 4 June 2021, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and prevent further damage to damaged tissue. Nevertheless, there are many conditions in which pain persists beyond its usefulness, or in which the patient would benefit from pain suppression. 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 general metabolic damage to nerves, and pain caused by specific nerve damage. Metabolic neuropathy includes postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Indications for specific nerve damage include post-amputation pain, postoperative nerve injury pain, and nerve compression injuries such as neuropathic back pain. Neuropathic pain is a leading cause of disability worldwide and negatively impacts patients' sleep, mood, and function. See Clin.Ther., 2018 40(6):p.828-49.

[0003] Voltage-gated sodium channels (Na V ) is involved in pain signaling. VNav1.8 mediates the rapid upstroke of action potentials in many excitable cell types (e.g., neurons, skeletal muscle cells, cardiomyocytes) and is therefore involved in the initiation of signal transduction in those cells (Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). Support for the claim that Nav plays a crucial and central role in pain signal transduction arises from (1) an evaluation of the role Nav plays in normal physiological function, (2) pathological conditions resulting from mutations in the Nav1.8 gene (SCN10A), (3) preclinical studies in animal models, and (4) the pharmacological effects of known Nav1.8 modulators. Furthermore, because Nav1.8 expression is limited to peripheral neurons, particularly those sensing pain (e.g., dorsal root ganglia), Nav1.8 inhibitors are less likely to be associated with the side effects commonly observed with other sodium channel modulators and the abuse tendencies associated with opioid therapy. Therefore, targeting the underlying biology of pain through selective Nav1.8 inhibition represents a novel approach to analgesic development that could address the urgent and unmet need for safe and effective acute and chronic pain therapy. (Rush, A.M. and TRCummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Nav1.8) V1.8 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 nerve signals. V Due to the role that Na plays, V Antagonists that reduce current can prevent or reduce nerve signaling, Na V Channels have been considered a likely target for pain reduction under conditions where hyperexcitability is observed (Chahine, M., Chatelier, A., Babich, O., and Krupp, JJ, Voltage-gated sodium channels in neurological disorders. CNS Neurol. Disord. Drug Targets 7(2), p.144-58 (2008)). Several clinically useful analgesics use Na V It has been identified as a channel inhibitor. Local anesthetics such as lidocaine are Na V Other compounds such as carbamazepine, lamotrigine, and tricyclic antidepressants, which have been shown to be effective in reducing pain by blocking channels, are also suggested to act by inhibiting sodium channels (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. Eur. J. Pain 6 Suppl. A, p.3-9 (2002), Wang, GK, Mitchell, J., and Wang, SY, Block of persistent late Na+ currents by antidepressant sertraline and paroxetine. J. Membr. Biol. 222(2), p.79-90 (2008)).

[0004] Na V forms a subfamily of the voltage-gated ion channel superfamily, and Na V 1.1~Na V includes nine isoforms designated as 1.9. The tissue localization of the nine isoforms differs. Na V 1.4 is the primary sodium channel of skeletal muscle, and Na V 1.5 is the primary sodium channel of cardiomyocytes. Na V 1.7, 1.8, and 1.9 are mainly localized in the peripheral nervous system, and Na V 1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the central nervous system and the peripheral nervous system. The functional behaviors of the nine isoforms are similar, but distinct in the details of their voltage dependence and kinetic behaviors (Catterall, W.A., Goldin, A.L., and Waxman, S.G., International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57(4), p.397 (2005)).

[0005] At the time of their discovery, Na V 1.8 channels were identified as highly likely to be targets for analgesia (Akopian, A.N., L. Sivilotti, and J.N. Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562): p.257-62). Thereafter, Na V1.8 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 V 1.8 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 V1.8 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,X.W.,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, HL, 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, JA, et al. 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 Small DRG neurons expressing 1.8 contain nociceptors involved in pain signaling.V 1.8 mediates large-amplitude action potentials in small neurons of the dorsal root ganglia (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 have been shown to increase in DRGs (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 found 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]

[0006] [Non-Patent Document 1] Dieleman,JP,et al.,Incidence rates and treatment of neuropathic pain conditions in the general population.Pain,2008.137(3):p.681-8 [Non-Patent Document 2] Clin.Ther.,2018 40(6):p.828-49 [Non-Patent Document 3] Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001) [Non-Patent Document 4] 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 5] 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 6] 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 7] 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 8] Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action.Eur.J.Pain 6 Suppl.A, p.3-9(2002) [Non-Patent Document 9] 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 10] 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 11] 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 12 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 13 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 14 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 15 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 16 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 17 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 18 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 19 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 20 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 21 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 22 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 23 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 24 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 25 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 26 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 27 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 28 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 29 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 30] 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] [Means for solving the problem]

[0007] In one embodiment, the present invention relates to compounds described herein, or pharmaceutically acceptable salts thereof.

[0008] 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.

[0009] 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.

[0010] 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 disease, incontinence, pathological cough, or cardiac arrhythmia, by administering a compound, a pharmaceutically acceptable salt, or a pharmaceutical composition to a subject. [Brief explanation of the drawing]

[0011] [Figure 1] The XRPD pattern characteristics of amorphous compound 6 are shown. [Figure 2] The XRPD pattern characteristics of amorphous compound 7 are shown. [Figure 3] The XRPD pattern characteristics of amorphous compound 86 are shown. [Figure 4] The XRPD pattern characteristics of amorphous compound 87 are shown. [Figure 5] The XRPD pattern characteristics of amorphous compound 123 are shown. [Figure 6] The XRPD pattern characteristics of amorphous compound 181 are shown. [Figure 7] The XRPD pattern characteristics of amorphous compound 224 are shown. [Modes for carrying out the invention]

[0012] In one embodiment, the present invention relates to a compound of formula (I), [ka] Or, with respect to the pharmaceutically acceptable salt thereof, in the formula, X 2a is N, N + -O - , or CR 2a And, X 4a is N, N + -O - , or CR4a And, X 5a is N, N + -O - , or CR 5a And, X 6a is N, N + -O - , or CR 6a And, R is OR a or NR Xa R Ya And, R 2a , R 4a , R 5a , and R 6a Each of these is independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or -Si(C1-C6 alkyl)3. R a is H or C1-C6 alkyl, R Xa is H or C1-C6 alkyl, R Ya H, OH, C1-C6 alkyl, -(C1-C6 alkylene)-R Za1 or a 4-6 membered heterocycline optionally substituted with one or more groups independently selected from C1-C6 alkyl and C1-C6 alkoxy, or R Xa and R Ya However, together with the nitrogen atoms to which they are bonded, they form a 5-9 member heterocycline, and this heterocycline contains one or more R Za2 It is replaced as needed, R Za1 This is a 5-6 membered heterocycline optionally substituted with one or more groups independently selected from OH, NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, and halo and C1-C6 alkyl. Each R Za2 These are independently selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, and -(C1-C6 alkylene)-(C1-C6 alkoxy), R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl, R 5b1 and R 5b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, or -(C1-C6 alkylene)-(C1-C6 alkoxy), or or R 5b1 and R 5b2 together with the carbon atom to which they are attached form a 4- to 6-membered heterocyclyl, X 3c is N or C-R 3c , X 4c is N or C-R 4c , X 5c is N or C-R 5c , X 6c is N or C-R 6c , R 2c is H, OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -(C1-C6 alkylene)-(C1-C6 alkoxy), -(C1-C6 alkylene)-O-(4- to 6-membered heterocyclyl), -O-(C2-C6 alkenylene)-(C1-C6 haloalkyl), -L 1 -L 2 -(C3-C7 cycloalkyl), or -O-L 3 -R Xc , wherein said cycloalkyl is optionally substituted with one or more groups independently selected from halo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, =NOH, -C(O)(C1-C6 alkyl), and -(C1-C6 alkylene)-OH, L 1 is a bond or O, L 2 is a bond or C1-C6 alkylene, L 3These are a bond, a C1-C6 alkylene, or a C2-C6 alkenylene. R Xc OH, CN, C1-C6 alkoxy, NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 haloalkyl), -NH(C1-C6 haloalkyl)2, -CH(CH2OH)2, -CH(CH2OH)(CH2OCH3), -CH(CH2OH)(OCH3), -CH(CH2OCH3)(OCH3), -CH(CH2OH)(CF3), -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -NH(4-6 member heterocyclyl The cycloalkyl groups are selected from -N=S(O)(C1-C6 alkyl)2, -C(=NOH)(C3-C6 cycloalkyl), 4-8 membered heterocyclyl, and 5-6 membered heteroaryl groups, wherein the cycloalkyl group is optionally substituted with one or more halos, and the heterocyclyl and heteroaryl groups are optionally substituted with one or more groups independently selected from OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -(C1-C6 alkylene)-OH. R 3c is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -(C1-C6 alkylene)-OH, or -(C1-C6 alkylene)-(C1-C6 alkoxy), Or, X 3c CR 3c And R 2c and R 3c Together with the carbon atoms to which they are bonded, the formula is: [ka] Forming a ring, Z 1 and Z 2 Each of these is independently O, CH2, or CF2. R Yc1 and R Yc2 Each of these is independently H or halo, R4c This is H, halo, OH, -OBn, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed. R 5c This is H, halo, OH, -OBn, C1-C6 alkyl, C1-C6 haloalkyl, or -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed. R 6c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl, However, X 2a , X 4a , X 5a , and X 6a Two or fewer of these are N or N + -O - And, However, X 3c , X 4c , X 5c , and X 6c One of these is less than or equal to N, however, R is OR a is or R stands for NR Xa R Ya And R Ya OH,-(C1-C6 alkylene)-R Za1 , or a 4- to 6-membered heterocycline optionally substituted with one or more groups independently selected from C1-C6 alkyl and C1-C6 alkoxy, R stands for NR Xa R Ya And R Xa and R Ya These, together with the N atoms to which they are bonded, form a 5-9 membered heterocycline, and this heterocycline contains one or more R Za2 It is replaced as needed, or R 2a , R4a , R 5a , or R 6a is -Si(C1-C6 alkyl) or R 5b1 Or R 5b2 is either -(C1-C6 alkylene)-(C1-C6 alkoxy) or R 5b1 and R 5b2 They either combine with the carbon atoms to which they are bonded to form a 4-6 membered heterocycline, or R 2c These are -(C1-C6 alkylene)-(C1-C6 alkoxy), -(C1-C6 alkylene)-O-(4-6 member heterocyclyl), -O-(C2-C6 alkenylene)-(C1-C6 haloalkyl), or -OL 3 -R Xc is or R 2c is, -L 1 -L 2 -(C3-C7 cycloalkyl), and the cycloalkyl is substituted with one or more groups independently selected from OH, CN, C1-C6 alkyl, C1-C6 alkoxy, =NOH, -C(O)(C1-C6 alkyl), and -(C1-C6 alkylene)-OH, or R 3c is either -(C1-C6 alkylene)-OH or -(C1-C6 alkylene)-(C1-C6 alkoxy), or R 2c and R 3c Together with the carbon atoms to which they are bonded, the formula is: [ka] To form a ring, or R 4c This is OH, -OBn, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed, or R 5cis OH, -OBn, or -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl group is substituted with 1-2 halos as needed.

[0013] In one embodiment, the present invention relates to a compound of formula (I'), [ka] Or, with respect to the pharmaceutically acceptable salt thereof, in the formula, X 2a is N, N + -O - , or CR 2a And, X 4a is N, N + -O - , or CR 4a And, X 5a is N, N + -O - , or CR 5a And, X 6a is N, N + -O - , or CR 6a And, R is OR a or NR Xa R Ya And, R 2a , R 4a , R 5a , and R 6a Each of these is independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -Si(C1-C6 alkyl)3, -Si(O-C1-C6 alkoxy)3, -Si(C1-C6 alkyl)(O-C1-C6 alkoxy)2, or -Si(C1-C6 alkyl)2(C1-C6 alkoxy), R a is H or C1-C6 alkyl, R Xa is H or C1-C6 alkyl, R Ya H, OH, C1-C6 alkyl, -(C1-C6 alkylene)-RZa1 or a 4-6 membered heterocycline optionally substituted with one or more groups independently selected from C1-C6 alkyl and C1-C6 alkoxy, or R Xa and R Ya However, together with the nitrogen atoms to which they are bonded, they form a 5-9 member heterocycline, and this heterocycline contains one or more R Za2 It is replaced as needed, R Za1 This is a 5-6 membered heterocycline optionally substituted with one or more groups independently selected from OH, NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, and halo and C1-C6 alkyl. Each R Za2 These are independently selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, and -(C1-C6 alkylene)-(C1-C6 alkoxy), R 4b1 and R 4b2 Each of these is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl. R 5b1 and R 5b2 Each of these is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, or -(C1-C6 alkylene)-(C1-C6 alkoxy), or R 5b1 and R 5b2 These, together with the carbon atoms to which they are bonded, form 4-6 membered heterocyclines. X 3c is N or CR 3c And, X 4c is N or CR 4c And, X 5c is N or CR 5c And, X 6c is N or CR 6c And, R2c H, OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -(C1-C6 alkylene)-(C1-C6 alkoxy), -(C1-C6 alkylene)-O-(4-6 member heterocyclyl), -O-(C2-C6 alkenylene)-(C1-C6 haloalkyl), -L 1 -L 2 -(C3-C7 cycloalkyl), or -OL 3 -R Xc The cycloalkyl group is optionally substituted with one or more groups independently selected from halo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, =NOH, -C(O)(C1-C6 alkyl), and -(C1-C6 alkylene)-OH. L 1 is a bond or O, L 2 This is a bond or C1-C6 alkylene, L 3 These are a bond, a C1-C6 alkylene, or a C2-C6 alkenylene. R XcOH, CN, C1-C6 alkoxy, NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 haloalkyl), -NH(C1-C6 haloalkyl)2, -CH(CH2OH)2, -CH(CH2OH)(CH2OCH3), -CH(CH2OH)(OCH3), -CH(CH2OCH3)(OCH3), -CH(CH2OH)(CF3), -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -NH(4-6 member heterocyclyl The cycloalkyl groups are selected from -N=S(O)(C1-C6 alkyl)2, -C(=NOH)(C3-C6 cycloalkyl), 4-8 membered heterocyclyl, and 5-6 membered heteroaryl groups, wherein the cycloalkyl group is optionally substituted with one or more halos, and the heterocyclyl and heteroaryl groups are optionally substituted with one or more groups independently selected from OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -(C1-C6 alkylene)-OH. R 3c is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -(C1-C6 alkylene)-OH, or -(C1-C6 alkylene)-(C1-C6 alkoxy), Or, X 3c CR 3c And R 2c and R 3c Together with the carbon atoms to which they are bonded, the formula is: [ka] Forming a ring, Z 1 and Z 2 Each of these is independently O, CH2, or CF2. R Yc1 and R Yc2 Each of these is independently H or halo, R 4cThis is H, halo, OH, -OBn, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed. R 5c This is H, halo, OH, -OBn, C1-C6 alkyl, C1-C6 haloalkyl, or -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed. R 6c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl, However, X 2a , X 4a , X 5a , and X 6a Two or fewer of these are N or N + -O - And, However, X 3c , X 4c , X 5c , and X 6c One of these is less than or equal to N, however, R is OR a is or R stands for NR Xa R Ya And R Ya OH,-(C1-C6 alkylene)-R Za1 , or a 4- to 6-membered heterocycline optionally substituted with one or more groups independently selected from C1-C6 alkyl and C1-C6 alkoxy, R stands for NR Xa R Ya And R Xa and R Ya These, together with the N atoms to which they are bonded, form a 5-9 membered heterocycline, and this heterocycline contains one or more R Za2 It is replaced as needed, or R 2a , R 4a , R5a , or R 6a is -Si(C1-C6 alkyl) or R 5b1 Or R 5b2 However, it is either -(C1-C6 alkylene)-(C1-C6 alkoxy) or R 5b1 and R 5b2 However, together with the carbon atoms to which they are bonded, they form a 4-6 membered heterocycline, or R 2c These are -(C1-C6 alkylene)-(C1-C6 alkoxy), -(C1-C6 alkylene)-O-(4-6 member heterocyclyl), -O-(C2-C6 alkylmenylene)-(C1-C6 haloalkyl), or -OL 3 -R Xc is or R 2c is, -L 1 -L 2 -(C3-C7 cycloalkyl), and the cycloalkyl is substituted with one or more groups independently selected from OH, CN, C1-C6 alkyl, C1-C6 alkoxy, =NOH, -C(O)(C1-C6 alkyl), and -(C1-C6 alkylene)-OH, or R 3c However, it is either -(C1-C6 alkylene)-OH or -(C1-C6 alkylene)-(C1-C6 alkoxy), or R 2c and R 3c Together with the carbon atoms to which they are bonded, the formula is: [ka] To form a ring, or R 4c This is OH, -OBn, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed, or R 5c is OH, -OBn, or -L 1-L 2 -(C3-C6 cycloalkyl), and the cycloalkyl group is substituted with 1-2 halos as needed.

[0014] For the purposes of this invention, chemical elements are as follows: Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th The general principles of organic chemistry are identified according to Ed. Furthermore, the general principles of organic chemistry are found in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry,” 5 th This is described in Ed.,Smith, MB and March, J., John Wiley & Sons, New York: 2001, and its entire contents are incorporated herein by reference.

[0015] As used herein, the term “compounds of the present invention” refers to the compounds of formula (I) described herein, and all of its embodiments (e.g., formulas (IA), (IB), (IC), etc.), as well as the compounds specified in Table A.

[0016] As described herein, the compounds of the present invention have a plurality of variable groups (e.g., X 2a , R 5b1 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, “stable” means a compound that remains substantially unchanged when subjected to conditions that enable their formation, detection, and, if necessary, 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.

[0017] The chemical structures illustrated herein will be understood by those skilled in the art, and are therefore intended to be understood. For example, with respect to formulas (I), (IA), (IB), and (IC), X 5a and X 6a They are joined by a double bond, X 4c and X 5c These groups are linked by single bonds, but the bonds between these groups can be obscured by atomic labeling in the chemical structure. Furthermore, substituents represented as "CF3" or "F3C" in the chemical structure refer to trifluoromethyl substituents, regardless of whether their representation appears in the chemical structure.

[0018] As used herein, the term "halo" means F, Cl, Br, or I.

[0019] 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.

[0020] As used herein, the term “alkenyl” refers to a linear or branched hydrocarbon chain radical group consisting only of carbon and hydrogen atoms, having one or more carbon-carbon double bonds and a specified number of carbon atoms, which are bonded to the rest of the molecule by single bonds. For example, a “C2-C6 alkenyl” group is an alkenyl group having 2 to 6 carbon atoms.

[0021] 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.

[0022] 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.

[0023] As used herein, the term "haloalkyl" refers to an alkoxy group having a specified number of carbon atoms, in which one or more 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 hydrogen atoms of the alkyl group are replaced by a halo group.

[0024] 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.

[0025] As used herein, the term "alkylene" refers to a divalent linear or branched hydrocarbon radical group consisting only of carbon and hydrogen atoms, which is unsaturated and has a specified number of carbon atoms, and is bonded to the rest of the molecule by two single bonds. For example, a "C1-C6 alkylene" group is an alkylene group having 1 to 6 carbon atoms.

[0026] As used herein, the term "alkenylene" refers to a divalent linear or molecular chain hydrocarbon radical group consisting only of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds, and having a specified number of carbon atoms, which are bonded to the rest of the molecule by two single bonds. For example, "C2-C6 alkenylene" is an alkenylene group having 1 to 6 carbon atoms.

[0027] As used herein, the terms “heterocyclic,” “heterocyclyl,” “heteroalicyclic,” “heterocycloalkyl,” or “heterocyclic” mean a non-aromatic, monocyclic, bicyclic, or tricyclic ring system in which one or more ring members are independently selected heteroatoms. The heterocyclic ring may be saturated or may contain one or more unsaturated bonds. In some embodiments, the “heterocyclic,” “heterocyclyl,” “heteroalicyclic,” “heterocycloalkyl,” or “heterocyclic” group has the indicated number of ring members, one or more of which are heteroatoms independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the ring system contains 3 to 7 ring members. For example, a 6-membered heterocyclyl has a total of 6 ring members, at least one of which is a heteroatom selected from N, S, O, and P.

[0028] As used herein, the term “heteroaryl” refers to monocyclic, bicyclic, and tricyclic ring systems having the indicated number of ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms selected from nitrogen, sulfur, oxygen, or phosphorus, and each ring in the system contains 3 to 7 ring members. For example, a 6-membered heteroaryl has 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.”

[0029] When used herein, labels such as "*2" and "*3" as shown in the following structures refer to the corresponding R groups (in this case, R 2c Base and R3c The base indicates the atom to which it is bonded. [ka]

[0030] 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 or not they are 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.

[0031] 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.

[0032] As used herein, in any chemical structure or formula, a non-bold, wavy bond attached to a double bond in a compound (for example) [ka] )teeth, [ka] This indicates that the compound was isolated as a mixture of geometric isomers (i.e., a mixture of compounds having (E) and (Z) stereochemistry around the double bond). Compounds isolated as a mixture of geometric isomers do not specify the stereochemical configuration of the double bond in the enumerated chemical name. Other stereocenters in known configurations within the compound may have appropriate stereochemical designations in the enumerated chemical name. As an example, the above reference compound is enumerated in Example 21 as 4-((2R,3S,4S,5R)-3-(2-(2-cyclopropyl-2-(hydroxyimino)ethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide.

[0033] 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.

[0034] 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 wedge-shaped bonds, indicated by thick or dashed lines, show the absolute stereochemistry of the stereocenter relative to other stereocenters to which they are bonded, as well as the relative stereochemistry of the stereocenter.

[0035] As used herein, the prefix "rac-" refers to a racemic mixture of compounds when used in relation to chiral compounds. In compounds having the "rac-" prefix, the (R)- and (S)- designations in the chemical name reflect the relative stereochemistry of the compound.

[0036] 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. In some cases, the prefix "rel-" is used with compounds that have geometric isomerism around a double bond (e.g., -C=C-, -C=N-, etc.) to indicate the relative stereochemistry of geometric isomers (i.e., (E) or (Z) stereochemistry). If the relative stereochemistry of a given stereocenter is unknown, no stereochemical designator is provided. 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 specifiers associated with stereocenters of known absolute configurations are marked with an asterisk (*), e.g., (R*)- and (S*)-, while stereochemical specifiers associated with stereocenters of unknown absolute configurations are not marked in this way. Unmarked stereochemical specifiers associated with stereocenters of unknown absolute configurations reflect the relative stereochemistry of those stereocenters with respect to other stereocenters of the unknown absolute configuration, but not necessarily their relative stereochemistry with respect to stereocenters of known absolute configurations.

[0037] 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.

[0038] As used herein, the term “amorphous” refers to a solid material that does not possess long-range order in its molecular positioning. Amorphous solids are generally glassy or supercooled liquids in which molecules are randomly arranged, such that there is no clearly defined arrangement, e.g., no molecular packing and no long-range order. Amorphous solids are generally rather isotropic, meaning they exhibit similar properties in all directions and do not have a distinct melting point. Instead, they typically exhibit a glass transition temperature, indicating a transition from a glassy amorphous state to a supercooled liquid amorphous state upon heating. For example, an amorphous material is a solid material that does not have a sharp, characteristic crystalline peak in its X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) are observed in its XRPD pattern. Broad peaks are characteristic of amorphous solids. For a comparison of XRPDs of amorphous and crystalline materials, see US2004 / 0006237. In some embodiments, the solid material may contain amorphous compounds, for example, the solid material may be characterized by the absence of sharp, characteristic crystalline peaks in its XRPD spectrum (i.e., the solid material is not crystalline but amorphous as determined by the XRPD). Instead, one or more broad peaks (e.g., halos) may be observed in the XRPD pattern of the solid material. For a typical comparison of XRPDs of amorphous and crystalline materials, see US2004 / 0006237. Solid materials containing amorphous compounds may be characterized by a broader temperature range of melting of the solid material compared to, for example, the melting range of a pure crystalline solid. Other techniques, such as solid-state NMR, may be used to characterize the crystalline or amorphous form.

[0039] 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.

[0040] 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 the Table of Nuclides (January 1980) by V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory.

[0041] 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.

[0042] 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 naturally occurring concentration of protium.

[0043] As used herein, "D", "d", and " 2 "H" refers to deuterium.

[0044] 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.

[0045] 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.

[0046] Isotope-labeled compounds and salts can be used in several beneficial ways, including 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.

[0047] 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.

[0048] 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.

[0049] 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).

[0050] In some embodiments, the present invention relates to compounds of formula (IA), [ka] or having a pharmaceutically acceptable salt thereof, wherein R, X 2a , X 4a , X 5a , X 6a , R 4b1 , R 4b2 , R 5b1 , R 5b2 , X 3c , X 4c , X 5c , X 6c , and R 2c It is defined as shown above in relation to equation (I).

[0051] In some embodiments, the present invention relates to a compound of formula (IA-1), [ka] or having a pharmaceutically acceptable salt thereof, wherein R, X 2a , X 4a , X 6a , R 4b1 , R 4b2 , R5b1 , R 5b2 , X 3c , R 2c 、 R 4c , and R 5c It is defined as shown above in relation to equation (I).

[0052] In some embodiments, the present invention relates to a compound of formula (IA-2), [ka] Or, with respect to the pharmaceutically acceptable salt thereof, in the formula, R, R 6a , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 2c , R 3c , R 4c , and R 5c It is defined as shown above in relation to equation (I).

[0053] In some embodiments, the present invention relates to a compound of formula (IA-3), [ka] Or, with respect to the pharmaceutically acceptable salt thereof, in the formula, R, R 6a , R 5b1 , R 5b2 , R 2c , R 3c , R 4c , and R 5c It is defined as shown above in relation to equation (I).

[0054] In some embodiments, the present invention relates to a compound of formula (IA-4), [ka] Or, with respect to its pharmaceutically acceptable salt, in the formula, R Xa , R Ya , R 6a , R 5b1 , R 5b2 , R 2c , R 3c, and R 4c It is defined as shown above in relation to equation (I).

[0055] In some embodiments, the present invention relates to a compound of formula (IB), [ka] Or, with respect to its pharmaceutically acceptable salt, in the formula, R, X 2a , X 4a , X 5a , X 6a , R 4b1 , R 4b2 , R 5b1 , R 5b2 , X 3c , X 4c , X 5c , X 6c , and R 2c It is defined as shown above in relation to equation (I).

[0056] In some embodiments, the present invention relates to a compound of formula (IB-1), [ka] Or, with respect to its pharmaceutically acceptable salt, in the formula, R, X 2a , X 4a , X 6a , R 4b1 , R 4b2 , R 5b1 , R 5b2 , X 3c , R 2c 、 R 4c , and R 5c It is defined as shown above in relation to equation (I).

[0057] In some embodiments, the present invention relates to a compound of formula (IB-2), [ka] Or, with respect to the pharmaceutically acceptable salt thereof, in the formula, R, R 6a , R 4b1 , R 4b2 , R5b1 , R 5b2 , R 2c , R 3c , R 4c , and R 5c It is defined as shown above in relation to equation (I).

