Heteroaryl compounds for the treatment of pain - Patents.com

Abstract

Provided are compounds and their pharma- ceutically acceptable salts that are useful as inhibitors of sodium channels.Also provided are pharmaceutical compositions that contain the compounds or pharma- ceutically acceptable salts, as well as methods of using the compounds, pharma- ceutically acceptable salts, and pharmaceutical compositions in the treatment of various disorders, including pain.Pain is a protective mechanism that allows healthy animals to avoid tissue damage and prevent further damage to damaged tissue.Nevertheless, there are many conditions in which pain persists beyond its usefulness, or in which patients would benefit from the suppression of pain.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 333,881, 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 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, AN, L. Sivilotti, and JNWood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons.Nature, 1996.379(6562):p.257-62 [Non-Patent Document 11] Blair, NTand BPBean, 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 Summary of the Invention [Means for solving the problem]

[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) or (II): [ka] or a pharmaceutically acceptable salt thereof, wherein: L is O, a single bond, -OC(R)2-, -C(R)2-, or -C(R)2-O-; X2 is N or CR2; X3 is N or CR3; X4 is N or CR4; X5 is N or CR5; X6 is N or CR6; X7 is N or CR7; each R is independently H or C1-C6 alkyl; R1, R2, and R3 are as follows: (i) R1 is H, halo, CN, OH, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkylene)-OH, NR8R9, or CH(OH)(CH2) m (CHOH) n (CH2) p H, R2 and R3 are each independently H, halo, CN, OH, C1-C6 alkyl optionally substituted with C(O)OR8, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, (C1-C6 alkylene)-OH, NR8R9, (C1-C6 alkylene)-O-(C1-C6 alkyl), C(O)NR8R9, CH(OR8)-C(O)NR8R9, C(O)OR8, CHR8-C(O)OR9, CH(OR8)-C(O)OR9, CH(OH)(CH2); m (CHOH) n (CH2) p H, O-(C1-C6 alkylene)-O-CH3, C1-C6 alkenyl optionally substituted with C(O)OR8, S(O)R8, C(O)C(O)NR8R9, CHR8-C(O)NR8R9, C(O)R 10 , S(=O)(=NR 8 )R 9 , S(O)NR8R9, a 3- to 7-membered cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 6-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, or heteroaryl in the 3- to 7-membered cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with 1 to 4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, and C(O)NR8R9; (ii) R2 is H; When R1 and R3, together with the carbon atom to which they are attached, form a group of the formula: [ka] is defined as forming a ring of R4, R5, R6, and R7 are as follows: (i) R4, R5, R6, and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with halo; (ii) R4 and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with halo, and R5 and R6, together with the carbon atom to which they are attached, form 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 optionally substituted with halo, and R5 and R6 together with the carbon atom to which they are attached form the formula: [ka] is defined as forming a ring of each R8 and R9 is independently H or C1-C6 alkyl; Each R 10 are independently C1-C4 alkyl; Each R 11 is independently H, halo, C1-C4 alkyl, or C1-C4 haloalkyl; R 12 and R 13 are each independently H, halo, C-C alkyl, C-C haloalkyl, C-C cycloalkyl optionally substituted with halo; 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, CH2OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy; m, n, and p are each independently 0 or 1; q is 1, 2, or 3; When X3 is CR3 and R3 is C(O)OR8, L is O, or L is a bond and X5 is N, or L is a bond and X7 is N; When X2 or X3 is N, L is O and Z1 is phenyl, 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; or L is a single bond; 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; The compound of formula (I) [ka] The present invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, which is not:

[0012] For purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, 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 formula (I) and (II) described herein, and all embodiments thereof (e.g., formula (IA), etc.), and compounds identified in Tables A and B.

[0014] As described herein, compounds of the invention include multiple variables (e.g., R, X, etc.). As one of ordinary skill in the art will recognize, combinations of groups envisioned by the present invention are those that result in the formation of stable or chemically feasible compounds. The term "stable" in this context refers to compounds that do not substantially change when subjected to conditions that allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, stable compounds or chemically viable compounds are compounds that do 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) and (IA), 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 "alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms containing one or more carbon-carbon triple 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 alkynyl" group is an alkynyl group having from 2 to 6 carbon atoms.

[0020] As used herein, the term "cycloalkyl" refers to a stable non-aromatic monocyclic or bicyclic (fused, bridged, or spiro) saturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having the specified number of carbon ring atoms, which is 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.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] As used herein, the term "alkylene" refers to a divalent straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, 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.

[0026] 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).

[0027] 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."

[0028] 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.

[0029] 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]

[0030] Similarly, labels such as "*3" and "*1", such as those shown in the structures below, indicate the atoms to which the corresponding R groups (in this case, the R3 and R1 groups, respectively) are attached. [ka]

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

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

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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).

[0040] As used herein in the specification and claims, "H" refers to hydrogen and includes any stable isotope of hydrogen, i.e. 1Includes 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.

[0041] 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.

[0042] As used herein, "D", "d", and " 2 "H" refers to deuterium.

[0043] 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.

[0044] 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.

[0045] 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- 23H-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.

[0046] deuterium( 2 H) labeled compounds and salts can manipulate the rate of oxidative metabolism of a compound through the primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction resulting from the exchange of an isotope nucleus, which in turn is caused by a change in the ground state energy of the covalent bond involved in the reaction. The exchange of a heavier isotope usually results in a lowering of the ground state energy of the chemical bond and therefore a decrease in 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.

[0047] 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.

[0048] 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).

[0049] In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R is H, halo, CN, OH, C-C alkyl, C-C alkoxy, (C-C alkylene)-OH, NR, or CH(OH)(CH). m (CHOH) n (CH2) p H, and R2 and R3 are each independently H, halo, CN, OH, C-C alkyl optionally substituted with C(O)OR8, C-C alkynyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, (C-C alkylene)-OH, NR8R9, (C-C alkylene)-O-(C-C alkyl), C(O)NR8R9, CH(OR8)-C(O)NR8R9, C(O)OR8, CHR8-C(O)OR9, CH(OR8)-C(O)OR9, CH(OH)(CH2). m (CHOH) n (CH2) p H, O-(C1-C6 alkylene)-O-CH3, C1-C6 alkenyl optionally substituted with C(O)OR8, S(O)R8, C(O)C(O)NR8R9, CHR8-C(O)NR8R9, C(O)R 10, S(=O)(=NR 8 )R 9 , S(O)2NR8R9, 3- to 7-membered cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, or heteroaryl in the 3- to 7-membered cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with 1 to 4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, and C(O)NR8R9, or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R is H, halo, CN, OH, C-C alkyl, C-C alkoxy, (C-C alkylene)-OH, NR, or CH(OH)(CH). m (CHOH) n (CH2) p H, and R2 and R3 are each independently H, halo, CN, OH, C-C alkyl optionally substituted with C(O)OR8, C-C alkynyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, (C-C alkylene)-OH, NR8R9, (C-C alkylene)-O-(C-C alkyl), C(O)NR8R9, CH(OR8)-C(O)NR8R9, C(O)OR8, CHR8-C(O)OR9, CH(OR8)-C(O)OR9, CH(OH)(CH2). m (CHOH) n (CH2) p H, O-(C1-C6 alkylene)-O-CH3, C1-C6 alkenyl optionally substituted with C(O)OR8, S(O)R8, C(O)C(O)NR8R9, CHR8-C(O)NR8R9, C(O)R 10 , S(=O)(=NR 8 )R 9 , S(O)2NR8R9, or a pharmaceutically acceptable salt thereof.

[0051] In some embodiments, the present invention provides a compound of formula (IA): [ka] or a pharmaceutically acceptable salt thereof, wherein R2, R3, X4, X5, X6, and X7 are defined as described above in relation to formula (I); R1 is H, halo, CN, OH, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkylene)-OH, or -NR8R9; R4, R5, R6, and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with halo; Z1 is a 5- to 10-membered cycloalkyl, phenyl, 4- to 10-membered heterocyclyl, or 5- to 6-membered heteroaryl, and the 5- to 10-membered cycloalkyl, 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, CH2OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0052] In some embodiments, the present invention relates to a compound of any one of Formula (I) and (IA), or a pharmaceutically acceptable salt thereof, wherein X4, X5, X6, or X7 is N. In some embodiments, X4 is N. In some embodiments, X5 is N. In some embodiments, X6 is N. In some embodiments, X7 is N.

[0053] In some embodiments, the present invention relates to a compound of any one of Formulas (I) and (IA), or a pharmaceutically acceptable salt thereof, wherein R1 is H, halo, CN, OH, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkylene)-OH, or NR8R9. In some embodiments, R1 is H. In some embodiments, R1 is halo. In some embodiments, R1 is CN. In some embodiments, R1 is OH. In some embodiments, R1 is C1-C6 alkyl. In some embodiments, R1 is C1-C6 alkoxy. In some embodiments, R1 is (C1-C6 alkylene)-OH. In some embodiments, R1 is NR8R9.

[0054] In some embodiments, the present invention relates to a compound of any one of formula (I) and (IA), or a pharmaceutically acceptable salt thereof, wherein X2 is CR2 and X3 is CR3. In some embodiments, X2 is N. In some embodiments, X3 is N.

[0055] In some embodiments, the present invention relates to a compound of any one of Formulas (I) and (IA), or a pharmaceutically acceptable salt thereof, wherein R2 is H, halo, CN, OH, C1-C6 alkyl optionally substituted with C(O)OR8, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, (C1-C6 alkylene)-OH, NRR, (C1-C6 alkylene)-O-(C1-C6 alkyl), C(O)NR8R9, CH(OR8)-C(O)NR8R9, C(O)OR8, CHR8-C(O)OR9, CH(OR8)-C(O)OR9, CH(OH)(CH2). m (CHOH) n (CH2) p H, O-(C1-C6 alkylene)-O-CH3, C1-C6 alkenyl optionally substituted with C(O)OR8, S(O)R8, C(O)C(O)NR8R9, CHR8-C(O)NR8R9, C(O)R 10 , S(=O)(=NR 8 )R9 or S(O)NRR. In some embodiments, R is H. In some embodiments, R is halo. In some embodiments, R is CN. In some embodiments, R is OH. In some embodiments, R is C-C alkyl. In some embodiments, R is C-C alkynyl. In some embodiments, R is C-C haloalkyl. In some embodiments, R is C-C alkoxy. In some embodiments, R is C-C haloalkoxy. In some embodiments, R is (C-C alkylene)-OH. In some embodiments, R is NR. In some embodiments, R is (C-C alkylene)-O-(C-C alkyl). In some embodiments, R is C(O)NRR. In some embodiments, R is C(O)OR. In some embodiments, R2 is CH(OR8)-C(O)OR9. In some embodiments, R2 is CH(OH)(CH2). m (CHOH) n (CH2) p In some embodiments, R2 is H. In some embodiments, R2 is O—(C1-C6 alkylene)-O—CH3. In some embodiments, R2 is C1-C6 alkenyl. In some embodiments, R2 is C1-C6 alkenyl substituted with C(O)OR8. In some embodiments, R2 is S(═O)(═NH)CH3. In some embodiments, R2 is S(O)R8. In some embodiments, R2 is C(O)C(O)NR8R9. In some embodiments, R2 is CHR8—C(O)NR8R9. In some embodiments, R2 is C(O)R 10 In some embodiments, R2 is S(O)2NR8R9. In some embodiments, R2 is C1-C6 alkyl substituted with C(O)OR8.

[0056] In some embodiments, the present invention relates to a compound of any one of Formulas (I) and (IA), or a pharmaceutically acceptable salt thereof, wherein R3 is H, halo, CN, OH, C1-C6 alkyl optionally substituted with C(O)OR8, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, (C1-C6 alkylene)-OH, NRR, (C1-C6 alkylene)-O-(C1-C6 alkyl), C(O)NR8R9, CHR8-C(O)NR8R9, CH(OR8)-C(O)NR8R9, C(O)OR8, CHR8-C(O)OR9, CH(OR8)-C(O)OR9, CH(OH)(CH2). m (CHOH) n (CH2) p H, O-(C1-C6 alkylene)-O-CH3, C1-C6 alkenyl optionally substituted with C(O)OR8, S(O)R8, C(O)C(O)NR8R9, CHR8-C(O)NR8R9, C(O)R 10 , S(=O)(=NR 8 )R 9 or S(O)NR8R9. In some embodiments, R3 is H. In some embodiments, R3 is halo. In some embodiments, R3 is CN. In some embodiments, R3 is OH. In some embodiments, R3 is C1-C6 alkyl. In some embodiments, R3 is C2-C6 alkynyl. In some embodiments, R3 is C1-C6 haloalkyl. In some embodiments, R3 is C1-C6 alkoxy. In some embodiments, R3 is C1-C6 haloalkoxy. In some embodiments, R3 is (C1-C6 alkylene)-OH. In some embodiments, R3 is NR8R9. In some embodiments, R3 is (C1-C6 alkylene)-O-(C1-C6 alkyl). In some embodiments, R3 is C(O)NR8R9. In some embodiments, R3 is C(O)OR8. In some embodiments, R3 is CH(OR8)-C(O)OR9. In some embodiments, R3 is CH(OH)(CH2). m (CHOH) n(CH2) p In some embodiments, R3 is O-(C1-C6 alkylene)-O-CH3. In some embodiments, R3 is C1-C6 alkenyl. In some embodiments, R3 is C1-C6 alkenyl substituted with C(O)OR8. In some embodiments, R3 is S(=O)(=NH)CH3. In some embodiments, R3 is S(O)R8. In some embodiments, R3 is C(O)C(O)NR8R9. In some embodiments, R3 is CHR8-C(O)NR8R9. In some embodiments, R3 is C(O)R 10 In some embodiments, R3 is S(O)2NR8R9. In some embodiments, R3 is C1-C6 alkyl substituted with C(O)OR8.

[0057] In some embodiments, the present invention relates to a compound of any one of Formulas (I) and (IA), or a pharmaceutically acceptable salt thereof, wherein R4, R5, R6, and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with halo. In some embodiments, R4, R5, R6, and R7 are each independently H, halo, C1-C6 haloalkyl, or C3-C6 cycloalkyl substituted with 1-4 halo. In some embodiments, R6 is C3-C6 cycloalkyl substituted with halo. In some embodiments, R6 is cyclobutyl substituted with 1-2 halo. In some embodiments, X4 is CR4, X5 is N, X6 is CR6, X7 is CR7, R4 is H, R6 is C3-C6 cycloalkyl substituted with halo, and R7 is H.

[0058] In some embodiments, the present invention relates to a compound of any one of Formulas (I) and (IA), 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, wherein 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, and C-C haloalkoxy.

[0059] In some embodiments, the present invention relates to a compound of any one of Formulas (I) and (IA), or a pharmaceutically acceptable salt thereof, wherein Z is a 5-10 membered cycloalkyl optionally substituted with 1-4 substituents selected from halo, CHOH, C-C alkyl, C-C alkoxy, C-C haloalkyl, and C-C haloalkoxy. In some embodiments, Z is a 5-10 membered cycloalkyl substituted with 1-4 substituents selected from halo, C-C alkyl, C-C alkoxy, C-C haloalkyl, and C-C haloalkoxy. In some embodiments, Z is a 5-7 membered cycloalkyl substituted with 1-4 substituents selected from halo, C-C alkyl, C-C alkoxy, C-C haloalkyl, and C-C haloalkoxy. In some embodiments, Z1 is a 6-membered cycloalkyl optionally substituted with 1-4 substituents selected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. In some embodiments, Z1 is a 6-membered cycloalkyl substituted with 1-4 substituents selected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. In some embodiments, Z1 is a 5-10 membered cycloalkyl optionally substituted with C1-C6 haloalkyl. In some embodiments, Z1 is a 5-10 membered cycloalkyl substituted with C1-C6 haloalkyl. In some embodiments, Z1 is a 6-membered cycloalkyl substituted with C1-C6 haloalkyl.

[0060] In some embodiments, the present invention relates to a compound of any one of formulas (I) and (IA), or a pharmaceutically acceptable salt thereof, wherein R1 is C1-C6 alkyl, R2 and R3 are each independently C1-C6 alkyl or C(O)OR8, X5 is N, R4, R5, R6, and R7 are each independently H or C3-C6 cycloalkyl substituted with 1-2 halo, and Z1 is a 5-10 membered cycloalkyl substituted with C1-C6 haloalkyl.

[0061] In some embodiments, the present invention relates to a compound of any one of Formulas (I) and (IA), or a pharmaceutically acceptable salt thereof, wherein each R is C-C alkyl. In some embodiments, R is C-C alkyl and R is H. In some embodiments, each R and R is H. In some embodiments, each R and R is C-C alkyl.

[0062] 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—.

[0063] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: L is O, X2 is CR2, X3 is CR3, R1 is C1-C6 alkyl.

[0064] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: L is O, Z1 is phenyl, which can be unsubstituted or substituted with 1 to 4 substituents selected from halo, CH2OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0065] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: L is -OC(R)2- or -C(R)2-O-; X2 is CR2, X3 is CR3, Z1 is a 3-membered cycloalkyl or a 4- to 10-membered cycloalkyl, wherein the 3-membered cycloalkyl is substituted with 1 to 2 substituents selected from halo, CH2OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy, and the 4- to 10-membered cycloalkyl can be unsubstituted or substituted with 1 to 4 substituents selected from halo, CH2OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0066] In some embodiments, the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X2 is CR2, X3 is CR3, and R2 and R3 are each independently selected from H, halo, CN, OH, C1-C6 alkyl optionally substituted with C(O)OR8, C1-C6 alkoxy, C1-C6 haloalkoxy, C(O)OR8, S(=O)(=NH)CH3, S(O)R8, C(O)R 10 or S(O)NRR. In some embodiments, R and R are each independently H, halo, C(O)OR, S(=O)(=NH)CH, S(O)R, or S(O)NRR.

[0067] In some embodiments, the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts thereof, wherein Z1 is phenyl substituted with 1-3 substituents selected from halo, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. In some embodiments, the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts thereof, wherein Z1 is phenyl substituted with 1-3 substituents selected from halo, CH2OH, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.

[0068] In some embodiments, the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X2 is CR2, X3 is CR3, X4 is CR4, X5 is CR5, X6 is CR6, and X7 is CR7. In some embodiments, R4, R5, R6, and R7 are each independently H, halo, C1-C6 alkyl, or C1-C6 haloalkyl.

[0069] In some embodiments, the present invention relates to compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein X5 is CR5, X6 is CR6, and R5 and R6, together with the carbon atom to which they are attached, form the formula: [ka] It forms a ring.

[0070] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R 11 is independently H or halo.

[0071] 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, X3 is CR3, Z1 is a 4- to 10-membered heterocyclyl or a 5- to 6-membered heteroaryl, and the 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, CH2OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0072] 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, X3 is CR3, Z1 is a 5- to 10-membered heterocyclyl or a 5- to 6-membered heteroaryl, and the 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, and C1-C6 haloalkoxy.

[0073] 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, Z1 is a 7-membered heterocyclyl, which can be unsubstituted or substituted with 1 to 4 substituents selected from halo, OH, CH2OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. In some embodiments, Z1 is azepanyl optionally substituted with halo. In some embodiments, Z1 is azepanyl substituted with halo.

[0074] In some embodiments, the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X2 is CR2, X3 is CR3, and R2 and R3 are each independently H, C1-C6 alkoxy, or C(O)OR8. In some embodiments, R2 and R3 are each independently C1-C6 alkoxy or C(O)OR8.

[0075] In some embodiments, the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R2 is a 3- to 7-membered cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 6-membered heteroaryl, and the cycloalkyl, heterocyclyl, or heteroaryl in the 3- to 7-membered cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl must be independently selected from 1 to 4 substituents: oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, and C(O)NR8R9. R3 is optionally substituted, and is C1-C6 alkyl optionally substituted with H, halo, CN, OH, C(O)OR8, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, (C1-C6 alkylene)-OH, NR8R9, (C1-C6 alkylene)-O-(C1-C6 alkyl), C(O)NR8R9, CH(OR8)-C(O)NR8R9, C(O)OR8, CHR8-C(O)OR9, CH(OR8)-C(O)OR9, CH(OH)(CH2) m (CHOH) n (CH2) p H, O-(C1-C6 alkylene)-O-CH3, C1-C6 alkenyl optionally substituted with C(O)OR8, S(O)R8, C(O)C(O)NR8R9, CHR8-C(O)NR8R9, C(O)R 10 , S(=O)(=NR 8 )R 9 or S(O)NR8R9. In other embodiments, R2 is a 4-7 membered heterocyclyl optionally substituted with 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, and C(O)NR8R9. In other embodiments, R2 is [ka] In another embodiment, R2 is a 5-6 membered heteroaryl, optionally substituted with 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, and C(O)NR8R9. In another embodiment, R2 is a 5-6 membered heteroaryl, optionally substituted with 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, and C(O)NR8R9. [ka] wherein the heteroaryl is optionally substituted with 1 to 4 C1-C6 alkyl substituents. In other embodiments, R2 is [ka] is.

[0076] In some embodiments, the present invention relates to compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein R3 is H or C1-C6 alkyl.

[0077] In some embodiments, the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R2 is H, halo, CN, OH, C1-C6 alkyl optionally substituted with C(O)OR8, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, (C1-C6 alkylene)-OH, NRR, (C1-C6 alkylene)-O-(C1-C6 alkyl), C(O)NR8R9, CH(OR8)-C(O)NR8R9, C(O)OR8, CHR8-C(O)OR9, CH(OR8)-C(O)OR9, CH(OH)(CH2). m (CHOH) n (CH2) p H, O-(C1-C6 alkylene)-O-CH3, C1-C6 alkenyl optionally substituted with C(O)OR8, S(O)R8, C(O)C(O)NR8R9, CHR8-C(O)NR8R9, C(O)R 10 , S(=O)(=NR 8 )R 9or S(O)NR8R9, where R3 is a 3- to 7-membered cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 6-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, or heteroaryl in the 3- to 7-membered cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, and C(O)NR8R9. In another embodiment, R2 is H or C(O)OR8, and R8 is C1-C6 alkyl. In another embodiment, R3 is a 3- to 7-membered cycloalkyl, wherein the cycloalkyl is optionally substituted with 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, and C(O)NR8R9. In another embodiment, R3 is [ka] In another embodiment, R3 is a 4-7 membered heterocyclyl, wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, and C(O)NR8R9. In another embodiment, R3 is a 4-7 membered heterocyclyl, wherein the heterocyclyl is [ka] wherein the heterocyclyl is substituted with one oxo substituent. In other embodiments, R3 is [ka] In another embodiment, R3 is a 5-6 membered heteroaryl, optionally substituted with 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, and C(O)NR8R9. In another embodiment, R3 is a 5-6 membered heteroaryl, optionally substituted with 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, and C(O)NR8R9. [ka] wherein the heteroaryl is optionally substituted with 1 to 4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, and C(O)NR8R9. In other embodiments, R3 is [ka] is.

[0078] In some embodiments, the present invention relates to a compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein L is a single bond, X2 is CH, X3 is CR3, R1 is C1-C6 alkyl, R3 is a 5- to 6-membered heteroaryl, the heteroaryl being optionally substituted with 1 to 4 C1-C6 alkyl substituents, R4 and R5 are each independently C1-C6 alkyl, and Z1 is a 3- to 10-membered cycloalkyl, which can be unsubstituted or substituted with 1 to 4 C1-C6 alkyl substituents.

[0079] In some embodiments, the present invention relates to a compound of any one of formulas (I), (II), and (IA), or any embodiment thereof, i.e., a compound in non-salt form.

[0080] 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 A-1] [Table A-2] [Table A-3] [Table A-4] [Table A-5]

Table A-6

Table A-7

Table A-8

Table A-9

Table A-10

Table A-11

Table A-12

Table A-13

Table A-14

Table A-15

Table A-16

Table A-17

Table A-18

Table A-19

Table A-20

Table A-21

Table A-22

Table A-23

Table A-24

Table A-25

Table A-26

Table A-27

Table A-28

Table A-30

Table A-31

Table A-32

Table A-33

Table A-34

Table A-35

Table A-36

Table A-37

Table A-38

Table A-39

Table A-40

Table A-41

Table A-42

Table A-43

Table A-44

Table A-45

Table A-46

Table A-47

Table A-48

Table A-49

Table A-50

Table A-51

Table A-52

Table A-53

Table A-54

Table A-55

Table A-56

[0081] 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 B-1] [Table B-2] [Table B-3] [Table B-4] [Table B-5] [Table B-6] [Table B-7] [Table B-8] [Table B-9] [Table B-10] [Table B-11]

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention," as that term is used herein.

[0088] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention," as that term is used herein.

[0089] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention," as that term is used herein.

[0090] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention," as that term is used herein.

