Heteroaryl compounds for the treatment of pain - Patents.com

Abstract

Provided are compounds and pharma- ceutically acceptable salts thereof 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 methods of inhibiting voltage-gated sodium channels in a subject by administering a compound, a pharma- ceutically acceptable salt, or a pharmaceutical composition to the subject.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 333,875, filed April 22, 2022, which is incorporated by reference in its entirety. [Background technology]

[0002] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and prevent further damage to injured tissue. Nevertheless, there are many conditions in which pain persists beyond its usefulness or in which patients would benefit from pain suppression. Neuropathic pain is a form of chronic pain caused by damage to sensory nerves (Dieleman, JP, et al., Incidence rates and treatment of neuropathic pain conditions in the general population. Pain, 2008. 137(3):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 injury. Metabolic neuropathies include postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Indications for discrete nerve injury include nerve entrapment injuries such as post-amputation pain, postoperative nerve injury pain, and neuropathic back pain.

[0003] Voltage-gated sodium channels (Na V ) is involved in pain signaling. V Sodium channel receptors (SCRs) are biological mediators of electrical signaling and mediate the rapid upstroke of action potentials in many excitable cell types (e.g., neurons, skeletal muscle cells, cardiac myocytes). Evidence for a role for these channels in normal physiology, pathological conditions resulting from mutations in sodium channel genes, preclinical studies in animal models, and clinical pharmacology of known sodium channel modulators all support the role of Na in pain sensation. V(Rush, A. M. and T. R. Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Na V 1.8 Sodium Channels.Mol.Interv.,2007.7(4):p.192-5), England,S.,Voltage-gated sodium channels:the search for subtype-selective analgesics.Expert Opin.Investig.Drugs 17(12),p.1849-64(2008),Krafte,DSand Bannon,AW,Sodium channels and nociception: recent concepts and therapeutic opportunities.Curr.Opin.Pharmacol.8(1),p.50-56(2008)). Na V Na mediates the rapid upstroke of action potentials in many excitable cell types (e.g., neurons, skeletal muscle cells, cardiac myocytes) and is therefore involved in the initiation of signal transduction in those cells (Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). Na plays a key role in the initiation and propagation of neuronal signals. V Because of the role played by Na V Antagonists that reduce current can prevent or reduce nerve signaling, VIt has been thought that these channels are likely to reduce pain in conditions where hyperexcitability is observed (Chahine, M., Chatelier, A., Babich, O., and Krupp, JJ, Voltage-gated sodium channels in neurological disorders. CNS Neurol. Disord. Drug Targets 7(2), p. 144-58 (2008)). Several clinically useful analgesics are known to be sodium-gated. 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 channels 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 primary sodium channel in skeletal muscle, and Na V 1.5 is the primary sodium channel in cardiac myocytes. Na V 1.7, 1.8, and 1.9 are primarily localized in the peripheral nervous system, and Na V1.1, 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 V 1.8 has been shown to be a carrier of the sodium current that sustains action potential firing in small dorsal root ganglion (DRG) neurons in nociceptive sensory neurons (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 V1.8 is involved in spontaneous firing in injured neurons, such as those that cause neuropathic pain (Roza, C., et al., The tetrodotoxin-resistant Na + Channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice.J.Physiol.,2003.550(Pt 3):p.921-6, Jarvis,MF,et al.,A-803467,a potent and selective Na V 1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat.Proc.Natl.Acad.Sci.USA,2007.104(20):p.8520-5, Joshi,SK,et al.,Involvement of the TTX-resistant sodium channel Na V 1.8 in inflammatory and neuropathic,but not post-operative,pain states.Pain,2006.123(1-2):pp.75-82, Lai, J., et al.,Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel,Na V 1.8.Pain,2002.95(1-2):p.143-52, Dong,XW,et al.,Small interfering RNA-mediated selective knockdown of Na V1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats.Neuroscience,2007.146(2):p.812-21, Huang, HL, et al., Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves.Mol.Pain,2008.4:p.33, Black, JA, et al. al.,Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas.Ann.Neurol.,2008.64(6):p.644-53, Coward,K.,et al.,Immunolocalization of SNS / PN3 and NaN / SNS2 sodium channels in human pain states.Pain,2000.85(1-2):p.41-50, Yiangou,Y.,et al.,SNS / PN3 and SNS2 / NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves.FEBS Lett.,2000.467(2-3):p.249-52, Ruangsri,S.,et al.,Relationship of axonal voltage-gated sodium channel 1.8(Na V 1.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats.J.Biol.Chem.286(46):p.39836-47). Na V The small DRG neurons in which Na1.8 is expressed contain nociceptors involved in pain signaling.V 1.8 mediates large amplitude action potentials in small neurons of the dorsal root ganglion (Blair, NT and BP Bean, Roles of tetrodotoxin (TTX)-sensitive Na + Current, TTX-resistant Na + current, and Ca 2+ current in the action potentials of nociceptive sensory neurons.J.Neurosci.,2002.22(23):p.10277-90). Na V 1.8 is required for rapid repetitive action potentials in nociceptors and for spontaneous activity of injured neurons. (Choi, JS and SG Waxman, Physiological interactions between Na V 1.7 and Na V 1.8 sodium channels: a computer simulation study.J.Neurophysiol.106(6):p.3173-84, Renganathan, M., TRCummins, and SGWaxman, Contribution of Na( V )1.8 sodium channels to action potential electrogenesis in DRG neurons.J.Neurophysiol.,2001.86(2):p.629-40, Roza,C.,et al.,The tetrodotoxin-resistant Na + Channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550(Pt 3): 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 The 1.8 mRNA expression level shows an increase in DRG (Sun, W., et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats. Brain, 135(Pt 2): 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 VIt has been discovered that selective Na 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] 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 3] England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics.Expert Opin.Investig.Drugs 17(12), p.1849-64(2008) [Non-patent document 4] 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 5] Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001) [Non-patent document 6] Chahine, M., Chatelier, A., Babich, O., and Krupp, JJ, Voltage-gated sodium channels in neurological disorders.CNS Neurol.Disord.Drug Targets 7(2), p.144-58(2008) [Non-Patent Document 7] Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action.Eur.J.Pain 6 Suppl.A, p.3-9(2002) [Non-patent document 8] Wang, GK, Mitchell, J., and Wang, SY, Block of persistent late Na+ currents by antidepressant sertraline and paroxetine.J.Membr.Biol.222(2),p.79-90(2008) [Non-Patent Document 9] Catterall, WA, Goldin, AL, and Waxman, SG, International Union of Pharmacology.XLVII.Nomenclature and structure-function relationships of voltage-gated sodium channels.Pharmacol.Rev.57(4), p.397(2005) [Non-Patent Document 10] Akopian, A.N., L. Sivilotti, and J.N. Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562): p. 257-62 [Non-Patent Document 11] Blair, N.T. and B.P. Bean, Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002. 22(23): p. 10277-90 [Non-Patent Document 12] Roza, C., et al., The tetrodotoxin-resistant Na+ channel NaV1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550(Pt 3): p. 921-6 [Non-Patent Document 13] Jarvis, M.F., et al., A-803467, a potent and selective NaV1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc. Natl. Acad. Sci. U S A, 2007. 104(20): p. 8520-5 [Non-Patent Document 14] Joshi, S.K., et al., Involvement of the TTX-resistant sodium channel NaV1.8 in inflammatory and neuropathic, but not post-operative, pain states. Pain, 2006. 123(1-2): pp. 75-82

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[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 methods 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 syndrome, incontinence, pathological cough, or cardiac arrhythmia, by administering a compound, pharmaceutically acceptable salt, or pharmaceutical composition to the subject. DETAILED DESCRIPTION OF THE INVENTION

[0011] In one aspect, the present invention provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: A, [ka] and L is -O-, a single bond, -OC(R)2-, -C(R)2-, -C(R)2-O-, or -N(R)-; each R is independently H, halo, or C1-C6 alkyl; X2 is N or CR2; X4 is N or CR4; X5 is N or CR5; X6 is N or CR6; X7 is N or CR7; Y1 is N or CR 1a and Y2 is N, + NO - , or CR 2a and Y3 is N or CR 3a and R2 is H, halo, C1-C6 alkyl, (C1-C6 alkylene)-NR8R9, C2-C6 alkenyl, C1-C6 alkoxy, (C1-C6 alkylene)-OH, C(O)OR8, or CH(OH)(CH2); m (CHOH) n (CH2) p H, R4, R5, R6, and R7 are as follows: (i) R, R, R, and R are each independently H, halo, C-C alkyl, C-C haloalkyl, or C-C cycloalkyl optionally substituted with one or more alkyl, halo, or OH; (ii) R4 and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with one or more halo; and R5 and R6, together with the carbon atoms to which they are attached, form a group of the formula: [ka] Assuming that it forms a ring of (iii) R4 and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl substituted with one or more halo; and R5 and R6, together with the carbon atoms to which they are attached, form a group of the formula: [ka] is defined as forming a ring of R8 and R9 are each independently H or C1-C6 alkyl; Each R 10 are independently H or halo; R 1a H, halo, CN, C1-C6 alkyl, OH, C(O)NR 12 R 13 , C1-C6 alkoxy, NR 12 R 13 , NR8C(O)NR8R9, (C1-C6 alkylene)-C(O)NR8R9, (C1-C6 alkylene)-OH, C(O)OR 12 , OR 12 , CH(OH)(CH2) m (CHOH) n (CH2) p H, N=S(=O)(CH3)2, N=S(=O)R'R'', 5- to 10-membered heteroaryl, or 4- to 10-membered heterocyclyl, wherein the heterocyclyl or heteroaryl in the 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclyl is optionally substituted by 1 to 4 substituents selected from OH, halo, oxo, C(O)NR8R9, NR8R9, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkylene)-OH, (C1-C6 alkylene)-O-(C1-C6 alkyl), and (C1-C6 alkylene)-NR8R9; R' and R'' together with the S atom to which they are attached form a 4- to 7-membered heterocyclyl; R 11 , R 2a , and R 3a are each independently H, halo, CN, C-C alkyl, C(O)NRR, or C-C alkoxy; R 12 and R 13 are each independently H, C(O)(C-C alkyl), (C-C alkylene)-NR, CHCH(OH)(CH) m (CHOH) n (CH2) pH, C1-C6 alkyl optionally substituted with one or more OH, indanyl, (C1-C6 alkylene)-(C3-C6 cycloalkyl), (C1-C6 alkylene)-phenyl, (C1-C6 alkylene)-(5-membered heterocyclyl), C4-C7 cycloalkyl, C6-C 10 Aryl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocyclyl, including indanyl, (C1-C6 alkylene)-(C3-C6 cycloalkyl), (C1-C6 alkylene)-phenyl, (C1-C6 alkylene)-(5-membered heterocyclyl), C4-C7 cycloalkyl, C6-C 10 the aryl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocyclyl is optionally substituted with 1 to 4 substituents selected from OH, oxo, C-C alkyl, (C-C alkylene)-OH, and C-C alkoxy; Z1 is a 3- to 10-membered cycloalkyl, a 3- to 10-membered cycloalkenyl, a phenyl, a 4- to 10-membered heterocyclyl, or a 5- to 6-membered heteroaryl, wherein the 3- to 10-membered cycloalkyl, the 3- to 10-membered cycloalkenyl, the phenyl, the 4- to 10-membered heterocyclyl, or the 5- to 6-membered heteroaryl can be unsubstituted or substituted with 1 to 4 substituents selected from halo, OH, CD3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, CH2OH, C(O)H, and C1-C6 haloalkoxy; m, n, and p are each independently 0 or 1; q is 1, 2, or 3; If X2 is N, L is O and Z1 is phenyl, wherein the phenyl is substituted with 2 to 4 substituents selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy; or L is a single bond, Z1 is a 4- to 10-membered heterocyclyl, and the 4- to 10-membered heterocyclyl is substituted by 2 to 4 substituents selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy; The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, in which when X2, X4, X5, X6, and X7 are each CH, L is a single bond, and Z1 is phenyl, the phenyl is substituted with 1 to 4 substituents selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0012] For purposes of this invention, chemical elements are identified according to the Periodic Table, Handbook of Chemistry and Physics, 75th Edition, CAS Edition. Further, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5 th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0013] As used herein, the term "compounds of the invention" refers to compounds of formulas (I), (II), and (III) described herein, and all embodiments thereof (e.g., formula (IA-1), etc.), and compounds identified in Tables A and B.

[0014] As described herein, the compounds of the present invention may be substituted with a number of variables (e.g., R, X, R 1aAs 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 allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or 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.

[0015] The chemical structures depicted herein are intended to be understood as they would be understood by one of ordinary skill in the art. For example, with respect to formulas (I), (IA-1), (IA-2), (IB-1), (IC-1), and (IC-2), X4 and X5 are joined by a single bond, X5 and X6 are joined by a double bond, and X6 and X7 are joined by a single bond, although the bonds between these groups may be hidden by atom labels in the chemical structure. Using different ChemDraw styles, formula (I) may be drawn as follows to indicate the bonds in question: [ka] Additionally, a substituent designated in a chemical structure as "CF3" or "F3C" refers to a trifluoromethyl substituent, regardless of where that depiction appears in the chemical structure.

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

[0017] As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain radical group, consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having 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.

[0018] 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.

[0019] 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 connected to the rest 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.

[0020] 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.

[0021] As used herein, the term "alkoxy" refers to a group of the formula -OR a where R a is an alkyl group having the specified number of carbon atoms. For example, 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.

[0022] As used herein, the term "haloalkoxy" refers to an alkoxy group having the specified number of carbon atoms, wherein one or more of the alkyl group's hydrogen atoms is replaced by a halo group.

[0023] 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.

[0024] As used herein, the term "cycloalkenyl" refers to a stable non-aromatic monocyclic or bicyclic (fused, bridged, or spiro) hydrocarbon radical, consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds, having the specified number of carbon ring atoms, and attached to the remainder of the molecule by a single bond. For example, a "C3-C8 cycloalkenyl" group is a cycloalkenyl group having from 3 to 8 carbon atoms.

[0025] As used herein, the term "heterocyclyl" refers to a stable non-aromatic monocyclic, bicyclic, or tricyclic (fused, bridged, or spiro) radical having a specified number of ring atoms and attached to the remainder of the molecule by a single bond, wherein one or more ring atoms are heteroatoms (e.g., heteroatoms independently selected from N, O, P, and S). The heterocycle may be saturated or may contain one or more double or triple bonds. In some embodiments, a "heterocyclyl" group has a specified number of ring members, wherein one or more ring members are heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, and each ring in the ring system contains 3 to 7 ring members. For example, a 6-membered heterocyclyl contains a total of 6 ring members, at least one of which is a heteroatom (e.g., a heteroatom independently selected from N, O, P, and S).

[0026] As used herein, the term "heteroaryl" refers to a stable monocyclic, bicyclic, or tricyclic radical having the specified number of ring atoms, wherein at least one ring in the system is aromatic and at least one aromatic ring in the system contains one or more heteroatoms (e.g., one or more heteroatoms independently selected from N, O, P, and S). In some embodiments, each ring in the system contains 3 to 7 ring members. For example, a 6-membered heteroaryl contains a total of 6 ring members, at least one of which is a heteroatom selected from N, S, O, and P. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic."

[0027] As used herein, the term "optionally substituted" refers to a group that is unsubstituted or substituted with the substituent(s) specified thereafter. For example, a group that is "optionally substituted with 1-2 halo" is either unsubstituted, substituted with 1 halo group, or substituted with 2 halo groups.

[0028] As used herein, labels such as "*5" and "*6", such as those shown in the structures below, indicate the atoms to which the corresponding R groups (in this case, the R5 and R6 groups, respectively) are attached. [ka]

[0029] Similarly, "*8" and "*9" in the following structures represent R 8a Groups and R 9a Indicates the atom to which the group is attached. [ka]

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

[0031] 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 configuration of a stereocenter is unspecified. The compound may have any configuration or a mixture of configurations at the stereocenter.

[0032] As used herein, in any chemical structure or formula, a 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 chiral center relative to the other stereocenter to which it is attached.

[0033] 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-shaped bond indicates the absolute stereochemistry of a chiral center relative to the other chiral center to which it is attached, as well as the relative stereochemistry of the chiral center.

[0034] 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.

[0035] 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, stereochemical designators associated with stereocenters of known absolute configuration are marked with an asterisk (*), e.g., (R*)- and (S*)-, while stereochemical designators associated with stereocenters of unknown absolute configuration are not. Unmarked stereochemical designators associated with stereocenters of unknown absolute configuration reflect the relative stereochemistry of those stereocenters relative to other stereocenters of unknown absolute configuration, but not necessarily relative stereochemistry to stereocenters of known absolute configuration.

[0036] 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.

[0037] 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.

[0038] 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).

[0039] 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.

[0040] 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 the designated position at least at the natural abundance concentration of protium.

[0041] As used herein, "D", "d", and " 2 "H" refers to deuterium.

[0042] 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.

[0043] 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.

[0044] 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. For example, deuterium ( 2 H) The labeled compounds and salts are therapeutically useful and non- 2 3H-labeled compounds have potential therapeutic advantages over H-labeled compounds. 2 H) Labeled compounds and salts may have higher metabolic stability compared to non-isotopically labeled 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.

[0045] deuterium( 2H) 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 rate-limiting bond scission. If 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.

[0046] 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.

[0047] 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).

[0048] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: A, [ka] and R 1a H, halo, CN, C1-C6 alkyl, OH, C(O)NR 12 R 13 , C1-C6 alkoxy, NR 12 R 13 , (C1-C6 alkylene)-C(O)NR8R9, (C1-C6 alkylene)-OH, C(O)OR 12 , CH(OH)(CH2) m (CHOH) n (CH2) p H, or N=S(=O)(CH3)2, R 12 and R 13 are each independently H, C(O)(C-C alkyl), (C-C alkylene)-NR, CHCH(OH)(CH) m (CHOH) n (CH2) pH, C1-C6 alkyl optionally substituted with one or more OH.

[0049] In some embodiments, the present invention relates to compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein A is: [ka] is.

[0050] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: L is a single bond or -C(R)2-; X2 is CR2, Z1 is a 4- to 10-membered cycloalkyl, a 3- to 10-membered cycloalkenyl, a phenyl, or a 5- to 6-membered heteroaryl, and the 4- to 10-membered cycloalkyl, a 3- to 10-membered cycloalkenyl, a phenyl, or a 5- to 6-membered heteroaryl can be unsubstituted or substituted with 1 to 4 substituents selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0051] In some embodiments, the present invention relates to compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein R is H or C1-C6 alkyl.

[0052] In some embodiments, the present invention provides a compound of formula (IA-1): [ka] or a pharmaceutically acceptable salt thereof, wherein L, X2, X4, X5, X6, X7, Y1, Y2, Y3, and Z1 are defined as described above in relation to formula (I), or any embodiment thereof.

[0053] In some embodiments, the present invention provides a compound of formula (IA-2): [ka] or a pharmaceutically acceptable salt thereof, wherein L, X2, X4, X5, X6, X7, Y1, Y2, and Y3 are defined as described above in relation to formula (I), or any embodiment thereof. 14 is selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0054] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: L is a single bond, X2 is CR2, R 1a H, halo, CN, OH, C(O)NR 12 R 13 , C1-C6 alkoxy, -NR 12 R 13 , (C1-C6 alkylene)-C(O)NR8R9, (C1-C6 alkylene)-OH, C(O)OR 12 , CH(OH)(CH2) m (CHOH) n (CH2) p H, or N=S(=O)(CH3)2, Z1 is a 4- to 10-membered heterocyclyl, which can be unsubstituted or substituted with 1 to 4 substituents selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0055] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: L is a single bond, X2 is CR2, R 1a H, halo, CN, OH, C(O)NR 12 R 13 , C1-C6 alkoxy, -NR 12 R 13 , (C1-C6 alkylene)-C(O)NR8R9, (C1-C6 alkylene)-OH, C(O)OR12 , CH(OH)(CH2) m (CHOH) n (CH2) p H, or N=S(=O)(CH3)2, Z1 is a 5- to 10-membered heterocyclyl, which may be unsubstituted or substituted with 1 to 4 substituents selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0056] In some embodiments, the present invention relates to compounds of formula (IA-1) or (IA-2), or a pharmaceutically acceptable salt thereof, wherein R is H or C1-C6 alkyl.

[0057] In some embodiments, the present invention provides a compound of formula (IB-1): [ka] or a pharmaceutically acceptable salt thereof, wherein X, X, X, X, X, X, Y, Y, and Z are defined as described above in relation to formula (I), or any embodiment thereof.

[0058] In some embodiments, the present invention provides a compound of formula (IB-2): [ka] or a pharmaceutically acceptable salt thereof, wherein X, X, X, X, X, X, Y, Y, Y, and Z are defined as described above in relation to formula (I), including any embodiment thereof. 14 is selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0059] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: L is O, —OC(R)2—, or —C(R)2—O—; Z1 is phenyl, a 4- to 10-membered heterocyclyl, or a 5- to 6-membered heteroaryl, and the phenyl, 4- to 10-membered heterocyclyl, or 5- to 6-membered heteroaryl can be unsubstituted or substituted with 1 to 4 substituents selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, CH2OH, C(O)H, and C1-C6 haloalkoxy.

[0060] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: L is O, —OC(R)2—, or —C(R)2—O—; Z1 is phenyl, a 5- to 10-membered heterocyclyl, or a 5- to 6-membered heteroaryl, and the phenyl, 5- to 10-membered heterocyclyl, or 5- to 6-membered heteroaryl can be unsubstituted or substituted with 1 to 4 substituents selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, CH2OH, C(O)H, and C1-C6 haloalkoxy.

[0061] In some embodiments, the compound of the present invention has the formula (IC-1): [ka] or a pharmaceutically acceptable salt thereof, wherein X, X, X, X, X, X, Y, Y, and Z are defined as described above in relation to formula (I), or any embodiment thereof.

[0062] In some embodiments, the compound of the present invention has the formula (IC-2): [ka] or a pharmaceutically acceptable salt thereof, wherein X, X, X, X, X, X, Y, Y, and Y are defined as described above in relation to formula (I), or any embodiment thereof. 14is selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0063] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: L is —O— or a single bond; X4 is CR4, X6 is CR6, R4, R5, R6, and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with one or more halo; Z1 is a 3- to 10-membered cycloalkyl or phenyl, which can be unsubstituted or substituted with 1 to 4 substituents selected from halo, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl.

[0064] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: A, [ka] and X2 is CR2, Y1 is CR 1a and Y2 is N or CR 2a and Y3, CR 3a and R 11 , R 2a , and R 3a are H, respectively, R 1a But C(O)NR 12 R 13 , N.R. 12 R 13 , NR8C(O)NR8R9, OR 12, N=S(=O)R'R'', 5- to 10-membered heteroaryl, or 4- to 10-membered heterocyclyl, wherein the heterocyclyl or heteroaryl in the 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclyl is optionally substituted by 1 to 4 substituents selected from OH, halo, oxo, C(O)NR8R9, NR8R9, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkylene)-OH, (C1-C6 alkylene)-O-(C1-C6 alkyl), and (C1-C6 alkylene)-NR8R9; R' and R'' together with the S atom to which they are attached form a 4- to 7-membered heterocyclyl; R 12 and R 13 are each independently H, C(O)(C-C alkyl), (C-C alkylene)-NR, CHCH(OH)(CH) m (CHOH) n (CH2) p H, C1-C6 alkyl optionally substituted with one or more OH, indanyl, (C1-C6 alkylene)-(C3-C6 cycloalkyl), (C1-C6 alkylene)-phenyl, (C1-C6 alkylene)-(5-membered heterocyclyl), C4-C7 cycloalkyl, C6-C 10 Aryl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocyclyl, including indanyl, (C1-C6 alkylene)-(C3-C6 cycloalkyl), (C1-C6 alkylene)-phenyl, (C1-C6 alkylene)-(5-membered heterocyclyl), C4-C7 cycloalkyl, C6-C 10 The aryl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocyclyl is optionally substituted with 1 to 4 substituents selected from OH, oxo, C1-C6 alkyl, (C1-C6 alkylene)-OH, and C1-C6 alkoxy.

[0065] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: L is -O-; A, [ka] and X2 is CR2, X4 is CR4, X5 is CR5, X6 is CR6, Y1 is CR 1a and Y3, CR 3a and R2 is H, R4, R5, R6, and R7 are each independently H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R8 and R9 are each independently H or C1-C6 alkyl; R 1a But C(O)NR 12 R 13 or NR8C(O)NR8R9, R 12 and R 13 are H, respectively,

[0066] Z1 is phenyl, which can be unsubstituted or substituted with 1 to 4 substituents selected from halo or C1-C6 alkyl. In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), and (IC-2), or a pharmaceutically acceptable salt thereof, wherein Y2 is N. In other embodiments, Y2 is + NO - In some embodiments, Y2 is CR 2a and R 2a is H, halo, CN, C-C alkyl, C(O)NRR, or C-C alkoxy. 2a is H. In some embodiments, R 2a is halo. In some embodiments, R 2a is CN. In some embodiments, R 2a is C1-C6 alkyl. In some embodiments, R 2ais C(O)NR8R9. In some embodiments, R 2a is C1-C6 alkoxy.

[0067] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), and (IC-2), or a pharmaceutically acceptable salt thereof, wherein X4 is CR4, X5 is N, X6 is CR6, and X7 is CR7. In some embodiments, X4 is CR4, X5 is N, X6 is CR6, and X7 is N. In some embodiments, X4 is CR4, X5 is CR5, X6 is CR6, and X7 is N. In some embodiments, X4 is CR4, X5 is CR5, X6 is CR6, and X7 is N.

[0068] In some embodiments, the present invention relates to a compound of any one of Formulas (I), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), and (IC-2), or a pharmaceutically acceptable salt thereof, wherein R, R, R, and R are each independently H, halo, C-C alkyl, C-C haloalkyl, or C-C cycloalkyl optionally substituted with one or more alkyl, halo, or OH. In some embodiments, R, R, R, and R are each independently H, halo, C-C alkyl, C-C haloalkyl, or C-C cycloalkyl substituted with one or more halo. In some embodiments, R4, R5, R6, and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl substituted with 1, 2, or 3 halo. In some embodiments, R4 is H, halo, or C1-C6 alkyl. In some embodiments, R5 is H, halo, or C1-C6 haloalkyl. In some embodiments, R5 is H or C1-C6 haloalkyl. In some embodiments, R5 is F. In some embodiments, R5 is -CF3. In some embodiments, R6 is H, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl substituted with 2 halo. In some embodiments, R6 is H. In some embodiments, R6 is -CF3. In some embodiments, R6 is C4 cycloalkyl substituted with 2 F. In some embodiments, R7 is H.