[0058] In some embodiments, the present invention relates to a compound of formula (IB-3), [ka] Or, with respect to the pharmaceutically acceptable salt thereof, in the formula, R, R 6a , R 5b1 , R 5b2 , R 2c , R 3c , R 4c , and R 5c It is defined as shown above in relation to equation (I).

[0059] In some embodiments, the present invention relates to a compound of formula (IB-4), [ka] Or, with respect to its pharmaceutically acceptable salt, in the formula, R Xa , R Ya , R 6a , R 5b1 , R 5b2 , R 2c , R 3c , and R 4c It is defined as shown above in relation to equation (I).

[0060] In some embodiments, the compounds of the present invention are of formula (IC), [ka] Or, with respect to its pharmaceutically acceptable salt, in the formula, R, X 2a , X 4a , X 5a , X 6a , R 4b1 , R 4b2 , R 5b1 , R 5b2 , X 3c, X 4c , X 5c , X 6c , and R 2c It is defined as shown above in relation to equation (I).

[0061] In some embodiments, the compounds of the present invention are of formula (IC-1), [ka] Or, with respect to its pharmaceutically acceptable salt, in the formula, R, X 2a , X 4a , X 6a , R 4b1 , R 4b2 , R 5b1 , R 5b2 , X 3c , R 2c 、 R 4c , and R 5c It is defined as shown above in relation to equation (I).

[0062] In some embodiments, the compound of the present invention is of formula (IC-2), [ka] Or, with respect to the pharmaceutically acceptable salt thereof, in the formula, R, R 6a , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 2c , R 3c , R 4c , and R 5c It is defined as shown above in relation to equation (I).

[0063] In some embodiments, the compound of the present invention is of formula (IC-3), [ka] Or, with respect to the pharmaceutically acceptable salt thereof, in the formula, R, R 6a , R 5b1 , R 5b2 , R 2c , R3c , R 4c , and R 5c It is defined as shown above in relation to equation (I).

[0064] In some embodiments, the compounds of the present invention are of formula (IC-4), [ka] Or, with respect to its pharmaceutically acceptable salt, in the formula, R Xa , R Ya , R 6a , R 5b1 , R 5b2 , R 2c , R 3c , and R 4c It is defined as shown above in relation to equation (I).

[0065] In some embodiments, the present invention relates to any one compound from formula (I), (IA), (IA-1), (IB), (IB-1), (IC), and (IC-1), or a pharmaceutically acceptable salt thereof, wherein X 2a However, N or CR 2a In other embodiments, X 2a In other embodiments, X 2a CR 2a In other embodiments, X 2a CR 2a And R 2a H is H.

[0066] In some embodiments, the present invention relates to any one compound from formula (I), (IA), (IA-1), (IB), (IB-1), (IC), and (IC-1), or a pharmaceutically acceptable salt thereof, wherein X 4a However, N, N + -O - , or CR 4a In other embodiments, X 4a is N, N + -O - , or CR 4a And R 4ais H or halo. In other embodiments, X 4a In other embodiments, X 4a is, N + -O - In other embodiments, X 4a CR 4a In other embodiments, X 4a CR 4a And R 4a is H or halo. In other embodiments, X 4a CR 4a And R 4a is H or F. In other embodiments, X 4a CR 4a And R 4a In other embodiments, X 4a CR 4a And R 4a It is F.

[0067] In some embodiments, the present invention relates to one compound from formulas (I), (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof, wherein X 5a However, CR 5a In other embodiments, X 5a CR 5a And R 5a H is H.

[0068] In some embodiments, the present invention relates to any one compound from formula (I), (IA), (IA-1), (IB), (IB-1), (IC), and (IC-1), or a pharmaceutically acceptable salt thereof, wherein X 6a However, N or CR 6a In other embodiments, X 6a is N or CR 6a And R 6a is H, halo, C1-C6 alkyl, or -Si(C1-C6 alkyl)3. In other embodiments, X 6a In other embodiments, X 6a CR 6a In other embodiments, X6a CR 6a And R 6a is H, halo, C1-C6 alkyl, or -Si(C1-C6 alkyl)3. In other embodiments, X 6a CR 6a And R 6a In other embodiments, X 6a CR 6a And R 6a In other embodiments, X 6a CR 6a And R 6a is a C1-C6 alkyl group. In other embodiments, X 6a CR 6a And R 6a is -Si(C1-C6 alkyl)3. In other embodiments, X 6a CR 6a And R 6a is H, F, CH3, or -Si(CH3)3. In other embodiments, X 6a CR 6a And R 6a In other embodiments, X 6a CR 6a And R 6a In other embodiments, X 6a CR 6a And R 6a It is -Si(CH3)3.

[0069] In some embodiments, the present invention relates to any one compound of formulas (IA-2), (IA-3), (IA-4), (IB-2), (IB-3), (IB-4), (IC-2), (IC-3), and (IC-4), or a pharmaceutically acceptable salt thereof, wherein R 6a However, this is H, halo, C1-C6 alkyl, or -Si(C1-C6 alkyl)3. In other embodiments, R 6a In other embodiments, R 6a In other embodiments, R 6a is a C1-C6 alkyl group. In other embodiments, R6a is -Si(C1-C6 alkyl)3. In other embodiments, R 6a is H, F, CH3, or -Si(CH3)3. In other embodiments, R 6a In other embodiments, R 6a In other embodiments, R 6a It is -Si(CH3)3.

[0070] In some embodiments, the present invention relates to formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IB), (IB-1), (IB-2), (IB-3), (IC), (IC-1), (IC-2), and (IC-3), or pharmaceutically acceptable salts thereof, where R is OR a or NR Xa R Ya And R a However, it is H or C1-C6 alkyl, and R Xa However, it is H or C1-C6 alkyl, and R Ya However, H, OH, C1-C6 alkyl, -(C1-C6 alkylene)-R Za1 , or a 4-6 membered heterocycline optionally substituted with one or more groups independently selected from C1-C6 alkyl and C1-C6 alkoxy, R Za1 However, R is a 5- to 6-membered heterocycline optionally substituted with OH, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, and one or more groups independently selected from halo and C1-C6 alkyl. In other embodiments, R is OR a In other embodiments, R is OR a And R a In other embodiments, R is NR Xa R Ya In other embodiments, R is NR Xa R Ya And R Xa is H or CH3, and R Ya H, OH, CH3, -(C1-C2 alkylene)-R Za1, or a 4-6 membered heterocycline optionally substituted with one or more groups independently selected from CH3, -OCH3, and -OCH2CH3, R Za1 is a 5- to 6-membered heterocycline optionally substituted with one or more groups independently selected from OH, -NH(CH3), -N(CH3)2, and F and CH3. In other embodiments, R Xa In other embodiments, R Xa In other embodiments, R Ya In other embodiments, R Ya In other embodiments, R Ya In other embodiments, R Ya is -(C1-C2 alkylene)-R Za1 And R Za1 is a 5- to 6-membered heterocycline optionally substituted with one or more groups independently selected from OH, -NH(CH3), -N(CH3)2, and F and CH3. In other embodiments, R Ya is -(C1-C2 alkylene)-R Za1 And R Za1 In other embodiments, R Ya is -(C1-C2 alkylene)-R Za1 And R Za1 In other embodiments, R Ya is -(C1-C2 alkylene)-R Za1 And R Za1 In other embodiments, R Ya is -(C1-C2 alkylene)-R Za1 And R Za1 is a 5-6 membered heterocycline optionally substituted with one or more groups independently selected from F and CH3. In other embodiments, R Ya is -(C1-C2 alkylene)-R Za1 And R Za1 R is an unsubstituted 5-6 member heterocycline. In other embodiments, R Ya is -(C1-C2 alkylene)-R Za1 And R Za1is a 5-6 membered heterocycline substituted with one or more groups independently selected from F and CH3. In other embodiments, R Ya is -(C1-C2 alkylene)-R Za1 And R Za1 This is a 5-6 member heterocycline substituted with one CH3. In other embodiments, R Ya is -(C1-C2 alkylene)-R Za1 And R Za1 is a 5-6 member heterocycline substituted with two Fs. In other embodiments, R Ya is -(C1-C2 alkylene)-R Za1 And R Za1 This is a 5-6 member heterocycline substituted with one CH3 and two Fs. In other embodiments, R Ya R is a 4- to 6-membered heterocycline optionally substituted with one or more groups independently selected from CH3, -OCH3, and -OCH2CH3. In other embodiments, R Ya This is a 4- to 6-membered heterocycline which is optionally substituted with one CH3. In other embodiments, R Ya is a 4- to 6-membered heterocycline which is optionally substituted with one -OCH3. In other embodiments, R Ya This is a 4- to 6-membered heterocycline, optionally substituted with one CH3 and one -OCH3. In other embodiments, R Ya It is a 4- to 6-membered heterocycline, optionally substituted with one CH3 and one -OCH2CH3.

[0071] In some embodiments, the present invention relates to formulas (IA-4), (IB-4), and (IC-4), or pharmaceutically acceptable salts thereof, wherein R Xa However, it is H or CH3, and R Ya However, H, OH, CH3, -(C1-C2 alkylene)-R Za1 , or a 4-6 membered heterocycline optionally substituted with one or more groups independently selected from CH3, -OCH3, and -OCH2CH3, R Za1However, it is a 5- to 6-membered heterocycline optionally substituted with one or more groups independently selected from OH, -NH(CH3), -N(CH3)2, and F and CH3. In other embodiments, R Xa In other embodiments, R Xa In other embodiments, R Ya In other embodiments, R Ya In other embodiments, R Ya In other embodiments, R Ya is -(C1-C2 alkylene)-R Za1 And R Za1 is a 5- to 6-membered heterocycline optionally substituted with one or more groups independently selected from OH, -NH(CH3), -N(CH3)2, and F and CH3. In other embodiments, R Ya is -(C1-C2 alkylene)-R Za1 And R Za1 In other embodiments, R Ya is -(C1-C2 alkylene)-R Za1 And R Za1 In other embodiments, R Ya is -(C1-C2 alkylene)-R Za1 And R Za1 In other embodiments, R Ya is -(C1-C2 alkylene)-R Za1 And R Za1 is a 5-6 membered heterocycline optionally substituted with one or more groups independently selected from F and CH3. In other embodiments, R Ya is -(C1-C2 alkylene)-R Za1 And R Za1 R is an unsubstituted 5-6 member heterocycline. In other embodiments, R Ya is -(C1-C2 alkylene)-R Za1 And R Za1 is a 5-6 membered heterocycline substituted with one or more groups independently selected from F and CH3. In other embodiments, R Ya is -(C1-C2 alkylene)-RZa1 And R Za1 This is a 5-6 member heterocycline substituted with one CH3. In other embodiments, R Ya is -(C1-C2 alkylene)-R Za1 And R Za1 is a 5-6 member heterocycline substituted with two Fs. In other embodiments, R Ya is -(C1-C2 alkylene)-R Za1 And R Za1 This is a 5-6 member heterocycline substituted with one CH3 and two Fs. In other embodiments, R Ya R is a 4- to 6-membered heterocycline optionally substituted with one or more groups independently selected from CH3, -OCH3, and -OCH2CH3. In other embodiments, R Ya This is a 4- to 6-membered heterocycline which is optionally substituted with one CH3. In other embodiments, R Ya is a 4- to 6-membered heterocycline which is optionally substituted with one -OCH3. In other embodiments, R Ya This is a 4- to 6-membered heterocycline, optionally substituted with one CH3 and one -OCH3. In other embodiments, R Ya It is a 4- to 6-membered heterocycline, optionally substituted with one CH3 and one -OCH2CH3.

[0072] In some embodiments, the present invention relates to formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IB), (IB-1), (IB-2), (IB-3), (IC), (IC-1), (IC-2), and (IC-3), or pharmaceutically acceptable salts thereof, wherein R is NR Xa R Ya And R Xa and R Ya Together with the nitrogen atom to which they are bonded, one or more R Za2 They form 5-9 member heterocyclines which are substituted as needed, and each R Za2R is independently selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, and -(C1-C6 alkylene)-(C1-C6 alkoxy). In other embodiments, R is NR Xa R Ya And R Xa and R Ya Together with the nitrogen atom to which they are bonded, they form one or more R Za2 This forms a 5-membered heterocycline which is substituted as needed. In other embodiments, R is NR Xa R Ya And R Xa and R Ya Together with the nitrogen atom to which they are bonded, they form one or more R Za2 This forms a 6-membered heterocycline which is substituted as needed. In other embodiments, R is NR Xa R Ya And R Xa and R Ya Together with the nitrogen atom to which they are bonded, they form one or more R Za2 This forms a 7-membered heterocycline which is substituted as needed. In other embodiments, R is NR Xa R Ya And R Xa and R Ya Together with the nitrogen atom to which they are bonded, they form one or more R Za2 This forms an 8-membered heterocycline which is substituted as needed. In other embodiments, R is NR Xa R Ya And R Xa and R Ya Together with the nitrogen atom to which they are bonded, they form one or more R Za2 This forms a 9-membered heterocycline which is substituted as needed. In other embodiments, R Xa and R Ya These, together with the nitrogen atoms to which they are bonded, form unsubstituted 5- to 9-membered heterocyclines. In some embodiments, R Xa and R Ya Together with the nitrogen atom to which they are bonded, they form one R Za2This forms a 5- to 9-membered heterocycline which is substituted as needed. In some embodiments, R Xa and R Ya Together with the nitrogen atom to which they are bonded, they form two R Za2 This forms a 5-9 member heterocycline which is substituted as needed. In other embodiments, each R Za2 These are independently selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, and -(C1-C6 alkylene)-(C1-C6 alkoxy). In other embodiments, at least one R Za2 is a halo. In other embodiments, at least one R Za2 is OH. In other embodiments, at least one R Za2 is a C1-C6 alkyl group. In other embodiments, at least one R Za2 is a C1-C6 alkoxy. In other embodiments, at least one R Za2 is NH2. In other embodiments, at least one R Za2 is -NH(C1-C6 alkyl). In other embodiments, at least one R Za2 is -N(C1-C6 alkyl)2. In other embodiments, at least one R Za2 is -(C1-C6 alkylene)-(C1-C6 alkoxy). In other embodiments, each R Za2 These are independently selected from F, OH, CH3, -OCH3, NH2, -NH(CH3), -N(CH3)2, and -CH2OCH3. In other embodiments, at least one R Za2 is F. In other embodiments, at least one R Za2 is CH3. In other embodiments, at least one R Za2 is -OCH3. In other embodiments, at least one R Za2 is -NH(CH3). In other embodiments, at least one R Za2 is -N(CH3)2. In other embodiments, at least one R Za2 It is -CH2OCH3.

[0073] In some embodiments, the present invention relates to one compound from formulas (IA-4), (IB-4), and (IC-4), or a pharmaceutically acceptable salt thereof, wherein R Xa and R Ya However, together with the nitrogen atom to which they are bonded, one or more R Za2 They form 5-9 member heterocyclines which are substituted as needed, and each R Za2 R is independently selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, and -(C1-C6 alkylene)-(C1-C6 alkoxy). In some embodiments, R Xa and R Ya Together with the nitrogen atom to which they are bonded, they form one or more R Za2 This forms a 5-membered heterocycline which is substituted as needed. In some embodiments, R Xa and R Ya Together with the nitrogen atom to which they are bonded, they form one or more R Za2 This forms a 6-membered heterocycline which is substituted as needed. In some embodiments, R Xa and R Ya Together with the nitrogen atom to which they are bonded, they form one or more R Za2 This forms a 7-membered heterocycline which is substituted as needed. In some embodiments, R Xa and R Ya Together with the nitrogen atom to which they are bonded, they form one or more R Za2 This forms an 8-membered heterocycline which is substituted as needed. In some embodiments, R Xa and R Ya Together with the nitrogen atom to which they are bonded, they form one or more R Za2 This forms a 9-membered heterocycline which is substituted as needed. In other embodiments, R Xa and R Ya These, together with the nitrogen atoms to which they are bonded, form unsubstituted 5- to 9-membered heterocyclines. In some embodiments, R Xa and RYa Together with the nitrogen atom to which they are bonded, they form one R Za2 This forms a 5- to 9-membered heterocycline which is substituted as needed. In some embodiments, R Xa and R Ya Together with the nitrogen atom to which they are bonded, they form two R Za2 This forms a 5-9 member heterocycline which is substituted as needed. In other embodiments, each R Za2 These are independently selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, and -(C1-C6 alkylene)-(C1-C6 alkoxy). In other embodiments, at least one R Za2 is a halo. In other embodiments, at least one R Za2 is OH. In other embodiments, at least one R Za2 is a C1-C6 alkyl group. In other embodiments, at least one R Za2 is a C1-C6 alkoxy. In other embodiments, at least one R Za2 is NH2. In other embodiments, at least one R Za2 is -NH(C1-C6 alkyl). In other embodiments, at least one R Za2 is -N(C1-C6 alkyl)2. In other embodiments, at least one R Za2 is -(C1-C6 alkylene)-(C1-C6 alkoxy). In other embodiments, each R Za2 These are independently selected from F, OH, CH3, -OCH3, NH2, -NH(CH3), -N(CH3)2, and -CH2OCH3. In other embodiments, at least one R Za2 is F. In other embodiments, at least one R Za2 is CH3. In other embodiments, at least one R Za2 is -OCH3. In other embodiments, at least one R Za2 is -NH(CH3). In other embodiments, at least one R Za2is -N(CH3)2. In other embodiments, at least one R Za2 It is -CH2OCH3.

[0074] In some embodiments, the present invention relates to any one compound from formula (I), (IA), (IA-1), (IA-2), (IB), (IB-1), (IB-2), (IC), (IC-1), and (IC-2), or a pharmaceutically acceptable salt thereof, wherein R 4b1 However, it is H or C1-C6 alkyl. In other embodiments, R 4b1 is H or CH3. In other embodiments, R 4b1 In other embodiments, R 4b1 is a C1-C6 alkyl group. In other embodiments, R 4b1 This is CH3.

[0075] In some embodiments, the present invention relates to any one compound from formula (I), (IA), (IA-1), (IA-2), (IB), (IB-1), (IB-2), (IC), (IC-1), and (IC-2), or a pharmaceutically acceptable salt thereof, wherein R 4b2 However, it is H or C1-C6 alkyl. In other embodiments, R 4b2 is H or CH3. In other embodiments, R 4b1 In other embodiments, R 4b2 is a C1-C6 alkyl group. In other embodiments, R 4b2 This is CH3.

[0076] In some embodiments, the present invention relates to any one compound from formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IC), (IC-1), (IC-2), (IC-3), and (IC-4), or a pharmaceutically acceptable salt thereof, wherein R 5b1However, it is a C1-C6 alkyl, a C1-C6 haloalkyl, or a -(C1-C6 alkylene)-(C1-C6 alkoxy). In other embodiments, R 5b1 is CH3, CF3, -CH2OCH3, or -CH2CH2OCH3. In other embodiments, R 5b1 is a C1-C6 alkyl group. In other embodiments, R 5b1 In other embodiments, R 5b1 is a C1-C6 haloalkyl. In other embodiments, R 5b1 In other embodiments, R 5b1 is -(C1-C6 alkylene)-(C1-C6 alkoxy). In other embodiments, R 5b1 In other embodiments, R 5b1 It is -CH2CH2OCH3.

[0077] In some embodiments, the present invention relates to any one compound from formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IC), (IC-1), (IC-2), (IC-3), and (IC-4), or a pharmaceutically acceptable salt thereof, wherein R 5b2 However, it is a C1-C6 alkyl, a C1-C6 haloalkyl, or a -(C1-C6 alkylene)-(C1-C6 alkoxy). In other embodiments, R 5b2 is CH3, CF3, -CH2OCH3, or -CH2CH2OCH3. In other embodiments, R 5b2 is a C1-C6 alkyl group. In other embodiments, R 5b2 In other embodiments, R 5b2 is a C1-C6 haloalkyl. In other embodiments, R 5b2 In other embodiments, R 5b2 is -(C1-C6 alkylene)-(C1-C6 alkoxy). In other embodiments, R 5b2 In other embodiments, R 5b2It is -CH2CH2OCH3.

[0078] In some embodiments, the present invention relates to any one compound from formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IC), (IC-1), (IC-2), (IC-3), and (IC-4), or a pharmaceutically acceptable salt thereof, R 5b1 and R 5b2 However, together with the carbon atoms to which they are bonded, they form a four-membered heterocycline. In other embodiments, the four-membered heterocycline is oxetanyl.

[0079] In some embodiments, the present invention relates to any one compound of formula (I), (IA), (IA-1), (IB), (IB-1), (IC), and (IC-1), or a pharmaceutically acceptable salt thereof, X 3c However, N or CR 3c And R 3c However, is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -(C1-C6 alkylene)-OH, or -(C1-C6 alkylene)-(C1-C6 alkoxy). In other embodiments, X 3c In other embodiments, X 3c CR 3c In other embodiments, X 3c CR 3c And R 3c is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -(C1-C6 alkylene)-OH, or -(C1-C6 alkylene)-(C1-C6 alkoxy). In other embodiments, X 3c CR 3c And R 3c In other embodiments, X 3c CR 3c And R 3c In other embodiments, X 3c CR 3c And R 3cis a C1-C6 alkyl group. In other embodiments, X 3c CR 3c And R 3c is a C1-C6 haloalkyl. In other embodiments, X 3c CR 3c And R 3c In other embodiments, X 3c CR 3c And R 3c is -(C1-C6 alkylene)-(C1-C6 alkoxy). In other embodiments, X 3c CR 3c And R 3c is H, F, Cl, CH3, CF3, -CH2OH, or -CH2OCH3. In other embodiments, X 3c CR 3c And R 3c In other embodiments, X 3c CR 3c And R 3c In other embodiments, X 3c CR 3c And R 3c In other embodiments, X 3c CR 3c And R 3c In other embodiments, X 3c CR 3c And R 3c In other embodiments, X 3c CR 3c And R 3c It is -CH2OCH3.

[0080] In some embodiments, the present invention relates to any one compound of formulas (IA-2), (IA-3), (IA-4), (IB-2), (IB-3), (IB-4), (IC-2), (IC-3), and (IC-4), or a pharmaceutically acceptable salt thereof, R 3cHowever, is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -(C1-C6 alkylene)-OH, or -(C1-C6 alkylene)-(C1-C6 alkoxy). In other embodiments, R 3c In other embodiments, R 3c In other embodiments, R 3c is a C1-C6 alkyl group. In other embodiments, R 3c is a C1-C6 haloalkyl. In other embodiments, R 3c is -(C1-C6 alkylene)-OH. In other embodiments, R 3c is -(C1-C6 alkylene)-(C1-C6 alkoxy). In other embodiments, R 3c is H, F, Cl, CH3, CF3, -CH2OH, or -CH2OCH3. In other embodiments, R 3c In other embodiments, R 3c In other embodiments, R 3c In other embodiments, R 3c In other embodiments, R 3c is -CH2OH. In other embodiments, R 3c It is -CH2OCH3.

[0081] In some embodiments, the present invention relates to one compound from formulas (I), (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof, wherein X 4c However, CR 4c And R 4c However, H, halo, OH, -OBn, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed, L 1 However, it is O and L 2 However, it is a bond or C1-C6 alkylene. In other embodiments, X 4c CR 4c And R 4cIn other embodiments, X 4c CR 4c And R 4c In other embodiments, X 4c CR 4c And R 4c In other embodiments, X 4c CR 4c And R 4c In other embodiments, X 4c CR 4c And R 4c In other embodiments, X 4c CR 4c And R 4c is a C1-C6 haloalkyl. In other embodiments, X 4c CR 4c And R 4c In other embodiments, X 4c CR 4c And R 4c is, -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed, L 1 It is O and L 2 In other embodiments, X 4c CR 4c And R 4c is, -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed, L 1 It is O and L 2 This is a bond. In other embodiments, X 4c CR 4c And R 4c is, -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed, L 1 It is O and L 2is C1-C6 alkylene. In other embodiments, X 4c is C-R 4c and R 4c is H, F, OH, -OBn, -OCH3, -OCH2CH3, CHF2, -OCHF2, -OCF3, -O-CH2-(cyclopropyl), or -O-(cyclobutyl), and the cyclobutyl is substituted with two F. In other embodiments, X 4c is C-R 4c and R 4c is F. In other embodiments, X 4c is C-R 4c and R 4c is -OCH3. In other embodiments, X 4c is C-R 4c and R 4c is -OCH2CH3. In other embodiments, X 4c is C-R 4c and R 4c is CHF2. In other embodiments, X 4c is C-R 4c and R 4c is -OCHF2. In other embodiments, X 4c is C-R 4c and R 4c is -OCF3. In other embodiments, X 4c is C-R 4c and R 4c is -O-CH2-(cyclopropyl). In other embodiments, X 4c is C-R 4c and R 4c is -O-(cyclobutyl), and the cyclobutyl is substituted with two F.

[0082] In some embodiments, the present invention relates to a compound of any one of Formula (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-C-1), (I-C-2), (I-C-3), and (I-C-4), wherein R 4cHowever, H, halo, OH, -OBn, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl, and the cycloalkyl is substituted with 1-2 halos as needed, L 1 However, it is O and L 2 However, it is a bond or a C1-C6 alkylene. In other embodiments, R 4c In other embodiments, R 4c In other embodiments, R 4c In other embodiments, R 4c is -OBn. In other embodiments, R 4c is a C1-C6 alkoxy. In other embodiments, R 4c is a C1-C6 haloalkyl. In other embodiments, R 4c In other embodiments, R 4c is, -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed, L 1 It is O and L 2 is a bond or C1-C6 alkylene. In other embodiments, R 4c is, -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed, L 1 It is O and L 2 This is a bond. In other embodiments, R 4c is, -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed, L 1 It is O and L 2 In other embodiments, R 4cis H, F, OH, -OBn, -OCH3, -OCH2CH3, CHF2, -OCHF2, -OCF3, -O-CH2-(cyclopropyl), or -O-(cyclobutyl), wherein the cyclobutyl is substituted with two F atoms. In other embodiments, R 4c In other embodiments, R 4c In other embodiments, R 4c In other embodiments, R 4c is -OBn. In other embodiments, R 4c In other embodiments, R 4c In other embodiments, R 4c In other embodiments, R 4c In other embodiments, R 4c In other embodiments, R 4c In other embodiments, R 4c This is -O-(cyclobutyl), and this cyclobutyl is substituted with two F atoms.

[0083] In some embodiments, the present invention relates to one compound from formulas (I), (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof, wherein X 5c However, CR 5c And R 5c However, H, halo, OH, -OBn, or -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed, L 1 However, it is O and L 2 However, this is a combination. In other embodiments, X 5c CR 5c And R 5c In other embodiments, X 5c CR 5c And R 5c In other embodiments, X 5c CR 5c And R5c is OH. In other embodiments, X 5c is C-R 5c and R 5c is -OBn. In other embodiments, X 5c is C-R 5c and R 5c is -L 1 -L 2 -(C3-C6 cycloalkyl), wherein said cycloalkyl is optionally substituted with 1 to 2 halo, and L 1 is O, and L 2 is a bond. In other embodiments, X 5c is C-R 5c and R5c is H, Cl, OH, -OBn, or -O-(cyclobutyl), wherein said cyclobutyl is substituted with two F. In other embodiments, X 5c is C-R 5c and R 5c is Cl. In other embodiments, X 5c is C-R 5c and R 5c is -O-(cyclobutyl), wherein said cyclobutyl is substituted with two F.

