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 TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 197,199, filed June 4, 2021, which is incorporated 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 patients 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 the nerve and pain caused by individual nerve damage. Metabolic neuropathies include post-herpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Indications for individual nerve damage include nerve entrapment injuries such as post-amputation pain, post-operative nerve injury pain, and neuropathic back pain. Neuropathic pain is a major cause of disability worldwide, adversely affecting patients' sleep, mood, and function. Please refer to 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, cardiac myocytes) 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 an important and central role in pain signal transduction comes from (1) evaluation of the role Nav plays in normal physiology, (2) pathological conditions resulting from mutations in the Nav1.8 gene (SCN10A), (3) preclinical studies in animal models, and (4) the pharmacological actions of known Nav1.8 modulators. Furthermore, because Nav1.8 expression is restricted to peripheral neurons, particularly those that sense pain (e.g., dorsal root ganglion), Nav1.8 inhibitors are unlikely to be associated with the side effects commonly observed with other sodium channel modulators and the abuse liability associated with opioid therapy. Thus, targeting the biology underlying pain through selective Nav1.8 inhibition represents a novel approach to analgesic development that may address the urgent unmet need for safe and effective acute and chronic pain therapies. (Rush, A. M. and T. R. Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Na 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 is important in the initiation and propagation of neural signals. V Due to the role played by Na V Antagonists that reduce the current can prevent or reduce nerve signaling. V Channels have been considered as potential targets for reducing pain under conditions of hyperexcitability (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 painkillers are V Local anesthetics such as lidocaine have been identified as inhibitors of the Na channel. V Other compounds that block pain by inhibiting the channel, such as carbamazepine, lamotrigine, and tricyclic antidepressants, which have been shown to be effective in reducing pain, have also been suggested to act by blocking 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 form a subfamily of voltage-gated ion channels that mediate the regulation of Na V 1.1~Na V It contains nine isoforms, designated 1.1 and 1.9. The tissue localization of the nine isoforms varies. V 1.4 is the primary sodium channel in skeletal muscle and is V 1.5 is the primary sodium channel in cardiac myocytes. Na V 1.7, 1.8, and 1.9 are primarily localized in the peripheral nervous system and V 1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the central and peripheral nervous systems. The functional behavior of the nine isoforms is similar, but distinct in the details of their voltage-dependence and kinetic behavior (Catterall, WA, Goldin, AL, and Waxman, SG, International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57(4), p. 397(2005)).

[0005] At the time of their discovery, Na V The 1.8 channel was identified as a likely target for analgesia (Akopian, AN, L. Sivilotti, and JN Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562):p.257-62). V1.8 has been shown to be a carrier of the sodium current that sustains action potential firing in small dorsal root ganglion (DRG) neurons in the action potentials of nociceptive sensory neurons (Blair, NT and BP Bean, Roles of tetrodotoxin (ttX)-sensitive Na+ current, TTX-resistant Na+ current, + 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 injured 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 The small DRG neurons in which Na1.8 is expressed contain nociceptors involved in pain signaling.V 1.8 mediates large amplitude action potentials in small neurons of the dorsal root ganglion (Blair, NT and BP Bean, 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 required for rapid repetitive action potentials in nociceptors and for spontaneous activity of injured 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). V1.8 appears to be a driver of 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 DRG (Sun, W., et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats. Brain, 135(Pt 2): p.359-75, Strickland, IT, et al., Changes in the expression of Na V 1.7,Na V 1.8 and Na V 1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain.Eur.J.Pain,2008.12(5):p.564-72, Qiu,F.,et al.,Increased expression of tetrodotoxin-resistant sodium channels Na V 1.8 and Na V 1.9 within dorsal root ganglia in a rat model of bone cancer pain.Neurosci.Lett,512(2):p.61-6). The inventors have found that some voltage-gated sodium channel inhibitors, for example, have a poor therapeutic window (e.g., Na VWe have found that selective NaCl has limitations as a therapeutic agent due to its lack of isoform selectivity, low efficacy, and / or other reasons. V There remains a need to develop selective voltage-gated sodium channel inhibitors, such as 1.8 inhibitors. [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

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

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

[0009] In yet another aspect, the invention relates to a method of inhibiting voltage-gated sodium channels in a subject by administering to the subject a compound, a pharma- ceutically acceptable salt, or a pharmaceutical composition.

[0010] In yet another aspect, the invention relates to a method of treating or reducing the severity in a subject 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, post-operative pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmias, by administering a compound, pharma- ceutically acceptable salt, or pharmaceutical composition to the subject. [Brief description of the drawings]

[0011] [Figure 1] 1 shows an XRPD pattern characteristic of amorphous Compound 6. [Diagram 2] 1 shows an XRPD pattern characteristic of amorphous Compound 7. [Diagram 3] 1 shows an XRPD pattern characteristic of amorphous compound 86. [Figure 4] 1 shows an XRPD pattern characteristic of amorphous compound 87. [Diagram 5] 1 shows an XRPD pattern characteristic of amorphous Compound 123. [Figure 6] 1 shows an XRPD pattern characteristic of amorphous compound 181. [Figure 7] 1 shows an XRPD pattern characteristic of amorphous compound 224. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] In one aspect, the present invention provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, 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 for OR a or NR Xa R Ya and R 2a , R 4a , R 5a , and R 6a are each independently H, halo, or C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or -Si(C 1 -C 6 Alkyl) 3 and R a is H or C 1 -C 6 is alkyl, R Xa is H or C 1 -C 6 is alkyl, R Ya is H, OH, C 1 -C 6 Alkyl, -(C 1 -C 6 Alkylene)-R Za1 , or C 1 -C 6 Alkyl and C 1 -C 6 a 4- to 6-membered heterocyclyl optionally substituted with one or more groups independently selected from alkoxy; or R Xa and R Ya together with the nitrogen atom to which they are attached form a 5- to 9-membered heterocyclyl, the heterocyclyl being one or more R Za2 where appropriate, R Za1OH, NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 Alkyl) 2 , and halo and C 1 -C 6 is a 5- to 6-membered heterocyclyl optionally substituted with one or more groups independently selected from alkyl; Each R Za2 , 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 alkoxy), R 4b1 and R 4b2 are each independently H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, or C 1 -C 6 is 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 or R 5b1 and R 5b2 together with the carbon atom to which they are attached form a 4- to 6-membered heterocyclyl; X3c 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 R 2c H, OH, halo, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, 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 alkylene)-O-(4-6 membered heterocyclyl), -O-(C 2 -C 6 Alkenylene)-(C 1 -C 6 haloalkyl), -L 1 -L 2 -(C 3 -C 7 cycloalkyl), or -OL 3 -R Xc wherein the cycloalkyl is 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 and optionally substituted with one or more groups independently selected from: L 1 is a bond or O, L 2is a bond or C 1 -C 6 is alkylene, L 3 is a bond, C 1 -C 6 Alkylene or C 2 -C 6 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 membered heterocyclyl), =NOH, =NO(C 1 -C 6 alkyl), -N=S(O)(C 1 -C 6 Alkyl) 2 , -C(=NOH)(C 3 -C 6cycloalkyl), 4- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the cycloalkyl is optionally substituted with one or more halo, and the heterocyclyl and heteroaryl are selected from 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 and optionally substituted with one or more groups independently selected from: 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 Or X 3c CR 3c and R 2c and R 3c together with the carbon atoms to which they are attached form the formula: [ka] Forming a ring of Z 1 and Z 2 are each independently O, CH 2 , or CF 2 and R Yc1 and R Yc2 are each 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 cycloalkyl), which is optionally substituted with 1 to 2 halo; 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 cycloalkyl), which is optionally substituted with 1 to 2 halo; R 6c H, halo, C 1 -C 6 Alkyl or C 1 -C 6 is haloalkyl, However, X 2a , X 4a , X 5a , and X 6a Two or less of the following are N or N + -O - and However, X 3c , X 4c , X 5c , and X 6c At most one of is N, however, R is for OR a or R is NR Xa R Ya and R Ya OH, -(C 1 -C 6 Alkylene)-R Za1 , or C 1 -C 6 Alkyl and C 1 -C 6a 4- to 6-membered heterocyclyl optionally substituted with one or more groups independently selected from alkoxy; R is NR Xa R Ya and R Xa and R Ya together with the N atom to which they are attached form a 5- to 9-membered heterocyclyl, which is Za2 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 together with the carbon atom to which they are attached form a 4- to 6-membered heterocyclyl, or R 2c is -(C 1 -C 6 Alkylene)-(C 1 -C 6 Alkoxy), -(C 1 -C 6 alkylene)-O-(4-6 membered heterocyclyl), -O-(C 2 -C 6 Alkenylene)-(C 1 -C 6 haloalkyl), or -OL 3 -R Xc or R 2c -L 1 -L 2 -(C 3 -C 7 cycloalkyl), where cycloalkyl is 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 alkylene)-OH; 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 attached form the formula: [ka] or R 4c OH, -OBn, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy or -L 1 -L 2 -(C 3 -C 6 cycloalkyl), which is optionally substituted with 1 to 2 halo, or R 5c is OH, -OBn, or -L 1 -L 2 -(C 3 -C 6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo.

[0013] In one aspect, the present invention provides a compound of formula (I'): [ka] or a pharma- ceutically acceptable salt thereof, 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 for OR a or NR Xa R Ya and R 2a , R 4a , R 5a , and R 6a are each independently H, halo, or C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -Si(C 1 -C 6 Alkyl) 3 , -Si(OC 1 -C 6 Alkoxy) 3 , -Si(C 1 -C 6 Alkyl)(OC 1 -C 6 Alkoxy) 2 , or -Si(C 1 -C 6 Alkyl) 2 (C 1 -C 6 alkoxy), R a is H or C 1 -C 6 is alkyl, R Xa is H or C 1 -C 6 is alkyl, R Ya is H, OH, C 1 -C 6Alkyl, -(C 1 -C 6 Alkylene)-R Za1 , or C 1 -C 6 Alkyl and C 1 -C 6 a 4- to 6-membered heterocyclyl optionally substituted with one or more groups independently selected from alkoxy; or R Xa and R Ya together with the nitrogen atom to which they are attached form a 5- to 9-membered heterocyclyl, the heterocyclyl being one or more R Za2 where appropriate, R Za1 OH, NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 Alkyl) 2 , and halo and C 1 -C 6 is a 5- to 6-membered heterocyclyl optionally substituted with one or more groups independently selected from alkyl; Each R Za2 , 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 alkoxy), R 4b1 and R 4b2 are each independently H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, or C 1 -C 6 is 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 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 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 R 2c H, OH, halo, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, 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 alkylene)-O-(4-6 membered heterocyclyl), -O-(C 2 -C 6 Alkenylene)-(C 1 -C 6 haloalkyl), -L 1 -L 2 -(C 3-C 7 cycloalkyl), or -OL 3 -R Xc wherein the cycloalkyl is 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 and optionally substituted with one or more groups independently selected from: L 1 is a bond or O, L 2 is a bond or C 1 -C 6 is alkylene, L 3 is a bond, C 1 -C 6 Alkylene or C 2 -C 6 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)(C1 -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 membered heterocyclyl), =NOH, =NO(C 1 -C 6 alkyl), -N=S(O)(C 1 -C 6 Alkyl) 2 , -C(=NOH)(C 3 -C 6 cycloalkyl), 4- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the cycloalkyl is optionally substituted with one or more halo, and the heterocyclyl and heteroaryl are selected from 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 and optionally substituted with one or more groups independently selected from: 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 Or X 3c CR 3c and R 2c and R 3c together with the carbon atoms to which they are attached form the formula: [ka] Forming a ring of Z 1 and Z 2 are each independently O, CH 2 , or CF 2 and R Yc1 and R Yc2 are each 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 cycloalkyl), which is optionally substituted with 1 to 2 halo; 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 cycloalkyl), which is optionally substituted with 1 to 2 halo; R 6c H, halo, C 1 -C 6 Alkyl or C 1 -C 6 is haloalkyl, However, X 2a , X 4a , X 5a , and X 6a Two or less of the following are N or N + -O - and However, X 3c , X 4c , X 5c , and X6c At most one of is N, however, R is for OR a or R is NR Xa R Ya and R Ya OH, -(C 1 -C 6 Alkylene)-R Za1 , or C 1 -C 6 Alkyl and C 1 -C 6 a 4- to 6-membered heterocyclyl optionally substituted with one or more groups independently selected from alkoxy; R is NR Xa R Ya and R Xa and R Ya together with the N atom to which they are attached form a 5- to 9-membered heterocyclyl, which is Za2 or R 2a , R 4a , R 5a , or R 6a is -Si(C 1 -C 6 alkyl), or R 5b1 Or R 5b2 But -(C 1 -C 6 Alkylene)-(C 1 -C 6 alkoxy), or R 5b1 and R 5b2 together with the carbon atom to which they are attached form a 4- to 6-membered heterocyclyl, or R 2c is -(C 1 -C 6 Alkylene)-(C 1 -C 6 Alkoxy), -(C 1 -C 6 alkylene)-O-(4-6 membered heterocyclyl), -O-(C 2-C 6 Alkimenylene)-(C 1 -C 6 haloalkyl), or -OL 3 -R Xc or R 2c -L 1 -L 2 -(C 3 -C 7 cycloalkyl), where cycloalkyl is 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 alkylene)-OH; or R 3c But -(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 attached form the formula: [ka] or R 4c OH, -OBn, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy or -L 1 -L 2 -(C 3 -C 6 cycloalkyl), which is optionally substituted with 1 to 2 halo, or R 5c is OH, -OBn, or -L 1 -L2 -(C 3 -C 6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo.

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

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

[0016] As described herein, the compounds of the present invention may include a number of variable groups (e.g., X 2a , R 5b1As one of skill in the art would recognize, combinations of groups contemplated by the present invention are those that result in the formation of stable or chemically feasible compounds. The term "stable" in this context refers to compounds that do not substantially change when subjected to conditions that permit their production, detection, and, optionally, their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or a chemically viable compound is one that does not substantially change when kept 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 depicted herein are intended to be understood as they would be understood by one of ordinary skill in the art. For example, with respect to formulas (I), (IA), (IB), and (IC), X 5a and X 6a are linked by a double bond, and X 4c and X 5c are connected by a single bond, but the bond between these groups may be hidden by atom labels in the chemical structure. 3 " or "F 3 A substituent designated as "C" refers to a trifluoromethyl substituent, regardless of whether that depiction 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 straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing no unsaturation, having a specified number of carbon atoms, which is attached to the remainder of the molecule by a single bond. For example, "C 1 -C 6 An "alkyl" group is an alkyl group having 1 to 6 carbon atoms.

[0020] As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds and having a specified number of carbon atoms, which is attached to the remainder of the molecule by a single bond. For example, "C 2 -C 6 An "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 (fused, bridged, or spiro) saturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having the specified number of carbon ring atoms, which is attached to the remainder of the molecule by a single bond. For example, "C 3 -C 8 A "cycloalkyl" group is a cycloalkyl group having 3 to 8 carbon atoms.

[0022] As used herein, the term "alkoxy" refers to a group of the formula -OR a where R a is an alkyl group having the specified number of carbon atoms. For example, "C 1 -C 6 An "alkoxy" group has the formula -OR a where R a is an alkyl group having 1 to 6 carbon atoms.

[0023] As used herein, the term "haloalkyl" refers to an alkoxy group having the specified number of carbon atoms, in which one or more of the alkyl group's hydrogen atoms are replaced by a halo group. For example, "C 1 -C 6 A "haloalkyl" group is an alkyl group having from 1 to 6 carbon atoms in which one or more of the alkyl group's hydrogen atoms is replaced by a halo group.

[0024] As used herein, the term "haloalkoxy" refers to an alkoxy group having the specified number of carbon atoms in which one or more of the alkyl group's hydrogen atoms is replaced by a halo group.

[0025] As used herein, the term "alkylene" refers to a divalent straight or branched hydrocarbon chain radical group, consisting solely of carbon and hydrogen atoms, containing no unsaturation and having the specified number of carbon atoms, which is attached to the remainder of the molecule by two single bonds. For example, "C 1 -C 6 An "alkylene" group is an alkylene group having 1 to 6 carbon atoms.

[0026] As used herein, the term "alkenylene" refers to a divalent straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds, having a specified number of carbon atoms, which is attached to the remainder of the molecule by two single bonds. For example, "C 2 -C 6 "Alkenylene" is an alkenylene group having 1 to 6 carbon atoms.

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

[0029] As used herein, labels such as "*2" and "*3" such as those shown in the structures below refer to the corresponding R group (in this case R 2c Groups and R 3c indicates the atom to which the alkyl group is attached. [ka]

[0030] Unless otherwise specified, the compounds of the invention, whether identified by chemical name or chemical structure, include all stereoisomers (e.g., enantiomers and diastereomers), double bond isomers (e.g., (Z) and (E)), conformational isomers, and tautomers of the compounds identified by the chemical names and chemical structures provided herein. Additionally, single stereoisomers, double bond isomers, conformational isomers, and tautomers, as well as mixtures of stereoisomers, double bond isomers, conformational isomers, and tautomers, are within the scope of the invention.

[0031] As used herein, in any chemical structure or formula, a straight, non-bold bond attached to a stereocenter of a compound, such as in the formula: [ka] Indicates that the configuration of a stereocenter is unspecified. The compound may have any configuration, or a mixture of configurations, at the stereocenter.

[0032] As used herein, in any chemical structure or formula, a non-bold, wavy bond (e.g., [ka] )teeth, [ka] Indicates that the compound was isolated as a mixture of geometric isomers (i.e., a mixture of compounds with (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 listed chemical name. Other stereocenters of known configuration within the compound may have the appropriate stereochemical designation within the listed chemical name. As an example, the above reference compound is listed 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 in Example 21.

[0033] As used herein, in any chemical structure or formula, a bold or dashed straight bond attached to a stereocenter of a compound, such as in the formula: [ka] A bold or dashed linear bond indicates the relative stereochemistry of a chiral center relative to the other stereocenter to which it is attached.

[0034] As used herein, in any chemical structure or formula, a bold or dashed wedge shaped bond attached to a stereocenter of a compound, such as in the formula: [ka] A bold or dashed wedge shaped bond indicates the absolute stereochemistry of a stereocenter relative to the other stereocenter to which it is attached, as well as the relative stereochemistry of the stereocenter.

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

[0036] As used herein, the prefix "rel-" when used in connection with a chiral compound refers to a single enantiomer of unknown absolute configuration. In compounds with the "rel-" prefix, the (R) and (S)- designators in the chemical name reflect the relative stereochemistry of the compound, but not necessarily the absolute stereochemistry of the compound. In some 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 stereochemical configuration of the 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 instances, the absolute configuration of some stereocenters is known, while only the relative configuration of other stereocenters is known. In these examples, stereochemical designators associated with stereocenters of known absolute configuration are marked with an asterisk (*), e.g., (R*)- and (S*)-, while stereochemical designators associated with stereocenters of unknown absolute configuration are not so marked. The unmarked stereochemical designators associated with stereocenters of unknown absolute configuration reflect the relative stereochemistry of those stereocenters relative to other stereocenters of unknown absolute configuration, but not necessarily relative stereochemistry to stereocenters of known absolute configuration.

[0037] As used herein, the term "compound" refers to a collection of molecules having the same chemical structure, except that there may be isotopic variations between the constituent atoms of the molecule, when referring to a compound of the present invention. The term "compound" includes a collection of such molecules, regardless of the purity of a given sample that contains the collection of molecules. Thus, the term "compound" includes a collection of such molecules in 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 a hydrate, solvate, or co-crystal.

[0038] As used herein, the term "amorphous" refers to a solid material that does not have long-range order in the position of its molecules. Amorphous solids are generally glasses or supercooled liquids in which the molecules are randomly arranged such that there is no well-defined arrangement, e.g., no molecular packing, and no long-range order. Amorphous solids are generally rather isotropic, i.e., they exhibit similar properties in all directions, and do not have a distinct melting point. Instead, they typically exhibit a glass transition temperature that indicates the 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 sharp characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) are seen in its XRPD pattern. Broad peaks are characteristic of amorphous solids. For a comparison of XRPD of amorphous and crystalline materials, see US2004 / 0006237. In some embodiments, a solid material may include an amorphous compound, for example, the solid material may be characterized by the lack of sharp characteristic crystalline peaks in its XRPD spectrum (i.e., the solid material is not crystalline but is amorphous as determined by XRPD). Instead, one or several broad peaks (e.g., halos) may be seen in the XRPD pattern of the solid material. For a representative comparison of XRPD of amorphous and crystalline materials, see US2004 / 0006237. A solid material including an amorphous compound may be characterized by a broader temperature range of melting of the solid material, for example, compared to the range of melting of a pure crystalline solid. Other techniques, such as, for example, solid-state NMR, may be used to characterize the crystalline or amorphous form.

[0039] In this specification and claims, unless otherwise specified, any atom not specifically designated as a specific 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 specific isotope of any compound of the present invention, no effort was made to enrich that atom in a specific isotope, and therefore, one skilled in the art will understand that such atom was likely present in about the natural abundance isotopic composition of the specified element.

[0040] As used herein, the term "stable" when referring to an isotope means that the isotope is not known to undergo spontaneous radioactive decay. Stable isotopes include, but are not limited to, isotopes whose decay mode is not specified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0041] As used herein in the specification and claims, "H" refers to hydrogen and includes any stable isotope of hydrogen, i.e. 1 Includes H and D. In the examples, when an atom is designated as "H," no attempt has been made to enrich that atom in a particular isotope of hydrogen, and thus, one of skill in the art will understand that such hydrogen atom was likely present in about the natural abundance isotopic composition of hydrogen.

[0042] As used herein, " 1 "H" refers to protium. When an atom in a compound of the invention, or a pharma- ceutically acceptable salt thereof, is designated as protium, protium is present at the designated position at least at the natural abundance concentration of protium.

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

[0044] In some embodiments, the compounds of the invention and pharma- ceutically acceptable salts thereof contain each constituent atom at about the natural abundance isotopic composition of the designated element.

[0045] In some embodiments, the compounds of the invention and their pharma- ceutically 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 designated element ("isotopically labeled" compounds and salts). Examples of stable isotopes that are commercially available and suitable for the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, e.g., 2 H, 13 C. 15 N, 18 O. 17 O, and 31 These include, but are not limited to, P.

[0046] The isotopically labeled compounds and salts can be used in a number of beneficial ways, including as medicines. In some embodiments, the isotopically labeled compounds and salts contain deuterium ( 2 H) labeled. For example, deuterium ( 2 H) The labeled compounds and salts are therapeutically useful and non- 2 3H-labeled compounds have potential therapeutic advantages over H-labeled compounds. 2 H) Labeled compounds and salts may have higher metabolic stability compared to non-isotopically labeled ones due to the kinetic isotope effect described below. Higher metabolic stability translates directly into increased in vivo half-life or lower dosage, which represents a preferred embodiment of the present invention under most circumstances. Isotopically labeled compounds and salts can be generally prepared by carrying out the procedures disclosed in the synthesis schemes, examples, and related descriptions, substituting readily available isotopically labeled reactants for non-isotopically labeled reactants.

[0047] deuterium( 2H) labeled compounds and salts can manipulate the rate of oxidative metabolism of a compound through the primary kinetic isotope effect, which is the change in the rate of a chemical reaction resulting from the exchange of an isotope nucleus, which in turn is caused by a change in the ground state energy of the covalent bonds involved in the reaction. The exchange of a heavier isotope usually results in a lowering of the ground state energy of the chemical bond and therefore a decrease in the rate-limiting bond cleavage. If the bond cleavage occurs in or near a saddle point region along the configuration of a multi-product reaction, the product distribution ratio can change significantly. For example, if deuterium is attached to a carbon atom in a non-exchangeable position, k H / k D A rate difference of 2 to 7 is typical. For further discussion, 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 by reference in its entirety.

