Substituted tetrahydrofuran-2-carboxamides as sodium channel modulators

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 invention relates to a method 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. TIFF2024520648000805.tif5264

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 197,253, filed June 4, 2021, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and prevent further damage to injured tissue. Nevertheless, there are many conditions in which pain persists beyond its usefulness or in which patients would benefit from pain inhibition. Neuropathic pain is a form of chronic pain caused by sensory nerve damage (Dieleman, JP, et al., Incidence rates and treatment of neuropathic pain conditions in the general population. Pain, 2008. 137(3):pp. 681-688). Neuropathic pain can be divided into two categories: pain caused by systemic metabolic damage to nerves and pain caused by discrete nerve damage. Metabolic neuropathies include postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Indications for discrete nerve damage include nerve entrapment injuries, such as pain after amputation surgery, postoperative nerve injury pain, and neuropathic back pain. 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 rise of action potentials in many excitable cell types (e.g., neurons, skeletal muscle cells, cardiac muscle cells) and is therefore involved in the initiation of electrical signaling 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 signaling 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 work in animal models, and (4) the pharmacological effects of known Nav1.8-modulating drugs. Furthermore, because Nav1.8 expression is restricted to peripheral neurons, particularly those that sense pain (e.g., dorsal root ganglia), 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 Nav1.8). V1.8 Sodium Channels. Mol. Interv., 2007.7(4):pp.192-5), England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin. Investig. Drugs 17(12), pp.1849-64(2008), Krafte, DS and Bannon, AW, Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8(1), pp.50-56(2008). Na plays a key role in the initiation and propagation of neural signals. V Because of the role played by Na V Antagonists that reduce 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 analgesics are known to inhibit sodium channels. V Local anesthetics such as lidocaine have been identified as inhibitors of the Na channel. V Other compounds, such as carbamazepine, lamotrigine, and tricyclic antidepressants, which block pain by inhibiting the channel and 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 the voltage-gated ion channel superfamily and 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 major sodium channel in skeletal muscle and is the Na V 1.5 is the major sodium channel in cardiac myocytes. V 1.7, 1.8, and 1.9 are primarily localized in the peripheral nervous system, and Na V 1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the central and peripheral nervous systems. The functional behavior of the nine isoforms is similar, but they differ 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):pp. 257-62). Subsequently, Na V1.8 has been shown to be a carrier of sodium currents that sustain action potential firing in small dorsal root ganglion (DRG) 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(Pt3):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 spontaneous activity of injured neurons (Choi, J.S. and S.G. 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): pp. 921-926. In depolarized or damaged DRG neurons, Na 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(Pt2): pp. 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 present inventors have found that some voltage-gated sodium channel inhibitors, for example, have a poor therapeutic window (e.g., Na VHowever, selective NaCl-containing steroids have been found to have limitations as therapeutic agents due to their 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.Drugs17(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 Targets7(2), p.144-58(2008) [Non-patent document 8] Soderpalm, B., Anticonvulsant: aspects of their mechanisms of action.Eur.J.Pain6 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(Pt3): p. 921-6 [Non-Patent Document 14] Jarvis, M.F., et al., A-803467, a potent and selective NaV1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc. Natl. Acad. Sci. U S A, 2007. 104(20): p. 8520-5 [Non-Patent Document 15] Joshi, S.K., et al., Involvement of the TTX-resistant sodium channel NaV1.8 in inflammatory and neuropathic, but not post-operative, pain states. Pain, 2006. 123(1-2): pp. 75-82

Non-Patent Document 16

Non-Patent Document 17

Non-Patent Document 18

Non-Patent Document 19

Non-Patent Document 20

Non-Patent Document 21

Non-Patent Document 22

Non-Patent Document 23

Non-Patent Document 24

Non-Patent Document 25

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

[0008] In another aspect, the invention relates to pharmaceutical compositions comprising a compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically 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 pharmaceutically acceptable salt, or a pharmaceutical composition.

[0010] In yet another aspect, the present invention relates to a method of treating or lessening 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 arrhythmia, by administering a compound, pharmaceutically acceptable salt, or pharmaceutical composition to the subject. [Brief explanation of the drawings]

[0011] [Figure 1] 1 shows an XRPD pattern characteristic of amorphous compound 105. [Figure 2] 1 shows an XRPD pattern characteristic of amorphous compound 145. [Figure 3] 1 shows an XRPD pattern characteristic of amorphous compound 183. [Figure 4] 1 shows an XRPD pattern characteristic of compound 213 in partially crystalline form. [Figure 5] 1 shows an XRPD pattern characteristic of amorphous compound 215. [Figure 6] 1 shows an XRPD pattern characteristic of amorphous compound 263. [Figure 7] 1 shows an XRPD pattern characteristic of amorphous compound 334. [Figure 8] 1 shows an XRPD pattern characteristic of amorphous compound 360. [Figure 9] 1 shows an XRPD pattern characteristic of amorphous compound 525. DETAILED DESCRIPTION OF THE INVENTION

[0012] In one aspect, the present invention provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: R a1 But -(C(Ra’ )2) p -R a’’ , [ka] a 5-membered heteroaryl, a 3- to 7-membered heterocycloalkyl, a 9- to 10-membered aryl, or a 9- to 10-membered heteroaryl, wherein the 5-membered heteroaryl, the 3- to 7-membered heterocycloalkyl, the 9- to 10-membered aryl, or the 9- to 10-membered heteroaryl is selected from the group consisting of one or more R a3 , substituted as necessary with R a2 Is H? or R a1 and R a2 together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl, and the 3- to 10-membered heterocycloalkyl is selected from one or more R a3 , substituted as necessary with Each R a’ are independently H or methyl optionally substituted with —OH, or two R a’ together with the atom or atoms to which they are attached form a C3-C6 cycloalkyl, a 3- to 7-membered heterocycloalkyl, or oxo; R a” is C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, 5- to 10-membered heteroaryl, phenyl, -NR 9 R 10 , -OR 11 or —CN, and the 5- to 10-membered heteroaryl, 3- to 7-membered heterocycloalkyl, or phenyl is selected from the group consisting of one or more R 13 , substituted as necessary with Each R a3 are independently halo, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 7-membered heterocycloalkyl, —C(O)C1-C6 alkyl, —OR 11 , -C(O)NR 9 R 10 , or -S(O)2R 7wherein the C1-C6 alkyl, C1-C6 haloalkyl, 3- to 7-membered heterocycloalkyl, or —C(O)C1-C6 alkyl is selected from one or more halo, —OR 11 , -CN, or -NR 9 R 10 or two R bonded to the same atom a3 are combined to form an oxo, or two R a3 together with the atoms to which they are attached combine to form a fused 3- to 7-membered ring containing up to two heteroatoms selected from the group consisting of N, O, and S; X 2a But, N, N + -O - , or CR 2a and X 3a But, N, N + -O - , or CR 3a and X 4a But, N, N + -O - , or CR 4a and X 5a But, N, N + -O - , C.R. 5a , or N + -(C1-C6 alkyl)Y - and Y - is a monovalent anion, X 6a But, N, N + -O - , or CR 6a and R 2a is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 3a is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 3- to 9-membered heterocycloalkyl, 5-membered heteroaryl, -CN, -OR 11 , -COOH, -NR 9 C(O)C1-C6 alkyl, -S(O)2R 7, -S(O)(NR 9 )R 7 , -S(O)NR 9 R 10 , -S(O)R 7 or —P(O)(C1-C6 alkyl)2, and the C1-C6 alkyl, C1-C6 alkoxy, 3- to 9-membered heterocycloalkyl, 5-membered heteroaryl, or —NR 9 C(O)C1-C6 alkyl is one or more R 12 , C3-C6 cycloalkyl, -NR 9 R 10 , -OR 11 , -CN, or one or more R 12 optionally substituted with 3- to 7-membered heterocycloalkyl optionally substituted with R 4a is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, C1-C6 alkoxy, 3- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, -CN, -C(O)NR 9 R 10 , -C(O)OH, -OR 11 , -NR 9 R 10 , -NR 9 C(O)C1-C6 alkyl, -S-C1-C6 alkyl, -S(O)(NR 9 )R 7 , -S(O)NR 9 R 10 or -P(O)(C1-C6 alkyl)2, wherein the C1-C6 alkyl, C1-C6 alkoxy, 3- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or C2-C6 alkynyl is selected from the group consisting of one or more halo, -OR 11 , 3- to 7-membered heterocycloalkyl, -NR 9 R 10 , C1-C6 alkyl, or -S(O)2R 7 , substituted as necessary with R 5a is H, halo, C-C alkyl, C-C haloalkyl, or -S(O)R 7 and R 6ais H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; or R 3a and R 4a together with the atoms to which they are attached form a ring of the formula: [ka] R 7 is C1-C6 alkyl or 3- to 7-membered heterocycloalkyl, and the C1-C6 alkyl or 3- to 7-membered heterocycloalkyl is one or more -OR 11 or C1-C6 alkyl optionally substituted; R 8 is H or C1-C6 alkyl; R 9 and R 10 are each independently H, C1-C6 alkyl, 3- to 7-membered heterocycloalkyl, C3-C6 cycloalkyl, —OH, —CN, or —S(O)2R 7 and the C1-C6 alkyl is one or more -OR 11 or R 9 and R 10 together with the atom to which they are attached form a 3- to 7-membered heterocycloalkyl; Each R 11 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 7-membered heterocycloalkyl optionally substituted with —OH, or 3- to 7-membered cycloalkyl optionally substituted with —OH; Each R 12 are independently halo, C1-C6 alkyl, or -OR 11 or two R 12 combine with the atom to which they are attached to form oxo, Each R 13 are independently halo, C1-C6 alkyl, or -CONH2, and the C1-C6 alkyl is selected from one or more -OR 11 or two R 13 combine with the atom to which they are attached to form oxo, R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; R 5b1 and R 5b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; 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 is H, -OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -L 1 -(C1-C6 alkylene)-OR 15 , -L 1 -(C1-C6 alkenylene)-OR 15 , -L 1 -(C1-C6 alkylene)-NR 16 R 17 , -L 1 -(C1-C6 alkylene)-N=S(O)(C1-C3 alkyl)2, or -L 1 -L 2 -R 14 and R 14 is C3-C6 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- or 6-membered heteroaryl, —C(O)O(C1-C6 alkyl), —COOH, or —C(O)NR 16 R 17 wherein the C3-C6 cycloalkyl, 3- to 8-membered heterocycloalkyl, or 5- or 6-membered heteroaryl is optionally substituted with one or more halo, —OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 15 is H, C1-C6 alkyl, or C1-C6 haloalkyl; R 16 and R 17 are each independently H, —OH, C1-C6 alkyl, or 3- to 7-membered heterocycloalkyl; R 3c is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or -(C1-C6 alkylene)-(C1-C6 alkoxy); R 4c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 5c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 6c is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy; L 1 is a bond or O, L 2 is a bond or C1-C6 alkylene; p is 1, 2, or 3; However, X 2a , X 3a , X 4a , X 5a , and X 6a Two or fewer of these are N or N + -O, X 3c , X 4c , X 5c , and X 6c At most one of is N, R 4a But CH(OH)-R 4a’ (R 4a’ H, or one or more halo, -OR 11 , 3- to 7-membered heterocycloalkyl, -NR 9 R 10 , C1-C6 alkyl, or -S(O)2R 7 C substituted as needed 1-or a pharmaceutically acceptable salt thereof, provided that:

[0013] For purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Further, general principles of organic chemistry are disclosed in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0014] As used herein, the term "compounds of the invention" refers to compounds of formula (I) described herein, and all of its embodiments (e.g., formula (IA), etc.), and compounds identified in Table A.

[0015] As described herein, the compounds of the present invention may contain multiple variables (e.g., R a1 , X 3a , R 5b1 As one of ordinary skill in the art will recognize, combinations of groups envisioned 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.

[0016] 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, the R a1 The formula in the definition of [ka] Regarding X 2a and X 3a is bonded by a single bond, and X 5a and X 6a are connected by a double bond, although the bond between these groups may be obscured by atom labels in the chemical structure. Further, with respect to formulas (I), (IA), (IB), and (IC), X 4c and X 5c are connected by a single bond, although the bond between these groups may be obscured by atom labels in the chemical structure. Additionally, a substituent designated as "CF3" or "F3C" in a chemical structure refers to a trifluoromethyl substituent, regardless of the designation in the chemical structure.

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

[0018] As used herein, the term alkyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, without unsaturation, having the specified number of carbon atoms, which is attached to the rest of the molecule by a single bond. For example, a "C1-C6 alkyl" group is an alkyl group having from 1 to 6 carbon atoms.

[0019] 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 rest of the molecule by a single bond. For example, a "C2-C6 alkenyl" group is an alkenyl group having from 2 to 6 carbon atoms.

[0020] 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, a "C3-C8 cycloalkyl" group is a cycloalkyl group having from 3 to 8 carbon atoms.

[0021] As used herein, the term heterocycloalkyl refers to a stable, non-aromatic, monocyclic, or bicyclic (fused, bridged, or spiro) saturated hydrocarbon radical consisting of carbon, hydrogen, and one or more heteroatoms such as nitrogen, oxygen, and sulfur having the specified number of ring atoms, which are attached to the rest of the molecule by a single bond. For example, a "3- to 7-membered heterocycloalkyl" group is a cycloalkyl group having 3 to 7 atoms and at least one heteroatom such as nitrogen, oxygen, and sulfur.

[0022] As used herein, the term "fused 3- to 7-membered ring containing up to two heteroatoms selected from the group consisting of N, O, and S" refers to two R atoms bonded to adjacent atoms together with the atoms to which they are bonded. a3 When used in reference to a ring formed by a group, refers to a saturated, unsaturated, or aromatic ring containing up to two heteroatoms selected from the group consisting of N, O, and S, fused to a heteroaryl, heterocycloalkyl, or aryl ring.

[0023] As used herein, the term "haloalkyl" refers to an alkoxy group having a 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, a "C1-C6 haloalkyl" group is an alkyl group having 1 to 6 carbon atoms, in which one or more of the alkyl group's hydrogen atoms are replaced by a halo group.

[0024] As used herein, the term "alkoxy" refers to a group of the formula -OR a where R ais an alkyl group having the specified number of carbon atoms. For example, a "C1-C6 alkoxy" group is a group of the formula -OR a where R a is an alkyl group having 1 to 6 carbon atoms.

[0025] As used herein, the term "haloalkoxy" refers to an alkoxy group having the specified number of carbon atoms, wherein one or more of the alkyl group's hydrogen atoms is replaced by a halo group.

[0026] As used herein, the term "alkylene" refers to a divalent straight or branched hydrocarbon chain radical group, consisting solely of carbon and hydrogen atoms, without unsaturation and having the specified number of carbon atoms, which is attached to the rest of the molecule by two single bonds. For example, a "C1-C6 alkylene" group is an alkylene group having from 1 to 6 carbon atoms.

[0027] As used herein, the term "alkenyl" refers to a divalent straight or branched hydrocarbon chain radical group, consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond and having a specified number of carbon atoms, which is attached to the rest of the molecule by two single bonds. For example, a "C1-C6 alkenylene" group is an alkenylene group having from 1 to 6 carbon atoms.

[0028] As used herein, the term "alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing no unsaturation and having the specified number of carbon atoms, which is attached to the rest of the molecule by a single bond, and the bond between any two other carbon atoms is a triple bond. For example, a "C1-C6 alkyl" group is an alkyl group having 1 to 6 carbon atoms. For example, a "C2-C6 alkynyl" group is an alkynyl group having 2 to 6 carbon atoms, and the bond between any two carbon atoms is a triple bond.

[0029] As used herein, the term "aryl" refers to a stable, aromatic, monocyclic or bicyclic ring radical having the specified number of ring atoms. For example, a "9- to 10-membered aryl" group is an aryl group having 9 to 10 carbons.

[0030] As used herein, the term "heteroaryl" refers to a stable, aromatic, monocyclic or bicyclic ring radical having the specified number of ring atoms and containing one or more heteroatoms individually selected from nitrogen, oxygen, and sulfur.

[0031] As used herein, the term "monovalent anion" refers to an anion having a single unit of negative charge. In some embodiments, the monovalent anion is pharmaceutically acceptable. As used herein, the term "pharmaceutically acceptable monovalent anion" refers to a monovalent anion that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable monovalent anions include any of the monovalent anions that are components of the pharmaceutically acceptable salts described herein. Illustratively, the monovalent anion can be a halide, e.g., chloride or bromide, hydroxide, carboxylate, sulfato, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Exemplary carboxylates include halogenated carboxylates such as acetate and trifluoroacetate.

[0032] As used herein, the term "optionally substituted" refers to a group that is unsubstituted or substituted with the substituent(s) specified thereafter. For example, an "optionally substituted group with 1 to 2 halo" is either unsubstituted, substituted with one halo group, or substituted with two halo groups.

[0033] 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. Furthermore, single stereoisomers, double bond isomers, conformational isomers, and tautomers, and mixtures of stereoisomers, double bond isomers, conformational isomers, and tautomers are within the scope of the invention.

[0034] As used herein, labels such as "*4" and "*3" as shown in the structures below refer to the corresponding R groups (in this case R 4a Groups and R 3a indicates the atom to which the (group) is bonded. [ka]

[0035] As used herein, in any chemical structure or formula, a straight, non-bold bond attached to a stereogenic center of a compound, such as in the formula: [ka] Indicates that the stereocenter is unspecified. The compound may have any configuration or a mixture of configurations at the stereocenter.

[0036] As used herein, in any chemical structure or formula, a bold or dashed straight bond attached to a stereogenic center of a compound, such as in the formula: [ka] A bold or dashed linear bond indicates the relative stereochemistry of a stereocenter with respect to the other stereocenter to which it is attached.

[0037] As used herein, in any chemical structure or formula, a bold or dashed wedge bond attached to a stereogenic center of a compound, such as in the formula: [ka] A bold or dashed wedge 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.

[0038] 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 compound.

[0039] As used herein, the prefix "rel-", when used in reference to 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. If the relative stereochemistry of a given stereocenter is unknown, no stereochemical designator is provided. In some instances, the absolute configurations of some stereocenters are known, while only the relative configurations of other stereocenters are known. In these instances, the stereochemical designators associated with stereocenters of known absolute configuration are marked with an asterisk (*), e.g., (R*)- and (S*)-, while the stereochemical designators associated with stereocenters of unknown absolute configuration are not so marked. 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 to stereocenters of known absolute configuration.

[0040] As used herein, the term "compound," when referring to a compound of the present invention, refers to a collection of molecules having the same chemical structure except that isotopic variations may exist among the constituent atoms of the molecule. The term "compound" includes a collection of molecules regardless of the purity of a given sample containing the collection of molecules. Thus, the term "compound" includes such a collection of molecules in pure form, in a mixture 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.

[0041] As used herein, the term "amorphous" refers to a solid material that does not have long-range order in the positions of its molecules. Amorphous solids are generally glasses or supercooled liquids in which 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 substance 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 observed 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 comprise 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 observed 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 comprising an amorphous compound may be characterized, for example, by a broader temperature range of melting of the solid material compared to the melting range of a pure crystalline solid. Other techniques, such as, for example, solid-state NMR, may also be used to characterize crystalline or amorphous forms.

[0042] As used herein, the term "crystalline" refers to a crystalline structure (or polymorph) having a particular molecular packing arrangement within a crystal lattice. Crystalline forms can be identified by, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, and solid-state nuclear magnetic resonance (e.g., 13 C. 19 F, 15 N, and 31They can be identified and distinguished from one another by one or more characterization techniques, including P SSNMR.

[0043] In this specification and claims, unless otherwise specified, any atom not specifically designated as a particular isotope of any compound of the invention is intended to represent any stable isotope of the specified element. In the examples, when an atom is not specifically designated as a particular isotope of any compound of the invention, no effort was made to enrich that atom in a particular isotope, and therefore, one of ordinary skill in the art would understand that such atom was likely present in about the natural abundance isotopic composition of the specified element.

[0044] 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 identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0045] 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.

[0046] As used herein, " 1 "H" refers to protium. When an atom in a compound of the invention or a pharmaceutically acceptable salt thereof is designated as protium, protium is present at at least the natural abundance concentration of protium at the designated position.

[0047] As used herein, "D", "d", and " 2 "H" refers to deuterium.

[0048] In some embodiments, the compounds of the invention and pharmaceutically acceptable salts thereof comprise each constituent atom at about the natural abundance isotopic composition of the specified element.

[0049] In some embodiments, the compounds of the present invention and pharmaceutically acceptable salts thereof contain one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the most abundant isotope of the specified element ("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 Examples include, but are not limited to, P.

[0050] Isotopically labeled compounds and salts can be used in several beneficial ways, including as pharmaceuticals. In some embodiments, isotopically labeled compounds and salts contain deuterium ( 2 H) labeled with 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 counterparts due to kinetic isotope effects, as described below. Higher metabolic stability translates directly into increased in vivo half-life or lower dosages, which under most circumstances represent preferred embodiments of the present invention. Isotopically labeled compounds and salts can generally be prepared by following the procedures disclosed in the synthetic schemes, examples, and related description, substituting readily available isotopically labeled reactants for non-isotopically labeled reactants.

[0051] deuterium( 2 H) labeled compounds and salts can manipulate the rate of oxidative metabolism of a compound through the primary kinetic isotope effect. The primary kinetic isotope effect is a 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 bond 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 scission. If the bond scission occurs within 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 at 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 herein by reference in its entirety.

[0052] The concentration of an isotope (e.g., deuterium) incorporated at a given position in an isotopically labeled compound of the present invention or a pharmaceutically 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.

[0053] When an atom in a compound of the invention or a pharmaceutically acceptable salt thereof is designated as deuterium, such compound (or salt) has an isotopic enrichment factor for such atom of at least 3000 (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).

[0054] In some embodiments, the present invention provides a compound of formula (IA): [ka] or a pharmaceutically acceptable salt thereof, wherein R a1 , R a2 , R 4b1 , R 4b2 , R 5b1 , R 5b2 , X 3c , X 4c , X 5c , X 6c , and R 2c is defined as set forth above in relation to formula (I).

[0055] In some embodiments, the present invention provides a compound of formula (IA-1): [ka] or a pharmaceutically acceptable salt thereof, wherein R a1 , R a2 , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 2c , R 3c, and R 4c is defined as set forth above in relation to formula (I).

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

[0057] In some embodiments, the present invention provides a compound of formula (IA-3): [ka] or a pharmaceutically acceptable salt thereof, wherein X 2a , X 3a , X 4a , X 5a , X 6a , R 4b2 , R 2c , R 3c , and R 4c is defined as set forth above in relation to formula (I).

[0058] In some embodiments, the present invention provides a compound of formula (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein R a1 , R a2 , R 4b1 , R 4b2 , R 5b1 , R 5b2 , X 3c , X 4c, X 5c , X 6c , and R 2c is defined as set forth above in relation to formula (I).

[0059] In some embodiments, the present invention provides a compound of formula (IB-1): [ka] or a pharmaceutically acceptable salt thereof, wherein R a1 , R a2 , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 2c , R 3c , and R 4c is defined as set forth above in relation to formula (I).

[0060] In some embodiments, the present invention provides a compound of formula (IB-2): [ka] or a pharmaceutically acceptable salt thereof, wherein X 2a , X 3a , X 4a , X 5a , X 6a , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 2c , R 3c , and R 4c is defined as set forth above in relation to formula (I).

[0061] In some embodiments, the present invention provides a compound of formula (IB-3): [ka] or a pharmaceutically acceptable salt thereof, wherein X 2a , X 3a , X 4a , X 5a , X 6a , R4b2 , R 2c , R 3c , and R 4c is defined as set forth above in relation to formula (I).

[0062] In some embodiments, the present invention provides a compound of formula (IC): [ka] or a pharmaceutically acceptable salt thereof, wherein R a1 , R a2 , R 4b1 , R 4b2 , R 5b1 , R 5b2 , X 3c , X 4c , X 5c , X 6c , and R 2c is defined as set forth above in relation to formula (I).

[0063] In some embodiments, the present invention provides a compound of formula (IC-1): [ka] or a pharmaceutically acceptable salt thereof, wherein R a1 , R a2 , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 2c , R 3c , and R 4c is defined as set forth above in relation to formula (I).

[0064] In some embodiments, the present invention provides a compound of formula (IC-2): [ka] or a pharmaceutically acceptable salt thereof, wherein X 2a , X 3a , X 4a , X 5a , X 6a , R 4b1 , R4b2 , R 5b1 , R 5b2 , R 2c , R 3c , and R 4c is defined as set forth above in relation to formula (I).