[0069] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), and (IC-2), or a pharmaceutically acceptable salt thereof, wherein Y is CR 1a In some embodiments, R 1a is C(O)NR 12 R 13 In some embodiments, R 1a is H. In some embodiments, R1a is halo. In some embodiments, R 1a is CN. In some embodiments, R 1a is C1-C6 alkyl. In some embodiments, R 1a is OH. In some embodiments, R 1a is C1-C6 alkoxy. In some embodiments, R 1a is NR 12 R 13 In some embodiments, R 1a is (C1-C6 alkylene)-C(O)NR8R9. In some embodiments, R 1a is (C1-C6 alkylene)-OH. In some embodiments, R 1a is C(O)OR 12 In some embodiments, R 1a is OR 12 In some embodiments, R 1a is NR8C(O)NR8R9. In some embodiments, R 1a is N=S(=O)R'R'' where R' and R'' together with the S atom to which they are attached form a 4-7 membered heterocyclyl. In some embodiments, R 1a is a 5-10 membered heteroaryl, which is optionally substituted with 1-4 substituents selected from OH, halo, oxo, C(O)NR8R9, NR8R9, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkylene)-OH, (C1-C6 alkylene)-O-(C1-C6 alkyl), and (C1-C6 alkylene)-NR8R9. In some embodiments, R 1a is a 4- to 10-membered heterocyclyl, which is optionally substituted with 1 to 4 substituents selected from OH, halo, oxo, C(O)NR8R9, NR8R9, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkylene)-OH, (C1-C6 alkylene)-O-(C1-C6 alkyl), and (C1-C6 alkylene)-NR8R9.

[0070] In some embodiments, the present invention relates to a compound of any one of Formulas (I), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), and (IC-2), or a pharmaceutically acceptable salt thereof, wherein X2 is CR2. In some embodiments, R2 is H. In some embodiments, R2 is halo. In some embodiments, R2 is C1-C6 alkyl. In some embodiments, R2 is (C1-C6 alkylene)-NR8R9. In some embodiments, R2 is C2-C6 alkenyl. In some embodiments, R2 is C1-C6 alkoxy. In some embodiments, R2 is (C1-C6 alkylene)-OH. In some embodiments, R2 is C(O)OR8. In some embodiments, R2 is CH(OH)(CH2) m (CHOH) n (CH2) p It's H.

[0071] In some embodiments, the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein L is O, a single bond, OC(R), C(R), C(R)-O, or N(R). In some embodiments, L is O. In some embodiments, L is a single bond. In some embodiments, L is OC(R). In some embodiments, L is C(R). In some embodiments, L is C(R)-O. In some embodiments, L is N(R).

[0072] In some embodiments, the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein L is O, a single bond, OC(R), C(R), C(R)-O, or N(R), and R is H or C-C alkyl. In some embodiments, L is O. In some embodiments, L is a single bond. In some embodiments, L is OC(R) and R is H or C-C alkyl. In some embodiments, L is C(R) and R is H or C-C alkyl. In some embodiments, L is C(R)-O and R is H or C-C alkyl. In some embodiments, L is N(R) and R is H or C-C alkyl.

[0073] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), and (IC-2), or a pharmaceutically acceptable salt thereof, wherein R 12 and R 13 are each H. In some embodiments, R 12 and R 13 are each independently H or C1-C6 alkyl. In some embodiments, R 12 and R 13 are each independently H or C1-C6 alkyl optionally substituted with one or more OH.

[0074] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), and (IC-2), or a pharmaceutically acceptable salt thereof, wherein R 12 is C(O)(C1-C6 alkyl). In some embodiments, R 12 is (C1-C6 alkylene)-NR8R9. In some embodiments, R 12 is CH2CH(OH)(CH2) m (CHOH) n (CH2) pH. In some embodiments, R 12 is indanyl, wherein the indanyl is optionally substituted with 1 to 4 substituents selected from OH, oxo, C-C alkyl, (C-C alkylene)-OH, and C-C alkoxy. 12 is (C1-C6 alkylene)-(C3-C6 cycloalkyl), wherein (C1-C6 alkylene)-(C3-C6 cycloalkyl) is optionally substituted with 1 to 4 substituents selected from OH, oxo, C1-C6 alkyl, (C1-C6 alkylene)-OH, and C1-C6 alkoxy. 12 is (C1-C6 alkylene)-phenyl, wherein the (C1-C6 alkylene)-phenyl is optionally substituted with 1 to 4 substituents selected from OH, oxo, C1-C6 alkyl, (C1-C6 alkylene)-OH, and C1-C6 alkoxy. 12 is a (C-C alkylene)-(5-membered heterocyclyl), wherein the (C-C alkylene)-(5-membered heterocyclyl) is optionally substituted with 1 to 4 substituents selected from OH, oxo, C-C alkyl, (C-C alkylene)-OH, and C-C alkoxy. 12 is a C4-C7 cycloalkyl, wherein the C4-C7 cycloalkyl is optionally substituted with 1 to 4 substituents selected from OH, oxo, C1-C6 alkyl, (C1-C6 alkylene)-OH, and C1-C6 alkoxy. 12 is C6-C 10 Aryl, C6-C 10 The aryl is optionally substituted with 1 to 4 substituents selected from OH, oxo, C-C alkyl, (C-C alkylene)-OH, and C-C alkoxy. In some embodiments, R 12is a 5-6 membered heteroaryl, which is optionally substituted with 1-4 substituents selected from OH, oxo, C-C alkyl, (C-C alkylene)-OH, and C-C alkoxy. 12 is a 4- to 7-membered heterocyclyl, which is optionally substituted with 1 to 4 substituents selected from OH, oxo, C-C alkyl, (C-C alkylene)-OH, and C-C alkoxy. 12 is a C3-C6 cycloalkyl or a 5- to 6-membered heterocyclyl, and the C3-C6 cycloalkyl or the 5- to 6-membered heterocyclyl is optionally substituted with 1 to 4 substituents selected from C1-C6 alkoxy.

[0075] In some embodiments, the present invention relates to a compound of any one of formulas (IA-2), (IB-2), and (IC-2), or a pharmaceutically acceptable salt thereof, wherein R 14 is halo, OH, C-C alkyl, C-C alkoxy, C-C haloalkyl, or C-C haloalkoxy. 14 is halo. In some embodiments, R 14 is C1-C6 alkyl. In some embodiments, R 14 is C1-C6 haloalkyl. In some embodiments, R 14 is C-C haloalkoxy. In some embodiments, R 14 is OH. In some embodiments, R 14 is C1-C6 alkoxy.

[0076] In some embodiments, the present invention relates to a compound of any one of Formulae (I), (IA-1), (IB-1), and (IC-1), or a pharmaceutically acceptable salt thereof, wherein Z is a 3- to 10-membered cycloalkyl, a 3- to 10-membered cycloalkenyl, a phenyl, a 5- to 10-membered heterocyclyl, or a 5- to 6-membered heteroaryl, and the 3- to 10-membered cycloalkyl, the 3- to 10-membered cycloalkenyl, the phenyl, the 5- to 10-membered heterocyclyl, or the 5- to 6-membered heteroaryl can be unsubstituted or substituted with 1 to 4 substituents selected from halo, OH, C-C alkyl, C-C alkoxy, C-C haloalkyl, CHOH, C(O)H, and C-C haloalkoxy. In some embodiments, the 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, phenyl, 5- to 10-membered heterocyclyl, or 5- to 6-membered heteroaryl is substituted with D, OCD3, or CD3.

[0077] In some embodiments, the present invention relates to a compound of any one of Formulas (I), (IA-1), (IB-1), and (IC-1), or a pharmaceutically acceptable salt thereof, wherein Z1 is a 4- to 10-membered cycloalkyl, a 3- to 10-membered cycloalkenyl, a phenyl, or a 5- to 6-membered heteroaryl. In some embodiments, Z1 is a 4- to 10-membered cycloalkyl. In some embodiments, Z1 is a 4- to 7-membered cycloalkyl. In some embodiments, Z1 is a 5- to 6-membered cycloalkyl. In some embodiments, Z1 is a cyclohexane. In some embodiments, Z1 is a phenyl. In some embodiments, Z1 is a 5- to 6-membered heteroaryl. In some embodiments, the 4- to 10-membered cycloalkyl, the 4- to 7-membered cycloalkyl, the 5- to 6-membered cycloalkyl, or the cyclohexane is substituted with 1, 2, 3, or 4 substituents selected from halo and C1-C6 haloalkyl. In some embodiments, the 4- to 10-membered cycloalkyl, 4- to 7-membered cycloalkyl, 5- to 6-membered cycloalkyl, or cyclohexane is substituted with 1, 2, 3, or 4 halo. In some embodiments, the 4- to 10-membered cycloalkyl, 4- to 7-membered cycloalkyl, 5- to 6-membered cycloalkyl, or cyclohexane is substituted with 1, 2, 3, or 4 C1-C6 haloalkyl.

[0078] In some embodiments, the present invention relates to a compound of any one of Formulae (I), (IA-1), (IB-1), and (IC-1), or a pharmaceutically acceptable salt thereof, wherein Z1 is a 4- to 10-membered heterocyclyl. In some embodiments, Z1 is a 5- to 10-membered heterocyclyl. In some embodiments, Z1 is a 5- to 9-membered heterocyclyl. In some embodiments, Z1 is a 6- to 9-membered heterocyclyl. In some embodiments, Z1 is a 6- to 8-membered heterocyclyl. In some embodiments, Z1 is a 6- to 7-membered heterocyclyl. In some embodiments, Z1 is a 7- to 8-membered heterocyclyl. In some embodiments, Z1 is a 7-membered heterocyclyl.

[0079] In some embodiments, the present invention relates to a compound of any one of Formulas (I), (IA-1), (IB-1), and (IC-1), or a pharmaceutically acceptable salt thereof, wherein Z1 is phenyl or 4-10 membered heterocyclyl. In some embodiments, Z1 or phenyl is 5-10 membered heterocyclyl. In some embodiments, Z1 is phenyl. In some embodiments, Z1 is 4-10 membered heterocyclyl. In some embodiments, Z1 is 5-10 membered heterocyclyl. In some embodiments, phenyl is substituted with 1, 2, 3, or 4 substituents selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, CH2OH, C(O)H, and C1-C6 haloalkoxy. In some embodiments, phenyl is substituted with 1, 2, 3, or 4 substituents selected from halo, C-C alkyl, C-C alkoxy, CHOH, C(O)H, and C-C haloalkyl. In some embodiments, phenyl is substituted with 2 substituents selected from halo, C-C alkyl, C-C alkoxy, CHOH, C(O)H, and C-C haloalkyl.

[0080] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), and (IC-2), or any embodiment thereof, i.e., a non-salt form of the compound.

[0081] In some embodiments, the present invention provides a compound of formula (II) or (III): [ka] or a pharmaceutically acceptable salt thereof, wherein: B, [ka] and L2 is a single bond or -CH2-, X 12is CH or N, R 14 is H, halo, or C1-C6 alkoxy; R 8a and R 9a However, the following (i)R 8a and R 9a are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 to 4 substituents selected from C1-C6 alkyl, halo, and C1-C6 haloalkyl; (ii)R 8a and R 9a together with the carbon atoms to which they are attached form the formula: [ka] and wherein the ring is optionally substituted with 1 to 4 C1-C6 alkyl; R 10a is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 to 4 substituents selected from C1-C6 alkyl, halo, and C1-C6 haloalkyl; R 11a is H or C1-C6 alkyl; R 15 But C(O)NR 16 R 17 or a 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted with 1 to 4 C1-C6 alkyl; R 16 and R 17 are each independently H or C1-C6 alkyl; Z2 is C4-C6 cycloalkyl or phenyl, wherein the C4-C6 cycloalkyl or phenyl is optionally substituted with 1 to 4 substituents selected from halo and C1-C6 alkyl; q2 is 1, 2, or 3.

[0082] In some embodiments, the present invention provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein R 14 , R 15 , R 8a , R 9a , L2, and Z2 are defined as described above in connection with formula (II), or any embodiment thereof.

[0083] In some embodiments, the present invention provides a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein R 14 , R 15 , R 10a , R 11a , L2, and Z2 are defined as described above in connection with formula (III), or any embodiment thereof.

[0084] In some embodiments, the present invention relates to a compound of any one of formulas (II) and (III), or a pharmaceutically acceptable salt thereof, wherein L2 is a single bond. In some embodiments, L2 is -CH2-.

[0085] In some embodiments, the present invention relates to a compound of any one of formulas (II) and (III), or a pharmaceutically acceptable salt thereof, wherein R 14 is H, halo, or C-C alkyloxy. In some embodiments, R 14 is H. In some embodiments, R 14 is halo. In some embodiments, R 14 is Br. In some embodiments, R 14 is C1-C6 alkoxy. In some embodiments, R 14 is methoxy.

[0086] In some embodiments, the present invention relates to a compound of any one of formulas (II) and (III), or a pharmaceutically acceptable salt thereof, wherein R 15 is C(O)NR 16 R 17 or a 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted with 1 to 4 C1-C6 alkyl. In some embodiments, R 15 is C(O)NR 16 R 17 In some embodiments, R 15 is a 5-membered heteroaryl, which is optionally substituted with 1 to 4 C1-C6 alkyl. In some embodiments, R 15 is a 5-membered heteroaryl, which is optionally substituted with 1 to 2 methyl.

[0087] In some embodiments, the present invention relates to a compound of any one of formulas (II) and (III), or a pharmaceutically acceptable salt thereof, wherein R 16 and R 17 are each independently H or C1-C6 alkyl. In some embodiments, R 16 and R 17 are each independently H. In some embodiments, R 16 and R 17 are each independently C1-C6 alkyl.

[0088] In some embodiments, the present invention relates to a compound of any one of formulas (II) and (III), or a pharmaceutically acceptable salt thereof, wherein R 8a is H, halo, C-C alkyl, C-C haloalkyl, or C-C cycloalkyl optionally substituted with 1 to 4 substituents selected from C-C alkyl, halo, and C-C haloalkyl. 8a is H. In some embodiments, R 8a is halo. In some embodiments, R 8a is C1-C6 alkyl. In some embodiments, R8a is C1-C6 haloalkyl. In some embodiments, R 8a is C-C cycloalkyl optionally substituted with 1 to 4 substituents selected from C-C alkyl, halo, and C-C haloalkyl. 8a is H. In some embodiments, R 8a is Br. In some embodiments, R 8a is Cl.

[0089] In some embodiments, the present invention relates to a compound of any one of formulas (II) and (III), or a pharmaceutically acceptable salt thereof, wherein R 9a is H, halo, C-C alkyl, C-C haloalkyl, or C-C cycloalkyl optionally substituted with 1 to 4 substituents selected from C-C alkyl, halo, and C-C haloalkyl. 9a is C1-C6 alkyl. In some embodiments, R 9a is C1-C6 haloalkyl. In some embodiments, R 9a is C-C cycloalkyl optionally substituted with 1 to 4 substituents selected from C-C alkyl, halo, and C-C haloalkyl. 9a is tert-butyl. In some embodiments, R 9a is —CH 2 CF 3 . In some embodiments, R 9a is C cycloalkyl optionally substituted with 1 to 4 substituents selected from C-C alkyl, halo, and C-C haloalkyl. 9a is a C cycloalkyl optionally substituted with one —CF. In some embodiments, R 9a is C4 cycloalkyl optionally substituted with 1 to 4 substituents selected from C1-C6 alkyl, halo, and C1-C6 haloalkyl. In some embodiments, R 9ais a C4 cycloalkyl optionally substituted with one substituent -CF3. In some embodiments, R 9a is a C4 cycloalkyl optionally substituted with 1-2 substituents of F. In some embodiments, R 9a is a C4 cycloalkyl optionally substituted with 1-2 substituents of C1-C6 alkyl. In some embodiments, R 9a is a C4 cycloalkyl optionally substituted with 1-2 substituents of methyl. In some embodiments, R 9a is C4 cycloalkyl optionally substituted with 1-2 substituents selected from halo and C1-C6 alkyl. In some embodiments, R 9a is a C4 cycloalkyl optionally substituted with 1-2 substituents selected from F and methyl. In some embodiments, R 9a is C5 cycloalkyl optionally substituted with 1 to 4 substituents selected from C1-C6 alkyl, halo, and C1-C6 haloalkyl. 9a is a C5 cycloalkyl optionally substituted with one substituent -CF3.

[0090] In some embodiments, the present invention relates to a compound of any one of formulas (II) and (III), or a pharmaceutically acceptable salt thereof, wherein R 10a is H, halo, C-C alkyl, C-C haloalkyl, or C-C cycloalkyl optionally substituted with 1 to 4 substituents selected from C-C alkyl, halo, and C-C haloalkyl. 10a is H. In some embodiments, R 10a is C1-C6 alkyl.

[0091] In some embodiments, the present invention relates to a compound of any one of formulas (II) and (III), or a pharmaceutically acceptable salt thereof, wherein R 11a is H, halo, or C-C alkyl. In some embodiments, R11a is H. In some embodiments, R 11a is C1-C6 alkyl. In certain embodiments, the present invention relates to a compound of any one of formulas (II) and (III), or a pharmaceutically acceptable salt thereof, wherein Z1 is 4-10 membered cycloalkyl, 3-10 membered cycloalkenyl, phenyl, or 5-6 membered heteroaryl. In certain embodiments, Z1 is 4-10 membered cycloalkyl.

[0092] In some embodiments, the present invention relates to a compound of any one of Formulas (II) and (III), or a pharmaceutically acceptable salt thereof, wherein Z2 is C1-C6 cycloalkyl or phenyl, wherein the C1-C6 cycloalkyl or phenyl is optionally substituted with 1-4 substituents selected from halo and C1-C6 alkyl. In some embodiments, Z2 is C4 cycloalkyl, wherein the C4 cycloalkyl is optionally substituted with 1-4 substituents selected from halo and C1-C6 alkyl. In some embodiments, Z2 is C4 cycloalkyl, wherein the C4 cycloalkyl is optionally substituted with 1-4 substituents selected from F. In some embodiments, Z2 is cyclohexane, wherein the cyclohexane is optionally substituted with 1-4 substituents selected from F and CF3. In some embodiments, Z2 is phenyl, wherein the phenyl is optionally substituted with 1-4 substituents selected from F and methyl.

[0093] In some embodiments, the present invention relates to a compound of any one of formulas (II) and (III), or any embodiment thereof, i.e., a compound in non-salt form.

[0094] 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 14-1]

Table 14-2

Table 14-3

Table 14-4

Table 14-5

Table 14-6

Table 14-7

Table 14-8

Table 14-9

Table 14-10

Table 14-11

Table 14-12

Table 14-13

Table 14-14

Table 14-15

Table 14-16

Table 14-17

Table 14-18

Table 14-19

Table 14-20

Table 14-21

Table 14-22

Table 14-23

Table 14-24

Table 14-25

Table 14-26

Table 14-27

Table 14-28

Table 14-29

Table 14-30

Table 14-31

Table 14-32

Table 14-33

Table 14-34

Table 14-35

[0095] In some embodiments, the present invention relates to a compound selected from Table B, or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to a compound selected from Table B, i.e., a compound in non-salt form. [Table 15-1]

Table 15-2

Table 15-3

Table 15-4

Table 15-5

Table 15-6

Table 15-7

Table 15-8

Table 15-9

Table 15-10

Table 15-11

Table 15-12

Table 15-13

Table 15-14

Table 15-15

Table 15-16

Table 15-17

Table 15-18

[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. 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. 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. 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.

[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. 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.

[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. 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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. Salts, Compositions, Uses, Formulations, Administration, and Additional Agents Pharmaceutically Acceptable Salts and Compositions

[0151] 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 syndrome, incontinence, pathological cough, or cardiac arrhythmia. Accordingly, in another aspect of the present invention, pharmaceutical compositions are provided, which comprise 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.

[0152] 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.

[0153] 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. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, 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, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, where appropriate.

[0154] 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, surfactants, 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.

[0155] 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.

[0156] 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.

[0157] Uses of the compounds and pharmaceutically acceptable salts and compositions In another aspect, the invention features a method of inhibiting a voltage-gated sodium channel in a subject, the method including 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.

[0158] 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 (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia in a subject, the method comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0159] 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 syndrome, incontinence, or cardiac arrhythmia in a subject, the method comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0160] 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, irritable bowel syndrome, endometriosis, polycystic ovarian disease, salpingitis, cervicitis, 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.

[0161] 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, neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some aspects, neuropathic pain includes 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.

[0162] 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 neuralgia, 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 neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, HIV-induced neuropathy; pain after spinal cord injury, spinal stenosis pain, 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.

[0163] In yet another aspect, the invention features a method for treating or reducing 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 pain.

[0164] In yet another aspect, the invention features a method of treating or lessening the severity of musculoskeletal pain in a subject, including osteoarthritis pain, 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.

[0165] 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, ankylosing spondylitis, 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.

[0166] 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.

[0167] 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.

[0168] In yet another aspect, the invention features a method of treating or lessening the severity of idiopathic pain in a subject, including pain of reflex sympathetic dystrophy, the method comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0169] 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.

[0170] 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-operative pain.

[0171] In yet another aspect, the invention features a method for treating or lessening the severity of post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, hemorrhoidectomy pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain) in a subject, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0172] 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.

[0173] In yet another aspect, the invention features a method for treating or reducing the severity of shoulder arthroplasty pain or shoulder arthroscopy 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.

[0174] In yet another aspect, the invention features a method for treating herniorrhaphy pain or reducing the 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.

[0175] 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.

[0176] 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.

[0177] In yet another aspect, the invention features a method for treating or reducing 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).

[0178] 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.

[0179] 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.

[0180] 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, tension headache, all other headache forms, trigeminal neuralgia, herpes zoster 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 pain, post-herpetic neuropathic pain, and rheumatoid arthritis. pain, 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, post-thoracotomy pain, post-mastectomy 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 lupus erythematosus, 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, chemosis The present invention features a method for treating or lessening the severity in a subject of chemotherapy-induced oral mucositis, Charcot arthropathy, temporomandibular joint disorders, painful knee replacement surgery, non-cardiac chest pain, pudendal neuralgia, renal colic, biliary tract disease, vascular leg ulcers, pain in Parkinson's disease, pain in Alzheimer's disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal motility, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0181] In another aspect, the present invention provides a method for treating femoral cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; splenic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral Nerve injury; painful neuroma; 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), 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 postoperative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tenosynovitis; injury pain; movement pain; acute visceral pain; renal 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; adiposity pain; phlebitis pain; Guillain-Barré syndrome pain; sore legs and moving toes; Haglund's syndrome syndrome; erythromelalgia pain; Fabry disease pain; 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 in a subject, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0182] In another aspect, the invention features a method for 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 plexopathy, 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 plexopathy, traumatic neuroma stump pain, or pain following amputation surgery, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Compounds, Pharmaceutically Acceptable Salts, and Compositions for Use - Patent application

[0183] 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.

[0184] 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.

[0185] 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 syndrome, incontinence, pathological cough, or cardiac arrhythmia.

[0186] 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 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 syndrome, incontinence, or cardiac arrhythmia.

[0187] 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 intestinal pain in a subject, including pain from inflammatory bowel disease, pain from Crohn's disease, pain from irritable bowel syndrome, endometriosis, polycystic ovarian disease, salpingitis, cervicitis, or interstitial cystitis.

[0188] 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, neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some aspects, neuropathic pain includes 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.

[0189] 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 neuralgia, 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 neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, HIV-induced neuropathy; pain after spinal cord injury, pain from spinal stenosis, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic headache.

[0190] 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 pain.

[0191] 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 musculoskeletal pain in a subject, where musculoskeletal pain includes osteoarthritis pain, back pain, cold pain, burn pain, or dental pain.

[0192] 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, ankylosing spondylitis, or vulvodynia.

[0193] 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 inflammatory pain includes rheumatoid arthritis pain.

[0194] 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 idiopathic pain in a subject, wherein the idiopathic pain includes the pain of fibromyalgia.

[0195] In yet 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 idiopathic pain in a subject, wherein the idiopathic pain includes the pain of reflex sympathetic dystrophy.

[0196] 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.

[0197] 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.

[0198] 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 of post-operative pain in a subject (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, hemorrhoidectomy pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain).

[0199] 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.

[0200] In yet 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 shoulder arthroplasty pain or shoulder arthroscopy pain in a subject.

[0201] 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 herniorrhaphy pain in a subject.

[0202] 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.

[0203] 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.

[0204] 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).

[0205] 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.

[0206] 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, the method 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.

[0207] 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, tension headache, all other headache forms, trigeminal neuralgia, herpes zoster 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 of multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, herpes. post-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, post-thoracotomy pain, post-mastectomy 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 cervical 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 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, spinal 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 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.

[0208] In another aspect, the present invention provides a method for treating femoral cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; splenic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; Peripheral nerve injury; painful neuroma; ectopic proximal and distal discharge; radiculopathy; chemotherapy-induced neuropathic pain; radiotherapy-induced neuropathic pain; persistent / chronic postoperative 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 postoperative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tenosynovitis; injury pain; movement pain; acute visceral pain Pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; Caesarean section pain; acute inflammatory pain, burn pain, traumatic pain; acute intermittent pain, endometriosis; acute shingles pain; sickle cell disease; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; toothache; pain in multiple sclerosis (MS); pain in depression; pain in leprosy; pain in Behcet's disease; adiposity; pain in phlebitis; pain in Guillain-Barré syndrome; sore legs and moving toes; 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 Haglund's syndrome; erythromelalgia pain; Fabry's disease pain; bladder and genitourinary disorders; urinary incontinence, pathological cough; overactive bladder; bladder pain syndrome; interstitial cystitis (IC); prostatitis; regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain.

[0209] 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 in a subject of trigeminal neuralgia, migraine treated with Botox, cervical spondylotic radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioinguinal neuralgia, pudendal neuralgia, femoral neuropathy, dysesthesias of the thigh, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain, or pain following amputation surgery. Drug manufacturing

[0210] 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.

[0211] 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.

[0212] 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.

[0213] 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 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 syndrome, incontinence, or cardiac arrhythmia in a subject.

[0214] 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, irritable bowel syndrome, endometriosis, polycystic ovarian disease, salpingitis, cervicitis, or interstitial cystitis pain.

[0215] 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, neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some aspects, neuropathic pain includes diabetic neuropathy (e.g., diabetic peripheral neuropathy).

[0216] 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 neuropathic pain includes post-herpetic neuralgia, diabetic neuralgia, 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 neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, HIV-induced neuropathy; pain after spinal cord injury, pain of spinal stenosis, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal-autonomic neuropathy.

[0217] 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, hi some aspects, the musculoskeletal pain includes osteoarthritis pain.

[0218] 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 pain, back pain, cold pain, burn pain, or dental pain.

[0219] 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, ankylosing spondylitis, or vulvodynia.

[0220] 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.

[0221] 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 the pain of fibromyalgia.

[0222] 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 the pain of reflex sympathetic dystrophy.

[0223] 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.

[0224] 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.

[0225] 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, post-thoracotomy pain, post-mastectomy pain, hemorrhoidectomy pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain).

[0226] 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.

[0227] 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.