[0048] The concentration of an isotope (e.g., deuterium) incorporated at a given position in an isotopically labeled compound of the present invention or a pharma- ceutically acceptable salt thereof can be defined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the abundance of an isotope at a given position in an isotopically labeled compound (or salt) and the natural abundance of the isotope.

[0049] When an atom in a compound of the invention or a pharma- ceutically acceptable salt thereof is designated as deuterium, such compound (or salt) has an isotopic enrichment factor for such atom of at least 3000 (about 45% deuterium incorporation). In some embodiments, the isotopic enrichment factor is at least 3500 (about 52.5% deuterium incorporation), at least 4000 (about 60% deuterium incorporation), at least 4500 (about 67.5% deuterium incorporation), at least 5000 (about 75% deuterium incorporation), at least 5500 (about 82.5% deuterium incorporation), at least 6000 (about 90% deuterium incorporation), at least 6333.3 (about 95% deuterium incorporation), at least 6466.7 (about 97% deuterium incorporation), at least 6600 (about 99% deuterium incorporation), or at least 6633.3 (about 99.5% deuterium incorporation).

[0050] In some embodiments, the present invention provides a compound of formula (IA): [ka] or a pharma- ceutically 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 is defined as set out above in relation to formula (I).

[0051] In some embodiments, the present invention provides a compound of formula (IA-1): [ka] or a pharma- ceutically 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 is defined as set out above in relation to formula (I).

[0052] In some embodiments, the present invention provides a compound of formula (IA-2): [ka] or a pharma- ceutically acceptable salt thereof, 6a , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 2c , R 3c , R 4c , and R 5c is defined as set out above in relation to formula (I).

[0053] In some embodiments, the present invention provides a compound of formula (IA-3): [ka] or a pharma- ceutically acceptable salt thereof, 6a , R 5b1 , R 5b2 , R 2c , R 3c , R 4c , and R 5c is defined as set out above in relation to formula (I).

[0054] In some embodiments, the present invention provides a compound of formula (IA-4): [ka] or a pharma- ceutically acceptable salt thereof, Xa , R Ya , R 6a , R 5b1 , R 5b2 , R 2c , R 3c, and R 4c is defined as set out above in relation to formula (I).

[0055] In some embodiments, the present invention provides a compound of formula (IB): [ka] or a pharma- ceutically acceptable salt thereof, 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 is defined as set out above in relation to formula (I).

[0056] In some embodiments, the present invention provides a compound of formula (IB-1): [ka] or a pharma- ceutically acceptable salt thereof, 2a , X 4a , X 6a , R 4b1 , R 4b2 , R 5b1 , R 5b2 , X 3c , R 2c 、 R 4c , and R 5c is defined as set out above in relation to formula (I).

[0057] In some embodiments, the present invention provides a compound of formula (IB-2): [ka] or a pharma- ceutically acceptable salt thereof, 6a , R 4b1 , R 4b2 , R5b1 , R 5b2 , R 2c , R 3c , R 4c , and R 5c is defined as set out above in relation to formula (I).

[0058] In some embodiments, the present invention provides a compound of formula (IB-3): [ka] or a pharma- ceutically acceptable salt thereof, 6a , R 5b1 , R 5b2 , R 2c , R 3c , R 4c , and R 5c is defined as set out above in relation to formula (I).

[0059] In some embodiments, the present invention provides a compound of formula (IB-4): [ka] or a pharma- ceutically acceptable salt thereof, Xa , R Ya , R 6a , R 5b1 , R 5b2 , R 2c , R 3c , and R 4c is defined as set out above in relation to formula (I).

[0060] In some embodiments, the compound of the present invention has the formula (IC): [ka] or a pharma- ceutically acceptable salt thereof, 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 is defined as set out above in relation to formula (I).

[0061] In some embodiments, the compound of the present invention has the formula (IC-1): [ka] or a pharma- ceutically acceptable salt thereof, 2a , X 4a , X 6a , R 4b1 , R 4b2 , R 5b1 , R 5b2 , X 3c , R 2c 、 R 4c , and R 5c is defined as set out above in relation to formula (I).

[0062] In some embodiments, the compound of the present invention has the formula (IC-2): [ka] or a pharma- ceutically acceptable salt thereof, 6a , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 2c , R 3c , R 4c , and R 5c is defined as set out above in relation to formula (I).

[0063] In some embodiments, the compound of the present invention has the formula (IC-3): [ka] or a pharma- ceutically acceptable salt thereof, 6a , R 5b1 , R 5b2 , R 2c , R3c , R 4c , and R 5c is defined as set out above in relation to formula (I).

[0064] In some embodiments, the compound of the present invention has the formula (IC-4): [ka] or a pharma- ceutically acceptable salt thereof, Xa , R Ya , R 6a , R 5b1 , R 5b2 , R 2c , R 3c , and R 4c is defined as set out above in relation to formula (I).

[0065] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IB), (IB-1), (IC), and (IC-1), or a pharma- ceutically acceptable salt thereof, wherein X 2a But N or CR 2a In another embodiment, X 2a is N. In other embodiments, X 2a CR 2a In another embodiment, X 2a CR 2a and R 2a is H.

[0066] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IB), (IB-1), (IC), and (IC-1), or a pharma- ceutically acceptable salt thereof, wherein X 4a But, N, N + -O - , or CR 4a In another embodiment, X 4a is N,N + -O - , or CR 4a and R 4ais H or halo. In other embodiments, X 4a is N. In other embodiments, X 4a is N + -O - In another embodiment, X 4a CR 4a In another embodiment, 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 another embodiment, X 4a CR 4a and R 4a is H. In other embodiments, X 4a CR 4a and R 4a is F.

[0067] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IB), and (IC), or a pharma- ceutically acceptable salt thereof, wherein X 5a But, CR 5a In another embodiment, X 5a CR 5a and R 5a is H.

[0068] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IB), (IB-1), (IC), and (IC-1), or a pharma- ceutically acceptable salt thereof, wherein X 6a But N or CR 6a In another embodiment, X 6a is N or CR 6a and R 6a H, halo, C 1 -C 6 Alkyl, or -Si(C 1 -C 6 Alkyl) 3 In another embodiment, X 6ais N. In other embodiments, X 6a CR 6a In another embodiment, X 6a CR 6a and R 6a H, halo, C 1 -C 6 Alkyl, or -Si(C 1 -C 6 Alkyl) 3 In another embodiment, X 6a CR 6a and R 6a is H. In other embodiments, X 6a CR 6a and R 6a In another embodiment, X is halo. 6a CR 6a and R 6a is C 1 -C 6 In another embodiment, X is an alkyl group. 6a CR 6a and R 6a is -Si(C 1 -C 6 Alkyl) 3 In another embodiment, X 6a CR 6a and R 6a are H, F, and CH 3 or -Si(CH 3 ) 3 In another embodiment, X 6a CR 6a and R 6a is F. In other embodiments, X 6a CR 6a and R 6a is CH 3 In another embodiment, X 6a CR 6a and R 6a is -Si(CH 3 ) 3 It is.

[0069] In some embodiments, the present invention relates to a compound of any one of formulas (IA-2), (IA-3), (IA-4), (IB-2), (IB-3), (IB-4), (IC-2), (IC-3), and (IC-4), or a pharma- ceutically acceptable salt thereof, wherein R 6a But, H, halo, C 1 -C 6 Alkyl, or -Si(C 1 -C 6 Alkyl) 3 In another embodiment, R 6a is H. In other embodiments, R 6a is halo. In other embodiments, R 6a is C 1 -C 6 In another embodiment, R 6a is -Si(C 1 -C 6 Alkyl) 3 In another embodiment, R 6a are H, F, and CH 3 or -Si(CH 3 ) 3 In another embodiment, R 6a is F. In other embodiments, R 6a is CH 3 In another embodiment, R 6a is -Si(CH 3 ) 3 It is.

[0070] In some embodiments, the present invention relates to a compound of formula (I), (IA), (IA-1), (IA-2), (IA-3), (IB), (IB-1), (IB-2), (IB-3), (IC), (IC-1), (IC-2), and (IC-3), or a pharma- ceutically acceptable salt thereof, wherein R is OR a or NR Xa R Ya and R a But H or C 1 -C 6 is alkyl, R Xa But H or C 1 -C 6is alkyl, R Ya But H, OH, C 1 -C 6 Alkyl, -(C 1 -C 6 Alkylene)-R Za1 , or C 1 -C 6 Alkyl and C 1 -C 6 R is a 4- to 6-membered heterocyclyl optionally substituted with one or more groups independently selected from alkoxy; Za1 OH, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 Alkyl) 2 , and halo and C 1 -C 6 In another embodiment, R is a 5- to 6-membered heterocyclyl optionally substituted with one or more groups independently selected from the group consisting of OR a In another embodiment, R is OR a and R a is H. In other embodiments, R is NR Xa R Ya In other embodiments, R is NR Xa R Ya and R Xa is H or CH 3 and R Ya are H, OH, and CH 3 , -(C 1 -C 2 Alkylene)-R Za1 , or C.H. 3 , -OCH 3 , and -OCH 2 CH 3 and R is a 4- to 6-membered heterocyclyl optionally substituted with one or more groups independently selected from Za1 -OH, -NH(CH 3 ), -N(CH 3 ) 2 , and F and CH 3 In another embodiment, R Xais H. In other embodiments, R Xa is CH 3 In another embodiment, R Ya is H. In other embodiments, R Ya is OH. In other embodiments, R Ya is CH 3 In another embodiment, R Ya is -(C 1 -C 2 Alkylene)-R Za1 and R Za1 -OH, -NH(CH 3 ), -N(CH 3 ) 2 , and F and CH 3 In another embodiment, R Ya is -(C 1 -C 2 Alkylene)-R Za1 and R Za1 is OH. In other embodiments, R Ya is -(C 1 -C 2 Alkylene)-R Za1 and R Za1 is -NH(CH 3 In another embodiment, R Ya is -(C 1 -C 2 Alkylene)-R Za1 and R Za1 is -N(CH 3 ) 2 In another embodiment, R Ya is -(C 1 -C 2 Alkylene)-R Za1 and R Za1 F and CH 3 In another embodiment, R Ya is -(C 1 -C 2 Alkylene)-R Za1 and R Za1is unsubstituted 5-6 membered heterocyclyl. In another embodiment, R Ya is -(C 1 -C 2 Alkylene)-R Za1 and R Za1 F and CH 3 In another embodiment, R Ya is -(C 1 -C 2 Alkylene)-R Za1 and R Za1 is one CH 3 In another embodiment, R Ya is -(C 1 -C 2 Alkylene)-R Za1 and R Za1 is a 5-6 membered heterocyclyl substituted with two F. In another embodiment, R Ya is -(C 1 -C 2 Alkylene)-R Za1 and R Za1 is one CH 3 and 5-6 membered heterocyclyl substituted with two F. In another embodiment, R Ya is CH 3 , -OCH 3 , and -OCH 2 CH 3 In another embodiment, R Ya is one CH 3 In another embodiment, R Ya 1 -OCH 3 In another embodiment, R Ya is one CH 3 and one -OCH 3 In another embodiment, R Ya is one CH 3 and one -OCH2 CH 3 and optionally substituted 4- to 6-membered heterocyclyl.

[0071] In some embodiments, the present invention relates to a compound of formula (IA-4), (IB-4), and (IC-4), or a pharma- ceutically acceptable salt thereof, wherein R Xa is H or CH 3 and R Ya H, OH, CH 3 , -(C 1 -C 2 Alkylene)-R Za1 , or C.H. 3 , -OCH 3 , and -OCH 2 CH 3 and R is a 4- to 6-membered heterocyclyl optionally substituted with one or more groups independently selected from Za1 OH, -NH(CH 3 ), -N(CH 3 ) 2 , and F and CH 3 In another embodiment, R Xa is H. In other embodiments, R Xa is CH 3 In another embodiment, R Ya is H. In other embodiments, R Ya is OH. In other embodiments, R Ya is CH 3 In another embodiment, R Ya is -(C 1 -C 2 Alkylene)-R Za1 and R Za1 -OH, -NH(CH 3 ), -N(CH 3 ) 2 , and F and CH 3 In another embodiment, R Ya is -(C 1 -C 2 Alkylene)-RZa1 and R Za1 is OH. In other embodiments, R Ya is -(C 1 -C 2 Alkylene)-R Za1 and R Za1 is -NH(CH 3 In another embodiment, R Ya is -(C 1 -C 2 Alkylene)-R Za1 and R Za1 is -N(CH 3 ) 2 In another embodiment, R Ya is -(C 1 -C 2 Alkylene)-R Za1 and R Za1 F and CH 3 In another embodiment, R Ya is -(C 1 -C 2 Alkylene)-R Za1 and R Za1 is unsubstituted 5-6 membered heterocyclyl. In another embodiment, R Ya is -(C 1 -C 2 Alkylene)-R Za1 and R Za1 F and CH 3 In another embodiment, R Ya is -(C 1 -C 2 Alkylene)-R Za1 and R Za1 is one CH 3 In another embodiment, R Ya is -(C 1 -C 2 Alkylene)-R Za1 and R Za1 is a 5-6 membered heterocyclyl substituted with two F. In another embodiment, R Yais -(C 1 -C 2 Alkylene)-R Za1 and R Za1 is one CH 3 and 5-6 membered heterocyclyl substituted with two F. In another embodiment, R Ya is CH 3 , -OCH 3 , and -OCH 2 CH 3 In another embodiment, R Ya is one CH 3 In another embodiment, R Ya 1 -OCH 3 In another embodiment, R Ya is one CH 3 and one -OCH 3 In another embodiment, R Ya is one CH 3 and one -OCH 2 CH 3 and optionally substituted 4- to 6-membered heterocyclyl.

[0072] In some embodiments, the present invention relates to a compound of formula (I), (IA), (IA-1), (IA-2), (IA-3), (IB), (IB-1), (IB-2), (IB-3), (IC), (IC-1), (IC-2), and (IC-3), or a pharma- ceutically acceptable salt thereof, wherein R is NR Xa R Ya and R Xa and R Ya together with the nitrogen atom to which they are attached, one or more R Za2 and forming an optionally substituted 5- to 9-membered heterocyclyl, each R Za2 are independent, halo, OH, C 1 -C 6 Alkyl, C 1 -C 6Alkoxy, 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 In another embodiment, R is selected from NR Xa R Ya and R Xa and R Ya together with the nitrogen atom to which they are attached, form one or more R Za2 In another embodiment, R is NR Xa R Ya and R Xa and R Ya together with the nitrogen atom to which they are attached, form one or more R Za2 In another embodiment, R is NR Xa R Ya and R Xa and R Ya together with the nitrogen atom to which they are attached, form one or more R Za2 In another embodiment, R is NR Xa R Ya and R Xa and R Ya together with the nitrogen atom to which they are attached, form one or more R Za2 In another embodiment, R is NR Xa R Ya and R Xa and R Ya together with the nitrogen atom to which they are attached, form one or more R Za2 In another embodiment, R Xa and R Yataken together with the nitrogen atom to which they are attached form an unsubstituted 5-9 membered heterocyclyl. In some embodiments, R Xa and R Ya together with the nitrogen atom to which they are attached form one R Za2 In some embodiments, R Xa and R Ya together with the nitrogen atom to which they are attached form two R Za2 In another embodiment, each R Za2 are independently 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 In another embodiment, at least one R Za2 is halo. In other embodiments, at least one R Za2 is OH. In other embodiments, at least one R Za2 is C 1 -C 6 In other embodiments, at least one R Za2 is C 1 -C 6 In another embodiment, at least one R Za2 NH 2 In other embodiments, at least one R Za2 is -NH(C 1 -C 6 In other embodiments, at least one R Za2 is -N(C 1 -C 6 Alkyl) 2In other embodiments, at least one R Za2 is -(C 1 -C 6 Alkylene)-(C 1 -C 6 In another embodiment, each R Za2 are independently F, OH, CH 3 , -OCH 3 , N.H. 2 , -NH(CH 3 ), -N(CH 3 ) 2 , and -CH 2 OCH 3 In another embodiment, at least one R Za2 is F. In other embodiments, at least one R Za2 is CH 3 In other embodiments, at least one R Za2 -OCH 3 In other embodiments, at least one R Za2 is -NH(CH 3 In other embodiments, at least one R Za2 is -N(CH 3 ) 2 In other embodiments, at least one R Za2 is -CH 2 OCH 3 It is.

[0073] In some embodiments, the present invention relates to a compound of any one of formulas (IA-4), (IB-4), and (IC-4), or a pharma- ceutically acceptable salt thereof, wherein R Xa and R Ya together with the nitrogen atom to which they are attached, one or more R Za2 and forming an optionally substituted 5- to 9-membered heterocyclyl, each R Za2 are independent, halo, OH, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, NH 2 , -NH(C 1 -C 6alkyl), -N(C 1 -C 6 Alkyl) 2 , and -(C 1 -C 6 Alkylene)-(C 1 -C 6 In some embodiments, R Xa and R Ya together with the nitrogen atom to which they are attached, form one or more R Za2 In some embodiments, R Xa and R Ya together with the nitrogen atom to which they are attached, form one or more R Za2 In some embodiments, R Xa and R Ya together with the nitrogen atom to which they are attached, form one or more R Za2 In some embodiments, R Xa and R Ya together with the nitrogen atom to which they are attached, form one or more R Za2 In some embodiments, R Xa and R Ya together with the nitrogen atom to which they are attached, form one or more R Za2 In another embodiment, R Xa and R Ya taken together with the nitrogen atom to which they are attached form an unsubstituted 5-9 membered heterocyclyl. In some embodiments, R Xa and R Ya together with the nitrogen atom to which they are attached form one R Za2 In some embodiments, R Xa and R Ya together with the nitrogen atom to which they are attached form two R Za2In another embodiment, each R Za2 are independently 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 In another embodiment, at least one R Za2 is halo. In other embodiments, at least one R Za2 is OH. In other embodiments, at least one R Za2 is C 1 -C 6 In other embodiments, at least one R Za2 is C 1 -C 6 In another embodiment, at least one R Za2 NH 2 In other embodiments, at least one R Za2 is -NH(C 1 -C 6 In other embodiments, at least one R Za2 is -N(C 1 -C 6 Alkyl) 2 In other embodiments, at least one R Za2 is -(C 1 -C 6 Alkylene)-(C 1 -C 6 In another embodiment, each R Za2 are independently F, OH, CH 3 , -OCH 3 , N.H. 2 , -NH(CH 3 ), -N(CH 3 )2 , and -CH 2 OCH 3 In another embodiment, at least one R Za2 is F. In other embodiments, at least one R Za2 is CH 3 In other embodiments, at least one R Za2 -OCH 3 In other embodiments, at least one R Za2 is -NH(CH 3 In other embodiments, at least one R Za2 is -N(CH 3 ) 2 In other embodiments, at least one R Za2 is -CH 2 OCH 3 It is.

[0074] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IA-2), (IB), (IB-1), (IB-2), (IC), (IC-1), and (IC-2), or a pharma- ceutically acceptable salt thereof, wherein R 4b1 But H or C 1 -C 6 In another embodiment, R 4b1 is H or CH 3 In another embodiment, R 4b1 is H. In other embodiments, R 4b1 is C 1 -C 6 In another embodiment, R 4b1 is CH 3 It is.

[0075] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IA-2), (IB), (IB-1), (IB-2), (IC), (IC-1), and (IC-2), or a pharma- ceutically acceptable salt thereof, wherein R 4b2 But H or C 1 -C6 In another embodiment, R 4b2 is H or CH 3 In another embodiment, R 4b1 is H. In other embodiments, R 4b2 is C 1 -C 6 In another embodiment, R 4b2 is CH 3 It is.

[0076] In some embodiments, the present invention relates to a compound of any one 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), or a pharma- ceutically acceptable salt thereof, wherein R 5b1 But, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or -(C 1 -C 6 Alkylene)-(C 1 -C 6 In another embodiment, R 5b1 is CH 3 , C.F. 3 , -CH 2 OCH 3 , or -CH 2 CH 2 OCH 3 In another embodiment, R 5b1 is C 1 -C 6 In another embodiment, R 5b1 is CH 3 In another embodiment, R 5b1 is C 1 -C 6 In another embodiment, R 5b1 CF 3 In another embodiment, R 5b1 is -(C 1 -C 6Alkylene)-(C 1 -C 6 In another embodiment, R 5b1 is -CH 2 OCH 3 In another embodiment, R 5b1 is -CH 2 CH 2 OCH 3 It is.

[0077] In some embodiments, the present invention relates to a compound of any one 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), or a pharma- ceutically acceptable salt thereof, wherein R 5b2 But, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or -(C 1 -C 6 Alkylene)-(C 1 -C 6 In another embodiment, R 5b2 is CH 3 , C.F. 3 , -CH 2 OCH 3 , or -CH 2 CH 2 OCH 3 In another embodiment, R 5b2 is C 1 -C 6 In another embodiment, R 5b2 is CH 3 In another embodiment, R 5b2 is C 1 -C 6 In another embodiment, R 5b2 CF 3 In another embodiment, R 5b2 is -(C 1 -C 6 Alkylene)-(C 1 -C6 In another embodiment, R 5b2 is -CH 2 OCH 3 In another embodiment, R 5b2 is -CH 2 CH 2 OCH 3 It is.

[0078] In some embodiments, the present invention relates to a compound of any one 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), or a pharma- ceutically acceptable salt thereof; 5b1 and R 5b2 together with the carbon atom to which they are attached form a 4-membered heterocyclyl. In other embodiments, the 4-membered heterocyclyl is oxetanyl.

[0079] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IB), (IB-1), (IC), and (IC-1), or a pharma- ceutically acceptable salt thereof, wherein X 3c But N or CR 3c and R 3c But, 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 In another embodiment, X is an alkoxy group. 3c is N. In other embodiments, X 3c CR 3c In another embodiment, X 3c CR 3c and R 3c H, halo, C1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -(C 1 -C 6 alkylene)-OH, or -(C 1 -C 6 Alkylene)-(C 1 -C 6 In another embodiment, X is an alkoxy group. 3c CR 3c and R 3c is H. In other embodiments, X 3c CR 3c and R 3c In another embodiment, X is halo. 3c CR 3c and R 3c is C 1 -C 6 In another embodiment, X is an alkyl group. 3c CR 3c and R 3c is C 1 -C 6 In another embodiment, X is haloalkyl. 3c CR 3c and R 3c is -(C 1 -C 6 In another embodiment, X is -OH. 3c CR 3c and R 3c is -(C 1 -C 6 Alkylene)-(C 1 -C 6 In another embodiment, X is an alkoxy group. 3c CR 3c and R 3c are H, F, Cl, CH 3 , C.F. 3 , -CH 2 OH or -CH 2 OCH 3 In another embodiment, X 3c CR 3c and R 3c is F. In other embodiments, X3c CR 3c and R 3c is Cl. In other embodiments, X 3c CR 3c and R 3c is CH 3 In another embodiment, X 3c CR 3c and R 3c CF 3 In another embodiment, X 3c CR 3c and R 3c is -CH 2 In another embodiment, X is OH. 3c CR 3c and R 3c is -CH 2 OCH 3 It is.