[0091] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention," as that term is used herein.

[0092] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention," as that term is used herein.

[0093] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention," as that term is used herein.

[0094] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. 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.

[0095] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention," as that term is used herein.

[0096] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention," as that term is used herein.

[0097] In some embodiments, the present invention provides a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof. 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 [ka] a compound selected from 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] Salts, Compositions, Uses, Formulations, Administration, and Additional Agents Pharmaceutically Acceptable Salts and Compositions As discussed herein, the present invention provides compounds and pharmaceutically acceptable salts thereof that are inhibitors of voltage-gated sodium channels. Accordingly, the present compounds and pharmaceutically acceptable salts thereof are useful for treating diseases, disorders, and conditions, including, but not limited to, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth 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, these compositions optionally further comprise one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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. Uses of the compounds and pharmaceutically acceptable salts and compositions

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] In yet another aspect, the invention features a method for treating or lessening the severity of acute pain in a subject, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, the acute pain includes acute post-surgical pain.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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).

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] 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

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or reducing the severity of acute pain in a subject. In some aspects, the acute pain includes acute post-operative pain.

[0146] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or 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).

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or reducing the severity of visceral pain in a subject. In some aspects, the visceral pain includes abdominoplasty visceral pain.

[0152] 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).

[0153] 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.

[0154] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method 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.

[0155] 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.

[0156] 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.

[0157] 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 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 post-amputation pain.

[0158] Drug manufacturing In another aspect, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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).

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] 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).

[0174] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating herniorrhaphy pain or reducing the severity thereof in a subject.

[0175] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of bunionectomy pain in a subject.

[0176] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of shoulder arthroplasty pain or shoulder arthroscopy pain in a subject.

[0177] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of abdominoplasty pain in a subject.

[0178] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of visceral pain in a subject, hi some aspects, the visceral pain includes abdominoplasty visceral pain.

[0179] 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).

[0180] In yet another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in 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.

[0181] 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 Provided is 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 lessening the severity of spondylolisthesis, chemotherapy-induced oral mucositis, Charcot arthropathy, temporomandibular joint disorder, painful knee replacement surgery, non-cardiac chest pain, pudendal pain, renal colic, biliary tract disease, vascular leg ulcers, pain in Parkinson's disease, pain in Alzheimer's disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal motility.

[0182] 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 pain in the toes; Haglund's syndrome; pain in erythromelalgia; pain in Fabry's disease; bladder and genitourinary disorders; urinary incontinence, pathological cough; overactive bladder; bladder pain syndrome; interstitial cystitis (IC); prostatitis; regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain.

[0183] In another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in the treatment or reduction of 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 thigh, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain, or pain following amputation surgery.

[0184] Administration of Compounds, Pharmaceutically Acceptable Salts, and Compositions In certain embodiments of the present invention, an "effective amount" of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is that amount effective to treat or lessen the severity of one or more of the conditions listed above.

[0185] The compounds, salts, and compositions of the present invention can be administered in any amount and via any route of administration effective for treating or reducing the severity of one or more of the pain or non-pain disorders listed herein. The exact amount required will vary from subject to subject, depending on the subject's species, age, and general condition, the severity of the condition, the specific drug, its mode of administration, and the like. The compounds, salts, and compositions of the present invention are 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.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] 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.

[0192] 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.

[0193] Solid compositions of a similar type can 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 can optionally contain opacifying agents and can 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 can 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.

[0194] 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.

[0195] 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.

[0196] 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 disease, condition, or disorder. V The present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation or overactivity of 1.8 is implicated in the disease state.

[0197] 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.

[0198] Additional medications 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.

[0199] 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, flurbiprofen, ibuprofen (including, but not limited to, intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketorolac (including, but not limited to, ketorolac tromethamine (e.g., Toradol®)), meclofenamic acid, mefenamic acid, meloxicam, IV meloxicam (e.g., Anjeso®), nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, or zomepirac, (3) 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 dichloralphenazone; (7) Skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphenadrine; (8) NMDA receptor antagonists, such as dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), a combination 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 / 1 96869);WO2012 / 112743(US2012 / 245136);WO2012 / 125613(US2012 / 264749), WO2012 / 116440(US2014 / 187533), WO2011026240(US2012220605), US8883840, US8466188, WO2013 / 109521(US2015 / 005304), CN111217776, WO2020 / 117626, WO2021 / 252822, WO2021 / 252818, WO2021 / 252820, WO2014 / 201173, WO2012 / 125973, WO2013 / 086229, WO2013 / 134518, WO2014 / 201206, or WO2016 / 141035 (the entire contents of each application are incorporated herein by reference); (38a)Na V1.7 Blockers, 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 / 144375, WO2020 / 261114, WO2020 / 140959, WO2020 / 151728, WO2021 / 032074, WO2021 / 047622(CN112479996), WO2021 / 257490, WO / 2021 / 257420, WO2021 / 257418, WO2022 / 263498, WO2022 / 235558, WO2022 / 235859, CN112390745, CN111808019, CN112225695, CN112457294, CN112300051, CN112300069, CN112441969, and CN114591293 (the entire contents of each application are incorporated herein by reference); (39a)Na V1.8 Blockers, 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).

[0200] 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.

[0201] 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.

[0202] 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.

[0203] In another embodiment, the additional therapeutic agent is oliceridine or ropivacaine (TLC590).

[0204] In another embodiment, the additional therapeutic agent is Na V 1.7 blockers, such as ST-2427, or ST-2578, and those disclosed in WO2010 / 129864, WO2015 / 157559, WO2017 / 059385, WO2018 / 183781, WO2018 / 183782, WO2020 / 072835, and / or WO2022 / 036297 (the entire contents of each application are incorporated herein by reference).

[0205] 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.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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).

[0213] Radiolabeled Analogs of the Compounds of the Invention In another aspect, the present invention relates to radiolabeled analogues of the compounds of the present invention.As used herein, the term "radiolabeled analogues of the compounds of the present invention" refers to compounds that are identical to the compounds of the present invention described herein, including all embodiments thereof, except that one or more atoms are replaced with radioactive isotopes of the atoms present in the compounds of the present invention.

[0214] 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).

[0215] 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.

[0216] 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.

[0217] 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.

[0218] In another aspect, the present invention relates to methods of inhibiting voltage-gated sodium channels and methods of treating or lessening the severity of various diseases and disorders, including pain, in a subject comprising administering an effective amount of a radiolabeled analogue, pharmaceutically acceptable salt thereof, and pharmaceutical composition thereof, according to any of the embodiments described herein with respect to the compounds of the invention.

[0219] 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.

[0220] 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.

[0221] 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]

[0222] Abbreviation Unless otherwise indicated, or where the context dictates otherwise, the following abbreviations shall be understood to have the following meanings: [Table 5-1] [Table 5-2]

[0223] Common method. 1 1 H NMR spectra were obtained as solutions in a suitable deuterated solvent such as dimethylsulfoxide-d6 (DMSO-d6).

[0224] Compound purity, retention time, and electrospray mass spectrometry (ESI-MS) data were determined by LC / MS analysis.

[0225] LC / MS method LC / MS determinations were performed using one of the following chromatographic conditions unless otherwise specified: 1) Waters BEH C8 (1.7 μm, 2.1 × 50 mm), 2–98% acetonitrile in water (10 mM ammonium formate, pH 9), 45°C, flow rate = 0.6 mL / min over 5.0 min; 2) Kinetex EVO C18 (2.6 μm, 2.1 × 50 mm), 2–98% acetonitrile in water (10 mM ammonium formate, pH 9), 45 °C, flow rate = 0.7 mL / min over 4.0 min; 3) Kinetex EVO C18 (2.6 μm, 2.1 × 50 mm), 2–98% acetonitrile in water (10 mM ammonium formate, pH 9), 45 °C, flow rate = 1.0 mL / min for 1.5 min; 4) Waters Acquity UPLC BEH C18 (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 3 min; 5) 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; 6) SunFire C18 (3.5 μm, 75 × 4.6 mm) initially 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 of 1.5 mL / min over 6 min; 7) XBridge C18 (5 μm, 4.6 × 75 mm) with an initial gradient of 5 to 95% acetonitrile (NH4HCO3) for 6 minutes and 1 minute, followed by an equilibration gradient of 95% acetonitrile from 0 to 3 minutes, held for 3 minutes, and a flow rate of 1.5 mL / min; 8) Waters CSH C18 (1.7 μm, 2.1 × 50 mm), 2–98% acetonitrile in water (0.1% TFA, pH 2), 45 °C, flow rate = 0.6 mL / min over 5.0 min; 9) Waters CSH C18 (1.7 μm, 2.1 × 50 mm), 2–95% acetonitrile in water (0.1% formic acid), 40°C, 0.8 mL / min flow rate over 4.6 min; 10) Waters BEH C18 (2.5 μm, 2.1 × 50 mm), 2–95% acetonitrile in water (0.1% NH ), 40°C, flow rate = 0.8 mL / min over 4.6 min; 11) Waters BEH C18 (3.5 μm, 75 × 4.6 mm), initial gradient 5 to 95% acetonitrile in water (0.1% formic acid), then linear gradient to 95% acetonitrile for 4 min, hold at 95% acetonitrile for 2 min, 45 °C, flow rate of 1.5 mL / min for 6 min; 12) Waters BEH C18 (2.5 μm, 2.1 × 50 mm), 2–50% acetonitrile in water (0.1% NH ), 40°C, flow rate = 0.8 mL / min over 4.6 min; 13) Waters CSH C18 (1.7 μm, 2.1 × 50 mm), 2–98% acetonitrile in water (0.1% TFA), 45 °C, flow rate = 1.0 mL / min for 1.5 min; 14) Waters CSH C18 (1.7 μm, 2.1 × 50 mm), 2–95% acetonitrile in water (0.1% formic acid), 40°C, 0.8 mL / min flow rate over 1.4 min; 15) YMC Triart C18 (3 μm, 33 × 2.1 mm), 2–98% acetonitrile in water (5 mM NH4OAc), flow rate of 1.0 mL / min over 3 min; 16) Waters BEH C18 (2.5 μm, 2.1 × 50 mm), 2–95% acetonitrile in water (0.1% NH ), 40°C, flow rate = 0.8 mL / min over 1.4 min; 17) Waters Acquity UPLC BEH C18 (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 5 min; 18) Waters BEH C18 (2.5 μm, 2.1 × 50 mm), 20–70% acetonitrile in water (0.1% NH ), 40°C, flow rate = 0.8 mL / min over 4.60 min; 19) 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 3 min; 20) 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 over 1 min; 21) YMC Triart C18 (3 μm, 33 × 2.1 mm), 2–98% acetonitrile in water (0.05% formic acid), flow rate = 1.0 mL / min for 3 min; 22) 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; 23) 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 over 4.0 min; 24) Acquity BEH C8 (1.7 μm, 50 × 2.1 mm), 2 to 98% 90:10 acetonitrile:water (0.05% formic acid), flow rate = 0.8 mL / min for 3 min; 25) XBridge C18 (5 μm, 50 × 4.6 mm), 10–90% acetonitrile in water (10 mM NH OAc), flow rate of 1.2 mL / min over 6 min; 26) YMC Triart C18 (3 μm, 33 × 2.1 mm), 5–95% acetonitrile in water (0.05% formic acid), flow rate = 1.0 mL / min over 12 min; 27) Waters BEH C8 (1.7 μm, 2.1 × 50 mm), 50–95% acetonitrile in water (0.1% NH), 40 °C, flow rate = 0.8 mL / min over 1.4 min.

[0226] Example 1 Preparation 1 Ethyl 4-benzyloxy-2-chloro-5-iodo-6-methyl-pyridine-3-carboxylate [ka] Step 1: Ethyl 2-hydroxy-5-iodo-6-methyl-4-oxo-1H-pyridine-3-carboxylate A suspension of ethyl 2-hydroxy-6-methyl-4-oxo-1H-pyridine-3-carboxylate (1.0 g, 5.1 mmol) and potassium carbonate (700 mg, 5.07 mmol) in water (10 mL) was heated to 100 °C. Iodine (1.29 g, 5.08 mmol) was added portionwise over 10 minutes. After 30 minutes, the reaction was cooled to room temperature and aqueous KHSO was added. The resulting solid was collected by suction filtration and washed with 1:1 EtO / acetonitrile to give ethyl 2-hydroxy-5-iodo-6-methyl-4-oxo-1H-pyridine-3-carboxylate (1.43 g, 83%) as a white solid. 1 H NMR(400 MHz,CDCl3)δ 4.44(q,J=7.0 Hz,2H),2.57(s,3H),1.42(t,J=7.1 Hz,3H).ESI-MS m / z calculated value .322.97, measured value 323.84(m+1) + .

[0227] Step 2: Ethyl 2,4-dichloro-5-iodo-6-methyl-pyridine-3-carboxylate A suspension of ethyl 2-hydroxy-5-iodo-6-methyl-4-oxo-1H-pyridine-3-carboxylate (1.434 g, 4.217 mmol) in POCl3 (16.5 g, 10 mL, 107 mmol) was heated at 120 °C for 2 h, concentrated, and azeotroped twice with toluene. The residue was neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2x). The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0–10% ethyl acetate / heptane) afforded ethyl 2,4-dichloro-5-iodo-6-methyl-pyridine-3-carboxylate (1.15 g, 73%) as a white solid. 1H NMR(400 MHz,CDCl3)δ 4.46(q,J=7.2 Hz,2H),2.83(s,3H),1.40(t,J=7.1 Hz,3H).ESI-MS m / z Calculated value .358.90, Actual value 359.79(m+1) + .

[0228] Step 3: Ethyl 4-benzyloxy-2-chloro-5-iodo-6-methyl-pyridine-3-carboxylate To a solution of benzyl alcohol (2.4 mL, 23 mmol) in THF (80 mL) and DMF (4 mL) at 0 °C, sodium hydride (972 mg, 60% dispersion in mineral oil, 24.3 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. Ethyl 2,4-dichloro-5-iodo-6-methyl-pyridine-3-carboxylate (8.3 g, 23.06 mmol) in THF (30 mL) was added at 0 °C, and the reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (3 × 200 mL) and brine (200 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0–10% ethyl acetate / heptane) to give ethyl 4-benzyloxy-2-chloro-5-iodo-6-methyl-pyridine-3-carboxylate (4.205 g, 42%). 1 H NMR(500 MHz,DMSO-d6)δ 7.50-7.47(m,2H),7.46-7.38(m,3H),5.10(s,2H),4.35(q,J=7.1 Hz,2H),2.71(s,3H),1.26(t,J=7.1 Hz,3H).ESI-MS m / z Calculated value .430.98, Actual value 432.0(m+1) + .

[0229] Preparation 2 4-benzyloxy-6-chloro-3-iodo-2-methyl-pyridine [ka] Step 1: 4-Benzyloxy-6-chloro-pyridine-3-carboxylic acid Sodium hydride (50.0 g, 60% dispersion in mineral oil, 1.25 mol) was added portionwise to a stirred solution of benzyl alcohol (140 g, 135 mL, 1.30 mol) in THF (500 mL) at 0°C under argon. After 90 min at room temperature, the reaction was cooled to 10°C, and a solution of 4,6-dichloropyridine-3-carboxylic acid (100 g, 469 mmol) in THF (500 mL) was added over 30 min, maintaining the reaction temperature below 30°C. After the addition, the reaction was stirred at room temperature for 4 h and then quenched by the dropwise addition of water (1 L) at 0°C. The mixture was adjusted to pH 4 with 2N aqueous HCl and extracted with ethyl acetate (2 x 500 mL). The combined organic extracts were concentrated and combined with toluene (500 mL). The mixture was filtered and the collected solid was washed successively with toluene (500 mL) followed by heptane (500 mL) and then air-dried to give 4-benzyloxy-6-chloro-pyridine-3-carboxylic acid (120 g, 96%) as a beige solid. 1 H NMR(400 MHz,CDCl3)δ 8.97(d,J=8.2 Hz,1H),7.51-7.37(m,5H),7.04(s,1H),5.32(d,J=17.4 Hz,2H).ESI-MS m / z Calculated value .263.04, Actual value 263.9(m+1) + .

[0230] Step 2: tert-Butyl N-(4-benzyloxy-6-chloro-3-pyridyl)carbamate DPPA (691 g, 540 mL, 2.51 mol) was added to a stirred suspension of 4-benzyloxy-6-chloro-pyridine-3-carboxylic acid (568 g, 2.05 mol), TEA (598 g, 823 mL, 5.91 mol), and tert-butanol (726 g, 937 mL, 9.80 mol) in toluene (8.5 L). The reaction was heated at 100 °C for 4 hours and then concentrated. The residue was partitioned between ethyl acetate (7.5 L) and saturated sodium bicarbonate solution (5 L). Some insoluble material was removed by filtration, and the organic phase was separated and concentrated to give tert-butyl N-(4-benzyloxy-6-chloro-3-pyridyl)carbamate (710 g, 93%) as a tan solid. 1 H NMR(400 MHz,CDCl3)δ 8.98(s,1H),7.47-7.35(m,5H),6.84(s,1H),6.74(s,1H),5.14(s,2H),1.51(s,9H).ESI-MS m / z calculated value.334.11,actual value 335.02(m+1) + .

[0231] Step 3: 4-Benzyloxy-6-chloro-pyridin-3-amine To a suspension of tert-butyl N-(4-benzyloxy-6-chloro-3-pyridyl)carbamate (10.9 g, 29.3 mmol) in dichloromethane (25 mL) was added trifluoroacetic acid (37 g, 25 mL, 325 mmol). The resulting solution was stirred for 2.5 hours and then added portionwise to saturated aqueous sodium carbonate (200 mL). The mixture was filtered, and the solid was washed with dichloromethane (50 mL). The organic phase was separated, dried over sodium sulfate, and concentrated to give a light brown solid. This was boiled in TBME (250 mL) and then cooled to room temperature. The mixture was filtered, and the filtrate was concentrated to give a light brown solid. This was stirred with heptane (50 mL), filtered, washed with heptane (50 mL), and dried in air to give 4-benzyloxy-6-chloro-pyridin-3-amine (6 g, 84%) as a light brown solid. 1H NMR(400 MHz,DMSO-d6)δ 7.61(t,J=7.6 Hz,1H),7.46(d,J=6.9 Hz,2H),7.39-7.29(m,3H),6.95(s,1H),5.30-5.15(m,2H),5.05(d,J=27.9 Hz,2H).ESI-MS m / z Calculated value.234.06, Actual value 233.0(m-1) - .

[0232] Step 4: 4-Benzyloxy-2-bromo-6-chloro-pyridin-3-amine To a cooled solution of 4-benzyloxy-6-chloro-pyridin-3-amine (103.8 g, 437.9 mmol) in DCM (2 L) was added NBS (84.3 g, 474 mmol) portionwise at 15–20 °C. The mixture was stirred at room temperature for 30 min, and then the solution was washed with water (2 × 1 L) and dried over sodium sulfate. The reaction was repeated twice, and all organics were combined and concentrated to give a red solid. This was stirred in 1:4 ethyl acetate-heptane (1.5 L) for 1 h. The solid was filtered, washed with 1:4 ethyl acetate-heptane (500 mL), then heptane (500 mL), and dried in air to give 4-benzyloxy-2-bromo-6-chloro-pyridin-3-amine (411.6 g, 100%) as an orange solid. 1 H NMR(400 MHz,CDCl3)δ 7.45-7.36(m,5H),6.76(s,1H),5.14(d,J=16.9 Hz,2H),4.12(t,J=7.1 Hz,2H).ESI-MS m / z Calculated value .311.97, Actual value 312.8(m+1) + .

[0233] Step 5: 4-Benzyloxy-6-chloro-2-methyl-pyridin-3-amine A mixture of 4-benzyloxy-2-bromo-6-chloro-pyridin-3-amine (10.0 g, 31.8 mmol), trimethylboroxine (4.8 g, 38 mmol), and potassium carbonate (8.80 g, 63.7 mmol) in 1,4-dioxane (100 mL) and water (10 mL) was degassed with argon and then treated with Pd(PPh3)4 (1.8 g, 1.6 mmol). The reaction mixture was heated under reflux for 7 h, then cooled to room temperature and partitioned between ethyl acetate (300 mL) and water (100 mL). The organic phase was dried over sodium sulfate and concentrated to give a dark oil. Purification by silica gel chromatography (0–25% ethyl acetate / heptane) afforded 4-benzyloxy-6-chloro-2-methyl-pyridin-3-amine (5 g, 63%) as a light brown solid. 1 H NMR(400 MHz,CDCl3)δ 7.40(t,J=3.7 Hz,5H),6.72(d,J=6.4 Hz,1H),5.12(d,J=23.4 Hz,2H),3.71(s,2H),2.37(s,3H).ESI-MS m / z calculated value.248.07,actual value 248.97(m+1) + .

[0234] Step 6: 4-Benzyloxy-6-chloro-3-iodo-2-methyl-pyridine To a cooled solution of 4-benzyloxy-6-chloro-2-methyl-pyridin-3-amine (25.0 g, 94.8 mmol) in 16% aqueous hydrochloric acid (250 mL) was added dropwise a solution of sodium nitrite (9.80 g, 142 mmol) in water (40 mL) at 0-2 °C. After stirring for 1 min at 0-2 °C, the solution was added to a mixture of sodium iodide (71.1 g, 474 mmol), water (250 mL), and dichloromethane (250 mL) at 0 °C. After stirring for 10 min at 0-2 °C, the mixture was allowed to warm to room temperature over 30 min. The organic phase was separated, dried over sodium sulfate, and concentrated. Purification by silica gel chromatography (0-20% ethyl acetate / heptane) followed by trituration with heptane gave 4-benzyloxy-6-chloro-3-iodo-2-methyl-pyridine (13.0 g, 35%). ESI-MS m / z calculated: 358.96, observed: 359.95 (m+1) + . 1 H NMR(400 MHz,CDCl3)δ 7.47-7.34(m,5H),6.61(s,1H),5.23-5.19(m,2H),2.77-2.73(m,3H).

[0235] Preparation 3 4-Benzyloxy-6-chloro-2-methyl-pyridine-3-carboxylic acid [ka] Step 1: Ethyl 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carboxylate A mixture of ethyl 4,6-dichloro-2-methyl-pyridine-3-carboxylate (20.0 g, 85.4 mmol) and benzyl alcohol (10.0 g, 92.5 mmol) in DMF (200 mL) was treated with potassium tert-butoxide (12.0 g, 107 mmol) and stirred at room temperature for 16 hours. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (2 × 400 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (5–8% ethyl acetate / heptane) gave ethyl 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carboxylate (12 g, 26%). 1 H NMR(400 MHz,CDCl3)δ 7.43-7.28(m,5H),6.77(s,1H),5.13(s,2H),4.36(q,J=7.1 Hz,2H),2.48(s,3H),1.30(t,J=7.1 Hz,3H).ESI-MS m / z Calculated value .305.08, Actual value 306.14(m+1) + .

[0236] Step 2: 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carboxylic acid To a solution of ethyl 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carboxylate (1.0 g, 3.2 mmol) in THF (10 mL) and methanol (10 mL) was added a solution of lithium hydroxide monohydrate (700 mg, 16.7 mmol) in water (10 mL) at room temperature, and the mixture was stirred at room temperature for 19 hours, followed by heating at 50 °C for 2 hours. An additional portion of lithium hydroxide monohydrate (700 mg, 16.7 mmol) was added at room temperature, and the mixture was stirred at 50 °C for 4 days. The mixture was concentrated, dissolved in water (20 mL), and acidified with 1 M aqueous HCl to pH 3-4. The precipitate was filtered and rinsed with water (50 mL). The solid was dried under high vacuum to give 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carboxylic acid (1 g, 104%) as a white solid. 1H NMR(400 MHz,DMSO-d6)δ 13.49(br s,1H),7.44-7.32(m,5H),7.23(s,1H),5.29(s,2H),2.37(s,3H).ESI-MS m / z calculated value .277.05, measured value 278.2(m+1) + .

[0237] Intermediate A-1 4-benzyloxy-2-bromo-3,5,6-trimethyl-pyridine [ka] Step 1: 4-Hydroxy-3,5,6-trimethyl-1H-pyridin-2-one Diethyl 2-methylpropanedioate (21.90 g, 125.7 mmol) was dissolved in toluene (5 mL) and sodium ethoxide in ethanol (40.7 mL of 21% w / v, 126 mmol) was added. The reaction was stirred at room temperature for 1 hour. Ethyl 3-amino-2-methyl-but-2-enoate (18.0 g, 126 mmol) was added and the reaction was heated to reflux for 18 hours. The condenser was left open to air at reflux for an additional 6 hours.