[0228] 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 shoulder arthroplasty pain or shoulder arthroscopy pain in a subject.

[0229] 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.

[0230] 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.

[0231] 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).

[0232] 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.

[0233] 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, tension headache, all other headache forms, trigeminal neuralgia, herpes zoster 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 pain, post-herpetic pain. menstrual pain, 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, post-thoracotomy pain, post-mastectomy 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 lupus erythematosus, 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, chemosis and the like. 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 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.

[0234] In another aspect, the present invention provides a method for treating femoral cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; splenic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy. ;Peripheral nerve injury;Painful neuroma;Ectopic proximal and distal discharge;Radiopathy;Chemotherapy-induced neuropathic pain;Radiation therapy-induced neuropathic pain;Persistent / chronic postoperative 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 postoperative pain;Acute musculoskeletal pain;Arthral pain;Mechanical low back pain;Neck pain;Tendonitis;Injury pain;Movement pain;Acute Visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, 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; pain in multiple sclerosis (MS); pain in depression; pain in leprosy; pain in Behcet's disease; adiposity; pain in phlebitis; pain in Guillain-Barré syndrome; painful legs and movements Provided is 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 toes; Haglund's syndrome; erythromelalgia pain; Fabry disease pain; bladder and genitourinary disorders; urinary incontinence, pathological cough; overactive bladder; bladder pain syndrome; interstitial cystitis (IC); prostatitis; regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain.

[0235] 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 treating or reducing the severity of trigeminal neuralgia, migraine treated with Botox, cervical spondylotic radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioinguinal neuralgia, pudendal neuralgia, femoral neuropathy, dysesthesias of the femoral nerve, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain, or pain following amputation surgery. Administration of Compounds, Pharmaceutically Acceptable Salts, and Compositions

[0236] 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.

[0237] 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 species, age, and general condition of the subject, the severity of the condition, the specific drug, its mode of administration, and the like. The compounds, salts, and compositions of the present invention are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, the 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.

[0238] 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 can 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.

[0239] 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.

[0240] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can 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 can 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 non-irritating fixed oil, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables.

[0241] 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.

[0242] 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.

[0243] 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.

[0244] 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.

[0245] 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.

[0246] The active compound or salt may also be in microencapsulated form containing 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.

[0247] 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.

[0248] 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 diseases, conditions, or disorders 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 may also be associated with Na V 1.8-mediated diseases, conditions, or disorders. Thus, in another aspect, the present invention provides a method for treating Na V The present invention provides methods for treating or lessening the severity of a disease, condition, or disorder where activation or overactivity of 1.8 contributes to the disease state.

[0249] 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 / 120808 A9 and U.S. 2014 / 0213616 A1 (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. Additional medications

[0250] 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, anesthetic (spinal injection, nerve blockade), neurosurgery (neurolysis of CNS pathways), neurostimulation (transcutaneous electrical nerve stimulation, dorsal column stimulation), physics (physical therapy, orthotic devices, diathermy), or psychology (cognitive-pulmonary, biofeedback, or behavioral) 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.

[0251] In another embodiment, the additional suitable therapeutic agent is selected from the following: (1) Opioid analgesics, such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, levorphanol, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butaphanol, nalbuphine, pentazocine, or difelikefalin; (2) nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen (intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketorolac (ketorolac tromethamine (e.g., Toradol®)), meclofenamic acid, mefenamic acid, meloxicam, IV meloxicam (e.g., Anjeso®), nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, or zomepirac, (3) Barbiturate sedatives, such as amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, methoherbital, methohexital, pentobarbital, phenobarbital, (4) benzodiazepines with sedative effects, such as chlordiazepoxide, clorazepatate, diazepam, flazepam, lorazepam, oxazepam, temazepam, or triazolam; (5) histamine (H1) antagonists with sedative effects, such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine, or chlorcyclidine; (6) sedatives, such as glutethimide, meprobamate, methaqualone, or dichlorphenazone; (7) Skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphenadrine; (8) NMDA receptor antagonists, such as dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), a combination preparation of morphine and dextromethorphan, topiramate, NR2B antagonists including neramexane or perzinfotel, such as ifenprodil, traxoprodil, or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-l-piperidinyl]-l-hydroxyethyl-3,4-dihydro-2(lH)-quinolinone, (9) alpha-adrenergic agents such as doxazosin, tamsulosin, clonidine, guanfacine, dexmetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinolin-2-yl)-5-(2-pyridyl)quinazoline; (10) Tricyclic antidepressants, such as desipramine, imipramine, amitriptyline, or nortriptyline, (11) anticonvulsants, such as carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®), or valproic acid; (12) Tachykinin (NK) antagonists, in particular 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-[l,4]diazocino[2,lg][l,7]-naphthyridine-6-13-dione (TAK-637), 5-[(2R,3S )-2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-l,2-dihydro-3H-l,2,4-triazol-3-one (MK-869), a precipitating agent, lanepitant, dapitant or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S), (13) Muscarinic antagonists, such as oxybutynin, tolterodine, propiverine, tropium chloride, darifenacin, solifenacin, temiverine, and ipratropium; (14) COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib; (15) Coal tar analgesics, especially paracetamol, (16) Neuroleptics, such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclineltant, Miraxion®, or sarizotan; (17) Vanilloid receptor agonists (e.g., resinferatoxin or siboamide) or antagonists (e.g., capsazepine, GRC-15300), (18) beta-adrenergics, e.g., propranolol; (19) Local anesthetics, such as mexiletine, (20) Corticosteroids, e.g., dexamethasone, (21) 5-HT receptor agonists or antagonists, in particular 5-HT receptor antagonists such as eletriptan, sumatriptan, naratriptan, zolitriptan, or rizatriptan. 1B / 1D agonist, (22)5-HT 2A Receptor antagonists, such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907), (23) Cholinergic (nicotinic) analgesics, such as isoprenicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), or nicotine. (24) Tramadol®, tramadol ER (Ultram ER®), IV tramadol, tapentazole ER (Nucynta®), (25) PDE5 inhibitors, such as 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulfonyl)phenyl]-1-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',l':6,l]-pyrido[3,4-b ]indole-l,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,lf][l,2,4]triazin-4-one (wardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(l-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4, 3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(l-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-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-(l-methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(l-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide, (26) Alpha-2-delta ligands, such as gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methylgabapentin, (1[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)- proline, [(lR,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(l-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(l-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid, and (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid, (27) Cannabinoids, such as KHK-6188, (28) Metabolic glutamate subtype 1 receptor (mGluRl) antagonists, (29) Serotonin reuptake inhibitors, such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ioxetine, cyanodothiepin, ritoxetine, dapoxetine, nefazodone, cericlamine, and trazodone. (30) noradrenaline (norepinephrine) reuptake inhibitors, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, the bupropion metabolite hydroxybupropion, nomifensine, and viloxazine (Vivalan®), in particular selective noradrenaline reuptake inhibitors, such as reboxetine, in particular (S,S)-reboxetine; (31) Dual serotonin-noradrenaline reuptake inhibitors, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran, and imipramine; (32) Inducible nitric oxide synthase (iNOS) inhibitors, such as S-[2-[(l-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(l-iminoethyl)amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(l-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(l-iminoethyl)amino]-5-heptenoic acid, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile; 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5- (1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN-462, or guanidinoethyl disulfide, (33) Acetylcholinesterase inhibitors, for example, donepezil, (34) Prostaglandin E2 subtype 4 (EP4) antagonists, such as N-[({2-[4-(2-ethyl-4,6-dimethyl-lH-imidazo[4,5-c]pyridin-l-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[(15)-l-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid; (35) Leukotriene B4 antagonists, such as l-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870, (36) 5-lipoxygenase inhibitors, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504), (37) Sodium channel blockers, such as lidocaine, lidocaine + tetracaine cream (ZRS-201) or eslicarbazepine acetate, (38)Na V1.7 Blockers, such as XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893 BIIB-074 (bixotrigine), BIIB-095, ASP-1807, DSP-3905, OLP-1002, RQ-00432979, FX-301, DWP-1706, DWP-17061, IMB-110, IMB-111, IMB-112, and WO2011 / 140425 (US2011 / 306607); WO2012 / 106499 (US2012 / 196869); WO2012 / 112743 (US2012 / 245136); WO2012 / 125613 (US2012 / 264749), WO2012 / 116440 (US2014 / 187533), W those disclosed in WO2011026240 (US2012220605), US8883840, US8466188, WO2013 / 109521 (US2015 / 005304), WO2020 / 117626, WO2021 / 252822, WO2021 / 252818, WO2021 / 252820, WO2014 / 201173, WO2012 / 125973, WO2013 / 086229, WO2013 / 134518, WO2014 / 201206, or WO2016 / 141035, and CN111217776 (the entire contents of each application are incorporated herein by reference); (38a)Na V1.7 Blockers, such as (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl)-(4-isopropoxy-3-methyl-phenyl)methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-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, (39)Na V1.8 blockers, such as PF-04531083, PF-06372865, and, for example, WO2008 / 135826 (US2009 / 048306), WO2006 / 011050 (US2008 / 312235), WO2013 / 061205 (US2014 / 296313), US2013 / 0303535, WO2013 / 131018, US8466188, WO2013 / 114250 (US2013 / 274243), WO2 014 / 120808(US2014 / 213616), WO2014 / 120815(US2014 / 228371), WO2014 / 120820(US2014 / 221435), WO2015 / 010065(US 2016 / 0152561), WO2015 / 089361(US2015 / 0166589), WO2019 / 014352(US2019 / 0016671), WO2018 / 213426, WO2020 / 146682 , WO2020 / 146612, WO2020 / 014243, WO2020 / 014246, WO2020 / 092187, WO2020 / 092667(US2020 / 140411), WO2020 / 261114, WO2020 / 140959, WO2020 / 144375, WO2020 / 151728, WO2021 / 032074, WO2021 / 257490, WO / 2021 / 257420, WO2021 / 257418, W those disclosed in WO2022 / 263498, WO2022 / 235558, WO2022 / 235859, CN112390745, CN111808019, CN112225695, CN112457294, CN112300051, CN112300069, CN112441969, CN112479996 (WO2021 / 047622), and CN114591293 (the entire contents of each application are incorporated herein by reference); (39a)Na V1.8 Blockers, such as 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 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]dihydrogen methyl phosphate, 2-(4-fluoro-2-(methyl-d3)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide yl)-4-(trifluoromethyl)benzamide, (4-(2-(4-fluoro-2-(methyl-d3)phenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate, 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-methoxyphenoxy)-N-( 3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-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-fluoro 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-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 4,5-dichloro -2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-Bis(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide amide, 5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3-sulfamoylphenyl)benzamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-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)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzamide, 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, 4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)- 3-(Difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2,3,4-Trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, N-(2-carbamoyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide, 4-[[6-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy) phenoxy]-3-(trifluoromethyl)benzamide, N-(4-carbamoyl-3-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-pentafluoroethyl)benzamide, 4-[[4-(difluoromethoxy)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[4-cyclopropyl-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-5-fluoro-2-[2 -Methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide, 5-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzamide, or 4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, (40)Na V 1.7 and Na V 1.8 Blocker combinations, such as DSP-2230, Lohocla201 or BL-1021, (41) 5-HT3 antagonists, such as ondansetron, (42) TPRV1 receptor agonists, such as capsaicin (NeurogesX®, Qutenza®), and pharmaceutically acceptable salts and solvates thereof; (43) Nicotinic receptor antagonists, for example, varenicline; (44) N-type calcium channel antagonists, such as Z-160; (45) Nerve growth factor antagonists, such as tanezumab; (46) Endopeptidase stimulators, such as senrebotase; (47) Angiotensin II antagonists, for example, EMA-401, (48) Acetaminophen (including but not limited to intravenous acetaminophen (e.g., Ofirmev®)); (49) Bupivacaine (including, but not limited to, bupivacaine liposomal injectable suspension (e.g., Exparel®), bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll), and transdermal bupivacaine (Eladur®)); and (50) Combination of bupivacaine and meloxicam (e.g., HTX-011).

[0252] 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), rufinamide, transdermal bupivacaine (Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561, or ARC-4558.

[0253] 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.

[0254] 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.

[0255] In another embodiment, the additional therapeutic agent is oliceridine or ropivacaine (TLC590).

[0256] In another embodiment, the additional therapeutic agent is Na V 1.7 blockers, such as ST-2427, or ST-2578, and / or 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).

[0257] In another embodiment, the additional therapeutic agent is selected from the group consisting of ASP18071, CC-8464, ANP-230, ANP-231, NOC-100, NTX-1175, ASN008, NW3509, AM-6120, AM-8145, AM-0422, BL-017881, NTM-006, opilanserin (Unafra™), bribolizide, SR419, NRD.E1, LX9211, LY3016859, ISC-17536, NFX-88, LAT-8881, AP-235, NYX 2925, CNTX-6016, S-600918, S-637880, RQ-00434739, KLS-2031, MEDI 7352 or XT-150.

[0258] 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 / ODM-111, ETX-801, OLP-1002, ANP-230 / DSP-2230, iN1011-N17, DSP-3905, or ACD440.

[0259] In another embodiment, the additional therapeutic agent is any of the above-identified Na V 1.7 and Na V and sodium channel inhibitors (also known as sodium channel blockers), such as 1.8 blockers.

[0260] 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 in the compositions of the present disclosure 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.

[0261] 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.

[0262] Another aspect of the present invention is to detect Na in a biological sample or subject. V With 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.

[0263] Na in biological samples VInhibition 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.

[0264] 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 analogous 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). Radiolabeled Analogs of the Compounds of the Invention

[0265] In another aspect, the present invention relates to radiolabeled analogues of the compounds of the present invention.As used herein, the term "radiolabeled analogues of the compounds of the present invention" refers to compounds that are identical to the compounds of the present invention described herein, including all embodiments thereof, except that one or more atoms are replaced with radioactive isotopes of the atoms present in the compounds of the present invention.

[0266] 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, 36Cl, as well as isotopes whose decay modes are identified in VS Shirley & CM Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0267] Radiolabeled analogs can be used in many beneficial ways, including various types of assays such as substrate tissue distribution assays. For example, tritium ( 3 H) labeling and / or carbon-14 ( 14 C) Labeled compounds are particularly useful in various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detectability.

[0268] 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.

[0269] 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.

[0270] 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 compositions thereof, according to any of the embodiments described herein with respect to the compounds of the invention.

[0271] 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.

[0272] 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.

[0273] In another aspect, the radiolabeled analogs, pharmaceutically acceptable salts thereof, 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. [Example]

[0274] Common method. 1 1 H NMR spectra were obtained as solutions in a suitable deuterated solvent such as dimethylsulfoxide-d6 (DMSO-d6).

[0275] Compound purity, retention time, and electrospray mass spectrometry (ESI-MS) data were determined by LC / MS analysis.

[0276] LC / MS Method: LC / MS determinations were performed using one of the following chromatographic conditions: 1) Waters BEH C8 (1.7 μm, 2.1 × 50 mm) 2–98% acetonitrile (10 mM ammonium formate, pH 9) in water at 45 °C with a flow rate of 0.6 mL / min for 5.0 min; 2) Kinetex EVO C18 (2.6 μm, 2.1 × 50 mm) 2–98% acetonitrile (10 mM ammonium formate, pH 9) in water at 45 °C with a flow rate of 0.7 mL / min for 4.0 min; 3) Kinetex EVO C18 (2.6 μm 2.1 × 50 mm) 2–98% acetonitrile (10 mM ammonium formate, pH 9) in water at 45 °C with a flow rate of 1.0 mL / min for 1.5 min; 4) Waters Acquity UPLC BEH C18 (1.7 μm, 30 × 2.1 mm) in water (0 1–99% acetonitrile (0.035% TFA) in water (0.05% TFA), 60°C, flow rate = 1.5 mL / min over 3 min; 6) Kinetex Polar C18 (2.6 μm, 3.0 × 50 mm) 5–95% acetonitrile in water (0.1% formic acid), flow rate = 1.2 mL / min over 6 min; 7) SunFire C18 (3.5 μm, 75 × 4.6 mm) first 5–95% acetonitrile in water (0.1% formic acid) for 1 min, then a linear gradient to 95% acetonitrile for 5 min, 45°C, flow rate = 1.5 mL / min over 6 min; 8) XBridge C18 (5 μm, 4.6 × 75 mm) first gradient 5–95% acetonitrile (NH4HCO3) for 6 min and 1 min, equilibrated gradient at 95% acetonitrile for 0–3 min, hold for 3 min, flow rate = 1.5 mL / min; 9) Waters CSH C18 (1.7 μm, 2.1 × 50 mm) 2–98% acetonitrile in water (0.1% TFA, pH 2) at 45 °C with a flow rate of 0.6 mL / min over 5.0 min; 10) Waters CSH C18 (1.7 μm, 2.1 × 50 mm) 2–95% acetonitrile in water (0.1% formic acid) at 40 °C with a flow rate of 0.8 mL / min over 4.6 min; 11) Waters BEH C18 (2.5 μm, 2.1 × 50 mm) 2–95% acetonitrile in water (0.1% NH3) at 40 °C with a flow rate of 0.8 mL / min over 4.6 min; 13) Waters BEH C18 (3.5 μm, 75 × 4.6 mm) Initial gradient: 5 to 95% acetonitrile in water (0.1% formic acid), followed by a linear gradient to 95% acetonitrile for 4 min, held at 95% acetonitrile for 2 min, 45 °C, 1.5 mL / min flow rate over 6 min; 14) Waters BEH C18 (2.5 μm, 2.1 × 50 mm) 2 to 50% acetonitrile in water (0.1% NH3) at 40 °C, 0.8 mL / min flow rate over 4.6 min; 15) Waters CSH C18 (1.7 μm, 2.1 × 50 mm) 2 to 98% acetonitrile in water (0.1% TFA) at 45 °C, 1.0 mL / min flow rate over 1.5 min; 16) Waters CSH C18 (1.7 μm, 2.1 × 50 mm) 2–95% acetonitrile in water (0.1% formic acid) at 40 °C, flow rate of 0.8 mL / min over 1.4 min; 17) YMC Triart C18 (3 μm, 33 × 2.1 mm) 2–98% acetonitrile in water (5 mM NH4OAc) at 1.0 mL / min over 3 min; 18) Waters BEH C18 (2.5 μm, 2.1 × 50 mm) 2–95% acetonitrile in water (0.1% NH3) at 40 °C, flow rate of 0.8 mL / min over 1.4 min; 19) Waters Acquity UPLC BEH C18 (1.7 μm, 30 × 2.1 mm) 1–99% acetonitrile in water (0.035% TFA) at 40 °C. TFA), 60 °C, flow rate = 1.5 mL / min for 5 min; 20) Waters BEH C18 (2.5 μm, 2.1 × 50 mm) 20–70% acetonitrile in water (0.1% NH3), 40 °C, flow rate = 0.8 mL / min for 4.60 min; 21) Kinetex Polar C18 (2.6 μm, 3.0 × 50 mm) 5–95% acetonitrile in water (0.1% formic acid), flow rate = 1.2 mL / min for 3 min; 22) Waters Acquity UPLC BEH C18 column (1.7 μm, 30 × 2.1 mm) 1–99% acetonitrile (0.035% TFA) in water (0.05% TFA), 60 °C, flow rate = 1.5 mL / min for 1 min; 23) YMC Triart C18 (3 μm, 33 × 2.1 mm) 2 to 98% acetonitrile in water (0.05% formic acid), 1.0 mL / min flow rate over 3 min; 24) Waters Acquity UPLC BEH C18 (1.7 μm, 30 × 2.1 mm) 1–99% acetonitrile (0.05% ammonium formate) in water (0.05% ammonium formate), 60 °C, flow rate = 1.5 mL / min for 5 min; 25) Waters CSH C18 (1.7 μm, 2.1 × 50 mm) 2–98% acetonitrile in water (0.1% TFA), 45 °C, flow rate = 0.6 mL / min for 4.0 min; 26) Acquity BEH C8 (1.7 μm, 50 × 2.1 mm) 2–98% 90:10 acetonitrile:water (0.05% formic acid), flow rate = 0.8 mL / min for 3 min; 27) XBridge C18 (5 μm, 50 × 4.6 mm) 10–90% acetonitrile in water (10 mM NH4OAc), flow rate = 1.2 mL / min for 6 min; 28) YMC Triart C18 (3 μm, 33 × 2.1 mm) 5–95% acetonitrile in water (0.05% formic acid), 1.0 mL / min flow rate over 12 min; 29) Waters BEH C8 (1.7 μm, 2.1 × 50 mm) 50–95% acetonitrile in water (0.1% NH3), 40 °C, 0.8 mL / min flow rate over 1.4 min.

[0277] Abbreviation Unless otherwise specified, or where the context dictates otherwise, the following abbreviations shall be understood to have the following meanings: [Table 16-1] [Table 16-2]

[0278] Example 1 Intermediate A-1 [ka]

[0279] Step 1: 4-benzyloxy-2-chloro-1,6-naphthyridine To a mixture of 2,4-dichloro-1,6-naphthyridine (1.0 g, 4.9 mmol) and benzyl alcohol (0.5 mL, 4.8 mmol) in DMF (10 mL) and 2-MeTHF (10 mL) was added sodium hydride (60% in mineral oil, 208 mg, 5.20 mmol) in portions at 0° C. The reaction mixture was stirred at 0° C. for 1 hour, then gradually warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into a stirred mixture of 0.1 M aqueous HCl (50 mL) and 2-MeTHF (50 mL). The layers were separated, and the aqueous layer was extracted with 2-MeTHF (2×100 mL). The combined organic layers were washed with water (2×50 mL), 1:1 water / brine (50 mL), and brine (50 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. Purification by silica gel chromatography (0-35% ethyl acetate / heptane) gave 4-benzyloxy-2-chloro-1,6-naphthyridine (528 mg, 38%) as an off-white solid. ESI-MS m / z calculated 270.06, found 271.1 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 9.58(s,1H),8.78(d,J=5.9Hz,1H),7.75(dd,J=5.9,0.6Hz,1H),7.54-7.37(m,5H),6.92(s,1H),5.34(s,2H).

[0280] Step 2: 4-benzyloxy-2-chloro-6-oxide-1,6-naphthyridin-6-ium To a solution of 4-benzyloxy-2-chloro-1,6-naphthyridine (1.75 g, 6.46 mmol) in DCM (14 mL) was added mCPBA (1.6 g, 7.14 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 18 h and then diluted with 2 M aqueous sodium carbonate (60 mL) and water (90 mL). The aqueous layer was extracted with additional DCM (3 × 100 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 4-benzyloxy-2-chloro-6-oxide-1,6-naphthyridin-6-ium (1.796 g, 97%) as an off-white solid. ESI-MS m / z calculated 286.05, found 287.1 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 9.02-8.94(m,1H),8.30(dd,J=7.3,2.1Hz,1H),7.79-7.72(m,1H),7.44(d,J=2.6Hz,5H),6.93(s,1H),5.29(s,2H).

[0281] Step 3: 4-benzyloxy-2-chloro-1,6-naphthyridine-5-carbonitrile To a solution of 4-benzyloxy-2-chloro-6-oxide-1,6-naphthyridin-6-ium (1.0 g, 3.5 mmol) in DCM (10 mL) under a nitrogen atmosphere was added trimethylsilylformonitrile (1.3 mL, 9.8 mmol), followed by TEA (1.25 mL, 8.97 mmol). The reaction mixture was stirred at room temperature for 20 h. The mixture was quenched with water, and the aqueous layer was extracted with DCM (3×). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (0–30% ethyl acetate / DCM) gave 4-benzyloxy-2-chloro-1,6-naphthyridine-5-carbonitrile (840 mg, 81%). ESI-MS m / z calculated: 295.05, found: 296.1 (M+1). + . 1H NMR(400MHz,DMSO-d6)δ 8.91(d,J=5.7Hz,1H),8.12(d,J=5.7Hz,1H),7.67-7.58(m,3H),7.50-7.34(m,3H),5.61(s,2H).

[0282] Intermediate A-2 [ka]

[0283] Step 1: 8-benzyloxy-6-chloro-1-oxide-1,5-naphthyridin-1-ium 8-Benzyloxy-6-chloro-1-oxide-1,5-naphthyridin-1-ium was prepared from 4-benzyloxy-2-chloro-1,5-naphthyridine (Intermediate A-31) using a procedure similar to that found in Intermediate A-4, Step 2. ESI-MS m / z calculated 286.05, found 287.1 (M+1). + ;Holding time: 1.62 minutes.

[0284] Step 2: 8-benzyloxy-6-chloro-1,5-naphthyridine-2-carbonitrile 8-Benzyloxy-6-chloro-1,5-naphthyridine-2-carbonitrile was prepared from 8-benzyloxy-6-chloro-1-oxide-1,5-naphthyridin-1-ium using a procedure similar to that found in Intermediate A-4, Step 3. 1 H NMR(400MHz,DMSO-d6)δ 8.55(d,J=8.6Hz,1H),8.34(d,J=8.7Hz,1H),7.63(s,1H),7.60-7.53(m,2H),7.51-7.39(m,3H),5.50(s,2H).ESI-MS m / z calc.295.05, actual value 296.1(M+1) + .

[0285] Intermediate A-3 Step 1: 4-benzyloxy-2-chloro-quinolin-5-ol [ka]

[0286] A mixture of 4-benzyloxy-2-chloro-5-methoxy-quinoline (100 mg, 0.334 mmol), hydrogen bromide (2.0 mL of 48% w / v, 11.7 mmol), and sodium iodide (50 mg, 0.33 mmol) was heated to 90 °C for 18 h. Purification by reverse-phase chromatography (1 to 100% CHCN / water) gave 4-benzyloxy-2-chloro-quinolin-5-ol (14 mg, 15%). ESI-MS m / z calculated 285.06, found 286.05 (M+1). + .

[0287] Intermediate A-4 Step 1: 4-benzyloxy-2-chloro-quinoline [ka]

[0288] Sodium hydride (16 mg, 0.68 mmol) was added portionwise to 2-chloroquinolin-4-ol (102 mg, 0.570 mmol) in DMF (1 mL) at 0 °C under a nitrogen atmosphere. The mixture was stirred at room temperature for 10 minutes, cooled again to 0 °C, and benzyl bromide (75 μL, 0.63 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours and then partitioned between brine (20 mL) and ethyl acetate (30 mL). The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (1-100% ethyl acetate / hexanes) afforded 4-benzyloxy-2-chloro-quinoline (139 mg, 90%) as a white solid. ESI-MS m / z calculated 269.06, found 270.11 (M+1). + .

[0289] Intermediate A-5 [ka]

[0290] Step 1: Ethyl 4-chloro-1-oxide-quinolin-1-ium-3-carboxylate Ethyl 4-chloro-1-oxide-quinolin-1-ium-3-carboxylate was prepared from ethyl 4-chloroquinoline-3-carboxylate using a procedure similar to that found in Intermediate A-4, Step 2, using chloroform as the solvent. 1 H NMR(300MHz,CDCl3)δ 8.95(s,1H),8.80(d,J=8.5Hz,1H),8.52-8.42(m,1H),7.97-7.89(m,1H),7.88-7.80(m,1H),4.49(q,J=7.1Hz,2H),1.46(t,J=7.2Hz,3H).ESI-MS m / z calc.251.03, actual value 252.1(M+1) + .