[0080] In some embodiments, the present invention relates to a compound of any one of formulas (IA-2), (IA-3), (IA-4), (IB-2), (IB-3), (IB-4), (IC-2), (IC-3), and (IC-4), or a pharma- ceutically acceptable salt thereof, wherein R 3c But, 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 In another embodiment, R 3c is H. In other embodiments, R 3c is halo. In other embodiments, R 3c is C 1 -C 6 In another embodiment, R 3c is C 1 -C 6 In another embodiment, R 3c is -(C 1 -C6 In another embodiment, R 3c is -(C 1 -C 6 Alkylene)-(C 1 -C 6 In another embodiment, R 3c are H, F, Cl, CH 3 , C.F. 3 , -CH 2 OH or -CH 2 OCH 3 In another embodiment, R 3c is F. In other embodiments, R 3c is Cl. In other embodiments, R 3c is CH 3 In another embodiment, R 3c CF 3 In another embodiment, R 3c is -CH 2 In another embodiment, R 3c is -CH 2 OCH 3 It is.

[0081] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IB), and (IC), or a pharma- ceutically acceptable salt thereof, wherein X 4c But, CR 4c and R 4c 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 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; L 1 is O and L 2 is a bond or C 1 -C 6 In another embodiment, X is an alkylene.4c CR 4c and R 4c is H. In other embodiments, X 4c CR 4c and R 4c In another embodiment, X is halo. 4c CR 4c and R 4c is OH. In other embodiments, X 4c CR 4c and R 4c In another embodiment, X is -OBn. 4c CR 4c and R 4c is C 1 -C 6 In another embodiment, X is alkoxy. 4c CR 4c and R 4c is C 1 -C 6 In another embodiment, X is haloalkyl. 4c CR 4c and R 4c is C 1 -C 6 In another embodiment, X is haloalkoxy. 4c CR 4c and R 4c -L 1 -L 2 -(C 3 -C 6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; L 1 is O and L 2 is a bond or C 1 -C 6 In another embodiment, X is an alkylene. 4c CR 4c and R 4c -L 1 -L 2 -(C 3 -C 6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; L 1 is O and L2 is a bond. In other embodiments, X 4c CR 4c and R 4c -L 1 -L 2 -(C 3 -C 6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; L 1 is O and L 2 is C 1 -C 6 In another embodiment, X is an alkylene. 4c CR 4c and R 4c are H, F, OH, -OBn, -OCH 3 , -OCH 2 CH 3 , CHF 2 , -OCHF 2 , -OCF 3 , -O-CH 2 -(cyclopropyl), or -O-(cyclobutyl), where the cyclobutyl is substituted with two F. In another embodiment, X 4c CR 4c and R 4c is F. In other embodiments, X 4c CR 4c and R 4c -OCH 3 In another embodiment, X 4c CR 4c and R 4c -OCH 2 CH 3 In another embodiment, X 4c CR 4c and R 4c is CHF 2 In another embodiment, X 4c CR 4c and R 4c , -OCHF 2 In another embodiment, X 4c CR 4c and R 4c -OCF 3In another embodiment, X 4c CR 4c and R 4c is -O-CH 2 In another embodiment, X is -(cyclopropyl). 4c CR 4c and R 4c is -O-(cyclobutyl), which is substituted with two F.

[0082] In some embodiments, the present invention relates to a compound of any one of formulas (IA-1), (IA-2), (IA-3), (IA-4), (IB-1), (IB-2), (IB-3), (IB-4), (IC-1), (IC-2), (IC-3), and (IC-4), wherein R 4c 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 cycloalkyl, optionally substituted with 1 to 2 halo, L 1 is O and L 2 is a bond or C 1 -C 6 In another embodiment, R 4c is H. In other embodiments, R 4c is halo. In other embodiments, R 4c is OH. In other embodiments, R 4c In another embodiment, R 4c is C 1 -C 6 In another embodiment, R 4c is C 1 -C 6 In another embodiment, R 4c is C 1 -C 6In another embodiment, R 4c -L 1 -L 2 -(C 3 -C 6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; L 1 is O and L 2 is a bond or C 1 -C 6 In another embodiment, R 4c -L 1 -L 2 -(C 3 -C 6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; L 1 is O and L 2 is a bond. In other embodiments, R 4c -L 1 -L 2 -(C 3 -C 6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; L 1 is O and L 2 is C 1 -C 6 In another embodiment, R 4c are H, F, OH, -OBn, -OCH 3 , -OCH 2 CH 3 , CHF 2 , -OCHF 2 , -OCF 3 , -O-CH 2 -(cyclopropyl), or -O-(cyclobutyl), where the cyclobutyl is substituted with two F. In another embodiment, R 4c is H. In other embodiments, R 4c is F. In other embodiments, R 4c is OH. In other embodiments, R 4c In another embodiment, R 4c -OCH 3 In another embodiment, R4c -OCH 2 CH 3 In another embodiment, R 4c is CHF 2 In another embodiment, R 4c , -OCHF 2 In another embodiment, R 4c -OCF 3 In another embodiment, R 4c is -O-CH 2 -(cyclopropyl). In another embodiment, R 4c is -O-(cyclobutyl), which is substituted with two F.

[0083] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IB), and (IC), or a pharma- ceutically acceptable salt thereof, wherein X 5c But, CR 5c and R 5c is H, halo, OH, -OBn, or -L 1 -L 2 -(C 3 -C 6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; L 1 is O and L 2 is a bond. In other embodiments, X 5c CR 5c and R 5c is H. In other embodiments, X 5c CR 5c and R 5c In another embodiment, X is halo. 5c CR 5c and R 5c is OH. In other embodiments, X 5c CR 5c and R 5c In another embodiment, X is -OBn. 5c CR 5c and R 5c -L 1 -L 2-(C 3 -C 6 cycloalkyl), wherein the 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 CR 5c and R5c is H, Cl, OH, -OBn, or -O-(cyclobutyl), wherein the cyclobutyl is substituted with two F. In another embodiment, X 5c CR 5c and R 5c is Cl. In other embodiments, X 5c CR 5c and R 5c is -O-(cyclobutyl), which is substituted with two F.

[0084] In some embodiments, the present invention relates to a compound of any one of formulas (IA-1), (IA-2), (IA-3), (IA-4), (IB-1), (IB-2), (IB-3), (IB-4), (IC-1), (IC-2), (IC-3), and (IC-4), wherein R 5c is H, halo, OH, -OBn, or -L 1 -L 2 -(C 3 -C 6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; 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 5c In another embodiment, R 5c -L 1 -L 2 -(C 3 -C 6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; L1 is O and L 2 is a bond. In other embodiments, R 5c is H, Cl, OH, -OBn, or -O-(cyclobutyl), which is substituted with two F. In other embodiments, R 5c is Cl. In other embodiments, R 5c is -O-(cyclobutyl), which is substituted with two F.

[0085] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IB), and (IC), or a pharma- ceutically acceptable salt thereof, wherein X 6c But, CR 6c and R 6c But it's H.

[0086] In some embodiments, the present invention relates to a compound of formula (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 pharma- ceutically acceptable salt thereof, wherein R 2c But, OH, halo, C 1 -C 6 Alkoxy, -(C 1 -C 6 Alkylene)-(C 1 -C 6 Alkoxy), -(C 1 -C 6 alkylene)-O-(4-6 membered heterocyclyl), -O-(C 2 -C 6 Alkenylene)-(C 1 -C 6 haloalkyl), -L 1 -L 2 -(C 3 -C 7 cycloalkyl), or -OL 3 -R Xc and the cycloalkyl is OH, CN, C 1 -C 6Alkyl, C 1 -C 6 Alkoxy, =NOH, -C(O)(C 1 -C 6 alkyl), and -(C 1 -C 6 L is optionally substituted with one or more groups independently selected from the group consisting of alkylene-OH; 1 is O and L 2 is a bond or C 1 -C 6 alkylene, L 3 But, bond, C 1 -C 6 Alkylene or C 2 -C 6 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 membered heterocyclyl), =NOH, =NO(C 1 -C 6 alkyl), -N=S(O)(C 1 -C 6 Alkyl) 2 , -C(=NOH)(C 3 -C 6 cycloalkyl), 4- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the cycloalkyl is optionally substituted with one or more halo, and the heterocyclyl and heteroaryl are selected from 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 and optionally substituted with one or more groups independently selected from: alkylene)-OH.

[0087] In another embodiment, the present invention relates to a compound of any one 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), or a pharma- ceutically acceptable salt thereof, wherein R 2c But, OH, halo, C 1 -C 6 Alkoxy, -(C 1 -C 6 Alkylene)-(C 1 -C 6 Alkoxy), -(C 1 -C 6 alkylene)-O-(4-6 membered heterocyclyl), -O-(C 2 -C 6 Alkenylene)-(C 1 -C 6 haloalkyl). In another embodiment, R 2c is OH. In other embodiments, R 2cis halo. In other embodiments, R 2c is C 1 -C 6 In another embodiment, R 2c is -(C 1 -C 6 Alkylene)-(C 1 -C 6 In another embodiment, R 2c is -(C 1 -C 6 In another embodiment, R 2c is -O-(C 2 -C 6 Alkenylene)-(C 1 -C 6 haloalkyl). In another embodiment, R 2c -OH, Cl, -OCH 3 , -CH 2 OCH 3 , -CH 2 -O-(4-membered heterocyclyl), or -O-(C 3 -C 4 Alkenylene)-CF 3 In another embodiment, R 2c is Cl. In other embodiments, R 2c -OCH 3 In another embodiment, R 2c is -CH 2 OCH 3 In another embodiment, R 2c is -CH 2 In another embodiment, R 2c is -O-(C 3 -C 4 Alkenylene)-CF 3 It is.

[0088] In some embodiments, the present invention relates to a compound of any one 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), or a pharma- ceutically acceptable salt thereof, wherein R 2c But -L 1 -L 2 -(C 3 -C 7 cycloalkyl), and L 1 is O and L 2 is a bond or C 1 -C 6 alkylene, and the cycloalkyl is OH, CN, -OCH 3 ,CH 3 , =NOH, -C(O)(CH 3 ), and -CH 2 In another embodiment, R 2c -L 1 -L 2 -(C 3 -C 7 cycloalkyl), and L 1 is O and L 2 is a bond, and the cycloalkyl is OH, CN, -OCH 3 , C.H. 3 , =NOH, -C(O)(CH 3 ), and -CH 2 R is substituted with one or more groups independently selected from OH. 2c -L 1 -L 2 -(C 3 -C 7 cycloalkyl), and L 1 is O and L 2 is C 1 -C 6 alkylene, and the cycloalkyl is OH, CN, -OCH 3 , C.H. 3 , =NOH, -C(O)(CH 3 ), and -CH 2In another embodiment, the cycloalkyl is substituted with one or more groups independently selected from -OH. In another embodiment, the cycloalkyl is substituted with at least one -OH. In another embodiment, the cycloalkyl is substituted with at least one -CN. In another embodiment, the cycloalkyl is substituted with at least one -OCH 3 In other embodiments, the cycloalkyl is substituted with at least one CH 3 In another embodiment, the cycloalkyl is substituted with at least one -C(O)(CH 3 In other embodiments, the cycloalkyl is substituted with at least one -CH 2 It is substituted with OH.

[0089] In some embodiments, the present invention relates to a compound of formula (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 pharma- ceutically acceptable salt thereof, wherein R 2c But, -OL 3 -R Xc And L 3 But, bond, C 1 -C 6 Alkylene or C 4 -C 5 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 membered heterocyclyl), =NOH, =NO(C 1 -C 6 alkyl), -N=S(O)(C 1 -C 6 Alkyl) 2 , -C(=NOH)(C 3 -C 6 cycloalkyl), 4- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the cycloalkyl is optionally substituted with one or more halo, and the heterocyclyl and heteroaryl are selected from 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 In another embodiment, R 2c -OL 3 -R Xc And L 3 is a bond. In other embodiments, R 2c -OL 3 -R Xc And L 3 is C1 -C 6 In another embodiment, R 2c -OL 3 -R Xc , and C 4 -C 5 In another embodiment, R 2c -OL 3 -R Xc and R Xc is OH. In other embodiments, R 2c -OL 3 -R Xc and R Xc is CN. In other embodiments, R 2c -OL 3 -R Xc and R Xc is C 1 -C 6 In another embodiment, R 2c -OL 3 -R Xc and R Xc NH 2 In another embodiment, R 2c -OL 3 -R Xc and R Xc is -NH(C 1 -C 6 In another embodiment, R 2c -OL 3 -R Xc and R Xc is -N(C 1 -C 6 Alkyl) 2 In another embodiment, R 2c -OL 3 -R Xc and R Xc is -NH(C 1 -C 6 haloalkyl). In another embodiment, R 2c -OL 3 -R Xc and R Xc is -N(C 1 -C 6 Haloalkyl)2 In another embodiment, R 2c -OL 3 -R Xc and R Xc is -CH(CH 2 OH) 2 In another embodiment, R 2c -OL 3 -R Xc and R Xc is -CH(CH 2 OH)(CH 2 OCH 3 In another embodiment, R 2c -OL 3 -R Xc and R Xc is -CH(CH 2 OH)(OCH 3 In another embodiment, R 2c -OL 3 -R Xc and R Xc is -CH(CH 2 OCH 3 )(OCH 3 In another embodiment, R 2c -OL 3 -R Xc and R Xc is -CH(CH 2 OH)(CF 3 In another embodiment, R 2c -OL 3 -R Xc and R Xc is -C(O)(C 1 -C 6 In another embodiment, R 2c -OL 3 -R Xc and R Xc is -C(O)NH 2 In another embodiment, R 2c -OL 3 -R Xc and R Xc is -C(O)NH(C 1 -C 6 In another embodiment, R2c -OL 3 -R Xc and R Xc is -C(O)N(C 1 -C 6 Alkyl) 2 In another embodiment, R 2c -OL 3 -R Xc and R Xc is -NH(4-6 membered heterocyclyl). In another embodiment, R 2c -OL 3 -R Xc and R Xc is =NOH. In another embodiment, R 2c -OL 3 -R Xc and R Xc =NO(C 1 -C 6 In another embodiment, R 2c -OL 3 -R Xc and R Xc is -N=S(O)(C 1 -C 6 Alkyl) 2 In another embodiment, R 2c -OL 3 -R Xc and R Xc is -C(=NOH)(C 3 -C 6 cycloalkyl), where the cycloalkyl is optionally substituted with one or more halo. In other embodiments, R 2c -OL 3 -R Xc and R Xc is a 4-8 membered heterocyclyl, the heterocyclyl being 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 -C6 In another embodiment, R 2c -OL 3 -R Xc and R Xc and 5-6 membered heteroaryl, the heteroaryl being 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 In another embodiment, R 2c -OL 3 -R Xc and R Xc 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 membered heterocyclyl);=NOH;=NO(CH 3 );-N=S(O)(CH 3 ) 2 ;-C(=NOH)(C 3 -C4 Cycloalkyl);OH, F, CH 3 , -OCH 3 , CHF 2 , C.F. 3 , -OCHF 2 , and -CH 2 4-8 membered heterocyclyl optionally substituted with one or more groups independently selected from OH; and CH 3 In another embodiment, R is a 5-membered heteroaryl optionally substituted with one F. 2c -OL 3 -R Xc and R Xc -OCH 3 In another embodiment, R 2c -OL 3 -R Xc and R Xc is -NH(CH 3 In another embodiment, R 2c -OL 3 -R Xc and R Xc is -NH(CH(CH 3 ) 2 In another embodiment, R 2c -OL 3 -R Xc and R Xc is -N(CH 3 ) 2 In another embodiment, R 2c -OL 3 -R Xc and R Xc is -NH(CH 2 CHF 2 In another embodiment, R 2c -OL 3 -R Xc and R Xc is -C(O)(CH 3 In another embodiment, R 2c -OL 3 -R Xc and R Xc is -C(O)NH(CH 3In another embodiment, R 2c -OL 3 -R Xc and R Xc is -NH(4-5 membered heterocyclyl). In another embodiment, R 2c -OL 3 -R Xc and R Xc =NO(CH 3 In another embodiment, R 2c -OL 3 -R Xc and R Xc is -C(=NOH)(C 3 -C 4 cycloalkyl), where the cycloalkyl is optionally substituted with one F. In other embodiments, R 2c -OL 3 -R Xc and R Xc OH, F, CH 3 , -OCH 3 , CHF 2 , C.F. 3 , -OCHF 2 , and -CH 2 4-8 membered heterocyclic group optionally substituted with one or more groups independently selected from OH In another embodiment, R 2c -OL 3 -R Xc and R Xc is CH 3 is a 5-membered heteroaryl optionally substituted with

[0090] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IB), (IB-1), (IC), and (IC-1), or a pharma- ceutically acceptable salt thereof, wherein X 3c But, CR 3c and R 2c and R 3c together with the carbon atom to which they are attached form the formula: [ka] Forming a ring of In the formula, Z 1 is O or CH 2 and Z 2 is O or CF 2 and R Yc1 and R Yc2 Each is independently H or F. In another embodiment, X 3c CR 3c and R 2c and R 3c together with the carbon atoms to which they are attached form the formula: [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 attached form the formula: [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 attached form the formula: [ka] It forms a ring.

[0091] In some embodiments, the present invention relates to a compound of any one of formulas (IA-2), (IA-3), (IA-4), (IB-2), (IB-3), (IB-4), (IC-2), (IC-3), and (IC-4), or a pharma- ceutically acceptable salt thereof, wherein R 2c and R 3c together with the carbon atom to which they are attached form the formula: [ka] Forming a ring of In the formula, Z 1 is O or CH 2 and Z 2 But O or CF 2 and R Yc1 and R Yc2 is each independently H or F. In other embodiments, R 2c and R 3c together with the carbon atoms to which they are attached form the formula: [ka] It forms a ring. In other embodiments, R 2c and R 3c together with the carbon atoms to which they are attached form the formula: [ka] It forms a ring. In other embodiments, R 2c and R 3c together with the carbon atoms to which they are attached form the formula: [ka] It forms a ring.

[0092] In some embodiments, the present invention relates to a compound of any one 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), or any embodiment thereof, in salt form. 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 a compound of any one 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), or any embodiment thereof, i.e., a non-salt form of the compound.

[0094] In some embodiments, the invention relates to a compound selected from Table A, or a pharma- ceutically acceptable salt thereof. In other embodiments, the invention relates to a compound selected from Table A, i.e., the compound in non-salt form. [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

[0095] In some embodiments, the invention relates to a compound selected from Table B, or a pharma- ceutically acceptable salt thereof. In other embodiments, the invention relates to a compound selected from Table B, i.e., a compound in non-salt form. [Table 2]

[0096] In some embodiments, the invention relates to a compound selected from Table A or Table B, or a pharma- ceutically acceptable salt thereof. In other embodiments, the invention relates to a compound selected from Table A or Table B, i.e., the compound in non-salt form.

[0097] In some embodiments, the present invention provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, the compound has the absolute stereochemistry of the second eluting 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 non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0098] In some embodiments, the present invention provides a compound of the formula: [ka] and pharma- ceutically acceptable salts thereof. In another embodiment, the invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0099] In some embodiments, the present invention provides a compound of the formula: [ka] and pharma- ceutically acceptable salts thereof. In another embodiment, the invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0100] In some embodiments, the present invention provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, the compound has the absolute stereochemistry of the second eluting 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 form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0101] In some embodiments, the present invention provides a compound of the formula: [ka] and pharma- ceutically acceptable salts thereof. In another embodiment, the invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0102] In some embodiments, the present invention provides a compound of the formula: [ka] and pharma- ceutically acceptable salts thereof. In another embodiment, the invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0103] In some embodiments, the present invention provides a compound of the formula: [ka] and pharma- ceutically acceptable salts thereof. In another embodiment, the invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0104] In some embodiments, the present invention provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, the compound has the absolute stereochemistry of the second eluting 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 form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0105] In some embodiments, the present invention provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, when 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 and rac-4-((2R,3S,4R,5S)-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 eluting isomer. In another embodiment, the present invention relates to the aforementioned compound in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0106] In some embodiments, the present invention provides a compound of the formula: [ka] and pharma- ceutically acceptable salts thereof. In another embodiment, the invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0107] In some embodiments, the present invention provides a compound of the formula: [ka] and pharma- ceutically acceptable salts thereof. In another embodiment, the invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0108] In some embodiments, the present invention provides a compound of the formula: [ka] and pharma- ceutically acceptable salts thereof. In another embodiment, the invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0109] In some embodiments, the present invention provides a compound of the formula: [ka] or a pharma- ceutically 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-(trifluoromethyl)tetrahydrofuran-2-carboxamide 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-carboxamido)picolinamide, including 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-(hydroxyimino)-3-methylbutoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide, is separated by SFC as described in Example 21, the compound has the absolute stereochemistry of the first eluting isomer. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the present invention" as that term is used herein.

[0110] In some embodiments, the present invention provides a compound of the formula: [ka] and pharma- ceutically acceptable salts thereof. In another embodiment, the invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0111] In some embodiments, the present invention provides a compound of the formula: [ka] and pharma- ceutically acceptable salts thereof. In another embodiment, the invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0112] In some embodiments, the present invention provides a compound of the formula: [ka] and pharma- ceutically acceptable salts thereof. In another embodiment, the invention relates to the aforementioned compounds in non-salt form. In another embodiment, the invention relates to the trifluoroacetate salts of the aforementioned compounds. Such compounds are considered to be "compounds of the invention" as that 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 pharma- ceutically acceptable salts thereof that are inhibitors of voltage-gated sodium channels, and thus the compounds and pharma- ceutically acceptable salts thereof are useful for treating diseases, disorders, and conditions, including, but not limited to, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia. Thus, in another aspect of the present invention, pharmaceutical compositions are provided, which comprise a compound as described herein, or a pharma- ceutically acceptable salt thereof, and optionally include a pharma- ceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0114] As used herein, the term "pharmaceutically acceptable" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" of a compound of the invention includes any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of the present disclosure or an inhibitory active metabolite or residue thereof. The salt may be in pure form, in admixture with one or more other substances (e.g., solution, suspension, or colloid), or in the form of a hydrate, solvate, or co-crystal. As used herein, the term "inhibitorily active metabolite or residue thereof" means that the metabolite or residue thereof is also an inhibitor of voltage-gated sodium channels.

[0115] Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge, et al. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. The pharmaceutically 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 the salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or 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 pharma- ceutically acceptable salts include adipate, 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, 2-hydroxy-ethanesulfonate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-type salts such as sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. + (C 1-4 Alkyl) 4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharma-ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0116] As used herein, the pharma- ceutically acceptable compositions of the present invention additionally include pharma- ceutically acceptable carriers, adjuvants, or vehicles, including any and all solvents, diluents, or other liquid vehicles, dispersing or suspending aids, surface active agents, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, appropriate for the particular dosage form desired, as used herein. Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharma- ceutical acceptable compositions and known techniques for their preparation. The use of any conventional carrier medium is contemplated within the scope of the present disclosure, except insofar as it is incompatible with the compounds of the present invention, for example, by causing any undesirable biological effects or otherwise interacting in a deleterious manner with any other component of the pharma- ceutical acceptable composition.Some examples of materials that may serve as pharma- ceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates, glycine, sorbic acid, and potassium sorbate, etc.), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., carboxymethylcellulose, cellulose esters ... 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 solutions, and other non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), as well as coloring agents, releasing agents, coating agents, sweetening, flavoring, and perfuming agents; preservatives and antioxidants can also be present in the composition according to the judgment of the formulator.

[0117] In another aspect, the invention features a pharmaceutical composition including a compound of the invention, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0118] In another aspect, the invention features a pharmaceutical composition that includes a therapeutically effective amount of a compound, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers or vehicles.

[0119] Uses of the Compounds and Pharmaceutically Acceptable Salts and Compositions In another aspect, the invention features a method of inhibiting a voltage-gated sodium channel in a subject, the method includes administering to the subject a compound of the invention, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. V It's 1.8.

[0120] In yet another aspect, the invention features a method of treating or lessening the severity in a subject of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia, the method includes administering an effective amount of a compound, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0121] In yet another aspect, the invention features a method of treating or lessening the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, or cardiac arrhythmia in a subject, the method includes administering an effective amount of a compound, a pharmacologic salt thereof, or a pharmaceutical composition thereof.