[0065] In some embodiments, the present invention provides a compound of formula (IC-3): [ka] or a pharmaceutically acceptable salt thereof, wherein X 2a , X 3a , X 4a , X 5a , X 6a , R 4b2 , R 2c , R 3c , and R 4c is defined as set forth above in relation to formula (I).

[0066] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IB), (IB-1), (IB-2), (IB-3), (IC), (IC-1), (IC-2), and (IC-3), or a pharmaceutically acceptable salt thereof, wherein X 2a is CR 2a In another embodiment, X 2a is CR 2a and R 2a is H.

[0067] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IB), (IB-1), (IB-2), (IB-3), (IC), (IC-1), (IC-2), and (IC-3), or a pharmaceutically acceptable salt thereof, wherein X 3a is N. In other embodiments, X 3a is N + -O - In another embodiment, X3a is CR 3a In other embodiments, R 3a is -S(O)2R 7 , -S(O)(NR 9 )R 7 , -S(O)NR 9 R 10 , -S(O)R 7 In other embodiments, R 3a is -S(O)2R 7 In other embodiments, R 3a is -S(O)(NR 9 )R 7 In other embodiments, R 3a is -S(O)NR 9 R 10 In other embodiments, R 3a is -S(O)R 7 In other embodiments, R 7 is methyl. In another embodiment, R 9 and R 10 is methyl. In another embodiment, R 3a is -NR 9 R 10 , or -OR 11 is C1-C6 alkyl optionally substituted with

[0068] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IB), (IB-1), (IB-2), (IB-3), (IC), (IC-1), (IC-2), and (IC-3), or a pharmaceutically acceptable salt thereof, wherein X 4a is N.

[0069] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IB), (IB-1), (IB-2), (IB-3), (IC), (IC-1), (IC-2), and (IC-3), or a pharmaceutically acceptable salt thereof, wherein X 5a is N or CR5a and R 5a is H, halo, or —CHOH. In other embodiments, X 5a is N. In other embodiments, X 5a is CR 5a In another embodiment, X 5a is CR 5a and R 5a is H, halo, or C1-C6 alkyl. In other embodiments, X 5a is CR 5a and R 5a is H, F, or C1-C6 alkyl. In other embodiments, X 5a is CR 5a and R 5a is H. In other embodiments, X 5a is CR 5a and R 5a is halo. In other embodiments, X 5a is CR 5a and R 5a is F. In other embodiments, X 5a is CR 5a and R 5a is CH3.

[0070] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof, wherein X 6a is N or CR 6a and R 6a is H. In other embodiments, X 6a is N. In other embodiments, X 6a is CR 6a In another embodiment, X 6a is CR 6a and R 6a is H.

[0071] 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 pharmaceutically acceptable salt thereof, wherein R a1 teeth, [ka] and R a2 is H. In other embodiments, R a1 teeth, [ka] and R a2 is H and X 5a is H and R 8 is H or CH. In other embodiments, R a1 teeth, [ka] and R a2 is H and X 5a is H and R 8 is CH3.

[0072] In some embodiments, the present invention relates to a compound of any one of (I), (IA), (IA-1), (IB), (IB-1), (IC), and (IC-1), or a pharmaceutically acceptable salt thereof, wherein R a1 teeth, [ka] and R a2 is H. In other embodiments, R a1 teeth, [ka] and R a2 is H and R 8 is H or CH. In other embodiments, R a1 teeth, [ka] and R a2 is H and R 8 is CH3.

[0073] In some embodiments, the present invention relates to a compound of any one of (I), (IA), (IA-1), (IB), (IB-1), (IC), and (IC-1), or a pharmaceutically acceptable salt thereof, wherein R a1 is one or more R a3 is a 5-membered heteroaryl optionally substituted with R a2 is H. In other embodiments, R a1 is one or more R a3 and R is a 9- to 10-membered aryl optionally substituted with a2 is H. In other embodiments, R a1 is one or more R a3 and R is a 9-10 membered heteroaryl optionally substituted with a2 is H. In other embodiments, R a3 is C1-C6 alkyl, C1-C6 haloalkyl, -OR 11 , -C(O)NR 9 R 10 , or -S(O)R 7 In other embodiments, R a3 is -S(O)2-CH3, -CH(OH)-CH(OH)-CH3, -CH(OH)-CH2-OH. In other embodiments, R a3 is -S(O)2-CH3.

[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 pharmaceutically acceptable salt thereof, wherein R 4b1 is H or C1-C6 alkyl. In other embodiments, R 4b1 is H. In other embodiments, R 4b1 is C1-C6 alkyl. In other embodiments, R 4b1is H or CH. In other embodiments, R 4b1 is CH3.

[0075] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IB), (IB-1), (IB-2), (IB-3), (IC), (IC-1), (IC-2), and (IC-3), or a pharmaceutically acceptable salt thereof, wherein R 4b2 is H or C1-C6 alkyl. In other embodiments, R 4b2 is H. In other embodiments, R 4b2 is C1-C6 alkyl. In other embodiments, R 4b2 is H or CH. In other embodiments, R 4b2 is CH3.

[0076] 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 pharmaceutically acceptable salt thereof, wherein R 5b1 is C1-C6 alkyl or C1-C6 haloalkyl. In other embodiments, R 5b1 is C1-C6 alkyl. In other embodiments, R 5b1 is C1-C6 haloalkyl. In other embodiments, R 5b1 is CH3 or CF3. In other embodiments, R 5b1 is CH3. In other embodiments, R 5b1 is CF3.

[0077] 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 pharmaceutically acceptable salt thereof, wherein R 5b2 is C1-C6 alkyl or C1-C6 haloalkyl. In other embodiments, R5b2 is C1-C6 alkyl. In other embodiments, R 5b2 is C1-C6 haloalkyl. In other embodiments, R 5b2 is CH3 or CF3. In other embodiments, R 5b2 is CH3. In other embodiments, R 5b2 is CF3.

[0078] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IB), (IB-1), (IB-2), (IB-3), (IC), (IC-1), (IC-2), and (IC-3), or a pharmaceutically acceptable salt thereof, wherein R 2c is OH, halo, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. 2c is OH. In other embodiments, R 2c is halo. In other embodiments, R 2c is C1-C6 alkyl. In other embodiments, R 2c is C1-C6 alkoxy. In other embodiments, R 2c is C1-C6 haloalkoxy. In other embodiments, R 2c is OH, Cl, CH, OCH, OCD, OCHCH, OCH(CH), OCHF, OCHCHF, or OCHCHF. 2c is Cl. In other embodiments, R 2c is CH3. In other embodiments, R 2c is OCH3. In other embodiments, R 2c is OCD3. In other embodiments, R 2c is OCH2CH3. In other embodiments, R 2c is OCH(CH). In other embodiments, R 2c is OCHF2. In other embodiments, R 2c is OCH2CH2F. In other embodiments, R 2c is OCH2CHF2.

[0079] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof, wherein X 3c is N or CR 3c and R 3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl. 3c is N. In other embodiments, X 3c is CR 3c In another embodiment, X 3c is CR 3c and R 3c is H. In other embodiments, X 3c is CR 3c and R 3c is halo. In other embodiments, X 3c is CR 3c and R 3c is C1-C6 alkyl. In other embodiments, X 3c is CR 3c and R 3c is C1-C6 haloalkyl. In other embodiments, X 3c is CR 3c and R 3c is H, F, CH3, CHF2, or CF3. In other embodiments, X 3c is CR 3c and R 3c is F. In other embodiments, X 3c is CR 3c and R 3c is CH3. In other embodiments, X 3c is CR 3c and R 3c is CHF2. In another embodiment, X 3c is CR 3c and R 3c is CF3.

[0080] In some embodiments, the present invention relates to a compound of any one of formulas (IA-1), (IA-2), (IA-3), (IB-1), (IB-2), (IB-3), (IC-1), (IC-2), and (IC-3), or a pharmaceutically acceptable salt thereof, wherein R 3c is H, halo, C-C alkyl, or C-C haloalkyl. 3c is H. In other embodiments, R 3c is halo. In other embodiments, R 3c is C1-C6 alkyl. In other embodiments, R 3c is C1-C6 haloalkyl. In other embodiments, R 3c is -(C1-C6 alkylene)-(C1-C6 alkoxy). In other embodiments, R 3c is H, F, CH3, CHF2, or CF3. In other embodiments, R 3c is F. In other embodiments, R 3c is CH3. In other embodiments, R 3c is CHF2. In another embodiment, R 3c is CF3.

[0081] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof, wherein X 4c is CR 4c and R 4c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl. 4c is CR 4c In another embodiment, X 4c teeth, CR 4c and R 4c is H. In other embodiments, X 4c is CR 4c and R 4c is halo. In other embodiments, X 4c is CR 4c and R 4cis C1-C6 alkyl. In other embodiments, X 4c is CR 4c and R 4c is C1-C6 haloalkyl. In other embodiments, X 4c is CR 4c and R 4c is H, F, or CHF2. In other embodiments, X 4c is CR 4c and R 4c is F. In other embodiments, X 4c is CR 4c and R 4c is CHF2. In another embodiment, X 4c is CR 4c and R 4c is CH2CH3. In another embodiment, X 4c is CR 4c and R 4c is CHF2. In another embodiment, X 4c is CR 4c and R 4c is CF3.

[0082] In some embodiments, the present invention relates to a compound of any one of formulas (IA-1), (IA-2), (IA-3), (IB-1), (IB-2), (IB-3), (IC-1), (IC-2), and (IC-3), or a pharmaceutically acceptable salt thereof, wherein R 4c is H, halo, C-C alkyl, or C-C haloalkyl. 4c is H. In other embodiments, R 4c is halo. In other embodiments, R 4c is C1-C6 alkyl. In other embodiments, R 4c is C1-C6 haloalkyl. In other embodiments, R 4c is H, F, CHF2, CH2CH3, CHF2, CF3. In other embodiments, R 4c is F. In other embodiments, R 4c is CHF2. In another embodiment, R 4cis CH2CH3. In other embodiments, R 4c is CHF2. In another embodiment, R 4c is CF3.

[0083] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof, wherein X 5c is CR 5c and R 5c is H.

[0084] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof, wherein X 6c is CR 6c and R 6c is H.

[0085] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IB), (IB-1), (IB-2), (IB-3), (IC), (IC-1), (IC-2), and (IC-3), or any embodiment thereof, i.e., a non-salt form of the compound.

[0086] In some embodiments, the present invention relates to a compound selected from Table A, or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to a compound selected from Table A, i.e., a 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

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

Table 1-75

Table 1-76

Table 1-77

Table 1-79

Table 1-80

Table 1-81

Table 1-82

Table 1-83

Table 1-84

Table 1-85

Table 1-86

Table 1-87

Table 1-88

Table 1-89

[0087] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, 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.

[0088] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, 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.

[0089] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, 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.

[0090] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, 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.

[0091] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof, the compound has the absolute and relative stereochemistry of the second eluting isomer when the four stereoisomers of the aforementioned formula are separated by SFC as described in Example 1. In another embodiment, 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.

[0092] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, 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.

[0093] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, 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.

[0094] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof, the compound has the absolute stereochemistry of the second eluting isomer when rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(tetrazolo[1,5-a]pyridin-6-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide is separated by SFC as described in Example 10. 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.

[0095] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, 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.

[0096] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, 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.

[0097] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof, the compound has the absolute stereochemistry of the second eluting isomer when the four stereoisomers of the aforementioned formula are separated by SFC as described in Example 4. In another embodiment, 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 following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, 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.

[0099] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, 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.

[0100] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof, the compound has the absolute stereochemistry of the second eluting isomer when rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-(methylsulfonyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide is separated by SFC as described in Step 12 of Example 1. In another embodiment, 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 following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, 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.

[0102] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, 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.

[0103] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof, the compound has the absolute stereochemistry corresponding to the second-eluting isomer when the two stereoisomers of (2R,3S,4S,5R)—N-(2-(1-((tert-butyldimethylsilyl)oxy)-2-fluoroethyl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide are separated by SFC as described in Example 7. 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.

[0104] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, 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 following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, 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.

[0106] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, 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.

[0107] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof, the compound has the absolute stereochemistry corresponding to the second-eluting isomer when the two stereoisomers of (2R,3S,4S,5R)—N-(2-(2-(tert-butoxy)-1-fluoroethyl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide are separated by SFC as described in Example 10. 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.

[0108] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, 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.

[0109] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, 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.

[0110] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, 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.

[0111] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof, the compound has the absolute stereochemistry corresponding to the second eluting isomer when the two enantiomers of rac-(2R,3S,4S,5R)—N-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide are separated by SFC as described in Example 1. 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.

[0112] Salts, Compositions, Uses, Formulations, Administration, and Additional Agents Pharmaceutically Acceptable Salts and Compositions As discussed herein, the present invention provides compounds and pharmaceutically acceptable salts thereof that are inhibitors of voltage-gated sodium channels. Accordingly, the present compounds and pharmaceutically 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. Accordingly, another aspect of the present invention provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, the compositions optionally further comprise one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0113] As used herein, the term "pharmaceutically acceptable" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and that is 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, a mixture with one or more other substances (e.g., a 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.

[0114] 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. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Non-limiting examples of pharmaceutically acceptable acid addition salts include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid; and salts formed using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, methylpropional ... Salts derived from appropriate bases include 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, etc. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0115] As used herein, a pharmaceutically acceptable composition of the present invention additionally includes pharmaceutically 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, as used herein, appropriate for the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for their preparation. Except insofar as any conventional carrier medium is incompatible with the compounds of the present invention, for example, by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, its use is contemplated within the scope of the present disclosure.Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), 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), and the like. sodium, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository waxes), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (e.g., propylene glycol and polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solution, and other non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), as well as 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.

[0116] In another aspect, the invention features a pharmaceutical composition including a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0117] In another aspect, the invention features a pharmaceutical composition including a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

[0118] Uses of compounds and pharmaceutically acceptable salts and compositions In another aspect, the invention features a method of inhibiting voltage-gated sodium channels in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. V It is 1.8.

[0119] In yet another aspect, the invention features a method for 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-surgical pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0120] 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-surgical pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, or cardiac arrhythmia in a subject, comprising administering an effective amount of a compound, a pharmaceutically 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 intestinal pain in a subject, including inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain, the method comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0122] In yet another aspect, the invention features a method for treating or reducing the severity of neuropathic pain in a subject, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, the neuropathic pain comprises 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.

[0123] In yet another aspect, the invention features a method of treating or lessening the severity of neuropathic pain in a subject, including postherpetic 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0124] In yet another aspect, the invention features a method for treating or lessening the severity of musculoskeletal pain in a subject, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, the musculoskeletal pain includes osteoarthritis.

[0125] In yet another aspect, the invention features a method of treating or lessening the severity of musculoskeletal pain in a subject, including osteoarthritis, back pain, cold pain, burn pain, or dental pain, the method comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0126] In yet another aspect, the invention features a method of treating or lessening the severity of inflammatory pain in a subject, including rheumatoid arthritis pain or vulvodynia, the method comprising administering an effective amount of a compound of the invention, a pharmaceutically 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, the method comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

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

[0129] In yet another aspect, the invention features a method for 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0130] In yet another aspect, the invention features a method for treating or lessening the severity of acute pain in a subject, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, the acute pain includes acute post-surgical pain.

[0131] In yet another aspect, the invention features 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, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0132] In yet another aspect, the invention features a method for treating or reducing the severity of bunionectomy pain in a subject, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

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

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

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

[0136] In yet another aspect, the invention features a method for treating or lessening the severity of a neurodegenerative disease in a subject, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt-Hopkins syndrome (PTHS).

[0137] 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, before, or after treatment with an effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0138] In another aspect, the invention features a method for inhibiting voltage-gated sodium channels in a biological sample, comprising contacting the biological sample with an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. V It is 1.8.

[0139] In another aspect, the present invention provides a method for the treatment of 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, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain in multiple sclerosis, comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. pain 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 pain Spinal syndrome, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, osteomyelitis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic osteoporosis, 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, neuropathies Featured are methods for treating or reducing the severity in a subject of fibromatosis, ophthalmopathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy-induced oral mucositis, Charcot arthropathy, temporomandibular joint disorders, painful knee replacement surgery, non-cardiac chest pain, pudendal pain, 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.

[0140] 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 lower 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, or other conditions, comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Trigeminal neuralgia, Charcot-Marie-Tooth neuropathy, hereditary sensory neuropathy, peripheral nerve injury, painful neuroma, ectopic proximal and distal discharge, 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, or mastectomy), intractable pain, acute pain, acute post-operative pain, acute musculoskeletal pain Systemic pain, joint pain, mechanical low back pain, neck pain, tenosynovitis, injury pain, exercise pain, acute visceral pain, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, cardiac pain, pelvic pain, renal colic pain, acute obstetric pain, labor 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, depression pain, leprosy pain, Behcet's disease pain and / or urinary tract disorders, urinary incontinence, pathological cough, overactive bladder, bladder pain syndrome, interstitial cystitis (IC), prostatitis, complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II, widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain in a subject.

[0141] Compounds, Pharmaceutically Acceptable Salts, and Compositions for Use - Patent application In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use as a medicament.

[0142] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting a voltage-gated sodium channel in a subject. V It is 1.8.

[0143] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for 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-surgical pain (e.g., herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia.

[0144] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for 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-surgical pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, or cardiac arrhythmia.

[0145] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or reducing the severity of intestinal pain in a subject, wherein the intestinal pain includes inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain.

[0146] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a 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 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.

[0147] In another aspect, the invention features a compound of the invention, or a pharmaceutically 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 postherpetic 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.

[0148] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or reducing the severity of musculoskeletal pain in a subject. In some aspects, the musculoskeletal pain includes osteoarthritis.

[0149] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for 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.

[0150] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or reducing the severity of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain or vulvodynia.

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

[0152] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating or lessening the severity of idiopathic pain in a subject, wherein the idiopathic pain includes the pain of fibromyalgia.

[0153] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating or reducing the severity of pathological cough in a subject.

[0154] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or reducing the severity of acute pain in a subject. In some aspects, the acute pain includes acute post-operative pain.

[0155] In yet another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or 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.

[0156] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating or reducing the severity of bunionectomy pain in a subject.

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

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

[0159] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or reducing the severity of visceral pain in a subject. In some aspects, the visceral pain includes abdominoplasty visceral pain.

[0160] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a 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).

[0161] In another aspect, the invention features a compound of the invention, or a pharmaceutically 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, before, or after treatment with the compound, pharmaceutically acceptable salt, or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0162] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of inhibiting a voltage-gated sodium channel in a biological sample, comprising contacting the biological sample with an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. V It is 1.8.

[0163] 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, cardiac 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. 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., post-stroke central neuropathic pain), traumatic neck syndrome, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic encephalopathy, Litematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, osteomyelitis, 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 pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of exercise-induced oral mucositis, Charcot arthropathy, temporomandibular joint disorders, painful knee replacement surgery, non-cardiac chest pain, pudendal pain, 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.

[0164] In another aspect, the present invention provides a method for treating pain associated with femoral cancer; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; splenic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; pain Neuromas associated with musculoskeletal pain; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiation therapy-induced neuropathic pain; persistent / chronic postoperative pain (e.g., after amputation, thoracotomy, cardiac surgery), postmastectomy pain; central pain; spinal cord injury pain; poststroke pain; thalamic pain; phantom limb pain (e.g., after lower limb, upper limb, or mastectomy); intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tenosynovitis; injury pain; movement pain; acute visceral pain; pyelonephritis ;Appendicitis;Cholecystitis;Intestinal obstruction;Hernia;Chest pain, cardiac pain;Pelvic pain, renal colic pain, acute obstetric pain, labor 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;Oro-facial pain;Sinusitis pain;Toothache;Multiple sclerosis (MS) pain;Pain in depression;Pain in leprosy;Pain in Behcet's disease;Adiposity pain;Pain in phlebitis;Pain in Guillain-Barré syndrome;Painful legs and moving toes;Haglun The present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating or reducing the severity in a subject of: bladder and genitourinary disorders; urinary incontinence, pathological cough; overactive bladder; bladder pain syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain.

[0165] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt, or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of trigeminal neuralgia, Botox-treated migraine, cervical spondylotic radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexus neuropathy, 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.

[0166] Drug manufacturing In another aspect, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament.

[0167] In another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in inhibiting a voltage-gated sodium channel. V It is 1.8.

[0168] In yet another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically 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 (e.g., herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia.

[0169] In yet another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically 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.

[0170] In yet another aspect, the present invention provides the use of a compound, pharmaceutically 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.

[0171] In yet another aspect, the present invention provides a compound of the present invention, a pharmaceutically 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 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).

[0172] In yet another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically 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.

[0173] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically 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. In some aspects, the musculoskeletal pain includes osteoarthritis.

[0174] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically 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.

[0175] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically 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 the inflammatory pain includes rheumatoid arthritis pain or vulvodynia.

[0176] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically 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.

[0177] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically 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.

[0178] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically 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.

[0179] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically 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 includes acute post-operative pain.

[0180] In yet another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically 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).

[0181] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically 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.

[0182] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically 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.

[0183] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically 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.

[0184] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically 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 includes abdominoplasty visceral pain.

[0185] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a 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).

[0186] In yet another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in combination with one or more additional therapeutic agents administered simultaneously with, before, or after treatment with the compound or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0187] 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, cardiac 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. 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., post-stroke central neuropathic pain), traumatic neck syndrome, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic encephalopathy, Litematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, osteomyelitis, 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 provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in the treatment or lessening of the severity of exercise-induced oral mucositis, Charcot arthropathy, temporomandibular joint disorder, painful knee replacement surgery, non-cardiac chest pain, pudendal pain, 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.

[0188] In another aspect, the present invention provides a method for treating pain associated with femoral cancer; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; splenic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; pain Neuromas associated with musculoskeletal pain; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiation therapy-induced neuropathic pain; persistent / chronic postoperative pain (e.g., after amputation, thoracotomy, cardiac surgery), postmastectomy pain; central pain; spinal cord injury pain; poststroke pain; thalamic pain; phantom limb pain (e.g., after lower limb, upper limb, or mastectomy); intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tenosynovitis; injury pain; movement pain; acute visceral pain; renal pelvic pain Inflammation; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor 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; depression pain; leprosy pain; Behcet's disease pain; adiposity pain; phlebitis pain; Guillain-Barré syndrome pain; sore legs and moving toes; haggard The present invention provides use of a compound of the present invention, a pharmaceutically 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: bladder and genitourinary disorders; urinary incontinence, pathological cough; overactive bladder; bladder pain syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain.

[0189] In another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in the treatment or lessening the severity of trigeminal neuralgia, migraine treated with Botox, cervical spondylotic radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexus neuropathy, 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.

[0190] 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is that amount effective to treat or lessen the severity of one or more of the conditions listed above.

[0191] The compounds, salts, and compositions of the present invention can be administered in any amount and via 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 from subject to subject, depending on the subject's species, age, and general condition, 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 optionally formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, the term "unit dosage form" refers to a physically discrete pharmaceutical unit appropriate for the subject being treated. However, it will be understood that the total daily dosage 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 specific 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, the 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.

[0192] The pharmaceutically 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), buccally 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 effective to obtain the desired therapeutic effect.

[0193] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the active compound or salt, 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 fragrances.

[0194] 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 solutions 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. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil, including synthetic monoglycerides or diglycerides, may be used. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables.

[0195] 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 before use.

[0196] In order to prolong the effect of a compound 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 dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be 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 compound-to-polymer ratio and the nature of the particular polymer used, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0197] Compositions for rectal or vaginal administration are preferably suppositories which can 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.

[0198] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound or salt is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as 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, cellulose, cellulose acetate, cellulose acetate, cellulose stearate, cellulose acetate, cellulose acetate stearate ... Calcium, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retardants 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 glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0199] 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. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may be of a composition that optionally releases the active ingredient only, or preferentially, in a certain part of the intestinal tract, 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.

[0200] The active compound or salt may also be in microencapsulated form with one or more of the excipients described above. Solid dosage forms such as 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. These dosage forms may also contain, as is common practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and may optionally be of a composition that releases the active ingredient(s) only, or preferentially, in a delayed manner in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0201] Dosage forms for topical or transdermal administration of the compounds or salts of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed 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. The present invention also 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.