[0084] In some embodiments, the present invention relates to a compound of any one of formula (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-C-1), (I-C-2), (I-C-3), and (I-C-4), wherein R 5c is H, halo, OH, -OBn, or -L 1 -L 2 -(C3-C6 cycloalkyl), wherein said cycloalkyl is optionally substituted with 1 to 2 halo, and L 1 is O, and L 2 is a bond. In other embodiments, R 5c is H. In other embodiments, R 5c is halo. In other embodiments, R 5c is OH. In other embodiments, R 5cis -OBn. In other embodiments, R 5c is, -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed, L 1 It is O and L 2 This is a bond. In other embodiments, R 5c is H, Cl, OH, -OBn, or -O-(cyclobutyl), wherein the cyclobutyl is substituted with two F atoms. In other embodiments, R 5c In other embodiments, R 5c This is -O-(cyclobutyl), and this cyclobutyl is substituted with two F atoms.

[0085] In some embodiments, the present invention relates to one compound from formulas (I), (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof, wherein X 6c However, CR 6c And R 6c However, it is H.

[0086] In some embodiments, the present invention relates to formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IC), (IC-1), (IC-2), (IC-3), and (IC-4), or pharmaceutically acceptable salts thereof, where R 2c However, OH, halo, C1-C6 alkoxy, -(C1-C6 alkylene)-(C1-C6 alkoxy), -(C1-C6 alkylene)-O-(4-6 member heterocyclyl), -O-(C2-C6 alkenylene)-(C1-C6 haloalkyl), -L 1 -L 2 -(C3-C7 cycloalkyl), or -OL 3 -R XcThe cycloalkyl group is optionally substituted with one or more groups independently selected from OH, CN, C1-C6 alkyl, C1-C6 alkoxy, =NOH, -C(O)(C1-C6 alkyl), and -(C1-C6 alkylene)-OH. 1 However, it is O and L 2 However, it is a bond or C1-C6 alkylene, L 3 However, the bond is C1-C6 alkylene or C2-C6 alkenylene, R Xc However, OH, CN, C1-C6 alkoxy, NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 haloalkyl), -NH(C1-C6 haloalkyl)2, -CH(CH2OH)2, -CH(CH2OH)(CH2OCH3), -CH(CH2OH)(OCH3), -CH(CH2OCH3)(OCH3), -CH(CH2OH)(CF3), -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -NH(4-6 member heterocyclyl The cycloalkyl group is selected from -N=S(O)(C1-C6 alkyl)2, -C(=NOH)(C3-C6 cycloalkyl), 4- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the cycloalkyl group is optionally substituted with one or more halos, and the heterocyclyl and heteroaryl groups are optionally substituted with one or more groups independently selected from OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -(C1-C6 alkylene)-OH.

[0087] In other embodiments, the present invention relates to any one compound from formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IC), (IC-1), (IC-2), (IC-3), and (IC-4), or a pharmaceutically acceptable salt thereof, wherein R 2cHowever, these are OH, halo, C1-C6 alkoxy, -(C1-C6 alkylene)-(C1-C6 alkoxy), -(C1-C6 alkylene)-O-(4-6 member heterocyclyl), and -O-(C2-C6 alkenylene)-(C1-C6 haloalkyl). In other embodiments, R 2c In other embodiments, R 2c In other embodiments, R 2c is a C1-C6 alkoxy. In other embodiments, R 2c is -(C1-C6 alkylene)-(C1-C6 alkoxy). In other embodiments, R 2c is -(C1-C6 alkylene)-O-(4-6 member heterocyclyl). In other embodiments, R 2c In other embodiments, R is -O-(C2-C6 alkenylene)-(C1-C6 haloalkyl). 2c is OH, Cl, -OCH3, -CH2OCH3, -CH2-O-(4-membered heterocyclyl), or -O-(C3-C4 alkenylene)-CF3. In other embodiments, R 2c In other embodiments, R 2c In other embodiments, R 2c In other embodiments, R 2c is -CH2-O- (a 4-membered heterocyclyl). In other embodiments, R 2c It is -O-(C3-C4 alkenylene)-CF3.

[0088] In some embodiments, the present invention relates to any one compound from formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IC), (IC-1), (IC-2), (IC-3), and (IC-4), or a pharmaceutically acceptable salt thereof, wherein R 2c However, -L 1 -L 2 -(C3-C7 cycloalkyl), L 1 However, it is O and L 2However, the cycloalkyl group is bonded or a C1-C6 alkylene, and the cycloalkyl group is substituted with one or more groups independently selected from OH, CN, -OCH3,CH3, =NOH, -C(O)(CH3), and -CH2OH. In other embodiments, R 2c is, -L 1 -L 2 -(C3-C7 cycloalkyl), L 1 It is O and L 2 The bond is such that the cycloalkyl group is substituted with one or more groups independently selected from OH, CN, -OCH3, CH3, =NOH, -C(O)(CH3), and -CH2OH. 2c is, -L 1 -L 2 -(C3-C7 cycloalkyl), L 1 It is O and L 2 In other embodiments, the cycloalkyl group is a C1-C6 alkylene, and the cycloalkyl group is substituted with one or more groups independently selected from OH, CN, -OCH3, CH3, =NOH, -C(O)(CH3), and -CH2OH. In other embodiments, the cycloalkyl group is substituted with at least one OH group. In other embodiments, the cycloalkyl group is substituted with at least one CN group. In other embodiments, the cycloalkyl group is substituted with at least one -OCH3 group. In other embodiments, the cycloalkyl group is substituted with at least one CH3 group. In other embodiments, the cycloalkyl group is substituted with at least one =NOH group. In other embodiments, the cycloalkyl group is substituted with at least one -C(O)(CH3) group. In other embodiments, the cycloalkyl group is substituted with at least one -CH2OH group.

[0089] In some embodiments, the present invention relates to formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IC), (IC-1), (IC-2), (IC-3), and (IC-4), or pharmaceutically acceptable salts thereof, where R 2c However, -OL3 -R Xc And L 3 However, the bond is C1-C6 alkylene or C4-C5 alkenylene, R Xc However, OH, CN, C1-C6 alkoxy, NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 haloalkyl), -NH(C1-C6 haloalkyl)2, -CH(CH2OH)2, -CH(CH2OH)(CH2OCH3), -CH(CH2OH)(OCH3), -CH(CH2OCH3)(OCH3), -CH(CH2OH)(CF3), -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -NH(4-6 member heterocyclyl) The following are selected from ,=NOH,=NO(C1-C6 alkyl),-N=S(O)(C1-C6 alkyl)2,-C(=NOH)(C3-C6 cycloalkyl), 4-8 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the cycloalkyl is optionally substituted with one or more halos, and the heterocyclyl and heteroaryl are optionally substituted with one or more groups independently selected from OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -(C1-C6 alkylene)-OH. In other embodiments, R 2c is, -OL 3 -R Xc And L 3 This is a bond. In other embodiments, R 2c is, -OL 3 -R Xc And L 3 In other embodiments, R 2c is, -OL 3 -R Xc , and C4-C5 alkenylene. In other embodiments, R 2c is, -OL 3 -R Xc And R Xc In other embodiments, R 2c is, -OL 3 -R Xc And R XcIn other embodiments, R 2c is, -OL 3 -R Xc And R Xc is a C1-C6 alkoxy. In other embodiments, R 2c is, -OL 3 -R Xc And R Xc In other embodiments, R 2c is, -OL 3 -R Xc And R Xc is -NH(C1-C6 alkyl). In other embodiments, R 2c is, -OL 3 -R Xc And R Xc In other embodiments, R 2c is, -OL 3 -R Xc And R Xc is -NH(C1-C6 haloalkyl). In other embodiments, R 2c is, -OL 3 -R Xc And R Xc In other embodiments, R 2c is, -OL 3 -R Xc And R Xc In other embodiments, R 2c is, -OL 3 -R Xc And R Xc In other embodiments, R 2c is, -OL 3 -R Xc And R Xc In other embodiments, R 2c is, -OL 3 -R Xc And R Xc is -CH(CH2OCH3)(OCH3). In other embodiments, R 2c is, -OL 3 -RXc And R Xc In other embodiments, R 2c is, -OL 3 -R Xc And R Xc is -C(O)(C1-C6 alkyl). In other embodiments, R 2c is, -OL 3 -R Xc And R Xc In other embodiments, R 2c is, -OL 3 -R Xc And R Xc is -C(O)NH(C1-C6 alkyl). In other embodiments, R 2c is, -OL 3 -R Xc And R Xc In other embodiments, R 2c is, -OL 3 -R Xc And R Xc is -NH (4-6 member heterocyclyl). In other embodiments, R 2c is, -OL 3 -R Xc And R Xc In other embodiments, R 2c is, -OL 3 -R Xc And R Xc In other embodiments, R 2c is, -OL 3 -R Xc And R Xc In other embodiments, R 2c is, -OL 3 -R Xc And R Xc is -C(=NOH)(C3-C6 cycloalkyl), and the cycloalkyl is optionally substituted with one or more halos. In other embodiments, R 2c is, -OL 3 -RXc And R Xc R is a 4- to 8-membered heterocycline, and the aforementioned heterocycline is optionally substituted with one or more groups independently selected from OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -(C1-C6 alkylene)-OH. In other embodiments, R 2c is, -OL 3 -R Xc And R Xc is a 5-6 member heteroaryl, which is optionally substituted with one or more groups independently selected from OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -(C1-C6 alkylene)-OH. In other embodiments, R 2c is, -OL 3 -R Xc And R Xc is OH;CN;-OCH3;-NH(CH3);-NH(CH(CH3)2);-N(CH3)2;-NH(CH2CHF2);-CH(CH2OH)2;-CH(CH2OH)(CH2OCH3);-C H(CH2OH)(OCH3);-CH(CH2OCH3)(OCH3);-CH(CH2OH)(CF3);-C(O)(CH3);-C(O)NH(CH3);-NH(4-5 membered heterocyclyl);=NO H;=NO(CH3);-N=S(O)(CH3)2;-C(=NOH)(C3-C4 cycloalkyl);4- to 8-membered heterocyclyls optionally substituted with one or more groups independently selected from OH, F, CH3, -OCH3, CHF2, CF3, -OCHF2, and -CH2OH; and 5-membered heteroaryls optionally substituted with CH3, wherein the cycloalkyl is optionally substituted with one F. In other embodiments, R 2c is, -OL 3 -R Xc And R Xc In other embodiments, R 2c is, -OL 3 -R Xc And R XcIn other embodiments, R 2c is, -OL 3 -R Xc And R Xc In other embodiments, R 2c is, -OL 3 -R Xc And R Xc In other embodiments, R 2c is, -OL 3 -R Xc And R Xc In other embodiments, R 2c is, -OL 3 -R Xc And R Xc In other embodiments, R 2c is, -OL 3 -R Xc And R Xc In other embodiments, R 2c is, -OL 3 -R Xc And R Xc is -NH (4-5 member heterocycline). In other embodiments, R 2c is, -OL 3 -R Xc And R Xc In other embodiments, R 2c is, -OL 3 -R Xc And R Xc is -C(=NOH)(C3-C4 cycloalkyl), and the cycloalkyl is optionally substituted with one F. In other embodiments, R 2c is, -OL 3 -R Xc And R Xc This is a 4- to 8-membered heterozygous compound optionally substituted with one or more groups independently selected from OH, F, CH3, -OCH3, CHF2, CF3, -OCHF2, and -CH2OH. In other embodiments, R 2c is, -OL3 -R Xc And R Xc It is a 5-membered heteroaryl nucleotide that is substituted with CH3 as needed.

[0090] In some embodiments, the present invention relates to any one compound from formula (I), (IA), (IA-1), (IB), (IB-1), (IC), and (IC-1), or a pharmaceutically acceptable salt thereof, wherein X 3c However, CR 3c And R 2c and R 3c However, together with the carbon atoms to which they are bonded, the formula is: [ka] Forming a ring, In the formula, Z 1 is O or CH2, Z 2 is O or CF2, and R Yc1 and R Yc2 Each of these is independently H or F. In other embodiments, X 3c CR 3c And R 2c and R 3c Together with the carbon atoms to which they are bonded, the formula is: [ka] It forms a ring. In other embodiments, X 3c CR 3c And R 2c and R 3c Together with the carbon atoms to which they are bonded, the formula is: [ka] It forms a ring. In other embodiments, X 3c CR 3c And R 2c and R 3c Together with the carbon atoms to which they are bonded, the formula is: [ka] It forms a ring.

[0091] In some embodiments, the present invention relates to any one compound of formulas (IA-2), (IA-3), (IA-4), (IB-2), (IB-3), (IB-4), (IC-2), (IC-3), and (IC-4), or a pharmaceutically acceptable salt thereof, wherein R 2c and R 3c However, together with the carbon atoms to which they are bonded, the formula is: [ka] Forming a ring, In the formula, Z 1 However, it is either O or CH2, and Z 2 However, O or CF2, and R Yc1 and R Yc2 Each of these is independently H or F. In other embodiments, R 2c and R 3c Together with the carbon atoms to which they are bonded, the formula is: [ka] It forms a ring. In other embodiments, R 2c and R 3c Together with the carbon atoms to which they are bonded, the formula is: [ka] It forms a ring. In other embodiments, R 2c and R 3c Together with the carbon atoms to which they are bonded, the formula is: [ka] It forms a ring.

[0092] In some embodiments, the present invention relates to any one compound of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IC), (IC-1), (IC-2), (IC-3), and (IC-4) in salt form, or any embodiment thereof. In other embodiments, the compound is a trifluoroacetate salt or a hydrochloride salt. In other embodiments, the compound is a trifluoroacetate salt. In other embodiments, the compound is a hydrochloride salt.

[0093] In some embodiments, the present invention relates to any one compound from formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IC), (IC-1), (IC-2), (IC-3), and (IC-4), or any embodiment thereof, i.e., a non-salt form of the compound.

[0094] 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 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 [Table 1-42] [Table 1-43] [Table 1-44] [Table 1-45] [Table 1-46] [Table 1-47] [Table 1-48] [Table 1-49]

[0095] 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 2]

[0096] In some embodiments, the present invention relates to compounds selected from Table A or Table B, or pharmaceutically acceptable salts thereof. In other embodiments, the present invention relates to compounds selected from Table A or Table B, i.e., compounds in non-salt forms.

[0097] In some embodiments, the present invention relates to compounds of the following formulas: [ka] With respect to the pharmaceutically acceptable salt thereof, the compound has the absolute stereochemistry of a second eluted isomer when rac-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide is separated by SFC as described in Example 1. In other embodiments, the present invention relates to the aforementioned compounds in unsalted forms. Such compounds are considered to be “compounds of the present invention” as the term is used herein.

[0098] In some embodiments, the present invention relates to compounds of the following formulas: [ka] The present invention relates to the compounds and their pharmaceutically acceptable salts. In other embodiments, the present invention relates to the aforementioned compounds in non-salt forms. Such compounds are considered to be “compounds of the present invention” as the term is used herein.

[0099] In some embodiments, the present invention relates to compounds of the following formulas: [ka] The present invention relates to the compounds and their pharmaceutically acceptable salts. In other embodiments, the present invention relates to the aforementioned compounds in non-salt forms. Such compounds are considered to be “compounds of the present invention” as the term is used herein.

[0100] In some embodiments, the present invention relates to compounds of the following formulas: [ka] With respect to the pharmaceutically acceptable salt thereof, the compound has the absolute stereochemistry of the second eluted isomer when rac-4-((2R,3S,5R)-3-(4-fluoro-2-(2-hydroxyethoxy)-3-methylphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide is separated by SFC as described in Example 5. In other embodiments, the present invention relates to the aforementioned compounds in non-salt forms. Such compounds are considered to be “compounds of the present invention” as the term is used herein.

[0101] In some embodiments, the present invention relates to compounds of the following formulas: [ka] The present invention relates to the compounds and their pharmaceutically acceptable salts. In other embodiments, the present invention relates to the aforementioned compounds in non-salt forms. Such compounds are considered to be “compounds of the present invention” as the term is used herein.

[0102] In some embodiments, the present invention relates to compounds of the following formulas: [ka] The present invention relates to the compounds and their pharmaceutically acceptable salts. In other embodiments, the present invention relates to the aforementioned compounds in non-salt forms. Such compounds are considered to be “compounds of the present invention” as the term is used herein.

[0103] In some embodiments, the present invention relates to compounds of the following formulas: [ka] The present invention relates to the compounds and their pharmaceutically acceptable salts. In other embodiments, the present invention relates to the aforementioned compounds in non-salt forms. Such compounds are considered to be “compounds of the present invention” as the term is used herein.

[0104] In some embodiments, the present invention relates to compounds of the following formulas: [ka] With respect to the pharmaceutically acceptable salt thereof, the compound has the absolute stereochemistry of a second eluted isomer when rac-4-((2R,3S,4S,5R)-3-(4-fluoro-2-methoxy-3-(methoxymethyl)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide is separated by SFC as described in Example 13. In other embodiments, the present invention relates to the aforementioned compounds in non-salt forms. Such compounds are considered to be “compounds of the present invention” as the term is used herein.

[0105] In some embodiments, the present invention relates to compounds of the following formulas: [ka] With respect to the pharmaceutically acceptable salt thereof, if a mixture of rac-4-((2R,3S,4S,5R)-4,5-dimethyl-3-(1,1,7-trifluoro-2,3-dihydro-1H-inden-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide is separated by SFC as described in Example 13, the compound has the absolute stereochemistry of the third eluted isomer. In other embodiments, the present invention relates to the aforementioned compounds in unsalted forms. Such compounds are considered to be “compounds of the present invention” as the term is used herein.

[0106] In some embodiments, the present invention relates to compounds of the following formulas: [ka] The present invention relates to the compounds and their pharmaceutically acceptable salts. In other embodiments, the present invention relates to the aforementioned compounds in non-salt forms. Such compounds are considered to be “compounds of the present invention” as the term is used herein.

[0107] In some embodiments, the present invention relates to compounds of the following formulas: [ka] The present invention relates to the compounds and their pharmaceutically acceptable salts. In other embodiments, the present invention relates to the aforementioned compounds in non-salt forms. Such compounds are considered to be “compounds of the present invention” as the term is used herein.

[0108] In some embodiments, the present invention relates to compounds of the following formulas: [ka] The present invention relates to the compounds and their pharmaceutically acceptable salts. In other embodiments, the present invention relates to the aforementioned compounds in non-salt forms. Such compounds are considered to be “compounds of the present invention” as the term is used herein.

[0109] In some embodiments, the present invention relates to compounds of the following formulas: [ka] Or with respect to the pharmaceutically acceptable salt thereof, 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-((E)-2-(hydroxyimino)-3-methylbutoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide and 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-((Z)-2-(hydroxyimino)-3-methylbutoxy)phenyl)-4,5-dimethyl-5-(tri When a mixture of geometric isomers of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-(hydroxyimino)-3-methylbutoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide, including fluoromethyl)tetrahydrofuran-2-carboxamide, is separated by SFC as described in Example 21, the compound has the absolute stereochemistry of the first eluted isomer. In other embodiments, the present invention relates to the aforementioned compounds in non-salt forms. Such compounds are considered to be “compounds of the present invention” as the term is used herein.

[0110] In some embodiments, the present invention relates to compounds of the following formulas: [ka] The present invention relates to the compounds and their pharmaceutically acceptable salts. In other embodiments, the present invention relates to the aforementioned compounds in non-salt forms. Such compounds are considered to be “compounds of the present invention” as the term is used herein.

[0111] In some embodiments, the present invention relates to compounds of the following formulas: [ka] The present invention relates to the compounds and their pharmaceutically acceptable salts. In other embodiments, the present invention relates to the aforementioned compounds in non-salt forms. Such compounds are considered to be “compounds of the present invention” as the term is used herein.

[0112] In some embodiments, the present invention relates to compounds of the following formulas: [ka] The present invention relates to the compounds and their pharmaceutically acceptable salts. In other embodiments, the present invention relates to the unsalted forms of the aforementioned compounds. In other embodiments, the present invention relates to trifluoroacetates of the aforementioned compounds. Such compounds are considered to be “compounds of the present invention” as the term is used herein.

[0113] 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 are 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 disease, 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 agents are sodium channel inhibitors.

[0114] 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 the 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 the recipient. The salt may be in pure form, a mixture with one or more other substances (e.g., a solution, suspension, or colloid), or in the form of a hydrate, solvate, or 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.

[0115] 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 1-4This includes alkyl) tetrasalts. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts include, where appropriate, 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.

[0116] As used herein, the pharmaceutically acceptable compositions of the present invention also include, as used herein, all solvents, diluents, or other liquid vehicles suitable for the desired specific dosage form, including pharmaceutically acceptable carriers, adjuvants, or vehicles, such as dispersing or suspending 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 becomes 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, but are not limited to, 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, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., carboxymethylcellulose). Examples of ingredients include sodium, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository wax), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (e.g., propylene glycol and polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solution, and other non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), as well as 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.

[0117] 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.

[0118] In another embodiment, the present invention is characterized by 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.

[0119] 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, the method 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.

[0120] In yet another aspect, the present invention features 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, hernia repair, or abdominal wall reconstruction), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia, the method comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0121] 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 disease, incontinence, or cardiac arrhythmias, the method comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0122] In yet another embodiment, the present invention is characterized by a method for treating or reducing the severity of intestinal pain in a subject, the intestinal pain including inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain, 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.

[0123] 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.

[0124] In yet another aspect, the present invention is characterized by a method for 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 neuropathy, cancer chemotherapy-induced neuropathy, antiretroviral therapy-induced neuropathy; pain after spinal cord injury, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal-autonomic headache, 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.

[0125] 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.

[0126] In yet another aspect, the present invention is characterized by a method for treating musculoskeletal pain or reducing its severity in a subject, wherein musculoskeletal pain includes osteoarthritis, 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.

[0127] 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 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.

[0128] In yet another embodiment, the present invention is characterized by a method for treating inflammatory pain or reducing its severity in a subject, wherein 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.

[0129] In yet another embodiment, the present invention is characterized by a method for treating idiopathic pain or reducing its severity in a subject thereof, wherein 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.

[0130] In yet another embodiment, the present invention is characterized by a method for treating a pathological cough or reducing its severity in a subject, the method comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0131] 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.

[0132] In yet another aspect, the present invention is characterized by a method for treating or reducing the severity of postoperative pain (e.g., pain from joint replacement, pain from soft tissue surgery, pain from hernia repair, pain from aponeurosis resection, or pain from abdominal wall reconstruction) 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.

[0133] 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.

[0134] 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.

[0135] In yet another aspect, the present invention is characterized by a method for treating pain during abdominoplasty 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.

[0136] 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.

[0137] 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).

[0138] 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.

[0139] In another embodiment, the present invention is characterized by a method for 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, the voltage-gated sodium channels are Na V It is 1.8.

[0140] 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, trigeminal neuralgia, herpes zoster neuralgia, general neuralgia, epilepsy, epileptic states, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, motor disorders, neuroendocrine disorders, ataxia, central neuropathic pain and irritable bowel syndrome associated with multiple sclerosis, incontinence, pathological cough, visceral pain, osteoarthritis, postherpetic neuralgia, diabetic neuralgia Lopathies, 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, soft tissue surgery, hernia repair, aponeurosis excision, or 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 Matodes, 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, spondylodiscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmic neuropathy, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy-induced osteopathy The present invention is characterized by a method for treating or reducing the severity of the following conditions in a subject: sacral mucositis, Charcot arthritis, temporomandibular joint disorder, painful total knee replacement, noncardiac chest pain, genital pain, 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, the method comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0141] 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, and pain. Neuromas accompanied by ectopic proximal and distal secretions, 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, 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 disease, 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 is characterized by a method for treating or reducing the severity of the following conditions in a subject: pain of erythromelopathy, pain of 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, widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain, the method comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0142] 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.

[0143] 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 inhibiting voltage-gated sodium channels in a subject. In another aspect, the voltage-gated sodium channel is Na V It is 1.8.

[0144] In another aspect, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, 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 disease, incontinence, pathological cough, or cardiac arrhythmias.

[0145] In another aspect, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, 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 disease, incontinence, or cardiac arrhythmias.

[0146] 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 or reducing the severity of intestinal pain in a subject, wherein intestinal pain includes pain of inflammatory bowel disease, pain of Crohn's disease, or pain of interstitial cystitis.

[0147] In other embodiments, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in a method of treating neuropathic pain or reducing its severity in a subject thereof. 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.

[0148] In another aspect, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in a method of treating neuropathic pain or reducing its severity in subjects thereof, including 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 neuropathy, cancer chemotherapy-induced neuropathy, antiretroviral therapy-induced neuropathy; pain after spinal cord injury, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal-autonomic headache.

[0149] 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 thereof. In some embodiments, musculoskeletal pain includes osteoarthritis.

[0150] 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 thereof, musculoskeletal pain including osteoarthritis, back pain, cold pain, burn pain, or toothache.

[0151] 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 inflammatory pain or reducing its severity in a subject thereof, wherein inflammatory pain includes pain of rheumatoid arthritis or vulvodynia.

[0152] 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 inflammatory pain or reducing its severity in a subject thereof, wherein inflammatory pain includes pain of rheumatoid arthritis.

[0153] In another embodiment, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in treating idiopathic pain or reducing its severity in subjects thereof, wherein idiopathic pain includes pain of fibromyalgia.

[0154] 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 a pathological cough or reducing its severity in a subject thereof.

[0155] 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 thereof. In some embodiments, acute pain includes acute postoperative pain.

[0156] In another embodiment, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in a method of treating or reducing the severity of postoperative pain (e.g., pain from joint replacement surgery, pain from soft tissue surgery, pain from hernia repair surgery, pain from aponeurosis resection surgery, or pain from abdominal wall reconstruction surgery).

[0157] 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 pain associated with aponeurosis resection or reducing the severity of such pain in a subject.

[0158] 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 pain associated with hernia repair or reducing the severity of such pain in a subject.

[0159] 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 pain during or reducing the severity of abdominal wall reconstruction surgery in a subject thereof.

[0160] 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 visceral pain or reducing its severity in a subject thereof. In some embodiments, visceral pain includes visceral pain resulting from abdominoplasty.

[0161] 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 thereof. In some embodiments, neurodegenerative diseases include multiple sclerosis. In some embodiments, neurodegenerative diseases include Pitt-Hopkins syndrome (PTHS).

[0162] 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.

[0163] 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.

[0164] 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, trigeminal neuralgia, herpes zoster neuralgia, general neuralgia, epilepsy, epileptic states, 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, postherpetic neuralgia, diabetic neuralgia Circadian rhythm disorders, 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, soft tissue surgery, hernia repair, aponeurosis excision, or 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 erythema 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, spondylodiscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmic neuropathy, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy The present invention is characterized by the 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 stress-induced oral mucositis, Charcot arthritis, temporomandibular joint disorder, painful total knee replacement, noncardiac chest pain, genital pain, 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.