[0291] Step 2: Ethyl 2-bromo-4-chloro-quinoline-3-carboxylate POBr3 (1.20 g, 3.98 mmol) was added to a solution of ethyl 4-chloro-1-oxide-quinoline-3-carboxylate (1.0 g, 3.5 mmol) in chloroform (15 mL). The reaction mixture was stirred at room temperature for 2 hours. Ice water (30 mL) was added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with DCM (2 × 25 mL), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 1.17 g of an orange solid. The crude product was adsorbed onto silica gel in vacuo and purified by silica gel chromatography (0–10% ethyl acetate / heptane) to give ethyl 2-bromo-4-chloro-quinoline-3-carboxylate (771 mg, 69%) as a white solid. 1 H NMR(300MHz,CDCl3)δ 8.24(dd,J=8.4,1.3Hz,1H),8.08(d,J=8.5Hz,1H),7.90-7.80(m,1H),7.76-7.68(m,1H),4.55(q,J=7.1Hz,2H),1.48(t,J=7.2Hz,3H).ESI-MS m / z Calculated value .312.95, Actual value 314.0(M+1)+ .

[0292] Step 3: Ethyl 4-benzyloxy-2-bromo-quinoline-3-carboxylate Ethyl 4-benzyloxy-2-bromo-quinoline-3-carboxylate was prepared from ethyl 2-bromo-4-chloro-quinoline-3-carboxylate using a procedure similar to that found in Intermediate A-1, Step 1, using DMF as solvent. ESI-MS m / z calculated 385.03, found 386.0 (M+1). + .

[0293] Intermediate A-6 [ka]

[0294] Step 1: Methyl 3-[(3-ethoxy-3-oxo-propanoyl)amino]pyridine-2-carboxylate To methyl 3-aminopyridine-2-carboxylate (20.0 g, 132 mmol) in DCM (200 mL) was added ethyl 3-chloro-3-oxopropanoate (19.8 g, 132 mmol). The reaction was stirred under reflux for 45 minutes and then cooled to room temperature over 20 minutes. DCM (600 mL) was added, and the organic solution was washed with saturated aqueous sodium bicarbonate (600 mL) and brine (400 mL), dried over magnesium sulfate, filtered, and concentrated to give methyl 3-[(3-ethoxy-3-oxopropanoyl)amino]pyridine-2-carboxylate (26.16 g, 72%) as a white solid. 1 H NMR(400MHz,CDCl3)δ 11.53(s,1H),9.11(d,1H,J=8.6Hz),8.46(d,1H,J=2.3Hz),7.52(m,1H),4.32-4.27(m ,2H),4.06(d,3H,J=1.8Hz),3.57(d,2H,J=1.1Hz),1.33(td,3H,J=7.1,1.8Hz).ESI-MS m / z calculated value .266.09, actual value 267.0(M+1) + .

[0295] Step 2: Ethyl 4-hydroxy-2-oxo-1H-1,5-naphthyridine-3-carboxylate To a solution of methyl 3-[(3-ethoxy-3-oxo-propanoyl)amino]pyridine-2-carboxylate (24.16 g, 87.65 mmol) in ethanol (240 mL) under argon at 5° C. was added sodium ethoxide (12.9 g, 190 mmol) in ethanol (120 mL) over 5 minutes. The reaction was stirred at room temperature for 1 hour, then cooled to 0° C. and adjusted to pH 7 using 4 M HCl. The solution was concentrated under reduced pressure to give crude ethyl 4-hydroxy-2-oxo-1H-1,5-naphthyridine-3-carboxylate (30.15 g, 147%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 10.96(s,1H),8.34(d,1H,J=3.4Hz),7.66-7.64(m,1H),7.51(dd,1H,J=8.3,4.4Hz),4.17(q,2H,J=7.1Hz),1.23(t,3H,J=7.1Hz).ESI-MS m / z Calculated value .234.06, Actual value 234.9(M+1) + .

[0296] Step 3: Ethyl 2,4-dichloro-1,5-naphthyridine-3-carboxylate To phosphorus oxychloride (33.5 g, 17 mL, 218 mmol) was added ethyl 4-hydroxy-2-oxo-1H-1,5-naphthyridine-3-carboxylate (1.75 g, 7.47 mmol). The reaction was heated at 120° C. for 16 hours. The reaction was allowed to cool to room temperature over 1 hour and then concentrated under reduced pressure. The residue was azeotroped using toluene (2×50 mL). The solid was added to ice water (100 mL) and neutralized with sodium carbonate. The aqueous mixture was extracted with DCM (2×50 mL). The organics were combined, washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure. Purification by silica gel chromatography (0–20% ethyl acetate / heptane) gave ethyl 2,4-dichloro-1,5-naphthyridine-3-carboxylate (1.05 g, 51%). 1 H NMR(400MHz,CDCl3)δ 9.14(dd,1H,J=4.2,1.6Hz),8.39(dd,1H,J=8.6,1.6Hz),7.81(dd,1H,J=8.5,4.2Hz),4.59(q,2H,J=7.1Hz),1.50(t,3H,J=7.2Hz).ESI-MS m / z Calculated value .270.00, Actual value 270.88(M+1) + .

[0297] Step 4: Ethyl 4-benzyloxy-2-chloro-1,5-naphthyridine-3-carboxylate Ethyl 4-benzyloxy-2-chloro-1,5-naphthyridine-3-carboxylate was prepared from ethyl 2,4-dichloro-1,5-naphthyridine-3-carboxylate using a procedure similar to that found in Intermediate A-1, Step 1. 1 H NMR(400MHz,CDCl3)δ 8.99(dd,1H,J=4.1,1.7Hz),8.32(dd,1H,J=8.6,1.7Hz),7.71(dd,1H,J=8.6,4.0Hz),7.50-7. 48(m,2H),7.41-7.33(m,3H),6.01(s,2H),4.42(q,2H,J=7.2Hz),1.34(t,3H,J=7.1Hz).ESI-MS m / z calculated value .342.08, actual value 343.0(M+1) + .

[0298] Intermediate A-7 [ka]

[0299] Step 1: 2-chloro-4-[(4-methoxyphenyl)methoxy]-1,6-naphthyridine To a mixture of 2,4-dichloro-1,6-naphthyridine (3.29 g, 16.5 mmol) and (4-methoxyphenyl)methanol (2.28 g, 2.05 mL, 16.47 mmol) in DMF (33 mL) and 2-MeTHF (33 mL) at 0° C. was added sodium hydride (715 mg, 60% in mineral oil, 17.88 mmol) in portions. The mixture was stirred at 0° C. for 1 h, then gradually warmed to room temperature and stirred for 19.5 h. The mixture was poured into a stirred mixture of 0.1 M aqueous HCl (100 mL) and 2-MeTHF (100 mL). The layers were separated, and the aqueous layer was extracted with additional 2-MeTHF (2 × 100 mL). The organic layers were combined and washed with water (2 × 50 mL), 1:1 water / brine (50 mL), and brine (50 mL). The solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (5 to 100% ethyl acetate / heptane) gave 2-chloro-4-[(4-methoxyphenoxy)methoxy]-1,6-naphthyridine (1.95 g, 39%) as a pale yellow solid. ESI-MS m / z calculated 300.06, found 301.2 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 9.44(s,1H),8.74(d,J=5.9Hz,1H),7.72-7.67(m,1H),7.48-7.42(m,2H),7.09(s,1H),6.97-6.88(m,2H),5.50(s,2H),3.83(s,3H).ESI-MS m / z Calculated value .300.06, Actual value 301.2(M+1) + .

[0300] Step 2: 2-chloro-4-[(4-methoxyphenyl)methoxy]-6-oxido-1,6-naphthyridin-6-ium A solution of 2-chloro-4-[(4-methoxyphenoxy)methyl]-1,6-naphthyridine (5.0 g, 16.6 mmol) in DCM (100 mL) was cooled to 0 °C and treated with solid 3-chlorobenzenecarboperoxoic acid (4.7 g, 21 mmol). The reaction was warmed to room temperature and stirred for 4 h. The mixture was quenched with saturated aqueous sodium bicarbonate (100 mL) and the layers were separated. The aqueous layer was extracted with additional DCM (3 × 25 mL). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 2-chloro-4-[(4-methoxyphenyl)methoxy]-6-oxide-1,6-naphthyridin-6-ium (5.1 g, 97%). ESI-MS m / z calculated 316.06, found 317.2 (M+1). + . 1 H NMR(400MHz,DMSO-d6)δ 8.66(d,J=2.1Hz,1H),8.40(dd,J=7.3,2.1Hz,1H),7.86(d,J=7.3Hz,1H),7 .53-7.47(m,2H),7.41(s,1H),7.05-6.95(m,2H),5.39(s,2H),3.78(s,3H).

[0301] Step 3: 2-chloro-4-[(4-methoxyphenyl)methoxy]-1,6-naphthyridine-5-carbonitrile To a solution of 2-chloro-4-[(4-methoxyphenyl)methoxy]-6-oxide-1,6-naphthyridin-6-ium (6.1 g, 19.3 mmol) in DCM (50 mL) under a nitrogen atmosphere was added trimethylsilyl cyanide (6.8 mL, 51 mmol), followed by TEA (8 mL, 57.4 mmol). The mixture was stirred for 20 h at room temperature. The reaction was quenched with water, and the aqueous layer was extracted with DCM (3×). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (0–100% ethyl acetate / DCM) gave 2-chloro-4-[(4-methoxyphenyl)methoxy]-1,6-naphthyridine-5-carbonitrile (5.5 g, 88%). 1 H NMR(400MHz,DMSO-d6)δ 8.90(d,J=5.8Hz,1H),8.11(d,J=5.7Hz,1H),7.61(s,1H),7.60-7.52(m,2H),7.03-6.95(m,2H),5.52(s,2H),3.77(s,3H).

[0302] Intermediate A-8 [ka]

[0303] Step 1: 4-Chloro-1-oxide-quinolin-1-ium-5-carbonitrile A mixture of 4-chloroquinoline-5-carbonitrile (840 mg, 4.45 mmol) and m-CPBA (1.36 g, 5.52 mmol) in DCM (12 mL) was stirred at room temperature for 2 h. The mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM (3×). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give 4-chloro-1-oxide-quinolin-1-ium-5-carbonitrile (910 mg, 100%). ESI-MS m / z calculated 204.01, found 205.0 (M+1). + .

[0304] Step 2: 2,4-Dichloroquinoline-5-carbonitrile A vial charged with 4-chloro-1-oxide-quinolin-1-ium-5-carbonitrile (900 mg, 4.40 mmol) and POCl3 (4.0 mL, 42.9 mmol) was heated at 50 °C for 4 h. The mixture was cooled to room temperature and poured onto ice. The resulting precipitate was filtered and washed with water. The solid was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution (2x). The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (0-20% ethyl acetate / hexanes) gave 2,4-dichloroquinoline-5-carbonitrile (680 mg, 69%). ESI-MS m / z calculated 221.97, found 223.0 (M+1). + .

[0305] Step 3: 4-benzyloxy-2-chloro-quinoline-5-carbonitrile To a solution of benzyl alcohol (232 μL, 2.24 mmol) in DMF (10 mL) at 0° C. was added sodium hydride (98 mg of 60% w / w, 2.45 mmol), and the mixture was warmed to room temperature and stirred for 30 min. The mixture was then cooled to −40° C., and 2,4-dichloroquinoline-5-carbonitrile (500 mg, 2.24 mmol) was added. The mixture was warmed to room temperature and stirred overnight. The mixture was cooled to 0° C., quenched with water, and extracted with ethyl acetate (3×). The organic phase was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (0–30% ethyl acetate / hexanes) afforded 4-benzyloxy-2-chloro-quinoline-5-carbonitrile (410 mg, 62%) as an off-white solid. ESI-MS m / z calculated: 294.05, observed: 295.6 (M+1) + . 1 H NMR ((400 MHz, DMSO-d6) δ (ppm) 8.23-8.15 (m, 2H), 7.92 (dd, J = 8.5, 7.4 Hz, 1H), 7.67-7.57 (m, 2H), 7.48 (s, 1H), 7.46-7.32 (m, 3H), 5.56 (s, 2H). The regioisomeric 2-benzyloxy-4-chloro-quinoline-5-carbonitrile was also isolated. ESI-MS m / z calculated 294.06, found 295.1 (M+1). + . 1 H NMR ( 400MHz,DMSO-d6)δ 8.17(m,2H),7.90(dd,J=8.4,7.4Hz,1H),7.58(s,1H),7.55-7.50(m,2H),7.44-7.32(m,3H),5.53(s,2H).

[0306] General scheme for the preparation of intermediate A [ka]

[0307] The intermediates in Table 1 were prepared using the corresponding dichloro-pyridines or -pyrimidines and procedures similar to those found in Intermediate A-1, Step 1. The dichloro-pyridines or -pyrimidines were obtained from commercial sources. Benzyl alcohol or substituted benzyl alcohols, such as 2-methoxybenzyl alcohol, can be used. DMF, THF, 2-MeTHF, or a mixture of these solvents can be used as the reaction solvent. [Table 1-1] [Table 1-2]

[0308] Intermediate B-1 [ka]

[0309] Step 1: 3-Bromo-2-(3,4-difluoro-2-methyl-phenoxy)quinoline To a mixture of 3-bromo-2-fluoro-quinoline (500 mg, 2.21 mmol) and 3,4-difluoro-2-methyl-phenol (478 mg, 3.32 mmol) in DMSO (12 mL) was added cesium carbonate (1.8 g, 5.5 mmol). The resulting mixture was stirred at 55 °C for 4 hours. The reaction was cooled to room temperature, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification using silica gel chromatography (0-20% ethyl acetate / hexanes) afforded 3-bromo-2-(3,4-difluoro-2-methyl-phenoxy)quinoline (596 mg, 77%). 1 H NMR(400MHz,DMSO-d6)δ 8.89(s,1H),7.95(dd,J=8.1,1.4Hz,1H),7.69(ddd,J=8.4,6.9,1.5Hz,1H),7.60(dd,J=8.1,1.0Hz,1H),7.5 4(ddd,J=8.1,6.8,1.3Hz,1H),7.40(m,1H),7.17(ddd,J=9.1,4.4,2.1Hz,1H),2.07(d,J=2.2Hz,3H).ESI-MS m / z calc.348.99,found 350.0(M+1) + .

[0310] Step 2: [2-(3,4-Difluoro-2-methyl-phenoxy)-3-quinolyl]boronic acid A solution of 3-bromo-2-(3,4-difluoro-2-methyl-phenoxy)quinoline (600 mg, 1.71 mmol) in THF (4 mL) was treated dropwise with n-BuLi (750 μL of 2.5 M in hexanes, 1.9 mmol) at −78° C. The reaction mixture was stirred for 30 minutes and then treated dropwise with triisopropyl borate (550 μL, 2.40 mmol). The mixture was stirred at −78° C. for 30 minutes, then removed from the cooling bath and quenched with saturated aqueous NH4Cl. The mixture was diluted with diethyl ether and the layers separated. The aqueous layer was extracted with additional diethyl ether (3×), and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give [2-(3,4-difluoro-2-methyl-phenoxy)-3-quinolyl]boronic acid (505 mg, 94%). ESI-MS m / z calculated: 315.09, observed: 316.2 (M+1) + . 1 H NMR(400MHz,DMSO-d6)δ 8.51(d,J=4.8Hz,1H),8.36(s,2H),7.94(dd,J=8.1,1.5Hz,1H),7.66-7.57(m,1H),7.54(d,J=8.7Hz ,1H),7.46(ddd,J=8.1,6.8,1.4Hz,1H),7.41-7.28(m,1H),7.13(m,1H),2.06(dd,J=5.4,2.3Hz,3H).

[0311] Intermediate B-2 [ka]

[0312] Step 1: 3-Bromo-4,5-dimethyl-pyridin-2-ol To a solution of 4,5-dimethylpyridin-2-ol (2.0 g, 16 mmol) in acetic acid (20 mL) was added bromide (2.8 g, 0.9 mL, 17.5 mmol). The reaction mixture was stirred at room temperature for 90 hours. It was poured into stirred 20% aqueous potassium carbonate solution (250 mL) and then diluted with water (50 mL). The crushed solid was collected by Buchner filtration and dried in vacuo to give 3-bromo-4,5-dimethyl-pyridin-2-ol (2.79 g, 82%) as a white solid. 1 H NMR(400MHz,CDCl3)δ 13.45(br.s,1H),7.21(s,1H),2.36(s,3H),2.10(s,3H).ESI-MS m / z calc.200.98,Actual value 202.1(M+1) + .

[0313] Step 2: 3-Bromo-2-chloro-4,5-dimethyl-pyridine A solution of 3-bromo-4,5-dimethyl-pyridin-2-ol (6.5 g, 29 mmol) in POCl3 (52.6 g, 32 mL, 343 mmol) was stirred at 110 °C for 30 h. Phosphorus oxychloride was removed under reduced pressure. The residue was dissolved in DCM (100 mL) and then poured into stirred saturated aqueous sodium bicarbonate (400 mL). The layers were separated and the aqueous layer was extracted with DCM (2 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was adsorbed onto silica gel in vacuo and purified by silica gel chromatography (120 g silica, 0–10% ethyl acetate / heptane) to afford 3-bromo-2-chloro-4,5-dimethyl-pyridine (6.06 g, 94%) as a white solid. 1 H NMR(400MHz,CDCl3)δ 8.05(s,1H),2.43(s,3H),2.29(s,3H).ESI-MS m / z calc.218.95,Actual value 220.0(M+1) + .

[0314] Step 3: 3-Bromo-2-(4-fluoro-2-methyl-phenoxy)-4,5-dimethyl-pyridine 3-Bromo-2-(4-fluoro-2-methyl-phenoxy)-4,5-dimethyl-pyridine was prepared from 3-bromo-2-chloro-4,5-dimethyl-pyridine and 4-fluoro-2-methyl-phenol using a procedure similar to that found in Intermediate B-1, Step 1. 1 H NMR(400MHz,CDCl3)δ 7.74(s,1H),7.01(dd,J=8.7,5.0Hz,1H),6.96(dd,J=9.0,2.9Hz,1H),6.94-6.88(m,1H),2.43(s,3H),2.23(s,3H),2.14(s,3H).ESI-MS m / z Calculated value .309.02, Actual value 310.1(M+1) + .

[0315] Step 4: 2-(4-Fluoro-2-methyl-phenoxy)-4,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine A mixture of 3-bromo-2-(4-fluoro-2-methyl-phenoxy)-4,5-dimethyl-pyridine (2.05 g, 6.60 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.3 g, 13 mmol), potassium acetate (1.9 g, 19.4 mmol), and Pd(dppf)Cl.DCM (430 mg, 0.527 mmol) in DMSO (30 mL) was stirred at 110 °C for 4 hours. The reaction mixture was cooled to room temperature and partitioned between water (100 mL) and MTBE (500 mL). The biphasic mixture was filtered through Celite®, and the layers were separated. The organic layer was washed with water (4x) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was adsorbed onto silica gel in vacuo and purified by silica chromatography (120 g silica, 0-10% ethyl acetate / heptane) to give 1.4 g of material. The solid was triturated with pentane (5 mL), filtered, and the solid was dried in vacuo to give 2-(4-fluoro-2-methyl-phenoxy)-4,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (749 mg, 31%) as a white solid. ESI-MS m / z calculated 357.19, found 358.2 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 7.81(s,1H),7.00(dd,J=8.8,5.1Hz,1H),6.92(dd,J=9.2,2.8Hz,1H),6.90-6.83(m,1H),2.31(s,3H),2.16(s,3H),2.13(s,3H),1.38(s,12H). 19 F NMR(377MHz,CDCl3)δ-119.47--119.80(m,1F).

[0316] Intermediate B-3 [ka]

[0317] Step 1: 3-Bromo-2-chloro-5,6-dimethyl-pyridine A solution of 3-bromo-5,6-dimethyl-pyridin-2-ol (2.0 g, 9.9 mmol) in POCl3 (17.2 g, 10.5 mL, 112 mmol) was purged with nitrogen for 10 minutes and then heated at 110 °C for 30 hours. Phosphorus oxychloride was removed under reduced pressure. The residue was dissolved in DCM (50 mL) and poured into stirred saturated aqueous sodium bicarbonate solution (150 mL). The layers were separated and the aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude gray residue. The crude residue was purified by silica gel chromatography (40 g silica, 0–15% ethyl acetate / heptane) to give 3-bromo-2-chloro-5,6-dimethyl-pyridine (2.11 g, 97%) as a white solid. ESI-MS m / z calculated: 218.95, observed: 220.0 (M+1) + . 1 H NMR(400MHz,CDCl3)δ 7.66(s,1H),2.44(s,3H),2.26(s,3H).

[0318] Step 2: 3-Bromo-2-(4-fluoro-2-methyl-phenoxy)-5,6-dimethyl-pyridine 3-Bromo-2-(4-fluoro-2-methyl-phenoxy)-5,6-dimethyl-pyridine was prepared from 3-bromo-2-chloro-5,6-dimethyl-pyridine and 4-fluoro-2-methyl-phenol using a procedure similar to that found in Intermediate B-1, Step 1. ESI-MS m / z calculated 309.02, found 310.2 (M+1). + . 1 H NMR ( 400MHz, CDCl3)δ 7.64(s,1H),6.99(dd,J=8.9,5.1Hz,1H),6.95(dd,J=9.0,3.1Hz,1H),6.91-6.85(m,1H),2.23(s,3H),2.21(s,3H),2.18(s,3H).

[0319] Step 3: [2-(4-fluoro-2-methyl-phenoxy)-5,6-dimethyl-3-pyridyl]boronic acid To a solution of 3-bromo-2-(4-fluoro-2-methyl-phenoxy)-5,6-dimethyl-pyridine (160 mg, 0.490 mmol) in diethyl ether (2.4 mL) at −78° C. under a nitrogen atmosphere, a solution of n-BuLi in hexane (210 μL of 2.5 M, 0.53 mmol) was slowly added. The mixture was then stirred at this temperature for 1 hour, after which a solution of trimethylborate (93 mg, 100 μL, 0.90 mmol) in diethyl ether (0.8 mL) was added dropwise. The resulting reaction mixture was allowed to warm to room temperature (1.5 hours) and stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (4 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3×8 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue. Purification by reverse-phase chromatography (C18, 5-100% CHCN / 0.1% formic acid) gave [2-(4-fluoro-2-methyl-phenoxy)-5,6-dimethyl-3-pyridyl]boronic acid (98 mg, 72%) as a white solid. ESI-MS m / z calculated 275.11, found 276.1 (M+1). + . 1 H NMR ( 400MHz,CD3OD)δ 7.54(s,1H),6.99(d,J=8.8Hz,1H),6.89-6.86(m,2H),2.28(s,3H),2.24(s,3H),2.16(s,3H).

[0320] Intermediate B-4 [ka]

[0321] Step 1: 4-tert-butyl-2-methyl-aniline To a solution of 2-bromo-4-tert-butyl-aniline (25 g, 110 mmol) in dioxane (750 mL) and water (85 mL) was added methylboronic acid (32.8 g, 548 mmol), tricyclohexylphosphine (6.3 g, 22.5 mmol), and potassium phosphate (70 g, 330 mmol). Nitrogen was bubbled through the mixture for 5 minutes, and then palladium acetate (2.5 g, 11 mmol) was added. The mixture was heated at 110° C. for 18 hours. The crude product was filtered over Celite® and washed with dichloromethane (300 mL). The filtrate was washed with brine (2×200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (330 g silica, 0-30% ethyl acetate / heptane) gave 4-tert-butyl-2-methyl-aniline (16.9 g, 94%) as a dark oil. ESI-MS m / z calculated 163.14, found 164.2 (M+1). + . 1 H NMR ( 400MHz, CDCl3)δ 7.12-7.05(m,2H),6.66(d,J=7.8Hz,1H),3.52(br s,2H),2.21(s,3H),1.31(s,9H).

[0322] Step 2: 2-Bromo-4-tert-butyl-6-methyl-aniline N-Bromosuccinimide (20.5 g, 115 mmol) was slowly added to a cooled (-30 °C) solution of 4-tert-butyl-2-methyl-aniline (19.57 g, 119.9 mmol) in dichloromethane (1.2 L). The reaction mixture was stirred at -30 °C for 3 h, and then the reaction was quenched with water (700 mL). After warming to room temperature, the organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to give crude 2-bromo-4-tert-butyl-6-methyl-aniline (29.14 g, 96%) as a dark oil. The crude product was used in the next step without further purification. ESI-MS m / z calculated 241.05, found 242.1 (M+1). + . 1 H NMR (400MHz, CDCl3)δ 7.32(d,J=2.2Hz,1H),7.06-7.02(m,1H),4.05-3.89(m,2H),2.24(s,3H),1.29(s,9H).

[0323] Step 3: N-(2-bromo-4-tert-butyl-6-methyl-phenyl)-2,2,2-trifluoro-acetamide Trifluoroacetic anhydride (20 mL, 144 mmol) was added dropwise to a solution of 2-bromo-4-tert-butyl-6-methyl-aniline (29.14 g, 114.6 mmol) and triethylamine (24 mL, 172 mmol) in dichloromethane (300 mL) at 0 °C. The reaction mixture was stirred at room temperature for 3 hours, then water (200 mL) was added and the mixture was extracted with dichloromethane (3 × 100 mL). The organic layer was washed with aqueous saturated sodium bicarbonate (2 × 150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give N-(2-bromo-4-tert-butyl-6-methyl-phenyl)-2,2,2-trifluoro-acetamide (40.05 g, 100%) as a brown solid. The crude material was used in the next step without further purification. ESI-MS m / z calculated: 337.03, observed: 338.0 (M+1) + . 1 H NMR ( 400MHz, CDCl3)δ 7.64-7.56(m,1H),7.51(d,J=1.5Hz,1H),7.26(s,1H),2.32(s,3H),1.33(s,9H).