[0202] As generally described above, the compounds of the present invention are useful as inhibitors of voltage-gated sodium channels. In one embodiment, the compounds V1.8 inhibitors, and therefore, without wishing to be bound by any particular theory, the compounds, salts, and compositions V These compounds are 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. V When activation or overactivity of 1.8 is involved in a particular disease, condition, or disorder, the disease, condition, or disorder is referred to as "Na V 1.8-mediated disease, condition, or disorder." Accordingly, 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 is implicated in the disease state.

[0203] 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.

[0204] Additional therapeutic agents It will also be understood that the compounds, salts, and pharmaceutically acceptable compositions of the present invention can be used in combination therapy, i.e., the compounds, salts, and pharmaceutically 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) to be used in a combination regimen will take into account the compatibility of the desired therapeutic agents and / or treatments and the desired therapeutic effect to be achieved. It will also be understood that the therapies used may achieve the desired effect for the same disorder (e.g., a compound of the present invention may be administered simultaneously with another agent used to treat the same disorder) or may 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 known as "appropriate for the disease or condition being treated." For example, exemplary additional therapeutic agents include, but are not limited to, non-opioid analgesics (indoles, e.g., etodolac, indomethacin, sulindac, tolmetin; naphthylalkanones, 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; salicylic acid Salts, such as aspirin, choline magnesium trisalicylate, diflunisal; fenamates, such as meclofenamic acid, mefenamic acid; and pyrazoles, such as phenylbutazone), or opioid (anesthetic) agonists (e.g., codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine). Additionally, non-drug analgesic approaches can be utilized in conjunction with the administration of one or more compounds of the present invention.For example, anesthesiology (spinal injection, nerve blockade), neurosurgery (neuroablation of CNS pathways), neurostimulation (transcutaneous electrical nerve stimulation, dorsal column stimulation), physical therapy (physical therapy, orthotic devices, 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 www.fda.gov), the entire contents of which are incorporated herein by reference.

[0205] In another embodiment, the additional suitable therapeutic agent is selected from:

[0206] (1) Opioid analgesics, such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, levalorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, pentazocine, or difelikefalin;

[0207] (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;

[0208] (3) barbiturate sedatives, such as amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal, or thiopental;

[0209] (4) benzodiazepines with sedative effects, such as chlordiazepoxide, clorazepate, diazepam, flazepam, lorazepam, oxazepam, temazepam, or triazolam;

[0210] (5) sedating histamine (H1) antagonists, such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine, or chlorcyclidine;

[0211] (6) sedatives, such as glutethimide, meprobamate, methaqualone, or dichloralphenazone;

[0212] (7) Skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphenadrine;

[0213] (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 (including 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);

[0214] (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;

[0215] (10) Tricyclic antidepressants, such as desipramine, imipramine, amitriptyline, or nortriptyline;

[0216] (11) Anticonvulsants, such as carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®), or valproate;

[0217] (12) Tachykinin (NK) antagonists, particularly NK-3, 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);

[0218] (13) Muscarinic antagonists, such as oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine, and ipratropium;

[0219] (14) COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

[0220] (15) Coal-tar analgesics, especially paracetamol;

[0221] (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;

[0222] (17) Vanilloid receptor agonists (e.g., resiniferatoxin or civamide) or antagonists (e.g., capsazepine, GRC-15300);

[0223] (18) beta-adrenergics, such as propranolol;

[0224] (19) Local anesthetics, e.g., mexiletine;

[0225] (20) Corticosteroids, e.g., dexamethasone;

[0226] (21) 5-HT receptor agonists or antagonists, especially 5-HT 1B / 1D agonists, such as eletriptan, sumatriptan, naratriptan, zolmitriptan, or rizatriptan;

[0227] (22)5-HT 2A Receptor antagonists, such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);

[0228] (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;

[0229] (24) Tramadol®, tramadol ER (Ultram ER®), IV tramadol, tapentadol ER (Nucynta®);

[0230] (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-l,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-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-(1-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]pyrimidine- 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;

[0231] (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;

[0232] (27) Cannabinoids, such as KHK-6188;

[0233] (28) metabotropic glutamate subtype 1 receptor (mGluRl) antagonists;

[0234] (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;

[0235] (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;

[0236] (31) Dual serotonin-norepinephrine reuptake inhibitors, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran, and imipramine;

[0237] (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-l-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN-462, or guanidinoethyl disulfide;

[0238] (33) Acetylcholinesterase inhibitors, for example, donepezil;

[0239] (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;

[0240] (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;

[0241] (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);

[0242] (37) Sodium channel blockers, such as lidocaine, lidocaine + tetracaine cream (ZRS-201), or eslicarbazepine acetate;

[0243] (38)Na V1.7 Blocking agents, 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), WO2012 / 125613 (US2012 / 264749), WO2012 / 116440 (US2014 / 187533), WO2011 / 026240 (US2012 / 220605), US8883840, US8466188, WO2013 / 109521 (US2015 / 005304), WO2020 / 117626, and CN111217776 (the entire contents of each application are incorporated herein by reference);

[0244] (38a)Na V1.7 Blocking agents, 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'-piperidin]-6-yl]ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]- 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'-piperidin]-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'-piperidin]-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'-piperidin]-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'-piperidin]-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'-piperidin]-6-yl]ethanone, (4-isopropoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl) spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 1-[(3S)-2,3-dimethyl-1'-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6- yl]-2,2,2-trifluoro-ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-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'-piperidin]-6-yl]ethanone, 1-[1'-[ 4-Methoxy-3-(trifluoromethyl)benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-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'-piperidin]-1'-yl]methanone, [2-methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-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'-piperidin]-1'-yl]methanone.

[0245] (39)Na V 1.8 Blockers, such as PF-04531083, PF-06372865, and 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 20 / 151728, WO2021 / 032074, CN112390745, CN111808019, CN112225695, CN112457294, CN112300051, CN112300069, CN112441969, and CN112479996 (WO2021 / 047622) (the entire contents of each application are incorporated herein by reference);

[0246] (39a)Na V1.8 Blocking agents, 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, 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-fluoro phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide, [4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate, 2-(4-fluoro-2-(methyl-d3)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide (4-(2-(4-fluoro-2-(methyl-d3)phenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate, 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-methoxyphenoxy)-N-( 3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide)picolinic acid, 2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide, 3-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoline-3-carboxamide, N-(3-sulfamoylphenyl)-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide, 3-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)quinoxaline- 2-carboxamide, 5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide)picolinic acid, 3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)quinoxaline-2-carboxamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(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)benzamido)picolinic acid, 5-(2-(2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)benzoic acid, 5-(4,5-dicolinic acid 4-(2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 4-(2-(2-chloro-4-fluorophenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)benzoic acid, 4-(4, 5-Dichloro-2-(4-chloro-2-methylphenoxy)benzamido)benzoic acid, 5-(4-(tert-butyl)-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)benzoic acid, 5-(4,5- Dichloro-2-(2,4-dimethoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(2-chloro-4-fluorophenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4-Difluorophenoxy)benzamido)picolinic acid, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-chloro-2-methyl 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-Dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-Dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6-Bis(trifluoromethyl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 5-fluoro-2-(4-fluoro-2-methylphenoxy)- N-(3-sulfamoylphenyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3-sulfamoylphenyl)benzamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(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)-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 -(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] )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-fluorophenyl)-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;

[0247] (40) Combined Na V 1.7 and Na V 1.8 Blocking agents, such as DSP-2230, Lohocla201, or BL-1021;

[0248] (41) 5-HT3 antagonists, such as ondansetron;

[0249] (42) TPRV1 receptor agonists, such as capsaicin (NeurogesX®, Qutenza®), and pharmaceutically acceptable salts and solvates thereof;

[0250] (43) Nicotinic receptor antagonists, such as varenicline;

[0251] (44) N-type calcium channel antagonists, such as Z-160;

[0252] (45) Nerve growth factor antagonists, such as tannezumab;

[0253] (46) Endopeptidase stimulators, such as senrebotase;

[0254] (47) Angiotensin II antagonists, such as EMA-401;

[0255] (48) Acetaminophen (including but not limited to intravenous acetaminophen (e.g., Ofirmev®));

[0256] (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

[0257] (50) Combination of bupivacaine and meloxicam (e.g., HTX-011).

[0258] 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.

[0259] 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.

[0260] 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.

[0261] In another embodiment, the additional therapeutic agent is oliceridine or ropivacaine (TLC590).

[0262] 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 application 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 blocking agent disclosed in WO2022 / 036297.V 1.7 is a blocker.

[0263] In another embodiment, the additional therapeutic agent is ASP18071, CC-8464, ANP-230, ANP-231, NOC-100, NTX-1175, ASN008, NW3509, AM-6120, AM-8145, AM-0422, BL-017881, NTM-006, opilanserin (Unafra™), brivolizide, SR419, NRD.E1, LX9211, LY3016859, ISC-17536, NFX-88, LAT-8881, AP-235, NYX2925, CNTX-6016, S-600918, S-637880, RQ-00434739, KLS-2031, MEDI7352, or XT-150.

[0264] 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.

[0265] In another embodiment, the additional therapeutic agent is any 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.

[0266] 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.

[0267] In another embodiment, the additional therapeutic agent is a NaV 1.7 and Na V and sodium channel inhibitors (also known as sodium channel blockers), such as 1.8 blockers.

[0268] The amount of additional therapeutic agent present in the compositions of the invention can be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. The amount of additional therapeutic agent present in the presently disclosed compositions can 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.

[0269] The compounds and salts of the present invention, or pharmaceutically acceptable compositions thereof, may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents, and catheters. Accordingly, in another aspect, the present invention includes compositions for coating implantable devices, comprising a compound or salt 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 a compound or salt 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 top coating of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart sustained release characteristics in the composition.

[0270] Another aspect of the present 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof, biopsies obtained from mammals or extracts thereof, as well as blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[0271] 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.

[0272] 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, 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 T.G.M.Wuts et al., Greene's Protective Groups in Organic Synthesis (4th ed. 2006).

[0273] Radiolabeled Analogs of the Compounds of the Invention In another aspect, the present invention relates to radiolabeled analogs of the compounds of the present invention.As used herein, the term "radiolabeled analogs of the compounds of the present invention" refers to compounds that are identical to the compounds of the present invention as described herein, including all embodiments herein, except that one or more atoms are replaced with radioactive isotopes of the atoms present in the compounds of the present invention.

[0274] 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).

[0275] Radiolabeled analogs can be used in many beneficial ways, including various types of assays such as substrate tissue distribution assays. For example, tritium ( 3 H) and / or carbon-14 ( 14 C) Labeled compounds are particularly useful in various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detectability.

[0276] In another aspect, the invention relates to a pharmaceutically acceptable salt of a radiolabeled analogue according to any of the embodiments described herein in relation to the compounds of the invention.

[0277] In another aspect, the invention relates to a pharmaceutical composition comprising a radiolabeled analogue, or a pharmaceutically acceptable salt thereof, according to any of the embodiments described herein in connection with the compounds of the invention, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0278] In another aspect, the present invention relates to methods of inhibiting voltage-gated sodium channels and methods of treating or lessening the severity of various diseases and disorders, including pain, in a subject comprising administering an effective amount of a radiolabeled analogue, pharmaceutically acceptable salt thereof, and pharmaceutical composition thereof, according to any of the embodiments described herein with respect to the compounds of the invention.

[0279] In another aspect, the invention relates to radiolabeled analogs, pharmaceutically 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.

[0280] In another aspect, the invention relates to the use of a radiolabeled analogue or a pharmaceutically acceptable salt thereof, according to any of the embodiments described herein in relation to the compounds of the invention, for the manufacture of a medicament, and pharmaceutical compositions thereof.

[0281] In another aspect, the radiolabeled analogs, their pharmaceutically 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.

[0282] 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 an embodiment of any of the following recited clauses. 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.

[0283] 1. A compound of formula (I), [ka] or a pharmaceutically acceptable salt thereof, wherein: R a1 But -(C(R a’ )2) p -R a’’ , [ka] a 5-membered heteroaryl, a 3- to 7-membered heterocycloalkyl, a 9- to 10-membered aryl, or a 9- to 10-membered heteroaryl, wherein the 5-membered heteroaryl, the 3- to 7-membered heterocycloalkyl, the 9- to 10-membered aryl, or the 9- to 10-membered heteroaryl is selected from the group consisting of one or more R a3 , substituted as necessary with R a2 Is H? or R a1 and R a2 together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl, and the 3- to 10-membered heterocycloalkyl is selected from one or more R a3 , substituted as necessary with Each R a’ are independently H or methyl optionally substituted with OH, or two R a’ together with the atom or atoms to which they are attached form a C3-C6 cycloalkyl, a 3- to 7-membered heterocycloalkyl, or oxo; R a” is C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, 5- to 10-membered heteroaryl, phenyl, -NR 9 R 10 , -OR 11 or —CN, and the 5- to 10-membered heteroaryl, 3- to 7-membered heterocycloalkyl, or phenyl is selected from the group consisting of one or more R 13 , substituted as necessary with Each R a3 are independently halo, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 7-membered heterocycloalkyl, —C(O)C1-C6 alkyl, —OR 11 , -C(O)NR 9 R 10 , or -S(O)2R 7 wherein the C1-C6 alkyl, C1-C6 haloalkyl, 3- to 7-membered heterocycloalkyl, or —C(O)C1-C6 alkyl is selected from one or more halo, —OR 11 , -CN, or -NR 9 R 10 or two R bonded to the same atom a3are combined to form an oxo, or two R a3 together with the atoms to which they are attached combine to form a fused 3- to 7-membered ring containing up to two heteroatoms selected from the group consisting of N, O, and S; X 2a But, N, N + -O - , or CR 2a and X 3a But, N, N + -O - , or CR 3a and X 4a But, N, N + -O - , or CR 4a and X 5a But, N, N + -O - , C.R. 5a , or N + -(C1-C6 alkyl)Y - and Y - is a monovalent anion, X 6a But, N, N + -O - , or CR 6a and R 2a is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 3a is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 3- to 9-membered heterocycloalkyl, 5-membered heteroaryl, -CN, -OR 11 , -COOH, -NR 9 C(O)C1-C6 alkyl, -S(O)2R 7 , -S(O)(NR 9 )R 7 , -S(O)NR 9 R 10 , -S(O)R 7 or -P(O)(C1-C6 alkyl)2, and the C1-C6 alkyl, C1-C6 alkoxy, 3- to 9-membered heterocycloalkyl, 5-membered heteroaryl, or -NR9 C(O)C1-C6 alkyl is one or more R 12 , C3-C6 cycloalkyl, -NR 9 R 10 , -OR 11 , -CN, or one or more R 12 optionally substituted with 3- to 7-membered heterocycloalkyl optionally substituted with R 4a is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, C1-C6 alkoxy, 3- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, -CN, -C(O)NR 9 R 10 , -C(O)OH, -OR 11 , -NR 9 R 10 , -NR 9 C(O)C1-C6 alkyl, -S-C1-C6 alkyl, -S(O)(NR 9 )R 7 , -S(O)NR 9 R 10 or -P(O)(C1-C6 alkyl)2, wherein the C1-C6 alkyl, C1-C6 alkoxy, 3- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or C2-C6 alkynyl is selected from the group consisting of one or more halo, -OR 11 , 3- to 7-membered heterocycloalkyl, -NR 9 R 10 , C1-C6 alkyl, or -S(O)2R 7 , substituted as necessary with R 5a is H, halo, C-C alkyl, C-C haloalkyl, or -S(O)R 7 and R 6a is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; or R 3a and R 4a together with the atoms to which they are attached form a ring of the formula: [ka] R 7is C1-C6 alkyl or 3- to 7-membered heterocycloalkyl, and the C1-C6 alkyl or 3- to 7-membered heterocycloalkyl is one or more -OR 11 or C1C6 alkyl optionally substituted, R 8 is H or C1-C6 alkyl; R 9 and R 10 are each independently H, C1-C6 alkyl, 3- to 7-membered heterocycloalkyl, C3-C6 cycloalkyl, —OH, —CN, or —S(O)2R 7 and the C1-C6 alkyl is one or more -OR 11 or R 9 and R 10 together with the atom to which they are attached form a 37-membered heterocycloalkyl; Each R 11 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 7-membered heterocycloalkyl optionally substituted with —OH, or 3- to 7-membered cycloalkyl optionally substituted with —OH; Each R 12 are independently halo, C1-C6 alkyl, or -OR 11 or two R 12 combine with the atom to which they are attached to form oxo, Each R 13 are independently halo, C1-C6 alkyl, or -CONH2, and the C1-C6 alkyl is selected from one or more -OR 11 or two R 13 combine with the atom to which they are attached to form oxo, R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; R 5b1 and R 5b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; 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 is N or CR 6c and R 2c is H, -OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -L 1 -(C1-C6 alkylene)-OR 15 , -L 1 -(C1-C6 alkenylene)-OR 15 , -L 1 -(C1-C6 alkylene)-NR 16 R 17 , -L 1 -(C1-C6 alkylene)-N=S(O)(C1-C3 alkyl)2, or L 1 -L 2 -R 14 and R 14 is C3-C6 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- or 6-membered heteroaryl, —C(O)O(C1-C6 alkyl), —COOH, or —C(O)NR 16 R 17 wherein the C3-C6 cycloalkyl, 3- to 8-membered heterocycloalkyl, or 5- or 6-membered heteroaryl is optionally substituted with one or more halo, —OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 15 is H, C1-C6 alkyl, or C1-C6 haloalkyl; R 16 and R 17 are each independently H, —OH, C1-C6 alkyl, or 3- to 7-membered heterocycloalkyl; R 3cis H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or -(C1-C6 alkylene)-(C1-C6 alkoxy); R 4c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 5c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 6c is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy; L 1 is a bond or O, L 2 is a bond or C1-C6 alkylene; p is 1, 2, or 3; However, X 2a , X 3a , X 4a , X 5a , and X 6a Two or fewer of these are N or N + -O, X 3c , X 4c , X 5c , and X 6c At most one of is N, R 4a But CH(OH)-R 4a’ (R 4a’ H, or one or more halo, -OR 11 , 3- to 7-membered heterocycloalkyl, -NR 9 R 10 , C1-C6 alkyl, or -S(O)2R 7 or a pharmaceutically acceptable salt thereof, provided that:

[0284] 2. The compound according to clause 1, wherein the compound has the formula (IA): [ka] or a pharmaceutically acceptable salt thereof.

[0285] 3. The compound according to clause 1, wherein the compound has the formula (IA-1): [ka] or a pharmaceutically acceptable salt thereof.

[0286] 4. The compound according to clause 1, wherein the compound has formula (IB): [ka] or a pharmaceutically acceptable salt thereof.

[0287] 5. The compound according to clause 1, wherein the compound has the formula (IB-1): [ka] or a pharmaceutically acceptable salt thereof.

[0288] 6.R a1 but, [ka] and R a2 6. The compound according to any one of clauses 1 to 5, wherein is H, or a pharmaceutically acceptable salt thereof.

[0289] 7.R a1 but, [ka] and R a2 6. The compound according to any one of clauses 1 to 5, wherein is H, or a pharmaceutically acceptable salt thereof.

[0290] 8.R a1 but, [ka] and R a2 6. The compound according to any one of clauses 1 to 5, wherein is H, or a pharmaceutically acceptable salt thereof.

[0291] 9.R a1 is a 5-membered heteroaryl, a 9- to 10-membered aryl, or a 9- to 10-membered heteroaryl, and the 5-membered heteroaryl, the 9- to 10-membered aryl, or the 9- to 10-membered heteroaryl is selected from the group consisting of one or more R a3 , substituted as necessary by R a2 6. The compound according to any one of clauses 1 to 5, wherein is H, or a pharmaceutically acceptable salt thereof.

[0292] 10.X 2a But, CR 2a and R 2a is H and X 5a CR 5a and R 5a is H and X 6a But, CR 6a and R 6a is H, or a pharmaceutically acceptable salt thereof.

[0293] 11.X 3a But N or CR 3a and R 3a But, -OR 11 , -COOH, -S(O)R 7 , -S(O)(NR 9 )R 7 , -S(O)NR 9 R 10 , or -S(O)R 7 11. The compound according to any one of clauses 1 to 6 or 10, wherein:

[0294] 12.X 4a 12. The compound according to any one of clauses 1 to 6, 10 or 11, wherein is N, or a pharmaceutically acceptable salt thereof.

[0295] 13.X 5a But, CR 5a and R 5a 9. The compound according to any one of clauses 1 to 5, 7 or 8, wherein is H, or a pharmaceutically acceptable salt thereof.

[0296] 14.R a1 is a 5-membered heteroaryl or a 9- to 10-membered heteroaryl, and the 5-membered heteroaryl or the 9- to 10-membered heteroaryl is one or more R a3 , substituted as necessary by R a2 10. The compound according to any one of clauses 1 to 5 or 9, wherein is H, or a pharmaceutically acceptable salt thereof.

[0297] 15.R 7 is methyl, and R 8 15. The compound according to any one of clauses 1 to 6, 9 to 12, or 14, or a pharmaceutically acceptable salt thereof, wherein is H or methyl.

[0298] 16.R 2c 16. The compound according to any one of clauses 1 to 15, or a pharmaceutically acceptable salt thereof, wherein is CH3 or OCH3.

[0299] 17.R 3c 17. The compound according to any one of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, wherein is halo or C1-C6 alkyl.

[0300] 18.R 3c 18. The compound according to clause 17, wherein is F, or a pharmaceutically acceptable salt thereof.

[0301] 19.R 3c 18. The compound according to clause 17, or a pharmaceutically acceptable salt thereof, wherein is CH3.

[0302] 20.R 4c 20. The compound according to any one of clauses 1 to 19, or a pharmaceutically acceptable salt thereof, wherein is halo.

[0303] 21.R 4c 21. The compound according to clause 20, wherein is F, or a pharmaceutically acceptable salt thereof.

[0304] 22.R 5c 22. The compound according to any one of clauses 1 to 21, wherein is H, or a pharmaceutically acceptable salt thereof.

[0305] 23.R 6c 23. The compound according to any one of clauses 1 to 22, wherein is H, or a pharmaceutically acceptable salt thereof.

[0306] 24.R 4b1 and R 4b2 24. The compound according to any one of clauses 1 to 23, wherein one of is H and one is methyl, or a pharmaceutically acceptable salt thereof.

[0307] 25.R 5b1 and R 5b2 24. The compound according to any one of clauses 1 to 23, wherein one of is methyl and one is trifluoromethyl, or a pharmaceutically acceptable salt thereof.

[0308] 26. A compound selected from Table A, or a pharmaceutically acceptable salt thereof.

[0309] 27. The compound according to any one of clauses 1 to 26, in non-salt form.

[0310] 28. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of clauses 1 to 26 or a pharmaceutically acceptable salt thereof, or a compound according to clause 27, and one or more pharmaceutically acceptable carriers or vehicles.

[0311] 29. A pharmaceutical composition comprising a compound according to any one of clauses 1 to 26 or a pharmaceutically acceptable salt thereof, or a compound according to clause 27, and one or more pharmaceutically acceptable carriers or vehicles.

[0312] 30. 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 clauses 1 to 26 or a pharmaceutically acceptable salt thereof, a compound according to clause 27, or a pharmaceutical composition according to clause 28 or 29.

[0313] 31. Voltage-gated sodium channels areV 1.8. The method according to clause 30.

[0314] 32. A method for 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, visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia in a subject, said method comprising administering to the subject an effective amount of a compound according to any one of clauses 1 to 26 or a pharmaceutically acceptable salt thereof, a compound according to clause 27, or a pharmaceutical composition according to clause 28 or 29.

[0315] 33. The method of clause 32, wherein the method comprises treating or reducing the severity of neuropathic pain in the subject.

[0316] 34. The method of clause 33, wherein the neuropathic pain comprises postherpetic neuralgia.

[0317] 35. The method of clause 33, wherein the neuropathic pain comprises small fiber neuropathy.

[0318] 36. The method of clause 33, wherein the neuropathic pain comprises idiopathic small fiber neuropathy.

[0319] 37. The method of clause 33, wherein the neuropathic pain includes diabetic neuropathy.

[0320] 38. The method according to clause 32, wherein the diabetic neuropathy comprises diabetic peripheral neuropathy.

[0321] 39. The method of clause 32, wherein the method comprises treating or reducing the severity of musculoskeletal pain in a subject.

[0322] 40. The method of clause 39, wherein the musculoskeletal pain comprises osteoarthritis pain.