[0165] 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; pain Associated neuromas; ectopic proximal and distal discharges; 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; haguru 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 subjects with: Brønd's syndrome; pain of erythromelopathy; pain of 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; widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain.

[0166] 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.

[0167] Pharmaceutical manufacturing In another aspect, 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.

[0168] 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.

[0169] 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 the treatment of or reduction of 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 disease, incontinence, pathological cough, or cardiac arrhythmias.

[0170] 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 the treatment of or reduction of 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 disease, incontinence, or cardiac arrhythmias.

[0171] 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 the treatment of intestinal pain or in reducing the severity thereof, wherein intestinal pain includes pain of inflammatory bowel disease, pain of Crohn's disease, or pain of interstitial cystitis.

[0172] In yet another embodiment, the present invention provides compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in the treatment of neuropathic pain or in reducing the severity of such pain 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).

[0173] 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 the treatment of neuropathic pain or in reducing the severity of such pain, including 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 neuropathy, cancer chemotherapy-induced neuropathy, antiretroviral therapy-induced neuropathy; pain after spinal cord injury, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal-autonomic neuropathy.

[0174] 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 the treatment of musculoskeletal pain or in reducing the severity thereof in subjects. In some embodiments, musculoskeletal pain includes osteoarthritis.

[0175] 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 the treatment of musculoskeletal pain or the reduction of its severity in subjects thereof, musculoskeletal pain including osteoarthritis, back pain, cold pain, burn pain, or toothache.

[0176] 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 pharmaceuticals for use in the treatment of inflammatory pain or the reduction of its severity in subjects thereof, wherein inflammatory pain includes rheumatoid arthritis pain or vulvodynia.

[0177] 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 a pharmaceutical for use in the treatment of inflammatory pain or the reduction of its severity in a subject thereof, wherein inflammatory pain includes pain of rheumatoid arthritis.

[0178] 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 a pharmaceutical for use in the treatment of idiopathic pain or in reducing the severity thereof, wherein idiopathic pain includes pain of fibromyalgia.

[0179] 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 the treatment of pathological cough or in reducing the severity thereof in subjects.

[0180] 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 the treatment of acute pain or in reducing the severity of such pain in subjects. In some embodiments, acute pain includes acute postoperative pain.

[0181] 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 the treatment of postoperative pain (e.g., pain from joint replacement surgery, pain from soft tissue surgery, pain from hernia repair surgery, pain from aponeurosis resection surgery, or pain from abdominal wall reconstruction surgery) or for reducing the severity of such pain in subjects.

[0182] 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 pain in hernia repair or reducing the severity in such patients.

[0183] 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 pain in aponeurosis resection or reducing the severity in such subjects.

[0184] 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 used for the treatment of pain in abdominoplasty or for reducing the severity in such patients.

[0185] 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 the treatment of visceral pain or in reducing the severity thereof in subjects. In some embodiments, visceral pain includes visceral pain resulting from abdominoplasty.

[0186] In other embodiments, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for the manufacture of agents for use in the treatment of neurodegenerative diseases or in reducing the severity of such diseases. In some embodiments, neurodegenerative diseases include multiple sclerosis. In some embodiments, neurodegenerative diseases include Pitt-Hopkins syndrome (PTHS).

[0187] 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.

[0188] 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, trigeminal neuralgia, herpes zoster neuralgia, general neuralgia, epilepsy, epileptic states, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, motor disorders, neuroendocrine disorders, ataxia, central neuropathic pain and irritable bowel syndrome associated with multiple sclerosis, incontinence, pathological cough, visceral pain, osteoarthritis, postherpetic neuralgia, and diabetic pain. Nerve disorders, 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, soft tissue surgery, hernia repair, aponeurosis excision, or 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 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, spondylodiscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmic neuropathy, sarcoidosis, spondylolysis, spondylolisthesis, chemical 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 therapy-induced oral mucositis, Charcot joint disorder, temporomandibular joint disorder, painful total knee replacement, noncardiac chest pain, genital pain, 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.

[0189] 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; pain Neuromas accompanied by ectopic proximal and distal discharges; 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 Nephritis; 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; ha 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 Grund's syndrome; erythromelalgia pain; Fabry disease pain; 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; widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain.

[0190] 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 pain following traumatic neuroma, or postoperative pain, including trigeminal neuralgia, Botox-treated migraines, cervical spondylotic radiculopathy, occipital neuralgia, axillary nerve disorder, radial nerve disorder, ulnar nerve disorder, brachial plexus disorder, thoracic nerve disorder, intercostal neuralgia, lumbosacral nerve disorder, ilioinguinal neuralgia, pudendal neuralgia, femoral nerve disorder, paresthesia of femoral pain, saphenous nerve disorder, sciatic nerve disorder, peroneal nerve disorder, tibial nerve disorder, lumbosacral plexus disorder, stump pain of traumatic neuroma, or pain following amputation surgery.

[0191] 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.

[0192] 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. A 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 of administration, route of administration, and excretion rate 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.

[0193] 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 or twice a day at a dosage level of about 0.001 mg / kg to about 1000 mg / kg, which is effective in obtaining the desired therapeutic effect.

[0194] 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, oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0195] Preparations for injection, such as sterile aqueous or oily suspensions for injection, may 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 may 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 injectable preparations.

[0196] 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.

[0197] 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 crystalline or amorphous material with poor water solubility. The absorption rate of the compound then depends on its dissolution rate, which 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.

[0198] 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.

[0199] 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.

[0200] Similar types of solid compositions may 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 may 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.

[0201] The active compound or salt may also be in the form of microcapsules having 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 a specific part of the intestinal tract, or preferentially. Examples of embedding compositions that may be used include polymeric substances and waxes.

[0202] 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 may 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.

[0203] 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.

[0204] 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 / 120808A9 and U.S. Publication No. 2014 / 0213616A1 (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.

[0205] Additional medications The compounds, salts, and pharmaceutically acceptable compositions of the present invention can be used in combination therapy, that is, 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 against 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 different effects (for example, control of any adverse effects). As used herein, additional therapeutic agents that are typically 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, but are not limited to, non-opioid analgesics (indoles, e.g., etodolac, indomethacin, 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, oxaprozin, salicylates, e.g., aspirin, choline magnesium trisalicylate, diflunisal, fenamet, e.g., Examples include 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, dezosine, 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, anesthesiological (spinal infusion, nerve block), neurosurgical (nerve decompression of CNS pathways), neurostimulation (percutaneous electroneural stimulation, spinal cord posterior column stimulation), physical therapy (physiotherapy, orthostatic devices, diathermy), or psychiatric (cognitive methods - hypnosis, biofeedback, or behavioral methods) approaches 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 the Food and Drug Administration (website www.fda.gov), the entire contents of which are incorporated herein by reference.

[0206] 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, propoxyfene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbufine, pentazocine, or diferikephalin; (2) Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, fluviprofen, ibuprofen (but not limited to intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketrolac (but not limited to ketrolactromethamine (e.g., Toradol®)), meclofenamic acid, mefenamic acid, meloxicam, IV meloxicam (e.g., Anjeso®), nabumetone, naproxen, nimeslide, nitroflurbiprofen, orsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, or zomepirac; (3) Barbiturate sedatives, such as amobarbital, aprobarbital, butabarbital, butarbital, mefobarbital, metalbital, methhexital, pentobarbital, phenobarbital, secobarbital, tarbutal, thiamylal, or thiopental; (4) Benzodiazepines having a sedative effect, such as chlordiazepoxide, chlorazepic acid, diazepam, furazepam, lorazepam, oxazepam, temazepam, or triazolam; (5) Histamine (H1) antagonists having a sedative effect, such as diphenhydramine, pyriramine, promethazine, chlorpheniramine, or chlorcyclidine; (6) Sedatives, such as glutethimide, meprobamate, methacaron, or dichlorphenazone; (7) Skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphenadrine; (8) NMDA receptor antagonists, such as 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 perzinfotel (NR2B antagonists, such as ifenprodil, traxoprodil, or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-l-piperidinyl]-l-hydroxyethyl-3,4-dihydro-2(lH)-quinolinone); (9) Alpha-adrenergic agonists, such as doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methanesulfonamide-1,2,3,4-tetrahydroisoquinoline-2-yl)-5-(2-pyridyl)quinazoline; (10) Tricyclic antidepressants, such as desipramine, imipramine, amitriptyline, or nortriptyline; (11) Anticonvulsants, such as carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®), or valproate; (12) Tachykinin (NK) antagonists, especially NK-, NK-2, or NK-1 antagonists, e.g., (alpha-R,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazosino[2,1-g][1,7]-naphthyridine-6-13-dione (TAK-637), 5-[[(2R,3S) -2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazole-3-one (MK-869), aprepitant, ranepitant, dapitant, or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S); (13) Muscarinic antagonists, such as 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, such as 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, osanetan, limonabant, meclinertan, Miraxion®, or sarizotan; (17) Vanilloid receptor agonists (e.g., resiniferatoxin or cibamide) or antagonists (e.g., capsazepine, GRC-15300); (18) Beta-adrenaline, e.g., propranolol; (19) Local anesthetics, e.g., mexiletine; (20) Corticosteroids, e.g., dexamethasone; (21) 5-HT receptor agonists or antagonists, in particular 5-HT 1B / 1D Agonists, such as eletriptan, sumatriptan, naratriptan, zolmitriptan, or rizatriptan; (22)5-HT 2A Receptor antagonists, e.g., 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-azetidinylmethoxy)-2-chloropyridine (ABT-594), or nicotine; (24) Tramadol®, Tramadol ER (Ultram ER®), IV Tramadol, Tapentador ER (Nucynta®); (25) PDE5 inhibitors, e.g., 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-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',1':6,1]-pyrido[3,4-b ]Indole-1,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4 ,3-d]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-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidine-5-yl)-N-[2-(1-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)-cycloheptayl]-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) Metabotropic glutamate subtype 1 receptor (mGluRl) antagonists; (29) Serotonin reuptake inhibitors, such as 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, e.g., donepezil; (34) Prostaglandin E2 subtype 4 (EP4) antagonists, e.g., 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 (Vixotrigine), 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 (US2012 / 245) 136); as disclosed in WO2012 / 125613 (US2012 / 264749), WO2012 / 116440 (US2014 / 187533), WO2011 / 026240 (US2012 / 220605), US8883840, US8466188, WO2013 / 109521 (US2015 / 005304), CN111217776, or WO2020 / 117626 (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 V 1.8 Blockers, e.g., PF-04531083, PF-06372865, and e.g., WO2008 / 135826 (US2009048306), WO2006 / 011050 (US2008312235), WO2013 / 061205 (US2014296313), US2013 / 0303535, WO2013 / 131018, US8466188, WO2013 / 114250(US2013 / 274243), WO2014 / 120808(US2014 / 213616), WO2014 / 120815(US2014 / 228371), WO20 14 / 120820(US2014 / 221435), WO2015 / 010065(US20160152561), WO2015 / 089361(US20150166589), WO2 019 / 014352(US2019 / 0016671), WO2018 / 213426, WO2020 / 146682, WO2020 / 146612, WO2020 / 014243, WO 2020 / 014246, WO2020 / 092187, WO2020 / 092667(US2020140411), WO2020 / 261114, WO2020 / 140959, WO20 Disclosed in 20 / 151728, WO2021 / 032074, WO2021 / 047622 (CN112479996), CN112390745, CN111808019, CN112225695, CN112457294, CN112300051, CN112300069, and CN112441969 (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)methyl dihydrogen phosphate, 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-methoxyphenoxy)-N-( 3-Sulfamoylphenyl)Quinoxaline-2-Carboxamide, 3-(4-Chloro-2-Methoxyphenoxy)-N-(3-Sulfamoylphenyl)Quinoxaline-2-Carboxamide, 4-(3-(4-(Trifluoromethoxy)phenoxy)Quinoxaline-2-Carboxamide)Picolinic Acid, 2-(2,4-Difluorophenoxy)-N-(3-Sulfamoylphenyl)Quinoline-3-Carboxamide, 2-(4-Fluoro-2-Methoxyphenoxy)-N-(3-Sulfamoylphenyl)Quinoline-3-Carboxamide, 3-(2,4-Difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoline-3-carboxamide, N-(3-sulfamoylphenyl)-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide, 3-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)quinoxaline- 2-Carboxamide, 5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide)picolinic acid, 3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazole-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-fluorophenoxy)-N-(3-s Sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-chloro-2-methyl) Toxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-Dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-Dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6-Bis(trifluoromethyl)benzamide, 5-Chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 4,5-Dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 5-Fluoro-2-(4-fluoro-2-methylphenoxy)- N-(3-sulfamoylphenyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3-sulfamoylphenyl)benzamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(triduteromethoxy)-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-(triduteromethoxy)-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-fluorophenyl)-2,3,4-Trifluoro-6-[2-Methoxy-4-(trifluoromethoxy)phenoxy]benzamide, N-(2-Carbamoyl-4-pyridyl)-3-fluoro-5-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide, 4-[[6-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-Carbamoyl-4-fluoro-phenyl)-6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-Carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy )phenoxy]-3-(trifluoromethyl)benzamide, N-(4-carbamoyl-3-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[2-fluoro-6-[2-(triduteromethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-Pentafluoroethyl)benzamide, 4-[[4-(difluoromethoxy)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[4-cyclopropyl-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoro Oromethyl)benzamide, 5-[[2-fluoro-6-[2-(triduteromethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluorophenyl)-2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzamide, 4-(2-fluoro-6-(2-methoxy-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzamide)picolinamide, or 4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide;, (40) Combined Na V 1.7 and Na V 1.8 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 (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).

[0207] 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), ralfinamide, transdermal bupivacaine (Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561, or ARC-4558.

[0208] 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-imidazole-2-yl)methyl)oxetane-3-amine.

[0209] 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.

[0210] In another embodiment, the additional therapeutic agent is oryceridine or ropivacaine (TLC590).

[0211] 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 WO2022 / 036297 (the entire contents of each application are incorporated herein by reference). In some embodiments, additional therapeutic agents are Na disclosed in WO2020 / 072835. V 1.7 Blockers. In some embodiments, additional therapeutic agents are disclosed in WO2022 / 036297. V 1.7 It is an antiblocker.

[0212] 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 It is either 7352 or XT-150.

[0213] In another embodiment, additional therapeutic agents include 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, ETX-801, or ACD440.

[0214] In another embodiment, additional therapeutic agents include WO2021 / 257490, WO2021 / 257420, WO2021 / 257418, WO2020 / 014246, WO2020 / 092187, WO2020 / 092667, WO2020 / 261114, CN112457294, CN112225695, CN111808019, WO2021 / 032074, WO2020 / 151728, WO2020 / 140959, WO2022 / 037641, WO2022 These are compounds disclosed in / 037647, CN112300051, CN112300069, WO2014 / 120808, WO2015 / 089361, WO2019 / 014352, WO2021 / 113627, WO2013 / 086229, WO2013 / 134518, WO2014 / 211173, WO2014 / 201206, WO2016 / 141035, WO2021 / 252818, WO2021 / 252822, and WO2021 / 252820.

[0215] In some embodiments, the additional therapeutic agent is a compound disclosed in WO2013 / 086229. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2013 / 134518. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2014 / 211173. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2014 / 201206. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2016 / 141035. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2021 / 252818. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2021 / 252822. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2021 / 252820. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2020 / 072835. In some embodiments, additional therapeutic agents are compounds disclosed in WO2022 / 036297.

[0216] In another embodiment, the additional therapeutic agent is Na as 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.

[0217] 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 present in the currently disclosed composition may range from about 10% to 100% of the amount typically present in a composition containing the agent as the sole therapeutically active agent.

[0218] 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.

[0219] Another aspect of the present invention is a biological sample or subject in which Na V1.8 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.

[0220] Na in biological samples V 1.8 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.

[0221] 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 those skilled in the art will understand, 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).

[0222] Radiolabeled analogues 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.

[0223] 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, 36 Examples include Cl, as well as isotopes whose decay modes have been identified in the Table of Nuclides (January 1980) by VS Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory.

[0224] Radiolabeled analogs can be used in several beneficial ways, including various types of assays such as substrate tissue distribution assays. For example, tritium ( 3 H) Labeling and / or carbon-14 ( 14 C) Labeled compounds can be useful in various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detection capabilities.

[0225] In another aspect, the present invention relates to pharmaceutically acceptable salts of radiolabeled analogs of compounds of the present invention, according to any of the embodiments described herein.

[0226] In another aspect, the present invention relates to a pharmaceutical composition comprising a radiolabeled analogue or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle, in accordance with any of the embodiments described herein relating to the compound of the present invention.

[0227] In another aspect, the present invention relates to a method for inhibiting voltage-gated sodium channels in a subject, comprising administering an effective amount of a radiolabeled analogue, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof, in accordance with any of the embodiments described herein relating to the compounds of the present invention, and a method for treating or reducing the severity of various diseases and disorders, including pain.

[0228] In another aspect, the present invention relates to radiolabeled analogues, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof for use in relation to the compounds of the present invention, according to any of the embodiments described herein.

[0229] In another aspect, the present invention relates to radiolabeled analogues or pharmaceutically acceptable salts thereof for the manufacture of pharmaceuticals, and the use of pharmaceutical compositions thereof, in accordance with any of the embodiments described herein relating to the compounds of the present invention.

[0230] In another embodiment, radiolabeled analogues, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof may be used in combination therapy in relation to the compounds of the present invention, according to any of the embodiments described herein.

[0231] Listed embodiments Additional embodiments, features, and advantages of this disclosure will become apparent from the following detailed description and from the implementation of this disclosure. The compounds and methods of this disclosure may be described as embodiments of any of the items listed below. Any embodiment described herein can be used in conjunction with any other embodiment described herein, to the extent that the embodiments are not inconsistent with each other.