[0324] Step 4: N-[4-tert-butyl-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-phenyl]-2,2,2-trifluoro-acetamide A mixture of N-(2-bromo-4-tert-butyl-6-methyl-phenyl)-2,2,2-trifluoro-acetamide (87.8 g, 235 mmol), 4-fluoro-2-methoxy-phenol (39.9 g, 32 mL, 281 mmol), cesium carbonate (230 g, 706 mmol), and N,N-dimethylglycine (24.2 g, 235 mmol) in dioxane (920 mL) was degassed with argon for 10 minutes, and then copper(I) iodide (13.4 g, 70.4 mmol) was added. The reaction was warmed to 60° C. under argon for 20 hours and then cooled. The reaction was filtered through Celite® and concentrated. The Celite® was washed with warm water (1.2 L) and ethyl acetate (600 mL), which was combined with the concentrate, and the phases were separated. The aqueous was extracted with ethyl acetate (3 x 400 mL). The combined organics were washed with water (3 x 400 mL), then brine (400 mL), dried over sodium sulfate and silica gel, filtered, and concentrated. The crude material was boiled in heptane (200 mL), cooled slowly to room temperature, and then cooled to 0 °C. The solid was collected by filtration to give N-[4-tert-butyl-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-phenyl]-2,2,2-trifluoro-acetamide (70.3 g, 75%). ESI-MS m / z calculated 399.15, found 400.16 (M+1). + . 1 H NMR(301MHz,CDCl3)δ 7.91(br s,1H),7.00(d,J=1.4Hz,1H),6.94(dd,J=8.9,5.4Hz,1H),6.73-6.69(m, 2H),6.61(td,J=8.4,2.9Hz,1H),3.80(s,3H),2.27(s,3H),1.21(s,9H).

[0325] Step 5: 4-tert-butyl-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-aniline To a solution of N-[4-tert-butyl-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-phenyl]-2,2,2-trifluoro-acetamide (70 g, 175 mmol) in ethanol (875 mL), NaOH (350 mL of 2 M, 700 mmol) was added and the mixture was stirred under reflux for 3 hours. The reaction was cooled, and then the ethanol was removed under reduced pressure. The residue was diluted with water (300 mL) and extracted with CPME (3 x 250 mL). The combined organic layers were washed with 1N NaOH (200 mL), then brine (200 mL), dried over sodium sulfate, filtered, and concentrated to give 4-tert-butyl-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-aniline (54.9 g, 100%). ESI-MS m / z calculated: 303.16, observed: 304.14 (M+1) + . 1 H NMR(301MHz,CDCl3)δ 6.87(d,J=1.7Hz,1H),6.79-6.71(m,2H),6.67(d,J=2.1Hz,1H),6.59-6.52(m,1H),3.87(s,3H),2.22(s,3H),1.20(s,9H).

[0326] Step 6: 2-Bromo-5-tert-butyl-1-(4-fluoro-2-methoxy-phenoxy)-3-methyl-benzene To a slurry of copper(II) bromide (48.6 g, 218 mmol), lithium bromide (45.4 g, 523 mmol), and tert-butyl nitrate (19.7 g, 16 mL, 172 mmol) in CHCN (700 mL) was added a solution of 4-tert-butyl-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-aniline (54.9 g, 174 mmol) in CHCN (420 mL) over 40 minutes at room temperature. The reaction was heated at 60° C. for 4 hours and then cooled. The reaction was quenched with 1N HCl (800 mL) and extracted with CPME (3×300 mL). The combined organic layers were washed with water (2×300 mL) and brine (300 mL), dried over sodium sulfate, and concentrated. Purification by silica gel chromatography (0-2% ethyl acetate / heptane) gave 2-bromo-5-tert-butyl-1-(4-fluoro-2-methoxy-phenoxy)-3-methyl-benzene (41.3 g, 62%). 1 H NMR(400MHz,CDCl3)δ 6.99(d,J=2.3Hz,1H),6.79-6.72(m,2H),6.63(d,J=2.3Hz,1H),6.61-6.56(m,1H),3.84(s,3H),2.45(s,3H),1.20(s,9H).

[0327] Step 7: 2-[4-tert-butyl-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane n-BuLi (1.2 mL of 2.5 M, 3.0 mmol) was slowly added to a solution of 2-bromo-5-tert-butyl-1-(4-fluoro-2-methoxy-phenoxy)-3-methyl-benzene (1.0 g, 2.7 mmol) in THF (20 mL) at −78° C. The reaction mixture was stirred for 15 minutes, and then a pre-cooled solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (684 mg, 0.75 mL, 3.68 mmol) in THF (5 mL) was slowly added. The reaction mixture was stirred at −78° C. for 1.5 hours and then warmed to 0° C. The reaction mixture was quenched with water (20 mL), poured into a 1:1 saturated sodium chloride / water solution (50 mL), and extracted using ethyl acetate (3×50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% ethyl acetate / heptane) to give 2-[4-tert-butyl-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (890 mg, 79%) as a clear oil. 1 H NMR(400MHz,CDCl3)δ 6.96(d,J=1.0Hz,1H),6.76-6.62(m,3H),6.59-6.47(m,1H),3.89(s,3H),2.45(s,3H),1.24(s,9H),1.24(s,12H).

[0328] Intermediate B-5 [ka]

[0329] Step 1: 5-Bromo-4-(3,4-difluoro-2-methyl-phenoxy)-2-(trifluoromethyl)pyridine 5-Bromo-4-(3,4-difluoro-2-methyl-phenoxy)-2-(trifluoromethyl)pyridine was prepared from 5-bromo-4-chloro-2-(trifluoromethyl)pyridine and 3,4-difluoro-2-methyl-phenol using a procedure similar to that found in Intermediate B-1, Step 1. ESI-MS m / z calculated 366.96, found 367.93 (M+1). + .

[0330] Step 2: 4-(3,4-Difluoro-2-methyl-phenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine 4-(3,4-Difluoro-2-methyl-phenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine was prepared using a procedure similar to that found in Intermediate B-2, Step 4. Purification by silica gel chromatography (40 g silica, 0-100% ethyl acetate / hexanes) afforded 4-(3,4-difluoro-2-methyl-phenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (402 mg, 54%) as a clear oil. ESI-MS m / z calculated 415.14, found 334.16 (M+1). + The product pinacol ester is expected to hydrolyze to the boronic acid under LC / MS conditions.

[0331] Intermediate B-6 [ka]

[0332] Step 1: 3-Bromo-2,5-dichloro-4-methyl-pyridine A mixture of 3-bromo-5-chloro-4-methyl-pyridin-2-ol (10 g, 45 mmol) and POCl3 (65.8 g, 40 mL, 429 mmol) was heated at 90°C for 24 hours. The temperature was increased to 105°C, and the reaction was stirred for 18 hours. It was then stirred at 120°C for 3 hours. It was cooled to room temperature, and POCl3 was evaporated under reduced pressure. The residue was poured onto a stirred mixture of water (400 mL), ethyl acetate (200 mL), and sodium carbonate (80 g). After 30 hours, the layers were separated. The aqueous layer was extracted with ethyl acetate (200 mL). The organic layers were combined, washed with water (100 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give 3-bromo-2,5-dichloro-4-methyl-pyridine (9.38 g, 87%) as a brown oil. ESI-MS m / z calculated: 238.89, observed: 240.0 (M+1) + . 1 H NMR(400MHz,CDCl3)δ 8.26(s,1H),2.59(s,3H).

[0333] Step 2: 3-Bromo-5-chloro-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-pyridine 3-Bromo-5-chloro-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-pyridine was prepared from 3-bromo-2,5-dichloro-4-methyl-pyridine and 4-fluoro-2-methyl-phenol using a procedure similar to that found in Intermediate B-1, Step 1. ESI-MS m / z calculated 328.96, found 329.9 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 7.94(s,1H),7.05-6.89(m,3H),2.58(s,3H),2.13(s,3H).

[0334] Step 3: [5-chloro-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-3-pyridyl]boronic acid 5-Chloro-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-3-pyridyl]boronic acid was prepared from 3-bromo-5-chloro-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-pyridine using a procedure similar to that found in Intermediate B-3, Step 3. ESI-MS m / z calculated 295.06, found 296.2 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 8.04(s,1H),7.05-6.86(m,3H),5.69(s,2H),2.67(s,3H),2.13(s,3H).

[0335] Intermediate B-7 [ka]

[0336] Step 1: 4-Methyl-5-(trifluoromethyl)pyridin-2-ol 2-Chloro-4-methyl-5-(trifluoromethyl)pyridine (5.0 g, 25.6 mmol), aqueous hydrochloric acid (20 mL of 37% w / v, 203 mmol), dioxane (40 mL), and water (20 mL) were stirred at 95° C. for 48 hours, then at 80° C. for an additional 24 hours. The mixture was diluted with 2 M aqueous sodium hydroxide (100 mL) and saturated aqueous sodium bicarbonate (100 mL) and then extracted with ethyl acetate (4×200 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give 4-methyl-5-(trifluoromethyl)pyridin-2-ol (4.82 g, 98%) as a white solid. ESI-MS m / z calculated 177.04, found 178.2 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 13.21(br.s,1H),7.70(s,1H),6.44(s,1H),2.35(s,3H). 19 F NMR(377MHz,CDCl3)δ-61.29(s,3F).

[0337] Step 2: 3-Bromo-4-methyl-5-(trifluoromethyl)pyridin-2-ol To a solution of 4-methyl-5-(trifluoromethyl)pyridin-2-ol (4.8 g, 25 mmol) in acetic acid (65 mL) was added bromine (8.7 g, 2.8 mL, 54 mmol). The mixture was stirred at room temperature for 65 hours and then poured into a stirred mixture of sodium carbonate (90 g), water (400 mL), and sodium thiosulfate pentahydrate (17 g). The aqueous layer was extracted with ethyl acetate (3 × 250 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give a beige solid (6.05 g). The solid was triturated with 1:1 MTBE / heptane (30 mL) and filtered. The solid was washed with 1:1 MTBE / heptane (15 mL) and dried to give 3-bromo-4-methyl-5-(trifluoromethyl)pyridin-2-ol (5.38 g, 84%) as a white solid. ESI-MS m / z calculated 254.95, found 256.0 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 13.23(br.s,1H),7.83(s,1H),2.53(s,3H). 19 F NMR(377MHz,CDCl3)δ-60.81(s,3F).

[0338] Step 3: 3-Bromo-2-chloro-4-methyl-5-(trifluoromethyl)pyridine A mixture of 3-bromo-4-methyl-5-(trifluoromethyl)pyridin-2-ol (4.09 g, 16.0 mmol) and POCl (65.8 g, 40 mL, 429 mmol) was stirred at 80 °C for 23 hours. The mixture was cooled and slowly poured into a stirred mixture of sodium carbonate (160 g), water (400 mL), and ethyl acetate (100 mL). Ice was added during the addition to control the exotherm. The mixture was stirred at room temperature for 30 minutes, and the layers were separated. The aqueous layer was extracted with additional ethyl acetate (3 × 100 mL). The combined extracts were washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give 3-bromo-2-chloro-4-methyl-5-(trifluoromethyl)pyridine (3.87 g, 87%) as a light brown oil. ESI-MS m / z calculated: 272.92, observed: 273.8 (M+1) + . 1 H NMR(400MHz,CDCl3)δ 8.54(s,1H),2.63(s,3H).19F NMR(377MHz,CDCl3)δ-61.06(s,3F).

[0339] Step 4: 3-Bromo-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine A mixture of 3-bromo-2-chloro-4-methyl-5-(trifluoromethyl)pyridine (11.30 g, 41.17 mmol), 4-fluoro-2-methyl-phenol (5.710 g, 45.27 mmol), and cesium carbonate (26.83 g, 82.35 mmol) in DMSO (80 mL) was stirred at room temperature for 90 minutes. The mixture was partitioned between water and diethyl ether, and the layers were separated. The aqueous layer was extracted with additional diethyl ether, and the combined organic layers were washed with 1N NaOH (2×) and brine, dried over MgSO, filtered, and concentrated. Purification by silica gel chromatography (220 g silica, 0–20% ethyl acetate / hexanes) gave 3-bromo-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine (14.22 g, 95%). ESI-MS m / z calculated: 362.99, observed: 365.1 (M+1)+ . 1 H NMR(400MHz,CD3OD)δ 8.22(s,1H),7.11-7.03(m,2H),6.98(td,J=8.5,3.4Hz,1H),2.63(app d,J=1.4Hz,3H),2.10(s,3H).

[0340] Step 5: [2-(4-fluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)-3-pyridyl]boronic acid A solution of n-BuLi (4.7 mL of 1.6 M in hexanes, 7.5 mmol) was slowly added to a stirred solution of 3-bromo-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine (2.56 g, 6.82 mmol) in diethyl ether (30 mL) at −78° C. under argon. The mixture was stirred at −78° C. for 1 hour. A solution of trimethylborate (1.2 g, 1.3 mL, 11.7 mmol) in diethyl ether (10 mL) was then added dropwise. The mixture was allowed to warm to room temperature and then quenched with saturated aqueous ammonium chloride (50 mL). The aqueous phase was extracted with additional diethyl ether (100 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Trituration with hexane and filtration gave [2-(4-fluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)-3-pyridyl]boronic acid (1.91 g, 83%) as a pale cream solid. 1 H NMR(400MHz,DMSO-d6)δ 8.61(m,2H),8.26(s,1H),7.14-7.00(m,3H),2.42(s,3H),2.04(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-59.3--58.9(3F),-118.3--117.9(1F).ESI-MS m / z Calculated value .329.09, Actual value 329.99(M+1) + .

[0341] Intermediate B-8 [ka]

[0342] Step 1: 3-Bromo-2-(3,4-difluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine A mixture of 3-bromo-2-chloro-4-methyl-5-(trifluoromethyl)pyridine (2.63 g, 9.58 mmol) and 3,4-difluoro-2-methyl-phenol (2.6 g, 18 mmol) was dissolved in DMSO (26 mL). To this solution was added cesium carbonate (7.73 g, 23.7 mmol), and the mixture was stirred at 90 °C for 2.5 h. The mixture was cooled to room temperature and then diluted with ethyl acetate. The organic solution was washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification using silica gel chromatography (120 g silica, 0–20% ethyl acetate / hexanes) afforded 3-bromo-2-(3,4-difluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine (3.340 g, 91%) as a bright orange solid. ESI-MS m / z calculated: 380.98, observed: 382.0 (M+1) + . 1 H NMR(400MHz,DMSO-d6)δ 8.41(s,1H),7.38(q,J=9.4Hz,1H),7.10(ddd,J=9.2,4.4,2.1Hz,1H),2.59(d,J=1.4Hz,3H),2.03(d,J=2.2Hz,3H).

[0343] Step 2: [2-(3,4-difluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)-3-pyridyl]boronic acid To a stirred solution of 3-bromo-2-(3,4-difluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine (2.0 g, 5.2 mmol) in diethyl ether (20 mL) was added a solution of n-BuLi (2.5 mL of 2.5 M in hexane, 6.25 mmol) slowly at −78° C. under a nitrogen atmosphere. The mixture was stirred at this temperature for 20 minutes, after which a solution of trimethylborate (1 mL, 9 mmol) in diethyl ether (6 mL) was added dropwise. The resulting mixture was warmed to room temperature and stirred for 90 minutes. The mixture was quenched with saturated aqueous ammonium chloride (150 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The material was purified by reverse-phase chromatography (C18, 5–95% acetonitrile / water containing 0.1% formic acid), and the product-containing fractions were concentrated to remove acetonitrile. The resulting aqueous solution was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give [2-(3,4-difluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)-3-pyridyl]boronic acid (1.64 g, 90%) as a white solid. 1 H NMR(400MHz,CDCl3)δ 8.32(s,1H),7.06(q,J=9.0Hz,1H),6.85-6.80(m,1H),5.45(s,2H),2.71-2.67(m,3H),2.10(d,J=2.0Hz,3H). 19 F NMR (377 MHz, CDCl3) δ -60.66 (s, 3F), -137.75 - 137.88 (m, 1F), -140.42 - 140.54 (m, 1F). ESI-MS m / z calculated 347.08, found 348.2 (M+1). + .

[0344] Intermediate B-9 [ka]

[0345] Step 1: 3-Bromo-2-(4-fluoro-2-methoxy-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine 3-Bromo-2-(4-fluoro-2-methoxy-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine was prepared from 3-bromo-2-chloro-4-methyl-5-(trifluoromethyl)pyridine and 4-fluoro-2-methoxy-phenol using a procedure similar to that found in Intermediate B-7, Step 4. ESI-MS m / z calculated 378.98, found 380.15 (M+1). + . 1 H NMR(400MHz,CD3OD)δ 8.18(s,1H),7.12(dd,J=8.8,5.7Hz,1H),6.92(dd,J=10.4,2.9Hz,1H),6.72(td,J=8.3,2.9Hz,1H),3.71(s,3H),2.61(d,J=1.2Hz,3H).

[0346] Step 2: [2-(4-fluoro-2-methoxy-phenoxy)-4-methyl-5-(trifluoromethyl)-3-pyridyl]boronic acid [2-(4-Fluoro-2-methoxy-phenoxy)-4-methyl-5-(trifluoromethyl)-3-pyridyl]boronic acid was prepared from 3-bromo-2-(4-fluoro-2-methoxy-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine using a procedure similar to that found in Intermediate B-1, Step 2, using diethyl ether as solvent. ESI-MS m / z calculated 345.08, found 346.1 (M+1). + . 1 H NMR(400MHz,CD3OD)δ 8.19(s,1H),7.09(dd,J=8.8,5.7Hz,1H),6.90(dd,J=10.4,2.9Hz,1H),6.71(td,J=8.4,2.9Hz,1H),3.70(s,3H),2.44(d,J=1.5Hz,3H).

[0347] Intermediate B-10 [ka]

[0348] Step 1: 6-chloro-2-methyl-3-(trifluoromethyl)pyridine A mixture of Fe(acac)3 (140 mg, 0.394 mmol) and 2,6-dichloro-3-(trifluoromethyl)pyridine (2.0 g, 9.3 mmol) in a sealed flask was evacuated and placed under a nitrogen atmosphere. THF (40 mL) was added, and the mixture was cooled to 0 °C. Methylmagnesium bromide (3.6 mL of 3 M in diethyl ether, 10.8 mmol) was added dropwise, and the mixture was stirred at 0 °C for 3 h. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 80 mL). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give 6-chloro-2-methyl-3-(trifluoromethyl)pyridine (1.91 g, 95%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.90(d,J=7.8Hz,1H),7.22(d,J=7.8Hz,1H),2.63(s,3H).

[0349] Step 2: 6-Methyl-5-(trifluoromethyl)pyridin-2-ol 6-Methyl-5-(trifluoromethyl)pyridin-2-ol was prepared from 6-chloro-2-methyl-3-(trifluoromethyl)pyridine using a procedure similar to that found in Intermediate B-7, Step 1. ESI-MS m / z calculated 177.04, found 178.0 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 13.20(s,1H),7.61(d,J=9.6Hz,1H),6.46(d,J=9.5Hz,1H),2.56-2.49(m,3H).

[0350] Step 3: 3-Bromo-6-methyl-5-(trifluoromethyl)pyridin-2-ol 3-Bromo-6-methyl-5-(trifluoromethyl)pyridin-2-ol was prepared from 6-methyl-5-(trifluoromethyl)pyridin-2-ol using a procedure similar to that found in Intermediate B-7, Step 2. ESI-MS m / z calculated 254.95, found 255.79 (M+1). + . 1 H NMR(400MHz,DMSO-d6)δ 12.66(s,1H),7.99(s,1H),2.33-2.25(m,3H).

[0351] Step 4: 3-Bromo-2-chloro-6-methyl-5-(trifluoromethyl)pyridine 3-Bromo-2-chloro-6-methyl-5-(trifluoromethyl)pyridine was prepared from 3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-ol using a procedure similar to that found in Intermediate B-6, Step 1. 1 H NMR(400MHz,CDCl3)δ 8.08(s,1H),2.66-2.63(m,3H).

[0352] Step 5: 3-Bromo-2-(3,4-difluoro-2-methyl-phenoxy)-6-methyl-5-(trifluoromethyl)pyridine 3-Bromo-2-(3,4-difluoro-2-methyl-phenoxy)-6-methyl-5-(trifluoromethyl)pyridine was prepared from 3-bromo-2-chloro-6-methyl-5-(trifluoromethyl)pyridine and 3,4-difluoro-2-methyl-phenol using a procedure similar to that found in Intermediate B-1, Step 1. ESI-MS m / z calculated 380.98, found 381.96 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 8.08(s,1H),7.02(q,J=9.0Hz,1H),6.83(m,1H),2.40(q,J=1.7Hz,3H),2.09(d,J=2.3Hz,3H).

[0353] Step 6: [2-(3,4-Difluoro-2-methyl-phenoxy)-6-methyl-5-(trifluoromethyl)-3-pyridyl]boronic acid [2-(3,4-Difluoro-2-methyl-phenoxy)-6-methyl-5-(trifluoromethyl)-3-pyridyl]boronic acid was prepared from 3-bromo-2-(3,4-difluoro-2-methyl-phenoxy)-6-methyl-5-(trifluoromethyl)pyridine using a procedure similar to that found in Intermediate B-3, Step 3. 1 H NMR(400MHz,CD3OD)δ 8.04(s,1H),7.10(q,J=9.3Hz,1H),6.87-6.84(m,1H),2.39(d,J=1.8Hz,3H),2.06(d,J=1.8Hz,3H).

[0354] Intermediate B-11 [ka]

[0355] Step 1: Methyl 2-hydroxy-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylate To a solution of methyl 3-amino-3-oxopropanoate (9.6 g, 82 mmol) and 4-ethoxy-1,1,1-trifluoro-3-methyl-but-3-en-2-one (15 g, 82 mmol) in methanol (120 mL) was added sodium methoxide in methanol (23 mL of 25% w / v, 106 mmol). The reaction mixture was heated under reflux for 1 hour and then cooled to room temperature. The precipitate was removed by filtration and washed with methanol (2 x 250 mL). The resulting solid was suspended in ethyl acetate (500 mL) and 2 M hydrochloric acid (500 mL). The solid was filtered and the filtrate separated. The aqueous phase was re-extracted with ethyl acetate (500 mL). The combined organic extracts were washed with brine (500 mL), dried over magnesium sulfate, and concentrated to give methyl 2-hydroxy-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylate (11.4 g, 56%) as an off-white solid. ESI-MS m / z calculated 235.04, found 233.97 (M-1). - . 1 H NMR(400MHz,CDCl3)δ 8.17(s,1H),4.03(s,3H),2.45(m,3H).

[0356] Step 2: Methyl 2-chloro-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylate A solution of methyl 2-hydroxy-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylate (10 g, 40.5 mmol) in the appropriate phenyl dichlorophosphate (56.5 g, 40 mL, 268 mmol) was heated at 155° C. for 6 hours. The reaction mixture was cooled to room temperature and then quenched into a vigorously stirred mixture of ethyl acetate (1000 mL), water (250 mL), and sodium carbonate (60 g) at a rate to maintain the temperature below 45° C. The mixture was then vigorously stirred for 2 hours. The layers were separated. The aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were washed with water (500 mL) and brine (500 mL), dried over magnesium sulfate, and concentrated. Purification by silica gel chromatography (0-20% ethyl acetate / heptane) gave methyl 2-chloro-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylate (6.15 g, 56%) as a white solid. ESI-MS m / z calculated 253.01, found 253.96 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 8.11(s,1H),3.99(s,3H),2.53(q,J=1.7Hz,3H).

[0357] Step 3: Methyl 2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylate Methyl 2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylate was prepared from methyl 2-chloro-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylate and 3,4-difluoro-2-methylphenol using a procedure similar to that found in Intermediate B-1, Step 1. ESI-MS m / z calculated 361.07, found 362.06 (M+1). + . 1H NMR(400MHz,CDCl3)δ 8.19(s,1H),6.99(q,J=9.2Hz,1H),6.84(m,1H),3.97(s,3H),2.45(q,J=1.8Hz,3H),2.11(d,J=2.3Hz,3H).

[0358] Step 4: 2-(3,4-Difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid To a mixture of methyl 2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylate (30 g, 78.5 mmol) in methanol (60 mL), THF (120 mL), and water (60 mL) was added lithium hydroxide monohydrate (6.5 g, 155 mmol). The mixture was stirred at room temperature for 2 hours, and then the volatiles were removed under reduced pressure. The residue was acidified (to approximately pH 6) using 2 M HCl. The resulting solid was collected by filtration and dried to give 2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid (27 g, 97%). ESI-MS m / z calculated: 347.06, found: 346.0 (M-1). - . 1 H NMR(400MHz,CDCl3)δ 8.39(s,1H),7.07-6.99(m,1H),6.86(m,1H),2.48-2.44(m,3H),2.15-2.08(m,3H).

[0359] Step 5: tert-butyl N-[2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)-3-pyridyl]carbamate To a solution of 2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid (27 g, 76 mmol) in toluene (240 mL) was added triethylamine (16 mL, 115 mmol) and DPPA (25.5 g, 20 mL, 93 mmol). The mixture was stirred at room temperature for 30 minutes, and t-BuOH (45 mL) was added. The mixture was then heated at 110° C. for 2 hours, cooled to room temperature, and partitioned between ethyl acetate (400 mL) and water (200 mL). The aqueous layer was extracted with additional ethyl acetate (2×200 mL). The combined organics were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification using silica gel chromatography (heptane, followed by 10% ethyl acetate / heptane) gave tert-butyl N-[2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)-3-pyridyl]carbamate (24 g, 74%). ESI-MS m / z calculated: 418.13, found: 417.05 (M-1). - . 1 H NMR(400MHz,CDCl3)δ 8.43(s,1H),7.18(s,1H),7.00(q,J=9.0Hz,1H),6.81(m,1H),2.40(q,J=2.0Hz,3H),2.09(d,J=2.3Hz,3H),1.56(t,J=5.0Hz,9H).

[0360] Step 6: 2-(3,4-Difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridin-3-amine A solution of tert-butyl N-[2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)-3-pyridyl]carbamate (24 g, 56 mmol) in HCl in dioxane (150 mL of 4 M, 600 mmol) was stirred at room temperature overnight. The mixture was concentrated in vacuo to give 2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridin-3-amine (21.5 g, 97%). ESI-MS m / z calculated 318.08, found 318.93 (M+1).+ . 1 H NMR(400MHz,CDCl3)δ 6.98(q,J=9.2Hz,1H),6.88(s,1H),6.84(m,1H),2.33(q,J=2.0Hz,3H),2.11(d,J=2.3Hz,3H).

[0361] Step 7: 3-Bromo-2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridine tert-Butyl nitrate (208 mg, 0.24 mL, 2.02 mmol) was added dropwise to a stirred mixture of 2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridin-3-amine (300 mg, 0.823 mmol) and copper(II) bromide (420 mg, 1.88 mmol) in anhydrous CH3CN (6 mL) at 0 °C under argon. After stirring at 0 °C for 30 min, the mixture was warmed to room temperature and stirred for 1 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (0 to 10% ethyl acetate in heptane) to give 3-bromo-2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridine (270 mg, 83%). 1 H NMR(400MHz,CDCl3)δ 7.92(s,1H),7.07-6.98(m,1H),6.91(qd,J=4.4,2.0Hz,1H),2.44(q,J=1.9Hz,3H),2.15(d,J=2.4Hz,3H).