[0122] In yet another aspect, the invention features a method of treating or lessening the severity of intestinal pain in a subject, where intestinal pain includes inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain, the method includes administering an effective amount of a compound of the invention, a pharmacologic acceptable salt thereof, or a pharmaceutical composition thereof.

[0123] In yet another aspect, the invention features a method for treating or reducing the severity of neuropathic pain in a subject, comprising administering an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, the neuropathic pain comprises postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some aspects, the neuropathic pain comprises diabetic neuropathy (e.g., diabetic peripheral neuropathy). As used herein, the phrase "idiopathic small fiber neuropathy" shall be understood to include any small fiber neuropathy.

[0124] In yet another aspect, the invention features a method of treating or lessening the severity of neuropathic pain in a subject, including post-herpetic neuralgia, diabetic neuropathy, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, pain after amputation surgery, phantom limb pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, medication-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, the method comprising administering an effective amount of a compound of the invention, a pharmacologic acceptable salt thereof, or a pharmaceutical composition thereof.

[0125] In yet another aspect, the invention features a method of treating or reducing the severity of musculoskeletal pain in a subject comprising administering an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, hi some aspects, the musculoskeletal pain comprises osteoarthritis.

[0126] In yet another aspect, the invention features a method of treating or lessening the severity of musculoskeletal pain in a subject, where musculoskeletal pain includes osteoarthritis, back pain, cold pain, burn pain, or dental pain, the method includes administering an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0127] In yet another aspect, the invention features a method of treating or lessening the severity of inflammatory pain in a subject, including rheumatoid arthritis pain or vulvodynia, the method including administering an effective amount of a compound of the invention, a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition thereof.

[0128] In yet another aspect, the invention features a method of treating or lessening the severity of inflammatory pain in a subject, including rheumatoid arthritis pain, the method including administering an effective amount of a compound of the invention, a pharmacologic acceptable salt thereof, or a pharmaceutical composition thereof.

[0129] In yet another aspect, the invention features a method of treating or lessening the severity of idiopathic pain in a subject, including fibromyalgia pain, the method including administering an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0130] In yet another aspect, the invention features a method of treating or reducing the severity of pathological cough in a subject, the method comprising administering an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0131] In yet another aspect, the invention features a method of treating or reducing the severity of acute pain in a subject comprising administering an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, hi some aspects, the acute pain comprises acute post-operative pain.

[0132] In yet another aspect, the invention features a method of treating or reducing the severity of post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain) in a subject comprising administering an effective amount of a compound of the invention, a pharmacologic salt thereof, or a pharmaceutical composition thereof.

[0133] In yet another aspect, the invention features a method of treating or reducing the severity of bunionectomy pain in a subject comprising administering an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0134] In yet another aspect, the invention features a method of treating herniorrhaphy pain or reducing its severity in a subject comprising administering an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

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

[0136] In yet another aspect, the invention features a method of treating or lessening the severity of visceral pain in a subject comprising administering an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, hi some aspects, the visceral pain comprises abdominoplasty visceral pain.

[0137] In yet another aspect, the invention features a method of treating or reducing the severity of a neurodegenerative disease in a subject, comprising administering an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt-Hopkins syndrome (PTHS).

[0138] In yet another aspect, the invention features a method in which a subject is treated with one or more additional therapeutic agents administered simultaneously with, prior to, or following treatment with an effective amount of a compound, pharma- ceutically acceptable salt, or pharmaceutical composition, hi some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0139] In another aspect, the invention features a method of inhibiting a voltage-gated sodium channel in a biological sample, the method including contacting the biological sample with an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. V It's 1.8.

[0140] In another aspect, the present invention provides a method for treating acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, algesic pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain in multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis, post-herpetic neuralgia, diabetic neuropathic pain, and inflammatory bowel disorders. rheumatoid arthropathy, radicular pain, sciatica, back pain, unspecified chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), cancer pain including chronic cancer pain and cancer breakthrough pain, stroke (e.g., central neuropathic pain after stroke), traumatic neck syndrome, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus rheumatoid arthritis, epidermolysis bullosa, gout, juvenile idiopathic arthritis, osteoporosis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic osteophytosis, degenerative / herniated disc pain, radiculopathy, facet joint syndrome, failed spinal surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylodiscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmopathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy-induced oral The present invention features a method of treating or reducing the severity in a subject of oral mucositis, Charcot arthropathy, temporomandibular joint disorders, painful knee replacement surgery, non-cardiac chest pain, pubic area, renal colic, biliary tract disease, vascular leg ulcers, pain in Parkinson's disease, pain in Alzheimer's disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastrointestinal motility, the method comprising administering an effective amount of a compound of the present invention, a pharmacologic salt thereof, or a pharmaceutical composition thereof.

[0141] In another aspect, the present invention provides a method for treating femoral cancer pain, non-malignant chronic bone pain, rheumatoid arthritis, osteoarthritis, spinal stenosis, neuropathic low back pain, myofascial pain syndrome, fibromyalgia, temporomandibular joint pain, chronic visceral pain, abdominal pain, splenic pain, IBS pain, chronic and acute headache pain, migraine, tension headache, cluster headache, chronic and acute neuropathic pain, post-herpetic neuralgia, diabetic neuropathy, HIV associated neuropathy, trigeminal neuralgia, Charcot-Marie-Tooth neuropathy, hereditary sensory neuropathy, peripheral nerve injury, pain Neuromas with ectopic proximal and distal secretions, Radiculopathy, Chemotherapy-induced neuropathic pain, Radiotherapy-induced neuropathic pain, Persistent / chronic post-operative pain (e.g. after amputation, thoracotomy, cardiac surgery), Post-mastectomy pain, Central pain, Spinal cord injury pain, Post-stroke pain, Thalamic pain, Phantom limb pain (e.g. after removal of lower limb, upper limb, breast), Intractable pain, Acute pain, Acute post-operative pain, Acute musculoskeletal pain, Joint pain, Mechanical low back pain, Neck pain, Tendonitis, 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, labour pain, Caesarean section pain, acute inflammatory pain, burn pain, traumatic pain, acute intermittent pain, endometriosis, acute shingles pain, sickle cell disease, acute pancreatitis, breakthrough pain, orofacial pain, sinusitis pain, toothache, multiple sclerosis (MS) pain, depression pain, leprosy pain, Behcet's disease pain, adiposity pain, phlebitis pain, Guillain-Barre syndrome pain, painful legs and moving toes, Haglund's syndrome The present invention also features a method of treating or reducing the severity in a subject of the following conditions: chronic pain, erythromelalgia pain, Fabry disease pain, bladder and genitourinary disorders, urinary incontinence, pathological cough, overactive bladder, bladder pain syndrome, interstitial cystitis (IC), prostatitis, CRPS type I, CRPS type II, widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina induced pain, the method comprising administering an effective amount of a compound of the present invention, a pharmacologic acceptable salt thereof, or a pharmaceutical composition thereof.

[0142] Compounds, Pharmacologically Acceptable Salts, and Compositions for Use - Patent application In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt, or pharmaceutical composition thereof, for use as a medicament.

[0143] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting a voltage-gated sodium channel in a subject. V It's 1.8.

[0144] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or reducing the severity in a subject of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain (e.g., herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia.

[0145] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, or cardiac arrhythmia.

[0146] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt, or pharmaceutical composition thereof, for use in a method of treating or reducing the severity of intestinal pain in a subject, wherein intestinal pain includes inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain.

[0147] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating or reducing the severity of neuropathic pain in a subject. In some aspects, the neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some aspects, the neuropathic pain includes diabetic neuropathy (e.g., diabetic peripheral neuropathy). As used herein, the phrase "idiopathic small fiber neuropathy" is understood to include any small fiber neuropathy.

[0148] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or lessening the severity of neuropathic pain in a subject, where neuropathic pain includes post-herpetic neuralgia, diabetic neuropathy, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, pain after amputation surgery, phantom limb pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, medication-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 cephalopathy.

[0149] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating or reducing the severity of musculoskeletal pain in a subject, hi some aspects, the musculoskeletal pain comprises osteoarthritis.

[0150] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt, or pharmaceutical composition thereof, for use in a method of treating or reducing the severity of musculoskeletal pain in a subject, wherein musculoskeletal pain includes osteoarthritis, back pain, cold pain, burn pain, or dental pain.

[0151] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt, or pharmaceutical composition thereof, for use in a method of treating or reducing the severity of inflammatory pain in a subject, where inflammatory pain includes rheumatoid arthritis pain or vulvodynia.

[0152] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt, or pharmaceutical composition thereof, for use in a method of treating or reducing the severity of inflammatory pain in a subject, where inflammatory pain includes rheumatoid arthritis pain.

[0153] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt, or pharmaceutical composition thereof, for use in a method of treating or reducing the severity of idiopathic pain in a subject, wherein idiopathic pain includes fibromyalgia pain.

[0154] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt, or pharmaceutical composition thereof, for use in a method for treating or reducing the severity of pathological cough in a subject.

[0155] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating or reducing the severity of acute pain in a subject, hi some aspects, the acute pain comprises acute post-operative pain.

[0156] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or reducing the severity of post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain) in a subject.

[0157] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt, or pharmaceutical composition thereof, for use in a method for treating or reducing the severity of bunionectomy pain in a subject.

[0158] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt, or pharmaceutical composition thereof, for use in a method for treating herniorrhaphy pain or reducing its severity in a subject.

[0159] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt, or pharmaceutical composition thereof, for use in a method for treating or reducing the severity of abdominoplasty pain in a subject.

[0160] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt, or pharmaceutical composition thereof, for use in a method for treating or reducing the severity of visceral pain in a subject, hi some aspects, the visceral pain includes abdominoplasty visceral pain.

[0161] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating or reducing the severity of a neurodegenerative disease in a subject. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt-Hopkins syndrome (PTHS).

[0162] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method in which a subject is treated with an effective amount of one or more additional therapeutic agents administered simultaneously with, prior to, or following treatment with the compound, pharma- ceutically acceptable salt, or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0163] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting a voltage-gated sodium channel in a biological sample, the method comprising contacting the biological sample with an effective amount of a compound of the invention, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof. V It's 1.8.

[0164] In another aspect, the present invention provides a method for treating acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, algesic pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain in multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis, post-herpetic neuralgia, diabetic neuropathy, rheumatoid arthritis ... meridian disorders, radicular pain, sciatica, back pain, unspecified chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), cancer pain including chronic cancer pain and cancer breakthrough pain, stroke (e.g., central neuropathic pain after stroke), traumatic neck syndrome, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic encephalopathy, erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, osteoporosis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic osteophytosis, degenerative / herniated disc pain, radiculopathy, facet joint syndrome, failed spinal surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylodiscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmopathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy The present invention features a compound of the present invention, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or reducing the severity in a subject of: osteoarthritis, Charcot arthropathy, temporomandibular joint disorders, painful knee replacement surgery, non-cardiac chest pain, pubic area, renal colic, biliary tract disease, vascular leg ulcers, pain in Parkinson's disease, pain in Alzheimer's disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal motility.

[0165] In another aspect, the present invention provides a method for treating femoral cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; splenic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; pain Neuromas with ulcers;Ectopic proximal and distal discharges;Radiculopathy;Chemotherapy-induced neuropathic pain;Radiation-induced neuropathic pain;Persistent / chronic post-operative pain (e.g., after amputation, thoracotomy, cardiac surgery), post-mastectomy pain;Central pain;Spinal cord injury pain;Post-stroke pain;Thalamic pain;Phantom limb pain (e.g., after lower limb, upper limb, breast removal);Intractable pain;Acute pain, acute post-operative pain;Acute musculoskeletal pain;Arthral pain;Mechanical low back pain;Neck pain;Tendonitis;Injury pain;Movement pain;Acute visceral pain;Pelvic-renal pain inflammation;appendicitis;cholecystitis;intestinal obstruction;hernia;chest pain, cardiac pain;pelvic pain, renal colic pain, acute obstetric pain, labour pain;cesarean section pain;acute inflammatory pain, burn pain, traumatic pain;acute intermittent pain, endometriosis;acute shingles pain;sickle cell disease;acute pancreatitis;breakthrough pain;orofacial pain;sinusitis pain;toothache;multiple sclerosis (MS) pain;pain in depression;leprosy pain;Behcet's disease pain;painful adiposity;phlebitis pain;Guillain-Barre syndrome pain;painful legs and moving toes;huggles The present invention features a compound of the present invention, or a pharmacologic acceptable salt or pharmaceutical composition thereof, for use in a method for treating or reducing the severity in a subject of: chronic urinary incontinence; ...

[0166] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt, or pharmaceutical composition thereof, for use in a method of treating or reducing the severity in a subject of trigeminal neuralgia, migraine treated with Botox, cervical spondylotic radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioinguinal neuralgia, pudendal neuralgia, femoral neuropathy, dysesthesias of the femoral nerve, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain, or pain following amputation surgery.

[0167] Drug manufacturing In another aspect, the present invention provides the use of a compound of the invention, or a pharma- ceutically acceptable salt, or a pharmaceutical composition thereof, for the manufacture of a medicament.

[0168] In another aspect, the present invention provides the use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in inhibiting a voltage-gated sodium channel. V It's 1.8.

[0169] In yet another aspect, the present invention provides use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in the treatment or reduction of the severity in a subject of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain (e.g., herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia.

[0170] In yet another aspect, the present invention provides use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity in a subject of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, or cardiac arrhythmia.

[0171] In yet another aspect, the invention provides the use of a compound, pharma- ceutically acceptable salt, or pharmaceutical composition as described herein for the manufacture of a medicament for use in treating or reducing the severity of intestinal pain in a subject, wherein intestinal pain includes inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain.

[0172] In yet another aspect, the present invention provides a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of neuropathic pain in a subject. In some aspects, the neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some aspects, the neuropathic pain includes diabetic neuropathy (e.g., diabetic peripheral neuropathy).

[0173] In yet another aspect, the invention provides use of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of neuropathic pain in a subject, wherein the neuropathic pain includes post-herpetic neuralgia, diabetic neuropathy, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, pain after amputation surgery, phantom limb pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, medication-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 aspect, the present invention provides the use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of musculoskeletal pain in a subject, hi some aspects, the musculoskeletal pain comprises osteoarthritis.

[0175] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of musculoskeletal pain in a subject, wherein musculoskeletal pain includes osteoarthritis, back pain, cold pain, burn pain, or dental pain.

[0176] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of inflammatory pain in a subject, wherein inflammatory pain includes rheumatoid arthritis pain or vulvodynia.

[0177] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of inflammatory pain in a subject, wherein inflammatory pain includes rheumatoid arthritis pain.

[0178] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of idiopathic pain in a subject, wherein idiopathic pain includes fibromyalgia pain.

[0179] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of pathological cough in a subject.

[0180] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of acute pain in a subject, hi some aspects, acute pain comprises acute post-operative pain.

[0181] In yet another aspect, the present invention provides use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of post-operative pain in a subject (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain).

[0182] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating herniorrhaphy pain or reducing the severity thereof in a subject.

[0183] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of bunionectomy pain in a subject.

[0184] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of abdominoplasty pain in a subject.

[0185] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of visceral pain in a subject, hi some aspects, the visceral pain comprises visceral pain due to abdominoplasty.

[0186] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of a neurodegenerative disease in a subject. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt-Hopkins syndrome (PTHS).

[0187] In yet another aspect, the invention provides the use of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in combination with one or more additional therapeutic agents administered concomitantly, prior to, or following treatment with the compound or pharmaceutical composition, hi some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0188] In another aspect, the present invention provides a method for treating acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, algesic pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain in multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis, post-herpetic neuralgia, diabetic Neuropathy, radicular pain, sciatica, back pain, unspecified chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), cancer pain including chronic cancer pain and cancer breakthrough pain, stroke (e.g., central neuropathic pain after stroke), traumatic neck syndrome, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic Lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, osteoporosis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic osteophytosis, degenerative / herniated disc pain, radiculopathy, facet joint syndrome, failed spinal surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylodiscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmopathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemical The present invention provides a use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in the treatment or lessening the severity of therapy-induced oral mucositis, Charcot arthropathy, temporomandibular joint disorders, painful knee replacement surgery, non-cardiac chest pain, pubic area, renal colic, biliary tract disease, vascular leg ulcers, pain in Parkinson's disease, pain in Alzheimer's disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal motility.

[0189] In another aspect, the present invention provides a method for treating femoral cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; splenic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; pain with ectopic proximal and distal discharges;radiculopathy;chemotherapy-induced neuropathic pain;radiotherapy-induced neuropathic pain;persistent / chronic post-operative pain (e.g., after amputation, thoracotomy, cardiac surgery), post-mastectomy pain;central pain;spinal cord injury pain;post-stroke pain;thalamic pain;phantom limb pain (e.g., after lower limb, upper limb, breast removal);intractable pain;acute pain, acute post-operative pain;acute musculoskeletal pain;arthritic pain;mechanical low back pain;neck pain;tendonitis;injury pain;motor pain;acute visceral pain;renal pelvis Nephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labour pain; caesarean section pain; acute inflammatory pain, burn pain, traumatic pain; acute intermittent pain, endometriosis; acute shingles pain; sickle cell disease; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; toothache; multiple sclerosis (MS) pain; depression pain; leprosy pain; Behcet's disease pain; painful adiposity; phlebitis pain; Guillain-Barre syndrome pain; sore legs and moving toes; ha The present invention provides a use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in the treatment or reduction of the severity of Grund's syndrome; erythromelalgia pain; Fabry's disease pain; bladder and genitourinary disorders; urinary incontinence, pathological cough; overactive bladder; bladder pain syndrome; interstitial cystitis (IC); prostatitis; 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 use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in the treatment or reduction of the severity of trigeminal neuralgia, migraine treated with Botox, cervical spondylotic radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexus pathology, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioinguinal neuralgia, pudendal neuralgia, femoral neuropathy, dysesthesias of the thigh, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexus pathology, traumatic neuroma stump pain, 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 a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof is that amount effective to treat or reduce the severity of one or more of the conditions listed above.

[0192] The compounds, salts, and compositions according to the method of the present invention may be administered using any amount and any route of administration effective for treating or reducing the severity of one or more of the pain or non-pain disorders listed herein. The exact amount required will vary between subjects, depending on the species, age, and general condition of the subject, the severity of the condition, the specific drug, its mode of administration, and the like. The compounds, salts, and compositions of the present invention are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, the expression "unit dosage form" refers to a physically discrete pharmaceutical unit appropriate for the subject to be treated. However, it will be understood that the total daily usage of the compounds, salts, and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The particular effective dosage level for any particular subject or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder, the activity of the particular compound or salt used, the particular composition used, the age, weight, general health, sex, and diet of the subject, the time of administration, route of administration, and rate of excretion of the particular compound or salt used, duration of treatment, drugs used in combination with or concomitantly with the particular compound or salt used, and similar factors well known in the medical arts. As used herein, the term "subject" or "patient" means an animal, preferably a mammal, and most preferably a human.

[0193] The pharma- ceutically acceptable compositions of the invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powder, ointment, or drops), bucally as an oral or nasal spray, etc., depending on the severity of the condition being treated. In certain embodiments, the compounds, salts, and compositions of the invention may be administered orally or parenterally, one or more times daily, at dosage levels of about 0.001 mg / kg to about 1000 mg / kg that are effective to obtain the desired therapeutic effect.

[0194] Liquid dosage forms for oral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the active compound or salt, liquid dosage forms may contain 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, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and aromatic agents.

[0195] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions 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 (USP), and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0196] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water, or other sterile injectable medium prior to use.

[0197] In order to prolong the effect of the compounds of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0198] Compositions for rectal or vaginal administration are preferably suppositories which may be prepared by mixing a compound or salt of the invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and 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 mixed with at least one inert pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants, such as glycerol, d) disintegrants, such as agar, carbonate, glycerol, d) glycerol, e) glycerol, f) glycerol, g ... Calcium, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0200] Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0201] The active compound or salt may also be in microencapsulated form with one or more of the excipients mentioned above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulation art. 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 the inert diluent, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose, as is normal practice. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient only, or preferentially, in a delayed manner, in a certain part of the intestinal tract. 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 pharma- ceutically acceptable carrier and any necessary preservatives or buffers, as may be required. Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of the present invention. Furthermore, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound into the body. Such dosage forms are prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0203] As generally described above, the compounds of the present invention are useful as inhibitors of voltage-gated sodium channels. In one embodiment, the compounds are V1.8 and therefore, without wishing to be bound by any particular theory, the compounds, salts and compositions are inhibitors of Na V It is particularly useful for treating or lessening the severity of a disease, condition, or disorder in which activation or overactivity of Na 1.8 is implicated in the disease, condition, or disorder. V Where activation or overactivity of 1.8 is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be associated with Na V 1.8-mediated disease, condition, or disorder. Thus, in another aspect, the present invention provides a method for treating a Na V The present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation or overactivity of 1.8 contributes to the disease state.

[0204] Na V The activity of the compounds utilized in this invention as inhibitors of 1.8 may be assayed according to the methods generally described in WO 2014 / 120808A9 and U.S. 2014 / 0213616A1 (both of which are incorporated by reference in their entireties), the methods described herein, as well as other methods known and available to those of skill in the art.

[0205] Additional medications It will also be understood that the compounds, salts, and pharma- ceutically acceptable compositions of the present invention can be used in combination therapy, i.e., the compounds, salts, and pharma- ceutically acceptable compositions can be administered simultaneously with, prior to, or after one or more other desired therapies or medical treatments. The particular combination of therapies (treatments or procedures) used in a combination regimen will take into account the compatibility of the desired therapeutic agent and / or treatment, and the desired therapeutic effect to be achieved. It will also be understood that the therapies used can achieve the desired effect for the same disorder (e.g., the compounds of the present invention can be administered simultaneously with another agent used to treat the same disorder), or can achieve a different effect (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease or condition are referred to as "as known 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, tolmetin, naphthyl alkanones, e.g., nabumetone, oxicams, e.g., piroxicam, para-aminophenol derivatives, e.g., acetaminophen, propionic acids, e.g., fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, oxaprozin, salicylates, e.g., aspirin, choline magnesium trisalicylate, diflunisal, fenamates, e.g., , meclofenamic acid, mefenamic acid, and pyrazoles, e.g., phenylbutazone), or opioid (anesthetic) agonists (e.g., codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine). In addition, non-pharmacological analgesic approaches may be utilized in conjunction with the administration of one or more compounds of the present invention. For example, anesthesiology (spinal injection, nerve block), neurosurgery (neuroablation of CNS pathways), neurostimulation (transcutaneous electrical nerve stimulation, spinal cord dorsal column stimulation), physical therapy (physiotherapy, orthotics, diathermy), or psychology (cognitive methods - hypnosis, biofeedback, or behavioral methods) approaches may also be utilized.Additional suitable 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 at www.fda.gov), the entire contents of which are incorporated herein by reference.