[0232] 1. Compound of formula (I), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 2a However, N, N + -O -, or CR 2a And, X 4a However, N, N + -O - , or CR 4a And, X 5a However, N, N + -O - , or CR 5a And, X 6a However, N, N + -O - , or CR 6a And, R, OR a or NR Xa R Ya And, R 2a , R 4a , R 5a , and R 6a Each of these is independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or -Si(C1-C6 alkyl)3. R a However, it is H or C1-C6 alkyl, R Xa However, it is H or C1-C6 alkyl, R Ya However, H, OH, C1-C6 alkyl, -(C1-C6 alkylene)-R Za1 or a 4-6 membered heterocycline optionally substituted with one or more groups independently selected from C1-C6 alkyl and C1-C6 alkoxy, or R Xa and R Ya However, together with the nitrogen atoms to which they are bonded, they form a 5-9 member heterocycline, and this heterocycline contains one or more R Za2 It is replaced as needed, R Za1 However, it is a 5-6 membered heterocycline optionally substituted with one or more groups independently selected from OH, NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, and halo and C1-C6 alkyl. Each R Za2However, these are independently selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, and -(C1-C6 alkylene)-(C1-C6 alkoxy), R 4b1 and R 4b2 Each of these is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl. R 5b1 and R 5b2 Each of these is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, or -(C1-C6 alkylene)-(C1-C6 alkoxy), or R 5b1 and R 5b2 However, together with the carbon atoms to which they are bonded, they form 4-6 membered heterocyclines. X 3c However, N or CR 3c And, X 4c However, N or CR 4c And, X 5c However, N or CR 5c And, X 6c However, N or CR 6c And, R 2c However, H, OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -(C1-C6 alkylene)-(C1-C6 alkoxy), -(C1-C6 alkylene)-O-(4-6 member heterocyclyl), -O-(C2-C6 alkenylene)-(C1-C6 haloalkyl), -L 1 -L 2 -(C3-C7 cycloalkyl), or -OL 3 -R Xc The cycloalkyl group is optionally substituted with one or more groups independently selected from halo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, =NOH, -C(O)(C1-C6 alkyl), and -(C1-C6 alkylene)-OH. L 1 However, it is a bond or O, L 2 However, it is a bond or C1-C6 alkylene, L 3 However, the bond is a C1-C6 alkylene or a C2-C6 alkenylene. R Xc However, OH, CN, C1-C6 alkoxy, NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 haloalkyl), -NH(C1-C6 haloalkyl)2, -CH(CH2OH)2, -CH(CH2OH)(CH2OCH3), -CH(CH2OH)(OCH3), -CH(CH2OCH3)(OCH3), -CH(CH2OH)(CF3), -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -NH(4-6 member heterocyclyl ),=NOH,=NO(C1-C6 alkyl),-N=S(O)(C1-C6 alkyl)2,-C(=NOH)(C3-C6 cycloalkyl), 4-8 membered heterocyclyl, and 5-6 membered heteroaryl are selected, and the cycloalkyl is optionally substituted with one or more halos, and the heterocyclyl and heteroaryl are optionally substituted with one or more groups independently selected from OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -(C1-C6 alkylene)-OH, R 3c However, is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -(C1-C6 alkylene)-OH, or -(C1-C6 alkylene)-(C1-C6 alkoxy)? Or, X 3c However, CR 3c And R 2c and R 3c Together with the carbon atoms to which they are bonded, the formula is: [ka] Forming a ring, Z 1 and Z 2Each of these is independently O, CH2, or CF2. R Yc1 and R Yc2 Each of these is independently H or halo. R 4c However, H, halo, OH, -OBn, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed. R 5c However, H, halo, OH, -OBn, C1-C6 alkyl, C1-C6 haloalkyl, or -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed. R 6c However, it is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl, However, X 2a , X 4a , X 5a , and X 6a Two or fewer of these are N or N + -O - And, However, X 3c , X 4c , X 5c , and X 6c One of these is less than or equal to N, however, R, OR a is or R, NR Xa R Ya And R Ya However, OH, -(C1-C6 alkylene)-R Za1 , or a 4- to 6-membered heterocycline optionally substituted with one or more groups independently selected from C1-C6 alkyl and C1-C6 alkoxy, R, NR Xa R Ya And R Xa and R YaHowever, together with the N atoms to which they are bonded, they form a 5-9 member heterocycline, and this heterocycline contains one or more R Za2 It is replaced as needed, or R 2a , R 4a , R 5a , or R 6a However, it is either -Si(C1-C6 alkyl) or R 5b1 Or R 5b2 However, it is either -(C1-C6 alkylene)-(C1-C6 alkoxy) or R 5b1 and R 5b2 However, together with the carbon atoms to which they are bonded, they form a 4-6 membered heterocycline, or R 2c However, -(C1-C6 alkylene)-(C1-C6 alkoxy), -(C1-C6 alkylene)-O-(4-6 member heterocyclyl), -O-(C2-C6 alkenylene)-(C1-C6 haloalkyl), or -OL 3 -R Xc is or R 2c However, -L 1 -L 2 -(C3-C7 cycloalkyl), wherein the cycloalkyl is substituted with one or more groups independently selected from OH, CN, C1-C6 alkyl, C1-C6 alkoxy, =NOH, -C(O)(C1-C6 alkyl), and -(C1-C6 alkylene)-OH, or R 3c However, it is either -(C1-C6 alkylene)-OH or -(C1-C6 alkylene)-(C1-C6 alkoxy), or R 2c and R 3c However, together with the carbon atoms to which they are bonded, the formula is: [ka] To form a ring, or R 4c However, OH, -OBn, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed, or R 5c However, OH, -OBn, or -L 1 -L 2 A compound of formula (I), or a pharmaceutically acceptable salt thereof, which is -(C3-C6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halos. 2. The compound is of formula (IA) [ka] A compound described in item 1, or a pharmaceutically acceptable salt thereof, having the above properties. 3. The compound is of formula (IA-1) [ka] A compound described in item 1 or 2, or a pharmaceutically acceptable salt thereof, having the above properties. 4. The compound is of formula (IB) [ka] A compound described in item 1 or 2, or a pharmaceutically acceptable salt thereof, having the above properties. 5. The compound is of formula (IB-1) [ka] A compound described in any one of items 1 to 4, or a pharmaceutically acceptable salt thereof, having the above properties. 6. The compound is of formula (IC) [ka] A compound described in item 1 or 2, or a pharmaceutically acceptable salt thereof, having the above properties. 7. The compound is of formula (IC-1) [ka] A compound described in any one of items 1 to 3 or 6, or a pharmaceutically acceptable salt thereof, having the above properties. 8.X 2a However, N or CR 2a And R 2a A compound listed in any one of items 1-7, or a pharmaceutically acceptable salt thereof, wherein H is present. 9.X 2a However, the compound listed in item 8, or a pharmaceutically acceptable salt thereof, is N. 10.X 2a However, CR 2a And R 2a However, the compound listed in item 8, or a pharmaceutically acceptable salt thereof, is H. 11.X 4a However, N, N + -O - , or CR 4a And R 4a A compound listed in any one of items 1 to 10, or a pharmaceutically acceptable salt thereof, which is H or a halo. 12.X 4a However, the compound listed in item 11, or a pharmaceutically acceptable salt thereof, is N. 13.X 4a However, N + -O, the compounds listed in item 11, or their pharmaceutically acceptable salts. 14.X 4a However, CR 4a And R 4a A compound listed in item 11, or a pharmaceutically acceptable salt thereof, which is H or F. 15.X 5a However, CR 5a And R 5a A compound listed in any one of items 1, 2, 4, 6, or 8-14, which is H, or a pharmaceutically acceptable salt thereof. 16.X 6a However, N or CR 6a And R 6a A compound listed in any one of items 1 to 15, wherein the compound is H, halo, C1-C6 alkyl, or -Si(C1-C6 alkyl)3, or a pharmaceutically acceptable salt thereof. 17.X 6aHowever, the compound listed in item 16, or a pharmaceutically acceptable salt thereof, is N. 18.X 6a However, CR 6a And R 6a The compounds listed in item 16, or pharmaceutically acceptable salts thereof, wherein the compound is H, F, CH3, or -Si(CH3)3. 19. R is OR a or NR Xa R Ya And, R a However, it is H or C1-C6 alkyl, R Xa However, it is H or C1-C6 alkyl, R Ya However, H, OH, C1-C6 alkyl, -(C1-C6 alkylene)-R Za1 , or a 4-6 membered heterocycline optionally substituted with one or more groups independently selected from C1-C6 alkyl and C1-C6 alkoxy, R Za1 A compound described in any one of items 1 to 18, or a pharmaceutically acceptable salt thereof, which is a 5- to 6-membered heterocycline optionally substituted with OH, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, and one or more groups independently selected from halo and C1-C6 alkyl. 20. R is OR a And R a A compound listed in item 19, or a pharmaceutically acceptable salt thereof, which is H. 21. R is NR Xa R Ya And, R Xa However, it is either H or CH3. R Ya However, H, OH, CH3, -(C1-C2 alkylene)-R Za1 , or a 4- to 6-membered heterocycline optionally substituted with one or more groups independently selected from CH3, -OCH3, and -OCH2CH3, R Za1The compounds described in item 19, or pharmaceutically acceptable salts thereof, which are 5- to 6-membered heterocyclines, which are optionally substituted with one or more groups independently selected from OH, -NH(CH3), -N(CH3)2, and F and CH3. 22.R is NR Xa R Ya And, R Xa and R Ya However, together with the nitrogen atom to which they are bonded, one or more R Za2 They form 5-9 member heterocyclines which are substituted as needed. Each R Za2 The compounds described in any one of items 1 to 18, or pharmaceutically acceptable salts, are independently selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, and -(C1-C6 alkylene)-(C1-C6 alkoxy). 23.Each R Za2 Compounds described in item 22, or pharmaceutically acceptable salts thereof, wherein each is independently selected from F, OH, CH3, -OCH3, NH2, -NH(CH3), -N(CH3)2, and -CH2OCH3. 24.R 4b1 A compound listed in any one of items 1 to 23, which is H or C1-C6 alkyl, or a pharmaceutically acceptable salt thereof. 25.R 4b1 The compounds listed in item 24, or their pharmaceutically acceptable salts, which are H or CH3. 26.R 4b2 A compound listed in any one of items 1 to 25, which is H or C1-C6 alkyl, or a pharmaceutically acceptable salt thereof. 27.R 4b2 A compound listed in item 26, or a pharmaceutically acceptable salt thereof, which is H or CH3. 28.R 5b1 A compound described in any one of items 1 to 27, which is a C1-C6 alkyl, a C1-C6 haloalkyl, or a -(C1-C6 alkylene)-(C1-C6 alkoxy), or a pharmaceutically acceptable salt thereof. 29.R5b1 The compounds listed in item 28, or pharmaceutically acceptable salts thereof, wherein the compound is CH3, CF3, -CH2OCH3, or -CH2CH2OCH3. 30.R 5b2 A compound described in any one of items 1 to 29, which is a C1-C6 alkyl, a C1-C6 haloalkyl, or a -(C1-C6 alkylene)-(C1-C6 alkoxy), or a pharmaceutically acceptable salt thereof. 31.R 5b2 The compounds listed in item 30, or pharmaceutically acceptable salts thereof, which are CH3, CF3, -CH2OCH3, or -CH2CH2OCH3. 32.R 5b1 and R 5b2 A compound described in any one of items 1 to 27, or a pharmaceutically acceptable salt thereof, wherein these compounds, together with the carbon atoms to which they are bonded, form a four-membered heterocycline. 33.X 3c However, N is a compound listed in any one of items 1 to 32, or a pharmaceutically acceptable salt thereof. 34.X 3c However, CR 3c And R 3c A compound listed in any one of items 1 to 32, wherein the compound is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -(C1-C6 alkylene)-OH, or -(C1-C6 alkylene)-(C1-C6 alkoxy), or a pharmaceutically acceptable salt thereof. 35.R 3c The compounds listed in item 34, or pharmaceutically acceptable salts thereof, wherein the compound is H, F, Cl, CH3, CF3, -CH2OH, or -CH2OCH3. 36.X 4c However, CR 4c And R 4c However, H, halo, OH, -OBn, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed, L 1 However, it is O and L 2A compound described in any one of items 1, 2, 4, 6, or 8-35, which is a bond or C1-C6 alkylene, or a pharmaceutically acceptable salt thereof. 37.R 4c However, H, halo, OH, -OBn, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed, L 1 However, it is O and L 2 A compound described in any one of items 3, 5, 7, or 8-35, which is a bond or C1-C6 alkylene, or a pharmaceutically acceptable salt thereof. 38.R 4c The compound is one of the compounds described in item 36 or 37, wherein the cyclobutyl is substituted with two F atoms. 39.X 5c However, CR 5c And R 5c However, H, halo, OH, -OBn, or -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed, L 1 However, it is O and L 2 However, the compound is a compound listed in any one of items 1, 2, 4, 6, or 8-38, or a pharmaceutically acceptable salt thereof. 40.R 5c However, H, halo, OH, -OBn, or -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed, L 1 However, it is O and L 2 However, the compound is a compound listed in any one of items 3, 5, 7, or 8-38, or a pharmaceutically acceptable salt thereof. 41.R 5cThe compound described in item 39 or 40, or a pharmaceutically acceptable salt thereof, wherein the compound is H, Cl, OH, -OBn, or -O-(cyclobutyl), and the cyclobutyl is substituted with two F atoms. 42.X 6c However, CR 6c And R 6c A compound listed in any one of items 1, 2, 4, 6, or 8-41, or a pharmaceutically acceptable salt thereof, wherein H is present. 43.R 2c However, OH, halo, C1-C6 alkoxy, -(C1-C6 alkylene)-(C1-C6 alkoxy), -(C1-C6 alkylene)-O-(4-6 member heterocyclyl), -O-(C2-C6 alkenylene)-(C1-C6 haloalkyl), -L 1 -L 2 -(C3-C7 cycloalkyl), or -OL 3 -R Xc The cycloalkyl group is optionally substituted with one or more groups independently selected from OH, CN, C1-C6 alkyl, C1-C6 alkoxy, =NOH, -C(O)(C1-C6 alkyl), and -(C1-C6 alkylene)-OH. L 1 However, it is O, L 2 However, it is a bond or C1-C6 alkylene, L 3 However, the bond is a C1-C6 alkylene or a C2-C6 alkenylene. R XcHowever, OH, CN, C1-C6 alkoxy, NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 haloalkyl), -NH(C1-C6 haloalkyl)2, -CH(CH2OH)2, -CH(CH2OH)(CH2OCH3), -CH(CH2OH)(OCH3), -CH(CH2OCH3)(OCH3), -CH(CH2OH)(CF3), -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -NH(4-6 member heterocyclyl), =NOH, =NO(C1-C6 alkyl) Compounds described in any one of items 1 to 42, or pharmaceutically acceptable salts thereof, selected from 1(C1-C6)(C1-C6 alkyl), -N=S(O)(C1-C6 alkyl)2, -C(=NOH)(C3-C6 cycloalkyl), 4- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the cycloalkyl is optionally substituted with one or more halos, and the heterocyclyl and heteroaryl are optionally substituted with one or more groups independently selected from OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -(C1-C6 alkylene)-OH. 44.R 2c The compounds listed in item 43, or pharmaceutically acceptable salts thereof, wherein the compound is OH, Cl, -OCH3, -CH2OCH3, -CH2-O-(4-membered heterocyclyl), or -O-(C3-C4 alkenylene)-CF3. 45.R 2c However, -L 1 -L 2 -(C3-C7 cycloalkyl), L 1 However, it is O, L 2 However, it is a bond or C1-C2 alkylene, The compound described in item 43, or a pharmaceutically acceptable salt thereof, wherein the cycloalkyl group is substituted with one or more groups independently selected from OH, CN, -OCH3, CH3, =NOH, -C(O)(CH3), and -CH2OH. 46.R 2c However, -OL 3 -RXc And, L 3 However, the bond is either C1-C6 alkylene or C4-C5 alkenylene. R Xc However, OH, CN, C1-C6 alkoxy, NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 haloalkyl), -NH(C1-C6 haloalkyl)2, -CH(CH2OH)2, -CH(CH2OH)(CH2OCH3), -CH(CH2OH)(OCH3), -CH(CH2OCH3)(OCH3), -CH(CH2OH)(CF3), -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -NH(4-6 member heterocyclyl), =NOH, =NO(C1- Compounds described in item 43, or pharmaceutically acceptable salts thereof, selected from C6 alkyl, -N=S(O)(C1-C6 alkyl)2, -C(=NOH)(C3-C6 cycloalkyl), 4- to 8-membered heterocyclil, and 5- to 6-membered heteroaryl, wherein the cycloalkyl is optionally substituted with one or more halos, and the heterocyclil and heteroaryl are optionally substituted with one or more groups independently selected from OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -(C1-C6 alkylene)-OH. 47.R Xcis OH;CN;-OCH3;-NH(CH3);-NH(CH(CH3)2);-N(CH3)2;-NH(CH2CHF2);-CH(CH2OH)2;-CH(CH2OH)(CH2OCH3);-CH(CH2OH) (OCH3);-CH(CH2OCH3)(OCH3);-CH(CH2OH)(CF3);-C(O)(CH3);-C(O)NH(CH3);-NH(4-5 membered heterocyclyl);=NOH;=NO(CH3);-N=S Compounds described in item 46, or pharmaceutically acceptable salts thereof, selected from (O)(CH3)2;-C(=NOH)(C3-C4 cycloalkyl); 4- to 8-membered heterocyclils optionally substituted with one or more groups independently selected from OH, F, CH3, -OCH3, CHF2, CF3, -OCHF2, and -CH2OH; and 5-membered heteroaryls optionally substituted with CH3, wherein the cycloalkyl is optionally substituted with one F. 48.X 3c However, CR 3c And R 2c and R 3c However, together with the carbon atoms to which they are bonded, the formula is: [ka] It forms a ring, and in the formula, Z 1 However, it is either O or CH2. Z 2 However, it is either O or CF2, R Yc1 and R Yc2 A compound described in any one of items 1 to 42, or a pharmaceutically acceptable salt thereof, wherein each of the elements is independently H or F. 49. The ring is, formula: [ka] A compound listed in item 48, or a pharmaceutically acceptable salt thereof, which is a ring of . 50. A compound selected from Table A or Table B, or a pharmaceutically acceptable salt thereof. 51. A compound listed in any one of items 1-50 that is in a non-salt form. 52. A pharmaceutical composition comprising a compound described in any one of items 1 to 50 in a therapeutically effective amount, or a pharmaceutically acceptable salt thereof, or a compound described in item 51, and one or more pharmaceutically acceptable carriers or vehicles. 53. A pharmaceutical composition comprising a compound described in any one of items 1 to 50, or a pharmaceutically acceptable salt thereof, or a compound described in item 51, and one or more pharmaceutically acceptable carriers or vehicles. 54. A method for inhibiting voltage-gated sodium channels in a subject, comprising administering to the subject a compound described in any one of items 1 to 50, or a pharmaceutically acceptable salt thereof, a compound described in item 51, or a pharmaceutical composition described in item 52 or 53. 55. Voltage-gated sodium channels, Na V 1.8, the method described in item 54. 56. 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, comprising administering to the subject an effective amount of a compound described in any one of items 1 to 50, or a pharmaceutically acceptable salt thereof, a compound described in item 51, or a pharmaceutical composition described in item 52 or 53. 57. The method described in item 56, wherein the method includes treating neuropathic pain or reducing its severity in a subject. 58. Neuropathic pain, including postherpetic neuralgia, as described in item 56. 59. Neuropathic pain, including small fiber neuropathy, as described in item 56. 60. Neuropathic pain, including idiopathic small fiber neuropathy, as described in item 56. 61. Neuropathic pain, including diabetic neuropathy, as described in item 56. 62. The method according to item 61, wherein diabetic neuropathy includes diabetic peripheral neuropathy. 63. The method described in item 56, wherein the method includes treating musculoskeletal pain or reducing its severity in a subject. 64. Musculoskeletal pain, including osteoarthritis pain, as described in item 63. 65. The method described in item 56, wherein the method includes treating acute pain or reducing its severity in a subject. 66. The method described in item 65, wherein acute pain includes acute postoperative pain. 67. The method described in item 56, wherein the method includes treating postoperative pain or reducing its severity in a subject. 68. Postoperative pain, including pain from banyon excision, as described in item 67. 69. Postoperative pain, including abdominal wall repair pain, as described in item 67. 70. Postoperative pain, including pain from hernia repair, as described in item 67. 71. The method described in item 56, wherein the method includes treating visceral pain or reducing its severity in a subject. 72. The method according to any one of items 54 to 71, wherein the subject is treated simultaneously with treatment with a compound, a pharmaceutically acceptable salt, or a pharmaceutical composition, with one or more additional therapeutic agents administered before or after such treatment. 73. Use as a pharmaceutical product any compound listed in any one of items 1 to 50, or a pharmaceutically acceptable salt thereof, any compound listed in item 51, or any pharmaceutical composition listed in item 52 or 53. [Examples]

[0233] A common method. 1 The 1H NMR spectrum was obtained as a solution in a suitable deuterated solvent such as dimethyl sulfoxide-d6 (DMSO-d6).

[0234] Compound purity, retention time, and electrospray mass spectrometry (ESI-MS) data were determined by LC / MS analysis. LC / MS analysis was performed using a Waters Acquity UPLC BEH C8 column (50 × 2.1 mm, 1.7 μm particles) (pn: 186002877) along with a Guard column (2.1 × 5 mm, 1.7 μm particles) (pn: 186003978), and a dual gradient run of 2–98% mobile phase B over 4.45 minutes. Mobile phase A = H2O (10 mM ammonium formate containing 0.05% ammonium hydroxide). Mobile phase B = acetonitrile. Flow rate = 0.6 mL / min, injection volume = 2 μL, and column temperature = 45°C.

[0235] X-ray powder diffraction analysis: X-ray powder diffraction (XRPD) analysis was performed in transmission mode at room temperature using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel 3D Medipix-3 detector (Malvern PANalytical Inc., Westborough, Massachusetts). The X-ray generator was operated with copper emission (1.54060 Å) at a voltage of 45 kV and a current of 40 mA. The powder sample was placed on a 96-well sample holder with Mylar film and filled into the instrument. The sample was scanned over a range of approximately 3° to approximately 40°²θ with a step size of 0.0131303° and a time of 49 seconds per step.

[0236] Abbreviation Unless otherwise stated, or as the context indicates, the following abbreviations should be understood to have the following meanings: [Table 3-1] [Table 3-2]

[0237] Example 1 rel-4-((2S,3R,4R,5S)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide (1) and rel-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide (2) [ka] Step 1: Et3N (7.7 mL, 55.2 mmol) was added to a stirred solution of ethyl 2-diazo-3-oxopentanoate (6.69 g, 39.3 mmol) in DCM (80 mL) under nitrogen at 0°C. Trimethylsilyl trifluoromethanesulfonate (8.5 mL, 47.0 mmol) was added dropwise over 5 minutes, and the mixture was stirred at 0°C for a further 30 minutes. The reaction mixture was diluted with pentane (100 mL), the layers were separated, and the organic phase was washed with diluted sodium bicarbonate aqueous solution (100 mL), followed by brine (100 mL). The organic layer was dried in (MgSO4) and concentrated under vacuum to obtain ethyl (Z)-2-diazo-3-trimethylsilyloxypent-3-enoate (9.4 g, 99%) as a red oil. 1 ¹H NMR (500MHz, chloroform-d) δ 5.33 (q, J=7.0Hz, 1H), 4.25 (q, J=7.1Hz, 2H), 1.67 (d, J=7.0Hz, 3H), 1.29 (t, J=7.1Hz, 3H), 0.22 (s, 9H) ppm.

[0238] Step 2: To a solution of 1,1,1-trifluoropropan-2-one (8 mL, 89.4 mmol) in 80 mL of DCM, stirred at -78°C, TiCl4 (1 M in DCM, 70 mL, 70.00 mmol) was added via a cannula. To the resulting solution, a solution of (Z)-2-diazo-3-trimethylsilyloxypent-3-enoate ethyl (31.3% w / w, 36.1 g, 46.6 mmol) in 40 mL of DCM was added dropwise over 15 minutes. After 100 minutes, the reaction mixture was carefully quenched with water, the temperature was slowly increased, and then extracted with DCM. The combined organic layers were dried (MgSO4), filtered, and concentrated under vacuum. Purification by flash chromatography (330 g SiO2, 0-20% ethyl rac-(4R,5S)-2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxohexanoate ethyl (8.82 g, 67%) was obtained and stored as a toluene solution. 1 H NMR(500MHz,chloroform-d)δ 4.33(q,J=7.1Hz,2H),4.14(q,J=7.0Hz,1H),3.98(s,1H),1.43(q,J=1.2Hz,3H),1.35(t,J=7.1Hz,3H),1.31(dq,J=7.0,1.4Hz,3H)ppm.ESI-MS m / z Calculated value 282.08273, actual value 283.1 (M+1) + , 281.0 (M-1) - ;Retention time: 0.76 minutes.

[0239] Step 3: A solution of dirhodium tetraacetate (245 mg, 0.55 mmol) in benzene (32 mL) was heated under reflux for 10 minutes. Then, a solution of rac-(4R,5S)-2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxohexanoate ethyl (10 g, 35.4 mmol) in benzene (13 mL) was slowly added via an addition funnel under reflux for 60 minutes. The mixture was then concentrated under vacuum to obtain rac-(4R,5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate ethyl (9.0 g, 100%) as a green residue containing residual catalyst and as a mixture of epimers adjacent to the ester. This material was used without further purification. 1 ¹H NMR (500MHz, chloroform-d) δ 4.83-4.57 (m, 1H), 4.38-4.16 (m, 2H), 2.60 (dddd, J=9.3, 8.2, 5.6, 1.4Hz, 1H), 1.73-1.63 (m, 3H), 1.30 (t, J=7.1Hz, 3H), 1.24 (ddq, J=6.4, 4.1, 1.9Hz, 3H) ppm.

[0240] Step 4: DIPEA (29.680 g, 40 mL, 229.64 mmol) was added to a stirred solution of ethyl rac-(4R,5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (48 g, 188.83 mmol) in 400 mL of DCM at -78°C. A solution of trifluoromethylsulfonyl trifluoromethanesulfonate (53.440 g, 32 mL, 189.41 mmol) in 200 mL of DCM was added to the reaction mixture over 1 hour at the same temperature. The reaction mixture was stirred at 0°C for 30 minutes and then quenched with 100 mL of saturated NaHCO3 aqueous solution. The organic layer was separated, and the aqueous layer was extracted with 160 mL of DCM. The combined organic layers were dried over MgSO4 and concentrated under vacuum to obtain rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate ethyl (71 g, 97%). 1¹H NMR (400 MHz, chloroform-d) δ 4.38-4.32 (m, 2H), 3.29-3.23 (m, 1H), 1.64 (s, 3H), 1.37-1.33 (m, 6H) ppm.

[0241] Step 5: To a stirred solution of rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate ethyl (26 g, 67.311 mmol) in toluene (130.00 mL), (3,4-difluoro-2-methoxyphenyl)boronic acid (14 g, 74.5 mmol), followed by K3PO4 (100 mL, 200.00 mmol of 2 M), was added under an argon atmosphere. After degassing the reaction mixture, tetrakis(triphenylphosphine)palladium(0) (4 g, 3.46 mmol) was added. After further degassing, the reaction mixture was heated at 100°C for 2 hours. The reaction mixture was diluted with water, and the aqueous layer was extracted with ELISA (2 × 100 mL). The combined organic layers were concentrated under vacuum. Purification by flash chromatography (SiO2, heptane with 0-10% ethyl ammonium compounds) yielded a 6:1 diastereomer mixture of rac-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate ethyl (24.4 g, 93%), and the major isomer is considered to be rac-(4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate ethyl. Major isomer: 1 H NMR(400MHz,chloroform-d)δ 6.88-6.79(m,2H),4.17-4.09(m,2H),3.90(s,3H),3.46(q,J=7.4Hz,1H), 1.67(s,3H),1.12(t,J=7.4Hz,3H),1.06(dd,J=5.4,2.7Hz,3H)ppm. Trace amount of isomer 1¹H NMR (400MHz, Chromo-d) δ 6.88–6.79 (m, 2H), 4.17–4.09 (m, 2H), 3.88 (s, 3H), 3.76–3.71 (m, 1H), 1.51 (s, 3H), 1.12 (t, J = 7.4 Hz, 3H), 0.99 (dd, J = 5.4, 2.7 Hz, 3H) ppm. ESI-MS m / z Calculated value 380.1047, Measured value 381.02 (M+1) + Duration: 2.09 minutes.

[0242] ステップ6: To an ice-cold solution of rac-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate ethyl (110 g, 243.0 mmol) in 360 mL of DCM at 0°C, BBr3 (1 M, 370.0 mmol) was added dropwise. Upon completion, the mixture was quenched by adding water, and then aqueous sodium bicarbonate solution. The aqueous layer was extracted with DCM, the combined organic layers were dried over MgSO4, and concentrated under vacuum. The residue was dissolved in 430 mL of DCM at ambient temperature, TFA (40 mL, 519.2 mmol) was added, and the reaction mixture was heated to 45°C. Upon completion, the mixture was quenched by adding aqueous sodium bicarbonate solution, the aqueous layer was extracted with DCM, dried over MgSO4, and concentrated under vacuum to obtain the desired product as a 5:1 mixture of diastereomers. Recrystallization was performed by solubilizing the crude product in the smallest possible amount of DCM and adding a layer of heptane on top of this solution (liquid-liquid diffusion). After about 1 hour, 56.5 g (dr97:3 syn:anti) was obtained from the first and second crystallizations, and an additional 4.6 g (dr96:4 syn:anti) was obtained from the third crystallization. Combining the first to third recrystallization batches, rac-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-flu[2,3-c]chromen-4-one (61 g, 78%) was obtained, and the major isomer is considered to be rac-(1S,2R)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-flu[2,3-c]chromen-4-one. ESI-MS m / z calculated value: 320.04718, measured value: 321.5 (M+1) + , 319.6 (M-1) - ;Retention time: 3.17 minutes.

[0243] Step 7: Rac-(1S,2R)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-flu[2,3-c]chromen-4-one (30 g, 93.69 mmol) was dissolved in SiO2 (400 mL) and stirred with activated carbon (6 g, 499.6 mmol) (0.2 g / g substrate) at ambient temperature for 4 hours and 30 minutes. The mixture was filtered through a Celite pad and washed with SiO2. The filtrate was concentrated under vacuum to obtain a white solid. The white solid was suspended in MeOH (600 mL) and added to a MeOH (150 mL) suspension of Pd(OH)2 (13.62 g, 19.40 mmol of 20% w / w) in a 2.25 L Parr bottle. The resulting mixture was shaken overnight in a Parr hydrogenator under a hydrogen pressure of 60 psi. The suspension was filtered through Celite under a nitrogen atmosphere, rinsed with MeOH, and then with ELISA. The resulting filtrate was concentrated under vacuum to obtain rac-(2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate methyl (32.75 g, 99%). 1 H NMR(400MHz, methanol-d4)δ 7.05(ddq,J=9.4,5.9,1.9Hz,1H),6.57(ddd,J=10.0,9.0,7.6Hz,1H),5.01(d,J=6.0Hz,1H),4.34(dd,J=8. 4,6.0Hz,1H),3.49(s,3H),3.01-2.86(m,1H),1.50(q,J=1.2Hz,3H),0.89(dq,J=7.6,1.9Hz,3H)ppm.ESI-MS m / z calculated value 354.08905, measured value 353.3(M-1) - ;Retention time: 0.81 minutes.

[0244] Step 8: A solution of rac-(2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate methyl (60.8 g, 171.6 mmol) in THF (620 mL) was cooled to 1°C. Potassium tert-butoxide (65.0472 g, 579.7 mmol) was added over 10 minutes while maintaining the internal temperature below 10°C. The mixture was stirred at 0°C for a further 5 minutes, and then the mixture was slightly warmed. When the temperature reached 13°C, the reaction mixture was cooled again in an ice bath, and then 2 M HCl (365 mL, pH 1) was added, maintaining the internal temperature below 15°C. Water (300 mL) was added, the layers were separated, and the aqueous layer was extracted with ELISA (110 mL). The combined organic extracts were washed with brine (300 mL), dried over MgSO4, filtered, and concentrated under vacuum to obtain rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (58.22 g, 100%). 1 H NMR(400MHz, methanol-d4)δ 7.00(ddd,J=8.4,5.6,2.3Hz,1H),6.69(ddd,J=10.1,8.8,7.5Hz,1H),4.98(d,J=10.5Hz,1H),4.18(dd, ESI-MS m / z calculated value 340.0734, measured value 339.0(M-1) - ;Retention time: 0.47 minutes.

[0245] Steps 9 and 10: 1-Bromo-2-methoxyethane (1.4 mL, 14.90 mmol) was added dropwise to a suspension of rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1 g, 2.939 mmol) and cesium carbonate (4.8 g, 14.73 mmol) in acetonitrile (50 mL). The reaction mixture was stirred at 70°C for 24 hours, filtered, and concentrated under vacuum to obtain 2-methoxyethyl rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate, which was used in the next step without further purification. 1 H NMR(400MHz,chloroform-d)δ 7.04-6.76(m,2H),5.06-4.87(m,1H),4.46-4.15(m,5H),3.73-3.61(m,3H),3.52-3.43(m,2H),3. 42(s,3H),3.27(s,3H),2.85(p,J=7.5Hz,1H),1.65(s,1H),0.76(dp,J=6.9,2.2Hz,4H)ppm.ESI-MS m / z calculated value 456.15714, measured value 455.1 (M-1) - ;Holding time: 1.02 minutes.

[0246] A 2M LiOH solution (1.5 mL, 3.00 mmol) was added to a solution of 2-methoxyethyl rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate in ethanol (30 mL). The mixture was stirred overnight at ambient temperature. The reaction mixture was acidified by adding 3M HCl in MeOH (1 mL). The mixture was then filtered, and the mother liquor was concentrated under vacuum to obtain rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1.1 g, 94%). ESI-MS m / z calculated value: 398.11526, measured value: 399.1 (M+1) + , 397.1 (M-1) - ;Retention time: 0.61 minutes.

[0247] Steps 11, 12, and 13: Oxalyl chloride (285 μL, 3.27 mmol) and DMF (5 μL, 0.065 mmol) were successively added to a solution of rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (260 mg, 0.65 mmol) in DCM (6.5 mL). The mixture was stirred at ambient temperature for 90 minutes. The mixture was then concentrated under vacuum. The residue was diluted with DCM (3 mL) and added dropwise over 5 minutes at ambient temperature to a stirred solution of methyl 4-aminopicolinate (150 mg, 0.99 mmol), DMAP (4.63 mg, 0.038 mmol), and Et3N (280 μL, 2.01 mmol) in DCM (5 mL). The reaction mixture was stirred overnight. Next, the mixture was concentrated under vacuum. Purification by flash chromatography (12 g SiO2, methanol) yielded rac-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)methyl picolinate (150 mg), which was used directly in the following reaction.

[0248] rac-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)methyl picolinate (150 mg) was dissolved in methanolic ammonia (7 M, 5 mL, 35.00 mmol) and stirred at ambient temperature for 24 hours. The reaction mixture was then concentrated under vacuum. Purification by reverse-phase preparative chromatography yielded rac-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide.

[0249] The enantiomer of rac-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide was separated by chiral SFC using a Berger Instruments Minigram SFC instrument with a Daicel Corporation Chiralpak AS-H column, 5 μm particle size, 25 cm × 10 mm (mobile phase: 25% methanol:acetonitrile (1:1 ratio, supplemented with 0.2% DMPA), 75% CO2, system pressure: 100 bar).

[0250] First eluted isomer (rt=4.93 min): rel-4-((2S,3R,4R,5S)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide (1, 18.2 mg, 10%). 1 ¹H NMR (400MHz, chloroform-d)δ 8.90 (s, 1H), 8.46 (d, J=5.5Hz, 1H), 8.20 (dd, J=5.5, 2.2Hz, 1H), 8.05-7.95 (m, 1H), 7.88 (s, 1H), 7.13 (ddd, J=8.1, 5.5, 2.1Hz, 1H), 6.95 (td, J=9.2, 7.5Hz, 1H), 5.82 ( d,J=4.2Hz,1H),5.04(d,J=11.5Hz,1H),4.41-4.17(m,3H),3.71-3.55(m,2H),3.30 (s,3H),2.89(p,J=7.5Hz,1H),1.73(s,3H),0.81(dt,J=7.4,2.4Hz,3H)ppm.ESI-MS m / z calculated value 517.16364, measured value 518.4 (M+1) + , 516.5 (M-1) - ;Holding time: 3.25 minutes.