[0362] Step 8: 2-(3,4-Difluoro-2-methyl-phenoxy)-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine 2-(3,4-Difluoro-2-methyl-phenoxy)-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine was prepared from 3-bromo-2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridine using a procedure similar to that found in Intermediate B-1, Step 2, using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. ESI-MS m / z calculated 429.15, found 346.0 (M-pinacol). - . 1 H NMR(400MHz,CDCl3)δ 8.01(s,1H),6.94(t,J=8.9Hz,1H),6.87(qd,J=4.4,1.8Hz,1H),2.40(q,J=2.0Hz,3H),2.16(d,J=2.3Hz,3H),1.34(s,12H).

[0363] Intermediate B-12 [ka]

[0364] Step 1: Methyl 5-(3,4-difluoro-2-methoxy-phenoxy)-2-(trifluoromethyl)pyridine-4-carboxylate. Methyl 5-(3,4-difluoro-2-methoxy-phenoxy)-2-(trifluoromethyl)pyridine-4-carboxylate was prepared from methyl 5-bromo-2-(trifluoromethyl)pyridine-4-carboxylate and 3,4-difluoro-2-methoxyphenol using a procedure similar to that found in Intermediate B-4, Step 4, but without N,N-dimethylglycine. ESI-MS m / z calculated 363.05, found 364.0 (M+1). + . 1H NMR(500MHz,CDCl3)δ 8.24(s,1H),8.12(s,1H),6.95(td,J=9.3,7.9Hz,1H),6.88(ddd,J=9.3,4.9,2.2Hz,1H),3.99(s,3H),3.95(d,J=1.8Hz,3H).

[0365] Step 2: 5-(3,4-Difluoro-2-methoxy-phenoxy)-2-(trifluoromethyl)pyridine-4-carboxylic acid 5-(3,4-Difluoro-2-methoxy-phenoxy)-2-(trifluoromethyl)pyridine-4-carboxylic acid was prepared from methyl 5-(3,4-difluoro-2-methoxy-phenoxy)-2-(trifluoromethyl)pyridine-4-carboxylate using a procedure similar to that found in Intermediate B-11, Step 4. ESI-MS m / z calculated 349.04, found 350.0 (M+1). + . 1 H NMR(500MHz,DMSO-d6)δ 14.07(s,1H),8.43(s,1H),8.17(s,1H),7.25(td,J=9.7,8.4Hz,1H),7.12-7.08(m,1H),3.88(d,J=1.2Hz,3H).

[0366] Step 3: 5-(3,4-Difluoro-2-methoxy-phenoxy)-2-(trifluoromethyl)pyridin-4-amine 5-(3,4-Difluoro-2-methoxy-phenoxy)-2-(trifluoromethyl)pyridin-4-amine was prepared from 5-(3,4-difluoro-2-methoxy-phenoxy)-2-(trifluoromethyl)pyridine-4-carboxylic acid using a procedure similar to that found in Intermediate B-11, Steps 5 to 7. ESI-MS m / z calculated 320.06, found 321.1 (M+1). + ;319.0(M-1) - . 1H NMR(400MHz,CDCl3)δ 7.91(s,1H),7.06(s,1H),6.90(td,J=9.3,8.0Hz,1H),6.80(ddd,J=9.3,4.9,2.3Hz,1H),4.72(s,2H),3.97(d,J=1.8Hz,3H).

[0367] Step 4: 4-Bromo-5-(3,4-difluoro-2-methoxy-phenoxy)-2-(trifluoromethyl)pyridine 4-Bromo-5-(3,4-difluoro-2-methoxy-phenoxy)-2-(trifluoromethyl)pyridine was prepared from 5-(3,4-difluoro-2-methoxy-phenoxy)-2-(trifluoromethyl)pyridin-4-amine using a procedure similar to that found in Intermediate B-4, Step 6. ESI-MS m / z calculated 382.96, found 384.2 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 8.02(s,1H),7.97(s,1H),7.02-6.84(m,2H),3.97(d,J=1.9Hz,3H).

[0368] Step 5: 5-(3,4-Difluoro-2-methoxy-phenoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine 5-(3,4-Difluoro-2-methoxy-phenoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine was prepared using a procedure similar to that found in Intermediate B-2, Step 4, using PdCl(PhP) catalyst. ESI-MS m / z calculated 431.13, found 350.1 (M-pinacol). + .

[0369] Intermediate B-13 [ka]

[0370] Step 1: 5-Fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid A solution of n-BuLi (62 mL of 2.5 M in hexane, 155 mmol) was added dropwise to a solution of diisopropylamine (16.3 g, 22.5 mL, 161 mmol) in THF (190 mL) at -30 °C, and the reaction mixture was allowed to warm slowly to 0 °C over 30 min. The reaction mixture was cooled to -78 °C, and a solution of 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine (23.87 g, 122.6 mmol) in THF (50 mL) was added dropwise over 25 min. After 1 h, solid carbon dioxide (55 g, 1.2497 mol) was added in one portion (exotherm = -74 to -60 °C). After 10 min, the reaction mixture was allowed to warm slowly to room temperature. After 1.5 hours, heptane (75 mL), tert-butyl methyl ether (100 mL), 1.5 M aqueous sodium hydroxide solution (200 mL, 8.4 vol), and water (100 mL, 4.2 vol) were added, and the biphasic mixture was filtered through Celite®. The organic layer was separated and extracted with water (150 mL). The aqueous layers were combined, washed with tert-butyl methyl ether (150 mL), acidified with 3.0 M aqueous hydrochloric acid solution (200 mL, 8.4 vol), and extracted with tert-butyl methyl ether (2 × 200 mL, 16.7 vol). The combined organic extracts were washed with 15% aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to a total weight of 42.6 g. The mixture was slowly cooled to 0 °C over 30 minutes, then diluted with heptane (50 mL), and the mixture was stirred at 0 °C for 15 minutes. The solid was filtered, rinsed with heptane (50 mL), and dried under vacuum to give 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid (15.59 g). The mother liquor was concentrated to dryness under vacuum (9.04 g), then taken up in tert-butyl methyl ether (9 mL), and the mixture was heated at 55 ° C. After 10 minutes, heptane (20 mL, 2.2 volumes) was added over 25 minutes, and the mixture was allowed to cool slowly to room temperature overnight. The resulting solid was filtered, rinsed with heptane (25 mL), and dried under vacuum to give a second crop of 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid (3.97 g).Both crops were combined to give 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid (19.56 g, 70%): ESI-MS m / z calculated 223.03, found 222.1 (M-1). - . 1 H NMR(400MHz,DMSO-d6)δ 14.74(br s,1H),8.73(s,1H),2.47-2.43(m,3H). 19 F NMR(377MHz,DMSO-d6)δ-62.99(s,1F),-125.50(s,1F).

[0371] Step 2: Methyl 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylate To a stirred mixture of 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid (5.0 g, 22 mmol) in methanol (50.0 mL) was added HSO (16 mL, 300 mmol) dropwise at room temperature. The reaction mixture was stirred at 80 °C for 48 h. After cooling to room temperature, the mixture was cooled to 0 °C and 2 M aqueous sodium hydroxide was added to adjust the solution to pH = 9. The solution was diluted with ethyl acetate (50 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to give methyl 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylate (4.23 g, 80%). ESI-MS m / z calculated 237.04, found 238.0 (M+1). + . 1 H NMR(500MHz,CDCl3)δ 8.45(s,1H),4.01(s,3H),2.50-2.48(m,3H).

[0372] Step 3: Methyl 5-(3,4-difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylate Methyl 5-(3,4-difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylate was prepared from methyl 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylate and 3,4-difluoro-2-methyl-phenol using a procedure similar to that found in Intermediate B-1, Step 1, using DMF as solvent. ESI-MS m / z calculated 361.07, found 362.2 (M+1). + . 1 H NMR(400MHz,DMSO-d6)δ 8.13(s,1H),7.37(q,J=9.4Hz,1H),7.03(ddd,J=9.2,4.2,2.0Hz,1H),3.93(s,3H),2.44-2.38(m,3H),2.13(d,J=2.2Hz,3H).

[0373] Step 4: 5-(3,4-difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid A solution of methyl 5-(3,4-difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylate (407 mg, 1.13 mmol) in ethanol (3 mL) was treated with NaOH (3 mL of 2 M, 6 mmol) and stirred at 70° C. for 45 minutes. The reaction was cooled to room temperature and partitioned between 1 M HCl (10 mL) and ethyl acetate (20 mL). The organic layer was separated, washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 5-(3,4-difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid (400 mg, quantitative yield). 1 H NMR(400MHz,DMSO-d6)δ 8.09(s,1H),7.36(q,J=9.4Hz,1H),6.99(ddd,J=9.3,4.2,2.0Hz,1H),2.46-2.41(m,3H),2.15(d,J=2.1Hz,3H).

[0374] Step 5: 5-(3,4-Difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridin-4-amine A solution of DPPA (429 mg, 1.56 mmol) in 1,4-dioxane (1 mL) was added dropwise to a stirred mixture of 5-(3,4-difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid (391 mg, 1.13 mmol) and DIPEA (300 μL, 1.72 mmol) in 1,4-dioxane (6 mL) and tert-butanol (2 mL). The reaction mixture was stirred at 70 °C for 21 h. After cooling to room temperature, the reaction mixture was partitioned between water (10 mL) and ethyl acetate (10 mL). The phases were separated, and the aqueous phase was extracted with ethyl acetate (2 × 10 mL). The combined organic extracts were dried (sodium sulfate), filtered, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (6 mL, 78 mmol) was added in one portion at room temperature and stirred overnight. The solvent was removed under reduced pressure, and the residue was neutralized using 2M sodium hydroxide. The aqueous layer was extracted with dichloromethane (3x), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-20% ethyl acetate / heptane) gave 5-(3,4-difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridin-4-amine (327 mg, 91%). ESI-MS m / z calculated 318.08, found 319.2 (M+1). + .

[0375] Step 6: 4-Bromo-5-(3,4-difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine 4-Bromo-5-(3,4-difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine was prepared from 5-(3,4-difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridin-4-amine using a procedure similar to that found in Intermediate B-11, Step 7. ESI-MS m / z calculated 380.98, found 382.0 (M+1).+ . 1 H NMR(400MHz,DMSO-d6)δ 8.05(s,1H),7.35(q,J=9.4Hz,1H),6.94(ddd,J=9.2,4.1,2.0Hz,1H),2.57(d,J=1.8Hz,3H),2.19(d,J=2.2Hz,3H).

[0376] Step 7: 5-(3,4-Difluoro-2-methyl-phenoxy)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine To a solution of 4-bromo-5-(3,4-difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine (125 mg, 0.3271 mmol) in 2-MeTHF (2 mL) was added isopropylmagnesium chloride lithium chloride complex (400 μL of 1.3 M in THF, 0.52 mmol) at 0 °C under nitrogen. After 20 min at room temperature, the reaction mixture was cooled to 0 °C and treated with a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (119 mg, 0.640 mmol) in 2-MeTHF (1.5 mL) at 0 °C under nitrogen. After 2 h at room temperature, saturated aqueous ammonium chloride solution (10 mL) was added, the aqueous phase was separated, and extracted with ethyl acetate (15 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (0-50% ethyl acetate / hexanes) gave 5-(3,4-difluoro-2-methyl-phenoxy)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (29.9 mg, 21%). ESI-MS m / z calculated 429.15, found 430.1 (M+1). + . 1 H NMR(400MHz,DMSO-d6)δ 8.03(s,1H),7.30(q,J=9.5Hz,1H),6.85-6.77(m,1H),2.48(d,J=2.1Hz,3H),2.18(d,J=2.1Hz,3H),1.27(s,12H).

[0377] Intermediate B-14 [ka]

[0378] Step 1: 3-Bromo-2-(3,4-difluoro-2-methyl-phenoxy)-5-(trifluoromethyl)pyridine 3-Bromo-2-(3,4-difluoro-2-methyl-phenoxy)-5-(trifluoromethyl)pyridine was prepared from 3-bromo-2-chloro-5-(trifluoromethyl)pyridine and 3,4-difluoro-2-methyl-phenol using a procedure similar to that found in Intermediate B-1, Step 1. ESI-MS m / z calculated 366.96, found 368.0 (M+1). + . 1 H NMR(400MHz,DMSO-d6)δ 8.74-8.67(m,1H),8.57-8.44(m,1H),7.39(q,J=9.4Hz,1H),7.19-7.05(m,1H),2.04(d,J=2.1Hz,3H).

[0379] Step 2: [2-(3,4-difluoro-2-methyl-phenoxy)-5-(trifluoromethyl)-3-pyridyl]boronic acid [2-(3,4-Difluoro-2-methyl-phenoxy)-5-(trifluoromethyl)-3-pyridyl]boronic acid was prepared from 3-bromo-2-(3,4-difluoro-2-methyl-phenoxy)-5-(trifluoromethyl)pyridine using a procedure similar to that found in Intermediate B-3, Step 3. ESI-MS m / z calculated 333.06, found 334.0 (M+1). + . 1 H NMR(400MHz,DMSO-d6)δ 8.54(s,2H),8.51-8.45(m,1H),8.28-8.23(m,1H),7.33(q,J=9.4Hz,1H),7.09-7.01(m,1H),2.10-2.01(m,3H).

[0380] Intermediate B-15 [ka]

[0381] Step 1: Methyl 5-(4-fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylate Methyl 5-(4-fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylate was prepared from methyl 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylate (Intermediate B-13, Step 2) and 4-fluoro-2-methyl-phenol using a procedure similar to that found in Intermediate B-13, Step 3. 1 H NMR(400MHz,CDCl3)δ 7.84(s,1H),7.04-6.88(m,3H),3.98(s,3H),2.48-2.42(m,3H),2.19(s,3H).ESI-MS m / z Calculated value .343.08, Actual value 344.1(M+1) + .

[0382] Step 2: 5-(4-fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid 5-(4-Fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid was prepared from methyl 5-(4-fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylate using a procedure similar to that found in intermediate B-13, step 4. 1 H NMR(400MHz,CDCl3)δ 7.87(s,1H),7.07-6.88(m,3H),2.56-2.52(m,3H),2.20(s,3H).ESI-MS m / z calculated value .329.07, measured value 330.2(M+1) + .

[0383] Step 3: 5-(4-Fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridin-4-amine 5-(4-Fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridin-4-amine was prepared from 5-(4-fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid using a procedure similar to that found in Intermediate B-13, Step 5. 1 H NMR(400MHz,DMSO-d6)δ 7.51(s,1H),7.22(dd,J=9.3,3.2Hz,1H),7.03(td,J=8.6,3.2Hz,1H),6.88(d d,J=8.9,4.9Hz,1H),6.29(s,2H),2.24(s,3H),2.22(d,J=1.7Hz,3H).ESI-MS m / z Calculated value .300.09, Actual value 301.2(M+1) + .

[0384] Step 4: 4-Bromo-5-(4-fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine 4-Bromo-5-(4-fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine was prepared from 5-(4-fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridin-4-amine using a procedure similar to that found in Intermediate B-11, Step 7. 1 H NMR(400MHz,DMSO-d6)δ 7.89(s,1H),7.33-7.26(m,1H),7.17-7.07(m,2H),2.57(d,J=1.7Hz,3H),2.20(s,3H).ESI-MS m / z calculated value.362.99,actual value 364.1(M+1) + .

[0385] Step 5: 5-(4-Fluoro-2-methyl-phenoxy)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine 5-(4-Fluoro-2-methyl-phenoxy)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine was prepared from 4-bromo-5-(4-fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine using a procedure similar to that found in Intermediate B-13, step 7. 1 H NMR(400MHz,DMSO-d6)δ 7.89(s,1H),7.24(dd,J=9.3,3.1Hz,1H),7.12-7.03(m,1H),7.03-6.97(m,1H),2.47(d,J=2.0Hz,3H),2.20(s,3H),1.29(s,12H).ESI-MS m / z Calculated value .411.16, Actual value 412.1(M+1) + .

[0386] Intermediate B-16 [ka]

[0387] Step 1: 5-chloro-3-iodo-6-(trifluoromethyl)pyridin-2-ol To a solution of 3-iodo-6-(trifluoromethyl)pyridin-2-ol (13.3 g, 45.2 mmol) in DMF (70 mL) was added 1,3-dichloro-5,5-dimethylhydantoin (15.960 g, 81.005 mmol). The reaction mixture was stirred at room temperature for 24 hours and then partitioned between ethyl acetate (500 mL) and water (200 mL). The biphasic mixture was cooled to 0-10 °C, vigorously stirred, and slowly treated with 10% aqueous sodium thiosulfate (200 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 100 mL). The pH of the aqueous layer was adjusted to 3 by adding 3 M aqueous HCl (approximately 10 mL) and extracted with additional ethyl acetate (200 mL). The combined organic layers were washed with 50% saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-5% methanol / dichloromethane) gave 5-chloro-3-iodo-6-(trifluoromethyl)pyridin-2-ol (8.68 g, 57%). ESI-MS m / z calculated: 322.88, found: 323.9 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 9.45-8.67(m,1H),8.22(s,1H). 19 F NMR(377MHz,CDCl3)δ-65.53--65.89(m,3F).

[0388] Step 2: Methyl 5-chloro-2-hydroxy-6-(trifluoromethyl)pyridine-3-carboxylate Palladium(II) acetate (250 mg, 1.11 mmol) was added to a solution of 5-chloro-3-iodo-6-(trifluoromethyl)pyridin-2-ol (7.08 g, 20.8 mmol), triethylamine (6.5 g, 9.0 mL, 64.6 mmol), and 1,1'-ferrocenediyl-bis(diphenylphosphine) (1.2 g, 2.2 mmol) in methanol (100 mL) in a sealed tube. Carbon monoxide was bubbled into the solution for 5 minutes, then the tube was sealed and the reaction mixture was stirred at 60°C under a CO atmosphere for 5 hours. Additional CO was bubbled into the solution, and the reaction mixture was stirred at 60°C under a CO atmosphere overnight. The mixture was cooled to room temperature, filtered over Celite®, washed with methanol, and the filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane (150 mL), washed with 1 M aqueous HCl (100 mL), water (50 mL), and brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. Purification by silica gel chromatography (0-5% methanol / dichloromethane) gave methyl 5-chloro-2-hydroxy-6-(trifluoromethyl)pyridine-3-carboxylate (4.99 g, 94%). 1 H NMR(400MHz,CDCl3)δ 11.30(br.s,1H),8.37(s,1H),4.08(s,3H). 19 F NMR (377 MHz, CDCl3) δ -66.91 (s, 3F). ESI-MS m / z calculated: 254.99, found: 256.0 (M+1). + .

[0389] Step 3: Methyl 5-chloro-6-(trifluoromethyl)-2-(trifluoromethylsulfonyloxy)pyridine-3-carboxylate To a solution of methyl 5-chloro-2-hydroxy-6-(trifluoromethyl)pyridine-3-carboxylate (4.59 g, 17.96 mmol) in DCM (100 mL) at 0 °C was added DIPEA (10.2 g, 13.8 mL, 79.2 mmol) and trifluoromethanesulfonic anhydride (15.4 g, 9.2 mL, 54.7 mmol). The resulting mixture was stirred at room temperature for 3 h, then diluted with saturated aqueous ammonium chloride (20 mL), and the layers were separated. The aqueous layer was extracted with DCM (3 × 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was adsorbed onto silica gel in vacuo and purified by silica gel chromatography (120 g silica, 0–20% ethyl acetate / heptane) to give methyl 5-chloro-6-(trifluoromethyl)-2-(trifluoromethylsulfonyloxy)pyridine-3-carboxylate (6.36 g, 91%). 1 H NMR(400MHz,CDCl3)δ 8.64(s,1H),4.07(s,3H). 19 F NMR (377 MHz, CDCl3) δ -66.81 (s, 3F), -72.64 (s, 3F). ESI-MS m / z calculated: 386.94, found: 387.9 (M+1). + .

[0390] Step 4: Methyl 5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxylate Methyl 5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxylate was prepared from methyl 5-chloro-6-(trifluoromethyl)-2-(trifluoromethylsulfonyloxy)pyridine-3-carboxylate and 3,4-difluoro-2-methyl-phenol using a procedure similar to that found in Intermediate B-1, Step 1, using DIPEA as the base and DMF as the solvent. 1H NMR(400MHz,CDCl3)δ 8.41(s,1H),7.05(dd,J=18.1,10.0Hz,1H),6.93-6.83(m,1H),4.03(s,3H),2.14(d,J=2.0Hz,3H). 19 F NMR(377MHz,CDCl3)δ-66.69(s,3F),-138.33(d,J=20.4Hz,1F),-140.88(d,J=21.8Hz,1F).ESI-MS m / z calculated value .381.02, measured value 382.0(M+1) + .

[0391] Step 5: 5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxylic acid 5-Chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxylic acid was prepared from methyl 5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxylate using a procedure similar to that found in Intermediate B-11, Step 4. ESI-MS m / z calculated 367.00, found 367.9 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 8.58(s,1H),7.08(dd,J=18.6,9.3Hz,1H),6.93-6.86(m,1H),2.15(d,J=2.0Hz,3H).

[0392] Step 6: tert-butyl N-[5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)-3-pyridyl]carbamate tert-Butyl N-[5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)-3-pyridyl]carbamate was prepared from 5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxylic acid using a procedure similar to that found in Intermediate B-11, Step 5, using tert-butanol as the solvent. ESI-MS m / z calculated 438.08, found 439.1 (M+1). + .

[0393] Step 7: 5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridin-3-amine 5-Chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridin-3-amine was prepared from tert-butyl N-[5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)-3-pyridyl]carbamate using a procedure similar to that found in Intermediate B-11, Step 6. ESI-MS m / z calculated 338.02, found 339.0 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 7.07(s,1H),7.06-6.98(m,1H),6.93-6.84(m,1H),4.42(br.s,2H),2.13(d,J=2.2Hz,3H). 19 F NMR(377MHz,CDCl3)δ-64.18(s,3F),-138.52(d,J=20.4Hz,1F),-141.43(d,J=20.4Hz,1F).

[0394] Step 8: 5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-3-iodo-6-(trifluoromethyl)pyridine To a suspension of 5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridin-3-amine (683 mg, 1.88 mmol) and p-toluenesulfonic acid monohydrate (462 mg, 2.43 mmol) in acetonitrile (20 mL) cooled at 0 °C, isoamyl nitrate (305 mg, 0.35 mL, 2.6 mmol) was slowly added dropwise. The resulting mixture was stirred at 0 °C for 90 minutes. Potassium iodide (400 mg, 2.41 mmol) was added to the mixture at 0 °C, which was stirred at that temperature for 2 hours. The mixture was allowed to warm to room temperature over 1 hour, and the resulting suspension was concentrated under reduced pressure. The mixture was solubilized in ethyl acetate (50 mL), and aqueous sodium bicarbonate (25 mL) was added, followed by water (25 mL). The phases were separated, and the organic layer was washed with aqueous sodium bicarbonate (25 mL), followed by aqueous sodium thiosulfate (2 x 25 mL) and brine (25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-10% ethyl acetate / heptane) gave 5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-3-iodo-6-(trifluoromethyl)pyridine (363 mg, 43%). ESI-MS m / z calculated 448.91, found 450.2 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 8.32(s,1H),7.06(dd,J=19.6,9.2Hz,1H),6.95-6.85(m,1H),2.14(d,J=2.0Hz,3H). 19 F NMR(377MHz,CDCl3)δ-66.31(s,3F),-138.21(d,J=21.8Hz,1F),-140.67(d,J=23.2Hz,1F).

[0395] Step 9: [5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)-3-pyridyl]boronic acid [5-Chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)-3-pyridyl]boronic acid was prepared from 5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-3-iodo-6-(trifluoromethyl)pyridine using a procedure similar to that found in Intermediate B-13, Step 7. ESI-MS m / z calculated 367.02, found 368.1 (M+1).

[0396] Intermediate B-17 [ka]

[0397] Step 1: 5-Fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid 5-Fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid was prepared from 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine using a procedure similar to that found in Intermediate B-13, Step 1. ESI-MS m / z calculated 223.03, found 222.1 (M-1). - . 1 H NMR(400MHz,DMSO-d6)δ 14.74(br s,1H),8.73(s,1H),2.47-2.43(m,3H). 19 F NMR(377MHz,DMSO-d6)δ-62.99(s,1F),-125.50(s,1F).

[0398] Step 2: Methyl 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylate To a stirred mixture of 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid (8.20 g, 36.8 mmol) in methanol (75 mL) at 0 °C, thionyl chloride (4.9 g, 3 mL, 41 mmol) was added dropwise. The reaction mixture was heated to 70 °C and stirred for 24 h. The reaction mixture was cooled to room temperature and partitioned between water and dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate (2x) and brine, dried over sodium sulfate, and then concentrated in vacuo. Purification by silica gel chromatography (0-20% ethyl acetate / heptane) gave methyl 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylate (1.085 g, 8%) as a clear, colorless oil. ESI-MS m / z calculated 237.04, found 238.03 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 8.45(s,1H),4.00(s,3H),2.50-2.48(m,3H). 19 F NMR(376MHz,CDCl3)δ-64.4(s,3F),-124.2(s,1F).

[0399] Step 3: Methyl 5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylate Methyl 5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylate was prepared from methyl 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylate and 2-methoxy-4-(trifluoromethoxy)phenol using a procedure similar to that found in Intermediate B-1, Step 1, using toluene as the solvent. ESI-MS m / z calculated 425.07, found 426.04 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 7.86(s,1H),7.13(d,1H),6.87-6.83(m,2H),3.97(s,3H),3.79(s,3H),2.44-2.44(m,3H).19 F NMR(376MHz,CDCl3)δ-57.9--58.0(m,3F),-64.0--64.0(m,3F).

[0400] Step 4: 5-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid 5-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid was prepared from methyl 5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylate using a procedure similar to that found in Intermediate B-13, Step 4. ESI-MS m / z calculated 411.05, found 411.98 (M+1). + .

[0401] Step 5: 5-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridin-4-amine 5-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridin-4-amine was prepared from 5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid using a procedure similar to that found in Intermediate B-13, Step 5. ESI-MS m / z calculated 382.08, found 383.02 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 7.69(s,1H),7.22(dd,J=8.7,7.3Hz,1H),7.02-6.99(m,1H),6.86-6.78(m,3H),3.83(s,3H),2.28(d,J=1.4Hz,3H). 19 F NMR(376MHz, CDCl3)δ-57.9--58.0(m,3F),-63.3(d,J=18.8Hz,3F).

[0402] Step 6: 4-Bromo-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine 4-Bromo-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine was prepared from 5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridin-4-amine using a procedure similar to that found in Intermediate B-4, Step 6. ESI-MS m / z calculated 444.98, found 445.89 (M+1). + .

[0403] Step 7: 5-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine 5-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine was prepared from 4-bromo-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine using a procedure similar to that found in Intermediate B-13, Step 7. ESI-MS m / z calculated 493.15, found 494.06 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 7.82(s,1H),7.02(d,J=8.2Hz,1H),6.84-6.79(m,2H),3.80(s,3H),2.52(d,J=1.8Hz,3H),1.34(s,12H). 19 F NMR(376MHz,CDCl3)δ-58.0(s,3F),-64.0(d,J=1.6Hz,3F).