[0238] The reaction was cooled to room temperature, diluted with water (100 mL), and stirred for 1 hour. The mixture was partitioned between water and toluene. The aqueous layer was washed with toluene (2×50 mL), and the pH of the aqueous layer was adjusted to pH 5. The resulting precipitate was filtered and dried under vacuum to give 4-hydroxy-3,5,6-trimethyl-1H-pyridin-2-one (3 g, 16%) as an off-white solid.

[0239] 1 H NMR(400 MHz,DMSO-d6)δ 10.80(s,1H),9.11(s,1H),2.08(s,3H),1.85(s,3H),1.82(s,3H).

[0240] Step 2: 2,4-Dibromo-3,5,6-trimethyl-pyridine 4-Hydroxy-3,5,6-trimethyl-1H-pyridin-2-one (3 g, 19.59 mmol) and POBr (12.0 g, 41.9 mmol) were combined in toluene (2 mL) and heated to 110 °C for 18 hours. The reaction was cooled to room temperature and then poured into ice water. The resulting solid was filtered to give 2,4-dibromo-3,5,6-trimethyl-pyridine (2 g, 37%). 1 H NMR(400 MHz,DMSO-d6)δ 2.50(dd,J=3.7,1.9 Hz,3H),2.47(s,3H),2.33(s,3H).ESI-MS m / z calculated value .278.97, measured value 279.9(m+1) + .

[0241] Step 3: 4-benzyloxy-2-bromo-3,5,6-trimethyl-pyridine 4-Benzyloxy-2-bromo-3,5,6-trimethyl-pyridine was prepared from 2,4-dibromo-3,5,6-trimethyl-pyridine and benzyl alcohol using a procedure similar to that found in Preparation 1, Step 3. 1 H NMR(500 MHz,DMSO-d6)δ 7.50-7.34(m,5H),4.86(s,2H),2.37(s,3H),2.21(s,3H),2.12(s,3H).ESI-MS m / z calculated value .305.04, measured value 306.0(m+1) + .

[0242] Intermediate A-2 4-(benzyloxy)-2-bromo-3-methoxy-6-methylpyridine [ka] Step 1: 2,4-Dibromo-3-methoxy-6-methylpyridine In a 2 L round-bottom flask immersed in a water bath, iodomethane (37.61 g, 16.50 mL, 265 mmol) was added slowly (non-exothermic) via syringe to a stirred suspension of 2,4-dibromo-6-methylpyridin-3-ol (50 g, 178.0 mmol) and potassium carbonate (36.90 g, 267 mmol) in acetone (1.24 L). The suspension was stirred at room temperature over the weekend. The reaction mixture was filtered, and the filter cake was washed with acetone. The brown filtrate was collected and concentrated in vacuo at 40° C. The residue was partitioned between MTBE (400 mL) and water (400 mL) and stirred at room temperature. The solid was filtered and rinsed with water (200 mL) to give 2,4-dibromo-3-methoxy-6-methylpyridine (49.72 g, 90%). 1 H NMR ( 400 MHz,DMSO-d6)δ 7.67(s,1H),3.82(s,3H),2.41(s,3H).ESI-MS m / z calculated value .278.89, measured value 279.8(m+1) + .

[0243] Step 2: 4-(benzyloxy)-2-bromo-3-methoxy-6-methylpyridine NaH (523 mg, 60% dispersion in mineral oil, 13.076 mmol) was added to a stirred solution of benzyl alcohol (1.35 g, 12.48 mmol) in DMF (24 mL) at −10° C., and the mixture was stirred for 1 h. A solution of 2,4-dibromo-3-methoxy-6-methylpyridine (3.5 g, 12.44 mmol) in DMF (5 mL) was added. The mixture was stirred at −10° C. for 1 h and then allowed to warm to room temperature over 30 min. The mixture was stirred at room temperature for an additional 1 h. The mixture was partitioned between water (75 mL) and ethyl acetate (100 mL), and the layers were separated. The organic phase was washed with water (3×75 mL) and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (120 g silica, 0-40% ethyl acetate / heptane) gave 4-(benzyloxy)-2-bromo-3-methoxy-6-methylpyridine (2.25 g, 58%) as a white solid. 1 H NMR (400 MHz, CDCl3)δ 7.42-7.33(m,5H),6.69(s,1H),5.14(s,2H),3.85(s,3H),2.43(s,3H).ESI-MS m / z calculated value.307.02,actual value 308.0(m+1) + .

[0244] The following intermediate was prepared using a procedure similar to that found for Intermediate A-2 using 2-iodopropane and 2-bromoethyl methyl ether in Step 1. [Table 6]

[0245] Intermediate A-5 Ethyl 4-(benzyloxy)-2-chloro-5-methoxy-6-methylnicotinate [ka] Step 1: Ethyl 4-(benzyloxy)-2-chloro-5-hydroxy-6-methylnicotinate A solution of iPrMgCl (544 mL, 2.0 M solution in EtO, 1.1 mol) was added over 40 min to a stirred solution of ethyl 4-(benzyloxy)-2-chloro-5-iodo-6-methylnicotinate (Preparation 1, 414 g, 906 mmol) in EtO (5 L) at −11 to −5 °C. The reaction mixture was stirred at −10 °C for 10 min. Trimethylborate (188 g, 1.81 mol) was added over 10 min at −10 °C. The reaction was allowed to warm to room temperature and stirred for 1 h. The mixture was quenched by adding a mixture of ammonium chloride (2 M, 1.5 L) and brine (1.5 L). The organic phase was separated, dried over sodium sulfate, filtered, and concentrated in vacuo to give (4-(benzyloxy)-6-chloro-5-(ethoxycarbonyl)-2-methylpyridin-3-yl)boronic acid (395 g, 94%) as a bright yellow solid.

[0246] The crude boronic acid was suspended in acetonitrile (4 L) and a solution of oxone (418 g, 680 mmol) in water (2 L) was added at 0 °C. The reaction mixture was warmed to room temperature and stirred for 16 h. Additional oxone (60 g, 98 mmol) was added, and the reaction was stirred at room temperature for an additional 20 h. The mixture was filtered, and the solid was rinsed with acetonitrile (2 × 250 mL). The solid was partitioned between brine (1 L) and ethyl acetate (2 L). The organic phase was separated, dried over sodium sulfate, and concentrated in vacuo. Heptane (3 L) was added, and the mixture was concentrated to a weight of approximately 1.5 kg, then cooled to room temperature and filtered. The solid was dissolved in MTBE (4 L) and washed with 1 M NaOH (2 × 1 L). The combined aqueous extracts were acidified to pH 2 by adding 3 N HCl and extracted with ethyl acetate (2 × 1 L). The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated in vacuo to approximately 750 g. Heptane (1.5 L) was added, and the mixture was concentrated to approximately 1.5 kg to induce crystallization of the product. Heptane (1.5 L) was added, and the mixture was concentrated to approximately 1.5 kg. The solid was filtered, rinsed with heptane (200 mL), and dried in vacuo to give ethyl 4-(benzyloxy)-2-chloro-5-hydroxy-6-methylnicotinate (209 g, 69%). 1 ESI-MS m / z Calculated value .321.08, Actual value 322.1(m+1) + .

[0247] Step 2: Ethyl 4-(benzyloxy)-2-chloro-5-methoxy-6-methylnicotinate Cesium carbonate (125 g, 384 mmol) and methyl iodide (43 g, 18.9 mL, 303 mmol) were added sequentially to a solution of ethyl 4-(benzyloxy)-2-chloro-5-hydroxy-6-methylnicotinate (83 g, 255 mmol) in acetonitrile (415 mL) at room temperature. The reaction mixture was stirred for 1 hour and then filtered. The cake was rinsed with acetonitrile (2 × 100 mL), and the filtrate was concentrated in vacuo. The residue was solubilized in DCM (100 mL) and filtered through a plug of silica (75 g), rinsing with DCM (1.5 L). The filtrate was concentrated in vacuo to give ethyl 4-(benzyloxy)-2-chloro-5-methoxy-6-methylnicotinate (81.4 g, 94%). 1 H NMR(400 MHz,DMSO-d6)δ 7.48-7.28(m,5H),5.24(s,2H),4.26(q,J=7.3 Hz,2H),3.82(s,3H),2.42(s,3H),1.19(t,J=7.1 Hz,3H).ESI-MS m / z Calculated value .335.09, Actual value 336.1(m+1) + .

[0248] Methyl 4-benzyloxy-2-chloro-5-methoxy-6-methylpyridine-3-carboxylate [ka] Step 1: 4-benzyloxy-2-chloro-5-methoxy-6-methyl-pyridine-3-carboxylic acid

[0249] A solution of ethyl 4-benzyloxy-2-chloro-5-methoxy-6-methyl-pyridine-3-carboxylate (490 mg, 1.39 mmol) in methanol (5 mL) and THF (3 mL) was treated with aqueous NaOH (3 mL of 1 M, 3 mmol) and stirred at 65° C. for 12 hours. The mixture was quenched with 1N HCl solution, diluted with ethyl acetate, and washed with saturated aqueous ammonium chloride and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was triturated with 1:2 dichloromethane / hexanes and filtered to give 4-benzyloxy-2-chloro-5-methoxy-6-methyl-pyridine-3-carboxylic acid. 1 H NMR(400 MHz,DMSO-d6)δ 13.88(br s,1H),7.63-7.18(m,5H),5.22(s,2H),3.81(s,3H),2.40(s,3H).ESI-MS m / z calculated value .307.06, measured value 308.2(m+1) + .

[0250] Step 2: 4-benzyloxy-2-chloro-5-methoxy-6-methyl-pyridine-3-carbonyl chloride A vial was charged with 4-benzyloxy-2-chloro-5-methoxy-6-methyl-pyridine-3-carboxylic acid from Step 1. DCM (10 mL) was added and the resulting slurry was cooled to 0 °C. A solution of (COCl)2 in DCM (1.5 mL of 2 M, 3 mmol) was added, followed by DMF (10 μL, 0.13 mmol). The resulting mixture was stirred at 0 °C for 30 min and then concentrated to give 4-benzyloxy-2-chloro-5-methoxy-6-methyl-pyridine-3-carbonyl chloride. ESI-MS m / z calculated 325.03, found 326.2 (m+1). + .

[0251] Step 3: Methyl 4-benzyloxy-2-chloro-5-methoxy-6-methyl-pyridine-3-carboxylate A solution of 4-benzyloxy-2-chloro-5-methoxy-6-methyl-pyridine-3-carbonyl chloride from Step 2 in DCM (5 mL) was treated with DIPEA (315 μL, 1.81 mmol), DMAP (17 mg, 0.14 mmol), and methanol (1 mL, 25 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 30 min, then diluted with methylene chloride and washed with a saturated aqueous solution of ammonium chloride and then with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0 to 70% ethyl acetate / hexanes over 20 min) afforded methyl 4-benzyloxy-2-chloro-5-methoxy-6-methyl-pyridine-3-carboxylate (346.1 mg, 73%). 1 H NMR(400 MHz,DMSO-d6)δ 7.46-7.32(m,5H),5.23(s,2H),3.82(s,3H),3.79(s,3H),2.42(s,3H).ESI-MS m / z calculated value .321.08, measured value 322.256(m+1) + .

[0252] Intermediate A-7 6-Bromo-4-((4-methoxybenzyl)oxy)-2,5-dimethylnicotinonitrile [ka] Step 1: 4-Hydroxy-2,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonitrile Diethyl 2-methylmalonate (10.3 g, 59.1 mmol) and 3-aminocrotononitrile (1.8 g, 22 mmol) were combined in a sealed tube and heated at 200 °C for 165 min. The reaction mixture was cooled to room temperature and treated with MTBE. The resulting precipitate was filtered and dried to give 4-hydroxy-2,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonitrile (1.3 g, 36%). ESI-MS m / z calculated 164.06, found 165.2 (m+1). + .

[0253] Step 2: 4,6-Dibromo-2,5-dimethylnicotinonitrile POBr3 (5.0 g, 17 mmol) was added to a stirred mixture of 4-hydroxy-2,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonitrile (1.3 g, 7.9 mmol) in acetonitrile (15 mL). The reaction mixture was stirred at reflux under nitrogen for 4 hours and 45 minutes. The mixture was concentrated in vacuo and partitioned between ethyl acetate and saturated sodium bicarbonate solution. The mixture was filtered to give a first crop of product (250 mg). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated in vacuo to give a second crop of product. The two crops were combined to give 4,6-dibromo-2,5-dimethylnicotinonitrile (1.54 g, 67%). ESI-MS m / z calculated 287.89, found 288.8 (m+1). + .

[0254] Step 3: 6-Bromo-4-((4-methoxybenzyl)oxy)-2,5-dimethylnicotinonitrile 6-Bromo-4-((4-methoxybenzyl)oxy)-2,5-dimethylnicotinonitrile was prepared from 4,6-dibromo-2,5-dimethylnicotinonitrile and (4-methoxyphenyl)methanol using a procedure similar to that found in Preparation 1, Step 3, using 2-MeTHF as solvent. ESI-MS m / z calculated 346.03, found 224.9 (m-PMB). + .

[0255] Intermediate A-8 4-(benzyloxy)-2-chloropyridine [ka] Cesium carbonate (1.89 g, 5.80 mmol) and benzyl bromide (700 μL, 5.89 mmol) were added sequentially to a solution of 2-chloropyridin-4-ol (500 mg, 3.86 mmol) in acetonitrile (8 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate (15 mL) and poured into saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was separated and extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were washed with brine (30 mL), dried over magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (24 g silica, 0–100% ethyl acetate / heptane) afforded 4-(benzyloxy)-2-chloropyridine (601 mg, 71%) as a crystalline white solid. 1 H NMR(500 MHz,CDCl3)δ 8.20(d,J=5.8 Hz,1H),7.44-7.35(m,5H),6.92(d,J=2.2 Hz,1H),6.82(dd,J=5.8,2.2 Hz,1H),5.11(s,2H).ESI-MS m / z Calculated value .219.05, Actual value 220.3(m+1) + ; 218.1(m-1) - .

[0256] Intermediate A-9 4-Benzyloxy-6-chloro-N,N-dimethyl-pyridin-2-amine [ka] Step 1: 4,6-Dichloro-N,N-dimethyl-pyridin-2-amine A solution of 4,6-dichloropyridin-2-amine (300 mg, 1.84 mmol) in THF (5 mL) was treated with sodium hydride (300 mg, 60% dispersion in mineral oil, 7.50 mmol) at 0 °C. Methyl iodide (732 mg, 5.16 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, evaporated, and purified by silica gel column chromatography (0-30% ethyl acetate / hexane) to give 4,6-dichloro-N,N-dimethyl-pyridin-2-amine (220 mg, 63%). ESI-MS m / z calculated 190.01, found 191.1 (m+1). + . 1 H NMR ( 400 MHz, CDCl3)δ 6.55(d,J=1.3 Hz,1H),6.34(d,J=1.3 Hz,1H),3.07(s,6H).

[0257] Step 2: 4-Benzyloxy-6-chloro-N,N-dimethyl-pyridin-2-amine 4-Benzyloxy-6-chloro-N,N-dimethyl-pyridin-2-amine was prepared from 4,6-dichloro-N,N-dimethyl-pyridin-2-amine and benzyl alcohol using a procedure similar to that found in Preparation 1, Step 3. ESI-MS m / z calculated 262.09, found 263.3 (m+1). + . 1 H NMR ( 400 MHz, CDCl3)δ 7.41-7.32(m,5H),6.26(d,J=1.7 Hz,1H),5.89(d,J=1.8 Hz,1H),5.05(s,2H),3.03(s,6H).

[0258] Intermediate A-10 [ka] 4-Benzyloxy-2-chloro-N,N,6-trimethyl-pyridin-3-amine Step 1: 2,4-Dichloro-6-methyl-3-nitro-pyridine A solution of 4-hydroxy-6-methyl-3-nitro-1H-pyridin-2-one (5.0 g, 28.8 mmol), diethylaniline (4.1 g, 4.5 mL, 27 mmol), and POCl3 (39.5 g, 24.5 mL, 252 mmol) was stirred at room temperature for 10 minutes and then at 120 °C for 12 hours. The mixture was cooled, diluted with ice water, and stirred for 1.5 hours. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 2,4-dichloro-6-methyl-3-nitro-pyridine (4.5 g, 72%). 1 H NMR(400 MHz,CDCl3)δ 7.29(s,1H),2.61(s,3H).ESI-MS m / z calculated value.205.97,actual value 206.80(m+1) + .

[0259] Step 2: 2,4-Dichloro-6-methyl-pyridin-3-amine A mixture of 2,4-dichloro-6-methyl-3-nitro-pyridine (3.0 g, 13.9 mmol) and iron (20 g, 350 mmol) in methanol (60 mL) and water (15 mL) was added with ammonium chloride (743 mg, 13.6 mmol) at 0° C. and stirred for 10 minutes. The resulting reaction mixture was heated to 80° C. and stirred for 5 hours. The reaction mixture was filtered. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 2,4-dichloro-6-methyl-pyridin-3-amine (2.2 g, 89%). 1 H NMR(400 MHz,CDCl3)δ 7.02(s,1H),4.29(s,2H),2.41(s,3H).ESI-MS m / z Calculated value.175.99, Actual value 177.0(m+1) + .

[0260] Step 3: 2,4-Dichloro-N,N,6-trimethyl-pyridin-3-amine To a solution of 2,4-dichloro-6-methyl-pyridin-3-amine (1.02 g, 5.76 mmol) in THF (28 mL) at 0 °C was added potassium tert-butoxide in THF (17.3 mL of 1.0 M, 17.3 mmol), and the mixture was stirred for 30 min. Methyl iodide (4.1 g, 1.8 mL, 29 mmol) was added dropwise, and the reaction was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with half-saturated brine (50 mL), and the mixture was extracted with ethyl acetate (2 × 50 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (5–20% ethyl acetate / heptane) afforded 2,4-dichloro-N,N,6-trimethyl-pyridin-3-amine (668 mg, 57%). 1 H NMR(400 MHz,CDCl3)δ 7.09(s,1H),2.84(s,6H),2.45(s,3H).ESI-MS m / z calculated value.204.02,actual value 205.07(m+1) + .

[0261] Step 4: 4-Benzyloxy-2-chloro-N,N,6-trimethyl-pyridin-3-amine 4-Benzyloxy-2-chloro-N,N,6-trimethyl-pyridin-3-amine was prepared from 2,4-dichloro-N,N,6-trimethyl-pyridin-3-amine and benzyl alcohol using a procedure similar to that found in Preparation 1, Step 3. 1 H NMR(400 MHz,CDCl3)δ 7.42-7.34(m,5H),6.66(s,1H),5.12(s,2H),2.79(s,6H),2.42(s,3H).ESI-MS m / z Calculated value.276.10, Actual value 276.95(m+1) + .

[0262] Intermediate A-11 Ethyl 4-benzyloxy-6-chloro-5-(dimethylamino)-2-methyl-pyridine-3-carboxylate [ka] Step 1: Ethyl 4,6-dihydroxy-2-methyl-5-nitro-pyridine-3-carboxylate To a solution of ethyl 4,6-dihydroxy-2-methyl-pyridine-3-carboxylate (10.0 g, 48.9 mmol) in sulfuric acid (75 mL) at 0° C. was added nitric acid (4.2 g, 3.0 mL, 67 mmol) dropwise over 15 minutes. The reaction mixture was then stirred at 0° C. for 2 hours. It was then poured onto crushed ice (200 g) and stirred vigorously at room temperature overnight. The precipitate was filtered, rinsed with cold water (2×150 mL), washed with heptane (3×150 mL), and air-dried to give ethyl 4,6-dihydroxy-2-methyl-5-nitro-pyridine-3-carboxylate (11.51 g, 97%) as a tan solid. 1 H NMR(400 MHz,DMSO-d6)δ 12.44(br s,2H),4.31(q,J=7.0 Hz,2H),2.43(s,3H),1.30(t,J=7.1 Hz,3H).ESI-MS m / z calculated value .242.05, measured value 243.2(m+1) + .

[0263] Step 2: Ethyl 4,6-dichloro-2-methyl-5-nitro-pyridine-3-carboxylate Ethyl 4,6-dichloro-2-methyl-5-nitro-pyridine-3-carboxylate was prepared from ethyl 4,6-dihydroxy-2-methyl-5-nitro-pyridine-3-carboxylate using a procedure similar to that found in Preparation 1, Step 2. 1 H NMR(400 MHz,CDCl3)δ 4.49(q,J=7.1 Hz,2H),2.63(s,3H),1.43(t,J=7.1 Hz,3H).ESI-MS m / z calculated value.277.99,actual value 279.0(m+1) + .

[0264] Step 3: Ethyl 5-amino-4,6-dichloro-2-methyl-pyridine-3-carboxylate Ethyl 5-amino-4,6-dichloro-2-methyl-pyridine-3-carboxylate was prepared from ethyl 4,6-dichloro-2-methyl-5-nitro-pyridine-3-carboxylate using a procedure similar to that found in Intermediate A-10, Step 2. 1 H NMR(400 MHz,DMSO-d6)δ 5.89(s,2H),4.37(q,J=7.1 Hz,2H),2.26(s,3H),1.31(t,J=7.1 Hz,3H).ESI-MS m / z calculated value .248.01, measured value 249.2(m+1) + .

[0265] Step 4: Ethyl 4,6-dichloro-5-(dimethylamino)-2-methyl-pyridine-3-carboxylate To a solution of ethyl 5-amino-4,6-dichloro-2-methyl-pyridine-3-carboxylate (200 mg, 0.794 mmol) and sodium cyanoborohydride (300 mg, 4.77 mmol) in THF (4 mL) was added a solution of formaldehyde in water (0.30 mL of 37% w / w, 4.0 mmol) at 0 °C, followed by the dropwise addition of sulfuric acid (0.25 mL, 4.7 mmol) over 5 minutes. The mixture was warmed to room temperature and stirred for 2.75 hours. A second portion of formaldehyde in water (0.30 mL of 37% w / w, 4.0 mmol) and sodium cyanoborohydride (150 mg, 2.39 mmol) was added to the mixture, which was stirred at room temperature for 1 hour. A third addition of formaldehyde in water (328 mg, 0.30 mL of 37% w / w, 4.0 mmol) and sodium cyanoborohydride (150 mg, 2.39 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was partitioned between water (50 mL) and ethyl acetate (30 mL), and the aqueous layer was extracted with additional ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (24 g silica, 0–5% ethyl acetate / heptane) afforded ethyl 4,6-dichloro-5-(dimethylamino)-2-methyl-pyridine-3-carboxylate (178 mg, 81%) as a light yellow oil.1 H NMR(400 MHz,CDCl3)δ 4.45(q,J=7.2 Hz,2H),2.87(s,6H),2.47(s,3H),1.42(t,J=7.1 Hz,3H).ESI-MS m / z calculated value.276.04, measured value 277.2(m+1) + .

[0266] Step 5: Ethyl 4-benzyloxy-6-chloro-5-(dimethylamino)-2-methyl-pyridine-3-carboxylate Ethyl 4-benzyloxy-6-chloro-5-(dimethylamino)-2-methyl-pyridine-3-carboxylate was prepared from ethyl 4,6-dichloro-5-(dimethylamino)-2-methyl-pyridine-3-carboxylate and benzyl alcohol using a procedure similar to that found in Preparation 1, Step 3. 1 H NMR(400 MHz,CDCl3)δ 7.42-7.33(m,5H),5.14(s,2H),4.29(q,J=7.1 Hz,2H),2.85(s,6H),2.45(s,3H),1.27(t,J=7.1 Hz,3H).ESI-MS m / z Calculated value .348.12, Actual value 349.1(m+1) + .

[0267] Intermediate A-12 4-benzyloxy-2-chloro-6-vinyl-pyridine [ka] Step 1: 4-benzyloxy-2,6-dichloro-pyridine

[0268] 2,6-Dichloropyridin-4-ol (4.65 g, 28.36 mmol) was dissolved in acetonitrile (55 mL) and then treated with cesium carbonate (13.9 g, 42.7 mmol) and benzyl bromide (8.4 mL, 71 mmol). The resulting mixture was stirred at 40 °C for 1 h, then filtered through Celite® and concentrated in vacuo. Purification by silica gel chromatography (0-35% ethyl acetate / heptane) afforded 4-benzyloxy-2,6-dichloro-pyridine (6.91 g, 85%) as a white solid. ESI-MS m / z calculated 253.01, found 254.0 (m+1). + . 1 H NMR(400 MHz,CDCl3)δ 7.48-7.33(m,5H),6.86(s,2H),5.11(s,2H).