[0251] Second eluted isomer (rt=5.37 min): rel-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide (2, 18.6 mg, 11%). 1 ¹H NMR (400MHz, chloroform-d)δ 8.88(s,1H),8.46(d,J=5.6Hz,1H),8.19(dd,J=5.6,2.2Hz,1H),8.01(dd,J=2.2,0.6Hz,1H),7.86(d,J=4.6Hz,1H),7.13(ddd,J=8.1,5.5,2.1Hz,1H),6.95(td,J=9.3,7.5Hz,1 H),5.82(d,J=4.2Hz,1H),5.04(d,J=11.5Hz,1H),4.41-4.17(m,3H),3.71-3.55(m,2H), 3.30(s,3H),2.89(p,J=7.5Hz,1H),1.73(s,3H),0.81(dt,J=7.6,2.3Hz,3H)ppm.ESI-MS m / z calculated value 517.16364, measured value 518.5(M+1) + , 516.5 (M-1) - ;Holding time: 3.20 minutes.

[0252] The following compounds were prepared using the method described in Example 1, except that Suzuki coupling step 5 was carried out at 50°C for 30 minutes using PdCl2(PPh3)2 as a catalyst, (4-fluoro-2-methoxy-3-methylphenyl)boronic acid (intermediate G) as the boronic acid, NaHCO3 as the base, and a mixture of water and 1,4-dioxane as the solvent. In step 9, K2CO3 was used as the base instead of Cs2CO3. In step 10, MeOH was used as the solvent instead of EtOH. The conditions used for amide coupling step 11 were those described in step 4 of Example 6, using methyl 4-aminopyrimidine-2-carboxylate as the coupling partner. In Step 13, the enantiomers were separated by chiral SFC using a Berger Instruments Minigram SFC instrument with a Daicel Corporation Chiralcel OD-H column, 5 mm particle size, 25 cm × 10 mm (mobile phase: 30% methanol (supplemented with 20 mM NH3), 70% CO2, system pressure: 100 bar): [Table 4]

[0253] Example 2 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-hydroxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide(5) [ka] Step 1: rac-(1S,2R)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-flu[2,3-c]chromen-4-one (Example 1, product of Step 6, 1348 g, 4.366 mol) was separated by chiral SFC using a Berger Instruments MultiGram III SFC instrument with a Regis Technologies (R,R)-Whelk-O1 column, 5 μm particle size, 15 cm × 3 cm (mobile phase: 10% isopropanol, 90% CO2, flow rate: 5 mL / min, system pressure: 100 bar, column temperature: 35 °C) to obtain the following:

[0254] The first eluted isomer (rt=1.85 min): (1R,2S)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-flu[2,3-c]chromen-4-one). 1 H NMR(400MHz,DMSO-d6)δ 7.57(ddd,J=9.0,5.5,2.0Hz,1H),7.51(ddd,J=10.3,9.0,7.0Hz,1H),4.03(q,J=7.2Hz,1H),1.65(s,3H),1.45(dt,J=6.9,2.2Hz,3H)ppm.ESI-MS m / z Calculated value 320.04718, actual value 321.3 (M+1) + , 319.4 (M-1) - ;Retention time: 3.19 minutes.

[0255] Second eluted isomer (rt=2.38 min): (1S,2R)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-flu[2,3-c]chromen-4-one (366.99 g, 26%). 1 H NMR(400MHz,DMSO-d6)δ 7.57(ddd,J=9.0,5.5,2.0Hz,1H),7.50(ddd,J=10.3,9.0,7.0Hz,1H),4.03(q,J=7.2Hz,1H),1.65(s,3H),1.45(dt,J=6.9,2.2Hz,3H)ppm.ESI-MS m / z Calculated value 320.04518, actual value 321.4 (M+1) +, 319.4 (M-1) - ;Holding time: 3.20 minutes.

[0256] Step 2: A solution of (1S,2R)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-flu[2,3-c]chromen-4-one (0.89 kg, 2.78 mol) and 20% palladium-carbon hydroxide (50% wet, 0.39 kg, 0.278 mol) in MeOH (12 L) was stirred overnight under hydrogen at a pressure of 40 psi. After the overnight reaction, it was observed that the reaction temperature rose to 37°C, and the mixture was cooled to 24°C. Hydrogenation was continued for a total of 48 hours. The mixture was filtered through Celite, washed with MeOH (20 L), and the filtrate was concentrated under vacuum. The residue was dissolved in toluene (4 L), concentrated under vacuum, and this process was repeated. The residue was dried overnight at 40°C under vacuum to obtain methyl(2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.0 kg, 100%) with 91% purity as a beige solid. 1 H NMR(400MHz,DMSO-d6)10.20(brs,1H),6.94(br t,J=7.4Hz,1H),6.79-6.69(m,1H),5.10(d,J=6.0Hz,1H),4.20(dd,J=6.1,8.2Hz,1H),3.43(s,3H),2.94(quin,J=7.7Hz,1H),1.46(s,3H),0.77(br d,J=6.8Hz,3H)ppm.

[0257] Step 3: Potassium carbonate (2.0 kg, 14.4 mol) and iodomethane (800 mL, 12.8 mol) were sequentially added to a solution of methyl (2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.0 kg, 2.82 mol) in acetonitrile (10 L) under nitrogen while stirring at ambient temperature. After stirring overnight, additional iodomethane (120 mL, 2 mmol) was added. After stirring again overnight, additional iodomethane (60 mL, 0.85 mmol) was added, and the mixture was stirred for a further 3 days. The reaction mixture was diluted with MTBE (30 L), treated with Celite (1 kg), and filtered through a Celite (1 kg) bed while washing with MTBE (10 L). The filtrate was filtered a second time through Celite (1 kg), washed with MTBE (4 L), and concentrated in vacuum. The residue was dissolved in toluene (4 L), concentrated in vacuum, and this process was repeated. The residue was dried overnight at 40°C under vacuum to obtain methyl (2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (0.99 kg, 95% purity at 90%) as a brown solid. 1 H NMR(400MHz,DMSO-d6)7.14-7.00(m,2H),5.14(d,J=6.0Hz,1H),4.15(dd,J=6.2, 8.4Hz,1H),3.88(d,J=1.7Hz,3H),2.97(quin,J=7.8Hz,1H),1.48(s,3H),0.72(br d,J=6.6Hz,3H)ppm.

[0258] Steps 4 and 5: Sodium methoxide (25% in methanol, 65 mL, 0.28 mol) was added to a solution of methyl (2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (0.98 kg, 2.66 mol) in THF (10 L), and the mixture was stirred under nitrogen at ambient temperature. After 5 hours, MeOH (1 L), water (1 L), and lithium hydroxide monohydrate (0.168 kg, 4.0 mol) were added sequentially, and the mixture was stirred overnight. The reaction mixture was poured into 1 M HCl (4.4 L, 4.4 mol) and then extracted with MTBE (20 L). The aqueous layer was further extracted with MTBE (2 × 5 L), the combined organic layers were washed with brine (2 L), dried over Na2SO4, filtered, and then treated with activated carbon (50 g, 5% w / w) with stirring for 1 hour. The mixture was filtered through Celite while washing with MTBE (2 × 4 L), and the filtrate was concentrated under vacuum. The residue was dissolved in toluene (4 L), concentrated under vacuum, then dissolved in MTBE (4 L), and concentrated again under vacuum to obtain (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1.06 kg at 77.7% purity) as an amber-colored oil, which was used without further purification.

[0259] Step 6: Crude (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (2.09 kg, 4.54 mol at 77% purity) was dissolved in MTBE (25 L) in a 100 L Chemglass reactor and then stirred at 84 rpm at ambient temperature. A mixture of (R)-1-phenylethylamine (0.704 kg, 5.81 mol) and MTBE (2 L), followed by the addition of MTBE, was added to the reactor to obtain a total volume of 30 L. After 2 hours, an additional MTBE (2 L) was added to the reaction mixture. After a total of 3.5 hours, the mixture was filtered while washing with MTBE (2 L). The reactor was rinsed with MTBE (4 L), and the solid was rinsed using it, which was then compressed and dried on a Buchner funnel for 2 hours. The solid product cake was loosened and then dried overnight in a Buchner funnel under a nitrogen stream and vacuum. The isolated solid was dried for 24 hours in a convection oven at 40°C to obtain (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (R)-1-phenylethane-1-amine salt (1.86 kg at 95.7% purity, 74% in 3 steps) as a grayish-white solid. 1 H NMR,400MHz,DMSO-d6)8.34(br s,2H),7.46-7.41(m,2H),7.36-7.27(m,3H),7.16-7.11(m,1H),7.10-7.03(m,1H),4.58(d,J=9.9Hz,1H),4.23(q,J=6.7Hz,1H),3.9 9(dd,J=7.8,9.8Hz,1H),3.90(d,J=2.0Hz,3H),2.60(quin,J=7.5Hz,1H),1.50(s,3H),1.40(d,J=6.7Hz,3H),0.71-0.59(m,3H)ppm.

[0260] Step 7: A suspension of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1R)-1-phenylethaneamine salt (10.6 g, 22.29 mmol) in MTBE (250 mL) was mixed with HCl (200 mL, 2 M, 400.0 mmol). The layers were separated, the organic layer was washed with water (200 mL), dried over MgSO4, filtered, and concentrated under vacuum to obtain (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (8.4 g, 99%) as oil. 1 H NMR(400MHz,chloroform-d)δ 6.96(ddd,J=7.9,5.6,2.0Hz,1H),6.88(td,J=9.2,7.3Hz,1H),4.96(d,J=10.5Hz,1H),4.15(dd,J=10.5,8.0 Hz,1H),4.02(d,J=2.8Hz,3H),2.74(p,J=7.6Hz,1H),1.64(t,J=1.2Hz,3H),0.79(dq,J=7.4,2.3Hz,3H)ppm.

[0261] Step 8: Oxalyl chloride (2.2 mL, 25.22 mmol) was added to a stirred solution of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (8 g, 16.83 mmol) and DMF (13 μL, 0.1679 mmol) in DCM (60 mL). The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated under vacuum. The residue dissolved in DCM (40 mL) was added at 0°C to a solution of methyl 4-aminopyridine-2-carboxylate (2.8 g, 18.40 mmol) and triethylamine (2.8 mL, 20.09 mmol). The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with a mixture of water (48 mL) and 1 M citric acid (24 mL, 24.00 mmol). The layers were separated, the organic phase was dried with 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 picolinate (8.38 g, 90%). 1 H NMR(400MHz,DMSO-d6)δ 10.77(s,1H),8.57(dd,J=5.4,0.6Hz,1H),8.36(dd,J=2.2,0.7Hz,1H),7.85(dd,J=5.5,2.2Hz,1H),7.25-7.07(m,2H),5.11(d,J=10.2Hz ,1H),4.25(dd,J=10.2,7.6Hz,1H),3.94(d,J=2.1Hz,3H),3.86(s,3H),2.77(p,J=7.5Hz,1H),1.60(s,3H),0.78-0.64(m,3H)ppm.ESI-MS m / z Calculated value: 488.13705, Measured value: 489.6 (M+1) + , 487.5 (M-1) - ;Retention time: 3.38 minutes.

[0262] Step 9: A solution of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)methyl picolinate (7.1 g, 14.54 mmol) in methanolic ammonia (7 M, 490.0 mmol) was stirred at room temperature for 19 hours. The mixture was concentrated under vacuum to obtain a pale orange solid. SiO (30 mL) was added, and the resulting slurry was heated to 60°C. The solution was cooled to 50°C, and heptane (17 mL) was slowly added through an addition funnel. At the end of the addition, the turbid solution was allowed to stand. The pale orange solid was filtered to obtain the first yield (5.091 g). The filtrate was concentrated to one-third of its volume, and the orange precipitate was filtered off to obtain the second yield (1.14 g). The harvested materials were combined to obtain 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide (6.23 g, 91%). 1 H NMR(400MHz,DMSO-d6)δ 10.72(s,1H),8.50(d,J=5.6Hz,1H),8.29(d,J=2.1Hz,1H),8.06(d,J=2.8H z,1H),7.84(dd,J=5.5,2.2Hz,1H),7.62(d,J=2.8Hz,1H),7.24-7.11(m,2H) ,5.11(d,J=10.2Hz,1H),4.26(dd,J=10.2,7.7Hz,1H),3.95(d,J=2.2Hz,3H) ,2.78(p,J=7.5Hz,1H),1.62(s,3H),0.73(dt,J=7.3,2.4Hz,3H)ppm.ESI-MS m / z Calculated value: 473.1374, Measured value: 474.1 (M+1) + ;Retention time: 0.92 minutes.

[0263] Step 10: BBr3 (830.0 μL, 1 M in DCM, 0.83 mmol) was added at 0°C to a stirred solution of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide (280 mg, 0.59 mmol) in DCM (6 mL). The reaction mixture was slowly warmed to ambient temperature and stirred for 24 hours. The mixture was cooled to 0°C, and BBr3 (800 μL, 1 M in DCM, 0.80 mmol) was added. The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was quenched by adding water and saturated sodium bicarbonate aqueous solution. After stirring the mixture for 30 minutes, the layers were separated. The aqueous phase was extracted with DCM, the combined organic layers were dried, filtered, and concentrated under vacuum. Purification by flash chromatography (12 g SiO2, 0-70% ethyl ammonium in heptane) yielded 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide (162 mg, 60%). 1 H NMR(500MHz,DMSO-d6)δ 10.73(s,1H),10.46(s,1H),8.50(d,J=5.6Hz,1H),8.27(s,1H),8.06(s,1H),7.86-7.82(m,1H),7.61(s,1H),7.06-7.00(m,1 H),6.89-6.83(m,1H),5.15-5.08(m,1H),4.29-4.22(m,1H),2.86-2.80(m,1H),1.61(s,3H),0.72(d,J=7.2Hz,3H)ppm.ESI-MS m / z calculated value 459.12173, measured value 460.7(M+1) + , 458.8 (M-1) - ;Retention time: 2.59 minutes.

[0264] Steps 11 and 12: (2-bromoethoxy)(tert-butyl)dimethylsilane (20 μL, 0.093 mmol) was added dropwise to a suspension of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide (20 mg, 0.045 mmol) and cesium carbonate (50 mg, 0.15 mmol) in acetonitrile (6 mL). The reaction mixture was heated at 61 °C overnight. The mixture was concentrated under vacuum. TBAF (1 mL, 1 M in THF) was added to the solution of the residue dissolved in THF. The mixture was stirred for 1 hour, and then concentrated under vacuum. Purification by reverse-phase preparative chromatography yielded 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-hydroxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide (5, 1.4 mg, 6%). 1 ¹H NMR (400MHz, chloroform-d)δ 8.86(s,1H),8.37(d,J=5.5Hz,1H),8.04(dd,J=5.5,2.3Hz,1H),7.90(td,J=2.1,0.6Hz,1H),7.03(ddd,J=8.1,5.5,2.1Hz,1H),6.86(td,J=9.2,7.5Hz,1H),4.96(d,J=1 0.9Hz,1H),4.34(dd,J=10.9,8.1Hz,1H),4.29-4.05(m,1H),3.80(s,2H),2.75(p,J =7.7Hz,1H),2.34(s,1H),1.66-1.55(m,3H),0.73(dt,J=7.6,2.3Hz,3H)ppm.ESI-MS m / z calculated value 503.14795, measured value 504.1(M+1) + , 502.1 (M-1) - ;Retention time: 0.81 minutes.

[0265] The following compounds were prepared using the method described in Example 2, except that step 11 was carried out using 5-(chloromethyl)oxazole as the alkylating agent and K2CO3 instead of Cs2CO3 as the base. Step 12 was omitted: [Table 5]

[0266] Compound 6 was analyzed by powder X-ray diffraction and determined to be amorphous (see Figure 1).

[0267] The following compounds were prepared using the method described in Example 2, except that step 11 was carried out at 80°C for 6 hours using (1s,3s)-3-(bromomethyl)-1-(trifluoromethyl)cyclobutan-1-ol as the alkylating agent, K2CO3 as the base, and DMF as the solvent. Step 12 was omitted: [Table 6]

[0268] Compound 7 was analyzed by powder X-ray diffraction and determined to be amorphous (see Figure 2).

[0269] The following compounds were prepared using the method described in Example 2, except that a different amine was used instead of methyl 4-aminopyridine-2-carboxylate in step 8. Steps 9-12 were omitted. [Table 7-1] [Table 7-2]

[0270] The following compounds were prepared using the method described in Example 2, except that the conditions used in amide coupling step 8 were the same as those described in step 4 of Example 6, and (2-aminopyridine-4-yl)(4-methylpiperazine-1-yl)methanone was used as the coupling partner in chloroform as the solvent. Steps 9-12 were omitted: [Table 8]

[0271] The following compounds were prepared using the method described in Example 2, except that a different amine was used in amide coupling step 8. Steps 9-12 were omitted. The final Boc deprotection step was carried out using excess TFA in DCM over 2 hours at ambient temperature under conditions well known in the art: [Table 9]

[0272] The following compounds were prepared using the method described in Example 2, except that the conditions used in amide coupling step 8 were the same as those described in step 4 of Example 6, a different amine was used as the coupling partner, and the reaction was carried out at 80°C for 48 hours using acetonitrile as the solvent. Steps 9-12 were omitted. The final Boc deprotection step was carried out at ambient temperature under conditions well known in the art, using excess TFA in DCM: [Table 10]

[0273] The following compounds were prepared using the same method as described in Example 2, except that the conditions used in amide coupling step 8 were the same as those described in step 4 of Example 6, with tert-butyl 4-(6-aminopyrimidine-4-carbonyl)piperazine-1-carboxylate as the coupling partner and the reaction carried out at 80°C for 48 hours using acetonitrile as the solvent. Steps 9-12 were omitted. The product of step 8 was deprotected by Boc using excess TFA in DCM over 2 hours at ambient temperature under conditions well known in the art, and then N-methylated by reductive amination over 90 minutes at ambient temperature using formaldehyde, sodium triacetoxyborohydride and acetic acid in methanol: [Table 11]

[0274] The following compounds were prepared using the same method as described in Example 2, except that in step 8, ammonium hydroxide was used instead of methyl 6-aminopyridine-2-carboxylate as the amide coupling partner. The product of step 8 was reacted with methyl 4-chloro-5-trimethylsilylpyridine-2-carboxylate using palladium-catalyzed amination conditions well known in the art (40 mol% Pd(OAc)2, 80 mol% Xantphos, cesium carbonate, dioxane, 100°C, 11 hours), and subsequently esterified using the conditions described in step 9. Steps 10-12 were omitted: [Table 12]

[0275] The following compounds can be prepared using the same method as in Example 2, except that rac-(1S,2R)-6-fluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-flu[2,3-c]chromen-4-one is used as the starting material instead of rac-(1S,2R)-6-fluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-flu[2,3-c]chromen-4-one. Steps 10-12 are omitted. Purification is carried out by recrystallization to obtain compound 303. [Table 13]

[0276] The following compounds can be prepared using the same method as in Example 2, except that rac-(1S,2R)-7-fluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-flu[2,3-c]chromen-4-one is used as the starting material instead of rac-(1S,2R)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-flu[2,3-c]chromen-4-one. Steps 10-12 are omitted. Purification is carried out by recrystallization to obtain compound 304. [Table 14]

[0277] Example 3 rel-4-((6S,7R)-7-(4-fluoro-2-methoxy-3-methylphenyl)-2,5-dioxaspiro[3.4]octane-6-carboxamide)picolinamide (24) and rel-4-((6R,7S)-7-(4-fluoro-2-methoxy-3-methylphenyl)-2,5-dioxaspiro[3.4]octane-6-carboxamide)picolinamide (25) [ka] Step 1: TiCl4 (1.2 mL, 1.20 mmol of 1 M) and Et3N (170 μL, 1.22 mmol) were added dropwise to a stirred solution of ethyl 2-diazo-3-oxobutanoate (150 μL, 1.09 mmol) in DCM (6 mL) at -78°C. After stirring the reaction mixture for 1 hour, a solution of Ti(OiPr)4 (325 μL, 1.10 mmol) and oxetane-3-one (70 μL, 1.09 mmol) in DCM (1.5 mL) was added via cannula. The reaction mixture was stirred for a further 5 hours. The mixture was quenched by adding saturated NH4Cl aqueous solution. The aqueous layer was separated and extracted with DCM. The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. Purification by flash chromatography (24 g SiO2, 0-70% ethyl ammonium in heptane) yielded ethyl 2-diazo-4-(1-hydroxycyclobutyl)-3-oxobutanoate (156 mg, 63%). 1 ¹H NMR (400MHz, chloroform-d) δ 4.73-4.65 (m, 2H), 4.47 (d, J=7.4Hz, 2H), 4.33 (q, J=7.1Hz, 2H), 3.80 (s, 1H), 3.49 (s, 2H), 1.35 (t, J=7.1Hz, 3H) ppm.

[0278] Step 2: A suspension of Rh2(OAc)4 (9.5 mg, 0.021 mmol) in toluene (4 mL) was heated at 100°C for 10 minutes. A solution of 2-diazo-4-(1-hydroxycyclobutyl)-3-oxobutanoate ethyl (250 mg, 1.10 mmol) in toluene (3 mL) was added dropwise, and the reaction mixture was stirred for 45 minutes. The mixture was cooled to ambient temperature and concentrated under vacuum to obtain rac-7-oxo-2,5-dioxaspiro[3.4]octane-6-carboxylate ethyl (219 mg), which was used in the next step without further purification. 1H NMR(500MHz,chloroform-d)δ 5.14(dt,J=7.3,0.7Hz,1H),4.99-4.92(m,1H),4.68(dt,J=7.2,1.1Hz,1H),4.61(dt,J=6.6,0.9Hz,1H),4.60 (s,1H),4.24(qd,J=7.1,4.4Hz,2H),3.05(d,J=19.2Hz,1H),2.90(d,J=18.9Hz,1H),1.30(t,J=7.1Hz,3H)ppm.

[0279] Step 3: Trifluoromethylsulfonyl trifluoromethanesulfonate (1.7 mL of 1 M, 1.70 mmol) was added dropwise at -78°C to a stirred solution of ethyl 7-oxo-2,5-dioxaspiro[3.4]octane-6-carboxylate (263 mg, 1.31 mmol) and DIPEA (700 μL, 4.019 mmol) in 12 mL of DCM. The reaction mixture was stirred at -78°C for 4 hours. The reaction was quenched by adding saturated aqueous NH4Cl solution. The aqueous layer was separated and extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to obtain ethyl 7-(((trifluoromethyl)sulfonyl)oxy)-2,5-dioxaspiro[3.4]octa-6-ene-6-carboxylate, which was used without further purification. 1 ¹H NMR (400MHz, chloroform-d) δ 5.03-4.95 (m, 2H), 4.67-4.59 (m, 2H), 4.36 (q, J=7.2Hz, 2H), 3.43 (s, 2H), 1.36 (t, J=7.1Hz, 3H) ppm.

[0280] Step 4: 7-(((trifluoromethyl)sulfonyl)oxy)-2,5-dioxaspiro[3.4]octa-6-ene-6-carboxylate ethyl (436.6 mg, 1.31 mmol), (4-fluoro-2-methoxy-3-methylphenyl)boronic acid (intermediate G, 290 mg, 1.58 mmol), Pd(PPh3)4 (90 mg, 0.078 mmol), and Na2CO3 (350 mg, 3.30 mmol) were dissolved in a mixture of toluene (7.5 mL), MeOH (750 μL), and H2O (750 μL). The mixture was degassed and heated at 80°C for 16 hours. The reaction product was cooled to ambient temperature, diluted with ethyl acetate, and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. Purification by flash chromatography (40 g SiO2, 0-30% ethyl ammonium in heptane) yielded 7-(4-fluoro-2-methoxy-3-methylphenyl)-2,5-dioxaspiro[3.4]octa-6-ene-6-carboxylate ethyl (356 mg, 76%) as a pale yellow oil. 1 H NMR(500MHz,chloroform-d)δ 6.98(dd,J=8.6,6.4Hz,1H),6.80(t,J=8.7Hz,1H),5.11-5.06(m,2H),4.70-4.63(m,2H),4.17(q ,J=7.1Hz,2H),3.63(s,3H),3.45(s,2H),2.20(d,J=2.1Hz,3H),1.14(t,J=7.1Hz,3H)ppm.ESI-MS m / z calculated value 322.12164, measured value 323.6(M+1) + ;Holding time: 0.8 minutes.

[0281] Step 5: EtOH (12 mL) was added to a mixture of 7-(4-fluoro-2-methoxy-3-methylphenyl)-2,5-dioxaspiro[3.4]octa-6-ene-6-carboxylate ethyl (356 mg, 1.10 mmol) and Pd / C (110 mg, 0.10 mmol). The reaction mixture was degassed and stirred under hydrogen balloon for 3 days. The reaction mixture was filtered through a Celite pad and washed with MeOH. The mother liquor was concentrated under vacuum to obtain rac-(6S,7S)-7-(4-fluoro-2-methoxy-3-methylphenyl)-2,5-dioxaspiro[3.4]octane-6-carboxylate ethyl (367 mg, 100%) as a white solid. ESI-MS m / z calculated value 324.1373, measured value 325.4 (M+1) + ;Holding time: 1.85 minutes.

[0282] Step 6: Potassium tert-butoxide (1.6 mL, 1.60 mmol, 1 M solution in THF) was added dropwise at 0°C to a stirred solution of rac-(6S,7S)-7-(4-fluoro-2-methoxy-3-methylphenyl)-2,5-dioxaspiro[3.4]octane-6-carboxylic acid ethyl (185 mg, 0.57 mmol) in THF (6.4 mL). After 1 hour, the reaction mixture was diluted with ethyl phosphate. The mixture was then quenched by adding 1 M aqueous HCl. The aqueous layer was separated and extracted with ethyl phosphate. The combined organic phase was dried over MgSO4, filtered, and concentrated under vacuum to obtain rac-(6R,7S)-7-(4-fluoro-2-methoxy-3-methylphenyl)-2,5-dioxaspiro[3.4]octane-6-carboxylic acid (221 mg), which was used in the next step without further purification. ESI-MS m / z calculated value: 296.106, measured value: 297.4 (M+1) + ;Holding time: 0.4 minutes.