[0404] Intermediate B-18 [ka]

[0405] Step 1: 2-Fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoic acid 2-Fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoic acid was prepared using a procedure similar to that found in Intermediate B-4, Step 4, without N,N-dimethylglycine, using toluene as the solvent. 1 H NMR(400MHz,CDCl3)δ 9.40(br.s,1H),7.54(t,J=8.5Hz,1H),7.04-6.99(m,2H),6.98-6.92(m,1H),6.45(d,J=8.9Hz,1H),2.19(s,3H). 19 F NMR(376MHz,CDCl3)δ-60.8(d,J=12.3Hz,3F),-112.1--112.2(m,1F),-116.3(s,1F).

[0406] Step 2: 2-Fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)aniline 2-Fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)aniline was prepared from 2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoic acid using a procedure similar to that found in Intermediate B-13, Step 5. ESI-MS m / z calculated 303.07, found 303.94 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 7.23-7.18(m,1H),6.93-6.89(m,2H),6.83-6.76(m,1H),6.31-6.26(m,1H),2.19(s,3H). 19 F NMR(376MHz,CDCl3)δ-60.6(d,J=12.3Hz,3F),-117.7(s,1F),-135.6(q,J=12.5Hz,1F).

[0407] Step 3: 2-Bromo-3-fluoro-1-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzene 2-Bromo-3-fluoro-1-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzene was prepared from 2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)aniline using a procedure similar to that found in Intermediate B-4, Step 6. 1 H NMR(400MHz,CDCl3)δ 7.43-7.37(m,1H),7.04-6.92(m,3H),6.43-6.37(m,1H),2.17(s,3H). 19 F NMR(376MHz,CDCl3)δ-60.9(d,J=12.3Hz,3F),-103.9--104.0(m,1F),-116.6(s,1F).

[0408] Step 4: 2-[2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2-[2-Fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was prepared from 2-bromo-3-fluoro-1-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzene using a procedure similar to that found in Intermediate B-13, Step 7. 1 H NMR(400MHz,CDCl3)δ 7.45(t,J=8.5Hz,1H),6.99-6.84(m,3H),6.39(d,J=8.8Hz,1H),2.18(s,3H),1.35(s,12H). 19 F NMR(376MHz,CDCl3)δ-60.8(d,J=12.2Hz,3F),-103.6--103.8(m,1F),-118.0(s,1F).

[0409] Intermediate B-19 [ka]

[0410] Step 1: 5-chloro-2-(4-fluoro-2-methyl-phenoxy)-4,6-dimethyl-pyridine-3-carbonitrile 5-Chloro-2-(4-fluoro-2-methyl-phenoxy)-4,6-dimethyl-pyridine-3-carbonitrile was prepared from 2,5-dichloro-4,6-dimethyl-pyridine-3-carbonitrile and 4-fluoro-2-methyl-phenol using a procedure similar to that found in Intermediate B-1, Step 1, using potassium carbonate as the base and NMP as the solvent. ESI-MS m / z calculated 290.06, found 291.2 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 7.04(dd,J=8.8,4.9Hz,1H),6.97(dd,J=8.9,2.8Hz,1H),6.95-6.88(m,1H),2.63(s,3H),2.45(s,3H),2.16(s,3H). 19 F NMR(377MHz,CDCl3)δ-117.65(s,1F).

[0411] Step 2: 5-chloro-2-(4-fluoro-2-methyl-phenoxy)-4,6-dimethyl-pyridine-3-carbonitrile To a solution of 5-chloro-2-(4-fluoro-2-methyl-phenoxy)-4,6-dimethyl-pyridine-3-carbonitrile (1.09 g, 3.75 mmol) in DMSO (25 mL) was added hydrogen peroxide (35% in water) (2.6 mL, 10.394 mmol) and NaOH (2.7 g, 67.5 mmol) at room temperature. The resulting mixture was stirred at 50° C. for 4 hours. The mixture was cooled to 0° C., and then 10% aqueous sodium thiosulfate solution (50 mL) and 5% aqueous citric acid solution (50 mL) were added slowly over 5 minutes. The resulting mixture was stirred for 10 minutes and then extracted with ethyl acetate (3×75 mL). The organic layers were combined, washed with brine (75 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (10-80% ethyl acetate / heptane) afforded 5-chloro-2-(4-fluoro-2-methyl-phenoxy)-4,6-dimethyl-pyridine-3-carboxamide (952 mg, 82%) as a white solid. ESI-MS m / z calculated 308.07, found 309.2 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 7.02-6.86(m,3H),6.13-5.82(m,2H),2.51(s,3H),2.40(s,3H),2.15(s,3H). 19 F NMR(377MHz,CDCl3)δ-118.51(s,1F).

[0412] Step 3: 5-chloro-2-(4-fluoro-2-methyl-phenoxy)-4,6-dimethyl-pyridine-3-carboxylic acid Sulfuric acid (10 g, 5.5 mL, 103 mmol) and 5-chloro-2-(4-fluoro-2-methyl-phenoxy)-4,6-dimethyl-pyridine-3-carboxamide (900 mg, 2.91 mmol) were stirred until dissolution was complete. The solution was cooled to 0 °C, and a solution of sodium nitrite (500 mg, 7.25 mmol) in water (2.5 mL) was added dropwise over 5 minutes. The resulting mixture was allowed to reach room temperature and stirred for 5 hours. 1 M aqueous sodium hydroxide solution was added to the reaction mixture until the pH reached 4-5, and the resulting suspension was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (75 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by reverse-phase chromatography (5-80% acetonitrile / 0.1% formic acid) gave 5-chloro-2-(4-fluoro-2-methyl-phenoxy)-4,6-dimethyl-pyridine-3-carboxylic acid (792 mg, 79%) as a white solid. ESI-MS m / z calculated 309.06, found 310.2 (M+1). + . 1 H NMR(400MHz,DMSO-d6)δ 13.78(br s,1H),7.16(dd,J=9.4,2.6Hz,1H),7.11-7.00(m,2H),2.36(s,3H),2.32(s,3H),2.07(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-118.27--118.47(m,1F).

[0413] Step 4: 5-chloro-2-(4-fluoro-2-methyl-phenoxy)-3-iodo-4,6-dimethyl-pyridine 5-Chloro-2-(4-fluoro-2-methyl-phenoxy)-3-iodo-4,6-dimethyl-pyridine was prepared from 5-chloro-2-(4-fluoro-2-methyl-phenoxy)-3-iodo-4,6-dimethyl-pyridine using a procedure similar to that found in Intermediate B-26, Step 2. ESI-MS m / z calculated 390.97, found 392.0 (M+1). + . 1H NMR(400MHz,CDCl3)δ 7.02-6.97(m,1H),6.95(dd,J=9.2,2.9Hz,1H),6.93-6.86(m,1H),2.67(s,3H),2.36(s,3H),2.15(s,3H). 19 F NMR(377MHz,CDCl3)δ-118.77(s,1F).

[0414] Step 5: 5-chloro-2-(4-fluoro-2-methyl-phenoxy)-4,6-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0415] 5-Chloro-2-(4-fluoro-2-methyl-phenoxy)-4,6-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was prepared from 5-chloro-2-(4-fluoro-2-methyl-phenoxy)-3-iodo-4,6-dimethyl-pyridine using a procedure similar to that found in Intermediate B-2, Step 4. ESI-MS m / z calculated 391.15, found 392.2 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 6.99-6.89(m,2H),6.88-6.82(m,1H),2.43(s,3H),2.38(s,3H),2.18(s,3H),1.37(s,12H). 19 F NMR(377MHz,CDCl3)δ-119.98(s,3F).

[0416] Intermediate B-20 [ka]

[0417] Step 1: 3-Bromo-2-(4,4-difluoroazepan-1-yl)quinoline A solution of 2,3-dibromoquinoline (8.16 g, 28.4 mmol) and 4,4-difluoroazepane hydrochloride (5.0 g, 29 mmol) in NMP (65 mL) was treated with KCO (7.9 g, 57.16 mmol) and heated at 80–85 °C for 2 h. Additional 4,4-difluoroazepane hydrochloride (0.5 g, 2.9 mmol) was added, and the mixture was stirred at 80–85 °C for an additional 19 h. Additional 4,4-difluoroazepane hydrochloride (0.5 g, 2.9 mmol) was added, and the mixture was stirred at 80–85 °C for an additional 6 h. The mixture was extracted with MTBE (250 mL) / water (500 mL), and the organic phase was washed with water (500 mL) and brine (200 mL). The aqueous phase was extracted with additional MTBE (100 mL) and the combined organic phases were dried, filtered and evaporated to give 3-bromo-2-(4,4-difluoroazepan-1-yl)quinoline (9.48 g, 94%). ESI-MS m / z calculated 340.04, found 341.0 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 8.26(s,1H),7.84-7.70(m,1H),7.66-7.52(m,2H),7.34(td,J=7.2,1.2Hz,1H), 3.86-3.61(m,4H),2.58-2.38(m,2H),2.35-2.13(m,2H),2.08-1.92(m,2H)ppm; 19 F NMR (376 MHz, CDCl3) δ -88.51.

[0418] Step 2: [2-(4,4-difluoroazepan-1-yl)-3-quinolyl]boronic acid n-BuLi (16 mL of 1.6 M in hexanes, 25.6 mmol) was added slowly to a stirred solution of 3-bromo-2-(4,4-difluoroazepan-1-yl)quinoline (7.42 g, 20.95 mmol) in diethyl ether (95 mL) at −78° C. under argon. The mixture was stirred at −78° C. for 1 hour and then treated dropwise with a solution of trimethyl borate (3.3 g, 3.5 mL, 31 mmol) in diethyl ether (35 mL). The reaction was allowed to warm to room temperature and stirred for 18 hours. The mixture was diluted with saturated aqueous ammonium chloride (200 mL) and extracted with ethyl acetate (200 mL). The organic extract was washed with brine (200 mL), dried over magnesium sulfate, filtered, and concentrated. The solid was triturated with 10% ethyl acetate in heptane (10 vol), filtered, and dried to give [2-(4,4-difluoroazepan-1-yl)-3-quinolyl]boronic acid (2.6 g, 32%) as a white solid. ESI-MS m / z calculated 306.14, found 307.15 (M+1). + . 1 H NMR(400MHz,CD3OD)δ 8.00(s,1H)7.64(t,J=7.1Hz,2H),7.54-7.50(m,1H),7.24-7.19(m,1H),3.8 5-3.82(m,2H),3.67(t,J=5.5Hz,2H),2.45-2.35(m,2H),2.08-2.00(m,4H). 19 F NMR(376MHz,CD3OD)δ-92.0--92.1(m,2F).

[0419] Intermediate B-21 [ka]

[0420] Step 1: Methyl 2-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylate Methyl 2-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylate was prepared from methyl 2-chloro-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylate (Intermediate B-11, Step 2) and 4,4-difluoroazepane using a procedure similar to that found in Intermediate B-20, Step 1, using cesium carbonate as the base and DMF as the solvent. ESI-MS m / z calculated 352.12, found 353.15 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 7.79(s,1H),3.89(s,3H),3.74-3.67(m,2H),3.31-3.24(m,2H),2.44-2.28(m,5H),2.02-1.89(m,4H).

[0421] Step 2: 2-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid 2-(4,4-Difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid was prepared from methyl 2-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylate using a procedure similar to that found in Intermediate B-11, Step 4. ESI-MS m / z calculated 338.11, found 338.99 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 8.09(s,1H),3.57-3.50(m,2H),3.32(t,J=6.0Hz,2H),2.43-2.30(m,5H),2.13-2.04(m,2H),1.97-1.90(m,2H).

[0422] Step 3: 1-[3-bromo-5-methyl-6-(trifluoromethyl)-2-pyridyl]-4,4-difluoro-azepane A vial was charged with 2-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid (1.5 g, 4.4 mmol), potassium phosphate (941 mg, 4.43 mmol), and tetrabutylammonium tribromide (3.2 g, 6.6 mmol). The vial was capped and purged with nitrogen. Acetonitrile (22 mL) was added via syringe, and the reaction was stirred at 90 °C for 1.5 h. The reaction was cooled and concentrated under reduced pressure. Purification by reverse-phase chromatography (C18, 1–99% acetonitrile / 5 mM HCl) afforded 1-[3-bromo-5-methyl-6-(trifluoromethyl)-2-pyridyl]-4,4-difluoroazepane (1.3 g, 79%) as a yellow oil. ESI-MS m / z calculated: 372.03, observed: 372.9 (M+1) + . 1 H NMR(400MHz,CDCl3)δ 7.70(s,1H),3.73-3.62(m,2H),3.64-3.56(m,2H),2.50-2.36(m,2H),2.34(s,3H),2.26-2.06(m,2H),2.06-1.86(m,2H).

[0423] Step 4: 4,4-Difluoro-1-[5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-2-pyridyl]azepane 4,4-Difluoro-1-[5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-2-pyridyl]azepane was prepared from 1-[3-bromo-5-methyl-6-(trifluoromethyl)-2-pyridyl]-4,4-difluoroazepane using a procedure similar to that found in Intermediate B-20, Step 2, and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. ESI-MS m / z calculated 420.21, found 339.12 (M-pinacol). + ; Mass of the corresponding boronic acid observed by LC / MS. 1H NMR(400MHz,CDCl3)δ 7.66(s,1H),3.73-3.70(m,2H),3.52(t,J=5.5Hz,2H),2.37-2.26(m,5H),2.01-1.91(m,4H),1.34(s,12H).

[0424] Intermediate B-22 [ka]

[0425] Step 1: 3-Bromo-2-(4,4-difluoro-1-piperidyl)-5-(trifluoromethyl)pyridine To a solution of 3-bromo-2-fluoro-5-(trifluoromethyl)pyridine (1.224 g, 5.017 mmol) in THF (6 mL) was added dropwise a solution of 4,4-difluoropiperidine (1.22 g, 10.1 mmol) in THF (2 mL) at 0 °C. The mixture was removed from the ice bath, allowed to reach room temperature over 1 h, and then heated at 50 °C for 24 h. The mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed with 50% saturated aqueous NH4Cl, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (40 g silica, 10–100% ethyl acetate / hexanes) gave 3-bromo-2-(4,4-difluoro-1-piperidyl)-5-(trifluoromethyl)pyridine (1.68 g, 97%). ESI-MS m / z calculated: 343.99, observed: 345.0 (M+1) + . 1 H NMR(400MHz,DMSO-d6)δ 8.62(dd,J=2.2,1.1Hz,1H),8.40-8.35(m,1H),3.58-3.51(m,4H),2.19-2.06(m,4H).

[0426] Step 2: [2-(4,4-Difluoro-1-piperidyl)-5-(trifluoromethyl)-3-pyridyl]boronic acid [2-(4,4-Difluoro-1-piperidyl)-5-(trifluoromethyl)-3-pyridyl]boronic acid was prepared from 3-bromo-2-(4,4-difluoro-1-piperidyl)-5-(trifluoromethyl)pyridine using intermediate B-3, a procedure similar to that found in step 3, and triisopropyl borate. ESI-MS m / z calculated 310.09, found 311.0 (M+1). + . 1 H NMR(400MHz,DMSO-d6)δ 8.42(dd,J=2.6,1.2Hz,1H),7.79(d,J=2.6Hz,1H),3.66-3.55(m,4H),2.16-1.98(m,4H).

[0427] Intermediate B-23 [ka]

[0428] Step 1: 1-[3-bromo-6-(trifluoromethyl)-2-pyridyl]-4,4-difluoro-azepane 1-[3-Bromo-6-(trifluoromethyl)-2-pyridyl]-4,4-difluoroazepane was prepared from 3-bromo-2-fluoro-6-(trifluoromethyl)pyridine using a procedure similar to that found in Intermediate B-20, Step 1, using DMSO as the solvent and DIEA as the base. ESI-MS m / z calculated 358.01, found 359.0 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 7.87(dd,J=7.8,0.9Hz,1H),6.97(d,J=7.9Hz,1H),3.77-3.65(m,4H),2.49-2.34(m,2H),2.23-2.08(m,2H),2.03-1.92(m,2H).

[0429] Step 2: [2-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)-3-pyridyl]boronic acid [2-(4,4-Difluoroazepan-1-yl)-6-(trifluoromethyl)-3-pyridyl]boronic acid was prepared from 1-[3-bromo-6-(trifluoromethyl)-2-pyridyl]-4,4-difluoroazepane using intermediate B-20, a procedure similar to that found in Step 2, and triisopropyl borate. ESI-MS m / z calculated: 324.11, found: 325.2 (M+1). + . 1 H NMR(400MHz,DMSO-d6)δ 7.72-7.62(m,1H),7.00(dd,J=7.3,1.3Hz,1H),3.71-3.60(m,2H),3.54-3.46(m,3H),2.39-2.18(m,2H),2.13-1.83(m,5H).

[0430] Intermediate B-24 [ka]

[0431] Step 1: 4,4-Difluoro-1-[6-methyl-5-(trifluoromethyl)-2-pyridyl]azepane 4,4-Difluoro-1-[6-methyl-5-(trifluoromethyl)-2-pyridyl]azepane was prepared from 6-chloro-2-methyl-3-(trifluoromethyl)pyridine using a procedure similar to that found in Intermediate B-20, Step 1, with DMSO as solvent. ESI-MS m / z calculated 294.12, found 295.5 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 7.60(d,J=8.9Hz,1H),6.30(d,J=8.9Hz,1H),3.81-3.76(m,2H),3.65(t ,J=6.1Hz,2H),2.54-2.49(m,3H),2.30-2.16(m,2H),2.11-1.94(m,4H).

[0432] Step 2: 1-[3-bromo-6-methyl-5-(trifluoromethyl)-2-pyridyl]-4,4-difluoro-azepane 4,4-Difluoro-1-[6-methyl-5-(trifluoromethyl)-2-pyridyl]azepane (1.29 g, 4.38 mmol) and NBS (786 mg, 4.42 mmol) were combined in DCM (25 mL) and stirred at room temperature for 16 h. The reaction was evaporated and the resulting material purified by silica gel chromatography (0-20% ethyl acetate / hexanes) to give 1-[3-bromo-6-methyl-5-(trifluoromethyl)-2-pyridyl]-4,4-difluoroazepane (1.34 g, 82%) as a clear oil. ESI-MS m / z calculated 372.03, found 373.2 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 7.86(s,1H),3.77(t,J=6.3Hz,2H),3.74-3.69(m,2H),2.50-2.46(m,3H),2.46-2.33(m,2H),2.19-2.06(m,2H),2.01-1.93(m,2H).

[0433] Step 3: [2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)-3-pyridyl]boronic acid [2-(4,4-Difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)-3-pyridyl]boronic acid was prepared from 1-[3-bromo-6-methyl-5-(trifluoromethyl)-2-pyridyl]-4,4-difluoroazepane using a procedure similar to that found in Intermediate B-20, Step 2. ESI-MS m / z calculated 338.12, found 339.3 (M+1). + . 1 H NMR(400MHz,CD3OD)δ 7.62(s,1H),3.80-3.75(m,2H),3.54-3.48(m,2H),2.48(s,3H),2.36-2.21(m,2H),2.00-1.92(m,4H).

[0434] Intermediate B-25 [ka]

[0435] Step 1: [5-chloro-3-iodo-6-(trifluoromethyl)-2-pyridyl]trifluoromethanesulfonate [5-Chloro-3-iodo-6-(trifluoromethyl)-2-pyridyl]trifluoromethanesulfonate was prepared from 5-chloro-3-iodo-6-(trifluoromethyl)pyridin-2-ol (Intermediate B-16, Step 1) using a procedure similar to that found in Intermediate B-16, Step 3. ESI-MS m / z calculated 454.83, found 456.0 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 8.45(s,1H). 19 F NMR(377MHz,CDCl3)δ-66.56(s,3F),-71.85(s,3F).

[0436] Step 2: 1-[5-chloro-3-iodo-6-(trifluoromethyl)-2-pyridyl]-4,4-difluoro-azepane 1-[5-Chloro-3-iodo-6-(trifluoromethyl)-2-pyridyl]-4,4-difluoroazepane was prepared from [5-chloro-3-iodo-6-(trifluoromethyl)-2-pyridyl]trifluoromethanesulfonate using a procedure similar to that found in Intermediate B-20, Step 1, using DIPEA as the base and DMF as the solvent. ESI-MS m / z calculated 439.96, found 441.2 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 8.17(s,1H),3.71-3.57(m,4H),2.47-2.33(m,2H),2.24-2.09(m,2H),2.02-1.92(m,2H). 19 F NMR(377MHz,CDCl3)δ-66.38(s,3F),-89.34(quin,J=15.0Hz,2F).

[0437] Step 3: [5-chloro-2-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)-3-pyridyl]boronic acid [5-Chloro-2-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)-3-pyridyl]boronic acid was prepared from 1-[5-chloro-3-iodo-6-(trifluoromethyl)-2-pyridyl]-4,4-difluoroazepane using a procedure similar to that found in Intermediate B-20, Step 2, with triisopropyl borate and THF as solvent. ESI-MS m / z calculated 358.07, found 359.1 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 7.14(s,1H),5.35(s,2H),3.80-3.72(m,2H),3.66(t,J=6.2Hz,2H),2.31-2.17(m,2H),2.12-1.94(m,4H). 19 F NMR(377MHz,CDCl3)δ-65.93(s,3F),-91.23(quin,J=14.3Hz,2F).

[0438] Intermediate B-26 [ka]

[0439] Step 1: 5-chloro-2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-pyridine-3-carboxylic acid 5-Chloro-2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-pyridine-3-carboxylic acid was prepared from 2,5-dichloro-4,6-dimethyl-pyridine-3-carboxylic acid and 4,4-difluoroazepane hydrochloride using a procedure similar to that found in Intermediate B-20, Step 1. ESI-MS m / z calculated 318.09, found 319.2 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 3.50-3.43(m,2H),3.36(t,J=6.0Hz,2H),2.74(s,3H),2.61(s,3H),2.51-2.37(m,2H),2.31-2.16(m,2H),2.02(dt,J=11.7,6.0Hz,2H). 19F NMR(377MHz,CDCl3)δ-88.93(br s,2F).

[0440] Step 2: 1-(5-chloro-3-iodo-4,6-dimethyl-2-pyridyl)-4,4-difluoro-azepane A solution of 5-chloro-2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-pyridine-3-carboxylic acid (1.0 g, 3.1 mmol), potassium phosphate (670 mg, 3.16 mmol), and iodine (2.42 g, 9.54 mmol) in acetonitrile (15 mL) was purged with nitrogen for 5 minutes. The reaction vessel was sealed, and the mixture was stirred at 100 °C for 3 hours. The reaction mixture was cooled to room temperature, diluted with 10% aqueous sodium thiosulfate (50 mL) and saturated aqueous sodium bicarbonate (50 mL), and extracted with dichloromethane (3 × 75 mL). The combined extracts were washed with 10% sodium thiosulfate (2 × 50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was adsorbed onto silica gel under vacuum and purified by silica gel chromatography (0-10% ethyl acetate / heptane) to give 1-(5-chloro-3-iodo-4,6-dimethyl-2-pyridyl)-4,4-difluoroazepane (1.03 g, 82%) as a light yellow oil. ESI-MS m / z calculated 400.00, found 401.0 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 3.42-3.33(m,4H),2.63(s,3H),2.50(s,3H),2.42-2.24(m,4H),1.98-1.91(m,2H). 19 F NMR(377MHz,CDCl3)δ-86.90(quin,J=15.7Hz,2F).

[0441] Step 3: [5-chloro-2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-3-pyridyl]boronic acid [5-Chloro-2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-3-pyridyl]boronic acid was prepared from 1-(5-chloro-3-iodo-4,6-dimethyl-2-pyridyl)-4,4-difluoroazepane using a procedure similar to that found in Intermediate B-20, Step 2. ESI-MS m / z calculated: 318.11, found: 319.1 (M+1). + . 1 H NMR(400MHz,DMSO-d6)δ 3.66-3.59(m,6H),2.41(s,3H),2.34-2.15(m,5H),2.11-1.93(m,2H),1.92-1.76(m,2H).

[0442] Intermediate B-27 [ka]

[0443] Step 1: 2-(4,4-difluoroazepan-1-yl)-5,6,7,8-tetrahydroquinoline 2-Chloro-5,6,7,8-tetrahydroquinoline (505 mg, 3.01 mmol), 4,4-difluoroazepane hydrochloride (535 mg, 3.12 mmol), potassium carbonate (1.321 g, 9.558 mmol), dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (88.6 mg, 0.190 mmol), and diacetoxypalladium (35 mg, 0.16 mmol) were combined in DMSO (2.5 mL). The reaction mixture was flushed with nitrogen and heated at 110 °C for 24 h. The reaction was cooled, diluted with DCM (2 mL), and purified by silica gel chromatography (0–10% methanol / dichloromethane) to give 2-(4,4-difluoroazepan-1-yl)-5,6,7,8-tetrahydroquinoline (532 mg, 66%). ESI-MS m / z calculated: 266.16, observed: 267.4 (M+1) + . 1H NMR(400MHz,CDCl3)δ 7.15(d,J=8.5Hz,1H),6.28(d,J=8.5Hz,1H),3.74-3.68(m,2H),3.60(t,J=6.2Hz,2H),2.72(t,J=6.4H z,2H),2.65-2.57(m,2H),2.28-2.14(m,2H),2.09-1.90(m,4H),1.87-1.79(m,2H),1.79-1.72(m,2H).

[0444] Step 2: 3-Bromo-2-(4,4-difluoroazepan-1-yl)-5,6,7,8-tetrahydroquinoline 3-Bromo-2-(4,4-difluoroazepan-1-yl)-5,6,7,8-tetrahydroquinoline was prepared from 2-(4,4-difluoroazepan-1-yl)-5,6,7,8-tetrahydroquinoline using a procedure similar to that found in Intermediate B-24, Step 2. ESI-MS m / z calculated 344.07, found 345.2 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 7.46(s,1H),3.56-3.47(m,4H),2.71(t,J=6.4Hz,2H),2.64(t,J=6.3Hz,2H),2.44-2. 29(m,2H),2.27-2.13(m,2H),1.97-1.88(m,2H),1.88-1.79(m,2H),1.79-1.71(m,2H).

[0445] Step 3: [2-(4,4-difluoroazepan-1-yl)-5,6,7,8-tetrahydroquinolin-3-yl]boronic acid [2-(4,4-difluoroazepan-1-yl)-5,6,7,8-t...