[0269] Step 2: 4-Benzyloxy-2-chloro-6-vinyl-pyridine To a solution of 4-benzyloxy-2,6-dichloro-pyridine (4.6 g, 18 mmol) in 1,4-dioxane (100 mL) and water (20 mL) was added potassium vinyltrifluoroborate (2.5 g, 19 mmol) and sodium carbonate (5.7 g, 54 mmol). Nitrogen was bubbled through the solution, and then Pd(PPh3)4 (3.0 g, 2.6 mmol) was added, and the mixture was bubbled with nitrogen for 15 minutes. The mixture was stirred at reflux for 18 hours, then cooled and partitioned between ethyl acetate (200 mL) and water (300 mL). The aqueous phase was extracted with additional ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-10% ethyl acetate / heptane) gave 4-benzyloxy-2-chloro-6-vinyl-pyridine (2.55 g, 57%) as a clear oil. 1H NMR(400 MHz,CDCl3)δ 7.49-7.35(m,5H),6.93-6.79(m,2H),6.69(dd,J=17.4,10.8 Hz,1H),6.25(dd,J=17.4,0.7 Hz,1H),5.53(d,J=10.5 Hz,1H),5.13(s,2H).ESI-MS m / z calculated value.245.06,actual value 246.0(m+1) + .

[0270] Suzuki coupling of 4-benzyloxy-2-chloro-6-vinyl-pyridine with Intermediate-B was followed by reduction of the alkene using standard hydrogenation conditions to give the corresponding ethyl analogue.

[0271] Intermediate A-13 (4-benzyloxy-2-chloro-6-methyl-3-pyridyl)methanol [ka] Ethyl 4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylate (Intermediate A-40, 150 mg, 0.491 mmol) was dissolved in THF (1.5 mL). The resulting solution was cooled to 0 °C, and then LAH in THF (490 μL of 1.0 M in THF, 0.49 mmol) was added. The resulting solution was stirred at 0 °C for 4 h and allowed to warm to room temperature. The resulting solution was diluted with ethyl acetate (20 mL) and washed with a saturated solution of potassium sodium tartrate (Rochelle's salt) and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (C18, 10–99% acetonitrile / 5 mM HCl) to afford (4-benzyloxy-2-chloro-6-methyl-3-pyridyl)methanol (126.3 mg, 98%) as a white solid. ESI-MS m / z calculated: 263.07, observed: 164.12 (m+1) + . 1H NMR(400 MHz,DMSO-d6)δ 7.49(d,J=7.0 Hz,2H),7.44-7.39(m,2H),7.38-7.33(m,1H),7.09(s,1H),5.24(s,2H),4.54(s,2H),2.39(s,3H).

[0272] Intermediate A-14 4-benzyloxy-2-chloro-3-(ethoxymethyl)-6-methyl-pyridine [ka] A stirred solution of (4-benzyloxy-2-chloro-6-methyl-3-pyridyl)methanol (188 mg, 0.713 mmol) in THF (3 mL) was treated with sodium hydride (53.6 mg, 60% dispersion in mineral oil, 1.34 mmol) at 0° C. and then stirred at room temperature for 20 minutes. The reaction mixture was then cooled to 0° C., and iodoethane (172 μL, 2.15 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred at room temperature for 20 hours. The mixture was cooled to 0° C., carefully quenched with ice-water, and then partitioned between ethyl acetate and water. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (0-30% ethyl acetate / hexanes) gave 4-benzyloxy-2-chloro-3-(ethoxymethyl)-6-methyl-pyridine (140.9 mg, 68%). 1 H NMR(400 MHz,DMSO-d6)δ 7.50-7.31(m,5H),7.12(s,1H),5.26(s,2H),4.50(s,2H),3.45(q,J=7.0 Hz,2H),2.40(s,3H),1.08(t,J=7.0 Hz,3H).ESI-MS m / z Calculated value.291.10, Actual value 292.2(m+1) + .

[0273] Intermediate A-15 Ethyl 4-benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylate [ka] Step 1: Ethyl 2,4-dichloro-5,6-dimethyl-pyridine-3-carboxylate Ethyl 4-hydroxy-5,6-dimethyl-2-oxo-1H-pyridine-3-carboxylate (500 mg, 2.37 mmol) was dissolved in POCl3 (1.5 mL, 16 mmol), and the solution was heated at 105 °C for 14 h. After cooling to room temperature, the mixture was poured onto ice and stirred for 30 min. The residue was dissolved in ethyl acetate, carefully washed with saturated sodium bicarbonate solution (3 × 5 mL), filtered, and concentrated in vacuo. Purification by silica gel chromatography (0–30% ethyl acetate / hexanes) afforded ethyl 2,4-dichloro-5,6-dimethyl-pyridine-3-carboxylate (494 mg, 83%) as a white solid. ESI-MS m / z calculated 247.02, found 248.1 (m+1). + .

[0274] Step 2: Ethyl 4-benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylate Ethyl 4-benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylate was prepared from ethyl 2,4-dichloro-5,6-dimethyl-pyridine-3-carboxylate and benzyl alcohol using a procedure similar to that found in Preparation 1, Step 3. ESI-MS m / z calculated 319.1, found 320.0 (m+1). + .

[0275] Intermediate A-16 Ethyl 4-benzyloxy-6-chloro-2,5-dimethyl-pyridine-3-carboxylate [ka] Step 1: Ethyl 4,6-dihydroxy-2,5-dimethyl-pyridine-3-carboxylate A mixture of ethyl (Z)-3-aminobut-2-enoate (32.7 g, 32.0 mL, 253 mmol) and 2-methylpropanedioic acid (30.0 g, 254 mmol) in acetic anhydride (260 g, 240 mL, 2.54 mol) was heated at 100° C. for 3 hours and then allowed to cool. The resulting solid was collected by filtration, washed with ethyl acetate (100 mL), and dried to give ethyl 4,6-dihydroxy-2,5-dimethyl-pyridine-3-carboxylate (20.15 g, 37%). 1 H NMR(400 MHz,DMSO-d6)δ 11.71(s,1H),11.45(s,1H),4.28(q,J=7.2 Hz,2H),2.43(s,3H),1.76(s,3H),1.28(t,J=7.1 Hz,3H).ESI-MS m / z Calculated value: 211.09, Actual value: 212.02(m+1) + .

[0276] Step 2: Ethyl 4,6-dichloro-2,5-dimethyl-pyridine-3-carboxylate A mixture of ethyl 4,6-dihydroxy-2,5-dimethyl-pyridine-3-carboxylate (20.15 g, 95.15 mmol) and tetramethylammonium chloride (11.5 g, 105 mmol) in POCl3 (146 g, 89 mL, 955 mmol) was heated to reflux for 4 hours and then cooled overnight. The mixture was carefully added dropwise to cold water (200 mL). Additional water (200 mL) was added and the aqueous phase was extracted with ethyl acetate (2 x 200 mL). The combined extracts were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated to give ethyl 4,6-dichloro-2,5-dimethyl-pyridine-3-carboxylate (24.13 g, 100%). 1 H NMR(400 MHz,CDCl3)δ 4.43(q,J=7.0 Hz,2H),2.48(s,3H),2.44(s,3H),1.40(q,J=7.2 Hz,3H).ESI-MS m / z Calculated value.247.02, Actual value 247.91(m+1) + .

[0277] Step 3: Ethyl 4-benzyloxy-6-chloro-2,5-dimethyl-pyridine-3-carboxylate Ethyl 4-benzyloxy-6-chloro-2,5-dimethyl-pyridine-3-carboxylate was prepared from ethyl 4,6-dichloro-2,5-dimethyl-pyridine-3-carboxylate and benzyl alcohol using a procedure similar to that found in Preparation 1, Step 3. 1 H NMR(400 MHz,CDCl3)δ 7.42-7.40(m,5H),5.01(s,2H),4.37(q,J=7.2 Hz,2H),2.52(s,3H),2.29(s,3H),1.34(t,J=7.1 Hz,3H).ESI-MS m / z Calculated value .319.10, Actual value 320.01(m+1) + .

[0278] Intermediate A-17 [6-chloro-4-[(4-methoxyphenyl)methoxy]-2-methyl-3-pyridyl]methanol [ka] To a stirred solution of ethyl 6-chloro-4-[(4-methoxyphenyl)methoxy]-2-methyl-pyridine-3-carboxylate (Intermediate A-39, 375 mg, 1.12 mmol) in THF (5 mL) at 0 °C, LAH (0.8 mL of 2.0 M in THF, 1.6 mmol) was added portionwise. The mixture was stirred at 0 °C for 30 min and then at room temperature for 4 h. The mixture was cooled to 0 °C, quenched with saturated sodium sulfate solution, filtered through Celite®, and extracted with DCM (2 × 10 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give [6-chloro-4-[(4-methoxyphenyl)methoxy]-2-methyl-3-pyridyl]methanol (350 mg, 107%). ESI-MS m / z calculated 293.08, found 294.0 (m+1). + .

[0279] Intermediate A-18 1-[6-chloro-4-[(4-methoxyphenyl)methoxy]-2-methyl-3-pyridyl]ethanone [ka] To a solution of ethyl 6-chloro-4-[(4-methoxyphenyl)methoxy]-2-methyl-pyridine-3-carboxylate (100 mg, 0.294 mmol) in THF (2 mL) at −5° C. was slowly added methylmagnesium bromide solution (0.25 mL of 3.0 M in diethyl ether, 0.75 mmol). The reaction mixture was stirred at 0° C. for 3 hours. An additional amount of methylmagnesium bromide solution (0.2 mL of 3.0 M in diethyl ether, 0.6 mmol) was added, and the reaction mixture was stirred at 0° C. for 2 hours. The mixture was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by reverse phase chromatography (C18, 10-70% acetonitrile / water, each containing 0.1% formic acid) gave 1-[6-chloro-4-[(4-methoxyphenyl)methoxy]-2-methyl-3-pyridyl]ethanone (20 mg, 21%). 1 H NMR(400 MHz,CDCl3)δ 7.27(dd,J=6.6,2.1 Hz,2H),6.92(dd,J=6.6,2.1 Hz,2H),6.81(s,1H),5.05(s,2H),3.82(s,3H),2.44(s,3H),2.41(s,3H).

[0280] Intermediate A-19 Benzyl 4-benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylate [ka] Step 1: 4-benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylic acid A solution of ethyl 4-benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylate (Intermediate A-15, 400 mg, 1.23 mmol) in methanol (6 mL) and THF (4 mL) was treated with aqueous NaOH (7 mL of 1 M, 7 mmol) and stirred at 65 °C overnight. The mixture was quenched with aqueous 1N HCl, diluted with ethyl acetate, and washed with saturated aqueous ammonium chloride and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The solid was triturated with dichloromethane / hexane (2:1) and then filtered to give 4-benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylic acid (318 mg, 89%). 1 H NMR(400 MHz,DMSO-d6)δ 13.96(br s,1H),7.49-7.34(m,5H),5.00(s,2H),2.43(s,3H),2.16(s,3H).ESI-MS m / z Calculated value .291.07, Actual value 292.2(m+1) + .

[0281] Step 2: Benzyl 4-benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylate A solution of 4-benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylic acid (62 mg, 0.20 mmol) in DCM (2 mL) was treated with benzyl alcohol (50 μL, 0.48 mmol), DIPEA (40 μL, 0.23 mmol), and DMAP (21 mg, 0.17 mmol). PyBOP (105 mg, 0.202 mmol) was added, and the resulting mixture was stirred for 3 h. The mixture was quenched with 1 N HCl solution, diluted with ethyl acetate, and washed with a saturated solution of ammonium chloride and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0–40% ethyl acetate / hexanes over 20 min) afforded benzyl 4-benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylate (64.1 mg, 77%) as a clear, thick oil that crystallized upon standing. 1H NMR(400 MHz,DMSO-d6)δ 7.50-7.28(m,10H),5.36(s,2H),4.91(s,2H),2.44(s,3H),2.15(s,3H).ESI-MS m / z calculated value .381.11, measured value 382.36(m+1) + .

[0282] Intermediate A-20 Isopropyl 4-benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylate [ka] Isopropyl 4-benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylate was prepared from 4-benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylic acid and 2-propanol using a procedure similar to that found in intermediate A-19. 1 H NMR(400 MHz,DMSO-d6)δ 7.47-7.33(m,5H),5.16(hept,J=6.2 Hz,1H),4.99(s,2H),2.44(s,3H),2.16(s,3H),1.26(d,J=6.3 Hz,6H).ESI-MS m / z Calculated value .333.11, Actual value 334.645(m+1) + .

[0283] Intermediate A-21 Ethyl 4-benzyloxy-2-chloro-5-cyano-6-methyl-pyridine-3-carboxylate [ka] Step 1: Ethyl 2,4-dichloro-5-cyano-6-methyl-pyridine-3-carboxylate A mixture of ethyl 2,4-dichloro-5-iodo-6-methyl-pyridine-3-carboxylate (Preparation 1, 100 mg, 0.280 mmol) and CuCN (28 mg, 0.31 mmol) in NMP (1 mL) was degassed under a nitrogen atmosphere and then heated at 100 °C in a sealed vial for 16 h. The mixture was filtered and washed with ethyl acetate. The filtrate was washed with brine (3x), dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (0-10% ethyl acetate / hexanes) gave ethyl 2,4-dichloro-5-cyano-6-methyl-pyridine-3-carboxylate (49 mg, 68%). ESI-MS m / z calculated 258.0, found 259.1 (m+1). + . 1 H NMR(400 MHz,DMSO-d6)δ 4.46(q,J=7.1 Hz,2H),2.71(s,3H),1.34(t,J=7.1 Hz,3H). 13 C NMR(101 MHz,DMSO-d6)δ 165.17,162.35,149.23,144.89,127.34,114.01,110.57,63.79,24.26,14.24.

[0284] Step 2: Ethyl 4-benzyloxy-2-chloro-5-cyano-6-methyl-pyridine-3-carboxylate Ethyl 4-benzyloxy-2-chloro-5-cyano-6-methyl-pyridine-3-carboxylate was prepared from ethyl 2,4-dichloro-5-cyano-6-methyl-pyridine-3-carboxylate and benzyl alcohol using a procedure similar to that found in Preparation 1, Step 3. ESI-MS m / z calculated 330.08, found 331.2 (m+1). + . 1 H NMR ( 400 MHz,DMSO-d6)δ 7.51-7.37(m,5H),5.47(s,2H),4.33(d,J=7.2 Hz,2H),3.29(s,3H),1.22(t,J=7.1 Hz,3H).

[0285] Intermediate A-22 Ethyl 4-benzyloxy-2-chloro-5-ethynyl-6-methyl-pyridine-3-carboxylate [ka] Step 1: Ethyl 4-benzyloxy-2-chloro-6-methyl-5-(2-trimethylsilylethynyl)pyridine-3-carboxylate Ethyl 4-benzyloxy-2-chloro-5-iodo-6-methyl-pyridine-3-carboxylate (Preparation 1, 100 mg, 0.232 mmol), ethynyl(trimethyl)silane (150 μL, 1.06 mmol), Na2PdCl4 (15.2 mg, 0.0517 mmol), CuI (10 mg, 0.053 mmol), and P( t A mixture of 4-benzyloxy-2-chloro-6-methyl-5-(2-trimethylsilylethynyl)pyridine-3-carboxylate (20.2 mg, 0.095 mmol) and 4-benzyloxy-2-chloro-6-methyl-5-(2-trimethylsilylethynyl)pyridine-3-carboxylate (20.2 mg, 0.095 mmol) was degassed for 1 minute and then stirred in a sealed tube under nitrogen at 80 °C for 1 hour. The mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), and washed with saturated aqueous ammonium chloride and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-40% ethyl acetate / hexanes over 15 minutes) gave ethyl 4-benzyloxy-2-chloro-6-methyl-5-(2-trimethylsilylethynyl)pyridine-3-carboxylate. ESI-MS m / z calculated 401.12, found 402.5 (m+1). + .

[0286] Step 2: Ethyl 4-benzyloxy-2-chloro-5-ethynyl-6-methyl-pyridine-3-carboxylate Ethyl 4-benzyloxy-2-chloro-6-methyl-5-(2-trimethylsilylethynyl)pyridine-3-carboxylate from Step 1 was dissolved in methanol (2 mL), followed by the addition of potassium carbonate (33.5 mg, 0.242 mmol). The mixture was stirred at room temperature for 1 hour, then diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (0 to 30% ethyl acetate / heptane over 15 minutes) gave ethyl 4-benzyloxy-2-chloro-5-ethynyl-6-methyl-pyridine-3-carboxylate (60 mg, 79%). 1 H NMR(400 MHz,DMSO-d6)δ 7.45-7.33(m,5H),5.38(s,2H),5.10(s,1H),4.27(q,J=7.1 Hz,2H),2.59(s,3H),1.20(t,J=7.1 Hz,3H).ESI-MS m / z Calculated value: 329.08, Actual value: 330.3(m+1) + .

[0287] Intermediate A-23 4-(Benzyloxy)-6-chloro-2-methyl-3-(methylthio)pyridine [ka] Step 1: 4-chloro-3-iodo-2-methylpyridine 1-oxide A solution of mCPBA (23.4 g, 70-75% w / w in water, 101.7 mmol) was added portionwise to a solution of 4-chloro-3-iodo-2-methylpyridine (17.2 g, 67.9 mmol) in DCM (250 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was diluted with DCM (250 mL) and washed with water (250 mL). The aqueous layer was separated and extracted with DCM (200 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated with methanol (2 × 30 mL), filtered, and dried to give 4-chloro-3-iodo-2-methylpyridine 1-oxide (15 g, 82%) as a white solid. 1H NMR ( 400 MHz, CDCl3)δ 8.17(d,J=7.3 Hz,1H),7.23(d,J=6.9 Hz,1H),2.90(s,3H).ESI-MS m / z calculated value .268.91, measured value 269.78(m+1) + .

[0288] Step 2: 4,6-Dichloro-3-iodo-2-methylpyridine A solution of 4-chloro-3-iodo-2-methylpyridine 1-oxide (1.75 g, 6.45 mmol) in POCl3 (16.5 g, 10.0 mL, 107 mmol) was heated at 85 °C for 5 h. The reaction mixture was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (20 mL). The aqueous layer was separated and extracted with additional ethyl acetate (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give 4,6-dichloro-3-iodo-2-methylpyridine (2.5 g, 70%). ESI-MS m / z calculated 286.88, found 287.73 (m+1). + .

[0289] Step 3: 4,6-Dichloro-2-methyl-3-(methylthio)pyridine A mixture of 4,6-dichloro-3-iodo-2-methylpyridine (212 mg, 0.710 mmol), sodium methanethiolate (50 mg, 0.70 mmol), Pd2dba3 (16 mg, 0.02 mmol), Xantphos (20 mg, 0.04 mmol), and DIPEA (185 mg, 250 μL, 1.42 mmol) in a mixture of 1,4-dioxane (2 mL) and water (0.2 mL) was stirred at 100 °C under microwave irradiation for 1 h. The mixture was partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (0–20% ethyl acetate / heptane) gave 4,6-dichloro-2-methyl-3-(methylthio)pyridine (186 mg, 94%). 1 H NMR (400 MHz, CDCl3)δ 7.30(s,1H),2.78(s,3H),2.34(s,3H).ESI-MS m / z calculated value.206.97,actual value 207.94(m+1) + .

[0290] Step 4: 4-(benzyloxy)-6-chloro-2-methyl-3-(methylthio)pyridine 4-(Benzyloxy)-6-chloro-2-methyl-3-(methylthio)pyridine was prepared from 4,6-dichloro-2-methyl-3-(methylthio)pyridine and benzyl alcohol using a procedure similar to that found in Preparation 1, Step 3, and NMP as the solvent. 1 H NMR ( 400 MHz, CDCl3)δ 7.47-7.35(m,5H),6.76(s,1H),5.18(s,2H),2.69(s,3H),2.30(s,3H).ESI-MS m / z calculated value .279.05, measured value 280.4(m+1) + .

[0291] Intermediate A-24 (4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-imino-methyl-oxo-λ6-sulfane [ka] 4-(Benzyloxy)-6-chloro-2-methyl-3-(methylthio)pyridine (2.0 g, 7.2 mmol) was dissolved in DCM (20 mL) and methanol (20 mL), and the solution was cooled to 0 °C. Ammonium carbamate (837 mg, 10.7 mmol) and (diacetoxyiodo)benzene (4.61 g, 14.3 mmol) were added, and the mixture was allowed to warm to room temperature and stirred for 2 h. Additional (diacetoxyiodo)benzene (1.15 g, 3.57 mmol) and ammonium carbamate (223 mg, 2.86 mmol) were added, and the resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (0-100% ethyl acetate / heptane) to give (4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-imino-methyl-oxo-λ6-sulfane (1.314 g, 59%) as a white solid. ESI-MS m / z calculated 310.05, found 311.2 (m+1). + . 1 H NMR(500 MHz,DMSO-d6)δ 7.56-7.54(m,2H),7.45-7.40(m,2H),7.39-7.35(m,2H),5.39(d,J=2.0 Hz,2H),4.59(s,1H),3.17(d,J=1.2 Hz,3H),2.74(s,3H).

[0292] The enantiomers were separated by chiral SFC using a Nexera UC Prep (Shimadzu) with a ChiralPak IC (250 x 20 mm), 5 μm (Daicel Corp.) column at 40 °C. Separation was achieved using an isocratic method with a mobile phase of 20% methanol (20 mM NH3), 80% CO2 at a flow rate of 100 mL / min. The detection wavelength was 215 nm. The retention times of peak 1 and peak 2 were 4.380 and 5.468 min, respectively.

[0293] Peak 1: (4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-imino-methyl-oxo-λ6-sulfane (561 mg, 51%), ESI-MS m / z calculated 310.05, found 311.1 (m+1)+ Retention time: 2.19 min. 98.1% ee.

[0294] Peak 2: (4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-imino-methyl-oxo-λ6-sulfane (523 mg, 47%), ESI-MS m / z calculated 310.05, found 311.1 (m+1) + Retention time: 2.19 min. 91.1% ee.

[0295] Intermediate A-25 Ethyl 4,5-dibenzyloxy-2-chloro-6-methylpyridine-3-carboxylate [ka] Step 1: (4-benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridyl)boronic acid Step 1: (4-benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridyl)boronic acid Ethyl 4-benzyloxy-2-chloro-5-iodo-6-methyl-pyridine-3-carboxylate (Preparation 1, 236 mg, 0.547 mmol) was dissolved in EtO (5 mL). The resulting mixture was cooled to −78° C. Then, n-BuLi (250 μL of 2.5 M, 0.63 mmol) was added dropwise over 5 minutes, and the resulting mixture was stirred at −78° C. for 15 minutes. (MeO)B (250 μL, 2.20 mmol) was added dropwise, and the resulting mixture was stirred at −78° C. for 2 hours. After 2 hours, the reaction was quenched with a saturated aqueous solution of ammonium chloride, diluted with ethyl acetate, and washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give (4-benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridyl)boronic acid ESI-MS m / z calculated 349.09, found 350.2 (m+1) + , and ethyl 4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylate, ESI-MS m / z calculated: 305.08, found: 306.2 (m+1)+ A mixture of

[0296] Step 2: Ethyl 4-benzyloxy-2-chloro-5-hydroxy-6-methyl-pyridine-3-carboxylate (4-Benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridyl)boronic acid from Step 1 was dissolved in EtO (2 mL) and THF (2 mL) and cooled to 0 °C, then HO (200 μL of 35% w / w, 2.34 mmol) was added dropwise, followed by aqueous NaOH (150 μL of 1 M, 0.15 mmol). The mixture was stirred at room temperature for 4 h, then cooled to 0 °C and quenched with saturated aqueous sodium thiosulfate (2 mL). The mixture was warmed to room temperature, diluted with ethyl acetate, and washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-50% ethyl acetate / hexanes over 15 min) gave ethyl 4-benzyloxy-2-chloro-5-hydroxy-6-methyl-pyridine-3-carboxylate, ESI-MS m / z calculated 321.08, found 322.256 (m+1). + , and ethyl 4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylate, ESI-MS m / z calculated: 305.08, found: 306.2 (m+1) + A 3:2 mixture of

[0297] Step 3: Ethyl 4,5-dibenzyloxy-2-chloro-6-methyl-pyridine-3-carboxylate The resulting mixture from Step 2 was dissolved in DMF (2 mL) and cooled to 0 °C. Benzyl bromide (30 μL, 0.25 mmol) and cesium carbonate (89 mg, 0.27 mmol) were added, and the mixture was stirred for 30 minutes. The mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0 to 30% ethyl acetate / hexanes over 15 minutes) gave ethyl 4,5-dibenzyloxy-2-chloro-6-methyl-pyridine-3-carboxylate (74.6 mg, 33%). 1 H NMR(400 MHz,DMSO-d6)δ 7.50-7.29(m,10H),5.24(s,2H),5.02(s,2H),4.27(q,J=7.1 Hz,2H),2.35(s,3H),1.20(t,J=7.1 Hz,3H).ESI-MS m / z Calculated value: 411.12, Actual value: 412.4(m+1) + .