[0206] In another embodiment, the additional suitable therapeutic agent is selected from the following: (1) an opioid analgesic, such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, pentazocine, or difelikefalin; (2) nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen (including but not limited to intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketorolac (including but not limited to ketorolac tromethamine (e.g., Toradol®)), meclofenamic acid, mefenamic acid, meloxicam, IV meloxicam (e.g., Anjeso®), nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, or zomepirac; (3) Barbiturates, such as amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal, or thiopental; (4) benzodiazepines with sedative effects, such as chlordiazepoxide, clorazepate, diazepam, flazepam, lorazepam, oxazepam, temazepam, or triazolam; (5) Histamine (H), which has a sedative effect 1 ) antagonists, such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine, or chlorcyclizine; (6) Sedatives, such as glutethimide, meprobamate, methaqualone, or dichloralphenazone; (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 dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), a combination formulation of morphine and dextromethorphan), topiramate, neramexane, or perzinfotel (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-methane-sulfonamido-1,2,3,4-tetrahydroisoquinolin-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, in particular NK-, NK-2, or NK-1 antagonists, such as (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[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-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant, or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S); (13) Muscarinic antagonists, such as oxybutynin, tolterodine, propiverine, tropium chloride, darifenacin, solifenacin, temiverine, and ipratropium; (14) COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib; (15) Coal-tar painkillers, especially paracetamol; (16) Neuroleptics, such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclineltant, Miraxion®, or sarizotan; (17) vanilloid receptor agonists (e.g., resiniferatoxin or civamide) or antagonists (e.g., capsazepine, GRC-15300); (18) beta-adrenergics, such as propranolol; (19) Local anesthetics, such as 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, such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907); (23) Cholinergic (nicotinic) analgesics, such as isoprenicline (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, tapentadol ER (Nucynta®); (25) PDE5 inhibitors, such as 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',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]triazin-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]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(l-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin- 7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide; (26) Alpha-2-delta ligands, such as gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methylgabapentin, (1[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)- Proline, [(lR,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(l-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(l-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid, and (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid; (27) Cannabinoids, such as 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, escitalopram, d,l-fenfluramine, femoxetine, ioxetine, cyanodothiepin, ritoxetine, dapoxetine, nefazodone, cericlamine, and trazodone; (30) noradrenaline (norepinephrine) reuptake inhibitors, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, the bupropion metabolite hydroxybupropion, nomifensine, and viloxazine (Vivalan®), in particular selective noradrenaline reuptake inhibitors, such as reboxetine, in particular (S,S)-reboxetine; (31) Dual serotonin-norepinephrine reuptake inhibitors, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran, and imipramine; (32) Inducible nitric oxide synthase (iNOS) inhibitors, such as S-[2-[(l-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(l-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(l-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(l-iminoethyl)amino]-5-heptenoic acid, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile; 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5- thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(lR,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN-462, or guanidinoethyl disulfide; (33) Acetylcholinesterase inhibitors, for example, donepezil; (34) Prostaglandin E2 subtype 4 (EP4) antagonists, such as N-[({2-[4-(2-ethyl-4,6-dimethyl-lH-imidazo[4,5-c]pyridin-l-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[(15)-l-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid; (35) Leukotriene B4 antagonists, such as l-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057), or DPC-11870; (36) 5-lipoxygenase inhibitors, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504); (37) Sodium channel blockers, such as lidocaine, lidocaine + tetracaine cream (ZRS-201), or eslicarbazepine acetate; (38)Na V1.7 Blockers such as XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893 BIIB-074 (Vixotrigine), BIIB-095, ASP-1807, DSP-3905, OLP-1002, RQ-00432979, FX-301, DWP-1706, DWP-17061, IMB-110, IMB-111, IMB-112 and WO2011 / 140425 (US2011 / 306607); WO2012 / 106499 (US2012 / 196869); WO2012 / 112743 (US2012 / 245 136); those 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 of which are incorporated herein by reference; (38a)Na V1.7 Blockers, such as (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl)-(4-isopropoxy-3-methyl-phenyl)methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydro 1-(4-benzhydrylpiperazin-1-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy]propan-2-ol, (4-butoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[ 3,4-Dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]-(5-isopropoxy-6-methyl-2-pyridyl)methanone, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4 '-piperidine]-1'-carbonyl]phenyl]pyridine-2-carbonitrile, (4-isopropoxy-3-methyl-phenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 2,2,2-Trifluoro-1-[1'-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-3,3-dimethyl-spiro[2,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, (4-isopropoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl 1-[(3S)-2,3-dimethyl-1'-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 1-[(3S)-2,3-dimethyl-1'-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, yl]-2,2,2-trifluoro-ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]-[3-methoxy-4-[(1R)-1-methylpropoxy]phenyl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 1-[1'-[ 4-Methoxy-3-(trifluoromethyl)benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]-2,2-dimethyl-propan-1-one, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, [2-methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-Piperidinyl]-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, such as PF-04531083, PF-06372865, as well as, for example, 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 those disclosed in 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, such as 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide, 5-chloro-2-(4 -fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)- 5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-((5-fluoro-2-hydroxybenzyl)oxy)-N-(2-oxo-1,2-Dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide, 2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl) benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide, [4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate, 2-(4-fluoro-2-(methyl-d, 3 )phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, (4-(2-(4-fluoro-2-(methyl-d 3)phenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate, 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-methylphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide 3-(4-(trifluoromethoxy)phenoxy)-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)quinoxaline-2-carboxamide Phosphorus-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-sulfa 3-(4-(trifluoromethoxy)phenoxy)-N-(2-oxo-2,5-difluorophenyl)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-2,5-difluorophenyl)quinoxaline-2-carboxamide3-dihydro-1H-benzo[d]imidazol-5-yl)quinoxaline-2-carboxamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4-yl)quinoxaline-2-carboxamide, 3-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, N-(4-carbamoylphenyl)-3-(4-fluoro -2-methoxyphenoxy)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-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)picoline acid, 4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methylphenoxy)benzamido) 4-(2-(4-fluoro-2-methylphenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4-trifluoromethoxy)phenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 4-(2-(2-chloro-4-fluorophenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4-chloro-2-methylphenoxy)benzamido)benzoic acid, 5-(4-(tert-butyl)-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4-dimethoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(2-chloro- 4-(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 ... phenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfa 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)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 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-(trideuteromethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl, N-(3-carbamoyl-4-fluorophenyl)-3-(trifluoromethoxy)benzamide, 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, 4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, 4-[[2-fluoro-6-[2-(trideuteromethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluorophenyl)-3-(trifluoromethoxy)benzamide, -(difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, 4-[[2-fluoro-6-[2-(trideuteromethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2,3,4-trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, N-(2-carbamoyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide, 4-[[6-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy) )phenoxy]-3-(trifluoromethyl)benzamide, N-(4-carbamoyl-3-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[2-fluoro-6-[2-(trideuteromethoxy)-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 N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzamide, 4-(2-fluoro-6-(2-methoxy-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzamido)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, such as DSP-2230, Lohocla201, or BL-1021; (41) 5-HT3 antagonists, such as ondansetron; (42) TPRV1 receptor agonists, such as capsaicin (NeurogesX®, Qutenza®), and pharma- ceutically acceptable salts and solvates thereof; (43) Nicotinic receptor antagonists, such as varenicline; (44) N-type calcium channel antagonists, such as Z-160; (45) Nerve growth factor antagonists, e.g., tanezumab; (46) Endopeptidase stimulators, such as senrebotase; (47) Angiotensin II antagonists, such as EMA-401; (48) Acetaminophen (including but not limited to intravenous acetaminophen (e.g., Ofirmev®)); (49) Bupivacaine (including, but not limited to, bupivacaine liposomal injectable suspension (e.g., Exparel®), bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll), and transdermal bupivacaine (Eladur®)); and (50) Combination of bupivacaine and meloxicam (e.g., HTX-011).

[0207] In one embodiment, the additional suitable therapeutic agent is selected from V-116517, pregabalin, extended 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, the additional suitable therapeutic agent is selected from N-(6-amino-5-(2,3,5-trichlorophenyl)pyridin-2-yl)acetamide, N-(6-amino-5-(2-chloro-5-methoxyphenyl)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide, or 3-((4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)methyl)oxetan-3-amine.

[0209] In another embodiment, the additional therapeutic agent is selected from a GlyT2 / 5HT2 inhibitor, e.g., Operanserin (VVZ149), a TRPV modulator, e.g., CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101, MDR16523, or MDR652, an EGR1 inhibitor, e.g., Brivoglide (AYX1), an NGF inhibitor, e.g., Tanezumab, Fasinumab, ASP6294, MEDI7352, a Mu opioid agonist, e.g., Cebranopadol, NKTR181 (Oxycodegol), a CB-1 agonist, e.g., NEO1940 (AZN1940), an imidazoline 12 agonist, e.g., CR4056, or a p75NTR-Fc modulator, e.g., LEVI-04.

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

[0211] In another embodiment, the additional therapeutic agent is Na V 1.7 blockers, such as ST-2427 or ST-2578, and those disclosed in WO2010 / 129864, WO2015 / 157559, WO2017 / 059385, WO2018 / 183781, WO2018 / 183782, WO2020 / 072835, and WO2022 / 036297, the entire contents of each of which are incorporated herein by reference. In some embodiments, the additional therapeutic agent is a Na V In some embodiments, the additional therapeutic agent is a Na 1.7 blocker as disclosed in WO2022 / 036297. V It is a 1.7 blocker.

[0212] In another embodiment, the additional therapeutic agent is selected from the group consisting of 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™), bribolidide, SR419, NRD.E1, LX9211, LY3016859, ISC-17536, NFX-88, LAT-8881, AP-235, NYX 2925, CNTX-6016, S-600918, S-637880, RQ-00434739, KLS-2031, MEDI 7352, or XT-150.

[0213] In another embodiment, the additional therapeutic agent is 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, the additional therapeutic agent is one or more of the following: 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 / 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, the additional therapeutic agent is a compound disclosed in WO2022 / 036297.

[0216] In another embodiment, the additional therapeutic agent is a NaV 1.7 and Na V Sodium channel inhibitors (also known as sodium channel blockers), such as 1.8 blockers.

[0217] The amount of additional therapeutic agent present in the compositions of the invention may be up to the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. The amount of additional therapeutic agent present in the presently disclosed compositions may range from about 10% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0218] The compounds and salts of the present invention or pharma- ceutically acceptable compositions thereof may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents, and catheters. Thus, in another aspect, the present invention includes compositions for coating implantable devices, comprising the compounds or salts of the present invention generally as described above, and the classes and subclasses herein, and a carrier suitable for coating the implantable device. In yet another aspect, the present invention includes an implantable device coated with a composition comprising the compounds or salts of the present invention generally as described above, and the classes and subclasses herein, and a carrier suitable for coating the implantable device. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Patent Nos. 6,099,562, 5,886,026, and 5,304,121. The coating is typically a biocompatible polymeric material, such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart sustained release characteristics in the composition.

[0219] Another aspect of the invention is to detect Na in a biological sample or subject. VWith respect to inhibiting 1.8 activity, the method includes administering to a subject or contacting the biological sample with a compound of the present invention, a pharma- ceutically 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, biopsies obtained from mammals or extracts thereof, as well as blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[0220] Na in biological samples V Inhibition of 1.8 activity is useful for a variety of purposes known to those of skill in the art, including, but not limited to, the study of sodium channels in biological and pathological phenomena and the comparative evaluation of new sodium channel inhibitors.

[0221] Synthesis of Compounds of the Invention The compounds of the present invention can be prepared from known materials by the methods described in the Examples, other similar methods, and other methods known to those skilled in the art. As will be understood by those skilled in the art, the functional groups of intermediate compounds in the methods described below 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 TGM Huts et al., Greene's Protective Groups in Organic Synthesis (4th ed.2006).

[0222] Radiolabeled Analogues of the Compounds of the Invention In another aspect, the present invention relates to radiolabeled analogues of the compounds of the present invention.As used herein, the term "radiolabeled analogues of the compounds of the present invention" refers to compounds that are identical to the compounds of the present invention described herein, including all embodiments thereof, except that one or more atoms are replaced with radioisotopes of the atoms present in the compounds of the present invention.

[0223] As used herein, the term "radioisotope" refers to an isotope of an element that is known to undergo spontaneous radioactive decay. Examples of radioisotopes include: 3 H, 14 C. 32 P, 35 S, 18 F, 36 Cl, as well as isotopes whose decay modes are identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0224] Radiolabeled analogs can be used in a number of 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 detectability.

[0225] In another aspect, the invention relates to a pharma- ceutically acceptable salt of a radiolabeled analog according to any of the embodiments described herein in relation to the compounds of the invention.

[0226] In another aspect, the invention relates to a pharmaceutical composition comprising a radiolabeled analog or a pharma- ceutically acceptable salt thereof according to any of the embodiments described herein in relation to the compounds of the invention, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

[0227] In another aspect, the invention relates to methods of inhibiting voltage-gated sodium channels in a subject, and methods of treating or lessening the severity of various diseases and disorders, including pain, comprising administering an effective amount of a radiolabeled analogue, pharma- ceutically acceptable salts thereof, and pharmaceutical compositions thereof, according to any of the embodiments described herein in connection with the compounds of the invention.

[0228] In another aspect, the invention relates to radiolabeled analogs, pharma- ceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use according to any of the embodiments described herein in connection with the compounds of the invention.

[0229] In another aspect, the invention relates to the use of a radiolabeled analogue, or a pharma- ceutically acceptable salt thereof, according to any of the embodiments described herein in connection with the compounds of the invention, for the manufacture of a medicament, and pharmaceutical compositions thereof.

[0230] In another aspect, the radiolabeled analogs, their pharma- ceutically acceptable salts, and pharmaceutical compositions thereof, may be used in combination therapy according to any of the embodiments described herein in connection with the compounds of the invention.

[0231] Enumerated Embodiments Additional embodiments, features, and advantages of the present disclosure will become apparent from the following detailed description and by practice of the disclosure. The compounds and methods of the present disclosure can be described as embodiments of any of the following listed items. Any of the embodiments described herein can be used in conjunction with any other embodiment described herein to the extent that the embodiments are not mutually exclusive.

[0232] 1. A compound of formula (I), [ka] or a pharma- ceutically acceptable salt thereof, wherein: X 2a But, N, N + -O -, or CR 2a and X 4a But, N, N + -O - , or CR 4a and X 5a But, N, N + -O - , or CR 5a and X 6a But, 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 are each independently H, halo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or -Si(C 1 -C 6 Alkyl) 3 and R a But H or C 1 -C 6 is alkyl, R Xa But H or C 1 -C 6 is alkyl, R Ya But H, OH, C 1 -C 6 Alkyl, -(C 1 -C 6 Alkylene)-R Za1 , or C 1 -C 6 Alkyl and C 1 -C 6 a 4- to 6-membered heterocyclyl optionally substituted with one or more groups independently selected from alkoxy; or R Xa and R Yatogether with the nitrogen atom to which they are attached form a 5- to 9-membered heterocyclyl, the heterocyclyl being one or more R Za2 where appropriate, R Za1 OH, NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 Alkyl) 2 , and halo and C 1 -C 6 is a 5- to 6-membered heterocyclyl optionally substituted with one or more groups independently selected from alkyl; Each R Za2 But, 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 alkoxy), R 4b1 and R 4b2 are each independently H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, or C 1 -C 6 is 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 6alkoxy) 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 But N or CR 3c and X 4c But N or CR 4c and X 5c But N or CR 5c and X 6c But N or CR 6c and R 2c But, H, OH, halo, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, 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 alkylene)-O-(4-6 membered heterocyclyl), -O-(C 2 -C 6 Alkenylene)-(C 1 -C 6 haloalkyl), -L 1 -L 2 -(C 3 -C 7 cycloalkyl), or -OL 3 -R Xc wherein the cycloalkyl is 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 6and optionally substituted with one or more groups independently selected from: L 1 is a bond or O, L 2 is a bond or C 1 -C 6 is alkylene, L 3 But, bond, C 1 -C 6 Alkylene or C 2 -C 6 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 membered heterocyclyl), =NOH, =NO(C 1 -C 6 alkyl), -N=S(O)(C 1-C 6 Alkyl) 2 , -C(=NOH)(C 3 -C 6 cycloalkyl), 4- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the cycloalkyl is optionally substituted with one or more halo, and the heterocyclyl and heteroaryl are selected from 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 and optionally substituted with one or more groups independently selected from: R 3c But, 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 Or X 3c But, CR 3c and R 2c and R 3c together with the carbon atoms to which they are attached form the formula: [ka] Forming a ring of Z 1 and Z 2 are each independently O, CH 2 , or CF 2 and R Yc1 and R Yc2 are each independently H or halo; R 4c H, halo, OH, -OBn, C1 -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 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; 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 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; R 6c But, H, halo, C 1 -C 6 Alkyl or C 1 -C 6 is haloalkyl, However, X 2a , X 4a , X 5a , and X 6a Two or less of the following are N or N + -O - and However, X 3c , X 4c , X 5c , and X 6c At most one of is N, however, R is OR a or R is NR Xa R Ya and R Ya OH, -(C 1 -C 6 Alkylene)-R Za1 , or C 1 -C 6Alkyl and C 1 -C 6 a 4- to 6-membered heterocyclyl optionally substituted with one or more groups independently selected from alkoxy; R is NR Xa R Ya and R Xa and R Ya together with the N atom to which they are attached form a 5- to 9-membered heterocyclyl, the heterocyclyl being one or more R Za2 or R 2a , R 4a , R 5a , or R 6a But -Si(C 1 -C 6 alkyl), or R 5b1 Or R 5b2 But -(C 1 -C 6 Alkylene)-(C 1 -C 6 alkoxy), or R 5b1 and R 5b2 together with the carbon atom to which they are attached form a 4- to 6-membered heterocyclyl, or R 2c But -(C 1 -C 6 Alkylene)-(C 1 -C 6 Alkoxy), -(C 1 -C 6 alkylene)-O-(4-6 membered heterocyclyl), -O-(C 2 -C 6 Alkenylene)-(C 1 -C 6 haloalkyl), or -OL 3 -R Xc or R 2c But -L 1 -L 2 -(C 3 -C 7 cycloalkyl), where the cycloalkyl is OH, CN, C1 -C 6 Alkyl, C 1 -C 6 Alkoxy, =NOH, -C(O)(C 1 -C 6 alkyl), and -(C 1 -C 6 alkylene)-OH; or R 3c But -(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 atom to which they are attached form the formula: [ka] or R 4c OH, -OBn, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy or -L 1 -L 2 -(C 3 -C 6 cycloalkyl), which is optionally substituted with 1 to 2 halo; or R 5c OH, -OBn, or -L 1 -L 2 -(C 3 -C 6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo, or a pharma- ceutically acceptable salt thereof. 2. The compound has the formula (IA) [ka] Item 2. The compound according to item 1, or a pharma- ceutically acceptable salt thereof, having the formula: 3. The compound has the formula (IA-1) [ka] 3. The compound according to item 1 or 2, or a pharma- ceutically acceptable salt thereof, having the formula: 4. The compound has the formula (IB) [ka] 3. The compound according to item 1 or 2, or a pharma- ceutically acceptable salt thereof, having the formula: 5. The compound has the formula (IB-1) [ka] 5. The compound according to any one of items 1 to 4, or a pharma- ceutically acceptable salt thereof, having the formula: 6. The compound has the formula (IC) [ka] 3. The compound according to item 1 or 2, or a pharma- ceutically acceptable salt thereof, having the formula: 7. The compound has the formula (IC-1) [ka] 7. The compound according to any one of items 1 to 3 or 6, or a pharma- ceutically acceptable salt thereof, having the formula: 8.X 2a But N or CR 2a and R 2a is H, or a pharma- ceutically acceptable salt thereof. 9.X 2a is N, or a pharma- ceutically acceptable salt thereof. 10.X 2a But, CR 2a and R 2a is H, or a pharma- ceutically acceptable salt thereof. 11.X 4a But, N, N+ -O - , or CR 4a and R 4a is H or halo, or a pharma- ceutically acceptable salt thereof. 12.X 4a is N, or a pharma- ceutically acceptable salt thereof. 13.X 4a But, N + Item 12. The compound according to item 11, wherein R is —O, or a pharma- ceutically acceptable salt thereof. 14.X 4a But, CR 4a and R 4a is H or F, or a pharma- ceutically acceptable salt thereof. 15.X 5a But, CR 5a and R 5a is H; or a pharma- ceutically acceptable salt thereof. 16.X 6a But N or CR 6a and R 6a But, H, halo, C 1 -C 6 Alkyl, or -Si(C 1 -C 6 Alkyl) 3 16. The compound according to any one of items 1 to 15, wherein: 17.X 6a is N, or a pharma- ceutically acceptable salt thereof. 18.X 6a But, CR 6a and R 6a But, H, F, CH 3 or -Si(CH 3 ) 3 17. The compound according to item 16, wherein: 19. R is OR a or NR Xa R Ya and R a But H or C1 -C 6 is alkyl, R Xa But H or C 1 -C 6 is alkyl, R Ya But H, OH, C 1 -C 6 Alkyl, -(C 1 -C 6 Alkylene)-R Za1 , or C 1 -C 6 Alkyl and C 1 -C 6 4- to 6-membered heterocyclyl optionally substituted with one or more groups independently selected from alkoxy; R Za1 OH, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 Alkyl) 2 , and halo and C 1 -C 6 19. The compound according to any one of items 1 to 18, wherein the heterocyclyl is 5- to 6-membered, optionally substituted with one or more groups independently selected from alkyl, or a pharma- ceutically acceptable salt thereof. 20. R is OR a and R a is H, or a pharma- ceutically acceptable salt thereof. 21.R is NR Xa R Ya and R Xa is H or CH 3 and R Ya H, OH, CH 3 , -(C 1 -C 2 Alkylene)-R Za1 , or C.H. 3 , -OCH 3 , and -OCH 2 CH 3 is a 4- to 6-membered heterocyclyl optionally substituted with one or more groups independently selected from RZa1 OH, -NH(CH 3 ), -N(CH 3 ) 2 , and F and CH 3 or a pharma- ceutically acceptable salt thereof. 22.R is NR Xa R Ya and R Xa and R Ya together with the nitrogen atom to which they are attached, one or more R Za2 forming an optionally substituted 5- to 9-membered heterocyclyl; Each R Za2 are independent, 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 19. The compound according to any one of items 1 to 18, or a pharma- ceutically acceptable salt thereof, selected from: 23.Each R Za2 are independent, F, OH, CH 3 , -OCH 3 , N.H. 2 , -NH(CH 3 ), -N(CH 3 ) 2 , and -CH 2 OCH 3 23. The compound according to item 22, selected from the group consisting of: 24.R 4b1 But H or C 1 -C 6 24. The compound according to any one of items 1 to 23, wherein R is alkyl, or a pharma- ceutically acceptable salt thereof. 25.R4b1 is H or CH 3 25. The compound according to item 24, wherein: 26.R 4b2 But H or C 1 -C 6 26. The compound according to any one of items 1 to 25, wherein R is alkyl, or a pharma- ceutically acceptable salt thereof. 27.R 4b2 is H or CH 3 27. The compound according to item 26, wherein: 28.R 5b1 But, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or -(C 1 -C 6 Alkylene)-(C 1 -C 6 28. The compound according to any one of items 1 to 27, wherein R is 1 or 2; and R is 1 or 2; or a pharma- ceutically acceptable salt thereof. 29.R 5b1 But, CH 3 , C.F. 3 , -CH 2 OCH 3 , or -CH 2 CH 2 OCH 3 29. The compound according to item 28, wherein: 30.R 5b2 But, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or -(C 1 -C 6 Alkylene)-(C 1 -C 6 alkoxy), or a pharma- ceutically acceptable salt thereof. 31.R 5b2 But, CH 3 , C.F. 3 , -CH 2 OCH 3 , or -CH 2 CH 2 OCH3 31. The compound according to item 30, wherein: 32.R 5b1 and R 5b2 taken together with the carbon atom to which they are attached form a 4-membered heterocyclyl, or a pharma- ceutically acceptable salt thereof. 33.X 3c is N, or a pharma- ceutically acceptable salt thereof. 34.X 3c But, CR 3c and R 3c But, 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 a pharma- ceutically acceptable salt thereof. 35.R 3c H, F, Cl, CH 3 , C.F. 3 , -CH 2 OH or -CH 2 OCH 3 35. The compound according to item 34, wherein: 36.X 4c But, CR 4c and R 4c 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 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; L 1is O and L 2 is a bond or C 1 -C 6 36. The compound according to any one of items 1, 2, 4, 6, or 8 to 35, wherein R is alkylene, or a pharma- ceutically acceptable salt thereof. 37.R 4c 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 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; L 1 is O and L 2 is a bond or C 1 -C 6 36. The compound according to any one of items 3, 5, 7, or 8 to 35, wherein R is alkylene, or a pharma- ceutically acceptable salt thereof. 38.R 4c are H, F, OH, -OBn, -OCH 3 , -OCH 2 CH 3 , CHF 2 , -OCHF 2 , -OCF 3 , -O-CH 2 38. The compound according to item 36 or 37, wherein -(cyclopropyl) or -O-(cyclobutyl), said cyclobutyl being substituted with two F. 39.X 5c But, CR 5c and R 5c is H, halo, OH, -OBn, or -L 1 -L 2 -(C 3 -C 6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; L 1 is O and L 2The compound according to any one of items 1, 2, 4, 6, or 8 to 38, or a pharma- ceutically acceptable salt thereof, wherein is a bond. 40.R 5c is H, halo, OH, -OBn, or -L 1 -L 2 -(C 3 -C 6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; L 1 is O and L 2 is a bond, or a pharma- ceutically acceptable salt thereof. 41.R 5c is H, Cl, OH, -OBn, or -O-(cyclobutyl), said cyclobutyl being substituted with two F; or a pharma- ceutically acceptable salt thereof. 42.X 6c But, CR 6c and R 6c is H; or a pharma- ceutically acceptable salt thereof. 43.R 2c But, OH, halo, C 1 -C 6 Alkoxy, -(C 1 -C 6 Alkylene)-(C 1 -C 6 Alkoxy), -(C 1 -C 6 alkylene)-O-(4-6 membered heterocyclyl), -O-(C 2 -C 6 Alkenylene)-(C 1 -C 6 haloalkyl), -L 1 -L 2 -(C 3 -C 7 cycloalkyl), or -OL 3 -R Xc and the cycloalkyl is OH, CN, C 1 -C 6 Alkyl, C 1 -C6 Alkoxy, =NOH, -C(O)(C 1 -C 6 alkyl), and -(C 1 -C 6 and optionally substituted with one or more groups independently selected from: L 1 is O, L 2 is a bond or C 1 -C 6 is alkylene, L 3 But, bond, C 1 -C 6 Alkylene or C 2 -C 6 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 membered heterocyclyl), =NOH, =NO(C 1 -C 6 alkyl), -N=S(O)(C 1 -C 6 Alkyl) 2 , -C(=NOH)(C 3 -C 6 cycloalkyl), 4- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the cycloalkyl is optionally substituted with one or more halo, and the heterocyclyl and heteroaryl are selected from 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 43. The compound according to any one of items 1 to 42, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more groups independently selected from: 44.R 2c OH, Cl, -OCH 3 , -CH 2 OCH 3 , -CH 2 -O-(4-membered heterocyclyl), or -O-(C 3 -C 4 Alkenylene)-CF 3 44. The compound according to item 43, which is, or a pharma- ceutically acceptable salt thereof. 45.R 2c But -L 1 -L 2 -(C 3 -C 7 cycloalkyl), L 1 is O, L 2 is a bond or C 1 -C 2 is alkylene, The cycloalkyl is OH, CN, -OCH 3 , C.H. 3, =NOH, -C(O)(CH 3 ), and -CH 2 44. The compound according to item 43, or a pharma- ceutically acceptable salt thereof, substituted with one or more groups independently selected from: OH. 46.R 2c But, -OL 3 -R Xc and L 3 But, bond, C 1 -C 6 Alkylene or C 4 -C 5 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 membered heterocyclyl), =NOH, =NO(C 1 -C 6alkyl), -N=S(O)(C 1 -C 6 Alkyl) 2 , -C(=NOH)(C 3 -C 6 cycloalkyl), 4- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the cycloalkyl is optionally substituted with one or more halo, and the heterocyclyl and heteroaryl are selected from 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 44. The compound according to item 43, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more groups independently selected from: (alkylene)-OH; 47.R Xc 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 membered heterocyclyl);=NOH;=NO(CH 3 );-N=S(O)(CH 3 ) 2 ;-C(=NOH)(C3 -C 4 Cycloalkyl);OH, F, CH 3 , -OCH 3 , CHF 2 , C.F. 3 , -OCHF 2 , and -CH 2 4-8 membered heterocyclyl optionally substituted with one or more groups independently selected from OH; and CH 3 47. The compound according to item 46, wherein said cycloalkyl is optionally substituted with one F, or a pharma- ceutically acceptable salt thereof. 48.X 3c But, CR 3c and R 2c and R 3c together with the carbon atom to which they are attached form the formula: [ka] forming a ring of the formula: Z 1 is O or CH 2 and Z 2 But O or CF 2 and R Yc1 and R Yc2 is each independently H or F, or a pharma- ceutically acceptable salt thereof. 49. A ring having the formula: [ka] 49. The compound according to item 48, wherein the ring is: 50. A compound selected from Table A or Table B, or a pharma- ceutically acceptable salt thereof. 51. The compound according to any one of items 1 to 50, in a non-salt form. 52. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of items 1 to 50, or a pharma- ceutically acceptable salt thereof, or a compound according to item 51, and one or more pharma- ceutically acceptable carriers or vehicles. 53. A pharmaceutical composition comprising a compound according to any one of items 1 to 50, or a pharma- ceutically acceptable salt thereof, or a compound according to item 51, and one or more pharma- ceutically acceptable carriers or vehicles. 54. A method for inhibiting voltage-gated sodium channels in a subject, the method comprising administering to the subject a compound according to any one of items 1 to 50, or a pharma- ceutically acceptable salt thereof, a compound according to item 51, or a pharmaceutical composition according to item 52 or 53. 55. Voltage-gated sodium channels are V 55. The method according to item 54, wherein the ratio is 1.8. 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 in a subject, comprising administering to the subject an effective amount of a compound according to any one of items 1 to 50, or a pharma- ceutically acceptable salt thereof, a compound according to item 51, or a pharmaceutical composition according to item 52 or 53. 57. The method of claim 56, wherein the method comprises treating or reducing the severity of neuropathic pain in the subject. 58. The method of claim 56, wherein the neuropathic pain comprises postherpetic neuralgia. 59. The method of item 56, wherein the neuropathic pain comprises small fiber neuropathy. 60. The method of item 56, wherein the neuropathic pain comprises idiopathic small fiber neuropathy. 61. The method of claim 56, wherein the neuropathic pain includes diabetic neuropathy. 62. The method according to item 61, wherein the diabetic neuropathy includes diabetic peripheral neuropathy. 63. The method of claim 56, wherein the method comprises treating or reducing the severity of musculoskeletal pain in a subject. 64. The method of claim 63, wherein the musculoskeletal pain comprises osteoarthritis pain. 65. The method of claim 56, wherein the method comprises treating or reducing the severity of acute pain in the subject. 66. The method according to item 65, wherein the acute pain comprises acute postoperative pain. 67. The method of claim 56, wherein the method comprises treating or reducing the severity of post-operative pain in the subject. 68. The method of claim 67, wherein the postoperative pain comprises bunionectomy pain. 69. The method of claim 67, wherein the postoperative pain comprises abdominoplasty pain. 70. The method of claim 67, wherein the postoperative pain comprises herniorrhaphy pain. 71. The method of item 56, wherein the method comprises treating or reducing the severity of visceral pain in the subject. 72. The method of any one of items 54 to 71, wherein the subject is treated with one or more additional therapeutic agents administered simultaneously with, prior to, or following treatment with the compound, pharma- ceutically acceptable salt, or pharmaceutical composition. 73. Use of a compound according to any one of items 1 to 50, or a pharma- ceutically acceptable salt thereof, a compound according to item 51, or a pharmaceutical composition according to item 52 or 53, as a medicament. EXAMPLES