[0323] 41. The method of clause 32, wherein the method comprises treating or reducing the severity of acute pain in the subject.

[0324] 42. The method of clause 41, wherein the acute pain includes acute post-operative pain.

[0325] 43. The method of clause 32, wherein the method comprises treating or reducing the severity of post-operative pain in the subject.

[0326] 44. The method of clause 43, wherein the postoperative pain comprises bunionectomy pain.

[0327] 45. The method according to clause 43, wherein the postoperative pain comprises abdominoplasty pain.

[0328] 46. ​​The method according to clause 43, wherein the postoperative pain includes pain from herniorrhaphy.

[0329] 47. The method of clause 32, wherein the method comprises treating or reducing the severity of visceral pain in the subject.

[0330] 48. The method of any one of clauses 30-47, wherein the subject is treated with one or more additional therapeutic agents administered simultaneously with, before, or after treatment with the compound, pharmaceutically acceptable salt, or pharmaceutical composition.

[0331] 49. Use of a compound according to any one of clauses 1 to 26 or a pharmaceutically acceptable salt thereof, a compound according to clause 27, or a pharmaceutical composition according to clause 28 or 29 as a medicament. [Example]

[0332] General method 1 1 H NMR spectra were obtained as solutions in a suitable deuterated solvent such as dimethylsulfoxide-d6 (DMSO-d6).

[0333] Compound purity, retention time, and electrospray ionization mass spectrometry (ESI-MS) data were determined by LC / MS analysis. LC / MS analysis was performed using a Waters Acquity UPLC BEH C8 column (50 × 2.1 mm, 1.7 μm particles) (pn: 186002877) with a (2.1 × 5 mm, 1.7 μm particles) guard column (pn: 186003978) and a dual gradient run of 2 to 98% mobile phase B over 4.45 min. Mobile phase A = HO (10 mM ammonium formate with 0.05% ammonium hydroxide). Mobile phase B = acetonitrile. Flow rate = 0.6 mL / min, injection volume = 2 μL, and column temperature = 45 °C.

[0334] Powder X-ray 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 approximately 3° to approximately 40° 2θ with a step size of 0.0131303° and 49 seconds per step.

[0335] Abbreviation Unless otherwise specified, or dictated otherwise by context, the following abbreviations shall be understood to have the following meanings: [Table 2-1] [Table 2-2] [Table 2-3]

[0336] General Method A: m-CPBA N-oxide formation (e.g., 2) [ka] To a solution of 5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide (1, 33 mg, 0.06971 mmol) in DCM (2 mL) was added m-CPBA (55 mg, 0.2390 mmol). The reaction was stirred at ambient temperature overnight. Additional m-CPBA (55 mg, 0.2390 mmol) was added and the reaction was stirred at ambient temperature overnight. The reaction was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was washed with EtOAc. The combined organics were washed with brine and dried over MgSO4. The crude product was purified by flash chromatography (0–100% EtOAc in heptane) and then further purified by preparative reverse-phase HPLC (basic eluent) to afford 2-carbamoyl-5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)pyridine 1-oxide (2, 14.9 mg, 43%) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 10.70(s,1H), 10.11(d,J=4.5Hz,1H), 8.86(d,J=2.0Hz,1H), 8.16(d,J=9. 0Hz,1H), 8.13(d,J=4.3Hz,1H), 7.73(dd,J=9.0,2.0Hz,1H), 7.21-7.12(m ,2H), 5.12(d,J=10.1Hz,1H), 4.25(dd,J=10.1,7.7Hz,1H), 3.94(d,J=2.0 Hz,3H), 2.77(p,J=7.5Hz,1H), 1.60(s,3H), 0.78-0.66(m,3H)ppm.ESI-MS m / z Calculated value 489.13232, measured value 490.2 (M+1) + ;488.1(M-1) - ;Retention time: 3.17 minutes.

[0337] General Method B: TFA Deprotection of Ketals to Obtain Diols (e.g., 3) [ka] A solution of rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-N-(2-(2,2,4-trimethyl-1,3-dioxolan-4-yl)pyridin-4-yl)tetrahydrofuran-2-carboxamide (1.190 g, 2.185 mmol) in DCM (20 mL) and TFA (5 mL, 64.90 mmol) was stirred at ambient temperature. Upon completion, the mixture was washed with 1 M NaOH (2 × 50 mL), dried (MgSO), and concentrated in vacuo. The residue was dissolved in MeCN and HO (3:1) and lyophilized to give rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(1,2-dihydroxypropan-2-yl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (3, 1.0886 g, 99%) as an amorphous white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.57(s,1H), 8.35(d,J=5.3Hz,1H), 7.84(s,1H), 7.52(s,1H), 7.24-7. 06(m,2H), 5.09(d,J=10.0Hz,1H), 5.05(s,1H), 4.59(s,1H), 4.25(dd,J =10.4,7.8Hz,1H), 3.95(d,J=2.3Hz,3H), 3.50(d,J=5.1Hz,2H), 2.85-2.70(m,1H), 1.60(s,3H), 1.34(s,3H), 0.72(d,J=5.6Hz,3H)ppm;ESI-MS m / z Calculated value 504.16837, measured value 505.3 (M+1) + ;503.5(M-1) - .

[0338] General Method D: Oxidation of Thioethers to Sulfones (e.g., 4) [ka] To a solution of rel-(2S,3R,4R,5S)-3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-N-(2-methylsulfanyl-4-pyridyl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (46 mg, 0.094 mmol) in dichloromethane (3 mL) was added m-CPBA (53 mg, 0.24 mmol) in one portion while stirring at 0 °C. The reaction was stirred at 0 °C for 1 h, then allowed to warm to ambient temperature and stirred for an additional 2 h. The reaction was quenched with saturated sodium bicarbonate solution and extracted with DCM (×3). The combined organic extracts were passed through a phase separation cartridge, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (4 g of SiO, 0–100% EtOAc / heptane in DCM, loaded onto a Telos nm) to give a yellow oil. The oil was repurified by preparative reverse-phase HPLC (basic eluent) to afford rel-(2S,3R,4R,5S)-3-(2-ethoxy-3,4-difluorophenyl)-4,5-dimethyl-N-(2-(methylsulfonyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (4, 26.8 mg, 54%) as an off-white solid. 1 H NMR(500MHz,DMSO-d6)δ 10.92(s,1H), 8.65(d,J=5.5Hz,1H), 8.38(d,J=2.0Hz,1H), 7.91(dd,J=5.5,2.1Hz,1H), 7.22-7.14(m,2H), 5.14(d,J=10.4Hz,1H), 4.29(dd, J=10.4,7.5Hz,1H), 4.25-4.12(m,2H), 3.25(s,3H), 2.77(p,J=7.5Hz,1H), 1.62(s,3H), 1.35(t,J=7.0Hz,3H), 0.78-0.70(m,3H)ppm.ESI-MS m / z Calculated value 522.12476, measured value 523.5 (M+1) + ;521.5(M-1) - .

[0339] General Method E: Formic Acid Deprotection of Ketals to Obtain Diols (e.g., 5) [ka] To a solution of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(5-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (80 mg, 0.1461 mmol) in formic acid (551 μL, 14.61 mmol), water (1 mL) was added and the mixture was heated at 50° C. for 1 hour. The reaction mixture was cooled and concentrated to dryness. The product was directly purified by preparative reverse-phase HPLC (basic eluent) and lyophilized to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(5-((S)-2,3-dihydroxypropyl)-1-methyl-1H-pyrazol-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (5, 30 mg, 40%) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 10.58(s,1H), 7.26-7.00(m,2H), 6.32(s,1H), 5.06(d,J=10.7Hz,1H), 4.7 4(d,J=5.2Hz,1H), 4.62(t,J=5.6Hz,1H), 4.21(dd,J=10.7,7.5Hz,1H), 3.9 5(d,J=2.0Hz,3H), 3.64(s,3H), 3.26(td,J=11.7,10.8,6.3Hz,1H), 2.78- 2.66(m,2H), 2.58-2.52(m,1H), 1.58(s,3H), 0.72-0.63(m,3H)ppm.ESI-MS m / z Calculated value 507.17926, measured value 508.4 (M+1) + ;Retention time: 2.96 minutes.

[0340] General Method F: Oxidation of Thioethers to Sulfoxides (e.g., 6, 7, 8, and 9) [ka] Step 1: To a solution of rac-(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-N-(2-methylsulfanyl-4-pyridyl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (86 mg, 0.18 mmol) in DCM (2 mL) was added m-CPBA (40 mg, 0.16 mmol) with stirring at 0 °C. The reaction was stirred for 10 min, after which an additional m-CPBA (10 mg) was added. After an additional 10 min, the reaction was quenched with saturated aqueous NaHCO and diluted with DCM. The mixture was passed through a phase separation cartridge, and the aqueous layer was washed with DCM. The filtrate was concentrated in vacuo. Purification by reverse-phase preparative HPLC (basic eluent) gave rac-(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-(methylsulfinyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (39.2 mg, 44%). ESI-MS m / z calculated 492.11423, found 493.1 (M+1). + ;491.3(M-1) - .

[0341] Step 2: rac-(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-(methylsulfinyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (39.2 mg, 0.080 mmol) was purified by chiral SFC. First, the two diastereomers were separated using a Daicel Chiralpak AS-H column, 5 μm particle size, 25 cm × 10 mm, on a Berger Instruments Minigram SFC instrument. Second, the individual enantiomers were separated using a Regis Technologies (R,R)-Whelk-O1 column, 5 μm particle size, 25 cm × 21.2 mm, to give the following:

[0342] First eluting isomer from separation 1, first eluting isomer from separation 2: rel-(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-(methylsulfinyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (6, 8 mg). 1 H NMR(500MHz,chloroform-d)δ 8.91(s,1H), 8.49(d,J=5.5Hz,1H), 8.09(dd,J=5.5,2.1Hz,1H), 7.82(d,J=2.0Hz ,1H), 7.07(ddd,J=8.0,5.5,2.0Hz,1H), 6.90(td,J=9.2,7.4Hz,1H), 5.03(dd,J=1 1.0,3.0Hz,1H), 4.10(dd,J=11.0,8.1Hz,1H), 4.01(d,J=2.8Hz,3H), 2.85(s,3H) , 2.76(p,J=7.7Hz,1H), 1.69(d,J=1.5Hz,3H), 0.80(dq,J=7.3,2.3Hz,3H);ESI-MS m / z calculated value 492.11423, measured value 493.2(M+1) + ;491.2(M-1) - .

[0343] First eluting isomer from separation 1, second eluting isomer from separation 2: rel-(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-(methylsulfinyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (7, 6 mg). 1H NMR (500 MHz, chloroform-d) δ 8.49(d,J=5.5Hz,1H), 8.06(dd,J=5.5,2.2Hz,1H), 7.80(d,J=2.1Hz,1H), 7 .06(ddd,J=8.0,5.4,2.0Hz,1H), 6.90(td,J=9.2,7.4Hz,1H), 5.03(d,J=11 .0Hz,1H), 4.10(dd,J=11.0,8.1Hz,1H), 4.01(d,J=2.8Hz,3H), 2.85(s,3H) , 2.75(p,J=7.7Hz,1H), 1.69(d,J=1.3Hz,3H), 0.87-0.76(m,3H)ppm;ESI-MS m / z Calculated value 492.11423, measured value 493.2 (M+1) + ;491.3(M-1) - .

[0344] Second eluting isomer from separation 1, first eluting isomer from separation 2: rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-(methylsulfinyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (8, 8 mg). 1 H NMR (500 MHz, chloroform-d) δ 8.88 (d, J = 8.2 Hz, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.07 (ddd, J = 9.3, 5.5, 2.2 Hz, 1H), 7.80 (d, J = 2.1 Hz, 1H), 7.12-7.03 (m, 1H), 6.90 (td, J = 9.2, 7.4 Hz, 1H), 5.03 (dd, J = 11.0, 3H) .0Hz,1H), 4.10(ddd,J=10.4,8.2,1.7Hz,1H), 4.01(d,J=2.7Hz,3H), 2.85(d,J=2.5H) ESI-MS m / z calculated value 492.11423, measured value 493.1(M+1) + ;491.2(M-1) - .

[0345] Second eluting isomer from separation 1, second eluting isomer from separation 2: rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-(methylsulfinyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (9, 8 mg). 1 H NMR(500MHz,chloroform-d)δ 8.85(s,1H), 8.49(d,J=5.5Hz,1H), 8.06(dd,J=5.5,2.2Hz,1H), 7.79(d,J=2.1Hz,1 H), 7.07(ddd,J=8.2,5.4,2.0Hz,1H), 6.90(td,J=9.2,7.4Hz,1H), 5.03(d,J=11.0H z,1H), 4.10(dd,J=11.1,8.1Hz,1H), 4.01(d,J=2.8Hz,3H), 2.85(d,J=3.1Hz,3H),2 .76(p,J=7.6Hz,1H), 1.69(d,J=1.4Hz,3H), 0.79(dt,J=7.5,2.3Hz,3H)ppm;ESI-MS m / z calculated value 492.11423, measured value 493.1(M+1) + ;491.2(M-1) - .

[0346] General Method G: Sulfoximine Formation by Thioether Oxidation (e.g., 10 and 11) [ka] Step 1: To a solution of rel-(2S,3R,4R,5S)-3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-N-(2-methylsulfanyl-4-pyridyl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (85 mg, 0.16 mmol) in MeOH (5 mL) was added (diacetoxyiodo)benzene (145 mg, 0.45 mmol) and ammonium carbamate (28 mg, 0.36 mmol). The reaction was stirred at ambient temperature for 5 hours and then concentrated in vacuo. The residue was partitioned between DCM and saturated aqueous Na2CO3, the layers were separated, and the aqueous layer was extracted with DCM (x3). The combined organic layers were passed through a phase separation cartridge and concentrated in vacuo. The residue was purified by flash column chromatography (4 g of SiO, 0–100% EtOAc in heptane, loaded onto Telos nM in DCM) to give rel-(2S,3R,4R,5S)-3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-N-[2-(methylsulfonimidoyl)-4-pyridyl]-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (65.8 mg, 75%). 1 H NMR (500 MHz, DMSO-d6) δ 10.89(s,1H), 8.58(d,J=5.5Hz,1H), 8.36(dd,J=4.3,2.0Hz,1H), 7.82(d dd,J=5.7,3.8,2.1Hz,1H), 7.22-7.14(m,2H), 5.12(d,J=10.4Hz,1H), 4. 37-4.27(m,2H), 4.26-4.12(m,2H), 3.12(d,J=1.0Hz,3H), 2.77(p,J=7.4 Hz,1H), 1.62(s,3H), 1.36(t,J=7.0Hz,3H), 0.79-0.69(m,3H)ppm;ESI-MS m / z Calculated value 521.14075, measured value 522.6 (M+1) + ;520.6(M-1) - .

[0347] Step 2: rel-(2S,3R,4R,5S)-3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-N-[2-(methylsulfonimidoyl)-4-pyridyl]-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (63.8 mg, 0.1165 mmol) was purified by chiral SFC [system: (R,R)-Whelk-O1 column from Regis Technologies, 5 μm particle size, 25 cm × 21.2 mm, MeOH, 20 mM NH] to give:

[0348] First eluting isomer (rt=5.04 min): rel-(2S,3R,4R,5S)-3-(2-ethoxy-3,4-difluorophenyl)-4,5-dimethyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (10, 25 mg) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ 10.89(s,1H), 8.57(d,J=5.5Hz,1H), 8.36(d,J=2.0Hz,1H), 7.81(dd,J=5.5,2.0Hz,1H), 7.22-7.11(m,2H), 5.12(d,J=10.4Hz,1H), 4.36-4. ESI-MS m / z calculated 521.14075, observed 522.6 (M+1) + ;520.6(M-1)

[0349] Second eluting isomer (rt=5.75 min): rel-(2S,3R,4R,5S)-3-(2-ethoxy-3,4-difluorophenyl)-4,5-dimethyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (11, 25 mg) as a white solid. 1H NMR(500MHz,DMSO-d6)δ 10.90(s,1H), 8.57(d,J=5.5Hz,1H), 8.35(d,J=2.0Hz,1H), 7.82(dd,J=5.5,2.1Hz,1H), 7.23-7.07(m,2H), 5.12(d,J=10.4Hz,1H), 4.38-4. 27(m,2H), 4.27-4.07(m,2H), 3.12(d,J=1.1Hz,3H), 2.76(p,J=7.5Hz,1H), 1.62(s,3H), 1.36(t,J=7.0Hz,3H), 0.79-0.65(m,3H)ppm;ESI-MS m / z Calculated value 521.14075, measured value 522.5 (M+1) + ;520.6(M-1) - .

[0350] General Method H: Methylation of Sulfoximines (e.g., 12) [ka] To a solution of rel-(2R,3S,4S,5R)-3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-N-[2-(methylsulfonimidoyl)-4-pyridyl]-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (14.4 mg, 0.027 mmol) in DCM (2 mL) was added trimethyloxonium tetrafluoroborate (5 mg, 0.034 mmol) in portions while stirring at ambient temperature under a nitrogen atmosphere. The reaction mixture was stirred at this temperature overnight and then quenched by the addition of saturated aqueous sodium bicarbonate (5 mL). The layers were separated, the aqueous layer was extracted with DCM (3 × 5 mL), and the combined organic layers were passed through a phase separation cartridge. The filtrate was concentrated in vacuo. Purification by reverse-phase preparative HPLC (basic eluent) gave rel-(2R,3S,4S,5R)-N-(2-(N,S-dimethylsulfonimidoyl)pyridin-4-yl)-3-(2-ethoxy-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (12, 10.2 mg, 68%). 1H NMR (500 MHz, DMSO-d6) δ 10.87(s,1H), 8.60(d,J=5.5Hz,1H), 8.31(d,J=2.1Hz,1H), 7.83(dd,J=5.5, 2.1Hz,1H), 7.23-7.08(m,2H), 5.10(d,J=10.3Hz,1H), 4.28(dd,J=10.5,7.6H z,1H), 4.16(ddd,J=16.4,8.1,6.7Hz,2H), 3.14(s,3H), 2.75(p,J=7.5Hz,1H ), 2.44(s,3H), 1.60(s,3H), 1.34(t,J=7.0Hz,3H), 0.72(d,J=7.0Hz,3H)ppm; 19 F NMR (471 MHz, DMSO-d6) δ -73.37, -13 8.18 (d, J = 22.5 Hz), -154.54 (d, J = 22.2 Hz) ppm; ESI-MS m / z calcd 535.15643, found 537.5 (M+1) + ;534.5(M-1) - .

[0351] General method I: Deprotection of TFA using Boc (example: 13)

change

[0352] General Method J: Deprotection of Silyl Groups with TBAF (e.g., 14) [ka] A solution of TBAF in THF (300 μL of 1 M, 0.3000 mmol) was added to a stirred solution of rel-(2R,3S,4S,5R)-N-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-pyridyl]-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (52 mg, 0.09049 mmol) in 2-methyltetrahydrofuran (5 mL) at 0 °C, and the reaction was stirred at ambient temperature for 2 h. The reaction mixture was quenched with water (1 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were dried (MgSO ) and concentrated in vacuo. The material was purified by preparative reverse-phase HPLC (basic eluent). The fractions were collected and lyophilized to give rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(hydroxymethyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (14, 23.5 mg, 56%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ 10.58(s,1H), 8.33(d,J=5.5Hz,1H), 7.71(dd,J=2.1,0.8Hz,1H), 7.50(dd,J=5.5,2.2Hz,1H), 7.20-7.12(m,2H), 5.39(s,1H), 5.09(d,J=10.3 Hz,1H), 4.50(s,2H), 4.25(dd,J=10.3,7.6Hz,1H), 3.96(d,J=2.1Hz,3H), 2.78(p,J=7.5Hz,1H), 1.60(s,3H), 0.74(dd,J=7.5,2.4Hz,3H)ppm; 19 F NMR(471MHz,DMSO-d6)δ-73.38,-138.09(d,J=21.1Hz),-154.91(d,J=21.3Hz)ppm;ESI-MS m / z calculated value 460.14215, measured value 461.7(M+1) + ;459.7(M-1) - ;Holding time: 3.13 minutes.

[0353] General Method K: N-Methylation via Reductive Amination (e.g., 15) [ka] To a solution of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(((1-methoxy-2-methylpropan-2-yl)amino)methyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (17.7 mg, 0.03244 mmol) in THF (1.0 mL) was added formaldehyde, 37% aqueous (104 μL, 3.775 mmol), followed by sodium triacetoxyborohydride (16 mg, 0.07585 mmol), followed by stirring at ambient temperature. The reaction mixture was diluted with EtOAc (2 mL), washed with saturated aqueous NaHCO (2 mL) and brine (2 mL), then loaded onto an SCX cartridge and washed with MeOH (10 mL), followed by 2 M ammonia in MeOH (10 mL). The ammonia washes were concentrated under reduced pressure and then lyophilized to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(((1-methoxy-2-methylpropan-2-yl)(methyl)amino)methyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (15, 12.0 mg, 62%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ 10.59(s,1H), 8.30(s,1H), 7.61(s,1H), 7.55(dd,J=5.6,2.1Hz,1H), 7.17(td, J=9.5,7.5Hz,1H), 7.13-7.07(m,1H), 5.08(d,J=10.3Hz,1H), 4.25(dd,J=10.3, 7.7Hz,1H), 3.95(d,J=2.1Hz,3H), 3.64(s,2H), 3.29-3.23(m,6H), 2.77(p,J=7 .5Hz,1H), 2.10(s,2H), 1.59(s,3H), 1.07(s,6H), 0.76-0.68(m,3H)ppm.ESI-MS m / z calculated value 559.24695, actual value 560.1 (M+1) + ;Retention time: 2.97 minutes.

[0354] General Method L: Amination of Esters (e.g., 1) [ka] A solution of methyl 5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinate (19, 70 mg, 0.1276 mmol) in ammonia (7 M in methanol solution) (1 mL of 7 M, 7.0000 mmol) was stirred at room temperature overnight and then concentrated in vacuo to give a colorless oil. The crude material was purified by reverse-phase chromatography (12 g of C18, 30-80% acetonitrile with 0.1% ammonium hydroxide, 0.1% ammonium hydroxide in water) to afford 5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide (1,32 mg, 52%) as a white solid. 1 H NMR(400MHz,chloroform-d)δ 8.68(q,J=1.0Hz,1H), 8.52(s,1H), 8.19-8.15(m,2H), 7.71(d,J=14.0Hz,1H), 7.10-7.06(m,1H), 6.93-6.87(m,1H), 5.53(s,1H), 5.0 4(d,J=11.0Hz,1H), 4.10(dd,J=10.9,7.9Hz,1H), 4.00(d,J=2.7Hz,3H), 2.79-2.72(m,1H), 1.69(s,3H), 0.80-0.78(m,3H)ppm.ESI-MS m / z Calculated value 473.1374, measured value 474.1 (M+1) + ;Holding time: 2.42 minutes.

[0355] General Method M: Deprotection of Silyl Groups with TFA (e.g., 17) [ka] rel-(2R*,3S*,4S*,5R*)-N-(7-((tert-butyldimethylsilyl)oxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (13.5 mg, 0.02247 mmol) was dissolved in DCM (1.0 mL) and water (100 μL) followed by the addition of TFA (150 μL, 1.947 mmol). The resulting mixture was allowed to stir at ambient temperature overnight. The reaction was heated to 35° C. and allowed to stir for an additional 3 hours, then allowed to stir at room temperature for an additional 72 hours. The reaction mixture was concentrated in vacuo and azeotroped with MeOH to remove excess TFA. The resulting residue was purified by preparative reverse-phase HPLC (basic eluent) to afford rel-(2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-N-(7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (17, 8.1 mg, 74%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ 10.32(s,1H), 8.54(d,J=2.2Hz,1H), 7.89(d,J=2.2Hz,1H), 7.20-7.11(m,2H), 5 .25(d,J=5.5Hz,1H), 5.08(d,J=10.3Hz,1H), 4.89-4.84(m,1H), 4.23(dd,J=10. 3,7.7Hz,1H), 3.94(d,J=2.0Hz,3H), 2.94-2.86(m,1H), 2.79-2.66(m,2H), 2.37 -2.28(m,1H), 1.85-1.77(m,1H), 1.60(s,3H), 0.73(d,J=6.3Hz,3H)ppm.ESI-MS m / z calculated value 486.1578, measured value 487.6(M+1) + ;485.5(M-1) - ;Holding time: 3.25 minutes.