[0298] Intermediate A-26 2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)acetamide [ka] Step 1: 4-benzyloxy-6-chloro-3-[(E)-2-ethoxyvinyl]-2-methyl-pyridine A mixture of 4-benzyloxy-6-chloro-3-iodo-2-methyl-pyridine (314 mg, 0.87 mmol) (Preparation 2, Step 2), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (173 mg, 0.87 mmol), PdCl(dtbpf) (66 mg, 0.1 mmol), and potassium phosphate (550 mg, 2.6 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was degassed for 5 minutes and heated in a sealed vial under nitrogen at 110 °C for 20 hours. The mixture was cooled and diluted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (0-50% ethyl acetate / hexane) gave 4-benzyloxy-6-chloro-3-[(E)-2-ethoxyvinyl]-2-methyl-pyridine (188 mg, 71%). ESI-MS m / z calculated: 303.10, found: 304.3 (m+1). + . 1 H NMR ( 400 MHz,CDCl3)δ 7.46-7.32(m,5H),7.13(d,J=12.7 Hz,1H),6.76(s,1H),5.73(d,J=12.7 Hz,1H),5.11(s,2H),3.81(q,J=7.0 Hz,2H),2.51(s,3H),1.26(t,J=7.0 Hz,3H). 1 H NMR ( 400 MHz,CD3OD)δ 7.54-7.32(m,5H),7.16(d,J=12.7 Hz,1H),7.02(s,1H),5.70(d,J=12.7 Hz,1H),5.20(s,2H),3.80(q,J=7.0 Hz,2H),2.44(s,3H),1.21(t,J=7.1 Hz,3H).

[0299] Step 2: 2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)acetaldehyde To a solution of 4-benzyloxy-6-chloro-3-[(E)-2-ethoxyvinyl]-2-methyl-pyridine from Step 1 in acetone (2 mL) was added aqueous HCl (2 mL of 1 M, 2 mmol), and the mixture was stirred at 65° C. for 3 hours. The mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of ammonium chloride and brine. The organic layer was dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to give 2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)acetaldehyde.

[0300] Step 3: 2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)acetic acid A solution of 2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)acetaldehyde from Step 2 in DMF (2 mL) was treated with OXONE (545 mg, 0.89 mmol) and stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of ammonium chloride and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. Purification by silica gel column chromatography (0-70% ethyl acetate / heptane) gave 2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)acetic acid (125 mg, 49%). ESI-MS m / z calculated 291.07, found 292.3 (m+1). + . 1 H NMR ( 400 MHz,DMSO-d6)δ 12.45(br s,1H),7.46-7.30(m,5H),7.09(s,1H),5.24(s,2H),3.60(s,2H),2.36(s,3H).

[0301] Step 4: 2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)acetamide A solution of 2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)acetic acid (55 mg, 0.19 mmol) in DMF (550 μL) was treated with HATU (80 mg, 0.21 mmol), DIPEA (50 μL, 0.29 mmol), and NH3 in methanol (150 μL of 7 M, 1.0 mmol) and stirred for 30 min. The mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of ammonium chloride and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (0-100% ethyl acetate / hexane) gave 2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)acetamide (47 mg, 81%). ESI-MS m / z calculated: 290.08, found: 291.3 (m+1). + . 1 H NMR ( 400 MHz,DMSO-d6)δ 7.50-7.28(m,6H),7.05(s,1H),6.94(br s,1H),5.23(s,2H),3.47(s,2H),2.34(s,3H).

[0302] Intermediate A-27 Diethyl 4-benzyloxy-2-chloro-6-methyl-pyridine-3,5-dicarboxylate [ka] Ethyl 4-benzyloxy-2-chloro-5-iodo-6-methyl-pyridine-3-carboxylate (Preparation 1, 265 mg, 0.6139 mmol) was dissolved in EtO (6 mL). The resulting mixture was cooled to −78° C. and placed under a nitrogen atmosphere. n-BuLi (300 μL of 2.5 M, 0.75 mmol) was added dropwise over 5 minutes, and the resulting mixture was stirred at −78° C. for 15 minutes. Ethyl carbonochloridate (200 μL, 2.09 mmol) was added dropwise, and the mixture was stirred at −78° C. for 60 minutes. After 60 minutes, the reaction was placed in a 0° C. bath and quenched with saturated aqueous ammonium chloride (5 mL). The mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-40% ethyl acetate / hexanes over 20 minutes) afforded diethyl 4-benzyloxy-2-chloro-6-methyl-pyridine-3,5-dicarboxylate (145 mg, 63%). 1 H NMR (400 MHz, DMSO-d6) δ 7.46-7.31 (m, 5H), 5.10 (s, 2H), 4.34 (q, J = 7.1 Hz, 2H) overlapping with 4.34 (q, J = 7.1 Hz, 2H), 2.46 (s, 3H), 1.24 (t, J = 7.1 Hz, 6H) (two overlapping triplets). ESI-MS m / z calculated 377.10, found 378.4 (m+1). + .

[0303] Intermediate A-28 Ethyl 4-benzyloxy-2-chloro-6-methyl-5-oxamoyl-pyridine-3-carboxylate [ka] Step 1: Ethyl 4-benzyloxy-2-chloro-5-(2-ethoxy-2-oxo-acetyl)-6-methyl-pyridine-3-carboxylate Ethyl 4-benzyloxy-2-chloro-5-iodo-6-methyl-pyridine-3-carboxylate (Preparation 1, 408 mg, 0.945 mmol) was dissolved in EtO (7 mL). The resulting mixture was cooled to −78° C. n-BuLi (500 μL of 2.5 M, 1.3 mmol) was added dropwise over 5 minutes, and the resulting mixture was stirred at −78° C. for 25 minutes. Ethyl 2-chloro-2-oxo-acetate (340 μL, 3.04 mmol) was added dropwise, and the resulting mixture was stirred at −78° C. for 30 minutes. After 30 minutes, the reaction was placed in a 0° C. bath and quenched with a saturated aqueous solution of ammonium chloride (5 mL). The mixture was diluted with ethyl acetate and then washed with brine. The organic layer was dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. Purification by silica gel chromatography (0-40% ethyl acetate / hexanes over 20 minutes) gave ethyl 4-benzyloxy-2-chloro-5-(2-ethoxy-2-oxo-acetyl)-6-methyl-pyridine-3-carboxylate (200 mg, 50%). 1 H NMR(400 MHz,DMSO-d6)δ 7.53-7.23(m,5H),5.08(s,2H),4.41(q,J=7.1 Hz,2H),3.95(q,J=7.1 Hz,2H),2.46(s,3H),1.30(t,J=7.1 Hz,3H),1.05(t,J=7.1 Hz,3H).ESI-MS m / z calculated value.405.10,actual value 406.4(m+1) + .

[0304] Step 2: Ethyl 4-benzyloxy-2-chloro-6-methyl-5-oxamoyl-pyridine-3-carboxylate A solution of ethyl 4-benzyloxy-2-chloro-5-(2-ethoxy-2-oxo-acetyl)-6-methyl-pyridine-3-carboxylate (200 mg, 0.468 mmol) in ethanol (1 mL) was treated dropwise with ammonia in methanol (550 μL of 2.0 M, 1.1 mmol) at 0° C. and then stirred at room temperature for 3 hours. The solvent was removed in vacuo to give ethyl 4-benzyloxy-2-chloro-6-methyl-5-oxamoyl-pyridine-3-carboxylate (166 mg, 89%). 1 H NMR(400 MHz,DMSO-d6)δ 8.43(s,1H),8.08(s,1H),7.47-7.27(m,5H),5.00(s,2H),4.36(q,J=7.1 Hz,2H),2.37(s,3H),1.27(t,J=7.1 Hz,3H).ESI-MS m / z Calculated value.376.08, Actual value 377.4(m+1) + .

[0305] Intermediate A-29 Ethyl 5-(2-amino-1-hydroxy-2-oxo-ethyl)-4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylate [ka] A solution of ethyl 4-benzyloxy-2-chloro-6-methyl-5-oxamoyl-pyridine-3-carboxylate (135 mg, 0.340 mmol) in ethanol (1 mL) and THF (1 mL) was treated with sodium borohydride (14 mg, 0.37 mmol) at 0° C. and stirred at room temperature for 10 minutes. The mixture was quenched with a saturated aqueous solution of ammonium chloride (5 mL), diluted with ethyl acetate, and then washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give ethyl 5-(2-amino-1-hydroxy-2-oxo-ethyl)-4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylate (128 mg, 99%). 1H NMR(400 MHz,DMSO-d6)δ 7.63(br s,1H),7.60(br s,1H),7.48-7.36(m,5H),6.49(d,J=5.2 Hz,1H),5.40(d,J=4.9 Hz,1H),5.14(d,J=10.7 Hz,1H),5.02(d,J=10.6 Hz,1H),4.41-4.27(m,2H),2.50(s,3H) overlap with DMSO,1.25(t,J=7.1 Hz,3H).ESI-MS m / z calculated value .378.10, measured value 379.3(m+1) + .

[0306] Intermediate A-30 Ethyl 5-(2-amino-1-methoxy-2-oxo-ethyl)-4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylate [ka] Step 1: Ethyl 4-benzyloxy-2-chloro-5-(2-methoxy-2-oxo-acetyl)-6-methyl-pyridine-3-carboxylate Ethyl 4-benzyloxy-2-chloro-5-iodo-6-methyl-pyridine-3-carboxylate (Preparation 1, 539 mg, 1.25 mmol) was dissolved in EtO (8 mL). The resulting mixture was cooled to −78° C. n-BuLi (650 μL of 2.5 M, 1.63 mmol) was added dropwise over 5 minutes, and the resulting mixture was stirred at −78° C. for 25 minutes. Methyl 2-chloro-2-oxoacetate (350 μL, 3.80 mmol) was then added dropwise, and the resulting mixture was stirred at −78° C. for 30 minutes. After 30 minutes, the reaction was placed in a 0° C. bath, quenched with a saturated aqueous solution of ammonium chloride (5 mL), diluted with ethyl acetate, and then washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-40% ethyl acetate / hexanes over 20 minutes) gave ethyl 4-benzyloxy-2-chloro-5-(2-methoxy-2-oxo-acetyl)-6-methyl-pyridine-3-carboxylate (300 mg, 61%).1 H NMR(400 MHz,DMSO-d6)δ 7.47-7.36(m,3H),7.36-7.29(m,2H),5.09(s,2H),4.42(q,J=7.1 Hz,2H),3.50(s,3H),2.46(s,3H),1.31(t,J=7.1 Hz,3H).ESI-MS m / z Calculated value.391.08, Actual value 392.3(m+1) + .

[0307] Step 2: Ethyl 4-benzyloxy-2-chloro-5-(2-ethoxy-1-hydroxy-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylate and ethyl 4-benzyloxy-2-chloro-5-(1-hydroxy-2-methoxy-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylate Ethyl 4-benzyloxy-2-chloro-5-(2-methoxy-2-oxo-acetyl)-6-methyl-pyridine-3-carboxylate (300 mg, 0.766 mmol) was dissolved in ethanol (1.5 mL) and THF (1.5 mL). The resulting mixture was cooled to 0° C. Sodium borohydride (20 mg, 0.53 mmol) was then added, and the resulting mixture was stirred at room temperature for 10 minutes. The mixture was quenched with saturated aqueous ammonium chloride (5 mL), diluted with ethyl acetate, and then washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the major ethyl ester transesterification product: ethyl 4-benzyloxy-2-chloro-5-(2-ethoxy-1-hydroxy-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylate. ESI-MS m / z calculated 407.11, found 408.55 (m+1). + and a minor methyl ester product: ethyl 4-benzyloxy-2-chloro-5-(1-hydroxy-2-methoxy-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylate, ESI-MS m / z calculated 393.10, found 394.46 (m+1) + A mixture of

[0308] Step 3: A solution of the mixture from Step 2 in DMF (3 mL) was cooled to 0 °C and treated with sodium hydride (33 mg, 60% dispersion in mineral oil, 1.4 mmol) at 0 °C for 5 min. Methyl iodide (150 μL, 2.41 mmol) was then added and the reaction was allowed to warm gradually to room temperature and stirred for 30 min. The mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of ammonium chloride, then brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the major product, ethyl 4-benzyloxy-2-chloro-5-(2-ethoxy-1-methoxy-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylate, ESI-MS m / z calculated 421.13, found 422.58 (m+1). + and the minor product ethyl 4-benzyloxy-2-chloro-5-(1,2-dimethoxy-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylate, ESI-MS m / z calculated 407.11, found 408.38 (m+1) + A mixture of Step 4: 2-(4-benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridyl)-2-methoxy-acetic acid

[0309] The mixture from Step 3 was dissolved in ethanol (5 mL), treated with aqueous NaOH (1.5 mL of 1 M, 1.5 mmol), and stirred under nitrogen at 25° C. for 40 minutes. The mixture was acidified to pH <5 using 1 M aqueous HCl and diluted with ethyl acetate. The organic phase was washed with saturated aqueous ammonium chloride and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 2-(4-benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridyl)-2-methoxy-acetic acid (250 mg, 77%). 1H NMR (400 MHz, DMSO-d6) δ 13.13 (br s, 1H), 7.46-7.34 (m, 5H), 5.18 (d, J = 10.7 Hz, 1H) overlap with 5.18 (s, 1H), 4.95 (d, J = 10.7 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 3.35 (s, 3H) overlap with HOH, 2.51 (s, 3H) overlap with DMSO, 1.24 (t, J = 7.1 Hz, 3H). ESI-MS m / z calculated 393.10, found 394.18 (m+1). + .

[0310] Step 5: Ethyl 5-(2-amino-1-methoxy-2-oxo-ethyl)-4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylate A solution of 2-(4-benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridyl)-2-methoxy-acetic acid (250 mg, 0.590 mmol) in DMF (1 mL) was treated with HATU (225 mg, 0.592 mmol), DIPEA (110 μL, 0.632 mmol), and NH in methanol (200 μL of 7 M, 1.4 mmol), then stirred for 20 min. The mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0 to 100% ethyl acetate / heptane over 25 min) gave ethyl 5-(2-amino-1-methoxy-2-oxo-ethyl)-4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylate (187 mg, 81%). 1 H NMR(400 MHz,DMSO-d6)δ 7.63(br s,1H),7.61(br s,1H),7.47-7.34(m,5H),5.15(d,J=10.8 Hz,1H),5.11(s,1H),4.99(d,J=10.8 Hz,1H),4.38-4.26(m,2H),3.21(s,3H),2.47(s,3H),1.25(t,J=7.1 Hz,3H).ESI-MS m / z calculated value.392.11,actual value 393.4(m+1) + .

[0311] Intermediate A-31 2-(4-benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridyl)acetic acid [ka] Step 1: Ethyl 4-benzyloxy-2-chloro-5-[(Z)-2-ethoxyvinyl]-6-methyl-pyridine-3-carboxylate A mixture of ethyl 4-benzyloxy-2-chloro-5-iodo-6-methyl-pyridine-3-carboxylate (Preparation 1, 573 mg, 1.327 mmol), tributyl-[(Z)-2-ethoxyvinyl]stannane (593 mg, 1.642 mmol), and PdCl(PPh) (182 mg, 0.260 mmol) in toluene (5 mL) was degassed for 5 minutes and placed under a nitrogen atmosphere. The tube was sealed and stirred at 110 °C for 20 hours. The mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The organic layer was dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. Purification by silica gel chromatography (0–50% ethyl acetate / heptane over 15 minutes) gave ethyl 4-benzyloxy-2-chloro-5-[(Z)-2-ethoxyvinyl]-6-methyl-pyridine-3-carboxylate (235 mg, 47%). 1 H NMR(400 MHz,DMSO-d6)δ 7.45-7.32(m,5H),6.58(d,J=6.8 Hz,1H),5.32(d,J=6.8 Hz,1H),5.04(s,2H),4.27(q,J=7.1 Hz,2H),3.94(q,J=7.0 Hz,2H),2.41(s,3H),1.21(t,J=7.1 Hz,3H),1.17(t,J=7.1 Hz,3H).ESI-MS m / z calculated value.375.12,actual value 376.1(m+1) + .

[0312] Step 2: Ethyl 4-benzyloxy-2-chloro-6-methyl-5-(2-oxoethyl)pyridine-3-carboxylate To a solution of ethyl 4-benzyloxy-2-chloro-5-[(Z)-2-ethoxyvinyl]-6-methyl-pyridine-3-carboxylate from Step 1 in acetone (4 mL) was added aqueous HCl (2.5 mL of 1 M, 2.500 mmol) and the mixture was stirred at 50° C. for 3 hours. The mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The organic layer was dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide ethyl 4-benzyloxy-2-chloro-6-methyl-5-(2-oxoethyl)pyridine-3-carboxylate, which was used directly in Step 3.

[0313] Step 3: 2-(4-benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridyl)acetic acid A solution of crude ethyl 4-benzyloxy-2-chloro-6-methyl-5-(2-oxoethyl)pyridine-3-carboxylate from Step 2 in DMF (3 mL) was treated with OXONE (813 mg, 1.32 mmol) and stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The organic layer was dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. Purification by silica gel chromatography (0 to 50% ethyl acetate / heptane over 20 min) gave 2-(4-benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridyl)acetic acid (285 mg, 59%). 1 H NMR(400 MHz,DMSO-d6)δ 12.72(br s,1H),7.48-7.35(m,5H),5.00(s,2H),4.35(q,J=7.1 Hz,2H),3.67(s,2H),2.44(s,3H),1.27(t,J=7.1 Hz,3H).ESI-MS m / z Calculated value.363.09, Actual value 364.4(m+1) + .

[0314] Intermediate A-32 Ethyl 4-benzyloxy-2-chloro-5-(2-methoxy-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylate [ka] A solution of 2-(4-benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridyl)acetic acid (285 mg, 0.783 mmol) in DCM (8 mL) was treated with oxalyl dichloride (600 μL of 2 M in DCM, 1.2 mmol) followed by DMF (6 μL, 0.08 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes and then slowly treated with DIPEA (150 μL, 0.861 mmol) followed by methanol (1 mL, 25 mmol). The mixture was stirred for 30 minutes and then diluted with ethyl acetate. The organic phase was washed with saturated aqueous ammonium chloride and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-50% ethyl acetate / heptane over 20 minutes) gave ethyl 4-benzyloxy-2-chloro-5-(2-methoxy-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylate (220 mg, 74%). 1 H NMR(400 MHz,DMSO-d6)δ 7.47-7.34(m,5H),5.00(s,2H),4.36(q,J=7.1 Hz,2H),3.74(s,2H),3.58(s,3H),2.43(s,3H),1.28(t,J=7.1 Hz,3H).ESI-MS m / z Calculated value.377.82, Actual value 379.3(m+1) + .

[0315] Intermediate A-33 Ethyl 4-benzyloxy-2-chloro-5-(2-methoxy-1-methyl-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylate [ka] A solution of ethyl 4-benzyloxy-2-chloro-5-(2-methoxy-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylate (220 mg, 0.577 mmol) in DMF (3 mL) at 0 °C was treated with sodium hydride (43 mg, 60% dispersion in mineral oil, 1.1 mmol) at 0 °C for 5 min. MeI (150 μL, 2.41 mmol) was added, and the reaction was allowed to warm gradually to room temperature and stirred for 30 min. The mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give ethyl 4-benzyloxy-2-chloro-5-(2-methoxy-1-methyl-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylate. ESI-MS m / z calculated 391.12, found 392.53 (m+1). + .

[0316] Intermediate A-34 Ethyl 5-(2-amino-1-methyl-2-oxo-ethyl)-4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylate [ka] Step 1: 2-(4-benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridyl)propanoic acid A solution of ethyl 4-benzyloxy-2-chloro-5-(2-methoxy-1-methyl-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylate (210 mg, 0.536 mmol) in ethanol (6 mL) was treated with aqueous NaOH (1 mL of 1 M, 1.0 mmol) and stirred at 45° C. under a nitrogen atmosphere for 6 hours. The mixture was acidified to pH<5 using aqueous 1 M HCl and diluted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 2-(4-benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridyl)propanoic acid. ESI-MS m / z calculated 377.10, found 378.4 (m+1). + .

[0317] Step 2: Ethyl 5-(2-amino-1-methyl-2-oxo-ethyl)-4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylate A solution of 2-(4-benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridyl)propanoic acid from Step 1 in DMF (1 mL) was treated with HATU (200 mg, 0.526 mmol), DIPEA (100 μL, 0.574 mmol), and NH in methanol (150 μL of 7 M, 1.1 mmol) and stirred for 30 min. The mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0 to 100% ethyl acetate / heptane over 25 min) gave ethyl 5-(2-amino-1-methyl-2-oxo-ethyl)-4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylate (214 mg, 99%). 1 H NMR(400 MHz,DMSO-d6)δ 7.47-7.33(m,5H),7.11(br s,1H),7.05(br s,1H),5.08-4.97(m,2H),4.38-4.26(m,2H),3.92(q,J=7.2 Hz,1H), 2.43(s,3H), 1.28(d,J=7.2 Hz,3H) overlaps with 1.25(t,J=7.1 Hz,3H).ESI-MS m / z calculated value.376.12, actual value 377.23(m+1) + .

[0318] Intermediate A-35 2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-N-methyl-acetamide Step 1: 2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-N-methyl-acetamide [ka] A solution of 2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)acetic acid (Intermediate A-26, Step 3, 73 mg, 0.25 mmol) was dissolved in DMF (750 μL). HATU (110 mg, 0.29 mmol), DIPEA (65 μL, 0.37 mmol), and MeNH were then added in ethanol (120 μL of 33% w / v, 1.28 mmol). The resulting mixture was stirred for 30 min. The resulting mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of ammonium chloride and then with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0–100% ethyl acetate / hexanes) afforded 2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-N-methyl-acetamide (70.1 mg, 92%). ESI-MS m / z calculated: 304.1, observed: 305.3 (m+1) + . 1 H NMR ( 400 MHz,DMSO-d6)δ 7.79(q,J=4.8 Hz,1H),7.45-7.29(m,5H),7.06(s,1H),5.22(s,2H),3.46(s,2H),2.56(d,J=4.6 Hz,3H),2.34(s,3H).

[0319] Intermediate A-36 4-benzyloxy-2-chloro-6-methyl-3-methylsulfanyl-pyridine [ka] Step 1: 2,4-Dichloro-3-iodo-6-methyl-pyridine 2,4-Dichloro-6-methyl-pyridin-3-amine (250 mg, 1.41 mmol) and p-TsOH hydrate (806 mg, 4.24 mmol) were suspended in acetonitrile (5.6 mL) and cooled to 0 °C. In a separate flask, sodium nitrite (195 mg, 2.83 mmol) and potassium iodide (586 mg, 3.53 mmol) were dissolved in water (0.84 mL). An aqueous NaNO / KI mixture was added dropwise to the amine / p-TsOH mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred for 2 h. The mixture was poured into water (20 mL) and diluted with TBME (20 mL). The organic layer was separated, and the aqueous layer was extracted with TBME (2 × 10 mL). The combined organic extracts were washed with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (24 g silica, 0-20% ethyl acetate / heptane) gave 2,4-dichloro-3-iodo-6-methyl-pyridine (223 mg, 55%) as a pale yellow oil. ESI-MS m / z calculated 286.88, found 288.2 (m+1). + . 1 H NMR(400 MHz,CDCl3)δ 7.16(d,J=0.6 Hz,1H),1.56(s,3H).

[0320] Step 2: 2,4-Dichloro-6-methyl-3-methylsulfanyl-pyridine 2,4-Dichloro-3-iodo-6-methyl-pyridine (200 mg, 0.695 mmol), Pd(dba) (16 mg, 0.018 mmol), and Xantphos (20 mg, 0.035 mmol) were added to a vial, which was then purged with N. 1,4-Dioxane (2.5 mL), DIPEA (250 μL, 1.44 mmol), and sodium thiomethoxide (230 μL of 21% w / v in water, 0.6891 mmol) were added, and the resulting mixture was stirred at 100 °C for 45 min. The mixture was poured into water (20 mL) and diluted with TBME (20 mL). The organic layer was separated, and the aqueous layer was extracted with TBME (20 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (24 g silica, 0-20% ethyl acetate / heptane) gave 2,4-dichloro-6-methyl-3-methylsulfanyl-pyridine (77 mg, 53%) as a yellow oil. ESI-MS m / z calculated 206.97, found 208.2 (m+1). + . 1 H NMR(400 MHz,CDCl3)δ 7.21(d,J=0.5 Hz,1H),2.50(d,J=0.5 Hz,3H),2.44(s,3H).