Claims

1. Compound of formula (I), 【Chemical 301】 or a pharmaceutically acceptable salt thereof, in the formula, A, 【Chemical 302】 And, L is -O-, single bond, -O-C(R) ２ -, -C(R) ２ -, -C(R) ２ -O- or -N(R)-, Each R can independently be H, halo, or C １ -C ６ It is alkyl, X ２ is N or CR ２ and X ４ is N or CR ４ and X ５ However, N or CR ５ And, X ６ However, N or CR ６ And, X ７ However, N or CR ７ And, Y １ However, N or CR １ａ And, Y ２ However, N, ＋ N-O － , or CR ２ａ And, Y ３ However, N or CR ３ａ And, R ２ However, H, Haro, C １ -C ６ Alkyl, (C １ -C ６ Alkylene)-NR ８ R ９ , C ２ -C ６ Alkenil, C １ -C ６ Alkoxy, (C １ -C ６ Alkylene)-OH,C(O)OR ８ , or CH(OH)(CH ２ ) ｍ (CHOH) ｎ (CH ２ ) ｐ It is H, R ４ , R ５ , R ６ , and R ７ However, (i) R ４ , R ５ , R ６ , and R ７ However, each is independent of H, Haro, and C. １ -C ６ Alkyl, C １ -C ６ C is a haloalkyl group, or a C group optionally substituted with one or more alkyl, halo, or OH groups. ３ -C ６ Assuming it is a cycloalkyl, (ii) R ４ and R ７ However, each is independent of H, Haro, and C. １ -C ６ Alkyl, C １ -C ６ C is substituted as needed with a haloalkyl or one or more halos. ３ -C ６ It is a cycloalkyl, R ５ and R ６ However, together with the carbon atoms to which they are bonded, the formula is: 【Chemical 303】 As forming a ring, or (iii) R ４ and R ７ However, each is independent of H, Haro, and C. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ C substituted with cycloalkyl or one or more halos ３ -C ６ It is a cycloalkyl, R ５ and R ６ However, together with the carbon atoms to which they are bonded, the formula is: 【Chemical 304】 Defined as forming a ring, R ８ and R ９ However, each independently, H or C １ -C ６ It is alkyl, Each R １０ However, independently, it is H or halo. R １ａ is H, halo, CN, C １ -C ６ -alkyl, OH, C(O)NR １２ R １３ , C １ -C ６ -alkoxy, NR １２ R １３ , NR ８ C(O)NR ８ R ９ , (C １ -C ６ -alkylene)-C(O)NR ８ R ９ , (C １ -C ６ -alkylene)-OH, C(O)OR １２ , OR １２ , CH(OH)(CH ２ ) ｍ (CHOH) ｎ (CH ２ ) ｐ H, N=S(=O)(CH ３ ) ２ , N=S(=O)R'R'', a 5- to 10-member heteroaryl, or a 4- to 10-member heterocyclyl, wherein the heterocyclyl or heteroaryl in the 5- to 10-member heteroaryl or 4- to 10-member heterocyclyl is OH, halo, oxo, C(O)NR ８ R[[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ R' and R'', together with the S atom to which they are bonded, form a 4- to 7-membered heterocycline. R １１ , R ２ａ , and R ３ａ However, each is independent of H, Halo, CN, and C. １ -C ６ Alkyl, C(O)NR ８ R ９ , or C １ -C ６ It is an alkoxy, R １２ and R １３ However, each is independent of H, C(O)(C １ -C ６ (Alkyl), (C １ -C ６ Alkylene)-NR ８ R ９ ,CH ２ CH(OH)(CH ２ ) ｍ (CHOH) ｎ (CH ２ ) ｐ H, and C which is substituted as needed with one or more OH groups. １ -C ６ Alkyl, indanyl, (C １ -C ６ Alkylene) - (C ３ -C ６ Cycloalkyl), (C １ -C ６ Alkylene)-phenyl, (C １ -C ６ Alkilen)-(5-membered heterocycline), C ４ -C ７ Cycloalkyl, C ６ -C １０ The aryl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, and the indanyl, (C １ -C ６ Alkylene) - (C ３ -C ６ Cycloalkyl), (C １ -C ６ Alkylene)-phenyl, (C １ -C ６ Alkilen)-(5-membered heterocycline), C ４ -C ７ Cycloalkyl, C ６ -C １０ Aryl, 5-6 member heteroaryl, or 4-7 member heterocyclyl are OH, oxo, C １ -C ６ Alkyl, (C １ -C ６ Alkylene)-OH, and C １ -C ６ Substituting as needed with 1 to 4 substituents selected from alkoxys, Z １ However, the 3-10 member cycloalkyl, 3-10 member cycloalkenyl, phenyl, 4-10 member heterocyclyl, or 5-6 member heteroaryl is unsubstituted, or halo, OH, CD ３ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, CH ２ OH, C(O)H, and C １ -C ６ It may be substituted with 1 to 4 substituents selected from haloalkoxys. m, n, and p are each independently 0 or 1. q is 1, 2, or 3, X ２ If it is N, L is O, Z １ However, it is phenyl, and the phenyl is halo, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl and C １ -C ６ Substituting with 2 to 4 substituents selected from haloalkoxys, or L is a single bond, Z １ However, it is a 4- to 10-membered heterocycline, and the said 4- to 10-membered heterocycline is a halo, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl and C １ -C ６ Substituted with 2 to 4 substituents selected from haloalkoxys, X ２ , X ４ , X ５ , X ６ , and X ７ However, each is CH, L is a single bond, and Z １ However, if it is phenyl, then the phenyl is halo, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl and C １ -C ６ A compound, or a pharmaceutically acceptable salt thereof, substituted with one to four substituents selected from haloalkoxys.

2. A, 【Chemical 305】 And, R １ａ However, H, Halo, CN, C １ -C ６ Alkyl, OH, C(O)NR １２ R １３ , C １ -C ６ Alkoxy, NR １２ R １３ , (C １ -C ６ Alkylene)-C(O)NR ８ R ９ , (C １ -C ６ Alkylene)-OH,C(O)OR １２ , CH(OH)(CH ２ ) ｍ (CHOH) ｎ (CH ２ ) ｐ H, or N=S (=O) (CH ３ ) ２ And, R １２ and R １３ However, each is independent of H, C(O)(C １ -C ６ (Alkyl), (C １ -C ６ Alkylene)-NR ８ R ９ ,CH ２ CH(OH)(CH ２ ) ｍ (CHOH) ｎ (CH ２ ) ｐ H, and C which is substituted as needed with one or more OH groups. １ -C ６ The compound according to claim 1, which is alkyl, or a pharmaceutically acceptable salt thereof.

3. L is a single bond or -C(R) ２ - and X ２ However, CR ２ And, Z １ However, the member is a 4-10 member cycloalkyl, a 3-10 member cycloalkenyl, a phenyl, or a 5-6 member heteroaryl, and the 4-10 member cycloalkyl, 3-10 member cycloalkenyl, phenyl, or 5-6 member heteroaryl may be unsubstituted, or halo, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl and C １ -C ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which can be substituted with one to four substituents selected from haloalkoxys.

4. The aforementioned compound is of formula (I-A-1) 【Chemical 306】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the above.

5. The aforementioned compound is of formula (I-A-2) 【Chemical 307】 It has, in the formula, Each R １４ However, halo, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl and C １ -C ６ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from haloalkoxys, wherein each R14 is optionally a halo or C1-C6 haloalkyl.

6. Y ２ However, N is, and / or, R4, R5, R6, and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl which may be optionally substituted with one or more alkyl, halo, or OH groups, and / or Y1 is CR1a, and optionally R1a is C(O)NR12R13, and optionally R12 and R13 are H, and / or R² is H, and / or, The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L is a single bond.

7. L is a single bond, X ２ However, CR ２ And, R １ａ However, H, Halo, CN, OH, C(O)NR １２ R １３ , C １ -C ６ Alkoxy, -NR １２ R １３ , (C １ -C ６ Alkylene)-C(O)NR ８ R ９ , (C １ -C ６ Alkylene)-OH,C(O)OR １２ , CH(OH)(CH ２ ) ｍ (CHOH) ｎ (CH ２ ) ｐ H, or N=S (=O) (CH ３ ) ２ And, Z １ However, it is a 4- to 10-membered heterocycline, and the 4- to 10-membered heterocycline may be unsubstituted, or halo, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl and C １ -C ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which can be substituted with one to four substituents selected from haloalkoxys.

8. The aforementioned compound is of formula (I-B-1) 【Chemical 309】 A compound according to claim 7, or a pharmaceutically acceptable salt thereof, having the above.

9. The aforementioned compound is of formula (I-B-2) 【Chemical 310】 It has, in the formula, Each R １４ However, halo, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl and C １ -C ６ A compound according to claim 7, or a pharmaceutically acceptable salt thereof, selected from haloalkoxys, wherein each R14 is optionally a halo.

10. Y ２ However, N is, and / or, R4, R5, R6, and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl which may be optionally substituted with one or more alkyl, halo, or OH groups, and / or Y1 is CR1a, and optionally R1a is C(O)NR12R13, and optionally R12 and R13 are H, and / or The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein R2 is a C1-C6 alkoxy.

11. L is O, -O-C(R) ２ - or -C(R) ２ -O-, Z １ However, the compound is phenyl, a 4-10 member heterocyclyl, or a 5-6 member heteroaryl, and the phenyl, 4-10 member heterocyclyl, or 5-6 member heteroaryl may be unsubstituted, or halo, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, CH ２ OH, C(O)H, and C １ -C ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which can be substituted with one to four substituents selected from haloalkoxys.

12. The aforementioned compound is of formula (I-C-1) 【Chemical 312】 A compound according to claim 11, or a pharmaceutically acceptable salt thereof, having the above.

13. The aforementioned compound is of formula (I-C-2) 【Chemistry 313】 It has, in the formula, each R １４ However, halo, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl and C １ -C ６ A compound according to claim 11, selected from haloalkoxys, or a pharmaceutically acceptable salt thereof.

14. Y ２ However, N is, and / or, R4, R5, R6, and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl which may be optionally substituted with one or more alkyl, halo, or OH groups, and / or Y1 is CR1a, and optionally R1a is C(O)NR12R13, and optionally R12 and R13 are H, and / or The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein X2 is CR2 and R2 is H.

15. L is either -O- or a single bond. X ４ However, CR ４ And, X ６ However, CR ６ And, R ４ , R ５ , R ６ , and R ７ However, each is independent of H, Haro, and C. １ -C ６ Alkyl, C １ -C ６ C is substituted as needed with a haloalkyl or one or more halos. ３ -C ６ It is a cycloalkyl, Z １ However, it is a 3- to 10-membered cycloalkyl or phenyl, and the 3- to 10-membered cycloalkyl or phenyl may be unsubstituted, or halo, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, and C １ -C ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which can be substituted with one to four substituents selected from haloalkyl groups.

16. A, 【Chemical Industry 315】 And, X ２ However, CR ２ And, Y １ However, CR １ａ And, Y ２ However, N or CR ２ａ And, Y ３ However, CR ３ａ And, R １１ , R ２ａ , and R ３ａ However, each of them is H, R １ａ However, C(O)NR １２ R １３ , NR １２ R １３ , NR ８ C(O)NR ８ R ９ , OR １２ , N=S(=O)R'R'', 5-10 member heteroaryl, or 4-10 member heterocyclyl, wherein the heterocyclyl or heteroaryl in the 5-10 member heteroaryl or 4-10 member heterocyclyl is OH, halo, oxo, C(O)NR ８ R ９ , NR ８ R ９ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, (C １ -C ６ Alkylene)-OH, (C １ -C ６ Alkylene)-O-(C) １ -C ６ (alkyl), and (C １ -C ６ Alkylene)-NR ８ R ９ Substituting as needed with 1 to 4 substituents selected from: R' and R'', together with the S atom to which they are bonded, form a 4- to 7-membered heterocycline. R １２ and R １３ However, each is independent of H, C(O)(C １ -C ６ (Alkyl), (C １ -C ６ Alkylene)-NR ８ R ９ ,CH ２ CH(OH)(CH ２ ) ｍ (CHOH) ｎ (CH ２ ) ｐ H, and C which is substituted as needed with one or more OH groups. １ -C ６ Alkyl, indanyl, (C １ -C ６ Alkylene) - (C ３ -C ６ Cycloalkyl), (C １ -C ６ Alkylene)-phenyl, (C １ -C ６ Alkilen)-(5-membered heterocycline), C ４ -C ７ Cycloalkyl, C ６ -C １０ The aryl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, and the indanyl, (C １ -C ６ Alkylene) - (C ３ -C ６ Cycloalkyl), (C １ -C ６ Alkylene)-phenyl, (C １ -C ６ Alkilen)-(5-membered heterocycline), C ４ -C ７ Cycloalkyl, C ６ -C １０ Aryl, 5-6 member heteroaryl, or 4-7 member heterocyclyl are OH, oxo, C １ -C ６ Alkyl, (C １ -C ６ Alkylene)-OH, and C １ -C ６ The compound according to claim 15, or a pharmaceutically acceptable salt thereof, optionally substituted with one to four substituents selected from alkoxys.

17. (i) R １ａ However, C(O)NR １２ R １３ And, R １２ and R １３ However, each is independently substituted with H and one or more OH groups as needed. １ -C ６ Alkyl, (C １ -C ６ Alkylene) - (C ３ -C ６ Cycloalkyl), (C １ -C ６ Alkylene)-phenyl, (C １ -C ６ Alkilen)-(5-membered heterocycline), C ４ -C ７ Cycloalkyl, C ６ -C １０ The aryl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, and the (C １ -C ６ Alkylene) - (C ３ -C ６ Cycloalkyl), (C １ -C ６ Alkylene)-phenyl, (C １ -C ６ Alkilen)-(5-membered heterocycline), C ４ -C ７ Cycloalkyl, C ６ -C １０ Aryl, 5-6 member heteroaryl, or 4-7 member heterocyclyl are OH, oxo, C １ -C ６ Alkyl, (C １ -C ６ Alkylene)-OH, and C １ -C ６ It may be substituted as needed with one to four substituents selected from alkoxys, or (ii) R1a is a 4- to 10-membered heterocycline, wherein the heterocycline in the 4- to 10-membered heterocycline is optionally substituted with 1 to 4 substituents selected from OH, oxo, C(O)NR8R9, NR8R9, C1-C6 alkyl, and C1-C6 alkoxy, (iii) R 1a is a 5- to 10-membered heteroaryl, and the heteroaryl in the 5- to 10-membered heteroaryl is optionally substituted with 1 to 4 substituents selected from halo, oxo, C(O)NR 8 R 9, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkylene)-OH, (C1-C6 alkylene)-O-(C1-C6 alkyl), and (C1-C6 alkylene)-NR 8 R 9, or (iv) R 1a is NR 12 R 13, R 12 is H, R 13 is a (C1-C6 alkylene)-(5-membered heterocycline), C4-C7 cycloalkyl, C6-C10 aryl, 5-6 membered heteroaryl, or 4-7 membered heterocycline, wherein the (C1-C6 alkylene)-(5-membered heterocycline), C4-C7 cycloalkyl, C6-C10 aryl, 5-6 membered heteroaryl, or 4-7 membered heterocycline is optionally substituted with 1-4 substituents selected from OH, oxo, C1-C6 alkyl, and (C1-C6 alkylene)-OH, or (v) R 1a is OR 12, R12 is a C3-C6 cycloalkyl or a 5-6 membered heterocycline, and the C3-C6 cycloalkyl or 5-6 membered heterocycline is optionally substituted with 1-4 substituents of a C1-C6 alkoxy, or (vi) R 1a is NR 12 R 13, R12 and R13 are each independently H, C(O)(C1-C6 alkyl), or (C1-C6 alkylene)-NR8R9, or (vii) R 1a is N = S (= O) R'R'', The compound according to claim 16, or a pharmaceutically acceptable salt thereof, wherein R' and R'', together with the S atom to which they are bound, form a 4- to 7-membered heterocycline.

18. L is -O-, A, 【Chemical 316】 And, X ２ However, CR ２ And, X ４ However, CR ４ And, X ５ However, CR ５ And, X ６ However, CR ６ And, Y １ However, CR １ａ And, Y ３ However, CR ３ａ And, R ２ However, it is H, R ４ , R ５ , R ６ , and R ７ However, each is independent of H, Haro, and C. １ -C ６ Alkyl, or C １ -C ６ It is a haloalkyl, R ８ and R ９ However, each independently, H or C １ -C ６ It is alkyl, R １ａ However, C(O)NR １２ R １３ Or NR ８ C(O)NR ８ R ９ And, R １２ and R １３ However, each of them is H, Z １ However, it is phenyl, and the phenyl may be unsubstituted, or a halo or C １ -C ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which can be substituted with one to four substituents selected from alkyl groups.

19. A, 【Chemical 317】 And, R １ａ However, NR ８ C(O)NR ８ R ９ The compound according to claim 18, or a pharmaceutically acceptable salt thereof.

20. A, 【Chemical 318】 And, R １ａ However, C(O)NR １２ R １３ The compound according to claim 18, or a pharmaceutically acceptable salt thereof.

21. Compounds of formula (II) or (III), 【Chem.320】 or a pharmaceutically acceptable salt thereof, in the formula, B, 【Chemistry 321】 And, L ２ However, single bonds or -CH ２ - and X １２ However, it is CH or N, R １４ However, H, halo, or C １ -C ６ It is an alkoxy, R ８ａ and R ９ａ However, (i) R ８ａ and R ９ａ However, each is independent of H, Haro, and C. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, or C １ -C ６ Alkyl, halo, and C １ -C ６ C is optionally substituted with 1 to 4 substituents selected from haloalkyl groups. ３ -C ６ Assuming it is a cycloalkyl, (ii) R ８ａ and R ９ａ However, together with the carbon atoms to which they are bonded, the formula is: 【Chemistry 322】 A ring is formed, and the ring has 1 to 4 C １ -C ６ Defined to be substituted with alkyl as needed, R １０ａ However, H, Haro, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, or C １ -C ６ Alkyl, halo, and C １ -C ６ C is optionally substituted with 1 to 4 substituents selected from haloalkyl groups. ３ -C ６ It is a cycloalkyl, R １１ａ However, H or C １ -C ６ It is alkyl, R １５ However, C(O)NR １６ R １７ Alternatively, it is a five-membered heteroaryl, and the five-membered heteroaryl has 1 to 4 C １ -C ６ Substituted with alkyl as needed, R １６ and R １７ However, each independently, H or C １ -C ６ It is alkyl, Z ２ However, C ４ -C ６ The C is cycloalkyl or phenyl, and ４ -C ６ Cycloalkyl or phenyl is a halo and C １ -C ６ Substituting as needed with 1 to 4 substituents selected from alkyl groups, q ２ A compound, or a pharmaceutically acceptable salt thereof, that is 1, 2, or 3.

22. R ８ａ and R ９ａ However, each is independent of H, Haro, and C. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, or C １ -C ６ Alkyl, halo, and C １ -C ６ C is optionally substituted with 1 to 4 substituents selected from haloalkyl groups. ３ -C ６ It is a cycloalkyl, as needed, R 8a is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl, and optionally R 8a is H, Br, Cl, -CF3, or methyl. R9a is a C3-C6 cycloalkyl which is optionally substituted with 1 to 4 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl, halo, and C1-C6 haloalkyl, and optionally R9a is a C3-C6 cycloalkyl which is optionally substituted with 1 to 4 substituents selected from t-butyl, -CH2CF3, or C1-C6 alkyl, halo, and C1-C6 haloalkyl, R 15 is C(O)NR 16 R 17, A compound of formula (II) according to claim 21, or a pharmaceutically acceptable salt thereof, wherein R16 and R17 are each H.

23. L ２ However, it is a single bond, R １４ However, it is H, R ８ａ and R ９ａ However, each is independent, C １ -C ６ It is alkyl, R １５ However, it is a 5-membered heteroaryl, and the 5-membered heteroaryl contains 1 to 4 C １ -C ６ Substituted with alkyl as needed, Z ２ However, C ４ -C ６ It is a cycloalkyl, and the C ４ -C ６ A compound of formula (II) according to claim 21, or a pharmaceutically acceptable salt thereof, wherein the cycloalkyl group is optionally substituted with one to four halo substituents.

24. L ２ However, it is a single bond, R １４ However, it is H, R １０ａ However, it is H, R １１ａ However, C １ -C ６ It is alkyl, R １５ However, C(O)NR １６ R １７ And, R １６ and R １７ However, each of them is H, Z ２ However, C ４ -C ６ It is a cycloalkyl, and the C ４ -C ６ A compound of formula (III) according to claim 21, or a pharmaceutically acceptable salt thereof, wherein the cycloalkyl group is optionally substituted with one to four halo substituents. 【Request Item 25】 【Table 14-1】 Table 14-2 Table 14-3 Table 14-4 Table 14-5 Table 14-6 Table 14-7 Table 14-8 Table 14-9 Table 14-10 Table 14-11 Table 14-12 Table 14-13 Table 14-14 Table 14-15 Table 14-16 Table 14-17 Table 14-18 Table 14-19 Table 14-20 Table 14-21 Table 14-22 Table 14-23 Table 14-24 Table 14-25 Table 14-26 Table 14-27 Table 14-28 Table 14-29 Table 14-30 Table 14-31 Table 14-32 Table 14-33 Table 14-34 Table 14-35 Table 14-36 Table 14-37 Table 14-38 Table 14-39 Table 14-40 Table 14-41 Table 14-42 Table 14-43 Table 14-44 Table 14-45 Table 14-46 Table 14-47 Table 14-48 A compound selected from, or a pharmaceutically acceptable salt thereof. 【Request Item 26】 【Table 15-1】 Table 15-2 Table 15-3 Table 15-4 Table 15-5 Table 15-6 Table 15-7 Table 15-8 Table 15-9 Table 15-10 Table 15-11 Table 15-12 Table 15-13 Table 15-14 Table 15-15 Table 15-16 Table 15-17 Table 15-18 Table 15-19 Table 15-20 Table 15-21 Table 15-22 Table 15-23 Table 15-24 Table 15-25 Table 15-26 Table 15-27 Table 15-28 Table 15-29 Table 15-30 A compound selected from, or a pharmaceutically acceptable salt thereof. 【Request Item 27】 【Chemistry 323-1】 【Chemistry 323-2】 【Chemistry 323-3】 【Chemistry 323-4】 【Chemistry 323-5】 【Chemistry 323-6】 A compound selected from, or a pharmaceutically acceptable salt thereof. 【Request Item 28】 【Chemistry 324-1】 【Chemistry 324-2】 A compound selected from, or a pharmaceutically acceptable salt thereof. 【Request Item 29】 【Chemistry 325】 A compound that is, or a pharmaceutically acceptable salt thereof. 【Request Item 30】 【Chemistry 326】 A compound that is, or a pharmaceutically acceptable salt thereof. 【Request Item 31】 【Chemistry 327】 A compound that is, or a pharmaceutically acceptable salt thereof. 【Request Item 32】 【Chemistry 328】 A compound that is, or a pharmaceutically acceptable salt thereof. 【Request Item 33】 【Chemistry 329】 A compound that is, or a pharmaceutically acceptable salt thereof. 【Request Item 34】 【Chemistry 330-1】 【Chemistry 330-2】 【Chemistry 330-3】 【Chemistry 330-4】 【Chemistry 330-5】 【Chemistry 330-6】 A compound selected from the following. 【Request Item 35】 【Chemistry 331-1】 【Chemistry 331-2】 A compound selected from the following. 【Request Item 36】 【Chemistry 332】 A compound that is 【Request Item 37】 【Chemistry 333】 A compound that is 【Request Item 38】 【Chemistry 334】 A compound that is 【Request Item 39】 【Chemistry 335】 A compound that is 【Request Item 40】 【Chemistry 336】 A compound that is

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

42. A pharmaceutical composition comprising a compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, or a compound according to any one of claims 34 to 40, or a compound according to any one of claims 1 to 33 in a non-salt form, and one or more pharmaceutically acceptable carriers or vehicles.

43. A composition for inhibiting voltage-gated sodium channels in a target, wherein the composition comprises a compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, or a compound according to any one of claims 34 to 40, or a compound according to any one of claims 1 to 33 in an unsalted form, and optionally the voltage-gated sodium channel is Na V 1.

8.

44. A pharmaceutical composition according to claim 42 for use in inhibiting voltage-gated sodium channels in a subject, wherein the voltage-gated sodium channel is optionally Na V 1.

8.

45. A composition for treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia, comprising a compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, or a compound according to any one of claims 34 to 40, or a non-salt form of a compound according to any one of claims 1 to 33.

46. The composition is in the subject (i) Neuropathic pain, and if necessary, The aforementioned neuropathic pain includes postherpetic neuralgia, or The aforementioned neuropathic pain includes small-diameter fiber neuropathy, or The aforementioned neuropathic pain includes idiopathic small-diameter fiber neuropathy, or The neuropathic pain includes diabetic neuropathy, and, if necessary, the diabetic neuropathy includes diabetic peripheral neuropathy, or (ii) Musculoskeletal pain, which, if necessary, includes musculoskeletal pain including pain of osteoarthritis, (iii) Acute pain, and if necessary, said acute pain includes acute postoperative pain, or (iv) Postoperative pain, if necessary, The aforementioned postoperative pain includes pain from aponeurosis excision, or The aforementioned postoperative pain includes pain from abdominal wall reconstruction surgery, or The aforementioned postoperative pain includes postoperative pain from hernia repair surgery, or (v) visceral pain The composition according to claim 45, for treating or reducing the severity in the subject.

47. The pharmaceutical composition according to claim 42 for use in treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia.

48. The pharmaceutical composition is in the target (i) Neuropathic pain, and if necessary, The aforementioned neuropathic pain includes postherpetic neuralgia, or The aforementioned neuropathic pain includes small-diameter fiber neuropathy, or The aforementioned neuropathic pain includes idiopathic small-diameter fiber neuropathy, or The neuropathic pain includes diabetic neuropathy, and, if necessary, the diabetic neuropathy includes diabetic peripheral neuropathy, or (ii) Musculoskeletal pain, which, if necessary, includes musculoskeletal pain including pain of osteoarthritis, (iii) Acute pain, and if necessary, said acute pain includes acute postoperative pain, or (iv) Postoperative pain, if necessary, The aforementioned postoperative pain includes pain from aponeurosis excision, or The aforementioned postoperative pain includes pain from abdominal wall reconstruction surgery, or The aforementioned postoperative pain includes postoperative pain from hernia repair surgery, or (v) visceral pain The pharmaceutical composition according to claim 47, for treating or reducing the severity of a disease.

49. A composition or pharmaceutical composition for treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia, wherein the composition comprises a compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition comprises a compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, or a compound according to any one of claims 34 to 40, or a compound according to any one of claims 1 to 33 in a non-salt form, and one or more pharmaceutically acceptable carriers or vehicles, wherein the subject is treated simultaneously with, or before or after, treatment with the compound, the pharmaceutically acceptable salt, or the pharmaceutical composition, with one or more additional therapeutic agents administered thereafter.

50. A composition for use as a pharmaceutical agent comprising a compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, or a compound according to any one of claims 34 to 40, or a non-salt form of a compound according to any one of claims 1 to 33.

51. The pharmaceutical composition according to claim 42 for use as a pharmaceutical agent.

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