[0356] General Method N: Deprotection of silyl groups with HCl (e.g., 18) [ka] HCl (60 μL of 37% w / v, 0.6089 mmol) was added to a solution of -(2R,3S,4S,5R)-N-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridazin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (40 mg, 0.06949 mmol) in MeOH (1 mL), and the reaction mixture was stirred at ambient temperature for 90 minutes. The mixture was concentrated in vacuo, filtered through a sodium bicarbonate cartridge, and washed with methanol. The filtrate was concentrated in vacuo to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-(hydroxymethyl)pyridazin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (18, 24.6 mg, 75%) as a white solid. 1 H NMR(400MHz,chloroform-d)δ 10.68(s,1H), 9.53(s,1H), 8.57(s,1H), 7.12(s,1H), 6.95-6.83(m,1H), 5.20(d,J=10.4Hz,1H), 5.00(d,J=6.7Hz ,2H), 4.25(s,1H), 4.03-3.96(m,3H), 2.75(dt,J=13.6,6.7Hz,1H), 1.71(s,3H), 0.79(d,J=7.3Hz,3H)ppm.ESI-MS m / z calculated value 461.1374, measured value 462.6(M+1) + ;460.5(M-1) - ;Holding time: 3.0 minutes.

[0357] General Method O: Ester Hydrolysis to Acid (e.g., 19) [ka] To a suspension of methyl 5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinate (1.54 g, 2.680 mmol) in MeOH (10 mL) was added aqueous LiOH (5.4 mL of 2 M, 10.80 mmol), followed by stirring at ambient temperature for 1.5 h. The reaction was then acidified to pH 1 with 1 M aqueous HCl (20 mL), and water (10 mL) was added, followed by extraction with EtOAc (3×30 mL). The combined organics were washed with brine (30 mL), dried (MgSO), and concentrated under reduced pressure to afford 5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinic acid (1.12 g, 86%) as a pale yellow glass. For characterization, a 50 mg sample of this material was repurified by preparative reverse-phase HPLC (basic eluent) to afford 5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinic acid (19, 31 mg) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ 10.69(s,1H), 8.82(d,J=2.4Hz,1H), 8.15(dd,J=8.6,2.5Hz,1H), 7.95(d,J=8.6Hz,1H), 7.16(dd,J=8.6,4.5Hz,2H), 5.14(d,J=10. 3Hz,1H), 4.26(dd,J=10.3,7.6Hz,1H), 3.95(d,J=2.0Hz,3H), 2.77(p,J=7.6Hz,1H), 1.61(s,3H), 0.73(d,J=4.7Hz,3H)ppm.ESI-MS m / z Calculated value 474.1214, measured value 475.3 (M+1) + ;473.2(M-1) - ;Holding time: 2.5 minutes.

[0358] General Method P: Reduction of esters to alcohols (e.g., 20) with LiAlH4 [ka] Methyl 5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-1-methyl-1H-pyrazole-3-carboxylate was dissolved in THF (3 mL) and treated with LiAlH in THF (375 μL of 1 M, 0.3750 mmol). The mixture was stirred at room temperature under nitrogen. The reaction was quenched with MeOH and concentrated. The residue was purified by preparative reverse-phase HPLC (basic eluent) to afford (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (20, 37.2 mg, 26%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ 10.15(s,1H), 7.19(dd,J=8.5,5.2Hz,2H), 6.11(s,1H), 5.13(d,J=10.4Hz,1H), 4.92(t,J=5.8Hz,1H), 4.29(d,J=5.7Hz,2H),4. 20(dd,J=10.4,7.6Hz,1H), 3.95(d,J=2.0Hz,3H), 3.50(s,3H), 2.75(t,J=7.5Hz,1H), 1.61(s,3H), 0.80-0.68(m,3H)ppm.ESI-MS m / z Calculated value 463.15305, measured value 464.3 (M+1) + ;Retention time: 3.04 minutes.

[0359] General Method Q: Cu-Catalyzed C-N Coupling (e.g., 21) [ka] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (60 mg, 0.1613 mmol), N,N'-dimethylethane-1,2-diamine (10 μL, 0.09393 mmol), cesium carbonate (105 mg, 0.3223 mmol), and (5-bromo-1-methylimidazol-2-yl)methanol (42 mg, 0.2199 mmol) were suspended in dioxane (1 mL). The reaction mixture was degassed and purged with nitrogen, followed by the addition of CuI (9 mg, 0.04726 mmol). The vial was sealed and thermally heated at 100 °C for 18 h and then at ambient temperature for 2 days. The mixture was filtered through a pad of Celite, washed with EtOAc, and concentrated in vacuo. The material was purified by preparative reverse-phase HPLC (basic eluent) to give a yellow oil. The oil was taken up in MeOH and loaded onto an SCX-2 (2 g) cartridge. The cartridge was flushed with MeOH (25 ml), and then the product was eluted with 2M NH in MeOH (30 ml). The basic eluent was concentrated in vacuo and further purified by achiral SFC using a Daicel Chiralpak ID column, 5 μm particle size, 25 cm × 20 mm, to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(hydroxymethyl)-1-methyl-1H-imidazol-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (21, 6 mg, 8%). 1 H NMR(400MHz,DMSO-d6)δ 9.90(s,1H), 7.30-7.11(m,2H), 6.66(s,1H), 5.21(s,1H), 5.10(d,J=10.6Hz,1H), 4.40(s,2H), 4.18(dd,J=10.5,7 .6Hz,1H), 3.94(d,J=2.1Hz,3H), 3.28(s,3H), 2.74(p,J=7.6Hz,1H), 1.61(s,3H), 0.74(d,J=7.0Hz,3H)ppm.ESI-MS m / z calculated value 463.15305, measured value 464.0(M+1) + ;462.0(M-1) - ;Retention time: 2.91 minutes.

[0360] General Method R: Benzyl Deprotection via Hydrogenation (e.g., 22) [ka] A solution of rel-(2R,3S,4S,5R)-N-(5-(2-(benzyloxy)-1-(methylamino)ethyl)-2-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (20 mg, 0.0327 mmol) in EtOH (20 mL) was flushed with nitrogen three times using a vacuum / nitrogen cycle. Pd / C (100 mg, 0.94 mmol) was added, and the solution was again placed under nitrogen. The mixture was placed under a hydrogen balloon and stirred overnight. The mixture was then filtered through Celite and concentrated. The crude product was purified by flash column chromatography (12 g SiO, eluting with 0–100% EtOAc in heptane). The product fractions were combined and concentrated in vacuo to give rel-(2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-N-(5-fluoro-2-(2-hydroxy-1-(methylamino)ethyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (22, 11 mg, 60%) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 10.46(s,1H), 8.64(s,1H), 8.28(s,1H), 7.19(s,2H), 5.38(d,J=10.4Hz ,1H), 5.35(s,1H), 4.31(d,J=5.7Hz,1H), 4.27(dd,J=10.4,7.5Hz,1H), 3.96(s,3H), 3.72(dq,J=28.6,6.0,5.5Hz,2H), 3.28(s,1H), 2.79(p,J=7.2Hz,1H), 2.44(s,3H), 1.61(s,3H), 0.74(d,J=7.4Hz,3H)ppm.ESI-MS m / z Calculated value 521.1749, measured value 523.4 (M+1) + ;Retention time: 3.26 minutes.

[0361] General Method S: Alcohol Mesylation and Displacement with Amine (e.g., 23) [ka] Step 1: (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(hydroxymethyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (14, 200 mg, 0.4344 mmol) in DCM (2 mL) was cooled in an ice bath under nitrogen, followed by the addition of triethylamine (150 μL, 1.076 mmol) followed by methanesulfonyl chloride (50 μL, 0.6460 mmol). The reaction was concentrated to give [4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-2-pyridyl]methyl methanesulfonate (triethylamine salt) (277.9 mg, 100%), which was used in the next step without purification.

[0362] Step 2: To a solution of [4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-2-pyridyl]methyl methanesulfonate (triethylamine salt) (100 mg, 0.1563 mmol) in acetonitrile (0.5 mL) was added (3R)-tetrahydrofuran-3-amine (45 mg, 0.5165 mmol). The reaction mixture was sealed and heated at 70° C. for 5 h. The reaction was then filtered and purified by preparative reverse-phase HPLC (basic eluent) to afford (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-((((R)-tetrahydrofuran-3-yl)amino)methyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (23, 34.2 mg, 41%).1 1H NMR (500 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.35 (d, J = 5.5 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.51 (dd, J = 5.6, 2.1 Hz, 1H), 7.30 - 7.06 (m, 2H), 5.09 (d, J = 10.3 Hz, 1H), 4.25 (dd, J = 10.3, 7.6 Hz, 1H), 3.96 (d, J = 2.0 Hz, 3H), 3.82 - 3.58 (m, 5H), 3.44 (dd, J = 8.6, 4.2 Hz, 1H), 3.29 (dd, J = 5.2, 1.7 Hz, 1H), 2.78 (p, J = 7.5 Hz, 1H), 2.39 (d, J = 22.7 Hz, 1H), 1.93 (dq, J = 12.5, 7.2 Hz, 1H), 1.74 - 1.63 (m, 1H), 1.60 (s, 3H), 0.73 (dd, J = 7.3, 2.4 Hz, 3H) ppm. ESI-MS m / z calculated value 529.2, measured value 530.3 (M + 1) + ; Retention time: 3.2 minutes.

[0363] General method T: Vinyl epoxidation and ring opening with a nucleophile (e.g., 24)

Chemical Structure

[0364] Step 2: SFC separation of (2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-N-(5-fluoro-2-(oxiran-2-yl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (1.00 g, 2.039 mmol) using a Daicel Chiralpak IG column, column, 5 μm particle size, 25 cm × 20 mm, gave the following:

[0365] First eluting isomer (rt=4.06 min): rel-(2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-N-(5-fluoro-2-(oxiran-2-yl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (348 mg, 33%). ESI-MS m / z calculated 490.13272, found 490.6 (M+1). + ;488.9(M-1) - ;Retention time: 3.54 minutes.

[0366] Second eluting isomer (rt=5.04 min): rel-(2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-N-(5-fluoro-2-(oxiran-2-yl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (377 mg, 35%). ESI-MS m / z calculated 490.13272, found 490.7 (M+1). + ;488.9(M-1) - ;Retention time: 3.54 minutes.

[0367] Step 3: rel-(2R*,3S*,4S*,5R*)-3-(3,4-difluoro-2-methoxyphenyl)-N-(5-fluoro-2-(oxiran-2-yl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (first eluting isomer by SFC, 50 mg, 0.09992 mmol) was dissolved in toluene (2.0 mL) and TBAF (in THF) (1.0 mL of 1 M, 1.000 mmol) was added. The resulting mixture was allowed to stir at 80 °C for 1 h and then at 100 °C overnight. The reaction mixture was concentrated in vacuo and purified by flash column chromatography (12 g of SiO, eluting with 0–100% EtOAc in heptane). The mixture was further purified by preparative reverse-phase HPLC (basic eluent) to afford rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(5-fluoro-2-(2-fluoro-1-hydroxyethyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (24, 4.9 mg, 9%) as a white solid. 1H NMR(500MHz,DMSO-d6)δ 10.27(s,1H), 8.49(d,J=2.3Hz,1H), 8.27(d,J=6.4Hz,1H), 7.22-7.15(m,2H), 5. 95(d,J=5.0Hz,1H), 5.34(d,J=10.4Hz,1H), 4.82-4.74(m,1H), 4.62(ddd,J=47.7 ,9.5,3.1Hz,1H), 4.48(ddd,J=47.7,9.5,6.0Hz,1H), 4.25(dd,J=10.4,7.6Hz,1H ), 3.95(s,3H), 2.81-2.73(m,1H), 1.61(s,3H), 0.73(d,J=5.2Hz,3H)ppm.ESI-MS m / z calculated value 510.13895, actual value 510.9(M+1) + ;509.0(M-1) - ;Holding time: 3.42 minutes.

[0368] Example 1 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(pyridazin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (25) and rel-(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(pyridazin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (26) [ka] Step 1: NEt (7.7 mL, 55.2 mmol) was added to a solution of ethyl 2-diazo-3-oxo-pentanoate (6.69 g, 39.3 mmol) in DCM (80 mL) with stirring 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 an additional 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) and brine (100 mL). The organic layer was dried (MgSO) and concentrated in vacuo to give ethyl (Z)-2-diazo-3-trimethylsilyloxy-pent-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.

[0369] Step 2: To a solution of 1,1,1-trifluoropropan-2-one (8 mL, 89.4 mmol) in DCM (80 mL) was added TiCl (70 mL of 1 M in DCM, 70.00 mmol) via cannula while stirring at −78° C. To the resulting solution was added a solution of ethyl (Z)-2-diazo-3-trimethylsilyloxy-pent-3-enoate (36.1 g, 31.3% w / w, 46.6 mmol) in 40 mL of DCM dropwise over 15 minutes. After 100 minutes, the reaction was carefully quenched with water, the temperature was allowed to slowly rise, and then extracted with DCM. The combined organic layers were dried (MgSO), filtered, and concentrated in vacuo. Purification by flash chromatography (330 g SiO, 0-20% EtOAc in heptane) gave ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxo-hexanoate (8.82 g, 67%), which was stored as a solution in toluene. 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) - .

[0370] Step 3: After heating a solution of rhodium tetraacetate (245 mg, 0.55 mmol) in benzene (32 mL) at reflux for 10 minutes, a solution of ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxo-hexanoate (10 g, 35.4 mmol) in benzene (13 mL) was added slowly via an addition funnel while refluxing for 60 minutes. 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 adjacent epimers of the ester. The 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.

[0371] 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) was added DIPEA (29.680 g, 40 mL, 229.64 mmol) with stirring at −78° C. A solution of trifluoromethylsulfonyl trifluoromethanesulfonate (53.440 g, 32 mL, 189.41 mmol) in DCM (200 mL) was added to the reaction mixture over 1 h at the same temperature. The reaction mixture was stirred at 0° C. for 30 min and then quenched with 100 mL of saturated aqueous NaHCO. The organic layer was separated, and the aqueous layer was extracted with DCM (160 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give ethyl rac-(4R,5R)-2,3-dimethyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-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.

[0372] Step 5: To a stirred solution of ethyl rac-(4R,5R)-2,3-dimethyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (26 g, 67.311 mmol) in toluene (130.00 mL) under an argon atmosphere was added (3,4-difluoro-2-methoxy-phenyl)boronic acid (14 g, 74.5 mmol), followed by KPO (100 mL of 2 M, 200.00 mmol). The reaction was degassed, and then tetrakis(triphenylphosphine)palladium(0) (4 g, 3.46 mmol) was added. After further degassing, the reaction was heated at 100 °C for 2 h. The reaction was diluted with water, and the aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were concentrated in vacuo. Purification by flash chromatography (SiO, 0-10% EtOAc in heptane) gave ethyl 4-(3,4-difluoro-2-methoxy-phenyl)-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (24.4 g, 93%) as a 6:1 diastereomeric mixture, the major isomer being believed to be ethyl rac-(4R,5R)-4-(3,4-difluoro-2-methoxy-phenyl)-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-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) + .

[0373] Step 6: To an ice-cold solution of ethyl 4-(3,4-difluoro-2-methoxy-phenyl)-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (110 g, 243.0 mmol) in DCM (360 mL) was added BBr3 (370 mL of 1 M, 370.0 mmol) dropwise. Upon completion, the mixture was quenched by adding water and aqueous sodium bicarbonate, the aqueous layer was extracted with DCM, and the combined organic layers were dried (MgSO4) 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 adding aqueous sodium bicarbonate, and the aqueous layer was extracted with DCM, dried (MgSO4), and concentrated in vacuo to give the desired product as a 5:1 mixture of diastereomers. Recrystallization was performed by solubilizing the crude material 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 (97:3 syn:anti) was obtained from the first and second crystallizations, and an additional 4.6 g (96:4 syn:anti) was obtained from the third crystallization. The first, second, and third batches were combined to yield 6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1H-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)-1H-furo[2,3-c]chromen-4-one. ESI-MS m / z calculated 320.04718, found 321.5 (M+1). + ;319.6(M-1) - .

[0374] Step 7: rac-(1S,2R)-6,7-Difluoro-1,2-dimethyl-2-(trifluoromethyl)-1H-furo[2,3-c]chromen-4-one (30 g, 93.69 mmol) was dissolved in EtOAc (400 mL) and stirred with activated carbon (6 g, 499.6 mmol) (0.2 g / g substrate) at ambient temperature for 4 hours and 30 minutes. The mixture was filtered through a 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 a suspension of Pd(OH) (13.62 g of 20% w / w, 19.40 mmol) in MeOH (150 mL) in a 2.25 L Parr bottle. The resulting mixture was shaken overnight under 60 psi hydrogen pressure in a Parr hydrogenator. The suspension was filtered through Celite under a nitrogen atmosphere, rinsed with MeOH and then EtOAc, and the resulting filtrate was concentrated in vacuo to give methyl rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (32.75 g, 99%). 1 H NMR(400MHz, methanol-d4)δ 7.05(ddq,J=9.4,5.9,1.9Hz,1H), 6.57(ddd,J=10.0,9.0,7.6Hz,1H), 5.01(d,J=6.0Hz,1H), 4.34(dd,J=8. 4,6.0Hz,1H), 3.49(s,3H), 3.01-2.86(m,1H), 1.50(q,J=1.2Hz,3H), 0.89(dq,J=7.6,1.9Hz,3H)ppm.ESI-MS m / z calculated value 354.08905, measured value 353.3(M-1) - .

[0375] Step 8: A solution of methyl rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (60.8 g, 171.6 mmol) in THF (620 mL) was cooled to 1 °C, and potassium tert-butoxide (65.0472 g, 579.7 mmol) was added over 10 minutes, keeping the internal temperature below 10 °C. The mixture was stirred at 0 °C for an additional 5 minutes, and then the mixture was allowed to warm slightly. Once the temperature reached 13 °C, the reaction was again cooled in an ice bath, after which 2 M HCl (365 mL, to 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), dried (MgSO4), filtered and concentrated in vacuo to give rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (58.22 g, 100%). 1 H NMR(400MHz, methanol-d4)δ 7.00(ddd,J=8.4,5.6,2.3Hz,1H), 6.69(ddd,J=10.1,8.8,7.5Hz,1H), 4.98(d,J=10.5Hz,1H), 4.18(dd, ESI-MS m / z calculated value 340.0734, measured value 339.0(M-1) - .

[0376] Step 9: To a solution of rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (58.39 g, 171.6 mmol) in acetonitrile (300 mL) was added KCO (82.6 g, 597.7 mmol) and MeI (37 mL, 594.3 mmol). The reaction was heated to 80 °C for 5 h (internal temperature reached 61 °C), then cooled to ambient temperature and diluted with DCM (350 mL). The mixture was filtered, the filter cake washed with additional DCM (350 mL), and the filtrate concentrated in vacuo to give methyl rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (64.7 g, 100%) as an orange oil containing some residual KCO. This material was used in the next step without further purification. 1 H NMR(400MHz,chloroform-d)δ 6.91(ddd,J=7.6,5.7,1.9Hz,1H), 6.85(td,J=9.1,7.2Hz,1H), 4.91(d,J=10.2Hz,1H), 4.13(dd,J=10.2,8.0Hz,1H ), 4.00(d,J=2.7Hz,3H), 3.71(s,3H), 2.72(p,J=7.7Hz,1H), 1.62(q,J=1.2Hz,3H), 0.76(dq,J=7.5,2.4Hz,3H)ppm.

[0377] Step 10: Methyl rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (63.2 g, 171.6 mmol) was dissolved in MeOH (500 mL) and water (300 mL). .HO (14.8882 g, 354.8 mmol) was added, and the resulting mixture was stirred at ambient temperature for 2 hours. The MeOH was removed in vacuo, and the mixture was diluted with MTBE (320 mL). 2 M HCl (440 mL) was added to pH 1, the layers were separated, and the aqueous layer was extracted twice with MTBE (100 mL). The combined organic layers were dried (MgSO), filtered, and concentrated in vacuo to afford rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (60.3 g, 99%) as an orange oil. 1 H NMR(400MHz,DMSO-d6)δ 12.96(s,1H), 7.40-6.82(m,2H), 4.96(dd,J=15.5,10.5Hz,1H), 4.08(dd,J=10.4,7.6Hz,1H), 3.93(d,J=2.2Hz,3H), 2.67(p,J=7.7Hz,1H), 1.59-1.49(m,3H), 0.77-0.63(m,3H)ppm.ESI-MS m / z calculated value 354.08905, measured value 353.1 (M-1) - .

[0378] Step 11: To a solution of rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (100 mg, 0.2823 mmol) in DCM (5 mL) was added DMF (2.2 μL, 0.02841 mmol) and carefully added oxalyl chloride (75 μL, 0.8598 mmol) with stirring under nitrogen at 0° C. Gas evolution was observed. The reaction was allowed to warm to ambient temperature and stirred for 15 minutes before being evaporated in vacuo. The residue was dissolved in DCM (3 mL) and added dropwise over 5 min to a solution of pyridazin-4-amine (40 mg, 0.4206 mmol), DMAP (1.75 mg, 0.01432 mmol), and NEt (120 μL, 0.8610 mmol) in DCM (5 mL) at 0 °C. The reaction was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was diluted with DCM (50 mL), washed with 2 M HCl solution (50 mL), dried using a phase separation cartridge, and concentrated in vacuo. The material was then purified by preparative reverse-phase HPLC (basic eluent) to give rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(pyridazin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide. ESI-MS m / z calculated 431.12683, observed 432.7 (M+1) + ;430.8(M-1) - ;Holding time: 3.15 minutes.

[0379] Step 12: The enantiomers of rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(pyridazin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide were separated by chiral SFC (Regis Technologies (R'R) Whelk O-1 column, 3-5 μm particle size, 5.0 cm × 3.0 mm, Solvent A: liquid CO2 [58-60 bar / 40 °C]; Solvent B: methanol HPLC grade with 20 mM NH3, using a Waters Corp. UPC2-SFC instrument) to give:

[0380] First eluting isomer (rt = 3.25 min): rel-(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(pyridazin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (25, 6.1 mg, 10%) ESI-MS m / z calculated 431.12683, found 432.7 (M+1) + ;430.8(M-1) - ;Holding time: 3.15 minutes.