[0233] Common method. 1 H NMR spectrum was obtained by dimethyl sulfoxide-d 6 It was obtained as a solution in a suitable deuterated solvent such as (DMSO-d6).

[0234] Compound purity, retention time, and electrospray ionization mass spectrometry (ESI-MS) data were determined by LC / MS analysis. A Waters Acquity UPLC BEH C with a (2.1×5 mm, 1.7 μm particles) guard column (pn: 186003978) was used. 8 LC / MS analysis was performed using a column (50 x 2.1 mm, 1.7 μm particles) (pn: 186002877) and a dual gradient run of 2-98% mobile phase B over 4.45 min. Mobile phase A = H 2O (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 at room temperature in transmission mode 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 radiation (1.54060 Å) at a voltage of 45 kV and a current of 40 mA. Powder samples were placed on a 96-well sample holder with mylar film and loaded into the instrument. Samples were scanned over the range of about 3° to about 40° 2θ with a step size of 0.0131303° and 49 seconds per step.

[0236] Abbreviation Unless otherwise indicated, or if the context dictates otherwise, the following abbreviations shall 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: Et 3 N (7.7 mL, 55.2 mmol) was added to a stirred solution of ethyl 2-diazo-3-oxo-pentanoate (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 min and the mixture was stirred at 0° C. for a further 30 min. The reaction mixture was diluted with pentane (100 mL), the layers were separated and the organic phase was washed with dilute aqueous sodium bicarbonate (100 mL) followed by brine (100 mL). The organic layer was dried (MgSO 4 ), which was concentrated in vacuo to give ethyl (Z)-2-diazo-3-trimethylsilyloxypent-3-enoate (9.4 g, 99%) as a red oil. 1 H NMR (500 MHz, chloroform-d) δ 5.33 (q, J = 7.0 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 1.67 (d, J = 7.0 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 0.22 (s, 9H) ppm.

[0238] Step 2: TiCl was added via cannula to a stirring solution of 1,1,1-trifluoropropan-2-one (8 mL, 89.4 mmol) in DCM (80 mL) at -78 °C. 4 (70 mL of 1M in DCM, 70.00 mmol) was added. To the resulting solution was added a solution of ethyl (Z)-2-diazo-3-trimethylsilyloxypent-3-enoate (36.1 g of 31.3% w / w, 46.6 mmol) in 40 mL of DCM dropwise over 15 min. After 100 min, the reaction was carefully quenched with water, the temperature was allowed to rise slowly, and then extracted with DCM. The combined organic layers were dried (MgSO 4 ), filtered and concentrated in vacuo. Flash chromatography (330 g SiO 2 Purification with hexane (0-20% EtOAc in heptane) gave ethyl rac-(4R,5S)-2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxohexanoate (8.82 g, 67%), which was stored as a toluene solution. 1H 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 at reflux for 10 min, after which a solution of ethyl rac-(4R,5S)-2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxohexanoate (10 g, 35.4 mmol) in benzene (13 mL) was added slowly via addition funnel at reflux for 60 min. The mixture was then concentrated in vacuo to give ethyl rac-(4R,5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (9.0 g, 100%) as a green residue containing residual catalyst and as a mixture of epimers next to the ester. This material was used without further purification. 1 H NMR (500 MHz, chloroform-d) δ 4.83-4.57 (m, 1H), 4.38-4.16 (m, 2H), 2.60 (dddd, J = 9.3, 8.2, 5.6, 1.4 Hz, 1H), 1.73-1.63 (m, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.24 (ddq, J = 6.4, 4.1, 1.9 Hz, 3H) ppm.

[0240] Step 4: To a stirred solution of ethyl rac-(4R,5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (48 g, 188.83 mmol) in DCM (400 mL) at -78 °C was added DIPEA (29.680 g, 40 mL, 229.64 mmol). A solution of trifluoromethylsulfonyl trifluoromethanesulfonate (53.440 g, 32 mL, 189.41 mmol) in DCM (200 mL) was added to the reaction mixture at the same temperature over 1 h. The reaction mixture was stirred at 0 °C for 30 min, followed by addition of 100 mL of saturated NaHCO 3 The mixture was quenched with aqueous solution of MgSO. The organic layer was separated and the aqueous layer was extracted with DCM (160 mL). The combined organic layers were washed with MgSO. 4 and concentrated in vacuo to give ethyl rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (71 g, 97%). 1 H 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 ethyl rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (26 g, 67.311 mmol) in toluene (130.00 mL) was added (3,4-difluoro-2-methoxyphenyl)boronic acid (14 g, 74.5 mmol) followed by K 3 PO 4 (100 mL of 2M, 200.00 mmol) was added. The reaction was degassed before adding tetrakis(triphenylphosphine)palladium(0) (4 g, 3.46 mmol). After further degassing, the reaction was heated at 100° C. for 2 h. The reaction mixture was diluted with water and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were concentrated in vacuo. Flash chromatography (SiO 2Purification with 10% EtOAc in heptane (0-10% EtOAc in heptane) afforded ethyl rac-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (24.4 g, 93%) as a 6:1 diastereomeric mixture, the major isomer is believed to be ethyl rac-(4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate. 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 1 H NMR(400MHz,chloroform-d)δ 6.88-6.79(m,2H),4.17-4.09(m,2H),3.88(s,3H),3.76-3.71(m,1H),1.51(s,3H),1.12(t,J=7.4Hz,3H),0.99(dd,J=5.4,2.7Hz,3H)ppm.ESI-MS m / z calculated value 380.1047, measured value 381.02 (M+1) + ;Retention time: 2.09 minutes.

[0242] Step 6: To an ice-cold solution of ethyl rac-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (110 g, 243.0 mmol) in DCM (360 mL) at 0 °C was added BBr 3 (370 mL of 1M, 370.0 mmol) was added dropwise. Upon completion, the mixture was quenched by the addition of water followed by aqueous sodium bicarbonate. The aqueous layer was extracted with DCM and the combined organic layers were washed with MgSO 4The mixture was dried over 1000 ml and concentrated in vacuo. The residue was dissolved in DCM (430 mL) at ambient temperature, TFA (40 mL, 519.2 mmol) was added and the reaction was then heated to 45° C. Upon completion, the mixture was quenched by the addition of aqueous sodium bicarbonate, the aqueous layer was extracted with DCM and MgSO 4 The crude was dried at 40° C. and concentrated in vacuo to give the desired product as a 5:1 mixture of diastereomers. Recrystallization was performed by solubilizing the crude in the minimum amount of DCM possible and adding a layer of heptane on top of this solution (liquid-liquid diffusion). After approximately 1 hour, 56.5 g (dr 97:3 syn:anti) was obtained from the first and second crystallizations, and an additional 4.6 g (dr 96:4 syn:anti) was obtained from the third crystallization. The first through third recrystallization batches were combined to give rac-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3-c]chromen-4-one (61 g, 78%), with the major isomer believed to be rac-(1S,2R)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3-c]chromen-4-one. ESI-MS m / z calculated 320.04718, found 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-furo[2,3-c]chromen-4-one (30 g, 93.69 mmol) was dissolved in EtOAc (400 mL) and stirred with activated charcoal (6 g, 499.6 mmol) (0.2 g / g of substrate) at ambient temperature for 4 h 30 min. The mixture was filtered through a pad of Celite and washed with EtOAc. The filtrate was concentrated in vacuo to give a white solid. The white solid was suspended in MeOH (600 mL) and added to Pd(OH) in a 2.25 L Parr bottle. 2To a suspension of (13.62 g of 20% w / w, 19.40 mmol) in MeOH (150 mL) was added. The resulting mixture was shaken overnight in a Parr hydrogenation apparatus under 60 psi hydrogen pressure. The suspension was filtered through Celite under a nitrogen atmosphere, rinsed with MeOH, then EtOAc, and the resulting filtrate was concentrated in vacuo to give methyl rac-(2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (32.75 g, 99%). 1 H NMR (400MHz, methanol-d 4 )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 methyl rac-(2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (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 min, keeping the internal temperature below 10 °C. The mixture was stirred at 0 °C for a further 5 min, after which the mixture was allowed to warm slightly. When the temperature reached 13 °C, the reaction was cooled again in an ice bath, after which 2 M HCl (365 mL, pH 1) was added, keeping the internal temperature below 15 °C. Water (300 mL) was added, the layers were separated, and the aqueous layer was extracted with EtOAc (110 mL). The combined organic extracts were washed with brine (300 mL) and diluted with MgSO 4The mixture was evaporated, dried at 40° C., filtered and concentrated in vacuo to give 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-d 4 )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, J=10.5,7.6Hz,1H),2.83(p,J=7.5Hz,1H),1.59(q,J=1.2Hz,3H),0.76(dq,J=7.2,2.2Hz,3H)ppm.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 was stirred at 70° C. for 24 hours, then filtered and concentrated in vacuo to give 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. 1H 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 at ambient temperature overnight. The reaction mixture was acidified by the addition of 3M HCl in MeOH (1 mL). The mixture was then filtered and the mother liquor was concentrated in vacuo to give 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 398.11526, found 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 added successively 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 min. The mixture was then concentrated in vacuo. The residue was diluted with DCM (3 mL) and mixed with methyl 4-aminopicolinate (150 mg, 0.99 mmol), DMAP (4.63 mg, 0.038 mmol), and Et in DCM (5 mL) at ambient temperature. 3 To a stirred solution of N (280 μL, 2.01 mmol) was added dropwise over 5 min. The reaction was stirred overnight. The mixture was then concentrated in vacuo. Flash chromatography (12 g SiO 2 Purification with hexanes (hexane, methanol) afforded 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 next reaction.

[0248] Methyl rac-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinate (150 mg) was dissolved in methanolic ammonia (5 mL of 7 M, 35.00 mmol) and stirred at ambient temperature for 24 hours. The reaction mixture was then concentrated in vacuo. Purification by reverse phase preparative chromatography afforded 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 enantiomers of rac-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide were separated on a Berger Instruments Minigram SFC system using a Daicel 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% CO 2 Separation was performed by chiral SFC using a 100 Hz HPLC system (system pressure: 100 bar).

[0250] First eluting 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 H 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 eluting 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 H NMR (400 MHz, chloroform-d) δ 8.88 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 8.19 (dd, J = 5.6, 2.2 Hz, 1H), 8.01 (dd, J = 2.2, 0.6 Hz, 1H), 7.86 (d, J = 4.6 Hz, 1H), 7.13 (ddd, J = 8.1, 5.5, 2.1 Hz, 1H), 6.95 (td, J = 9.3, 7.5 Hz, 1H). 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 compound was prepared by the Suzuki coupling step 5 using PdCl as a catalyst. 2 (PPh 3 ) 2 with (4-fluoro-2-methoxy-3-methylphenyl)boronic acid (Intermediate G) as the boronic acid and NaHCO as the base. 3 The method described in Example 1 was used for the preparation of the 1,2-dichlorophenyl ether (Cs) in step 9, except that the procedure was carried out at 50° C. for 30 minutes using a mixture of water and 1,4-dioxane as the solvent. 2 CO 3 Instead of K 2 CO 3was used as the base. In step 10, MeOH was used as the solvent instead of EtOH. The conditions used for the 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 on a Berger Instruments Minigram SFC apparatus using a Daicel Chiralcel OD-H column, 5 mm particle size, 25 cm x 10 mm (mobile phase: 30% methanol (20 mM NH 3 ), 70% CO 2 Separation was performed by chiral SFC using a 100 Hz HPLC system (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-furo[2,3-c]chromen-4-one (product of Example 1, step 6, 1348 g, 4.366 mol) was purified using a Berger Instruments MultiGram III SFC system with a Regis Technologies (R,R)-Whelk-O1 column, 5 μm particle size, 15 cm × 3 cm (mobile phase: 10% isopropanol, 90% CO 2 Separation was performed by chiral SFC using a 200 rpm, flow rate: 5 mL / min, system pressure: 100 bar, column temperature: 35° C. to give the following:

[0254] First eluting isomer (rt=1.85 min): (1R,2S)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3-c]chromen-4-one). 1 H NMR (400MHz, DMSO-d 6 )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, measured value 321.3(M+1) + , 319.4(M-1) - ;Retention time: 3.19 minutes.

[0255] Second eluting isomer (rt = 2.38 min): (1S,2R)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3-c]chromen-4-one (366.99 g, 26%). 1 H NMR (400MHz, DMSO-d 6 )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, measured 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-furo[2,3-c]chromen-4-one (0.89 kg, 2.78 mol) and 20% palladium hydroxide on carbon (50% wet, 0.39 kg, 0.278 mol) in MeOH (12 L) was stirred under 40 psi pressure of hydrogen overnight. After overnight reaction, the reaction temperature was observed to increase 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 in vacuo. The residue was dissolved in toluene (4 L) and concentrated in vacuo and the process was repeated. The residue was dried under vacuum at 40° C. overnight to give methyl (2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.0 kg at 91% purity, 100%) as a beige solid. 1 H NMR (400MHz, DMSO-d 6 )10.20(br s,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 added sequentially 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 with 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 an additional 3 days. The reaction mixture was diluted with MTBE (30 L), treated with Celite (1 kg), and filtered through a bed of Celite (1 kg), washing with MTBE (10 L). The filtrate was filtered a second time through Celite (1 kg), washed with MTBE (4 L) and the filtrate was concentrated in vacuo. The residue was dissolved in toluene (4 L) and concentrated in vacuo, and the process was repeated. The residue was dried under vacuum at 40° C. overnight to give methyl (2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (0.99 kg at 90% purity, 95%) as a brown solid. 1 H NMR (400MHz, DMSO-d 6 )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 stirred at ambient temperature under nitrogen. After 5 h, 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 1M 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) and the combined organic layers were washed with brine (2 L) and concentrated to 100 mL with Na 2 SO 4 The mixture was dried at 75° C., filtered, and then treated with activated charcoal (50 g, 5% w / w) with stirring for 1 h. The mixture was filtered through Celite, washing with MTBE (2×4 L), and the filtrate was concentrated in vacuo. The residue was dissolved in toluene (4 L), concentrated in vacuo, then dissolved in MTBE (4 L) and concentrated in vacuo again to give (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 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) was added to the reactor followed by additional MTBE to give a total volume of 30 L in the reactor. After 2 hours, additional MTBE (2 L) was added to the reaction. After a total of 3.5 hours, the mixture was filtered, washing with MTBE (2 L). The reactor was rinsed with MTBE (4 L) which was used to rinse the solids which were then pressed and dried on a Buchner funnel for 2 hours. The solid product cake was loosened and then dried overnight on a Buchner funnel under nitrogen flow and vacuum. The isolated solid was dried in a convection oven at 40° C. for 24 hours to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (R)-1-phenylethan-1-amine salt (1.86 kg at 95.7% purity, 74% for 3 steps) as an off-white solid. 1 H NMR, 400MHz, DMSO-d 6 )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: To a suspension of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1R)-1-phenylethanamine salt (10.6 g, 22.29 mmol) in MTBE (250 mL) was added HCl (200 mL of 2 M, 400.0 mmol). The layers were separated and the organic layer was washed with water (200 mL) and MgSO 4 The mixture was dried at rt, filtered and concentrated in vacuo to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (8.4 g, 99%) as an 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-methoxy-phenyl)-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 h. The reaction mixture was concentrated in vacuo. The residue dissolved in DCM (40 mL) was added to a solution of methyl 4-aminopyridine-2-carboxylate (2.8 g, 18.40 mmol) and triethylamine (2.8 mL, 20.09 mmol) at 0° C. The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with a mixture of water (48 mL) and 1 M citric acid (24 mL, 24.00 mmol). Separate the layers and remove the organic phase with MgSO 4Drying at 40° C., filtering and concentrating in vacuo gave methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinate (8.38 g, 90%). 1 H NMR (400MHz, DMSO-d 6 )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 (70 mL of 7 M, 490.0 mmol) was stirred at room temperature for 19 h. The mixture was concentrated in vacuo to give a pale orange solid. EtOAc (30 mL) was added and the resulting slurry was heated at 60° C. The solution was cooled to 50° C. and heptane (17 mL) was added slowly through an addition funnel. At the end of the addition, the cloudy solution was allowed to settle. The pale orange solid was filtered to give the first crop (5.091 g). The filtrate was concentrated to one third of the volume and the orange precipitate was filtered off to give a second crop (1.14 g). The crops were combined to give 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-d 6 )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: BBr 3(830.0 μL, 1 M in DCM, 0.83 mmol) was added 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) at 0° C. The reaction mixture was allowed to warm slowly to ambient temperature and stirred for 24 h. The mixture was cooled to 0° C. and further diluted with BBr 3 (800 μL, 1M in DCM, 0.80 mmol) was added. The reaction was stirred at ambient temperature for 16 h. The reaction mixture was quenched by the addition of water and saturated aqueous sodium bicarbonate. The mixture was allowed to stir for 30 min before the layers were separated. The aqueous phase was extracted with DCM and the combined organic layers were dried, filtered and concentrated in vacuo. Flash chromatography (12 g SiO 2 Purification with 0% EtOAc in heptane (0-70% EtOAc in heptane) gave 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-d 6 ) 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,1H), 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 459.12173, found 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 to 61° C. overnight. The mixture was concentrated in vacuo. TBAF (1 mL, 1 M in THF) was added to a solution of the residue dissolved in THF. The mixture was stirred for 1 h and then the mixture was concentrated in vacuo. Purification by reverse phase preparative chromatography afforded 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-hydroxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide (5, 1.4 mg, 6%). 1 H NMR (400 MHz, chloroform-d) δ 8.86 (s, 1H), 8.37 (d, J = 5.5 Hz, 1H), 8.04 (dd, J = 5.5, 2.3 Hz, 1H), 7.90 (td, J = 2.1, 0.6 Hz, 1H), 7.03 (ddd, J = 8.1, 5.5, 2.1 Hz, 1H), 6.86 (td, J = 9.2, 7.5 Hz, 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 compound is prepared by reacting 5-(chloromethyl)oxazole as the alkylating agent and Cs as the base in step 11. 2 CO 3 Instead of K 2 CO 3The samples were prepared using the method described in Example 2, except that the procedure was performed using: [Table 5]

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

[0267] The following compound was prepared in step 11 using (1s,3s)-3-(bromomethyl)-1-(trifluoromethyl)cyclobutan-1-ol as the alkylating agent and K as the base. 2 CO 3 This was made using the method described in Example 2, except that it was performed at 80° C. for 6 hours using 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 FIG. 2).