[0283] Step 7: 33 mg, 0.22 mmol of methyl 4-aminopyridine-2-carboxylate was added to a stirred solution of rac-(6R,7S)-7-(4-fluoro-2-methoxy-3-methylphenyl)-2,5-dioxaspiro[3.4]octane-6-carboxylic acid (58.5 mg, 0.20 mmol) in 2 mL of MeCN. 55 μL, 0.69 mmol of 1-methylimidazole and 65 mg, 0.2317 mmol of TCFH were successively added to the reaction mixture. The solution was stirred at ambient temperature for 16 hours. 6 mL, 42.00 mmol of methanolic ammonia solution (7 M) was added, and the reaction was stirred at ambient temperature for a further 24 hours. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and concentrated on silica gel under vacuum. Purification by flash chromatography (24 g SiO2, 0-100% ethyl phosphate in heptane) yielded rac-4-((6R,7S)-7-(4-fluoro-2-methoxy-3-methylphenyl)-2,5-dioxaspiro[3,4]octane-6-carboxamide)picolinamide (30 mg, 37%) as a colorless oil. ESI-MS m / z calculated value: 415.15436, measured value: 416.7 (M+1). + , 414.7 (M-1) - ;Holding time: 0.7 minutes.

[0284] Step 8: The enantiomer of rac-4-((6R,7S)-7-(4-fluoro-2-methoxy-3-methylphenyl)-2,5-dioxaspiro[3,4]octane-6-carboxamide)picolinamide was separated by chiral SFC using a Berger Instruments Minigram SFC instrument with a Daicel Corporation Chiralpak AS-H column, 5 μm particle size, 25 cm × 10 mm (mobile phase: 30% methanol (supplemented with 20 mM NH3), 70% CO2, system pressure: 100 bar).

[0285] First eluted isomer (rt=3.09 min): rel-4-((6S,7R)-7-(4-fluoro-2-methoxy-3-methylphenyl)-2,5-dioxaspiro[3.4]octane-6-carboxamide)picolinamide (24, 4.5 mg, 29%). 1 H NMR(500MHz,DMSO-d6)δ 10.48(s,1H),8.48(d,J=5.4Hz,1H),8.29(d,1H),8.05(d,J=2.8Hz,1H),7.81(dd,J=5.5,2.2Hz,1 H),7.60(d,J=2.8Hz,1H),7.24(dd,J=8.7,6.6Hz,1H),6.99(t,J=8.8Hz,1H),4.88(d,J=6.8Hz,1H ),4.77(d,J=6.9Hz,1H),4.60(d,J=6.7Hz,1H),4.59-4.54(m,2H),3.87(q,J=7.6Hz,1H),3.61(s, 3H),2.78(dd,J=12.8,7.6Hz,1H),2.33(dd,J=12.8,8.7Hz,1H),2.12(d,J=2.0Hz,3H)ppm.ESI-MS m / z calculated value 415.15436, measured value 416.3(M+1) + , 414.3 (M-1) - ;Holding time: 2.35 minutes.

[0286] The second eluted isomer (rt=4.08 min): rel-4-((6R,7S)-7-(4-fluoro-2-methoxy-3-methylphenyl)-2,5-dioxaspiro[3.4]octane-6-carboxamide)picolinamide, which required further purification by reverse-phase preparative HPLC (25, 4.5 mg, 29%). ESI-MS m / z calculated value 415.15436, measured value 416.3 (M+1). + , 414.2 (M-1) - ;Holding time: 2.35 minutes.

[0287] Example 4 rel-4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxamide)picolinamide (26) and rel-4-((2S,3R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxamide)picolinamide (27) rel-4-((2R,3S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxamide)picolinamide (28) and rel-4-((2S,3R,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxamide)picolinamide (29) [ka] Step 1: Et3N (9.56 g, 13.3 μL, 93.52 mmol) was added at 0°C to a stirred solution of ethyl 2-diazo-3-oxobutanoate (6 g, 37.66 mmol) in DCM (50 mL). TBSOTf (11.95 g, 10.6 mL, 44.29 mmol) was added very slowly to the reaction mixture and stirred at 0°C for a further 30 minutes. The reaction mixture was washed with 30% NaHCO3 solution (200 mL). The organic layer was separated, washed with water (500 mL), dried over MgSO4, filtered, and concentrated under vacuum to obtain ethyl 3-((tert-butyldimethylsilyl)oxy)-2-diazobuto-3-enoate (10 g, 98%), which was used without purification.

[0288] Step 2: A solution of TiCl4 (9.23 g, 5.4 mL, 48.16 mmol) in DCM (20 mL) was added dropwise to a stirred solution of 1-methoxypropan-2-one (4.36 g, 4.7 mL, 48.04 mmol) in DCM (40 mL) at -78°C. A solution of 3-((tert-butyldimethylsilyl)oxy)-2-diazobuta-3-ethyl (36.982 mmol) in DCM (50 mL) was added dropwise to the reaction mixture at the same temperature. The reaction mixture was stirred at -78°C for 30 minutes, then quenched with water (250 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered, and concentrated under vacuum. Purification by flash chromatography (SiO2) yielded ethyl rac-2-diazo-5-hydroxy-6-methoxy-5-methyl-3-oxohexanoate (7.5 g, 81%) as a pale yellow oil. 1 H NMR(400MHz,chloroform-d)δ 4.28(q,J=7.1Hz,2H),3.79(s,1H),3.37-3.26(m,6H),2.84(d,J=15.6Hz,1H),1.31(t,J=7.1Hz,3H),1.23(s,3H)ppm.ESI-MS m / z calculated value 244.1059, actual value 245.0(M+1) + ;Retention time: 2.71 minutes.

[0289] Step 3: A solution of rac-2-diazo-5-hydroxy-6-methoxy-5-methyl-3-oxohexanoate ethyl (7.5 g, 28.87 mmol) in toluene (230 mL) was added dropwise to a stirred and degassed solution of dirhodium tetraacetate (130 mg, 0.29 mmol) in toluene (70 mL) at 100°C under N2. The reaction mixture was heated to 110°C for 10 minutes and then cooled to ambient temperature. The mixture was filtered through a Celite pad. The filtrate was collected and concentrated under vacuum to obtain rac-5-(methoxymethyl)-5-methyl-3-oxotetrahydrofuran-2-carboxylate ethyl (6.2 g, 99%) as a light brown oil and as a 1:1 mixture of diastereomers. 1H NMR(400MHz,chloroform-d)δ 4.70(s,1H),4.28-4.15(m,2H),3.50(t,J=9.3Hz,1H),3.31(t,J=9.92Hz,1H),3.30(s,3H) )2.67(d,J=13.48Hz,1H),2.35(d,J=17.52Hz,1H),1.39(s,3H),1.27(q,J=7.1Hz,3H)ppm.

[0290] Step 4: A solution of Tf2O (8.97 g, 5.4 mL, 31.46 mmol) in DCM (15 mL) was added dropwise over 7 minutes at -78°C to a stirred solution of rac-5-(methoxymethyl)-5-methyl-3-oxotetrahydrofuran-2-carboxylate ethyl (6.2 g, 28.67 mmol) and DIPEA (4.45 g, 6 mL, 34.45 mmol) in DCM (50 mL). The reaction mixture was stirred at -78°C for 15 minutes, then at 0°C for another 15 minutes. The reaction mixture was quenched by adding saturated NaHCO3 solution (10 mL). The phases were separated, and the aqueous layer was extracted with DCM (2 × 50 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. Purification by flash chromatography yielded rac-5-(methoxymethyl)-5-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate ethyl (9g, 88%) as a light brown oil. 1 H NMR(400MHz,chloroform-d)δ 4.33(q,J=7.2Hz,2H),3.46(d,J=10.0Hz,1H),3.39(s,3H),3.35(d,J=10.1Hz,1H),3.20 (d,J=16.5Hz,1H),2.70(d,J=16.6Hz,1H),1.44(s,3H),1.33(t,J=7.1Hz,3H)ppm.ESI-MS m / z calculated value 348.0491, measured value 349.0(M+1) + ;Retention time: 3.59 minutes.

[0291] Step 5: Pd(PPh3)4 (614 mg, 0.53 mmol) was added to a stirred, argon-degassed solution of rac-5-(methoxymethyl)-5-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate ethyl (3.7 g, 10.623 mmol) and (3,4-difluoro-2-methoxyphenyl)boronic acid (2.5 g, 13.302 mmol) in toluene (50 mL). The reaction mixture was further degassed, and 2 M K3PO4 aqueous solution (16 mL, 32.0 mmol) was added. The reaction mixture was heated for 3 hours and then cooled to ambient temperature. The mixture was filtered through a Celite pad. The filtrate was concentrated under vacuum. The residue was diluted with ELISA (50 mL), washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum. Purification by flash chromatography (SiO2, 5-10% ethyl hexane) yielded rac-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyl-4,5-dihydrofuran-2-carboxylate ethyl (3g, 79%) as a pale yellow oil. 1 H NMR(400MHz,chloroform-d)δ 6.88-6.79(m,2H),4.13(q,J=7.1Hz,2H),3.88(d,J=1.24Hz,3H),3.52(d,J=9.9Hz,1H),3.43(d,J=4.8Hz,3H),3. 42(d,J=9.6Hz,1H),3.16(d,J=16.7Hz,1H),2.71(d,J=16.7Hz,1H),1.46(s,3H),1.12(t,J=7.1Hz,3H)ppm.ESI-MS m / z calculated value 342.1279, actual value 343.0(M+1) + ;Retention time: 3.59 minutes.

[0292] Step 6: Pd / C (1 g, 8.23 ​​mmol) was added to a stirred, argon-degassed solution of rac-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyl-4,5-dihydrofuran-2-carboxylate ethyl (2 g, 5.84 mmol) in ethanol (50 mL). The reaction mixture was further degassed under argon for 5 minutes, and then shaken in a Parr reactor under hydrogen at 500 psi at ambient temperature. After 16 hours, the reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under vacuum. Purification by flash chromatography (SiO2, hexane with 10-15% Â) yielded rac-(2S,3S)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxylate ethyl (1.5 g, 73%) as a pale yellow oil and as a mixture of four stereoisomers. ESI-MS m / z calculated value: 344.1435, measured value: 345.0 (M+1) + ;Retention time: 3.62 minutes.

[0293] Step 7: Potassium tert-butoxide (1.5 g, 13.37 mmol) was added in small amounts under argon at 0°C to a stirred solution of a mixture of stereoisomers of rac-(2S,3S)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxylate ethyl (1.3 g, 3.78 mmol) in dry THF (60 mL). The reaction mixture was stirred at 0°C for 30 minutes and then warmed to ambient temperature. The reaction mixture was recooled to 0°C, quenched with 2N HCl solution (2 mL), and extracted with ethyl phosphate. The organic phase was collected, dried over MgSO4, filtered, and concentrated under vacuum. Purification by flash chromatography (SiO2, 40-50% Â in hexane) yielded rac-(2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxylic acid (700 mg, 55%) as a colorless oil and as a mixture of four stereoisomers. 1H NMR(400MHz,DMSO-d6)δ 12.50(br s,1H),7.29-7.21(m,1H),7.17-7.10(m,1H),4.39(d,J=9.56Hz,1H),3.86(s,3H),3.80(d,J=10.12Hz,1H),3.35(d,J=9.56Hz,1H) ),3.32(s,3H),3.24(d,J=9.56Hz,1H),2.35(dd,J=12.4,8.0Hz,1H),1.79(t,J=11.8Hz,1H),1.27(d,J=12.44Hz,3H)ppm.ESI-MS m / z Calculated value: 316.1122, Measured value: 317.0 (M+1) + ;Holding time: 1.45 minutes.

[0294] Step 8: Oxalyl chloride (2M, 450 μL, 0.9000 mmol) was added at 0°C to a stirred solution of rac-(2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxylic acid (90 mg, 0.27 mmol) and DMF (5 μL, 0.065 mmol) in DCM (2.6 mL). The reaction mixture was stirred for 20 minutes and then concentrated under vacuum. The residue was diluted with DCM (2.2 mL), and the resulting solution was added dropwise at 0°C to a stirred solution of 4-aminopyridine-2-carboxylate methyl (65 mg, 0.43 mmol), DMAP (3 mg, 0.025 mmol), and Et3N (300 μL, 2.15 mmol) in DCM (2 mL). After 10 minutes, the reaction mixture was warmed to ambient temperature and stirred for 16 hours. The reaction mixture was diluted with DCM, washed with 1M HCl solution, dried over MgSO4, filtered, and concentrated directly on silica gel under vacuum. Purification by flash chromatography (24g SiO2, 0-100% ethyl phosphate in heptane) yielded rac-4-((2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxamide)methyl picolinate (120mg, 90%) as a colorless oil in a 3:1 mixture of diastereoisomers. ESI-MS m / z calculated value: 450.16025, measured value: 451.6 (M+1). +, 449.7 (M-1) - ;Retention time: 0.88 minutes.

[0295] Step 9: A solution of rac-4-((2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxamide)methyl picolinate (120 mg, 0.27 mmol) in methanolic ammonia (7 M, 15 mL, 105.0 mmol) was stirred overnight at ambient temperature. The reaction mixture was concentrated under vacuum to obtain rac-4-((2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxamide)picolinamide (113 mg, 97%) as a 3:1 mixture of diastereoisomers. ESI-MS m / z calculated value: 435.16058, measured value: 436.6 (M+1). + , 434.6 (M-1) - ;Retention time: 0.82 minutes.

[0296] Step 10: The stereoisomers of rac-4-((2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxamide)picolinamide were separated by chiral SFC using a Berger Instruments Minigram SFC system with a Phenomenex, Inc. Lux Cellulose-2 column, 5 μm particle size, 25 cm × 21.2 mm (mobile phase: 35% IPA:MeCN (1:1 ratio, supplemented with 0.2% DMIPA), 65% CO2, system pressure: 100 bar), and the following results were obtained.

[0297] First eluted isomer (rt=3.46 min): rel-4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxamide)picolinamide (26, 5.7 mg, 5%). ESI-MS m / z calculated value 435.16058, measured value 436.3 (M+1) +, 434.2 (M-1) - ;Retention time: 2.68 minutes.

[0298] The second eluted isomer (rt=4.00 min): rel-4-((2S,3R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxamide)picolinamide, which required further purification by reverse-phase preparative HPLC (27 mg, 4.7 mg, 4%). 1 H NMR(500MHz,DMSO-d6)δ 10.23(s,1H),8.47(d,J=5.5Hz,1H),8.30(d,J=2.2Hz,1H),8.04(d,J=2.9Hz,1H), 7.85(dd,J=5.5,2.2Hz,1H),7.58(d,J=2.9Hz,1H),7.28-7.22(m,1H),7.22-7.13( m,1H),4.50(d,J=9.6Hz,1H),4.03-3.92(m,1H),3.81(d,J=1.7Hz,3H),3.41(s,2H) ),3.36(s,3H),2.19(t,J=11.9Hz,1H),2.15-2.06(m,1H),1.34(s,3H)ppm.ESI-MS m / z calculated value 435.16058, measured value 436.3(M+1) + , 434.2 (M-1) - ;Retention time: 2.68 minutes.

[0299] A third eluted isomer (rt=4.53 min): a mixture of both rel-4-((2R,3S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxamide)picolinamide (28) and rel-4-((2S,3R,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxamide)picolinamide (29), which required further separation.

[0300] The third elution peak, containing the two enantiomers of the main diastereoisomer, was further separated by chiral SFC using a Berger Instruments Minigram SFC instrument with a Daicel Corporation Chiralcel OD-H column, 5 μm particle size, 25 cm × 10 mm (mobile phase: 5% MeCN:IPA (1:1 ratio, supplemented with 0.2% DMIPA), 95% CO2, system pressure: 100 bar), yielding the following results.

[0301] First eluted isomer (rt=3.48 min): rel-4-((2R,3S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxamide)picolinamide (28, 20.5 mg, 18%). ESI-MS m / z calculated value 435.16058, measured value 436.3 (M+1) + , 434.3 (M-1) - ;Retention time: 2.77 minutes.

[0302] Second eluted isomer (rt=4.55 min): rel-4-((2S,3R,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxamide)picolinamide (29, 20.0 mg, 17%). 1 H NMR(500MHz,DMSO-d6)δ 10.10(s,1H),8.48(d,J=5.5Hz,1H),8.30(d,J=2.2Hz,1H),8.05(d,J=2.9Hz,1H),7.81(dd, J=5.5,2.2Hz,1H),7.60(d,J=2.9Hz,1H),7.34-7.25(m,1H),7.22-7.09(m,1H),4.56(d,J=9. 0Hz,1H),4.06-3.96(m,1H),3.83(d,J=1.6Hz,3H),3.51(d,J=9.6Hz,1H),3.39(d,1H),3.34 (s,3H),2.42(dd,J=12.4,8.2Hz,1H),1.92(dd,J=12.5,11.2Hz,1H),1.36(s,3H)ppm.ESI-MS m / z calculated value 435.16058, measured value 436.3(M+1) +, 434.3 (M-1) - ;Retention time: 2.77 minutes.

[0303] The following compounds were prepared using the method described in Example 4, except that 4-methoxybutan-2-one was used instead of 1-methoxypropan-2-one in step 2. The conditions used in amide coupling step 8 were the same as those described in the first part of step 7 of Example 3. In step 10, purification was performed by chiral SFC using a Berger Instruments Minigram SFC instrument with a Daicel Corporation Chiralpak AS-H column, 5 μm particle size, 25 cm × 10 mm (mobile phase: 25% methanol (supplemented with 20 mM NH3), 75% CO2, system pressure: 100 bar). [Table 15]

[0304] Example 5 rel-4-((2R,3S,5R)-3-(3,4-difluoro-2-(2-hydroxy-2-methylpropoxy)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide(32) [ka] Step 1: BBr3 (2 mL, 1 M in DCM, 2.00 mmol) was added at 0°C to a solution of rel-4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide (intermediate A-2, 749 mg, 1.61 mmol) in DCM (20 mL). The reaction mixture was warmed to ambient temperature over 24 hours. Water (5 mL) and saturated sodium bicarbonate (10 mL) were added, and the reaction mixture was stirred for 30 minutes. The aqueous layer was extracted using DCM (3 × 15 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. Flash chromatography (40 g SiO2) was used to analyze the results. 2、Purification with 0-100% ethyl ammonium compounds in heptane yielded rel-4-((2R,3S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide (418.8 mg, 58%) as a white solid. 1 1H NMR (500MHz, DMSO-d6)δ 10.45(s,1H),10.42(s,1H),8.49(d,J=5.5Hz,1H),8.28(d,J=1.9Hz,1H),8.05 (d,J=2.3Hz,1H),7.82(dd,J=5.5,2.2Hz,1H),7.60(d,J=2.4Hz,1H),7.05(ddd, J=8.4,5.9,2.0Hz,1H),6.83(q,J=8.7Hz,1H),4.75(d,J=10.1Hz,1H),4.04-4.0 0(m,1H),2.63(t,J=12.3Hz,1H),2.37(dd,J=12.5,8.0Hz,1H),1.57(s,3H)ppm; 19 F NMR (471MHz, DMSO-d6): δ -80.05, -139.44 (d, J=24.0Hz), -159.72 (d, J=24.4Hz) ppm. ESI-MS m / z: Calculated value 445.1061, Measured value 446.5 (M+1). + , 444.4 (M-1) - ;Retention time: 0.73 minutes.

[0305] Step 2: A mixture of rel-4-((2R,3S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide (80 mg, 0.18 mmol), K2CO3 (65 mg, 0.47 mmol), and 1-chloro-2-methylpropan-2-ol (280 μL, 2.73 mmol) in MeCN (2 mL) was heated in a sealed tube at 80°C for 17 hours. An additional amount of 1-chloro-2-methylpropan-2-ol (280 μL, 2.73 mmol) was added, and the reaction mixture was heated further at 80°C for 22 hours. DMF (1 mL) was added, and the reaction mixture was heated at 80°C for 24 hours. Further amounts of 1-chloro-2-methylpropan-2-ol (550 μL, 5.36 mmol) were added, and the reaction mixture was heated at 100°C for 120 hours. The mixture was cooled to ambient temperature and partitioned between water (5 mL) and ethyl acetate (10 mL). The aqueous layer was separated and extracted with ethyl acetate (2 × 5 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. Purification by reverse-phase HPLC (mobile phase: acetonitrile and water (supplemented with 0.1% ammonium hydroxide), flow rate: 19 mL / min; sample dissolved in undiluted acetonitrile and injected at 1 mL / min) using a Waters X-bridge C18 column (150 × 19 mm, particle size 5 mm) yielded rel-4-((2R,3S,5R)-3-(3,4-difluoro-2-(2-hydroxy-2-methylpropoxy)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide (32, 3.7 mg, 4%) as an off-white solid. 11H NMR (500MHz, DMSO-d6)δ 10.41(s,1H),8.48(d,J=5.5Hz,1H),8.26(d,J=2.3Hz,1H),8.05(s,1H),7.84( dd,J=5.5,2.2Hz,1H),7.60(s,1H),7.29-7.25(m,1H),7.23-7.18(m,1H),4.68( d,J=10.3Hz,1H),4.62(s,1H),4.28-4.22(m,1H),3.77(q,J=9.0Hz,2H),2.56- 2.52(m,1H),2.30(t,J=12.4Hz,1H),1.56(s,3H),1.19(s,3H),1.15(s,3H)ppm; 19 F NMR(471MHz,DMSO-d6)δ-80.02,-138.29(d,J=22.3Hz),-154.19(d,J=22.1Hz).ESI-MS m / z calculated value 517.16364, measured value 518.5(M+1) + , 516.6 (M-1) - ;Retention time: 2.9 minutes.

[0306] The following compounds were prepared using the method described in Example 5, except that a different alkylating agent was used instead of 1-chloro-2-methylpropan-2-ol in step 2. [Table 16]

[0307] The following compounds were prepared using the method described in Example 5, except that in Step 1, rac-4-((2R,3S,5R)-3-(4-fluoro-2-methoxy-3-methylphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide (intermediate H) was used as the starting material. In Step 2, 2-chloroethane-1-ol was used as the alkylating agent instead of 1-chloro-2-methylpropan-2-ol. At the end of the synthesis, the enantiomers were further separated by chiral SFC using a Berger Instruments Minigram SFC apparatus with a Daicel Corporation Chiralpak IG column, 5 mm particle size, 25 cm × 10 mm (mobile phase: 12% methanol (supplemented with 20 mM NH3), 88% CO2, system pressure: 134 bar): [Table 17]

[0308] Example 6 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-hydroxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)-N-methylpicolinamide(38) [ka] Step 1: Potassium tert-butoxide (1.90 g, 16.93 mmol) was added in small amounts to a solution of (2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate methyl (Example 2, product of Step 2, 2.00 g, 5.645 mmol) in 2-MeTHF (40 mL). The reaction mixture was stirred overnight at ambient temperature. The mixture was quenched by adding 1 M HCl (60 mL) and diluted with DCM (100 mL). The aqueous layer was separated and extracted with DCM (2 × 50 mL). The organic extracts were combined, washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under vacuum to obtain (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1.964 g, 100%) as a yellow foam. 1 ¹H NMR (500MHz, chloroform-d) δ 6.95-6.90 (m, 1H), 6.73-6.66 (m, 1H), 4.98 (d, J=10.3Hz, 1H), 4.17 (dd, J=10.3, 7.8Hz, 1H), 2.86-2.78 (m, 1H), 1.60 (s, 3H), 0.79-0.75 (m, 3H) ppm; no alcohols or acid OH groups were observed.

[0309] Step 2: 2-iodoethoxy(triisopropyl)silane (intermediate R-1) (1.08 mL, 3.553 mmol) was added to a stirred mixture of (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (5.47 g, 11.41 mmol) and potassium carbonate (6.3 g, 45.58 mmol) in DMF (25 mL). The reaction mixture was stirred in a sealed vial at 80°C for 24 hours. The reaction mixture was partitioned between MTBE (50 mL) and water (50 mL). The aqueous solution was extracted with MTBE (50 mL). The combined organic extract was washed with brine (25 mL), passed through a phase separation cartridge, and concentrated under vacuum. Purification by flash chromatography (60 g SiO2, 0-100% ethyl in heptane) yielded 2-((triisopropylsilyl)oxy)ethyl(2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (9.85 g, 70%) as an oily substance. 1 H NMR(500MHz,DMSO-d6)δ 7.18(dd,J=8.6,6.2Hz,1H),7.10(q,J=8.9Hz,1H),5.11(d,J=10.3Hz,1H),4.24-4.16(m,3H),4.14-4.10(m,2H),3.99(t, J=4.7Hz,2H),3.75(dd,J=5.6,4.0Hz,2H),2.73(p,J=7.6Hz,1H),1.53(s,3H),1.07-0.95(m,42H),0.73-0.68(m,3H)ppm.

[0310] Step 3: 2M LiOH (2.75 mL, 5.500 mmol) was added to a solution of 2-((triisopropylsilyl)oxy)ethyl(2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (2.73 g, 3.684 mmol) in MeOH (25 mL). The reaction mixture was stirred overnight at room temperature and then concentrated under vacuum. The mixture was partitioned between 1 M HCl (10 mL) and MTBE (10 mL). The aqueous phase was separated and extracted with MTBE (10 mL). The combined organic extract was washed with brine (5 mL), passed through a phase separation cartridge, and concentrated under vacuum. Purification by flash chromatography (24 g SiO2, 0-20% ethyl ammonium in heptane) yielded (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1.79 g, 90%) as a colorless oil. 1 H NMR(500MHz,DMSO-d6)δ 12.98(s,1H),7.19(ddd,J=7.7,5.9,1.7Hz,1H),7.16-7.08(m,1H),5.00(d,J=10.5Hz,1H),4.27-4.11(m,3H),4 .00(t,J=4.5Hz,2H),2.71(p,J=7.5Hz,1H),1.52(s,3H),1.03(d,J=6.3Hz,21H),0.69(dd,J=7.6,2.4Hz,3H)ppm. 19 F NMR(471MHz,DMSO-d6)δ-73.65,-138.38(d,J=21.1Hz),-154.75(d,J=20.9Hz)ppm.ESI-MS m / z Calculated value 540.23303, Actual value 541.1(M+1) + , 539.2 (M-1) - ;Retention time: 0.91 minutes.

[0311] Step 4: T3P (770 μL, 2.589 mmol) was added to a solution of (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (350 mg, 0.6474 mmol), methyl 4-aminopyridine-2-carboxylate (225 mg, 1.479 mmol), and Et3N (361 μL, 2.590 mmol) in ethyl acetate (3 mL). The mixture was stirred at ambient temperature for 4 hours. The mixture was partitioned between ethyl acetate (30 mL) and water (30 mL). The aqueous layer was separated and extracted with ethyl acetate (50 mL). The combined organic extract was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under vacuum. Purification by flash chromatography (12 g SiO2, 0-100% ethyl hexane) yielded 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)methyl picolinate (360 mg, 82%). ESI-MS m / z calculated value: 674.28107, measured value: 67.0 (M+1). + , 673.9 (M-1) - ;Retention time: 1.36 minutes.