[0321] Step 3: 4-Benzyloxy-2-chloro-6-methyl-3-methylsulfanyl-pyridine 4-Benzyloxy-2-chloro-6-methyl-3-methylsulfanyl-pyridine was prepared from 2,4-dichloro-6-methyl-3-methylsulfanyl-pyridine and benzyl alcohol using a procedure similar to that found in Preparation 1, Step 3, and NMP as the solvent. ESI-MS m / z calculated 279.05, found 280.4 (m+1). + . 1 H NMR(400 MHz,CDCl3)δ 7.46-7.35(m,5H),6.67(s,1H),5.20(s,2H),2.47(d,J=0.5 Hz,3H),2.38(s,3H).

[0322] Intermediate A-37 N-Benzyl-4-benzyloxy-6-chloro-N,2-dimethyl-pyridine-3-sulfonamide [ka] Step 1: 4-Benzyloxy-3-benzylsulfanyl-6-chloro-2-methyl-pyridine To a solution of 4-benzyloxy-6-chloro-3-iodo-2-methyl-pyridine (Preparation 2, 1.5 g, 4.2 mmol) in 1,4-dioxane (30 mL) was added phenylmethanethiol (640 mg, 0.6 mL, 5.1 mmol), followed by DIPEA (1.1 g, 1.5 mL, 8.6 mmol). The solution was purged with argon, treated with Xantphos (240 mg, 0.415 mmol) and Pd(dba) (190 mg, 0.208 mmol), and then heated at 80 °C for 2 h. The mixture was filtered through a Celite® pad and concentrated in vacuo. Purification by silica gel chromatography (10-12% ethyl acetate / hexanes) gave 4-benzyloxy-3-benzylsulfanyl-6-chloro-2-methyl-pyridine (810 mg, 55%). ESI-MS m / z calculated: 355.08, observed: 356.08 (m+1) + .

[0323] Step 2: 4-Benzyloxy-6-chloro-2-methyl-pyridine-3-sulfonyl chloride To a solution of 4-benzyloxy-3-benzylsulfanyl-6-chloro-2-methyl-pyridine (800 mg, 2.25 mmol) in acetonitrile (25 mL), AcOH (1 mL), and water (0.5 mL) was added 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (900 mg, 4.57 mmol) portionwise at 0°C. The mixture was stirred at 0-5°C for 2 hours and then concentrated in vacuo. The residue was diluted with DCM (30 mL), and the solution was cooled to 0°C. A solution of 5% saturated aqueous sodium bicarbonate (30 mL) was added slowly (maintaining a temperature of <10°C) and stirred at 0-5°C for 15 minutes. The organic layer was separated, washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo to give 4-benzyloxy-6-chloro-2-methyl-pyridine-3-sulfonyl chloride (520 mg, 70%) as a white solid.

[0324] Step 3: N-benzyl-4-benzyloxy-6-chloro-N,2-dimethyl-pyridine-3-sulfonamide To a solution of 4-benzyloxy-6-chloro-2-methyl-pyridine-3-sulfonyl chloride (250 mg, 0.753 mmol) in DCM (5 mL) was added pyridine (0.3 mL, 3.7 mmol), followed by N-methylbenzylamine (110 mg, 0.908 mmol). The mixture was stirred at room temperature for 5 hours, then quenched with water (20 mL) and extracted with DCM (2 × 25 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (5–8% ethyl acetate / hexanes) afforded N-benzyl-4-benzyloxy-6-chloro-N,2-dimethyl-pyridine-3-sulfonamide (142 mg, 43%). 1H NMR (400 MHz, CDCl3) δ 7.48-7.35 (m, 5H), 7.31-7.19 (m, 2H), 7.11-7.04 (m, 2H), 6.91 (s, 1H), 5.17 (s, 2H), 4.04 (s, 2H), 2.88 (s, 3H), 2.54 (s, 3H). (1H missing, likely due to solvent signal). ESI-MS m / z calculated 416.09, found 417.33 (m+1). + .

[0325] Intermediate A-38 N,N-Dibenzyl-4-benzyloxy-6-chloro-2-methyl-pyridine-3-sulfonamide [ka] N,N-Dibenzyl-4-benzyloxy-6-chloro-2-methyl-pyridine-3-sulfonamide was prepared from 4-benzyloxy-6-chloro-2-methyl-pyridine-3-sulfonyl chloride and dibenzylamine using a procedure similar to that used to prepare intermediate A-37. 1 H NMR(400 MHz,DMSO-d6)δ 7.42(s,5H),7.36(s,1H),7.23(h,J=3.6 Hz,6H),6.89(dd,J=7.2,2.4 Hz,4H),5.22(s,2H),4.03(s,4H),2.71(s,3H).ESI-MS m / z calculated value.492.13,actual value 493.33(m+1) + .

[0326] General scheme for the preparation of intermediate A [ka] The intermediates in Table 1 were prepared using the corresponding dichloro-pyridines or -pyrimidines and procedures similar to those found in Preparation 1, Step 3. 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]

[0327] Intermediate A-52 [ka] Step 1: tert-butyl N-[(4-benzyloxy-6-chloro-2-methyl-pyridine-3-carbonyl)amino]carbamate To a stirred solution of 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carboxylic acid (1.0 g, 2.9 mmol) and DMF (95 mg, 100 μL, 1.3 mmol) in dichloromethane (10 mL) at 0° C. was added oxalyl chloride (1.5 g, 1.0 mL, 11.5 mmol) dropwise. The mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction was concentrated, then redissolved in dichloromethane (10 mL) and added dropwise to a solution of Hunig's base (1.1 g, 1.5 mL, 8.6 mmol) and tert-butyl carbazate (420 mg, 3.18 mmol) in dichloromethane (10 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred for 5 hours. Additional Hunig's base (1.1 g, 1.5 mL, 8.6 mmol) and tert-butyl carbazate (420 mg, 3.18 mmol) were added, and the reaction mixture was stirred for 18 hours. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with 1 M HCl (100 mL), saturated aqueous sodium bicarbonate (100 mL), water (100 mL), and brine (100 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (0-50% ethyl acetate / heptane) gave tert-butyl N-[(4-benzyloxy-6-chloro-2-methyl-pyridine-3-carbonyl)amino]carbamate (808 mg, 70%). ESI-MS m / z calculated 391.13, found 392.15 (m+1). + . 1 H NMR(400 MHz,CDCl3)δ 7.66(br s,1H),7.43-7.34(m,5H),6.80(s,1H),6.61(br s,1H),5.15(s,2H),2.61(s,3H),1.50(s,9H).

[0328] Step 2: 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carbohydrazide A solution of tert-butyl N-[(4-benzyloxy-6-chloro-2-methyl-pyridine-3-carbonyl)amino]carbamate (808 mg, 1.98 mmol) in HCl in dioxane (10 mL of 4 M, 40 mmol) was stirred at room temperature for 4 days. The mixture was diluted with diethyl ether, and the resulting solid was filtered and dried to give 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carbohydrazide (dihydrochloride salt) (722 mg, 95%) as a pale yellow solid. ESI-MS m / z calculated 291.07, found 292.04 (m+1). + . 1 H NMR(400 MHz,DMSO-d6)δ 11.72(s,1H),7.44-7.33(m,5H),7.27(s,1H),5.29(s,2H),2.37(s,3H).

[0329] Step 3: 2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-5-methyl-1,3,4-oxadiazole A solution of 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carbohydrazide (100 mg, 0.27 mmol) in triethyl orthoacetate (89 mg, 1.0 mL, 5.5 mmol) was subjected to microwave irradiation at 120 °C for 1 h. The reaction mixture was cooled and partitioned between ethyl acetate (10 mL) and saturated aqueous sodium bicarbonate (10 mL). The organic layer was separated, washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated. Purification by reverse-phase column chromatography (C18, 5-95% acetonitrile / water containing 0.1% formic acid) gave 2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-5-methyl-1,3,4-oxadiazole (45 mg, 44%). ESI-MS m / z calculated 315.07, found 316.04 (m+1). + . 1 H NMR(400 MHz,CDCl3)δ 7.39-7.30(m,5H),6.86(s,1H),5.15(s,2H),2.58(s,3H),2.52(s,3H).

[0330] Intermediate A-53 2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-1,3,4-oxadiazole [ka] Step 1: tert-butyl N-[(4,6-dichloro-2-methylpyridine-3-carbonyl)amino]carbamate A mixture of 4,6-dichloro-2-methyl-pyridine-3-carboxylic acid (7.0 g, 34 mmol) and SOCl (24.5 g, 15.0 mL, 206 mmol) was refluxed for 2 h. The mixture was concentrated in vacuo, then dissolved in toluene and evaporated under reduced pressure to give 9 g of the corresponding acid chloride. A solution of the above acid chloride (9 g) in DCM (40 mL) was slowly added to a mixture of tert-butyl carbazate (4.5 g, 34 mmol) and TEA (10.9 g, 15.0 mL, 108 mmol) in DCM (80 mL) at 0 °C. After stirring for 2 h, the reaction mixture was diluted with water (60 mL) and extracted with EtOAc (2 × 300 mL), and the organic layer was washed with sodium bicarbonate solution (100 mL) and brine (100 mL). The combined organic layers were dried over magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography (16-20% ethyl acetate / hexanes) to give tert-butyl N-[(4,6-dichloro-2-methyl-pyridine-3-carbonyl)amino]carbamate (7 g, 64%). ESI-MS m / z calculated: 319.05, found: 320.1 (m+1). + .

[0331] Step 2: 4,6-Dichloro-2-methyl-pyridine-3-carbohydrazide A mixture of tert-butyl N-[(4,6-dichloro-2-methyl-pyridine-3-carbonyl)amino]carbamate (7.0 g, 22 mmol) and a solution of hydrochloric acid in dioxane (120 mL of 4.0 M, 480 mmol) was stirred at room temperature for 3 hours. The solvent was evaporated to give 4,6-dichloro-2-methyl-pyridine-3-carbohydrazide (5 g, 98%). ESI-MS m / z calculated 218.99, found 220.07 (m+1). + .

[0332] Step 3: 2-(4,6-dichloro-2-methyl-3-pyridyl)-1,3,4-oxadiazole A mixture of 4,6-dichloro-2-methyl-pyridine-3-carbohydrazide (5.0 g, 27 mmol) and triethyl orthoformate (22 g, 25 mL, 150 mmol) was heated at 140 °C for 16 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (80 mL), dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel column chromatography (10–15% ethyl acetate / hexane) gave 2-(4,6-dichloro-2-methyl-3-pyridyl)-1,3,4-oxadiazole (3 g, 56%). ESI-MS m / z calculated 228.98, found 230.14 (m+1). + . 1 H NMR(400 MHz,DMSO-d6)δ 9.60(s,1H),7.99(s,1H),2.43(s,3H).

[0333] Step 4: 2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-1,3,4-oxadiazole To a mixture of 2-(4,6-dichloro-2-methyl-3-pyridyl)-1,3,4-oxadiazole (3.0 g, 13 mmol) and benzyl alcohol (1.5 g, 1.4 mL, 13.5 mmol) in DMF (40 mL) was added potassium tert-butoxide (2.0 g, 18 mmol) in portions at 0 °C. The reaction mixture was gradually warmed to room temperature and stirred for 3 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were washed with brine (2 × 80 mL), dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel column chromatography (20–25% ethyl acetate / hexane) gave 2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-1,3,4-oxadiazole (1.7 g, 43%). ESI-MS m / z calculated: 301.06, observed: 302.27 (m+1) + . 1 H NMR(400 MHz,DMSO-d6)δ 9.48(s,1H),7.44-7.28(m,6H),5.34(s,2H),2.37(s,3H).

[0334] Intermediate A-54 3-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-5-methyl-1,2,4-oxadiazole [ka] Step 1: 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carboxamide To a stirred solution of 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carboxylic acid (1.0 g, 2.9 mmol) and Hunig's base (1.1 g, 1.5 mL, 8.6 mmol) in DMF (5 mL) and dichloromethane (10 mL) at 0 °C was added ammonium chloride (460 mg, 0.301 mL, 8.60 mmol). The mixture was stirred for 30 minutes, and then HATU (1.3 g, 3.4 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 20 hours. Additional ammonium chloride (230 mg, 0.150 mL, 4.30 mmol), Hunig's base (560 mg, 0.75 mL, 4.3 mmol), and HATU (650 mg, 1.71 mmol) were added, and the reaction was stirred for 4 days. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was dried over magnesium sulfate and concentrated, and purified by silica gel chromatography (0-100% ethyl acetate / heptane) to give 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carboxamide (743 mg, 89%) as a white solid. 1 H NMR(400 MHz,CDCl3)δ 7.44-7.35(m,5H),6.83(s,1H),5.88(d,J=18.8 Hz,2H),5.16(s,2H),2.59(s,3H).ESI-MS m / z calculated value.276.07,actual value 277.05(m+1) + .

[0335] Step 2: 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carbonitrile To a stirred mixture of 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carboxamide (640 mg, 2.20 mmol), triethylamine (1.0 mL, 7.2 mmol), and DMF (20 μL, 0.26 mmol) in DCM (6 mL) was added dropwise oxalyl chloride (0.39 mL, 4.5 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred for 20 hours. The mixture was partitioned between DCM (50 mL) and water (50 mL). The organic phase was separated, washed with 1 M aqueous HCl (50 mL) and brine (50 mL), dried over magnesium sulfate, and concentrated to give 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carbonitrile (1.1 g, 97%). 1 H NMR(400 MHz,CDCl3)δ 7.46-7.37(m,5H),6.84(s,1H),5.25(s,2H),2.70(s,3H).ESI-MS m / z Calculated value .258.06, Actual value 259.08(m+1) + .

[0336] Step 3: 4-benzyloxy-6-chloro-N'-hydroxy-2-methyl-pyridine-3-carboxamidine A mixture of 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carbonitrile (440 mg, 1.70 mmol), sodium carbonate (450 mg, 4.25 mmol), and hydroxylamine hydrochloride (590 mg, 8.49 mmol) in methanol (10 mL) and water (1 mL) was stirred at 65° C. for 3 days. The mixture was cooled and partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was separated, washed with brine (100 mL), dried over magnesium sulfate, and concentrated to give 4-benzyloxy-6-chloro-N'-hydroxy-2-methyl-pyridine-3-carboxamidine (371 mg, 58%). ESI-MS m / z calculated 291.08, found 292.05 (m+1). + .

[0337] Step 4: 3-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-5-methyl-1,2,4-oxadiazole To a solution of 4-benzyloxy-6-chloro-N'-hydroxy-2-methyl-pyridine-3-carboxamidine (371 mg, 0.983 mmol) and triethylamine (0.35 mL, 2.5 mmol) in acetone (5 mL) at 0 °C was added acetyl chloride (99 mg, 90 μL, 1.3 mmol). The reaction was allowed to warm to room temperature and stirred for 20 hours. The mixture was cooled to 0 °C, and additional triethylamine (0.35 mL, 2.5 mmol) and acetyl chloride (99 mg, 90 μL, 1.3 mmol) were added. The mixture was allowed to warm to room temperature and stirred for 20 hours. The mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The organic phase was separated, washed with brine (20 mL), dried over magnesium sulfate, and concentrated. The residue was dissolved in DMSO (3 mL), and potassium hydroxide (70 mg, 1.25 mmol) was added. The mixture was stirred at room temperature for 2 hours and purified directly by reverse-phase chromatography (C18, 5-95% acetonitrile in water, 0.1% v / v ammonia) to give 3-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-5-methyl-1,2,4-oxadiazole (55 mg, 17%) as a white solid. 1 H NMR(400 MHz,CDCl3)δ 7.39-7.30(m,5H),6.83(s,1H),5.15(s,2H),2.69(s,3H),2.43(s,3H).ESI-MS m / z Calculated value .315.08, Actual value 316.04(m+1) + .

[0338] Intermediate A-55 5-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-3-methyl-1,2,4-oxadiazole [ka] Step 1: 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carbonyl chloride To a solution of 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carboxylic acid (200 mg, 0.67 mmol) in DCM (2 mL) was added oxalyl chloride (102 mg, 0.07 mL, 0.8 mmol) and DMF (11 mg, 12 μL, 0.15 mmol) at 0° C., and the mixture was allowed to warm to room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and co-evaporated with DCM (3 × 10 mL) to give 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carbonyl chloride (200 mg, 100%).

[0339] Step 2: 5-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-3-methyl-1,2,4-oxadiazole A mixture of 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carbonyl chloride (2.22 g, 6.37 mmol), potassium carbonate (2.65 g, 19.17 mmol), and acetamide oxime (710 mg, 9.58 mmol) in DMF (20 mL) was stirred at room temperature for 3 days. Additional acetamide oxime (350 mg, 4.72 mmol) and potassium carbonate (1.3 g, 9.4 mmol) were added, and the reaction was stirred at 100° C. for 3 hours. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate (100 mL) and water (100 mL). The layers were separated, and the organic layer was washed with water (100 mL) and brine (100 mL), dried over magnesium sulfate, filtered, and concentrated. Purification by reverse-phase column chromatography (C18, 5-95% acetonitrile in water, both containing 0.1% formic acid) gave 5-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-3-methyl-1,2,4-oxadiazole (383 mg, 18%). ESI-MS m / z calculated: 315.07, found: 316.06 (m+1). + . 1 H NMR(400 MHz,CDCl3)δ 7.41-7.32(m,5H),6.87(s,1H),5.19(s,2H),2.52(s,3H),2.51(s,3H).

[0340] Intermediate A-56 4-benzyloxy-6-chloro-2-methyl-3-(2-methyltetrazol-5-yl)pyridine [ka] A microwave vial was charged with 4-benzyloxy-6-chloro-3-iodo-2-methyl-pyridine (206 mg, 0.572 mmol), tributyl-(2-methyltetrazol-5-yl)stannane (273 mg, 0.732 mmol), CuI (15 mg, 0.078 mmol), and Pd(PPh3)2Cl2 (82.6 mg, 0.118 mmol). The mixture was dissolved in toluene (3 mL), degassed for 5 minutes, and placed under a nitrogen atmosphere. The tube was sealed and stirred at 110 °C for 20 hours. The mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (0-70% ethyl acetate / hexanes over 20 minutes) afforded 4-benzyloxy-6-chloro-2-methyl-3-(2-methyltetrazol-5-yl)pyridine (172.5 mg, 91%). 1 H NMR(400 MHz,DMSO-d6)δ 7.40-7.25(m,6H),5.29(s,2H),4.46(s,3H),2.23(s,3H).ESI-MS m / z Calculated value .315.09, Actual value 316.2(m+1) + .

[0341] The intermediates in Table 2 were prepared from 4-benzyloxy-6-chloro-3-iodo-2-methyl-pyridine and the appropriate stannane using procedures similar to those described for intermediate A-56 (4-benzyloxy-6-chloro-2-methyl-3-(2-methyltetrazol-5-yl)pyridine). [Table 2]

[0342] Intermediate A-65 4-Benzyloxy-6-chloro-2-methyl-3-(1-methylpyrazol-4-yl)pyridine [ka] A mixture of 4-benzyloxy-6-chloro-3-iodo-2-methyl-pyridine (107 mg, 0.298 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (76 mg, 0.37 mmol), PdCl(dtbpf) (32.5 mg, 0.0499 mmol), and potassium phosphate (275 mg, 1.29 mmol) in dioxane (2 mL) and water (500 μL) in a microwave vial was degassed with nitrogen for 5 minutes and then stirred at 45° C. for 1 hour. The mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (0-75% ethyl acetate / hexanes over 20 minutes) gave 4-benzyloxy-6-chloro-2-methyl-3-(1-methylpyrazol-4-yl)pyridine (67 mg, 72%). 1 H NMR(400 MHz,CD3OD)δ 7.73(s,1H),7.56(s,1H),7.40-7.25(m,5H),7.08(s,1H),5.18(s,2H),3.91(s,3H),2.43(s,3H).ESI-MS m / z Calculated value .313.10, Actual value 314.26(m+1) + .

[0343] The intermediates in Table 3 were prepared from 4-benzyloxy-6-chloro-3-iodo-2-methylpyridine or ethyl 4-benzyloxy-2-chloro-5-iodo-6-methyl-pyridine-3-carboxylate and the appropriate boronic acid or boronic ester using procedures similar to those described for intermediate A-65 (4-benzyloxy-6-chloro-2-methyl-3-(1-methylpyrazol-4-yl)pyridine). [Table 3-1] [Table 3-2]

[0344] Intermediate A-77 5-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)oxazolidin-2-one [ka] Step 1: 1-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-2-chloro-ethanone A solution of 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carbonyl chloride (10.9 g, 35.0 mmol) in THF (200 mL) was treated dropwise with diazomethyl(trimethyl)silane (35 mL of 2.0 M in hexane, 70 mmol) at 0° C. The mixture was warmed to room temperature and stirred overnight. Additional (trimethylsilyl)diazomethane (17.5 mL of 2.0 M, 35 mmol) was added, and the mixture was stirred at room temperature for 72 hours. The mixture was cooled to 0° C., and hydrochloric acid in 1,4-dioxane (17.5 mL of 4.0 M, 70 mmol) was added dropwise. The mixture was stirred at 0° C. for 30 minutes, then at room temperature for 1 hour. The mixture was added to saturated aqueous sodium bicarbonate (600 mL) and extracted with ethyl acetate (1 L). The organic phase was washed with brine (250 mL), dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (0-20% EtOAc / heptane) to give 1-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-2-chloro-ethanone (6.78 g, 60%). 1 H NMR(400 MHz,CDCl3)δ 7.44-7.34(m,5H),6.84(s,1H),5.14(s,2H),4.37(s,2H),2.45(s,3H).ESI-MS m / z Calculated value .309.03, Actual value 309.97(m+1) + .

[0345] Step 2: 2-[2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-2-oxo-ethyl]isoindoline-1,3-dione A mixture of 1-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-2-chloro-ethanone (9.18 g, 28.1 mmol) and phthalimide potassium salt (5.75 g, 31.0 mmol) in DMF (200 mL) was stirred at room temperature for 48 hours. The mixture was partitioned between ethyl acetate (800 mL) and water (800 mL), and the layers were separated. The organic phase was washed with water (2 × 600 mL) and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was triturated with diethyl ether (2 × 100 mL). The resulting solid was isolated by filtration and dried under reduced pressure at 50 °C to give 2-[2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-2-oxo-ethyl]isoindoline-1,3-dione (9.77 g, 81%). 1 H NMR(400 MHz,CDCl3)δ 7.92-7.83(m,2H),7.80-7.69(m,2H),7.47-7.36(m,5H),6.85(s,1H),5.23(s,2H),4.84(s,2H),2.50(s,3H).ESI-MS m / z Calculated value .420.09, Actual value 421.12(m+1) + .

[0346] Step 3: 2-[2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-2-hydroxy-ethyl]isoindoline-1,3-dione To a solution of 2-[2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-2-oxo-ethyl]isoindoline-1,3-dione (50 mg, 0.11 mmol) in acetic acid (1.5 mL) was added sodium cyanoborohydride (14 mg, 0.22 mmol). The mixture was stirred at room temperature for 2 hours, then treated with additional sodium cyanoborohydride (14 mg, 0.22 mmol) and stirred for 16 hours. A further batch of sodium cyanoborohydride (50 mg, 0.80 mmol) was added, and the mixture was stirred for 24 hours. Additional sodium cyanoborohydride (100 mg, 1.59 mmol) was added, and the mixture was stirred for 48 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated. Purification by reverse phase chromatography (C18, 20-80% acetonitrile / water, each containing 0.1% formic acid) gave 2-[2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-2-hydroxy-ethyl]isoindoline-1,3-dione (30 mg, 61%). 1 H NMR(400 MHz,CDCl3)δ 7.83-7.80(m,2H),7.74-7.69(m,2H),7.54-7.40(m,5H),6.86(s,1H),5.35-5.14(m,3H),4.28-4.15(m,1H),3.91(dd,J=13.7,5.3 Hz,1H),3.35(d,J=11.4 Hz,1H),2.54(s,3H).ESI-MS m / z calculated value.422.10,actual value 423.13(m+1) + .

[0347] Step 4: 2-amino-1-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)ethanol To a solution of 2-[2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-2-hydroxy-ethyl]isoindoline-1,3-dione (2.47 g, 5.45 mmol) in ethanol (100 mL) was added hydrazine hydrate (2.73 g, 2.65 mL, 54.5 mmol). The mixture was stirred at room temperature for 48 h. The precipitate was removed by filtration, and the residue was concentrated under reduced pressure. Purification by reverse-phase chromatography (C18, 20-70% acetonitrile / water, each containing 0.1% ammonia) gave 2-amino-1-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)ethanol (1.65 g, 87%). 1 H NMR(400 MHz,CD3OD)δ 7.51-7.31(m,5H),7.01(s,1H),5.22-5.17(m,2H),5.16-5.11(m,1H),3.13-3.00(m,1H),2.80-2.70(m,1H),2.56(s,3H).ESI-MS m / z Calculated value .292.10, Actual value 293.05(m+1) +.