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

[0270] The following compounds were made using the methods described in Example 2, except that the conditions used in the amide coupling step 8 were those described in step 4 of Example 6, using (2-aminopyridin-4-yl)(4-methylpiperazin-1-yl)methanone as the coupling partner in chloroform as the solvent. Steps 9-12 were omitted: [Table 8]

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

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

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

[0274] The following compounds were made using a method similar to that 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 converted to methyl 6-aminopyridine-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 h), reacted with methyl 4-chloro-5-trimethylsilyl-pyridine-2-carboxylate, followed by ester amination using the conditions described in step 9. Steps 10-12 were omitted: [Table 12]

[0275] The following compound can be made using a method similar to that described in Example 2, except that rac-(1S,2R)-6-fluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3-c]chromen-4-one is used instead of rac-(1S,2R)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3-c]chromen-4-one as the starting material. Steps 10-12 are omitted. Purification is performed by recrystallization to give compound 303. [Table 13]

[0276] The following compound can be made using a method similar to that described in Example 2, except that rac-(1S,2R)-7-fluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3-c]chromen-4-one is used instead of rac-(1S,2R)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3-c]chromen-4-one as the starting material. Steps 10-12 are omitted. Purification is performed by recrystallization to give 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-carboxamido)picolinamide (24) and rel-4-((6R,7S)-7-(4-fluoro-2-methoxy-3-methylphenyl)-2,5-dioxaspiro[3.4]octane-6-carboxamido)picolinamide (25) [ka] Step 1: TiCl 4 (1.2 mL of 1M, 1.20 mmol) and Et 3 N (170 μL, 1.22 mmol) was added dropwise to a stirred solution of ethyl 2-diazo-3-oxobutanoate (150 μL, 1.09 mmol) in DCM (6 mL) at −78° C. The reaction mixture was stirred for 1 h, and then Ti(OiPr) 4 A solution of (325 μL, 1.10 mmol) and oxetan-3-one (70 μL, 1.09 mmol) was added via cannula. The reaction was stirred for an additional 5 h. The mixture was washed with saturated NH 4 The mixture was quenched by the addition of aqueous Cl. The aqueous layer was separated and extracted with DCM. The combined organic phases were washed with brine and MgSO. 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated in vacuo. Flash chromatography (24 g SiO 2 Purification by elution with 0% EtOAc in heptane (0-70%) gave ethyl 2-diazo-4-(1-hydroxycyclobutyl)-3-oxobutanoate (156 mg, 63%). 1 H NMR (400 MHz, chloroform-d) δ 4.73-4.65 (m, 2H), 4.47 (d, J = 7.4 Hz, 2H), 4.33 (q, J = 7.1 Hz, 2H), 3.80 (s, 1H), 3.49 (s, 2H), 1.35 (t, J = 7.1 Hz, 3H) ppm.

[0278] Step 2: toluene( 4 mL) 2 A suspension of (OAc)4 (9.5 mg, 0.021 mmol) was heated at 100° C. for 10 min. A solution of ethyl 2-diazo-4-(1-hydroxycyclobutyl)-3-oxobutanoate (250 mg, 1.10 mmol) in toluene (3 mL) was added dropwise and the reaction was stirred for 45 min. The mixture was cooled to ambient temperature and concentrated in vacuo to give ethyl rac-7-oxo-2,5-dioxaspiro[3.4]octane-6-carboxylate (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 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 DCM (12 mL) at −78° C. The reaction mixture was stirred at −78° C. for 4 h. The reaction was quenched with saturated NH 4 The mixture was quenched by the addition of aqueous Cl. The aqueous layer was separated and extracted with DCM. The combined organic layers were washed with MgSO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo to give ethyl 7-(((trifluoromethyl)sulfonyl)oxy)-2,5-dioxaspiro[3.4]oct-6-ene-6-carboxylate which was used directly without further purification. 1 H NMR (400 MHz, chloroform-d) δ 5.03-4.95 (m, 2H), 4.67-4.59 (m, 2H), 4.36 (q, J = 7.2 Hz, 2H), 3.43 (s, 2H), 1.36 (t, J = 7.1 Hz, 3H) ppm.

[0280] Step 4: Ethyl 7-(((trifluoromethyl)sulfonyl)oxy)-2,5-dioxaspiro[3.4]oct-6-ene-6-carboxylate (436.6 mg, 1.31 mmol), (4-fluoro-2-methoxy-3-methylphenyl)boronic acid (Intermediate G, 290 mg, 1.58 mmol), Pd(PPh 3 ) 4 (90 mg, 0.078 mmol), and Na 2CO 3 (350 mg, 3.30 mmol) in toluene (7.5 mL), MeOH (750 μL), and H 2 The mixture was degassed and heated at 80° C. for 16 h. The reaction was cooled to ambient temperature, diluted with EtOAc, and washed with brine. The organic layer was washed with MgSO 4 The mixture was dried over 400 ml of ethyl acetate, filtered and concentrated in vacuo. 2 Purification with 0% EtOAc in heptane (0-30%) afforded ethyl 7-(4-fluoro-2-methoxy-3-methylphenyl)-2,5-dioxaspiro[3.4]oct-6-ene-6-carboxylate (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 ethyl 7-(4-fluoro-2-methoxy-3-methylphenyl)-2,5-dioxaspiro[3.4]oct-6-ene-6-carboxylate (356 mg, 1.10 mmol) and Pd / C (110 mg, 0.10 mmol). The reaction mixture was degassed and stirred under a balloon of hydrogen for 3 days. The reaction mixture was filtered through a pad of Celite and washed with MeOH. The mother liquor was concentrated in vacuo to give ethyl rac-(6S,7S)-7-(4-fluoro-2-methoxy-3-methylphenyl)-2,5-dioxaspiro[3.4]octane-6-carboxylate (367 mg, 100%) as a white solid. ESI-MS m / z calculated 324.1373, found 325.4 (M+1). + ;Holding time: 1.85 minutes.

[0282] Step 6: Potassium tert-butoxide (1.6 mL of a 1 M solution in THF, 1.60 mmol) was added dropwise to a stirred solution of ethyl rac-(6S,7S)-7-(4-fluoro-2-methoxy-3-methylphenyl)-2,5-dioxaspiro[3.4]octane-6-carboxylate (185 mg, 0.57 mmol) in THF (6.4 mL) at 0 °C. After 1 h, the reaction mixture was diluted with EtOAc. The mixture was then quenched by the addition of 1 M aqueous HCl. The aqueous layer was separated and extracted with EtOAc. The combined organic phase was washed with MgSO 4 The mixture was dried at 40° C. for 24 hours, filtered and concentrated in vacuo to give 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 296.106, found 297.4 (M+1). + ;Holding time: 0.4 minutes.

[0283] Step 7: Methyl 4-aminopyridine-2-carboxylate (33 mg, 0.22 mmol) 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 MeCN (2 mL). 1-Methylimidazole (55 μL, 0.69 mmol) and TCFH (65 mg, 0.2317 mmol) were added successively to the reaction mixture. The solution was stirred at ambient temperature for 16 h. Methanolic ammonia solution (6 mL of 7 M, 42.00 mmol) was added and the reaction was stirred at ambient temperature for an additional 24 h. The reaction mixture was diluted with EtOAc, washed with brine and diluted with MgSO 4 The mixture was dried at 4°C, filtered and concentrated in vacuo onto silica gel. Flash chromatography (24 g SiO 2Purification with 0% EtOAc in heptane (0-100%) gave rac-4-((6R,7S)-7-(4-fluoro-2-methoxy-3-methylphenyl)-2,5-dioxaspiro[3.4]octane-6-carboxamido)picolinamide (30 mg, 37%) as a colorless oil. ESI-MS m / z calculated 415.15436, found 416.7 (M+1). + , 414.7(M-1) - ;Holding time: 0.7 minutes.

[0284] Step 8: The enantiomers of rac-4-((6R,7S)-7-(4-fluoro-2-methoxy-3-methylphenyl)-2,5-dioxaspiro[3.4]octane-6-carboxamide)picolinamide were separated by HPLC on a Berger Instruments Minigram SFC system using a Daicel Chiralpak AS-H column, 5 μm particle size, 25 cm × 10 mm (mobile phase: 30% methanol (20 mM NH 3 ), 70% CO 2 The separation was carried out by chiral SFC using a 1000 Hz HPLC system (system pressure: 100 bar).

[0285] First eluting 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-d 6)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, actual value 416.3(M+1) + , 414.3(M-1) - ;Holding time: 2.35 minutes.

[0286] Second eluting 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 reversed-phase preparative HPLC (25, 4.5 mg, 29%). ESI-MS m / z calculated 415.15436, found 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: Et 3 N (9.56 g, 13.3 μΛ, 93.52 mmol) was added to a stirred solution of ethyl 2-diazo-3-oxobutanoate (6 g, 37.66 mmol) in DCM (50 mL) at 0 °C. TBSOTf (11.95 g, 10.6 mL, 44.29 mmol) was added very slowly to the reaction mixture, which was stirred at 0 °C for another 30 min. The reaction mixture was diluted with 30% NaHCO 3 The organic layer was separated and washed with water (500 mL) and MgSO 4 The mixture was dried at rt, filtered and concentrated in vacuo to give ethyl 3-((tert-butyldimethylsilyl)oxy)-2-diazobut-3-enoate (10 g, 98%) which was used without purification.

[0288] Step 2: TiCl in DCM (20 mL) 4A solution of (9.23 g, 5.4 mL, 48.16 mmol) 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 ethyl 3-((tert-butyldimethylsilyl)oxy)-2-diazobut-3-enoate (10 g, 36.982 mmol) in DCM (50 mL) was added dropwise to the reaction mixture at the same temperature. The reaction was stirred at −78° C. for 30 min and then quenched with water (250 mL). The organic layer was separated and washed with anhydrous MgSO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated in vacuo. 2 ) to give 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 ethyl rac-2-diazo-5-hydroxy-6-methoxy-5-methyl-3-oxohexanoate (7.5 g, 28.87 mmol) in toluene (230 mL) was added to a stirred and degassed solution of dirhodium tetraacetate (130 mg, 0.29 mmol) in toluene (70 mL) with N 2 The mixture was added dropwise at 100° C. under reduced pressure. The reaction mixture was heated to 110° C. for 10 minutes and then cooled to ambient temperature. The mixture was filtered through a pad of Celite. The filtrate was collected and concentrated in vacuo to give ethyl rac-5-(methoxymethyl)-5-methyl-3-oxotetrahydrofuran-2-carboxylate (6.2 g, 99%) as a light brown oil 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: Tf in DCM (15 mL) 2 A solution of 2,4-dimethyl-3,5-tetrahydrofuran-2-carboxylate (8.97 g, 5.4 mL, 31.46 mmol) was added dropwise over 7 min to a stirred solution of ethyl rac-5-(methoxymethyl)-5-methyl-3-oxotetrahydrofuran-2-carboxylate (6.2 g, 28.67 mmol) and DIPEA (4.45 g, 6 mL, 34.45 mmol) in DCM (50 mL) at -78°C. The reaction mixture was stirred at -78°C for 15 min and then at 0°C for an additional 15 min. The reaction mixture was diluted with saturated NaHCO 3 The mixture was quenched by the addition of a solution of MgSO (10 mL). The phases were separated and the aqueous layer was extracted with DCM (2×50 mL). The combined organic extracts were washed with MgSO 4 It was dried at 40° C., filtered and concentrated in vacuo. Purification by flash chromatography afforded ethyl rac-5-(methoxymethyl)-5-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (9 g, 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, actual value 349.0(M+1) + ;Retention time: 3.59 minutes.

[0291] Step 5: Pd(PPh 3 )4 (614 mg, 0.53 mmol) was added to a stirred, argon degassed solution of ethyl rac-5-(methoxymethyl)-5-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (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 diluted with 2M K 3 PO 4 Aqueous solution (16 mL, 32.0 mmol) was added. The reaction mixture was heated for 3 h and then cooled to ambient temperature. The mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo. The residue was diluted with EtOAc (50 mL), washed with water and brine, and washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated in vacuo. 2 Purification with 5% EtOAc in hexanes (5-10% EtOAc in hexanes) afforded ethyl rac-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyl-4,5-dihydrofuran-2-carboxylate (3 g, 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, measured 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 ethyl rac-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyl-4,5-dihydrofuran-2-carboxylate (2 g, 5.84 mmol) in ethanol (50 mL). The reaction mixture was further degassed under argon for 5 min and then shaken in a Parr reactor under 500 psi of hydrogen at ambient temperature. After 16 h, the reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. Flash chromatography (SiO 2 Purification with 10-15% EtOAc in hexanes) gave ethyl rac-(2S,3S)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxylate (1.5 g, 73%) as a pale yellow oil and as a mixture of four stereoisomers. ESI-MS m / z calculated 344.1435, found 345.0 (M+1). + ;Retention time: 3.62 minutes.

[0293] Step 7: Potassium tert-butoxide (1.5 g, 13.37 mmol) was added in portions to a stirred solution of a mixture of stereoisomers of ethyl rac-(2S,3S)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxylate (1.3 g, 3.78 mmol) in dry THF (60 mL) at 0° C. under argon. The reaction mixture was stirred at 0° C. for 30 min and then allowed to warm to ambient temperature. The reaction mixture was recooled to 0° C., quenched with 2N HCl solution (2 mL) and extracted with EtOAc. The organic phase was collected and washed with MgSO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated in vacuo. 2 Purification with hexanes (40-50% EtOAc in hexanes) afforded 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-d 6 )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, actual value 317.0(M+1) + ;Holding time: 1.45 minutes.

[0294] Step 8: Oxalyl chloride (450 μL of 2M, 0.9000 mmol) was added to a stirred solution of a mixture 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) at 0° C. The reaction mixture was stirred for 20 min and then concentrated in vacuo. The residue was diluted with DCM (2.2 mL) and the resulting solution was diluted with methyl 4-aminopyridine-2-carboxylate (65 mg, 0.43 mmol), DMAP (3 mg, 0.025 mmol), and Et 3 To a stirred solution of N (300 μL, 2.15 mmol) was added dropwise at 0 °C. After 10 min, the reaction was allowed to warm to ambient temperature and stirred for 16 h. The reaction mixture was diluted with DCM, washed with 1M HCl solution, and MgSO 4 The mixture was dried at 4°C, filtered, and concentrated in vacuo directly onto silica gel. Flash chromatography (24 g SiO 2Purification with 100% EtOAc in heptane (0-100%) afforded methyl rac-4-((2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxamido)picolinate (120 mg, 90%) as a colorless oil of a 3:1 mixture of diastereoisomers. ESI-MS m / z calculated 450.16025, found 451.6 (M+1). + , 449.7(M-1) - ;Retention time: 0.88 minutes.

[0295] Step 9: A solution of methyl rac-4-((2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxamide)picolinate (120 mg, 0.27 mmol) in methanolic ammonia (15 mL of 7 M, 105.0 mmol) was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo to give 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 435.16058, found 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 purified on a Berger Instruments Minigram SFC system using 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% CO 2 Separation by chiral SFC using a 100 Hz NMR spectrometer (system pressure: 100 bar) gave:

[0297] First eluting 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 435.16058, found 436.3 (M+1). + , 434.2(M-1) - ;Retention time: 2.68 minutes.

[0298] The second eluting 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, 4.7 mg, 4%). 1 H NMR (500MHz, DMSO-d 6 )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] Third eluting 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-carboxamido)picolinamide (28) and rel-4-((2S,3R,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-(methoxymethyl)-5-methyltetrahydrofuran-2-carboxamido)picolinamide (29), which required further separation.

[0300] The third eluting peak, containing the two enantiomers of the major diastereoisomer, was purified on a Berger Instruments Minigram SFC system using a Daicel 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% CO 2 Further separation by chiral SFC using 100 rpm, system pressure: 100 bar) gave:

[0301] First eluting 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 435.16058, found 436.3 (M+1). + , 434.3(M-1) - ;Retention time: 2.77 minutes.

[0302] Second eluting 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-d 6)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 made using the method described in Example 4, except that in step 2, 4-methoxybutan-2-one was used instead of 1-methoxypropan-2-one. The conditions used in the amide coupling step 8 were those described in the first part of step 7 in Example 3. In step 10, the amide coupling was performed on a Berger Instruments Minigram SFC system using a Daicel Chiralpak AS-H column, 5 μm particle size, 25 cm×10 mm (mobile phase: 25% methanol (20 mM NH 3 ), 75% CO 2 Purification was carried out by chiral SFC using a 100 rpm HPLC system (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: BBr 3 (2 mL, 1 M in DCM, 2.00 mmol) was added 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) at 0 °C. The reaction mixture was allowed to warm to ambient temperature over 24 h. Water (5 mL) and saturated sodium bicarbonate (10 mL) were added and the reaction was stirred for 30 min. The aqueous layer was extracted with DCM (3 x 15 mL). The combined organic extracts were washed with MgSO 4 The mixture was dried over 400 ml of ethyl acetate, filtered and concentrated in vacuo. 2、 Purification with 0-100% EtOAc in heptane) gave 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 H NMR (500MHz, DMSO-d 6 )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-d 6) δ-80.05,-139.44(d,J=24.0Hz),-159.72(d,J=24.4Hz)ppm.ESI-MS m / z calculated 445.1061, found 446.5(M+1) + , 444.4(M-1) - ;Retention time: 0.73 minutes.

[0305] Step 2: rel-4-((2R,3S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide (80 mg, 0.18 mmol) in MeCN (2 mL), K 2 CO 3 A mixture of 1-chloro-2-methylpropan-2-ol (65 mg, 0.47 mmol) and 1-chloro-2-methylpropan-2-ol (280 μL, 2.73 mmol) was heated in a sealed tube at 80 °C for 17 h. An additional portion of 1-chloro-2-methylpropan-2-ol (280 μL, 2.73 mmol) was added and the reaction was further heated at 80 °C for 22 h. DMF (1 mL) was added and the reaction was heated at 80 °C for 24 h. An additional portion of 1-chloro-2-methylpropan-2-ol (550 μL, 5.36 mmol) was added and the reaction was heated at 100 °C for 120 h. The mixture was cooled to ambient temperature and partitioned between water (5 mL) and EtOAc (10 mL). The aqueous layer was separated and extracted with EtOAc (2 × 5 mL). The combined organic extracts were washed with MgSO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. Purification by reversed-phase HPLC using a Waters X-bridge C18 column (150×19 mm, 5 mm particle size) (mobile phase: acetonitrile and water (supplemented with 0.1% ammonium hydroxide), flow rate: 19 mL / min; sample was dissolved in neat acetonitrile and injected at 1 mL / min) gave 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. 1 H 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-d 6 )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 made using the method described in Example 5, except that in step 2, different alkylating agents were used instead of 1-chloro-2-methylpropan-2-ol. [Table 16]

[0307] The following compounds were made 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-chloroethan-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 purified using a Berger Instruments Minigram SFC apparatus with a Daicel Chiralpak IG column, 5 mm particle size, 25 cm x 10 mm (mobile phase: 12% methanol (20 mM NH 3 ), 88% CO 2 Further separation was performed by chiral SFC using 1000 rpm, 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 portions to a solution of methyl (2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (product of Example 2, 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 the addition of 1 M HCl (60 mL) and diluted with DCM (100 mL). The aqueous layer was separated and extracted with DCM (2 x 50 mL). The organic extracts were combined, washed with brine (50 mL) and diluted with MgSO 4 The mixture was dried at rt, filtered and concentrated in vacuo to give (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 H NMR (500 MHz, chloroform-d) δ 6.95-6.90(m, 1H), 6.73-6.66(m, 1H), 4.98(d, J=10.3 Hz, 1H), 4.17(dd, J=10.3, 7.8 Hz, 1H), 2.86-2.78(m, 1H), 1.60(s, 3H), 0.79-0.75(m, 3H) ppm; no alcohol or acid OH 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 at 80° C. for 24 h in a sealed vial. The reaction mixture was partitioned between MTBE (50 mL) and water (50 mL). The aqueous was extracted with MTBE (50 mL). The combined organic extracts were washed with brine (25 mL), passed through a phase separation cartridge and concentrated in vacuo. Flash chromatography (60 g SiO 2 Purification with 0% EtOAc in heptane (0-100%) gave 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 oil. 1 H NMR (500MHz, DMSO-d 6 )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 at room temperature overnight and then concentrated in vacuo. 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 extracts were washed with brine (5 mL), passed through a phase separation cartridge and concentrated in vacuo. Flash chromatography (24 g SiO 2 Purification with 0-20% EtOAc in heptane) gave (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-d 6 )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-d 6 )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 dissolved in ethyl acetate (3 mL) with (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 Et 3 A solution of N (361 μL, 2.590 mmol) was added. The mixture was stirred at ambient temperature for 4 h. The mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). The aqueous layer was separated and extracted with EtOAc (50 mL). The combined organic extracts were washed with brine (20 mL) and MgSO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated in vacuo. 2 Purification with 0% EtOAc in hexanes (0-100%) gave 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)methyl picolinate (360 mg, 82%). ESI-MS m / z calculated 674.28107, found 67.0 (M+1). + , 673.9(M-1) - ;Retention time: 1.36 minutes.