[0312] Step 5: A solution of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)methyl picolinate (370 mg, 0.5483 mmol) in MeOH (3 mL) was treated with 425 μL of MeNH2 (40% w / v in water, 5.474 mmol). The mixture was stirred at ambient temperature for 40 minutes and then concentrated under vacuum. 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)-N-methylpicolinamide (290 mg, 77%) was obtained by purification using reversed-phase HPLC (gradient: 47.4%~94.7% acetonitrile in water (supplemented with 0.1% ammonium hydroxide) (9 minutes), flow rate: 19 mL / min; sample dissolved in undiluted acetonitrile and injected at 1 mL / min) with a Waters X-bridge C18 column (150 × 19 mm, particle size 5 mm). ESI-MS m / z calculated value: 673.29706, measured value: 675.0 (M+1). + ;Retention time: 3.73 minutes.

[0313] Step 6: TBAF (1M, 542 μL, 0.5420 mmol) was added to a solution of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)-N-methylpicolinamide (100 mg, 0.1465 mmol) in THF (2 mL). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated under vacuum. Purification by reverse-phase preparative HPLC yielded 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-hydroxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)-N-methylpicolinamide (38, 59 mg, 78%). 1H NMR(500MHz,DMSO-d6)δ 10.72(s,1H),8.73(d,J=5.0Hz,1H),8.47(d,J=5.5Hz,1H),8.30-8.15(m,1H),7.8 3(dd,J=5.5,2.1Hz,1H),7.25-7.04(m,2H),5.10(d,J=10.7Hz,1H),4.41(dd,J=10. 7,7.3Hz,1H),4.18-4.06(m,2H),3.70(t,J=4.6Hz,2H),2.91(p,J=7.4Hz,1H),2.80 (d,J=4.8Hz,3H),1.61(s,3H),1.31(h,J=7.3Hz,1H),0.77-0.64(m,3H)ppm.ESI-MS m / z calculated value 517.16364, measured value 518.7(M+1) + , 516.7 (M-1) - ;Retention time: 2.97 minutes.

[0314] The following compounds were prepared using the method described in Example 6, except that in step 2, 4-(2-chloroethyl)morpholine was used as the alkylating agent along with Cs2CO3 as the base. The conditions used in aminolysis step 5 were the same as those described in step 9 of Example 2. Deprotection step 6 was not required. [Table 18]

[0315] The following compounds were prepared using the method described in Example 6, except that the conditions used in Step 1 were the same as those described in Step 4 of Example 2, and only MeOH was used as the solvent. The conditions used in Step 2 were the same as those described in Step 1 of Example 10, using a different alcohol. Step 3 was carried out in THF as the solvent. Step 4 was carried out in DMF as the solvent, in the presence of HATU as the activator and Et3N as the base, at ambient temperature until the reaction was complete, under conditions well known in the art. Step 6 was not required. In Step 5, for compounds 40 and 42, a 7M methanolic ammonia solution was used instead of MeNH2 in a mixture of water and MeOH. [Table 19]

[0316] Example 7 4-((2R,3S,4S,5R)-3-(2-(2-(dimethylamino)ethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide(44) [ka] Steps 1 and 2: Et3N (50 μL, 0.3587 mmol) and methanesulfonyl chloride (20 μL, 0.2584 mmol) were successively added to a solution of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-hydroxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide (5) (100 mg, 0.199 mmol) in DCM (3 mL). The reaction mixture was stirred for 20 minutes. The mixture was partitioned between MTBE (10 mL) and water (10 mL). The aqueous layer was separated and extracted with MTBE (5 mL). The combined organic extracts were washed with brine (1 x 3 mL), dried over MgSO4, filtered, and concentrated under vacuum to obtain 2-(6-((2R,3S,4S,5R)-2-((2-carbamoylpyridine-4-yl)carbamoyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-3-yl)-2,3-difluorophenoxy)ethylmethanesulfonate (100 mg, 73%) as an oil. ESI-MS m / z calculated value 581.1255, measured value 582.7 (M+1). + , 580.6 (M-1) - ;Retention time: 0.88 minutes.

[0317] N-methylmethanamine (40% w / w in water, 500 μL, 3.993 mmol) was added to 2-(6-((2R,3S,4S,5R)-2-((2-carbamoylpyridine-4-yl)carbamoyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-3-yl)-2,3-difluorophenoxy)ethylmethanesulfonate (100 mg). The mixture was stirred at ambient temperature for 2 hours. The reaction mixture was partitioned between MTBE (20 ml) and water (20 ml). The aqueous layer was separated and extracted with MTBE (10 mL). The combined organic extract was washed with brine (1 × 10 mL), dried over MgSO4, filtered, and concentrated under vacuum. Purification by reverse-phase preparative HPLC yielded 4-((2R,3S,4S,5R)-3-(2-(2-(dimethylamino)ethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide (44, 50 mg, 46%). 1 H NMR(500MHz,DMSO-d6)δ 10.67(s,1H),8.49(d,J=5.5Hz,1H),8.30(d,J=2.2Hz,1H),8.09(d,J=2.8Hz,1H),7.86(dd,J=5.5,2.2 Hz,1H),7.64(d,J=2.8Hz,1H),7.17(dd,J=8.6,4.4Hz,2H),5.13(d,J=10.7Hz,1H),4.44(dd,J=10.7,7 .3Hz,1H),4.27(dt,J=10.7,5.1Hz,1H),4.11(dt,J=10.9,5.2Hz,1H),2.87(p,J=7.4Hz,1H),2.55(ddd ,J=8.8,6.3,4.0Hz,1H),2.14(s,6H),2.04-1.96(m,1H),1.63(s,3H),0.70(d,J=7.3Hz,3H)ppm.ESI-MS m / z calculated value 530.19525, actual value 531.7(M+1) + , 529.7 (M-1) - ;Holding time: 3.22 minutes.

[0318] The following compounds were prepared using the method described in Example 7, except that the conditions used in Step 2 were the same as those described in Step 5 of Example 8, which uses a different amine. [Table 20-1] [Table 20-2]

[0319] The following compounds were prepared using the method described in Example 7, except that the conditions used in Step 2 were the same as those described in Step 2 of Example 5, which uses a different amine. [Table 21]

[0320] The following compounds were prepared using the method described in Example 7, except that the conditions used in Step 2 were the same as those described in Step 5 of Example 8, which use different amines that are in excess and do not contain base. [Table 22]

[0321] Example 8 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(oxetane-3-yloxy)phenyl)-4,5-dimethyl...

Claims

1. Compound of formula (I), 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, X ２ａ N, N ＋ -O － , or CR ２ａ And, X ４ａ N, N ＋ -O － , or CR ４ａ And, X ５ａ is N, N ＋ -O － or C-R ５ａ , and is X ６ａ N, N ＋ -O － , or CR ６ａ And, R stands for OR ａ Or NR Ｘａ R Ｙａ And, R ２ａ , R ４ａ , R ５ａ , and R ６ａ These are H, Haro, and C, each independent of the others. １ -C ６ Alkyl, C １ -C ６ Haloalkyl or -Si(C) １ -C ６ Alkyl) ３ And, R ａ C １ -C ６ It is alkyl, R Ｘａ is H or C １ -C ６ It is alkyl, R Ｙａ H, OH, C １ -C ６ Alkyl, -(C １ -C ６ Alkylene)-R Ｚａ１ , or non-substituted or C １ -C ６ Alkyl and C １ -C ６ A 4- to 6-membered heterocycline substituted with one or more groups independently selected from the alkoxy, or R Ｘａ and R Ｙａ These, together with the nitrogen atoms to which they are bonded, form a 5- to 9-membered heterocycline, and the heterocycline is either unsubstituted or has one or more R Ｚａ２ It has been replaced with, R Ｚａ１ OH, NH ２ ,-NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , as well as non-substituted or halo and C １ -C ６ A 5-6 membered heterocycline substituted with one or more groups independently selected from alkyl groups, Each R Ｚａ２ is Halo, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, NH ２ ,-NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , and -(C １ -C ６ Alkylene) - (C １ -C ６ Selected independently from alkoxy, R ４ｂ１ and R ４ｂ２ H and C are independent of each other. １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ It is a haloalkyl, R ５ｂ１ and R ５ｂ２ are each independently H, C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, C １ -C ６ haloalkyl, or -(C １ -C ６ alkylene)-(C １ -C ６ alkoxy), or R ５ｂ１ and R ５ｂ２ These, together with the carbon atoms to which they are bonded, form a 4-6 membered heterocycline. X ３ｃ is N or C-R ３ｃ , and is X ４ｃ is N or C-R ４ｃ And, X ５ｃ is N or C-R ５ｃ And, X ６ｃ is N or C-R ６ｃ And, R ２ｃ H, OH, halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, -(C) １ -C ６ Alkylene) - (C １ -C ６ Alkoxy), -(C １ -C ６ Alkilen)-O-(4-6 member heterocyclyl),-O-(C) ２ -C ６ Alkenylene) - (C １ -C ６ Haloalkyl), -L １ -L ２ - (C ３ -C ７ Cycloalkyl), or -O-L ３ -R Ｘｃ The cycloalkyl group is either unsubstituted or halo, OH, CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, =NOH, -C(O)(C １ -C ６ Alkyl), and -(C １ -C ６ It is substituted with one or more groups independently selected from the alkylene-OH group, L １ is a bond or O, L ２ is a combination or C １ -C ６ It is alkylene, L ３ C １ -C ６ Alkylene, or C ２ -C ６ It is alkenylene, R Ｘｃ OH, CN, C １ -C ６ Alkoxy, NH ２ ,-NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ ,-NH(C １ -C ６ Haloalkyl), -NH(C) １ -C ６ (Haloalkyl) ２ , -CH(CH ２ OH) ２ , -CH(CH ２ OH) (CH ２ OCH ３ ), -CH(CH ２ OH) (OCH ３ ), -CH(CH ２ OCH ３ ) (OCH ３ ), -CH(CH ２ OH) (CF ３ ), -C(O)(C １ -C ６ Alkyl), -C(O)NH ２ , -C(O)NH(C １ -C ６ Alkyl), -C(O)N(C １ -C ６ Alkyl) ２ -NH (4-6 member heterocyclyl), =NOH, =NO(C) １ -C ６ Alkyl), -N=S(O)(C １ -C ６ Alkyl) ２ , -C(=NOH)(C ３ -C ６ Selected from cycloalkyls, 4-8 membered heterocyclines, and 5-6 membered heteroaryls, wherein the cycloalkyl is unsubstituted or substituted with one or more halos, and the heterocyclines and heteroaryls are unsubstituted or substituted with OH, halo, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy and -(C １ -C ６ It is substituted with one or more groups independently selected from the alkylene-OH group, R ３ｃ H, Halo, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -(C) １ -C ６ Alkylene)-OH, or -(C) １ -C ６ Alkylene) - (C １ -C ６ (alkoxy) Or, X ３ｃ , CR ３ｃ And R ２ｃ and R ３ｃ Together with the carbon atoms to which they are bonded, the formula is: 【Chemistry 2】 Forming a ring, Z １ and Z ２ Each of them is independent of O and CH. ２ , or CF ２ And, R Ｙｃ１ and R Ｙｃ２ Each of these is independently H or halo, R ４ｃ H, Halo, OH, -OBn, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy or -L １ -L ２ - (C ３ -C ６ The cycloalkyl group is either unsubstituted or substituted with one or two halos. R ５ｃ H, Halo, OH, -OBn, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, or -L １ -L ２ - (C ３ -C ６ The cycloalkyl group is either unsubstituted or substituted with one or two halos. R ６ｃ H, Halo, C １ -C ６ Alkyl, or C １ -C ６ It is a haloalkyl, However, X ２ａ , X ４ａ , X ５ａ , and X ６ａ Two or fewer of these are N or N ＋ -O － The condition is that, However, X ３ｃ , X ４ｃ , X ５ｃ , and X ６ｃ The condition is that one or less of them is N, however, R stands for OR ａ is or R stands for NR Ｘａ R Ｙａ And R Ｙａ is OH, -(C １ -C ６ Alkylene)-R Ｚａ１ , or non-substituted or C １ -C ６ Alkyl and C １ -C ６ It is a 4- to 6-membered heterocycline substituted with one or more groups independently selected from the alkoxy, or R stands for NR Ｘａ R Ｙａ And R Ｘａ and R Ｙａ These, together with the N atoms to which they are bonded, form a 5- to 9-membered heterocycline, and the heterocycline is either unsubstituted or has one or more R Ｚａ２ It is replaced with, or R ２ａ , R ４ａ , R ５ａ , or R ６ａ is -Si(C １ -C ６ Alkyl) or R ５ｂ１ Or R ５ｂ２ is, -(C １ -C ６ Alkylene) - (C １ -C ６ (alkoxy) or R ５ｂ１ and R ５ｂ２ They, together with the carbon atoms to which they are bonded, form a 4-6 membered heterocycline, or R ２ｃ is, -(C １ -C ６ Alkylene) - (C １ -C ６ Alkoxy), -(C １ -C ６ Alkilen)-O-(4-6 member heterocyclyl),-O-(C) ２ -C ６ Alkenylene) - (C １ -C ６ Haloalkyl), or -OL-L ３ -R Ｘｃ is or R ２ｃ is, -L １ -L ２ - (C ３ -C ７ It is a cycloalkyl group, and the cycloalkyl group consists of OH, CN, and C １ -C ６ Alkyl, C １ -C ６ Alkoxy, =NOH, -C(O)(C １ -C ６ Alkyl), and -(C １ -C ６ It is substituted with one or more groups independently selected from the alkylene-OH group, or R ３ｃ is, -(C １ -C ６ Alkylene)-OH or -(C １ -C ６ Alkylene) - (C １ -C ６ (alkoxy) or R ２ｃ and R ３ｃ Together with the carbon atoms to which they are bonded, the formula is: 【Transformation 3】 To form a ring, or R ４ｃ OH, -OBn, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy or -L １ -L ２ - (C ３ -C ６ The cycloalkyl is either unsubstituted or substituted with one or two halos, or R ５ｃ is OH, -OBn, or -L １ -L ２ - (C ３ -C ６ A compound or a pharmaceutically acceptable salt thereof, wherein the cycloalkyl is unsubstituted or substituted with one or two halos.

2. The aforementioned compound is of formula (I-A) 【Chemistry 4】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the above.

3. The aforementioned compound is of formula (I-A-1) 【Transformation 5】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the above.

4. The aforementioned compound is of formula (I-B) or (I-C) 【Transformation 6】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the above.

5. The compound is of formula (I-B-1) or (I-C-1) 【Transformation 7】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the above.

6. X ２ａ However, N or C-R ２ａ And R ２ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein H is present.

7. X ４ａ However, N, N ＋ -O － , or CR ４ａ And R ４ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is H or a halo.

8. X ５ａ However, C-R ５ａ And R ５ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein H is present.

9. X ６ａ However, N or C-R ６ａ And R ６ａ However, H, Haro, C １ -C ６ Alkyl, or -Si(C １ -C ６ Alkyl) ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. R is OR ａ Or NR Ｘａ R Ｙａ And, R ａ However, C １ -C ６ It is alkyl, R Ｘａ However, H or C １ -C ６ It is alkyl, R Ｙａ However, H, OH, C １ -C ６ Alkyl, -(C １ -C ６ Alkylene)-R Ｚａ１ , or non-substituted or C １ -C ６ Alkyl and C １ -C ６ A 4-6 membered heterocycline substituted with one or more groups independently selected from the alkoxy, R Ｚａ１ However, OH, -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , as well as non-substituted or halo and C １ -C ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is a 5- to 6-membered heterocycline substituted with one or more groups independently selected from alkyl groups.

11. R is NR Ｘａ R Ｙａ And, R Ｘａ and R Ｙａ However, together with the nitrogen atom to which they are bonded, they are either unsubstituted or have one or more R Ｚａ２ It forms a 5- to 9-membered heterocycline that is substituted with Each R Ｚａ２ However, halo, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, NH ２ ,-NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , and -(C １ -C ６ Alkylene) - (C １ -C ６ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, independently selected from alkoxys.

12. R ４ｂ１ However, H or C １ -C ６ The compound according to claim 1, which is alkyl, or a pharmaceutically acceptable salt thereof.

13. R ４ｂ２ However, H or C １ -C ６ The compound according to claim 1, which is alkyl, or a pharmaceutically acceptable salt thereof.

14. R ５ｂ１ However, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl or -(C １ -C ６ Alkylene) - (C １ -C ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is an alkoxy.

15. R ５ｂ２ However, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl or -(C １ -C ６ Alkylene) - (C １ -C ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is an alkoxy.

16. R ５ｂ１ and R ５ｂ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein these atoms, together with the carbon atoms to which they are bonded, form a four-membered heterocycline.

17. X ３ｃ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein N is present.

18. X ３ｃ However, C-R ３ｃ And R ３ｃ However, H, Haro, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -(C) １ -C ６ Alkylene)-OH, or -(C) １ -C ６ Alkylene) - (C １ -C ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is an alkoxy.

19. X ４ｃ However, C-R ４ｃ And R ４ｃ However, H, Halo, OH, -OBn, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy or -L １ -L ２ - (C ３ -C ６ L is a cycloalkyl group, and the cycloalkyl group is either unsubstituted or substituted with one or two halos. １ However, it is O and L ２ However, bond or C １ -C ６ A compound according to claim 1, which is alkylene, or a pharmaceutically acceptable salt thereof.

20. R ４ｃ However, H, Halo, OH, -OBn, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy or -L １ -L ２ - (C ３ -C ６ L is a cycloalkyl group, and the cycloalkyl group is either unsubstituted or substituted with one or two halos. １ However, it is O and L ２ However, bond or C １ -C ６ The compound according to claim 3, which is alkylene, or a pharmaceutically acceptable salt thereof.

21. R ４ｃ is H, F, OH, -OBn, -OCH ３ , -OCH ２ CH ３ CHF ２ , -OCHF ２ , -OCF ３ , -O-CH ２ The compound according to claim 19, or a pharmaceutically acceptable salt thereof, wherein the compound is -(cyclopropyl) or -O-(cyclobutyl), and the cyclobutyl is substituted with two F atoms.

22. X ５ｃ However, C-R ５ｃ And R ５ｃ However, H, halo, OH, -OBn, or -L １ -L ２ - (C ３ -C ６ L is a cycloalkyl group, and the cycloalkyl group is either unsubstituted or substituted with one or two halos. １ However, it is O and L ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is bonded.

23. R ５ｃ However, H, halo, OH, -OBn, or -L １ -L ２ - (C ３ -C ６ The cycloalkyl group is either unsubstituted or substituted with one or two halos, L １ However, it is O and L ２ The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein the compound is bonded.

24. R ５ｃ The compound according to claim 22, or a pharmaceutically acceptable salt thereof, wherein is H, Cl, OH, -OBn, or -O-(cyclobutyl), and the cyclobutyl is substituted with two F atoms.

25. X ６ｃ However, C-R ６ｃ And R ６ｃ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein H is present.

26. R ２ｃ But, OH, Halo, C １ -C ６ Alkoxy, -(C １ -C ６ Alkylene) - (C １ -C ６ Alkoxy), -(C １ -C ６ Alkilen)-O-(4-6 member heterocyclyl),-O-(C) ２ -C ６ Alkenylene) - (C １ -C ６ Haloalkyl), -L １ -L ２ - (C ３ -C ７ Cycloalkyl), or -O-L ３ -R Ｘｃ The cycloalkyl group is either unsubstituted or OH, CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, =NOH, -C(O)(C １ -C ６ Alkyl), and -(C １ -C ６ It is substituted with one or more groups independently selected from the alkylene-OH group, L １ However, it is O, L ２ However, bond or C １ -C ６ It is alkylene, L ３ However, bond, C １ -C ６ Alkylene, or C ２ -C ６ It is alkenylene, R Ｘｃ However, OH, CN, C １ -C ６ Alkoxy, NH ２ ,-NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ ,-NH(C １ -C ６ Haloalkyl), -NH(C) １ -C ６ (Haloalkyl) ２ , -CH(CH ２ OH) ２ , -CH(CH ２ OH) (CH ２ OCH ３ ), -CH(CH ２ OH) (OCH ３ ), -CH(CH ２ OCH ３ ) (OCH ３ ), -CH(CH ２ OH) (CF ３ ), -C(O)(C １ -C ６ Alkyl), -C(O)NH ２ , -C(O)NH(C １ -C ６ Alkyl), -C(O)N(C １ -C ６ Alkyl) ２ -NH (4-6 member heterocyclyl), =NOH, =NO(C) １ -C ６ Alkyl), -N=S(O)(C １ -C ６ Alkyl) ２ , -C(=NOH)(C ３ -C ６ Selected from cycloalkyl, 4-8 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the cycloalkyl is unsubstituted or substituted with one or more halos, and the heterocyclyl and heteroaryl are unsubstituted or substituted with OH, halo, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy and -(C １ -C ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is substituted with one or more groups independently selected from the alkylene)-OH group.

27. R ２ｃ However, -L １ -L ２ - (C ３ -C ７ It is a cycloalkyl group, L １ However, it is O, L ２ However, bond or C １ -C ２ It is alkylene, The cycloalkyl group is OH, CN, -OCH ３ ,CH ３ , =NOH, -C(O)(CH ３ ), and -CH ２ The compound according to claim 26, or a pharmaceutically acceptable salt thereof, which is substituted with one or more groups independently selected from OH.

28. R ２ｃ However, -O-L ３ -R Ｘｃ And, L ３ However, bond, C １ -C ６ Alkylene, or C ４ -C ５ It is alkenylene, R Ｘｃ However, OH, CN, C １ -C ６ Alkoxy, NH ２ ,-NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ ,-NH(C １ -C ６ Haloalkyl), -NH(C) １ -C ６ (Haloalkyl) ２ , -CH(CH ２ OH) ２ , -CH(CH ２ OH) (CH ２ OCH ３ ), -CH(CH ２ OH) (OCH ３ ), -CH(CH ２ OCH ３ ) (OCH ３ ), -CH(CH ２ OH) (CF ３ ), -C(O)(C １ -C ６ Alkyl), -C(O)NH ２ , -C(O)NH(C １ -C ６ Alkyl), -C(O)N(C １ -C ６ Alkyl) ２ -NH (4-6 member heterocyclyl), =NOH, =NO(C) １ -C ６ Alkyl), -N=S(O)(C １ -C ６ Alkyl) ２ , -C(=NOH)(C ３ -C ６ Selected from cycloalkyl, 4-8 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the cycloalkyl is unsubstituted or substituted with one or more halos, and the heterocyclyl and heteroaryl are unsubstituted or substituted with OH, halo, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy and -(C １ -C ６ The compound according to claim 26, or a pharmaceutically acceptable salt thereof, which is substituted with one or more groups independently selected from the alkylene)-OH group.

29. R Ｘｃ But,OH;CN;-OCH ３ ;-NH(CH ３ );-NH(CH(CH ３ ) ２ ); -N(CH ３ ) ２ ;-NH(CH ２ CHF ２ ); -CH(CH ２ OH) ２ ;-CH(CH ２ OH) (CH ２ OCH ３ ); -CH(CH ２ OH) (OCH ３ ); -CH(CH ２ OCH ３ ) (OCH ３ ); -CH(CH ２ OH) (CF ３ );-C(O)(CH ３ );-C(O)NH(CH ３ ); -NH (4-5 member heterocyclyl); = NOH; = NO (CH ３ );-N=S(O)(CH ３ ) ２ ;-C(=NOH)(C ３ -C ４ Cycloalkyl; unsubstituted or OH, F, CH ３ , -OCH ３ CHF ２ CF ３ , -OCHF ２ , and -CH ２ 4- to 8-membered heterocyclines substituted with one or more groups independently selected from OH; and unsubstituted or CH ３ A compound according to claim 28, or a pharmaceutically acceptable salt thereof, selected from a five-membered heteroaryl substituted with, wherein the cycloalkyl is unsubstituted or substituted with one F.

30. X ３ｃ However, C-R ３ｃ And R ２ｃ and R ３ｃ However, together with the carbon atoms to which they are bonded, the formula is: 【Transformation 8】 It forms a ring, and in the formula, Z １ However, O or CH ２ And, Z ２ However, O or CF ２ And, R Ｙｃ１ and R Ｙｃ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each of them is independently H or F.

31. The aforementioned ring is given by the formula: 【Chemistry 9】 A compound according to claim 30, or a pharmaceutically acceptable salt thereof, which is a ring of the compound. 【Request Item 32】 【Chemistry 101】 【Chemical Engineering 102】 【Chemistry 103】 【Chemical 104】 【Chemistry 105】 【Chemistry 106】 【Chemistry 107】 【Chemistry 108】 【Chemistry 109】 【Chemical 110】 【Chemistry 111】 【Chemistry 112】 【Chemistry 113】 【Chemical 114】 【Chemical 115】 【Chemistry 116】 【Chemistry 117】 【Chemistry 118】 【Chemical 119】 【Chemical 120】 【Chemistry 121】 【Chemistry 122】 【Chemical 123】 【Chemistry 124】 【Chemistry 125】 【Chemistry 126】 【Chemistry 127】 【Chemistry 128】 【Chemistry 129】 【Chemistry 130】 【Chemistry 131】 【Chemistry 132】 【Chemistry 133】 【Chemistry 134】 【Chemistry 135】 【Transformation 136】 【Chemistry 137】 【Chemistry 138】 【Chemistry 139】 [Chemistry 140] 【Chemistry 141】 【Chemistry 142】 【Chemistry 143】 【Chemistry 144】 【Chemistry 145】 【Chemistry 146】 【Chemistry 147】 【Chemistry 148】 【Chemistry 149】 [Chemical 150] 【Chemistry 151】 【Chemistry 152】 【Chemistry 153】 【Chemistry 154】 【Chemistry 155】 【Chemistry 156】 【Chemistry 157】 【Chemistry 158】 【Chemistry 159】 [Chemical 160] 【Chemistry 161】 【Chemistry 162】 【Chemistry 163】 【Chemistry 164】 A compound selected from, or a pharmaceutically acceptable salt thereof.

33. A compound according to any one of claims 1 to 32, which is in a non-salt form.

34. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

35. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

36. A composition for use in a method for inhibiting voltage-gated sodium channels, comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof.

37. The composition according to claim 36, wherein the voltage-gated sodium channel is Na V 1.

8.

38. A composition 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, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia, comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof.

39. The composition according to claim 38, wherein the method comprises treating neuropathic pain; musculoskeletal pain; acute pain; postoperative pain; or visceral pain, or reducing the severity thereof in the subject.

40. The composition according to claim 39, wherein the method comprises treating musculoskeletal pain or reducing its severity in the subject, and the musculoskeletal pain includes osteoarthritis pain.

41. The composition according to claim 39, wherein the method comprises treating neuropathic pain or reducing its severity in the subject, and the neuropathic pain comprises one or more of postherpetic neuralgia; small fiber neuropathy; idiopathic small fiber neuropathy; or diabetic neuropathy.

42. The composition according to claim 41, wherein the neuropathic pain includes diabetic neuropathy, and the diabetic neuropathy includes diabetic peripheral neuropathy.

43. The composition according to claim 39, wherein the method comprises treating postoperative pain or reducing its severity in the subject, and the postoperative pain includes one or more of bunion resection pain, abdominal wall reconstruction pain, or hernia repair pain.

44. The composition according to claim 38, characterized in that the subject is treated simultaneously with treatment by the composition, or with one or more additional therapeutic agents administered before or after such treatment.

45. A composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

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