[0348] Step 5: 5-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)oxazolidin-2-one To a solution of 2-amino-1-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)ethanol (1.55 g, 4.43 mmol) in DCM (25 mL) was added CDI (755 mg, 4.66 mmol), and the mixture was stirred at room temperature overnight. The mixture was partitioned between DCM (250 mL) and water (100 mL), and the phases were separated. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (0-3% methanol / DCM) gave 5-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)oxazolidin-2-one (762 mg, 53%). 1H NMR(400 MHz,DMSO-d6)δ 7.61(s,1H),7.44-7.42(m,2H),7.38-7.28(m,3H),7.18(s,1H),5.89(t,J=9.2 Hz,1H),5.31-5.21(m,2H),3.72(t,J=8.9 Hz,1H),3.48-3.43(m,1H),2.41(s,3H).ESI-MS m / z calculated value .318.08, measured value 319.03(m+1) + .

[0349] Intermediate A-78 4-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)oxazolidin-2-one [ka] Step 1: 4-benzyloxy-6-chloro-2-methyl-3-vinyl-pyridine A solution of 4-benzyloxy-6-chloro-3-iodo-2-methyl-pyridine (7.13 g, 19.4 mmol), vinylboronic acid pinacol ester (3.6 g, 4.0 mL, 24 mmol), Pd(dppf)Cl (1.43 g, 1.95 mmol), and aqueous sodium carbonate (30 mL of 2.0 M, 60 mmol) in dioxane (60 mL) was stirred at 70 °C under argon for 20 h. The mixture was cooled and partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was extracted with additional ethyl acetate (100 mL), and the combined organic extracts were washed with brine, dried over magnesium sulfate, and concentrated. Purification by silica gel chromatography (0–5% ethyl acetate / heptane) gave 4-benzyloxy-6-chloro-2-methyl-3-vinyl-pyridine (4.79 g, 75%). 1 H NMR(400 MHz,CDCl3)δ 7.48-7.35(m,5H),6.78(s,1H),6.72-6.62(m,1H),5.75(dd,J=17.9,1.8 Hz,1H),5.58(dd,J=11.4,1.8 Hz,1H),5.13(s,2H),2.55(s,3H).ESI-MS m / z calculated value.259.08,actual value 260.03(m+1) + .

[0350] Step 2: 4-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)oxazolidin-2-one To a solution of diphenyl diselenide (120 mg, 0.385 mmol), ammonium persulfate (105 mg, 0.460 mmol), and triflic acid (34 μL, 0.38 mmol) in dioxane (1 mL) was added a solution of 4-benzyloxy-6-chloro-2-methyl-3-vinyl-pyridine (100 mg, 0.381 mmol) and ethyl carbamate (102 mg, 1.15 mmol) in dioxane (1 mL). The mixture was stirred at 100° C. for 18 hours. Additional diphenyl diselenide (120 mg, 0.385 mmol), ammonium persulfate (105 mg, 0.460 mmol), and triflic acid (34 μL, 0.38 mmol) were combined in dioxane (1 mL) and added to the reaction mixture, which was stirred at 100° C. for an additional 18 hours. Ammonium persulfate (105 mg, 0.4601 mmol) was added and the reaction was stirred for 3 hours. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate (20 mL) and water (20 mL). The organic phase was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated. Purification by reverse-phase chromatography (5-80% acetonitrile in water, 0.1% v / v formic acid) gave 4-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)oxazolidin-2-one (20 mg, 14%). 1 H NMR (400 MHz, CDCl3) δ 7.44-7.36 (m, 5H), 6.84 (s, 1H), 5.37 (dd, J = 10.1, 6.0 Hz, 1H), 5.18 (s, 2H), 4.69 (dd, J = 9.8, 8.5 Hz, 1H), 4.37 (dd, J = 8.7, 6.0 Hz, 1H), 2.56 (s, 3H). No NH was observed. ESI-MS m / z calculated 318.08, found 319.07 (m+1). + .

[0351] Intermediate A-79 4-benzyloxy-2-chloro-3-(2,5-dihydrofuran-3-yl)-5,6-dimethyl-pyridine [ka] Step 1: 3-Bromo-5,6-dimethyl-pyridine-2,4-diol To a solution of 5,6-dimethylpyridine-2,4-diol (15.0 g, 108 mmol) in dichloromethane (1 L) at 0 °C was added a solution of bromine (18.6 g, 6.0 mL, 116 mmol) in dichloromethane (50 mL), and the mixture was stirred at room temperature for 1 h. The resulting yellow precipitate was filtered and washed with dichloromethane. The solid was combined with sodium bicarbonate (15 g, 179 mmol) in THF (1 L) and heated at 70 °C for 15 min. The mixture was filtered and concentrated to give 3-bromo-5,6-dimethyl-pyridine-2,4-diol (16.26 g, 69%). ESI-MS m / z calculated 216.97, found 218.0 (m+1). + .

[0352] Step 2: 3-Bromo-2,4-dichloro-5,6-dimethyl-pyridine A mixture of 3-bromo-5,6-dimethyl-pyridine-2,4-diol (15.0 g, 68.8 mmol), POCl3 (49 g, 30 mL, 322 mmol), and DMF (1.9 g, 2.0 mL, 26 mmol) was heated at 100 °C for 5 h. The mixture was quenched with ice water (200 mL), followed by saturated aqueous sodium bicarbonate (200 mL) and extracted with ethyl acetate (2 × 500 mL). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (0–3% ethyl acetate / hexanes) gave 3-bromo-2,4-dichloro-5,6-dimethyl-pyridine (12.24 g, 57%). 1 H NMR (400 MHz, DMSO-d6) δ 2.37 (s, 3H), 3H was further obscured by the solvent peak. ESI-MS m / z calculated 252.91, found 254.0 (m+1). + .

[0353] Step 3: 2,4-Dichloro-3-(2,5-dihydrofuran-3-yl)-5,6-dimethyl-pyridine To a solution of 3-bromo-2,4-dichloro-5,6-dimethyl-pyridine (2.0 g, 6.4 mmol) in THF (35 mL) and water (5 mL) was added potassium phosphate (2.8 g, 13 mmol), followed by 2-(2,5-dihydro-3-furanyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.6 g, 8.2 mmol), and the mixture was purged with argon. PdCl2(dtbpf) (210 mg, 0.322 mmol) was added, and the mixture was heated at 60 °C for 3 h. The mixture was filtered, and the filtrate was washed with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (5-7% ethyl acetate / hexanes) gave 2,4-dichloro-3-(2,5-dihydrofuran-3-yl)-5,6-dimethyl-pyridine (860 mg, 55%). 1 H NMR (400 MHz, DMSO-d6) δ 6.12 (t, J = 2.0 Hz, 1H), 4.81-4.72 (m, 2H), 4.68 (td, J = 5.2, 2.2 Hz, 2H), 2.31 (s, 3H), with the 3H obscured by the solvent peak. ESI-MS m / z calculated 243.02, found 244.08 (m+1). + .

[0354] Step 4: 4-Benzyloxy-2-chloro-3-(2,5-dihydrofuran-3-yl)-5,6-dimethyl-pyridine To a solution of benzyl alcohol (0.4 mL, 3.8 mmol) in DMSO (8 mL), potassium tert-butoxide (500 mg, 4.46 mmol) was added portionwise at 0° C., and the mixture was stirred at 0° C. for 30 minutes. A solution of 2,4-dichloro-3-(2,5-dihydrofuran-3-yl)-5,6-dimethyl-pyridine (850 mg, 3.48 mmol) in DMSO (5 mL) was added, and the mixture was stirred at room temperature for 24 hours. The mixture was quenched with ice-cold water (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water (2×50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (5-7% ethyl acetate / hexanes) gave 4-benzyloxy-2-chloro-3-(2,5-dihydrofuran-3-yl)-5,6-dimethyl-pyridine (776 mg, 70%). 1 H NMR(400 MHz,DMSO-d6)δ 7.46-7.33(m,5H),6.17-6.12(m,1H),4.85(s,2H),4.70(s,4H),2.41(s,3H),2.14(s,3H).ESI-MS m / z calculated value.315.10, measured value 316.15(m+1) + .

[0355] Suzuki coupling of 4-benzyloxy-2-chloro-3-(2,5-dihydrofuran-3-yl)-5,6-dimethyl-pyridine with Intermediate-B can be followed by reduction of the alkene using standard hydrogenation conditions to give the corresponding tetrahydrofuran analog.

[0356] Intermediate A-80 4-benzyloxy-2-chloro-3-(3,6-dihydro-2H-pyran-4-yl)-5,6-dimethyl-pyridine [ka] 4-Benzyloxy-2-chloro-3-(3,6-dihydro-2H-pyran-4-yl)-5,6-dimethyl-pyridine was prepared in a similar manner to 4-benzyloxy-2-chloro-3-(2,5-dihydrofuran-3-yl)-5,6-dimethyl-pyridine using 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester. 1 H NMR(400 MHz,DMSO-d6)δ 7.44(s,1H),7.43-7.34(m,4H),5.79(s,1H),4.89(s,2H),4.20-4.13(m,2H),3.75(t,J=5.3 Hz,2H),2.40(s,3H),2.24(s,2H),2.14(s,3H).ESI-MS m / z calculated value.329.12,actual value 330.23(m+1) + .

[0357] Suzuki coupling of 4-benzyloxy-2-chloro-3-(3,6-dihydro-2H-pyran-4-yl)-5,6-dimethyl-pyridine with Intermediate-B can be followed by reduction of the alkene using standard hydrogenation conditions to give the corresponding tetrahydropyran analogue.

[0358] Intermediate A-81 4-(4-benzyloxy-2-chloro-6-methyl-3-pyridyl)morpholine [ka] Step 1: Diethyl 2-morpholinopropanedioate To a solution of diethyl 2-bromopropanedioate (25.0 g, 105 mmol) in acetonitrile (1 L) was added potassium carbonate (40.0 g, 289 mmol), followed by morpholine (25 g, 25 mL, 287 mmol), and the mixture was stirred at room temperature for 3 h. The mixture was filtered, concentrated, and purified by silica gel chromatography (10–15% ethyl acetate / hexanes) to give diethyl 2-morpholinopropanedioate (22.53 g, 88%). 1H NMR(400 MHz,DMSO-d6)δ 4.26(s,1H),4.16(q,J=7.1 Hz,4H),3.60-3.54(m,4H),2.71-2.64(m,4H),1.20(t,J=7.1 Hz,6H).ESI-MS m / z Calculated value .245.13, Actual value 246.23(m+1) + .

[0359] Step 2: 4-hydroxy-6-methyl-3-morpholino-1H-pyridin-2-one A mixture of ethyl (E)-3-aminobut-2-enoate (5.0 g, 39 mmol) and diethyl 2-morpholinopropanedioate (10.0 g, 40.8 mmol) was heated at 220° C. for 45 minutes. The residue was then dissolved in aqueous NaOH (200 mL 2 M, 400 mmol) and heated at 130° C. for 24 hours. The mixture was cooled and acidified with aqueous 1N HCl. The precipitated solid was collected by filtration and dried in vacuo to give crude 4-hydroxy-6-methyl-3-morpholino-1H-pyridin-2-one (3.12 g, 38%). 1 H NMR(400 MHz,DMSO-d6)δ 10.96(s,1H),5.67(s,1H),3.66(t,J=4.7 Hz,4H),2.96-2.86(m,4H),2.06(s,3H).ESI-MS m / z calculated value.210.10,actual value 211.39(m+1) +

[0360] Step 3: 4-(2,4-dichloro-6-methyl-3-pyridyl)morpholine A solution of 4-hydroxy-6-methyl-3-morpholino-1H-pyridin-2-one (3.0 g, 14 mmol) and phenyl dichlorophosphate (28.2 g, 20.0 mL, 134 mmol) was heated at 180 °C for 1 h. The mixture was quenched with ice water (50 mL), followed by saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (5–8% ethyl acetate / hexanes) gave 4-(2,4-dichloro-6-methyl-3-pyridyl)morpholine (1.56 g, 44%). 1 H NMR(400 MHz,DMSO-d6)δ 7.46(s,1H),3.70(t,J=4.5 Hz,4H),3.09(s,4H),2.39(s,3H).ESI-MS m / z calculated value .246.03, measured value 247.31(m+1) + .

[0361] Step 4: 4-(4-benzyloxy-2-chloro-6-methyl-3-pyridyl)morpholine To a solution of benzyl alcohol (800 mg, 7.40 mmol) in DMSO (15 mL) was added potassium tert-butoxide (902 mg, 8.04 mmol) portionwise at 0 °C and stirred for 30 min at 0 °C. A solution of 4-(2,4-dichloro-6-methyl-3-pyridyl)morpholine (1.5 g, 6.1 mmol) in DMSO (10 mL) was added, and the reaction mixture was stirred at room temperature for 24 h. The mixture was quenched with ice-cold water (50 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with water (2 × 200 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (20–50% ethyl acetate / hexanes) gave 4-(4-benzyloxy-2-chloro-6-methyl-3-pyridyl)morpholine (1.03 g, 53%). 1H NMR(400 MHz,DMSO-d6)δ 7.49(d,J=7.0 Hz,2H),7.44(t,J=7.4 Hz,2H),7.40-7.33(m,1H),7.11(s,1H),5.22(s,2H),3.62(s,4H),2.96(s,4H),2.35(s,3H).ESI-MS m / z calculated value .318.11, measured value 319.28(m+1) + .

[0362] Intermediate A-82 2-(4-(benzyloxy)-2-chloro-6-methylpyridin-3-yl)-1,3,4-oxadiazole [ka] Step 1: 2,4-Dichloro-6-methyl-pyridine-3-carboxylic acid To a solution of ethyl 2,4-dichloro-6-methyl-pyridine-3-carboxylate (1.0 g, 4.3 mmol) in ethanol (10 mL) was added LiOH (6.5 mL of 2 M, 13 mmol). The mixture was stirred at room temperature for 2 hours and then heated at 75° C. for 20 hours. Additional LiOH (5 mL of 2 M, 10 mmol) was added and the mixture was heated at 80° C. for 3 hours. The mixture was cooled, concentrated, and then acidified with 2 M HCl. The mixture was extracted with ethyl acetate (×3), then dried and filtered using Whatman 1PS hydrophobic phase separation filter paper. The filtrate was concentrated to give 2,4-dichloro-6-methyl-pyridine-3-carboxylic acid (823 mg, 94%). 1 H NMR(400 MHz,CD3OD)δ 7.44(d,J=0.7 Hz,1H),2.53(d,J=0.6 Hz,3H).

[0363] Step 2: tert-Butyl N-[(2,4-dichloro-6-methyl-pyridine-3-carbonyl)amino]carbamate A mixture of 2,4-dichloro-6-methyl-pyridine-3-carboxylic acid (7.0 g, 34 mmol) and SOCl (24.5 g, 15 mL, 206 mmol) was refluxed for 2 hours. The mixture was concentrated, and the residue was dissolved in benzene and evaporated under reduced pressure to give the corresponding acid chloride (9 g). A solution of the acid chloride (9 g) in dichloromethane (40 mL) was slowly added to a mixture of tert-butyl carbazate (4.5 g, 34 mmol) and TEA (10.9 g, 15.0 mL, 108 mmol) in dichloromethane (80 mL) at 0 °C. The mixture was stirred for 2 hours, then diluted with water (60 mL) and extracted with ethyl acetate (2 × 300 mL). The combined organic layer was washed with aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (25-30% ethyl acetate / hexanes) gave tert-butyl N-[(2,4-dichloro-6-methyl-pyridine-3-carbonyl)amino]carbamate (6.3 g, 54%). 1 H NMR(400 MHz,DMSO-d6)δ 10.32(s,1H),9.17(s,1H),7.59(s,1H),2.48(s,3H),1.43(s,9H).ESI-MS m / z Calculated value .319.05, Actual value 320.2(m+1) + .

[0364] Step 3: 2,4-Dichloro-6-methyl-pyridine-3-carbohydrazide Hydrochloric acid (in dioxane) (34 mL 4 M, 136.00 mmol) was added to tert-butyl N-[(4,6-dichloro-2-methyl-pyridine-3-carbonyl)amino]carbamate (2.0 g, 5.8 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated to give 4,6-dichloro-2-methyl-pyridine-3-carbohydrazide (1.27 g, 94%) as a white solid. 1 H NMR(400 MHz,CD3OD)δ 7.53(s,1H),2.55(s,3H).ESI-MS m / z calculated value .219.00, measured value 219.9(m+1) + .

[0365] Step 4: 2-(2,4-Dichloro-6-methyl-3-pyridyl)-1,3,4-oxadiazole A solution of 4,6-dichloro-2-methyl-pyridine-3-carbohydrazide (1.27 g, 5.44 mmol) in triethyl orthoformate (5.3 g, 6.0 mL, 36 mmol) was heated at 140 °C for 17 h. After cooling to room temperature, the mixture was poured into water (10 mL) and extracted with ethyl acetate (×3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (5–20% ethyl acetate / heptane) gave 2-(4,6-dichloro-2-methyl-3-pyridyl)-1,3,4-oxadiazole (0.75 g, 59%). 1 H NMR(400 MHz,CDCl3)δ 8.64(s,1H),7.33(s,1H),2.63(s,3H).ESI-MS m / z Calculated value.228.98, Actual value 229.85(m+1) + .

[0366] Step 5: 2-(4-(benzyloxy)-2-chloro-6-methylpyridin-3-yl)-1,3,4-oxadiazole A solution of benzyl alcohol (350 mg, 0.34 mL, 3.3 mmol) in 2-MeTHF (15 mL) was cooled to 0° C. under argon, and NaH in mineral oil (155 mg, 60% w / w, 3.9 mmol) was added in one portion. The mixture was stirred at 0° C. for 30 minutes and then cooled to −25° C. A solution of 2-(4,6-dichloro-2-methyl-3-pyridyl)-1,3,4-oxadiazole (0.75 g, 3.2 mmol) in 2-MeTHF (3 mL) was added, and the reaction was stirred at room temperature for 3 hours. The mixture was partitioned between water and ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate (×3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (0-40% ethyl acetate / heptane) gave the first 2-(2-benzyloxy-4-chloro-6-methyl-3-pyridyl)-1,3,4-oxadiazole (276 mg, 25%) as a clear oil. 1H NMR(400 MHz,CDCl3)δ 8.43(s,1H),7.24-7.16(m,5H),6.84(s,1H),5.32(s,2H),2.39(s,3H).ESI-MS m / z Calculated value .301.06, Actual value 302.05(m+1) + Subsequently, the desired 2-(4-benzyloxy-2-chloro-6-methyl-3-pyridyl)-1,3,4-oxadiazole (644 mg, 66%) was obtained as a white crystalline solid. 1 H NMR(400 MHz,CDCl3)δ 8.58(s,1H),7.39-7.26(m,5H),6.79(s,1H),5.17(s,2H),2.56(s,3H).ESI-MS m / z calculated value .301.06, measured value 302.04(m+1) +

[0367] Intermediate A-83 4-benzyloxy-2-chloro-6-methyl-3-(1-methylpyrazol-3-yl)pyridine [ka] Step 1: 4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylic acid To a stirred solution of ethyl 4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylate (300 mg, 0.981 mmol) in THF (3 mL) and MeOH (1 mL) was added aqueous NaOH (4.9 mL of 1.0 M, 4.9 mmol), and the mixture was stirred at 65 °C overnight. The mixture was diluted with ethyl acetate and washed with 1 N HCl, water, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by reverse-phase HPLC (C18, 1-99% acetonitrile / 5 mM HCl in water) gave 4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylic acid (203 mg, 75%). ESI-MS m / z calculated 277.05, found 278.1 (m+1). + .

[0368] Step 2: Triazolo[4,5-b]pyridin-3-yl 4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylate To a stirred solution of 4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylic acid (500 mg, 1.35 mmol) in acetonitrile (4 mL) was added HATU (720 mg, 1.89 mmol), followed by DIPEA (455 mg, 3.52 mmol). The mixture was stirred at room temperature under an argon atmosphere for 16 hours and then partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with additional ethyl acetate (×2). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was then stirred with ethyl acetate (25 mL) for 30 minutes, and the resulting solid was collected by filtration to give triazolo[4,5-b]pyridin-3-yl 4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylate (623 mg, 88%). ESI-MS m / z calculated 395.08, found 394.1 (m-1). - . 1 H NMR(400 MHz,DMSO-d6)δ 8.88(d,J=3.9 Hz,1H),8.77(d,J=7.8 Hz,1H),7.70(dd,J=8.4 Hz,4.3 Hz,1H),7.60-7.54(m,3H),7.46-7.36(m,3H),5.50(s,2H),2.57(s,3H).

[0369] Step 3: 1-(4-benzyloxy-2-chloro-6-methyl-3-pyridyl)ethanone To a stirred solution of triazolo[4,5-b]pyridin-3-yl 4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylate (330 mg, 0.628 mmol) in THF (6 mL) was added dropwise over 5 min at -40 °C. The mixture was stirred at the same temperature for 30 min and then quenched with saturated aqueous ammonium chloride solution (10 mL). Water (5 mL) was added, and the aqueous phase was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (0–50% ethyl acetate / heptane) gave 1-(4-benzyloxy-2-chloro-6-methyl-3-pyridyl)ethanone (136 mg, 47%). ESI-MS m / z calculated: 275.07, observed: 276.03 (m+1) + . 1 H NMR(400 MHz,CDCl3)δ 7.34-7.24(m,5H),6.62(s,1H),5.05(s,2H),2.43(s,3H),2.40(s,3H).

[0370] Step 4: (E)-1-(4-benzyloxy-2-chloro-6-methyl-3-pyridyl)-3-(dimethylamino)prop-2-en-1-one To a stirred solution of 1-(4-benzyloxy-2-chloro-6-methyl-3-pyridyl)ethanone (1.3 g, 4.5 mmol) in DMF (30 mL) was added DMF-DMA (1.11 g, 1.24 mL, 9.33 mmol), and the mixture was heated at 80 °C for 3 h. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give (E)-1-(4-benzyloxy-2-chloro-6-methyl-3-pyridyl)-3-(dimethylamino)prop-2-en-1-one (1.7 g, 92%). ESI-MS m / z calculated 330.11, found 331.11 (m+1). + . 1H NMR(400 MHz,DMSO-d6)δ 7.43(d,J=4.8 Hz,1H),7.39-7.33(m,4H),7.11(s,1H),5.28-5.21(m,3H),5.12(d,J=12.9 Hz,1H),3.03(s,3H),2.80(s,3H),2.41(s,3H).

[0371] Step 5: 4-Benzyloxy-2-chloro-6-methyl-3-(1H-pyrazol-5-yl)pyridine To a stirred solution of (E)-1-(4-benzyloxy-2-chloro-6-methyl-3-pyridyl)-3-(dimethylamino)prop-2-en-1-one (90 mg, 0.23 mmol) in ethanol (3 mL) was added hydrazine in THF (0.6 mL of 1 M, 0.6 mmol) at room temperature. The mixture was refluxed at 90 °C for 16 h. The mixture was concentrated and purified by silica gel chromatography (80% ethyl acetate / hexanes) to give 4-benzyloxy-2-chloro-6-methyl-3-(1H-pyrazol-5-yl)pyridine (40 mg, 55%). ESI-MS m / z calculated 299.08, found 300.1 (m+1).

[0372] Step 6: 4-benzyloxy-2-chloro-6-methyl-3-(1-methylpyrazol-3-yl)pyridine and 4-benzyloxy-2-chloro-6-methyl-3-(2-methylpyrazol-3-yl)pyridine To a stirred solution of 4-benzyloxy-2-chloro-6-methyl-3-(1H-pyrazol-5-yl)pyridine (30 mg, 0.10 mmol) in DMF (5 mL) was added potassium carbonate (45 mg, 0.33 mmol) followed by MeI (46 mg, 0.02 mL, 0.32 mmol) at room temperature. The mixture was stirred for 16 h at room temperature. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (200 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (20-30% ethyl acetate / hexanes) gave 4-benzyloxy-2-chloro-6-methyl-3-(2-methylpyrazol-3-yl)pyridine (1.01 g, 30%). 1 ESI-MS m / z Calculated value .313.10, Actual value 314.17(m+1) + , and 4-benzyloxy-2-chloro-6-methyl-3-(1-methylpyrazol-3-yl)pyridine (440 mg, 13%) were obtained. 1 H NMR(400 MHz,DMSO-d6)δ 7.73(d,J=2.2 Hz,1H),7.38-7.30(m,5H),7.14(s,1H),6.28(d,J=2.2 Hz,1H),5.20(s,2H),3.87(s,3H),2.43(s,3H).ESI-MS m / z calculated value.313.10,actual value 314.17(m+1) + .