[0381] Second eluting isomer (rt=7.15 min): rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(pyridazin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (26, 6.5 mg, 10%). 1 H NMR(500MHz,chloroform-d)δ 9.08(s,1H), 8.90(s,1H), 8.59(s,1H), 7.92(s,1H), 6.90(d,J=7.9Hz,1H), 6.79-6.70(m,1H), 4.90(d,J=10.4Hz) ,1H), 3.96(t,J=9.2Hz,1H), 3.85(d,J=2.7Hz,3H), 2.64-2.57(m,1H), 1.82(s,3H), 0.67-0.61(m,3H)ppm.ESI-MS m / z calculated value 431.12683, measured value 432.7(M+1) + ;430.8(M-1) - ;Holding time: 3.15 minutes

[0382] The following compounds were made using a method similar to that described in Example 1, except that different coupling partners were used in the amide coupling step 11. In the table below, "MS rt" means mass spectrometry retention time. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6]

[0383] The following compounds were made using the method described in Example 1, except that different coupling partners were used in the amide coupling step 11 and general method B was used as the final step. In the table below, "MS rt" means mass spectrometry retention time. [Table 4-1] [Table 4-2] [Table 4-3]

[0384] The following compounds were made using the method described in Example 1, except that different coupling partners were used in the amide coupling step 11 and similar conditions to general method N were used for silyl deprotection as the final step: In the table below, "MS rt" means mass spectrometry retention time. [Table 5]

[0385] The following compounds were made using the method described in Example 1, except that different coupling partners were used in the amide coupling step 11 and general method D was used as the penultimate step before SFC. In the table below, "MS rt" means mass spectrometry retention time. [Table 6-1] [Table 6-2]

[0386] The following compounds were made using the methods described in Example 1, except that 2-(methylthio)pyridin-4-amine was used in the amide coupling step 11 and general method F was used instead of step 12. In the tables below, "MS rt" means mass spectrometry retention time. [Table 7-1] [Table 7-2]

[0387] The following compounds were made using the method described in Example 1, except that 2-(methylthio)pyridin-4-amine was used in the amide coupling step 11. This was followed by general method G (using 1:1 MeOH and DCM as solvents in step 1) in place of step 12. The enantiomers were separated by chiral SFC as the final step. In the tables below, "MS rt" means mass spectrometry retention time. [Table 8-1] [Table 8-2]

[0388] The following compounds were made using the method described in Example 1, except that different coupling partners were used in the amide coupling step 11 and general method I was used as the final step. In the table below, "MS rt" means mass spectrometry retention time. [Table 9-1] [Table 9-2]

[0389] The following compounds were made using the methods described in Example 1, except for using 2-[[tert-butyl(dimethyl)silyl]oxymethyl]pyridin-4-amine in the amide coupling step 11 and general method J as the final step, as described below:

[0390] To an ice-cold solution of rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (150 mg, 0.3895 mmol) in 2-methyltetrahydrofuran (5 mL), DMF (45 μL of 0.86 M, 0.03870 mmol) was added as a solution in THF, and oxalyl chloride (70 μL, 0.8024 mmol) was carefully added. The mixture was stirred and allowed to warm to ambient temperature over 30 minutes. The reaction mixture was concentrated in vacuo, and the residue was dissolved in 2-methyltetrahydrofuran (3 mL). This solution was added to an ice-cold solution of 2-[[tert-butyl(dimethyl)silyl]oxymethyl]pyridin-4-amine (100 mg, 0.4195 mmol) and TEA (265 μL, 1.901 mmol) in 2-methyltetrahydrofuran (3 mL). The resulting mixture was stirred and allowed to warm to ambient temperature over 2 h. The reaction mixture was then quenched with water (10 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 10 mL), and the combined organic extracts were dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (12 g of SiO, eluting with 0–30% EtOAc in heptane, loaded in DCM) to give rac-(2R,3S,4S,5R)-N-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (142.3 mg, 64%) as a colorless oil. 1H NMR (500 MHz, chloroform-d) δ 8.45 (s, 1H), 8.40 (d, J = 5.6 Hz, 1H), 7.63 (d, J = 5.5 Hz, 1H), 7.41 (s, 1H), 7.10-7.07 (m, 1H), 6.91 (td, J = 9.3, 7.5 Hz, 1H), 5.00 (d, J = 10.8 Hz, 1H), 4.81 (s, 2H), 4. 11(dd,J=10.7,8.1Hz,1H), 4.00(d,J=2.7Hz,3H), 2.75(p,J=7.7Hz,1H), 1.67(s ,3H), 0.96(s,9H), 0.81-0.79(dd,J=7.5,2.3Hz,3H), 0.13(d,J=1.9Hz,6H)ppm; 19 F NMR (471 MHz, chloroform-d) δ -74.59, -137.08 (d, J = 23.1 Hz), -154.52 (d, J = 21.5 Hz) ppm; ESI-MS m / z calculated 574.22864, found 575.7 (M+1). + ;573.8(M-1) - ;Holding time: 1.23 minutes.

[0391] The enantiomers of rac-(2R,3S,4S,5R)-N-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (142 mg, 0.2471 mmol) were separated by chiral SFC on a Berger Instruments Minigram SFC instrument using a Regis Technologies (R,R)-Whelk-O1 column, 5 μm particle size, 25 cm × 21.2 mm (mobile phase: 30% acetonitrile:methanol (1:1 ratio, supplemented with 0.2% DMIPA), system pressure: 100 bar) to give:

[0392] First eluting isomer (rt=2.19 min): rel-(2S,3R,4R,5S)—N-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (56.2 mg, 79%) as a white solid. 1 H NMR (500 MHz, chloroform-d) δ 8.46(s,1H), 8.40(d,J=5.6Hz,1H), 7.63(s,1H), 7.42(s,1H), 7.10-7. 07(m,1H), 6.93-6.88(m,1H), 5.01(d,J=10.8Hz,1H), 4.82(s,2H), 4.11 (dd,J=10.8,8.0Hz,1H), 4.00(d,J=2.7Hz,3H), 2.75(p,J=7.7Hz,1H), 1.67(s,3H), 0.96(s,9H), 0.81-0.79(m,3H), 0.13(d,J=2.0Hz,6H)ppm. 19 F NMR (471 MHz, chloroform-d): δ -74.59, -137.27 (d, J = 19.0 Hz), -154.51 (d, J = 18.9 Hz) ppm. ESI-MS m / z calculated: 574.22864, found: 575.2 (M+1). + ;573.3(M-1) - ;Retention time: 4.27 minutes.

[0393] Second eluting isomer (rt=3.90 min): rel-(2R,3S,4S,5R)—N-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (52.5 mg, 74%) as a white solid. 1H NMR (500 MHz, chloroform-d) δ 8.46(s,1H), 8.40(d,J=5.7Hz,1H), 7.64(s,1H), 7.43(s,1H), 7.10-7. 07(m,1H), 6.93-6.88(m,1H), 5.01(d,J=10.7Hz,1H), 4.83(s,2H), 4.11 (dd,J=10.8,8.0Hz,1H), 4.00(d,J=2.7Hz,3H), 2.75(p,J=7.8Hz,1H), 1.67(s,3H), 0.96(s,9H), 0.81-0.79(m,3H), 0.13(d,J=1.8Hz,6H)ppm. 19 F NMR (471 MHz, chloroform-d) δ -74.59, -137.07, -154.50 ppm. ESI-MS m / z calculated 574.22864, found 575.2 (M+1). + ;573.3(M-1) - ;Retention time: 4.26 minutes.

[0394] In the tables below, "MS rt" means mass spectrometry retention time. [Table 10]

[0395] The following compounds were made using the method described in Example 1, except that different coupling partners were used in the amide coupling step 11. SFC step 12 was omitted and general method D was used followed by general method J as the final step. In the table below, "MS rt" means mass spectrometry retention time. [Table 11]

[0396] Example 2 rel-(2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-N-(pyridazin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (63) and rel-(2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-N-(pyridazin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (64). [ka] Step 1: To a solution of rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (9.30 g, 27.33 mmol) in DCM (50 mL) was added a solution of KOH (18.4 g, 328.0 mmol) in HO (50 mL) with stirring at 0 °C, and the solution was stirred vigorously. [Bromo(difluoro)methyl]-trimethyl-silane (22.5 g, 110.8 mmol) was added, and stirring was continued at this temperature. Upon complete consumption of the starting material, the mixture was acidified by adding HCl 1N, extracted with DCM, and concentrated in vacuo. The resulting oil was dissolved in tert-butanol (50 mL) at ambient temperature, and KOH (7.5 g, 66.84 mmol) was added. After complete conversion, the mixture was acidified with 1N HCl, diluted with DCM, the layers were separated, and the aqueous layer was extracted. The organic phase was washed with water and concentrated in vacuo to give rac-(2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (10.10 g, 95%), which was used without further purification.

[0397] Step 2: To an ice-cold solution of rac-(2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (10.10 g, 25.88 mmol) in DCM (100 mL) was added DMF (400 μL, 5.17 mmol) and oxalyl chloride (4.85 mL, 55.60 mmol) with stirring at 0° C. The mixture was allowed to warm to ambient temperature over 30 minutes and then concentrated in vacuo. The residue was dissolved in DCM (2 mL), cooled in an ice bath, and TEA (49 μL, 0.3516 mmol) and pyridazin-4-amine (35.9 mg, 0.3775 mmol) were added over time. The reaction was stirred for 90 minutes, warmed to ambient temperature, quenched with MeOH, and concentrated in vacuo. The crude product was purified by flash chromatography (4 g SiO, 0 to 100% EtOAc in heptane) to give rac-(2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-N-(pyridazin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (79.5 mg, 66%). ESI-MS m / z calculated 467.108, found 468.6 (M+1). + ;466.7(M-1) - ;Retention time: 0.89 minutes.

[0398] Step 3: rac-(2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-N-(pyridazin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (50 mg, 0.1070 mmol) was purified by chiral SFC [System: Regis Technologies (R'R) Whelk O-1 column, 3-5 um particle size, 5.0 cm x 3.0 mm, Solvent A: liquid CO; Solvent B: 20 ​​mM NH in methanol, Waters Corp. UPC2-SFC instrument] to give:

[0399] First eluting isomer (retention time = 4.28 min): rel-(2S,3R,4R,5S)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-N-(pyridazin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (63, 23.0 mg, 80%). 1 H NMR(500MHz,chloroform-d)δ 9.19(dd,J=2.7,1.0Hz,1H), 9.04(dd,J=5.9,0.9Hz,1H), 8.61(s,1H), 7.98(dd,J=5.9,2.8Hz,1H), 7.24-7.09(m,2H), 6.65(d,J=73.7Hz,1 H), 5.00(d,J=11.1Hz,1H), 4.19(dd,J=11.1,8.2Hz,1H), 2.82(p,J=7.8Hz,1H), 1.69(d,J=1.2Hz,3H), 0.84(dq,J=7.3,2.3Hz,3H).ESI-MS m / z Calculated value 467.108, measured value 468.2 (M+1) + ;466.1(M-1) - ;Retention time: 3.17 minutes.

[0400] Second eluting isomer (retention time = 7.52 min): rel-(2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-N-(pyridazin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (64, 21.4 mg, 84%). 1 H NMR(500MHz,chloroform-d)δ 9.17(dd,J=2.8,1.0Hz,1H), 9.04(dd,J=5.8,0.9Hz,1H), 8.48(s,1H), 7.97(dd,J=5.9,2.8Hz,1H), 7.23-7.12(m,2H), 6.65(ddd,J=74.6,73.7,0 .9Hz,1H), 5.00(d,J=11.1Hz,1H), 4.18(dd,J=11.1,8.3Hz,1H), 2.82(p,J=7.7Hz,1H), 1.70(d,J=1.1Hz,3H), 0.85(dd,J=7.6,2.3Hz,3H).ESI-MS m / z Calculated value 467.108, measured value 468.2 (M+1) +;466.1(M-1) - ;Retention time: 3.17 minutes.

[0401] The following compounds were made using a method similar to that described in Example 2, except that a different amine was used as the coupling partner in Step 2. In the table below, "MS rt" means mass spectrometry retention time. [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4] [Table 12-5] [Table 12-6]

[0402] The following compounds were made using a method similar to that described in Example 2, except that 2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-4-amine (second eluting isomer by SFC) was used as the coupling partner in step 2 and general method B was used as the final step. In the tables below, "MS rt" means mass spectrometry retention time. [Table 13]

[0403] The following compounds were made using a method similar to that described in Example 2, except that 2-(2-((trimethylsilyl)oxy)propan-2-yl)pyridin-4-amine was used as the coupling partner in step 2 and TMS deprotection using conditions similar to general method N with 1 M HCl in THF was used as the final step. In the table below, "MS rt" means mass spectrometry retention time. [Table 14]

[0404] The following compounds were made using a method similar to that described in Example 2, except that a different amine was used as the coupling partner in step 2 and general method D was used as the penultimate step before SFC separation. In the table below, "MS rt" means mass spectrometry retention time. [Table 15-1] [Table 15-2] [Table 15-3]

[0405] The following compounds were made using a method similar to that described in Example 2, except that 2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-amine was used as the coupling partner in step 2 and general method J was used as the final step. In the tables below, "MS rt" means mass spectrometry retention time. [Table 16]

[0406] The following compounds were made using a method similar to that described in Example 2, except that methyl 5-aminopicolinate was used as the coupling partner in step 2 and general method L was used as the penultimate step before SFC separation. In the tables below, "MS rt" means mass spectrometry retention time. [Table 17]

[0407] The following compound was made using a similar method to that described in Example 2, except that 5-(methylthio)pyridin-3-amine was used as the coupling partner in Step 2. Oxidation using general method F followed by N-oxide reduction using the conditions outlined below was carried out on the product of Step 2 prior to SFC separation.

[0408] N-oxide reduction: To a solution of rac-3-((2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-5-(methylsulfonyl)pyridine 1-oxide (220 mg, 0.39 mmol) in MeCN (0.4 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (105 mg, 0.41 mmol) with stirring under nitrogen. The mixture was heated at 70° C. for 4 hours and then concentrated in vacuo. Purification by flash chromatography (SiO) gave rac-(2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-N-(5-(methylsulfonyl)pyridin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (205 mg, 96%). ESI-MS m / z calculated 544.0903, found 545.6 (M+1). + ;543.7(M-1) - .

[0409] In the tables below, "MS rt" means mass spectrometry retention time. [Table 18]

[0410] The following compound was made using a method similar to that described in Example 2, except that rac-(2R,3S,4S,5R)-3-(2-(difluoromethoxy)-4-fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used as the starting material in Step 2. Rac-(2R,3S,4S,5R)-3-(2-(difluoromethoxy)-4-fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was prepared using a method similar to that described for other intermediates in this application. 2-Methylsulfanylpyridin-4-amine (hydrochloride salt) was used as the amine in Step 2, SFC was omitted in Step 3, and general method D was used as the final step. In the tables below, "MS rt" means mass spectrometry retention time. [Table 19]

[0411] The following compound was made using a method similar to that described in Example 2, except that rac-(2R,3S,4S,5R)-3-(2-(difluoromethoxy)-4-fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used as the starting material in Step 2. Rac-(2R,3S,4S,5R)-3-(2-(difluoromethoxy)-4-fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was prepared using a method similar to that described for other intermediates in this application. 4-Amino-1-methyl-pyridin-2-one (hydrochloride salt) was used as the amine in Step 2, and purification by chiral SFC was omitted in Step 3. In the tables below, "MS rt" means mass spectrometry retention time. [Table 20]

[0412] The following compound was made using a method similar to that described in Example 2, except that rac-(2R,3S,4S,5R)-3-(2-(difluoromethoxy)-4-fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used as the starting material in Step 2. Rac-(2R,3S,4S,5R)-3-(2-(difluoromethoxy)-4-fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was prepared using a method similar to that described for other intermediates in this application. 4-Amino-1-methyl-pyridin-2-one (hydrochloride salt) was used as the amine in Step 2, and purification by chiral SFC in Step 3 was performed using a (R,R)-Whelk-O1 column from Regis Technologies, 5 μm particle size, 25 cm × 21.2 mm. In the tables below, "MS rt" means mass spectrometry retention time. [Table 21]

[0413] Example 3 rel-(2S,3R,4R,5S)-3-(2-ethoxy-3,4-difluorophenyl)-4,5-dimethyl-N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (102) and rel-(2R,3S,4S,5R)-3-(2-ethoxy-3,4-difluorophenyl)-4,5-dimethyl-N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (103) [ka] Step 1: MeOH (620 mL) was added to a Parr shake flask containing rac-(1S,2R)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3-c]chromen-4-one (32.3 g, 100.9 mmol) and Pd(OH) (24 g, 34.18 mmol). The mixture was degassed, repressurized to 55 psi of hydrogen, and left to shake for 2 days. The mixture was filtered, the catalyst washed with DCM, followed by EtOAc and methanol, and the filtrate 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 (34 g, 95%). 1 H NMR(500MHz, methanol-d4)δ 7.05(ddt,J=9.1,7.5,2.0Hz,1H), 6.57(ddd,J=10.1,9.0,7.6Hz,1H), 5.01(d,J=6.0Hz,1H), 4.34(dd,J=8.5, 6.0Hz,1H), 3.49(s,3H), 2.93(h,J=7.4Hz,1H), 1.50(d,J=1.2Hz,3H), 0.89(dd,J=7.6,1.9Hz,3H)ppm.ESI-MS m / z calculated value 354.08905, measured value 353.6 (M-1) -.

[0414] Step 2: To a solution of rac-(2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (7 g, 20.57 mmol) in acetonitrile (42 mL) was added KCO (11.4 g, 82.49 mmol) and iodoethane (7.2 mL, 90.02 mmol), and the reaction was heated at 80° C. for 4.5 h. The reaction was cooled to ambient temperature, diluted with EtOAc (70 mL), filtered (pad washed with an additional 70 mL of EtOAc), and the filtrate was concentrated in vacuo to afford rac-ethyl (3S,4S,5R)-3-(2-ethoxy-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (6.39 g, 78%) as an orange oil. 1 H NMR(500MHz,chloroform-d)δ 6.97-6.93(m,1H), 6.89-6.84(m,1H), 4.90(d,J=10.4Hz,1H), 4.34-4.24(m,1H), 4.20-4.11(m,4H), 2.74(p,J=7.6 Hz,1H), 1.65(d,J=1.2Hz,3H), 1.43(td,J=7.0,0.7Hz,3H), 1.21(t,J=7.1Hz,3H), 0.79(dq,J=7.4,2.4Hz,3H)ppm. 19 F NMR (471 MHz, chloroform-d) δ -74.61, -137.35 (d, J = 19.8 Hz), -153.97 (d, J = 19.9 Hz) ppm; ESI-MS m / z calculated 396.136, found 397.7 (M+1). + ;Holding time: 1.1 minutes.

[0415] Step 3: LiOH (17 mL of 2 M, 34.00 mmol) was added to a stirred solution of rac-ethyl (3S,4S,5R)-3-(2-ethoxy-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (6.3874 g, 16.12 mmol) in methanol (70 mL) / water (20 mL), and the mixture was stirred at ambient temperature for 2 hours. The reaction was concentrated in vacuo and partitioned between MTBE (30 mL) and 1 M HCl (20 mL). The layers were separated, and the aqueous layer was extracted with MTBE (2 × 20 mL). The combined organic extracts were dried (MgSO), filtered, and concentrated in vacuo to give rac-(2R,3S,4S,5R)-3-(2-ethoxy-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (6.4494 g, 96%) as an orange oil that solidified on standing. 1 H NMR(500MHz,chloroform-d)δ 6.95(ddd,J=7.9,5.5,2.0Hz,1H), 6.85(td,J=9.2,7.3Hz,1H), 4.92(d,J=10.8Hz,1H), 4.28(dqd,J=8.9,7.0,1.8Hz,1H), 4.21 -4.08(m,2H), 2.73(p,J=7.6Hz,1H), 1.61(d,J=1.3Hz,3H), 1.39(td,J=7.1,0.7Hz,3H), 0.76(dq,J=7.3,2.3Hz,3H)ppm.ESI-MS m / z calculated value 368.1047, measured value 367.5(M+1) + ;Retention time: 0.59 minutes.

[0416] Step 4: A solution of rac-(2R,3S,4S,5R)-3-(2-ethoxy-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (150 mg, 0.3617 mmol) in DCM (3 mL) was cooled using an ice bath. To this was added DMF (6 μL, 0.07749 mmol) (1 drop of DMF), followed by the careful addition of oxalyl chloride (100 μL, 1.146 mmol). The solution was stirred in the ice bath for 20 minutes, then concentrated in vacuo and azeotroped with DCM to give a cream-colored solid. This acid chloride was taken up in DCM (3 mL) and added to an ice-bath cooled solution of 4-amino-1-methyl-pyridin-2-one (hydrochloride) (64 mg, 0.3985 mmol) and DIPEA (243 μL, 1.395 mmol) in DCM (3 mL). The resulting suspension was stirred in the ice bath for 1 h and then at room temperature over the weekend. The reaction mixture was then partitioned between DCM and water, the layers were separated using a phase separator cartridge, and the organics were concentrated in vacuo. The residue was purified by flash chromatography (4 g of SiO, 0–50% EtOAc in heptane, loaded onto Telos nm) to give rac-(2R,3S,4S,5R)-3-(2-ethoxy-3,4-difluorophenyl)-4,5-dimethyl-N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (101, 53.9 mg, 29%) as a yellow oil. 1 H NMR(500MHz,DMSO-d6)δ 10.28(s,1H), 7.59(d,J=7.5Hz,1H), 7.16(td,J=9.5,7.5Hz,1H), 7.12-7.03(m,1H), 6.73(d,J=2.4Hz,1H), 6.38(dd,J=7.4,2.4Hz,1H), 5.03(d,J=10.4Hz,1H), 4.29-4.10(m,3H), 3.33(s,3H), 2.73(p,J=7.4Hz,1H), 1.57(s,3H), 1.35(t,J=7.0Hz,3H), 0.75-0.66(m,3H)ppm. 19F NMR (471 MHz, DMSO-d6) δ -73.42, -138.10 (d, J = 2 1.4 Hz), -152.65--156.46 (m) ppm. ESI-MS m / z calculated 474.1578, found 475.1 (M+1). + ;473.0(M-1) - ;Holding time: 3.21 minutes.

[0417] Step 5: rac-(2R,3S,4S,5R)-3-(2-ethoxy-3,4-difluorophenyl)-4,5-dimethyl-N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (51.2 mg, 0.09713 mmol) was purified by chiral SFC using a Regis Technologies (R,R)-Whelk-O1 column, 5 μm particle size, 25 cm×21.2 mm, to give:

[0418] First eluting isomer (rt=2.48 min): rel-(2S,3R,4R,5S)-3-(2-ethoxy-3,4-difluorophenyl)-4,5-dimethyl-N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (102, 14.5 mg, 59%). 1 H NMR(500MHz,DMSO-d6)δ 10.28(s,1H), 7.60(d,J=7.4Hz,1H), 7.17(dt,J=9.8,8.2Hz,1H), 7.12-7.05(m,1H), 6.74(d,J=2.4Hz,1H), 6.39(dd,J=7.4,2.4Hz,1H), 5.04(d,J=10.4Hz,1H), 4.30-4.11(m,3H), 3.34(s,3H), 2.74(p,J=7.5Hz,1H), 1.58(s,3H), 1.36(t,J=7.0Hz,3H), 0.78-0.64(m,3H)ppm. 19F NMR (471 MHz, DMSO-d) δ -73.42, -138.11 (d, J = 21.6 Hz), -154.41 (d, J = 21.6 Hz) ppm. ESI-MS m / z calculated 474.1578, found 475.6 (M+1). + ;473.5(M-1) - ;Holding time: 3.24 minutes.

[0419] Second eluting isomer (rt=4.07 min): rel-(2R,3S,4S,5R)-3-(2-ethoxy-3,4-difluorophenyl)-4,5-dimethyl-N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (103, 13.64 mg, 58%). 1 H NMR(500MHz,DMSO-d6)δ 10.30(s,1H), 7.58(d,J=7.4Hz,1H), 7.22-7.02(m,2H), 6.73(d,J=2.3Hz,1H), 6.38(dd,J=7.5,2.4Hz,1H), 5.03(d,J=10. 4Hz,1H), 4.29-4.07(m,3H), 3.32(s,3H), 2.73(q,J=7.6Hz,1H), 1.57(s,3H), 1.34(t,J=7.0Hz,3H), 0.76-0.65(m,3H)ppm. 19 F NMR(471MHz,DMSO-d6)δ-73.42,-138.11(d,J=2 1.3Hz), -15 4.41(d,J=2 1.3Hz)ppm.ESI-MS m / z Calculated value 474.1578, Actual value 475.6(M+1) + ;473.7(M-1) - ;Retention time: 3.23 minutes.

[0420] The following compounds were prepared using the method described in Example 3, except that (2R,3S,4S,5R)-3-(2-ethoxy-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid and (R) or (S)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-4-amine (first or second eluting isomer by SFC) were used in amide coupling step 4, and general method B was used as the final step. (2R,3S,4S,5R)-3-(2-ethoxy-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was prepared using a method similar to that described in Example 7. In the tables below, "MS rt" means mass spectrometry retention time. [Table 22]

[0421] Compound 105 was analyzed by powder X-ray diffraction and determined to be amorphous (see Figure 1).