[0312] Step 5: A solution of methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinate (370 mg, 0.5483 mmol) in MeOH (3 mL) was diluted with MeNH 2(425 μL of 40% w / v in water, 5.474 mmol). The mixture was stirred at ambient temperature for 40 min and then concentrated in vacuo. Purification by reverse phase HPLC using a Waters X-bridge C18 column (150×19 mm, 5 mm particle size) (gradient: 47.4% to 94.7% acetonitrile in water (supplemented with 0.1% ammonium hydroxide) (9 min), flow rate: 19 mL / min; sample dissolved in neat acetonitrile and injected at 1 mL / min) gave 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%). ESI-MS m / z calculated 673.29706, found 675.0 (M+1) + ;Retention time: 3.73 minutes.

[0313] Step 6: TBAF (542 μL of 1 M, 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-carboxamido)-N-methylpicolinamide (100 mg, 0.1465 mmol) in THF (2 mL). The reaction mixture was stirred at ambient temperature for 2 h and then concentrated in vacuo. Purification by reverse phase preparative HPLC afforded 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-hydroxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-N-methylpicolinamide (38, 59 mg, 78%). 1 H NMR (500MHz, DMSO-d 6)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 compound was synthesized in step 2 using 4-(2-chloroethyl)morpholine as the alkylating agent and Cs as the base. 2 CO 3 This compound was made using the methods described in Example 6, except that with was used. The conditions used for aminolysis step 5 were those described in step 9 of Example 2. Deprotection step 6 was not required. [Table 18]

[0315] The following compounds were made using the method described in Example 6, except that the conditions used in step 1 were those described in step 4 of Example 2, and only MeOH was used as the solvent. The conditions used in step 2 were those described in step 1 of Example 10 using different alcohols. Step 3 was carried out in THF as solvent. Step 4 was carried out in DMF as solvent, with HATU as activating agent and Et as base. 3 N at ambient temperature until reaction completion, under conditions well known in the art. Step 6 was not required. In step 5, for compounds 40 and 42, MeNH in a mixture of water and MeOH was used. 2Instead, a 7M methanolic ammonia solution was used. [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: Et 3 N (50 μL, 0.3587 mmol) and methanesulfonyl chloride (20 μL, 0.2584 mmol) were added successively 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 min. 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 (1×3 mL) and diluted with MgSO 4 The mixture was dried at 40° C. for 1 hour, filtered and concentrated in vacuo to give 2-(6-((2R,3S,4S,5R)-2-((2-carbamoylpyridin-4-yl)carbamoyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-3-yl)-2,3-difluorophenoxy)ethyl methanesulfonate (100 mg, 73%) as an oil. ESI-MS m / z calculated 581.1255, found 582.7 (M+1). + , 580.6(M-1) - ;Retention time: 0.88 minutes.

[0317] N-Methylmethanamine (500 μL of 40% w / w in water, 3.993 mmol) was added to 2-(6-((2R,3S,4S,5R)-2-((2-carbamoylpyridin-4-yl)carbamoyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-3-yl)-2,3-difluorophenoxy)ethyl methanesulfonate (100 mg). The mixture was stirred at ambient temperature for 2 h. 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 extracts were washed with brine (1×10 mL) and diluted with MgSO 4 It was dried at 40° C., filtered and concentrated in vacuo. Purification by reverse phase preparative HPLC afforded 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-d 6 )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 made using the method described in Example 7, except that the conditions used in Step 2 were those described in Step 5 of Example 8 using different amines. [Table 20-1] [Table 20-2]

[0319] The following compounds were made using the method described in Example 7, except that the conditions used in Step 2 were those described in Step 2 of Example 5 using different amines. [Table 21]

[0320] The following compounds were made using the method described in Example 7, except that the conditions used in Step 2 were those described in Step 5 of Example 8 using a different amine in excess and without base. [Table 22]

[0321] Example 8 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(oxetan-3-yloxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide (58) [ka] Step 1: Benzyl bromide was added to a stirred mixture of methyl (2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (product of Example 2, Step 2, 15 g, 42.34 mmol) and potassium carbonate (7.8 g, 56.44 mmol) in DMF (20 mL). The reaction mixture was stirred overnight at ambient temperature. An additional amount of BnBr (2 ml) was added and the reaction was stirred at 60° C. for a further 3 h. The mixture was partitioned between ethyl acetate (100 ml) and water (150 ml). The aqueous phase was separated and extracted with ethyl acetate (50 mL). The combined organic extracts were washed with water (2×100 ml), brine (1×25 mL) and diluted with MgSO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated in vacuo. 2 Purification with ethyl acetate in heptane (0 to 100% ethyl acetate in heptane) gave methyl (2S,3S,4S,5R)-3-(2-(benzyloxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (17.57 g, 93%) as a colorless oil which crystallized on standing. 1 H NMR(400MHz,chloroform-d)δ 7.49-7.35(m,5H),7.17(t,J=7.6Hz,1H),6.82(td,J=9.3,7.6Hz,1H),5.12(dd,J=71.3,11.2Hz,2H),4.83(d,J=6.1Hz,1 H),4.25(dd,J=8.6,6.2Hz,1H),3.53(s,3H),2.73(p,J=7.8Hz,1H),1.49(s,3H),0.83(dd,J=7.6,2.0Hz,3H)ppm.ESI-MS m / z calculated value 444.136, actual value 443.1 (M-1) - ;Retention time: 1.09 minutes.

[0322] Step 2: Potassium tert-butoxide (3.53 g, 31.46 mmol) was added in portions to a solution of methyl (2S,3S,4S,5R)-3-(2-(benzyloxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (14 g, 31.50 mmol) in 2-MeTHF (10 mL) at 0° C. The reaction mixture was stirred at 0° C. for 5 min and then at ambient temperature for a further 30 min. The mixture was diluted with MTBE (5 ml) and quenched with 1M HCl. The aqueous layer was separated and extracted with MTBE (5 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give (2R,3S,4S,5R)-3-(2-(benzyloxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (10.5 g, 74%) as an oil. 1 H NMR (500 MHz, chloroform-d) δ 7.44-7.28 (m, 5H), 6.98-6.87 (m, 2H), 5.29-5.18 (m, 1H), 5.11 (dd, J = 11.3, 1.2 Hz, 1H), 4.87 (d, J = 11.0 Hz, 1H), 4.05-3.88 (m, 1H), 2.48 (p, J = 7.6 Hz, 1H), 1.42 (d, J = 1.2 Hz, 3H), 0.70 (dq, J = 7.3, 2.3 Hz, 3H) ppm; no acid OH observed. ESI-MS m / z calculated 430.12036, found 431.2 (M+1). + , 429.1(M-1) - ;Retention time: 0.68 minutes.

[0323] Step 3: T3P (12.9 mL, 43.38 mmol) was dissolved in EtOAc (27 mL) and (2R,3S,4S,5R)-3-(2-(benzyloxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (2.918 g, 6.780 mmol), methyl 4-aminopyridine-2-carboxylate (1.656 g, 10.88 mmol), and Et 3To a stirred solution of N (3.0 mL, 21.52 mmol) was added. The mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with EtOAc (20 mL) and poured into water (50 mL). The aqueous layer was separated and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (10 mL) and MgSO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated in vacuo. Flash chromatography (80 g SiO 2 Purification with hexanes (0-100% EtOAc in hexanes) gave methyl 4-((2R,3S,4S,5R)-3-(2-(benzyloxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinate (2.193 g, 57%) as a white foam. 1 H NMR (500MHz, chloroform-d) δ 8.74 (br.s, 1H), 8.65 (d, J = 5.5Hz, 1H), 8.16-8.12 (m, 1H), 7.99-7.95 (m, 1H), 7.34-7.29 (m, 2H), 7.28-7.22 (m, 2H), 7.18 (t, J = 7.3Hz, 1H), 7.12-7.06 (m, 1H), 6.97-6.9 1(m,1H),5.24(d,J=11.3Hz,1H),5.08(d,J=11.3Hz,1H),4.94(d,J=11.3Hz,1H),4. 01(s,3H),3.83-3.77(m,1H),2.53-2.45(m,1H),1.43(s,3H),0.73-0.68(m,3H)ppm.

[0324] Step 4: A solution of 4-((2R,3S,4S,5R)-3-(2-(benzyloxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)methyl picolinate (1.678 g, 2.973 mmol) in EtOH (35 mL) was added to Pd / C (87 mg, 0.8175 mmol). The mixture was purged with nitrogen for 5 min and then sparged with hydrogen for 5 min. The reaction mixture was stirred under a hydrogen atmosphere (via balloon) at ambient temperature for 16 h. The reaction mixture was filtered through a pad of Celite and w...

Claims

1. A compound of formula (I), 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein X ２ａ is N, N ＋ -O － or C-R ２ａ and X ４ａ is N, N ＋ -O － or C-R ４ａ and X ５ａ is N, N ＋ -O － or C-R ５ａ and X ６ａ is N, N ＋ -O － or C-R ６ａ and R is OR ａ or NR Ｘａ R Ｙａ and R ２ａ 、R ４ａ 、R ５ａ 、and R ６ａ each independently is H, halo, C １ -C ６ alkyl, C １ -C ６ haloalkyl, or -Si(C １ -C ６ alkyl) ３ and R ａ is H or C １ -C ６ alkyl, R Ｘａ is H or C １ -C ６ is alkyl, R Ｙａ is a 4- to 6-membered heterocyclyl optionally substituted with one or more groups independently selected from H, OH, C １ -C ６ -alkyl, -(C １ -C ６ -alkylene)-R Ｚａ１ , or C １ -C ６ -alkyl and C １ -C ６ -alkoxy, or is a 4- to 6-membered heterocyclyl optionally substituted with one or more groups independently selected from H, OH, C or R Ｘａ and R Ｙａ together with the nitrogen atom to which they are attached form a 5- to 9-membered heterocyclyl, said heterocyclyl being optionally substituted with one or more R Ｚａ２ and optionally substituted with R Ｚａ１ is a 5- to 6-membered heterocyclyl optionally substituted with one or more groups independently selected from OH, NH ２ , -NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , and halo and C １ -C ６ alkyl, and is Each R Ｚａ２ is selected independently from 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 -alkoxy), and is selected independently therefrom R ４ｂ１ and R ４ｂ２ each independently is H, C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, or C １ -C ６ 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 or R ５ｂ１ and R ５ｂ２ together with the carbon atoms to which they are attached form a 4- to 6-membered heterocyclyl, X ３ｃ is N or C—R ３ｃ wherein X ４ｃ is N or C—R ４ｃ and X ５ｃ is N or C—R ５ｃ wherein X ６ｃ is N or C—R ６ｃ and R ２ｃ is H, OH, halo, C １ -C ６ -alkyl, C ２ -C ６ -alkenyl, 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 -alkylene)-O-(4- to 6-membered 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 wherein said cycloalkyl is optionally substituted with one or more groups independently selected from 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 -alkylene)-OH, L １ is either a bond or O, L ２ is a linking or C １ -C ６ alkylene, and L ３ is a bond, C １ -C ６ alkylene, or C ２ -C ６ alkenylene, and R Ｘｃ is 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 membered heterocyclyl), =NOH, =NO(C １ -C ６ alkyl), -N=S(O)(C １ -C ６ alkyl) ２ , -C(=NOH)(C ３ -C ６ 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 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 Selected independently from alkylene)-OH and optionally substituted with one or more groups, R ３ｃ is 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 Or, X ３ｃ is C—R ３ｃ where R ２ｃ and R ３ｃ together with the carbon atom to which they are attached form a group having the formula: [Chemical 2] forms a ring of Z １ and Z ２ each independently is O, CH ２ , or CF ２ and R Ｙｃ１ and R Ｙｃ２ each independently is H or halo, R ４ｃ is 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 cycloalkyl), where the cycloalkyl is optionally substituted with 1 to 2 halos, R ５ｃ is H, halo, OH, -OBn, C １ -C ６ alkyl, C １ -C ６ haloalkyl, or -L １ -L ２ -(C ３ -C ６ cycloalkyl), where the cycloalkyl is optionally substituted with 1 to 2 halos, R ６ｃ is H, halo, C １ -C ６ -alkyl, or C １ -C ６ -haloalkyl, and However, X ２ａ X ４ａ X ５ａ and X ６ａ Among them, two or less are N or N ＋ -O － on the condition that However, X ３ｃ X ４ｃ X ５ｃ and X ６ｃ are subject to the condition that one or less of them is N provided that R is OR ａ or R is NR Ｘａ R Ｙａ wherein R Ｙａ is a 4- to 6-membered heterocyclyl optionally substituted with one or more groups independently selected from OH, -(C １ -C ６ -alkylene)-R Ｚａ１ or C １ -C ６ alkyl and C １ -C ６ -alkoxy, or R is NR Ｘａ R Ｙａ wherein R Ｘａ and R Ｙａ together with the N atom to which they are attached form a 5- to 9-membered heterocyclyl, said heterocyclyl being optionally substituted with one or more R Ｚａ２ 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 together with the carbon atoms to which they are attached form a 4- to 6-membered heterocyclyl or R ２ｃ is -(C １ -C ６ -alkylene)-(C １ -C ６ -alkoxy), -(C １ -C ６ -alkylene)-O-(4- to 6-membered heterocyclyl), -O-(C ２ -C ６ -alkenylene)-(C １ -C ６ -haloalkyl), or -O-L ３ -R Ｘｃ or R ２ｃ is -L １ -L ２ -(C ３ -C ７ cycloalkyl), and the cycloalkyl is 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 alkylene)-OH, and is substituted with one or more groups independently selected from, 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 attached form a group having the formula: 【Chemical Formula 3】 forms a ring of, or R ４ｃ is OH, -OBn, C １ -C ６ alkoxy, C １ -C ６ haloalkoxy, or -L １ -L ２ -(C ３ -C ６ cycloalkyl), where the cycloalkyl is optionally substituted with 1 to 2 halos, or R ５ｃ is OH, -OBn, or -L １ -L ２ -(C ３ -C ６ -cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halos, a compound, or a pharmaceutically acceptable salt thereof.

2. The compound has the formula (I-A) [Chemical Formula 4] The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The compound has the formula (I-A-1) 【Chemical Formula 5】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. The compound has the formula (I-B) or (I-C) 【Chemical Formula 6】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. The compound has the formula (I-B-1) or (I-C-1) 【Chemical Formula 7】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. X ２ａ is N or C—R ２ａ wherein R ２ａ is H, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. X ４ａ is N, N ＋ -O － or C-R ４ａ wherein R ４ａ is H or halo, optionally F, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. X ５ａ is C—R ５ａ and R ５ａ is H, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

9. X ６ａ is N or C—R ６ａ where R ６ａ is H, halo, optionally F, C １ —C ６ alkyl, optionally CH ３ , or —Si(C １ —C ６ alkyl) ３ , optionally —Si(CH ３ ) ３ and 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 is H or C １ -C ６ alkyl, R Ｘａ is H or C １ -C ６ alkyl, R Ｙａ is a 4- to 6-membered heterocyclyl optionally substituted with one or more groups independently selected from H, OH, C １ -C ６ -alkyl, -(C １ -C ６ -alkylene)-R Ｚａ１ , or C １ -C ６ -alkyl and C １ -C ６ -alkoxy, optionally CH ３ , -OCH ３ , or -OCH ２ CH ３ and is optionally substituted with one or more groups independently selected from R Ｚａ１ is OH, -NH(C １ -C ６ -alkyl), optionally -NH(CH ３ ), -N(C １ -C ６ -alkyl), ２ optionally -N(CH ３ ), ２ and halo, optionally F, and C １ -C ６ -alkyl, optionally CH ３ optionally substituted with one or more groups independently selected from, a 5- to 6-membered heterocyclyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. R is NR Ｘａ R Ｙａ and R Ｘａ and R Ｙａ together with the nitrogen atom to which they are attached form a 5- to 9-membered heterocyclyl optionally substituted with one or more R Ｚａ２ groups, Each R Ｚａ２ is halo, optionally F, OH, C １ -C ６ alkyl, optionally CH ３ , C １ -C ６ alkoxy, optionally -OCH ３ , NH ２ , -NH(C １ -C ６ alkyl), optionally -NH(CH ３ ), -N(C １ -C ６ alkyl) ２ , optionally -N(CH ３ ) ２ , and -(C １ -C ６ alkylene)-(C １ -C ６ alkoxy), optionally -CH ２ OCH ３ independently selected from, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. R ４ｂ１ is H or C １ -C ６ alkyl, optionally CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is H or C-C alkyl, optionally CH.

13. R ４ｂ２ is H or C １ -C ６ alkyl, optionally CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is

14. R ５ｂ１ is C １ -C ６ alkyl, optionally CH ３ , C １ -C ６ haloalkyl, optionally CF ３ , or -(C １ -C ６ alkylene)-(C １ -C ６ alkoxy), optionally -CH ２ OCH ３ or -CH ２ CH ２ OCH ３ and is the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

15. R ５ｂ２ is C １ -C ６ alkyl, optionally CH ３ , C １ -C ６ haloalkyl, optionally CF ３ , or -(C １ -C ６ alkylene)-(C １ -C ６ alkoxy), optionally -CH ２ OCH ３ or -CH ２ CH ２ OCH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

16. R ５ｂ１ and R ５ｂ２ which, together with the carbon atoms to which they are attached, form a 4-membered heterocyclyl, of the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

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

18. X ３ｃ is C—R ３ｃ where R ３ｃ is H, halo, optionally F or Cl, C １ —C ６ alkyl, optionally CH ３ , C １ —C ６ haloalkyl, optionally CF ３ , —(C １ —C ６ alkylene)—OH, optionally —CH ２ OH, or —(C １ —C ６ alkylene)—(C １ —C ６ alkoxy), optionally —CH ２ OCH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

19. X ４ｃ is C—R ４ｃ where R ４ｃ is 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 cycloalkyl), where said cycloalkyl is optionally substituted with 1 to 2 halos, and L １ is O, and L ２ is a bond or C １ —C ６ alkylene, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

20. R ４ｃ is 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 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halos, L １ is O, L ２ is a bond or C １ -C ６ alkylene, the compound according to claim 3, 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 -(cyclopropyl), or -O-(cyclobutyl), wherein the cyclobutyl is substituted with two Fs, the compound according to claim 19, or a pharmaceutically acceptable salt thereof.

22. X ５ｃ is C—R ５ｃ wherein R ５ｃ is H, halo, OH, —OBn, or —L １ —L ２ —(C ３ —C ６ cycloalkyl), said cycloalkyl being optionally substituted with 1 or 2 halos, and L １ is O, and L ２ is a bond, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

23. R ５ｃ is H, halo, OH, -OBn, or -L １ -L ２ -(C ３ -C ６ -cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halos, and L １ is O, and L ２ is a bond, the compound according to claim 3, or a pharmaceutically acceptable salt thereof.

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

25. X ６ｃ is C-R ６ｃ and R ６ｃ is H, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

26. R ２ｃ is OH, halo, optionally Cl, C １ -C ６ alkoxy, optionally -OCH ３ , -(C １ -C ６ alkylene)-(C １ -C ６ alkoxy, optionally -CH ２ OCH ３ , -(C １ -C ６ alkylene)-O-(4- to 6-membered heterocyclyl), optionally -CH ２ -O-(4-membered heterocyclyl), -O-(C ２ -C ６ alkenylene)-(C １ -C ６ haloalkyl, optionally -O-(C ３ -C ４ alkenylene)-CF ３ , -L １ -L ２ -(C ３ -C ７ cycloalkyl), or -O-L ３ -R Ｘｃ wherein said cycloalkyl is optionally substituted with one or more groups independently selected from 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 alkylene)-OH, L １ is O, L ２ is a bond or C １ -C ６ alkylene, and L ３ is a bond, C １ -C ６ alkylene, or C ２ -C ６ alkenylene, and R Ｘｃ is 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 membered heterocyclyl), =NOH, =NO(C １ -C ６ alkyl), -N=S(O)(C １ -C ６ alkyl) ２ , -C(=NOH)(C ３ -C ６ 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 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, optionally substituted with one or more groups independently selected from alkylene)-OH.

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

28. R ２ｃ is -O-L ３ -R Ｘｃ and L ３ is a bond, C １ -C ６ alkylene, or C ４ -C ５ alkenylene, and R Ｘｃ is 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 membered heterocyclyl), =NOH, =NO(C １ -C ６ alkyl), -N=S(O)(C １ -C ６ alkyl) ２ , -C(=NOH)(C ３ -C ６ 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 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, optionally substituted with one or more groups independently selected from -alkylene)-OH.

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

30. X ３ｃ is C-R ３ｃ where R ２ｃ and R ３ｃ together with the carbon atom to which they are attached form a group of the formula: 【Chemical 8】 forms a ring of, wherein Z １ is O or CH ２ and Z ２ is O or CF ２ and R Ｙｃ１ and R Ｙｃ２ each independently is H or F, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

31. The ring is of the formula: 【Chemical Formula 9】 The compound according to claim 30, or a pharmaceutically acceptable salt thereof.

32. 【Fig. 101】 【Chemical 102】 【Chemical Formula 103】 【Chemical 104】 【Chemical 105】 【Chemical 106】 【Chemical 107】 【Chemical 108】 【Chemical 109】 【Chemical 110】 【Chemical 111】 【Chemical 112】 【Chemical 113】 【Chemical 114】 【Chemical 115】 【Chemical 116】 【Chemical 117】 【Chemical 118】 【Chemical 119】 【Chemical 120】 【Chemical 121】 【Chemical 122】 【Chemical 123】 【Chemical 124】 【Chemical 125】 【Chemical 126】 【Chemical 127】 【Chemical 128】 【Chemical Formula 129】 【Chemical 130】 【Chemical 131】 【Chemical 132】 【Chemical 133】 【Chemical 134】 【Chemical 135】 【Chemical 136】 【Chemical 137】 【Chemical 138】 【Chemical 139】 【Chemical 140】 【Chemical 141】 【Chemical Formula 142】 【Chemical 143】 【Chemical 144】 【Chemical 145】 【Chemical 146】 【Chemical 147】 【Chemical 148】 【Chemical 149】 【Chemical 150】 【Chemical 151】 【Chemical 152】 【Chemical 153】 【Chemical 154】 【Chemical 155】 【Chemical 156】 【Chemical 157】 【Chemical 158】 【Chemical 159】 【Chemical 160】 【Chemical 161】 【Chemical 162】 【Chemical 163】 【Chemical 164】 A compound selected from, or a pharmaceutically acceptable salt thereof.

33. The compound according to any one of claims 1 to 32 in non-salt form.

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

35. A pharmaceutical composition comprising the compound according to 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 of inhibiting a voltage-dependent sodium channel in a subject, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and optionally, wherein the voltage-dependent sodium channel is Na Ｖ 1.8, the composition.

37. A composition for use in treating chronic pain, visceral 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 or reducing the severity thereof in a subject, the composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

38. The composition according to claim 37, wherein the method comprises treating one or more of neuropathic pain; musculoskeletal pain, optionally osteoarthritis pain; acute pain; postoperative pain; or visceral pain, or reducing the severity thereof in said subject.

39. The composition according to claim 38, wherein the neuropathic pain comprises one or more of postherpetic neuralgia; small fiber neuropathy; idiopathic small fiber neuropathy; or diabetic neuropathy, optionally diabetic peripheral neuropathy.

40. The composition according to claim 38, wherein the postoperative pain comprises one or more of pain after appendectomy, pain after abdominoplasty, or pain after hernia suture.

41. The composition according to claim 36, wherein the subject is treated with one or more additional therapeutic agents administered concomitantly with, prior to, or after treatment with the composition.

42. A composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof for use as a medicament.

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