[0373] Intermediate A-84 4-(4-benzyloxy-2-chloro-5,6-dimethyl-3-pyridyl)morpholine [ka] Step 1: 4-(2,4-dichloro-5,6-dimethyl-3-pyridyl)morpholine To a solution of 3-bromo-2,4-dichloro-5,6-dimethyl-pyridine (4.0 g, 13 mmol) in 2-MeTHF (50 mL) was added sodium tert-butoxide (1.8 g, 19 mmol), followed by morpholine (1.3 g, 1.3 mL, 15 mmol), and the mixture was purged with argon. Xantphos (750 mg, 1.30 mmol) and Pd2(dba)3 (590 mg, 0.644 mmol) were added, and the mixture was heated at 100 °C for 48 h. The mixture was filtered, washed with ethyl acetate, and the filtrate was concentrated. Purification by silica gel chromatography (5-7% ethyl acetate / hexane) gave 4-(2,4-dichloro-5,6-dimethyl-3-pyridyl)morpholine (1.62 g, 30%). ESI-MS m / z calculated: 260.05, observed: 261.2 (m+1) + .

[0374] Step 2: 4-(4-benzyloxy-2-chloro-5,6-dimethyl-3-pyridyl)morpholine To a solution of benzyl alcohol (520 mg, 0.50 mL, 4.8 mmol) in DMF (10 mL) was added sodium hydride (dispersion in mineral oil) (200 mg, 60% w / w, 5.0 mmol) portionwise at 0° C., and the mixture was stirred for 30 min at 0° C. A solution of 4-(2,4-dichloro-5,6-dimethyl-3-pyridyl)morpholine (1.6 g, 3.8 mmol) in DMF (5 mL) was added to the reaction mixture, and 100 The mixture was heated at °C for 24 h. The mixture was quenched with ice-cold water (30 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with water (2 × 50 mL) and brine (30 mL), dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (5–7% ethyl acetate / hexanes) gave 4-(4-benzyloxy-2-chloro-5,6-dimethyl-3-pyridyl)morpholine (915 mg, 72%). 1H NMR(400 MHz,DMSO-d6)δ 7.53-7.35(m,5H),5.00(s,2H),3.66(t,J=4.5 Hz,4H),3.10(t,J=4.6 Hz,4H),2.34(s,3H),2.07(s,3H).ESI-MS m / z Calculated value .332.13, Actual value 333.24(m+1) + .

[0375] Intermediate B-1 [2-(3,4-difluoro-2-methyl-phenoxy)-3-quinolyl]boronic acid [ka] 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 ( 400 MHz,DMSO-d6)δ 8.89(s,1H),7.95(dd,J=8.1,1.4 Hz,1H),7.69(ddd,J=8.4,6.9,1.5 Hz,1H),7.60(dd,J=8.1,1.0 Hz,1H),7.54(ddd,J=8.1,6.8,1.3 Hz,1H),7.40(m,1H),7.17(ddd,J=9.1,4.4,2.1 Hz,1H),2.07(d,J=2.2 Hz,3H).ESI-MS m / z calculated value.348.99,actual value 350.0(m+1) + .

[0376] 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 ammonium chloride. 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 ( 400 MHz,DMSO-d6)δ 8.51(d,J=4.8 Hz,1H),8.36(s,2H),7.94(dd,J=8.1,1.5 Hz,1H),7.66-7.57(m,1H),7.54(d,J=8.7 Hz,1H),7.46(ddd,J=8.1,6.8,1.4 Hz,1H),7.41-7.28(m,1H),7.13(m,1H),2.06(dd,J=5.4,2.3 Hz,3H).

[0377] Intermediate B-2 4-(3,4-Difluoro-2-methyl-phenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine [ka] Step 1: 5-Bromo-4-(3,4-difluoro-2-methyl-phenoxy)-2-(trifluoromethyl)pyridine 3,4-Difluoro-2-methyl-phenol (588 mg, 4.08 mmol), 5-bromo-4-chloro-2-(trifluoromethyl)pyridine (1.00 g, 3.84 mmol), and cesium carbonate (2.68 g, 8.23 ​​mmol) were combined in DMF (5.0 mL) and stirre...

Claims

1. Compounds of formula (I) or (II), 【Chemical 168】 or a pharmaceutically acceptable salt thereof, in the formula, L is O, single bond, -C(R) ２ - or -C(R) ２ -O-, X ２ However, N or CR ２ And, X ３ However, N or CR ３ And, X ４ However, N or CR ４ And, X ５ is N or CR ５ and X ６ However, N or CR ６ And, X ７ However, N or CR ７ And, Each R independently becomes H or C １ -C ６ It is alkyl, R １ , R ２ , and R ３ However, (i) R １ However, H, Halo, CN, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, (C １ -C ６ Alkylene)-OH,NR ８ R ９ , or CH(OH)(CH ２ ) ｍ (CHOH) ｎ (CH ２ ) ｐ It is H, R ２ and R ３ However, each is independent of H, Hal, CN, OH, C(O)OR ８ C is replaced as needed. １ -C ６ Alkyl, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, (C １ -C ６ Alkylene)-OH,NR ８ R ９ , (C １ -C ６ Alkylene)-O-(C) １ -C ６ Alkyl), C(O)NR ８ R ９ CH(OR ８ )-C(O)NR ８ R ９ , C(O)OR ８ _CHR ８ -C(O)OR ９ CH(OR ８ )-C(O)OR ９ , CH(OH)(CH ２ ) ｍ (CHOH) ｎ (CH ２ ) ｐ H, O-(C １ -C ６ Alkylene)-O-CH ３ , C(O)OR ８ C is replaced as needed. １ -C ６ Alkenil, S(O)R ８ ,C(O)C(O)NR ８ R ９ _CHR ８ -C(O)NR ８ R ９ , C(O)R １０ , S(=O)(=NR ８ ) R ９ , S(O) ２ NR ８ R ９ , 3- to 7-membered cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, or heteroaryl in the 3- to 7-membered cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl is independently oxo, OH, C １ -C ６ alkyl, C １ -C ６ alkoxy, and C(O)NR ８ R ９ is optionally substituted with 1 to 4 substituents selected from, or alternatively (ii) R ２ However, it is H, R １ and R ３ However, together with the carbon atoms to which they are bonded, the formula is: 【Chemistry 169】 Defined as forming a ring, R ４ 、R ５ 、R ６ 、and R ７ are as follows (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 substituted with haloalkyl or halo as needed. 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 with haloalkyl or halo as needed. 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: 【Chemistry 170】 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 C is substituted with haloalkyl or halo as needed. 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: 【Chemistry 171】 Defined as forming a ring, Each R ８ and R ９ However, independently, H or C １ -C ６ It is alkyl, Each R １０ However, independently, C １ -C ４ It is alkyl, Each R １１ However, they became independent: H, Halo, C １ -C ４ Alkyl, or C １ -C ４ It is a haloalkyl, R １２ and R １３ However, each is independent of H, Haro, and C. １ -C ６ Alkyl, C １ -C ６ C is substituted with haloalkyl or halo as needed. ３ -C ６ It is a cycloalkyl, Z １ However, the member is a 3-10 member cycloalkyl, a 3-10 member cycloalkenyl, a phenyl, a 4-10 member heterocyclyl, or a 5-6 member heteroaryl, and the 3-10 member cycloalkyl, 3-10 member cycloalkenyl, phenyl, a 4-10 member heterocyclyl, or a 5-6 member heteroaryl may be unsubstituted, or halo, OH, CH ２ OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl 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 ３ However, CR ３ And R ３ However, C(O)OR ８ If that is the case, L is O, or L is a combination, X ５ However, is N, or L is a combination, X ７ However, N is, X ２ or X ３ However, if N, L is O, Z １ However, it is phenyl, and the phenyl may be unsubstituted, or halo, OH, CH ２ OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl and C １ -C ６ It can be substituted with 1 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 4- to 10-membered heterocycline may be unsubstituted, or halo, OH, CH ２ OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl and C １ -C ６ It may be substituted with 1 to 4 substituents selected from haloalkoxys. The compound of formula (I) above, 【Chemistry 172】 Compounds of formula (I) or (II), or pharmaceutically acceptable salts thereof, that are not.

2. R １ However, H, Halo, CN, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, (C １ -C ６ Alkylene)-OH,NR ８ R ９ , or CH(OH)(CH ２ ) ｍ (CHOH) ｎ (CH ２ ) ｐ It is H, R ２ and R ３ However, each is independent of H, Hal, CN, OH, C(O)OR ８ C is replaced as needed. １ -C ６ Alkyl, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, (C １ -C ６ Alkylene)-OH,NR ８ R ９ , (C １ -C ６ Alkylene)-O-(C) １ -C ６ Alkyl), C(O)NR ８ R ９ CH(OR ８ )-C(O)NR ８ R ９ , C(O)OR ８ _CHR ８ -C(O)OR ９ CH(OR ８ )-C(O)OR ９ , CH(OH)(CH ２ ) ｍ (CHOH) ｎ (CH ２ ) ｐ H, O-(C １ -C ６ Alkylene)-O-CH ３ , C(O)OR ８ C is replaced as needed. １ -C ６ Alkenil, S(O)R ８ ,C(O)C(O)NR ８ R ９ _CHR ８ -C(O)NR ８ R ９ , C(O)R １０ , S(=O)(=NR ８ ) R ９ , S(O) ２ NR ８ R ９ The cycloalkyl, heterocyclyl, or heteroaryl in the 3-7 member cycloalkyl, 4-7 member heterocyclyl, or 5-6 member heteroaryl is independently oxo, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy and C(O)NR ８ R ９ A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, optionally substituted with one to four substituents selected from the above.

3. R １ However, H, Halo, CN, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, (C １ -C ６ Alkylene)-OH,NR ８ R ９ , or CH(OH)(CH ２ ) ｍ (CHOH) ｎ (CH ２ ) ｐ It is H, R ２ and R ３ However, each is independent of H, Hal, CN, OH, C(O)OR ８ C is replaced as needed. １ -C ６ Alkyl, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, (C １ -C ６ Alkylene)-OH,NR ８ R ９ , (C １ -C ６ Alkylene)-O-(C) １ -C ６ Alkyl), C(O)NR ８ R ９ CH(OR ８ )-C(O)NR ８ R ９ , C(O)OR ８ _CHR ８ -C(O)OR ９ CH(OR ８ )-C(O)OR ９ , CH(OH)(CH ２ ) ｍ (CHOH) ｎ (CH ２ ) ｐ H, O-(C １ -C ６ Alkylene)-O-CH ３ , C(O)OR ８ C is replaced as needed. １ -C ６ Alkenil, S(O)R ８ ,C(O)C(O)NR ８ R ９ _CHR ８ -C(O)NR ８ R ９ , C(O)R １０ , S(=O)(=NR ８ ) R ９ , or S(O) ２ NR ８ R ９ The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

4. The aforementioned compound is of formula (I-A) 【Chemistry 173】 It has, in the formula, R １ However, H, Halo, CN, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, (C １ -C ６ Alkylene)-OH, or NR ８ R ９ 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 with haloalkyl or halo as needed. ３ -C ６ It is a cycloalkyl, Z １ However, the member is a 5-10 member cycloalkyl, phenyl, 4-10 member heterocyclyl, or 5-6 member heteroaryl, and the 5-10 member cycloalkyl, phenyl, 4-10 member heterocyclyl, or 5-6 member heteroaryl may be unsubstituted or CH ２ OH, halo, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl and C １ -C ６ A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, which may be substituted with one to four substituents selected from haloalkoxys.

5. X ４ , X ５ , X ６ , or X ７ A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein at least one of the elements is N.

6. R １ However, C １ -C ６ A compound of formula (I) according to claim 1, which is alkyl, or a pharmaceutically acceptable salt thereof.

7. R ２ and R ３ However, each is independent of H, Hal, CN, OH, C(O)OR ８ C is replaced as needed. １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, C(O)OR ８ , S(=O)(=NH)CH ３ S(O)R ８ , C(O)R １０ , or S(O) ２ NR ８ R ９ The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

8. R ４ , R ５ , R ６ , and R ７ However, each is independent of H, halo, C1-C6 alkyl, and C. １ -C ６ C substituted with haloalkyl or 1 to 4 halos ３ -C ６ A compound of formula (I) according to claim 1, which is a cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

9. Z １ However, CH ２ OH, halo, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl and C １ -C ６ A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, which is a 5- to 10-membered cycloalkyl group optionally substituted with 1 to 4 substituents selected from haloalkoxys.

10. L is O, X ２ However, CR ２ And, X ３ However, CR ３ And, R １ However, C １ -C ６ A compound of formula (I) according to claim 1, which is alkyl, or a pharmaceutically acceptable salt thereof.

11. L is O, Z １ However, it is phenyl, and the phenyl may be unsubstituted, or CH ２ OH, halo, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl and C １ -C ６ A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, which may be substituted with one to four substituents selected from haloalkoxys.

12. L is -C(R) ２ -O-, X ２ However, CR ２ And, X ３ However, CR ３ And, Z １ However, it is a 3-membered cycloalkyl or a 4- to 10-membered cycloalkyl, and the 3-membered cycloalkyl is a halo, CH ２ OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl and C １ -C ６ Substituted with one or two substituents selected from haloalkoxys, the 4-10 membered cycloalkyl group may be unsubstituted or CH ２ OH, halo, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl and C １ -C ６ A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, which may be substituted with one to four substituents selected from haloalkoxys.

13. Z １ However, CH ２ OH, halo, C １ -C ６ Alkyl, C １ -C ６ Alkoxy and C １ -C ６ A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, which is a phenyl substituted with one to three substituents selected from haloalkoxys.

14. R ５ and R ６ However, together with the carbon atoms to which they are bonded, the formula is: 【Chemistry 175】 A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein a ring is formed, and each R 11 is independently H or a halo, as is necessary.

15. X ７ A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X6 is N, or X6 is N.

16. L is a single bond, X ２ However, CR ２ And, X ３ However, CR ３ And, Z １ However, it is a 4-10 member heterocyclyl or a 5-6 member heteroaryl, and the 4-10 member heterocyclyl or 5-6 member heteroaryl may be unsubstituted, or halo, OH, CH ２ OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl and C １ -C ６ A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, which may be substituted with one to four substituents selected from haloalkoxys, and optionally Z1 is a seven-membered heterocycline, the seven-membered heterocycline being unsubstituted or substituted with one to four substituents selected from halo, OH, CH2OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

17. X ５ However, CR ５ X ６ However, CR ６ And R ５ and R ６ However, together with the carbon atoms to which they are bonded, the formula is: 【Chemistry 177】 A compound of formula (I) according to claim 16, or a pharmaceutically acceptable salt thereof, wherein a ring is formed, and each R 11 is independently H or a halo, as is necessary.

18. X ２ However, CR ２ X ３ However, CR ３ And, R ２ and R ３ However, H and C are independent of each other. １ -C ６ Alkoxy, or C(O)OR ８ A compound of formula (I) according to claim 17, or a pharmaceutically acceptable salt thereof, wherein, if necessary, R2 and R3 are each independently a C1-C6 alkoxy or C(O)OR8.

19. R ２ However, the cycloalkyl, heterocyclyl, or heteroaryl in the 3-7 member cycloalkyl, 4-7 member heterocyclyl, or 5-6 member heteroaryl is independently oxo, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy and C(O)NR ８ R ９ Substituting as needed with 1 to 4 substituents selected from: R ３ However, H, Halo, CN, OH, C(O)OR ８ C is replaced as needed. １ -C ６ Alkyl, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, (C １ -C ６ Alkylene)-OH,NR ８ R ９ , (C １ -C ６ Alkylene)-O-(C) １ -C ６ Alkyl), C(O)NR ８ R ９ CH(OR ８ )-C(O)NR ８ R ９ , C(O)OR ８ _CHR ８ -C(O)OR ９ CH(OR ８ )-C(O)OR ９ , CH(OH)(CH ２ ) ｍ (CHOH) ｎ (CH ２ ) ｐ H, O-(C １ -C ６ Alkylene)-O-CH ３ , C(O)OR ８ C is replaced as needed. １ -C ６ Alkenil, S(O)R ８ ,C(O)C(O)NR ８ R ９ _CHR ８ -C(O)NR ８ R ９ , C(O)R １０ , S(=O)(=NR ８ ) R ９ , or S(O) ２ NR ８ R ９ The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

20. R ２ but, 【Chemistry 179】 The compound of formula (I) according to claim 19, or a pharmaceutically acceptable salt thereof.

21. The aforementioned hepatic aryl is 【Chemistry 180】 The heteroaryl is composed of 1 to 4 C １ -C ６ Substituting with alkyl substituents as needed, and R2 as needed, 【Chemistry 181】 The compound of formula (I) according to claim 19, or a pharmaceutically acceptable salt thereof.

22. R ２ However, H, Halo, CN, OH, C(O)OR ８ C is replaced as needed. １ -C ６ Alkyl, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, (C １ -C ６ Alkylene)-OH,NR ８ R ９ , (C １ -C ６ Alkylene)-O-(C) １ -C ６ Alkyl), C(O)NR ８ R ９ CH(OR ８ )-C(O)NR ８ R ９ , C(O)OR ８ _CHR ８ -C(O)OR ９ CH(OR ８ )-C(O)OR ９ , CH(OH)(CH ２ ) ｍ (CHOH) ｎ (CH ２ ) ｐ H, O-(C １ -C ６ Alkylene)-O-CH ３ , C(O)OR ８ C is replaced as needed. １ -C ６ Alkenil, S(O)R ８ ,C(O)C(O)NR ８ R ９ _CHR ８ -C(O)NR ８ R ９ , C(O)R １０ , S(=O)(=NR ８ ) R ９ , or S(O) ２ NR ８ R ９ And, R ３ However, the cycloalkyl, heterocyclyl, or heteroaryl in the 3-7 member cycloalkyl, 4-7 member heterocyclyl, or 5-6 member heteroaryl is independently oxo, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy and C(O)NR ８ R ９ A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, optionally substituted with one to four substituents selected from the above.

23. R ３ but, 【Chemistry 182】 The compound of formula (I) according to claim 22, or a pharmaceutically acceptable salt thereof.

24. The aforementioned heterocycline, 【Chemistry 183】 The heterocyclyl is substituted with one oxo substituent, and R3 is, if necessary. 【Chemistry 184】 The compound of formula (I) according to claim 22, or a pharmaceutically acceptable salt thereof.

25. The aforementioned hepatic aryl is 【Chemistry 185】 The heteroaryl is independently oxo, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy and C(O)NR ８ R ９ It is optionally substituted with 1 to 4 substituents selected from, and R3 is optionally, 【Chemistry 186】 The compound of formula (I) according to claim 22, or a pharmaceutically acceptable salt thereof.

26. L is a single bond, X ２ However, it is CH, X ３ However, CR ３ And, R １ However, C １ -C ６ It is alkyl, R ３ However, it is a 5-6 member heteroaryl, and the heteroaryl has 1-4 C １ -C ６ Substituting with alkyl substituents as needed, R ４ and R ５ However, each is independent, C １ -C ６ It is alkyl, Z １ However, it is a 3- to 10-membered cycloalkyl group, and the 3- to 10-membered cycloalkyl group may be unsubstituted or have 1 to 4 carbon atoms. １ -C ６ A compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, which may be substituted with an alkyl substituent. 【Request Item 27】 【Chemical 201】 【Chemical Engineering 202】 【Chemical 203】 【Chemical 204】 【Chemical 205】 【Chemical 206】 【Chemical 207】 【Chemical 208】 【Chemical Engineering 209】 【Chemical 210】 【Chemistry 211】 【Chemical Engineering 212】 【Chemistry 213】 【Chemical 214】 【Chemical 215】 【Chemical 216】 【Chemical 217】 【Chemical 218】 【Chemical 219】 【Chemical 220】 【Chemistry 221】 【Chemistry 222】 【Chemistry 223】 【Chemistry 224】 【Chemical 225】 【Chemistry 226】 【Chemistry 227】 【Chemistry 228】 【Chemistry 229】 【Chemistry 230】 【Chemistry 231】 【Chemistry 232】 【Chemical 233】 【Chemistry 234】 【Chemical 235】 【Chemistry 236】 【Chemistry 237】 【Chemical 238】 【Chemistry 239】 【Chemistry 240】 【Chemistry 241】 【Chemistry 242】 【Chemistry 243】 【Chemistry 244】 【Chemistry 245】 【Chemistry 246】 【Chemistry 247】 【Chemistry 248】 【Chemistry 249】 [Chemical 250] 【Chemistry 251】 【Chemistry 252】 【Chemistry 253】 【Chemistry 254】 【Chemistry 255】 【Chemistry 256】 【Chemistry 257】 【Chemistry 258】 【Chemistry 259】 【Chemical 260】 【Chemistry 261】 A compound selected from, or a pharmaceutically acceptable salt thereof. 【Request Item 28】 【Chemistry 262】 【Chemical 263】 【Chemistry 264】 【Chemical 265】 【Chemical 266】 【Chemistry 267】 【Chemical 268】 【Chemistry 269】 【Chemistry 270】 【Chemistry 271】 【Chemistry 272】 A compound selected from, or a pharmaceutically acceptable salt thereof.

29. The aforementioned compound, 【Chemical 189】 A compound selected from the compounds described in claim 1, or a pharmaceutically acceptable salt thereof.

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

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

32. A composition for inhibiting voltage-gated sodium channels in a target, comprising a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, wherein the voltage-gated sodium channel is optionally Na V 1.

8.

33. A pharmaceutical composition according to claim 31 for use in inhibiting voltage-gated sodium channels in a subject, wherein the voltage-gated sodium channel is optionally Na V 1.

8.

34. 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 or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 29.

35. (i) The composition is for treating or reducing the severity of chronic pain in the subject; or (ii) The composition is for treating or reducing the severity of neuropathic pain in the subject, and if necessary, (a) The neuropathic pain includes postherpetic neuralgia; or (b) The neuropathic pain includes small fiber neuropathy; or (c) The neuropathic pain includes idiopathic small-diameter fiber neuropathy; or (d) The neuropathic pain includes diabetic neuropathy, and if applicable, the diabetic neuropathy includes diabetic peripheral neuropathy; or (iii) The composition is for treating or reducing the severity of musculoskeletal pain in the subject, and the musculoskeletal pain, if applicable, includes pain of osteoarthritis; or (iv) The composition is for treating or reducing the severity of acute pain in the subject, and the acute pain includes, if necessary, acute postoperative pain; or (v) The composition is for treating or reducing the severity of postoperative pain in the subject, and may, if necessary, (a) The postoperative pain includes pain from aponeurosis excision; or (b) The postoperative pain includes pain from abdominal wall reconstruction; or (c) The postoperative pain includes pain from hernia repair surgery; or (vi) The composition according to claim 34, wherein the composition is for treating or reducing the severity of visceral pain in the subject.

36. The pharmaceutical composition according to claim 31 for use in the treatment of or reduction of the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia.

37. (i) The pharmaceutical composition is for treating or reducing the severity of chronic pain in the subject; or (ii) The pharmaceutical composition is for treating or reducing the severity of neuropathic pain in the subject, and if necessary, (a) The neuropathic pain includes postherpetic neuralgia; or (b) The neuropathic pain includes small fiber neuropathy; or (c) The neuropathic pain includes idiopathic small-diameter fiber neuropathy; or (d) The neuropathic pain includes diabetic neuropathy, and if applicable, the diabetic neuropathy includes diabetic peripheral neuropathy; or (iii) The pharmaceutical composition is for treating or reducing the severity of musculoskeletal pain in the subject, and if necessary, the musculoskeletal pain includes pain of osteoarthritis; or (iv) The pharmaceutical composition is for treating or reducing the severity of acute pain in the subject, and the acute pain includes, if necessary, acute postoperative pain; or (v) The pharmaceutical composition is for treating or reducing the severity of postoperative pain in the subject, and may, if necessary, (a) The postoperative pain includes pain from aponeurosis excision; or (b) The postoperative pain includes pain from abdominal wall reconstruction; or (c) The postoperative pain includes pain from hernia repair surgery; or (vi) The pharmaceutical composition according to claim 36, wherein the pharmaceutical composition is for treating or reducing the severity of visceral pain in the subject.

38. A composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29 for inhibiting voltage-gated sodium channels in a subject, or for treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia in a subject, or a composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, or a compound according to any one of claims 1 to 29 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.

39. A composition for use as a pharmaceutical, comprising a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

40. The pharmaceutical composition according to claim 31 for use as a drug.

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