[0422] The following compounds were made using the method described in Example 3, except that 5-(methylthio)pyridin-3-amine was used in the amide coupling step 4 and general method D was used prior to chiral SFC purification using a Regis Technologies (R,R)-Whelk-O1 column, 5 μm particle size, 25 cm×21.2 mm. In the tables below, "MS rt" means mass spectrometry retention time. [Table 23]

[0423] The following compounds were made using the method described in Example 3, except that 4-methylsulfonylpyridin-2-amine was used in the amide coupling step 4. Purification in step 5 was performed by chiral SFC using a Lux Cellulose-2 column, 5 μm particle size, 25 cm×10 mm, from Phenomenex, Inc., on a Berger Instruments Minigram SFC instrument, and general method D was used as the final step for separating isomers. In the tables below, "MS rt" means mass spectrometry retention time. [Table 24]

[0424] The following compound was made using the method described in Example 3, except that 4-methylsulfonylpyridin-2-amine was used in the amide coupling step 4. Purification in step 5 was performed by chiral SFC using a Lux Cellulose-2 column, 5 μm particle size, 25 cm×10 mm, from Phenomenex, Inc., on a Berger Instruments Minigram SFC instrument, and step 1 of general method G was used as the final step for the separated isomers. In the table below, "MS rt" means mass spectrometry retention time. [Table 25]

[0425] The following compounds were made using the method described in Example 3, except that 4-methylsulfonylpyridin-2-amine was used in the amide coupling step 4. Purification in step 5 was performed by chiral SFC using a Phenomenex, Inc. Lux Cellulose-2 column, 5 μm particle size, 25 cm×10 mm on a Berger Instruments Minigram SFC instrument, with general method G used for the separated isomers as the final step. In the tables below, "MS rt" means mass spectrometry retention time. [Table 26-1] [Table 26-2]

[0426] The following compounds were made using the method described in Example 3, except that 2-(methylthio)pyridin-4-amine was used in the amide coupling step 4. Purification in step 5 was performed by chiral SFC using a Lux Cellulose-2 column, 5 μm particle size, 25 cm×10 mm, from Phenomenex, Inc., on a Berger Instruments Minigram SFC instrument, and the separated isomers were subjected to general method G followed by general method H as the final step. In the tables below, "MS rt" means mass spectrometry retention time. [Table 27]

[0427] The following compound was made using the method described in Example 3, except that 5-(methylthio)pyridin-3-amine was used in the amide coupling step 4. Purification in step 5 was performed by chiral SFC using a Lux Cellulose-2 column from Phenomenex, Inc., 5 μm particle size, 25 cm×10 mm on a Berger Instruments Minigram SFC instrument, with the first eluting isomer subjected to general method G followed by general method H as the final step. In the table below, "MS rt" means mass spectrometry retention time. [Table 28]

[0428] The following compounds were made using the method described in Example 3, except that 2-bromopropane was used as the alkylating agent in step 2, KOt-Bu in t-BuOH was used for epimerization / hydrolysis in step 3, and 4-methylsulfonylpyridin-2-amine was used as the amine in step 4. Purification in step 5 was performed by chiral SFC using a Regis Technologies (R,R)-Whelk-O1 column, 5 μm particle size, 25 cm × 21.2 mm. In the tables below, "MS rt" means mass spectrometry retention time. [Table 29]

[0429] The following compounds were made using the method described in Example 3, except that 2-bromopropane was used as the alkylating agent in step 2, KOt-Bu in t-BuOH was used for epimerization / hydrolysis in step 3, and 2-methylsulfanylpyridin-4-amine was used as the amine in step 4. General method G was used in place of step 5, and the four isomers produced were separated by chiral SFC. In the tables below, "MS rt" means mass spectrometry retention time. [Table 30-1] [Table 30-2]

[0430] Example 4 rac-(2R,3S,4S,5R)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-N-(tetrazolo[1,5-a]pyridin-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (121), rel-(2S,3R,4R,5S)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-N-(tetrazolo[1,5-a]pyridin-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (122), tetrazolo[1,5-a]pyridin-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (122), and rel-(2R,3S,4S,5R)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-N-(tetrazolo[1,5-a]pyridin-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (123). [ka] Step 1 A 2 L, three-necked round-bottom flask equipped with a thermometer was charged with a mixture of ethyl rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (39.05 g, 101.1 mmol), (4-fluoro-2-methoxy-3-methyl-phenyl)boronic acid (20.4 g, 110.9 mmol), PdCl(PPh) (1.4 g, 1.995 mmol), and NaHCO (120 mL) in 1,4-dioxane (400 mL). The orange mixture was slowly heated to 50 °C (internal temperature) and stirred for 20 minutes. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (100 mL) and water (100 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (4 × 100 mL). The combined organic extracts were washed with brine (1 × 50 mL), dried (MgSO), filtered, and concentrated in vacuo to 100 mL. Charcoal (10 g) was added, and the reaction mixture was stirred for 2 h. The mixture was filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo to give 50 g of solid-free crude product. Purification by flash chromatography (330 g SiO, 0–35% ethyl acetate in heptane) afforded ethyl rac-(4S,5R)-3-(4-fluoro-2-methoxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (27.3 g, 72%) as a pale yellow oil. 1 H NMR(500MHz,chloroform-d)δ 6.98-6.88(m,1H), 6.81(t,J=8.7Hz,1H), 4.20-4.07(m,2H), 3.66(s,3H), 3.58-3.49(m,1H), 2 .21(d,J=2.1Hz,3H), 1.7(s,3H), 1.12(t,J=7.1Hz,3H), 1.06(dq,J=7.2,2.3Hz,3H)ppm.ESI-MS m / z calculated value 376.12976, actual value 377.5(M+1) + ;Retention time: 1.09 minutes.

[0431] Step 2 To a 1 L three-neck flask equipped with a thermometer was added ethyl rac-(4S,5R)-3-(4-fluoro-2-methoxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (27.35 g, 72.67 mmol), followed by DCM (200 mL). The mixture was cooled to 5 °C in an ice bath. A solution of boron tribromide in DCM (112 mL of 1 M, 112.0 mmol) was added via cannula over 30 minutes, maintaining the temperature at approximately 5 °C, and the reaction mixture was allowed to stir for 1 hour. Upon completion, the mixture was quenched with water (100 mL) (very slowly, as the first few drops resulted in an effervescent reaction). A saturated solution of NaHCO (100 mL) was added, and the mixture was stirred for 30 minutes. The aqueous phase was extracted with DCM (3 × 50 mL), and the organic layer was washed with NaHCO (5 × 100 mL). The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The solid was redissolved in ethyl acetate (100 mL), charcoal (15 g) was added, and the mixture was stirred at ambient temperature overnight. The reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo to give ethyl rac-(4S,5R)-3-(4-fluoro-2-hydroxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (27.7 g, 100%) as a yellow waxy solid. ESI-MS m / z calculated 362.11414, found 363.5 (M+1). + ;361.5(M-1) - ;Holding time: 0.99 minutes.

[0432] Step 3 TFA (9.8 mL, 127.2 mmol) was added to a solution of ethyl rac-(4S,5R)-3-(4-fluoro-2-hydroxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (27.7 g, 76.45 mmol) in DCM (200 mL) with stirring at ambient temperature. The reaction mixture was heated to reflux and stirred at this temperature for 2.5 h. The reaction mixture was cooled to ambient temperature, quenched with saturated aqueous NaHCO3 (100 mL), and the layers were separated. The DCM layer was washed with saturated aqueous NaHCO3 (4 x 100 mL). The organic extract was dried (Na2SO4) and concentrated in vacuo to give a waxy solid. This solid was redissolved in ethyl acetate (200 mL). Activated charcoal (10 g) was added to the mixture and stirred at ambient temperature overnight. The mixture was filtered through a Celite cartridge and washed with ethyl acetate (3 x 100 ml). The filtrate was concentrated in vacuo to give rac-(1S,2R)-7-fluoro-1,2,6-trimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3-c]chromen-4-one (24.18 g, 100%) as a waxy solid. ESI-MS m / z calculated 316.07227, found 317.4 (M+1). + ;315.4(M-1) - ;Retention time: 0.94 minutes.

[0433] Step 4: rac-(1S,2R)-7-Fluoro-1,2,6-trimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3-c]chromen-4-one (1.5 g, 3.273 mmol) was dissolved in EtOAc (20 mL) and stirred with activated charcoal (300 mg, 24.98 mmol) for 18 hours. The solution was then filtered through Celite and concentrated in vacuo to give a yellow solid. This solid was then redissolved in methanol (20 mL) and added to a flask containing dihydroxypalladium (460 mg of 20% w / w, 0.655 mmol). The reaction mixture was evacuated and refilled with nitrogen (×3), then evacuated and refilled with hydrogen (×3), and finally left under a hydrogen balloon for 120 hours. The reaction mixture was filtered through a Celite cartridge and washed with MeOH. The mixture was then concentrated to 20 mL, and dihydroxypalladium (230 mg of 20% w / w, 0.3276 mmol) was recharged to the flask. The reaction mixture was evacuated and backfilled with nitrogen (×3), then evacuated and backfilled with hydrogen (×3), and finally placed under a hydrogen balloon for 12 h. The reaction mixture was filtered through a Celite cartridge, washed with methanol, and concentrated to give rac-methyl (2S,3S,4S,5R)-3-(4-fluoro-2-hydroxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (939.3 mg, 82%) as an off-white solid. 1 H NMR(500MHz,chloroform-d)δ 7.20(t,J=7.7Hz,1H), 6.57(t,J=8.9Hz,1H), 4.88(d,J=6.1Hz,2H), 4.28(dd,J=8.4 ,6.1Hz,1H), 3.56(s,3H), 2.81(p,J=7.8Hz,1H), 2.14(d,J=1.6Hz,3H), 1.4(3H-peak under water), 0.92(dq,J=7.6,1.9Hz,3H).ESI-MS m / z calculated value 350.11414, measured value 349.0(M-1) - ;Holding time: 0.95 minutes.

[0434] Step 5: Potassium tert-butoxide (905 mg, 8.065 mmol) was added to a stirred solution of rac-methyl (2S,3S,4S,5R)-3-(4-fluoro-2-hydroxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (939.3 mg, 2.681 mmol) in THF (15 mL), and the reaction mixture was stirred at ambient temperature for 5 minutes. 1 M HCl (3 mL) was added, and the layers were separated. The aqueous layer was extracted with DCM (3 × 5 mL), and the combined organic extracts were dried (MgSO), filtered, and concentrated in vacuo to give rac-(2R,3S,4S,5R)-3-(4-fluoro-2-hydroxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1.0268 g, 99%). ESI-MS m / z calculated 336.09848, observed 335.0 (M-1) - ;Retention time: 0.63 minutes.

[0435] Step 6: rac-(2R,3S,4S,5R)-3-(4-fluoro-2-hydroxy-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid in acetonitrile (3 mL)

[0436] To a solution of (513 mg, 1.327 mmol) was added K2CO3 (735 mg, 5.318 mmol) and iodoethane (470 μL, 5.876 mmol). The reaction mixture was heated in a sealed tube at 80 °C overnight. The reaction was then diluted with DCM, filtered, and the solid was washed with DCM. The filtrate was carefully concentrated using a cold water bath to give ethyl rac-(2R,3S,4S,5R)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (522.6 mg, 100%) as a yellow oil. ESI-MS m / z calculated 392.16107, found 393.5 (M+1). + ;Retention time: 1.09 minutes.

[0437] Step 7: LiOH (1.4 mL of 2 M, 2.800 mmol) was added to a stirred solution of ethyl rac-(2R,3S,4S,5R)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (522.6 mg, 1.332 mmol) in methanol (6 mL) / water (1 mL), and the mixture was stirred at ambient temperature for 1 h. The reaction was concentrated in vacuo and quenched with 1 M HCl. The layers were separated, and the aqueous layer was extracted with DCM (2 × 5 mL). The combined organic extracts were dried by using a phase separation cartridge, filtered, and concentrated in vacuo to give rac-(2R,3S,4S,5R)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (330.9 mg, 68%). 1 H NMR(500MHz,chloroform-d)δ 7.09-6.99(m,1H), 6.81(t,J=8.7Hz,1H), 4.90(d,J=10.9Hz,1H), 4.13(dd,J=11.0,7.9Hz,1H), 3.92-3.83(m,1H), 3.77(dq,J=9.6, 7.0Hz,1H), 2.71(q,J=7.6Hz,1H), 2.24-2.13(m,3H), 1.62(d,J=11.2Hz,3H), 1.47-1.34(m,3H), 0.75(dq,J=4.7,2.3Hz,3H).ESI-MS m / z Calculated value 364.12976, measured value 363.6 (M-1) - ;Retention time: 0.62 minutes.

[0438] Step 8: A solution of rac-(2R,3S,4S,5R)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (110 mg, 0.3019 mmol) in DCM (4 mL) was cooled using an ice bath. To this was added DMF (13 μL, 0.1679 mmol) (1 drop of DMF), followed by the careful addition of oxalyl chloride (81 μL, 0.9285 mmol). The solution was placed in an ice bath and stirred for 10 minutes. The solution was concentrated in vacuo and azeotroped with DCM to give a yellow solid. This acid chloride was taken up in DCM (4 mL) and added to an ice-bath cooled solution of tetrazolo[1,5-a]pyridin-7-amine (45 mg, 0.333 mmol) and DIPEA (260 μL, 1.493 mmol) in DCM (4 mL). The resulting dark suspension was placed in an ice bath and stirred for 72 h. The reaction mixture was partitioned between DCM and water. The layers were separated using a phase separator cartridge, and the organics were concentrated in vacuo. The residue was purified by flash chromatography (4 g SiO, 0–100% EtOAc in heptane, loaded in DCM) to afford rac-(2R,3S,4S,5R)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-N-(tetrazolo[1,5-a]pyridin-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (121, 75.4 mg, 49%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ 10.98(s,1H), 9.21(dd,J=7.5,0.9Hz,1H), 8.46(dd,J=2.1,0.8Hz,1H), 7.46(dd,J=7 .5,2.1Hz,1H), 7.24-7.17(m,1H), 6.98(t,J=8.8Hz,1H), 5.11(d,J=10.6Hz,1H), 4.35 (dd,J=10.6,7.5Hz,1H), 3.86(ddq,J=30.7,9.3,6.9Hz,2H), 2.74(q,J=7.4Hz,1H), 2. 15(d,J=2.0Hz,3H), 1.63(s,3H), 1.40(t,J=7.0Hz,3H), 0.74(d,J=7.5Hz,3H).ESI-MS m / z calculated value 481.1737, measured value 482.6(M+1)+ ;480.5(M-1) - ;Holding time: 3.75 minutes.

[0439] Step 9: rac-(2R,3S,4S,5R)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-N-(tetrazolo[1,5-a]pyridin-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (122) (73.4 mg, 0.1448 mmol) was purified by chiral SFC [system: (R,R)-Whelk-O1 column from Regis Technologies, 5 μm particle size, 25 cm × 21.2 mm] to give:

[0440] First eluting isomer (retention time = 2.35 min): rel-(2S,3R,4R,5S)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-N-(tetrazolo[1,5-a]pyridin-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (122, 23.80 mg, 62%). 1 H NMR(500MHz,DMSO-d6)δ 10.97(s,1H), 9.21(dd,J=7.5,0.8Hz,1H), 8.46(dd,J=2.1,0.9Hz,1H), 7.46(dd,J=7 .4,2.1Hz,1H), 7.21(dd,J=8.8,6.4Hz,1H), 6.98(t,J=8.8Hz,1H), 5.11(d,J=10.7Hz, 1H), 4.35(dd,J=10.7,7.4Hz,1H), 3.86(ddq,J=30.4,9.3,7.0Hz,2H), 2.75(p,J=7.4 Hz,1H), 2.15(d,J=2.0Hz,3H), 1.63(s,3H), 1.40(t,J=7.0Hz,3H), 0.79-0.65(m,3H). 19 F NMR (471 MHz, DMSO-d) δ -73.37, -115.75. ESI-MS m / z calculated 481.1737, found 482.6 (M+1) + ;480.6(M-1) - ;Holding time: 3.5 minutes.

[0441] Second eluting isomer (retention time = 3.76 min): rel-(2R,3S,4S,5R)-3-(2-ethoxy-4-fluoro-3-methylphenyl)-4,5-dimethyl-N-(tetrazolo[1,5-a]pyridin-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (123, 18.96 mg, 54%) H NMR (500 MHz, DMSO-d) δ 10.98(s,1H), 9.21(dd,J=7.4,0.8Hz,1H), 8.46(dd,J=2.0,0.8Hz,1H), 7.46(dd,J=7. 4,2.1Hz,1H), 7.21(dd,J=8.8,6.5Hz,1H), 6.98(t,J=8.8Hz,1H), 5.11(d,J=10.6Hz,1 H), 4.35(dd,J=10.6,7.5Hz,1H), 3.86(ddq,J=30.2,9.4,6.9Hz,2H), 2.75(p,J=7.4Hz ,1H), 2.15(d,J=2.0Hz,3H), 1.63(s,3H), 1.40(t,J=7.0Hz,3H), 0.79-0.67(m,3H).19 F NMR(47 1 MHz,DMSO-d 6)δ-73.37,-115.76.ESI-MS m / z calculated value 481.1737, measured value 482.6(M+1) + ;480.6(M-1) - ;Holding time: 3.51 minutes

[0442] The following compounds were made using the method described in Example 4, except that 2-methylsulfanylpyridin-4-amine (dihydrochloride salt) was used in the amide coupling step 8, and the SFC purification in step 9 was performed using chiral SFC using a Lux Cellulose-2 column, 5 μm particle size, 25 cm × 10 mm, from Phenomenex, Inc., on a Berger Instruments Minigram SFC instrument. The separated isomers from SFC were subjected to the conditions described in General Method G (Step 1 only) as the final step. In the tables below, "MS rt" means mass spectrometry retention time. [Table 31]

[0443] The following compounds were made using the method described in Example 4, except that 2-methylsulfanylpyridin-4-amine (dihydrochloride salt) was used in the amide coupling step 8, and purification in step 9 was carried out via chiral SFC using a Phenomenex, Inc. Lux Cellulose-2 column, 5 μm particle size, 25 cm×10 mm on a Berger Instruments Minigram SFC instrument. The separated isomers from SFC were subjected to the conditions described in General Method G as the final step. In the tables below, "MS rt" means mass spectrometry retention time. [Table 32-1] [Table 32-2]

[0444] The following compounds were prepared using the method described in Example 4, except that 2-methylsulfanylpyridin-4-amine (dihydrochloride salt) was used in the amide coupling step 8, and chiral SFC purification in step 9 was performed using a Lux Cellulose-2 column from Phenomenex, Inc., 5 μm particle size, 25 cm × 10 mm, on a Berger Instruments Minigram SFC instrument. The second eluting isomer from SFC was treated under the conditions described in step 1 of general method G, then methylated using general method H, and finally subjected to chiral SFC as the final step using a Regis Technologies (R,R)-Whelk-O1 column, 5 μm particle size, 25 cm × 21.2 mm. In the tables below, "MS rt" refers to mass spectrometry retention time. [Table 33]

[0445] The following compounds were made using the method described in Example 4, except that iodomethane was used in step 6. For 132, a final step SFC separation of isomers was not performed. In the table below, "MS rt" means mass spectrometry retention time. [Table 34]

[0446] The following compounds were made using the method described in Example 4, except that iodomethane was used in step 6 and 2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-4-amine (first or second eluting isomer) was used in the amide coupling step 8. Purification by SFC in step 9 used a Regis Technologies (R,R)-Whelk-O1 column, 5 μm particle size, 25 cm × 21.2 mm, and the separated isomers were then subjected to general method B as the final step. In the tables below, "MS rt" means mass spectrometry retention time. [Table 35-1] [Table 35-2]

[0447] The following compound was made using the method described in Example 4, except for the use of iodomethane in step 6 and rac-2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-4-amine in the amide coupling step 8. The first eluting isomer (major) from flash chromatography (SiO, 0-30% EtOAc in heptane) in step 8 was further purified by chiral SFC in step 9 using a Regis Technologies (R,R)-Whelk-O1 column, 5 μm particle size, 25 cm × 21.2 mm. The first eluting isomer from SFC was subjected to general method A as the final step, followed by general method B. In the tables below, "MS rt" means mass spectrometry retention time. [Table 36]

[0448] The following compounds were made using the method described in Example 4, except for the use of iodomethane in step 6 and 2-(2,2-dimethyl-1,3-dioxolan-4-yl)-5-fluoro-pyridin-4-amine (first or second eluting isomer) in the amide coupling step 8. Purification by SFC in step 9 used a Regis Technologies (R,R)-Whelk-O1 column, 5 m particle size, 25 cm x 21.2 mm, and the separated isomers were then deprotected as the final step using general method B. In the tables below, "MS rt" means mass spectrometry retention time. [Table 37-1] [Table 37-2]

[0449] The following compounds were made using the method described in Example 4, except for the use of iodomethane in step 6 and 2-(2,2-dimethyl-1,3-dioxolan-4-yl)-5-fluoro-pyridin-4-amine (syn or antidiol) in the amide coupling step 8. The separated isomers from step 9 were subjected to general method B as the final step. In the tables below, "MS rt" means mass spectrometry retention time. [Table 38-1] [Table 38-2] [Table 38-3] [Table 38-4]

[0450] Compound 145 was analyzed by powder X-ray diffraction and determined to be amorphous (see Figure 2).

[0451] The following compounds were made using the method described in Example 4, except for the use of iodomethane in step 6 and 2-(methylthio)pyridin-4-amine in the amide coupling step 8. Purification by chiral SFC in step 9 used a Lux Cellulose-2 column, 5 μm particle size, 25 cm×10 mm, from Phenomenex, Inc., on a Berger Instruments Minigram SFC instrument. Step 1 of general method G was used as the final step for separating isomers. In the tables below, "MS rt" means mass spectrometry retention time. [Table 39]

[0452] The following compound was made using the method described in Example 4, except that iodomethane was used in step 6 and 2-(methylthio)pyridin-4-amine was used in the amide coupling step 8. Purification by chiral SFC in step 9 used a Lux Cellulose-2 column from Phenomenex, Inc., 5 μm particle size, 25 cm × 10 mm on a Berger Instruments Minigram SFC instrument. Step 1 of general method G, followed by methylation using general method H, and finally SFC using a Regis Technologies (R,R)-Whelk-O1 column, 5 μm particle size, 25 cm × 21.2 mm, was used as the final step on the second eluting isomer from step 9. In the tables below, "MS rt" means mass spectrometry retention time. [Table 40]

[0453] Example 5 rel-(2S,3R,4R,5S)-3-(3,4-difluorophenyl)-4,5-dimethyl-N-(2-(methylsulfonyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (154) and rel-(2R,3S,4S,5R)-3-(3,4-difluorophenyl)-4,5-dimethyl-N-(2-(methylsulfonyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (155) [ka] Step 1: To a degassed solution of ethyl rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (2 g, 4.85 mmol) in toluene (25 mL) was added aqueous KPO (8.5 mL of 2 M, 17.00 mmol) and (3,4-difluorophenyl)boronic acid (860 mg, 5.45 mmol). The mixture was further degassed for 10 min, after which tetrakis(triphenylphosphine)palladium(0) (285 mg, 0.25 mmol) was added. The reaction was stirred at 100 °C for 2 h, after which the solvent was removed in vacuo and the residue was diluted with water. The aqueous layer was extracted with EtOAc (3 × 100 mL), and the combined organic layers were dried (MgSO) and concentrated in vacuo. Purification by flash chromatography (SiO, 2–5% EtOAc in hexanes) afforded rac-ethyl (4S,5R)-3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (1.7 g, 98%) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 7.55-7.38(m,2H), 7.21(ddt,J=8.4,4.1,1.6Hz,1H), 4.20-3.98(m,2H), 3.78(q,J =7.3Hz,1H), 1.63(s,3H), 1.08(t,J=7.1Hz,3H), 1.02(d,J=5.64Hz,3H)ppm.ESI-MS m / z calculated value 350.0941, actual value 351.0(M+1) + .

[0454] Step 2: Pd / C (10 wt% loading, 456 mg, 0.43 mmol) was added to a solution of rac-ethyl (4S,5R)-3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (1.00 g, 2.86 mmol) in EtOH (50 mL), and the mixture was degassed under vacuum. The flask was backfilled with hydrogen, and a balloon of hydrogen was bubbled through the solution for 5 minutes. The reaction was stirred under a balloon of hydrogen at ambient temperature for 3 hours, after which the balloon was replaced and the bubbling repeated. The reaction was then left stirring under a balloon of hydrogen for 3 days. The reaction mixture was filtered through Celite, and the filtrate was dried in vacuo to give rac-ethyl (2S,3S,4S,5R)-3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1000 mg, 99%) as a colorless oil that crystallized on standing. 1 H NMR(500MHz,chloroform-d)δ 7.16-7.10(m,1H), 7.09-6.95(m,2H), 4.83(d,J=5.8Hz,1H), 4.02(dq,J=7.1,3.5Hz,2H), 3.67(dd,J=8.5 ,5.8Hz,1H), 2.86-2.70(m,1H), 1.55-1.50(m,3H), 0.96(t,J=7.1Hz,3H), 0.86(dq,J=7.6,1.9Hz,3H)ppm.

[0455] Step 3: A solution of rac-ethyl (2S,3S,4S,5R)-3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.26 g, 3.58 mmol) and KOt-Bu (801 mg, 7.14 mmol) in tert-butanol (34 mL) was stirred at ambient temperature for 16 hours. The reaction was diluted with EtOAc and acidified to pH 2 with 1 M HCl. The aqueous layer was further extracted with EtOAc. The combined organic layers were dried (MgSO), filtered, and concentrated in vacuo to afford rac-(2R,3S,4S,5R)-3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1.22 g, 76%) as a pale yellow oil. 1 H NMR(500MHz,chloroform-d)δ 7.17(dt,J=10.0,8.3Hz,1H), 7.07(ddd,J=11.3,7.4,2.3Hz,1H), 6.97(ddd,J=8.5,3.9,1.8Hz,1H), 4.93(d, ESI-MS m / z calculated value 324.0785, measured value 323.1(M-1) - .

[0456] Step 4: Oxalyl chloride (28 μL, 0.3210 mmol) was added to an ice-cold solution of rac-(2R,3S,4S,5R)-3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (50 mg, 0.1311 mmol) and DMF (5 μL of 0.86 M, 0.004300 mmol) in DCM (1 mL), and the mixture was allowed to warm to ambient temperature over 30 minutes before being concentrated in vacuo. The residue was dissolved in toluene (3 mL), and the mixture was concentrated in vacuo. The residue was then dissolved in DCM (1 mL), and DIPEA (51 μL, 0.2928 mmol) was added. 2-Methylsulfonylpyridin-4-amine (hydrochloride) (30 mg, 0.1438 mmol) was quickly added to the mixture, and the reaction was stirred at room temperature for 1 hour. Methanol was added, and the mixture was concentrated in vacuo. The residue was purified by preparative reverse-phase HPLC (basic eluent) to give rac-(2R,3S,4S,5R)-3-(3,4-difluorophenyl)-4,5-dimethyl-N-(2-(methylsulfonyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (42 mg, 67%). ESI-MS m / z calculated 478.09857, found 479.1 (M+1). + ;477.0(M-1) - ;Retention time: 3.26 minutes.

[0457] Step 5: rac-(2R,3S,4S,5R)-3-(3,4-difluorophenyl)-4,5-dimethyl-N-(2-(methylsulfonyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (42 mg, 67%) was separated by chiral SFC using a Regis Technologies (R,R)-Whelk-O1 column, 5 μm particle size, 25 cm × 21.2 mm, to give two single isomers of unknown absolute configuration:

[0458] First eluting isomer (rt=3.83 min): rel-(2S,3R,4R,5S)-3-(3,4-difluorophenyl)-4,5-dimethyl-N-(2-(methylsulfonyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (154, 5 mg, 8%). 1 H NMR(500MHz,DMSO-d6)δ 10.83(s,1H), 8.64(dd,J=5.5,0.6Hz,1H), 8.40(dd,J=2.1,0.6Hz,1H), 7.92(d d,J=5.5,2.1Hz,1H), 7.48(ddd,J=12.3,7.8,2.1Hz,1H), 7.42(dt,J=10.7,8.6H z,1H), 7.20(d,J=9.2Hz,1H), 5.15(d,J=9.6Hz,1H), 4.19(dd,J=9.6,7.7Hz,1H) , 3.25(s,3H), 2.76(p,J=7.5Hz,1H), 1.62(s,3H), 0.84-0.66(m,3H)ppm.ESI-MS m / z calculated value 478.09857, measured value 479.8(M+1) + ;477.8(M-1) - ;Holding time: 3.24 minutes.

[0459] Second eluting isomer: (rt=7.73 min): rel-(2R,3S,4S,5R)-3-(3,4-difluorophenyl)-4,5-dimethyl-N-(2-(methylsulfonyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (155, 4 mg, 6%). 1H NMR(500MHz,DMSO-d6)δ 10.87(br s,1H), 8.63(d,J=5.5Hz,1H), 8.40(d,J=2.0Hz,1H), 7.92(dd,J=5.5,2.1H z,1H), 7.48(ddd,J=12.4,7.8,2.2Hz,1H), 7.42(dt,J=10.8,8.6Hz,1H),7 .29-7.10(m,1H), 5.15(d,J=9.6Hz,1H), 4.19(dd,J=9.6,7.7Hz,1H), 3.25 (s,3H), 2.76(p,J=7.5Hz,1H), 1.62(s,3H), 0.78-0.72(m,3H)ppm.ESI-MS m / z Calculated value 478.09857, measured value 479.1 (M+1) + ;477.0(M-1) - ;Retention time: 3.23 minutes.

[0460] The following compounds were made using a method similar to that described in Example 5, except that [2-methoxy-3-(trifluoromethyl)phenyl]boronic acid was used in step 1 using Pd(dppf)Cl, DCM, KCO in dioxane:water at 80°C. Methyl 5-aminopyridine-2-carboxylate was used in step 4, and general method L was used as the final step before SFC. Final chiral SFC purification used a Daicel Chiralpak IG column, 5 um particle size, 25 cm x 10 mm. In the tables below, "MS rt" refers to mass spectrometry retention time. [Table 41]

[0461] The following compound was made using a method similar to that described in Example 5, except that an alternative Suzuki coupling reaction was used in step 1. Methyl 5-aminopyridine-2-carboxylate was used in step 4, and general method L was used prior to SFC. The final step of chiral SFC purification was performed using a Daicel Chiralpak IG column, 5 μm particle size, 25 cm × 10 mm, on a Berger Instruments Minigram SFC instrument.

[0462] Step 1 Alternative Suzuki reaction: To a solution of rac-((4S,5R)-2-(ethoxycarbonyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-3-yl)boronic acid (950 mg, 3.369 mmol), 1-bromo-4-(difluoromethyl)-3-fluoro-2-methoxybenzene (902 mg, 3.537 mmol), and Pd(dppf)Cl.DCM (138 mg, 0.1690 mmol) in dioxane (20 mL) was added 2 M aqueous KPO (3.4 mL, 6.800 mmol), and the mixture was degassed and flushed with nitrogen (×3). The reaction was stirred at 100 °C for 2 h, cooled to ambient temperature, filtered through a pre-packed Celite pad, and washed with EtOAc and water. The layers were then separated, and the aqueous layer was extracted with EtOAc (2 × 5 mL). The combined organic phases were dried over MgSO, filtered, and concentrated in vacuo. The resulting oil was purified by flash column chromatography (SiO, eluting with 0–10% EtOAc in heptane) to afford rac-ethyl (4S,5R)-3-(4-(difluoromethyl)-3-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (915.6 mg, 57%) as a colorless oil. 1H NMR(500MHz,chloroform-d)δ 7.26-7.20(m,1H), 7.02-6.74(m,2H), 4.19-4.07(m,2H), 3.89(d,J=2.0Hz,3H), 3.51(q,J=7.4Hz,1H), 1.70(s,3H), 1.16-1.04(m,3H)ppm.ESI-MS m / z calculated value 412.11093, measured value 413.3(M+1) + ;Retention time: 1.06 min. In the tables below, "MS rt" means mass spectrometry retention time. [Table 42]

[0463] Example 6 rel-(2S,3R,4R,5S)-N-([1,2,3]triazolo[1,5-a]pyridin-6-yl)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (160) and rel-(2R,3S,4S,5R)-N-([1,2,3]triazolo[1,5-a]pyridin-6-yl)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (161) [ka] Step 1: A mixture of ethyl rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (1.44 g, 3.169 mmol), 2-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (900 mg, 2.592 mmol), Pd(Ph3)4 (148 mg, 0.1281 mmol), and aqueous K2CO3 (2.6 mL of 2 M, 5.200 mmol) in 1,4-dioxane (25 mL) was heated at 100 °C for 2 h. The mixture was concentrated in vacuo and loaded onto a solid support. Purification by flash chromatography (SiO, 0–25% EtOAc in heptane) afforded ethyl rac-(4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (708 mg, 66%) as a colorless oil. 1 H NMR(400MHz,chloroform-d)δ 7.25(ddt,J=7.3,6.2,1.2Hz,1H), 6.95(td,J=53.6,0.7Hz,1H), 6.94(tt,J=8.7,0.9Hz,1H), 4.17(qd,J=7.1,1.3Hz,2H ), 3.77(s,3H), 3.62-3.53(m,1H), 1.71(q,J=1.0Hz,3H), 1.15(t,J=7.1Hz,3H), 1.07(dq,J=7.1,2.2Hz,3H)ppm.ESI-MS m / z calculated value 412.11093, measured value 413.2(M+1) + ;Holding time: 1.05 minutes.

[0464] Step 2: A solution of ethyl rac-(4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (3.5 g, 8.488 mmol) in MeOH (100 mL) was added to a two-necked flask containing magnesium (2.07 g, 85.17 mmol). The reaction mixture was heated at 70° C. for 3 h. The mixture was concentrated in vacuo and partitioned between aqueous AcOH and EtOAc. The aqueous layer was separated and extracted twice with EtOAc. The combined organic phases were washed with aqueous NaHCO and twice with water. The organic phase was dried (MgSO4) and concentrated in vacuo to give methyl rac-(2S,3S,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate and methyl rac-(2R,3R,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (2.87 g, 84%) as an orange oil. 1 H NMR (400 MHz, chloroform-d) δ 7.43-7.32 (m, 1H), 7.01-6.95 (m, 1H), 7.09-6.80 (m, 1H), 4.89 (d, J = 10.2 Hz, 1H), 4.21-4.15 (m, 1H), 3.84 (s, 3H), 3.71 (s, 3H), 2.73 (p, J = 7.7 Hz, 1H), 1.63 (q, J = 1.2 Hz, 3H), 0.78 (ddq, J = 7.2, 4.7, 2.3 Hz, 3H) ppm.

[0465] Step 3: Potassium tert-butoxide (1.66 g, 14.79 mmol) was added to a solution of methyl rac-(2S,3S,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate and methyl rac-(2R,3R,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (2.87 g, 7.169 mmol) in 2-MeTHF (35 mL) in a water bath at ambient temperature. An exotherm of approximately 3° was observed during the addition. The reaction mixture was stirred for 2 hours, after which an additional portion of potassium tert-butoxide (860 mg) was added. The mixture was stirred for an additional 1 hour at ambient temperature and then quenched with aqueous HCl. The aqueous layer was separated, washed with EtOAc, dried (MgSO), and concentrated in vacuo to give rac-(2R,3S,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid and rac-(2S,3R,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (3.32 g, 74%) in a ratio of approximately 3:2 (not determined) as an orange oil. 1 H NMR (400 MHz, chloroform-d) δ 7.43-7.35 (m, 1H), 6.98 (ddd, J = 13.4, 9.3, 4.2 Hz, 1H), 6.93 (t, J = 53.6 Hz, 1H), 4.93 (d, J = 10.3 Hz, 1H), 4.18-4.14 (m, 1H), 3.84 (s, 3H), 2.76 (p, J = 7.7 Hz, 1H), 1.67-1.62 (m, 3H), 0.82-0.75 (m, 3H) ppm; no OH acid was observed. ESI-MS m / z calculated 386.09528, found 385.1 (M-1). - ;Retention time: 0.57 minutes.

[0466] Major diastereomer: rac-(2R,3S,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1 H NMR (400 MHz, chloroform-d) δ 7.43-7.35 (m, 1H), 7.04-6.91 (m, 1H), 6.93-6.72 (m, 1H), 4.93 (d, J = 10.3 Hz, 1H), 4.18-4.14 (m, 1H), 3.84 (s, 3H), 2.76 (m, 1H), 1.27 (m, 3H), 1.03 (m, 3H); no OH acid was observed.

[0467] Minor diastereomer: rac-(2S,3R,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid. 1 H NMR (400 MHz, chloroform-d) δ 7.43-7.35 (m, 1H), 7.04-6.91 (m, 1H), 6.93-6.72 (m, 1H), 4.62 (d, J = 9.9 Hz, 1H), 3.97 (m, 2H), 3.81 (s, 3H), 2.26 (m, 1H), 1.23 (m, 3H), 0.78 (m, 3H); no OH acid was observed.

[0468] ...

Claims

1. A compound of formula (I), 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein R ａ１ is -(C(R ａ’ )) ２ )) ｐ -R ａ’’ , ​ is a 5-membered heteroaryl, 3- to 7-membered heterocycloalkyl, 9- to 10-membered aryl, or 9- to 10-membered heteroaryl, wherein the 5-membered heteroaryl, 3- to 7-membered heterocycloalkyl, 9- to 10-membered aryl, or 9- to 10-membered heteroaryl is optionally substituted with one or more R ａ３ and is optionally substituted as required, R ａ２ is H or not or R ａ１ and R ａ２ together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl, said 3- to 10-membered heterocycloalkyl being optionally substituted with one or more R ａ３ and Each R ａ’ is independently H, methyl optionally substituted with OH, or two Rs ａ’ together with one or more atoms to which they are attached form C ３ -C ６ cycloalkyl, 3- to 7-membered heterocycloalkyl, or oxo R ａ” is C ３ -C ６ cycloalkyl, 3- to 7-membered heterocycloalkyl, 5- to 10-membered heteroaryl, phenyl, -NR ９ R １０ , -OR １１ , or -CN, and the 5- to 10-membered heteroaryl, 3- to 7-membered heterocycloalkyl, or phenyl is optionally substituted with one or more R １３ s, Each R ａ３ But independently, Halo, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, 3- to 7-membered heterocycloalkyl, —C(O)C １ -C ６ Alkyl, -OR １１ , -C(O)NR ９ R １０ , or -S(O) ２ R ７ and said C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, 3- to 7-membered heterocycloalkyl, or -C(O)C １ -C ６ The alkyl may be one or more halo, -OR １１ , -CN, or -NR ９ R １０ or two R bonded to the same atom ａ３ are combined to form an oxo, or two R ａ３ together with the atoms to which they are attached combine to form a fused 3- to 7-membered ring containing up to two heteroatoms selected from the group consisting of N, O, and S; X ２ａ is N, N ＋ -O － or C-R ２ａ and X ３ａ is N, N ＋ -O － or C-R ３ａ wherein X ４ａ is N, N ＋ -O － or C-R ４ａ wherein X ５ａ is N, N ＋ -O － C-R ５ａ or N ＋ -(C １ -C ６ alkyl)Y － where Y － is a monovalent anion, X ６ａ is N, N ＋ -O － or C-R ６ａ wherein R ２ａ is H, halo, C １ -C ６ alkyl, or C １ -C ６ haloalkyl, and R ３ａ is H, halo, C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ alkoxy, 3- to 9-membered heterocycloalkyl, 5-membered heteroaryl, -CN, -OR １１ , -COOH, -NR ９ C(O)C １ -C ６ alkyl, -S(O) ２ R ７ , -S(O)(NR ９ )R ７ , -S(O)NR ９ R １０ , -S(O)R ７ , or -P(O)(C １ -C ６ alkyl) ２ wherein said C １ -C ６ alkyl, C １ -C ６ alkoxy, 3- to 9-membered heterocycloalkyl, 5-membered heteroaryl, or -NR ９ C(O)C １ -C ６ alkyl is optionally substituted with one or more R １２ , C ３ -C ６ cycloalkyl, -NR ９ R １０ , -OR １１ , -CN, or optionally substituted 3- to 7-membered heterocycloalkyl optionally substituted with one or more R １２ and R ４ａ is H, halo, C １ -C ６ alkyl, C １ -C ６ haloalkyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, 3- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, -CN, -C(O)NR ９ R １０ , -C(O)OH, -OR １１ , -NR ９ R １０ , -NR ９ C(O)C １ -C ６ alkyl, -S-C １ -C ６ alkyl, -S(O)(NR ９ )R ７ , -S(O)NR ９ R １０ , or -P(O)(C １ -C ６ alkyl) ２ and the C １ -C ６ alkyl, C １ -C ６ alkoxy, 3- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or C ２ -C ６ alkynyl is optionally substituted with one or more halo, -OR １１ , 3- to 7-membered heterocycloalkyl, -NR ９ R １０ , C １ -C ６ alkyl, or -S(O) ２ R ７ as needed, R ５ａ is H, halo, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, or -S(O) ２ R ７ wherein R ６ａ is H, halo, C １ -C ６ -alkyl, or C １ -C ６ -haloalkyl, and or R ３ａ and R ４ａ together with the atoms to which they are attached form a ring of the following formula, 【Chemical Formula 3】 R ７ is C １ -C ６ alkyl or 3- to 7-membered heterocycloalkyl, and said C １ -C ６ alkyl or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -OR １１ or C １ -C ６ alkyl, R ８ is H or C １ -C ６ is alkyl, R ９ and R １０ are each independently H, C １ -C ６ alkyl, 3- to 7-membered heterocycloalkyl, C ３ -C ６ cycloalkyl, -OH, -CN, or -S(O) ２ R ７ wherein the C １ -C ６ alkyl is optionally substituted with one or more -OR １１ or R ９ and R １０ together with the atom to which they are attached form a 3- to 7-membered heterocycloalkyl, Each R １１ is independently H, C １ -C ６ alkyl, C １ -C ６ haloalkyl, 3- to 7-membered heterocycloalkyl optionally substituted with -OH, or 3- to 7-membered cycloalkyl optionally substituted with -OH, Each R １２ is independently halo, C １ -C ６ alkyl, or -OR １１ or two Rs １２ together with the atom to which they are attached combine to form oxo, Each R １３ is independently halo, C １ -C ６ -alkyl, or -CONH ２ wherein said C １ -C ６ -alkyl is optionally substituted with one or more -OR １１ or two Rs １３ together with the atoms to which they are attached combine to form oxo, R ４ｂ１ and R ４ｂ２ are each independently H, C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, or C １ -C ６ haloalkyl, and R ５ｂ１ and R ５ｂ２ are each independently H, C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, or C １ -C ６ haloalkyl, and X ３ｃ is N or C—R ３ｃ and X ４ｃ is N or C—R ４ｃ wherein X ５ｃ is N or C—R ５ｃ and 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, -L １ -(C １ -C ６ alkylene)-OR １５ , -L １ -(C １ -C ６ alkenylene)-OR １５ , -L １ -(C １ -C ６ alkylene)-NR １６ R １７ , -L １ -(C １ -C ６ alkylene)-N=S(O)(C １ -C ３ alkyl) ２ , or L １ -L ２ -R １４ and R １４ is C ３ -C ６ cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -C(O)O(C １ -C ６ alkyl), -COOH, or -C(O)NR １６ R １７ and the C ３ -C ６ cycloalkyl, 3- to 8-membered heterocycloalkyl, or 5- or 6-membered heteroaryl is optionally substituted with one or more halo, -OH, C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ alkoxy, or C １ -C ６ haloalkoxy, R １５ is H, C １ -C ６ alkyl, or C １ -C ６ haloalkyl, and R １６ and R １７ are each independently H, -OH, C １ -C ６ alkyl, or 3- to 7-membered heterocycloalkyl, R ３ｃ is H, halo, C １ -C ６ alkyl, C １ -C ６ haloalkyl, or -(C １ -C ６ alkylene)-(C １ -C ６ alkoxy), and R ４ｃ is H, halo, C １ -C ６ -alkyl, or C １ -C ６ -haloalkyl, and R ５ｃ is H, halo, C １ -C ６ -alkyl, or C １ -C ６ -haloalkyl, and R ６ｃ is H, halo, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, or C １ -C ６ -alkoxy, and L １ is either a bond or O, L ２ is a linking or C １ -C ６ alkylene, and p is 1, 2, or 3, However, X ２ａ X ３ａ X ４ａ X ５ａ and X ６ａ Among them, two or less are N or N ＋ -O, X ３ｃ 、 X ４ｃ 、 X ５ｃ 、 and X ６ｃ One or less of them is N, R ４ａ is not CH(OH)-R ４ａ’ (where R ４ａ’ is H, or one or more halo, -OR １１ , 3- to 7-membered heterocycloalkyl, -NR ９ R １０ , C １ -C ６ alkyl, or -S(O) ２ R ７ optionally substituted C １ -C ５ alkyl, when the case), a compound, or a pharmaceutically acceptable salt thereof.

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

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

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

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

6. R ａ１ is 【Chemical Formula 8】 and R ａ２ is H, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. R ａ１ is 【Chemical Formula 9】 and R ａ２ The compound according to claim 1, wherein R is H, or a pharmaceutically acceptable salt thereof.

8. R ａ１ is 【Chemical 10】 wherein R ａ２ is H, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

9. R ａ１ is a 5-membered heteroaryl, 9- to 10-membered aryl, or 9- to 10-membered heteroaryl, and the 5-membered heteroaryl, 9- to 10-membered aryl, or 9- to 10-membered heteroaryl is optionally substituted with one or more R ａ３ and R ａ２ is H, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. X ２ａ is C-R ２ａ and R ２ａ is H; X ５ａ is C-R ５ａ and R ５ａ is H; X ６ａ is C-R ６ａ and R ６ａ is H, the compound according to claim 6, or a pharmaceutically acceptable salt thereof.

11. X ３ａ is N or C—R ３ａ where R ３ａ is —OR １１ , —COOH, —S(O) ２ R ７ , —S(O)(NR ９ ), R ７ , —S(O)NR ９ R １０ , or —S(O)R ７ and the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. X ４ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is N.

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

14. R ａ１ is a 5-membered heteroaryl or a 9- to 10-membered heteroaryl, and the 5-membered heteroaryl or 9- to 10-membered heteroaryl is optionally substituted with one or more R ａ３ , and R ａ２ is H, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

15. R ７ is methyl, and R ８ is H or methyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

16. R ２ｃ is CH ３ or OCH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

17. R ３ｃ is halo, optionally F, or C １ -C ６ alkyl, optionally CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein it is

18. R ４ｃ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is halo and optionally F.

19. R ５ｃ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is H.

20. R ６ｃ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is H.

21. R ４ｂ１ and R ４ｂ２ wherein one of R and R is H and one is methyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

22. R ５ｂ１ and R ５ｂ２ wherein one of them is methyl and one of them is trifluoromethyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

23. 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】 【Table 1-22】 【Table 1-23】 【Table 1-24】 【Table 1-25】 【Table 1-26】 【Table 1-27】 【Table 1-28】 【Table 1-29】 【Table 1-30】 【Table 1-31】 【Table 1-32】 【Table 1-33】 【Table 1-34】 【Table 1-35】 【Table 1-36】 【Table 1-37】 【Table 1-38】 【Table 1-39】 【Table 1-40】 【Table 1-41】 【Table 1-42】 【Table 1-43】 【Table 1-44】 【Table 1-45】 【Table 1-46】 【Table 1-47】 【Table 1-48】 【Table 1-49】 【Table 1-50】 【Table 1-51】 【Table 1-52】 【Table 1-53】 【Table 1-54】 【Table 1-55】 【Table 1-56】 【Table 1-57】 【Table 1-58】 【Table 1-59】 【Table 1-60】 【Table 1-61】 【Table 1-62】 【Table 1-63】 【Table 1-64】 【Table 1-65】 【Table 1-66】 【Table 1-67】 【Table 1-68】 【Table 1-69】 【Table 1-70】 【Table 1-71】 【Table 1-72】 【Table 1-73】 【Table 1-74】 【Table 1-75】 【Table 1-76】 【Table 1-77】 【Table 1-78】 【Table 1-79】 【Table 1-80】 【Table 1-81】 【Table 1-82】 【Table 1-83】 【Table 1-84】 【Table 1-85】 【Table 1-86】 【Table 1-87】 【Table 1-88】 【Table 1-89】 【Table 1-90】 【Table 1-91】 【Table 1-92】 【Table 1-93】 【Table 1-94】 【Table 1-95】 【Table 1-96】 【Table 1-97】 A compound selected from, or a pharmaceutically acceptable salt thereof.

24. The compound according to any one of claims 1 to 23 in non-salt form.

25. 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.

26. 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.

27. A composition for use in a method of inhibiting voltage-dependent sodium channels in a subject, the composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

28. wherein the voltage-dependent sodium channel is Na Ｖ The composition according to claim 27, wherein it is 1.

8.

29. A composition 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, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia, the composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

30. The composition according to claim 29, wherein the method comprises treating or reducing the severity in the subject of one or more of neuropathic pain, musculoskeletal pain, preferably osteoarthritic pain, acute pain, preferably acute postoperative pain, postoperative pain, or visceral pain.

31. The composition according to claim 30, wherein the neuropathic pain comprises one or more of postherpetic neuralgia, small fiber neuropathy, idiopathic small fiber neuropathy, or diabetic neuropathy, preferably diabetic peripheral neuropathy.

32. The composition according to claim 30, wherein the postoperative pain comprises one or more of pain after bunionectomy, pain after abdominoplasty, or pain after hernia suture.

33. The composition according to claim 27, wherein the subject is treated with one or more additional therapeutic agents administered concomitantly with, prior to, or after treatment with the composition.

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

Images