Heteroaryl compounds for treatment of pain

Abstract

Compounds and pharmaceutically acceptable salts thereof useful as inhibitors of sodium channels are provided. Also provided are pharmaceutical compositions comprising the compounds or the pharmaceutically acceptable salts, and methods of using the compounds, the pharmaceutically acceptable salts, and the pharmaceutical compositions in the treatment of various conditions, including pain.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 333,881, filed April 22, 2022, which is incorporated by reference in its entirety. Background Art

[0003] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and prevent further damage to injured tissue. Nevertheless, in many cases, pain persists beyond its scope of action, or patients benefit from pain suppression. Neuropathic pain is a form of chronic pain caused by sensory nerve damage (Dieleman, JP et al., Incidence rates and treatment of neuropathic pain conditions in the general population. Pain, 2008.137 (3): p. 681-8). Neuropathic pain can be divided into two categories: pain caused by systemic metabolic damage to nerves and pain caused by discrete nerve damage. Metabolic neuropathy includes post-herpetic neuropathy, diabetic neuropathy and drug-induced neuropathy. Discrete nerve damage indications include post-amputation pain, postoperative nerve damage pain and nerve entrapment injuries such as neuropathic back pain.

[0004] Voltage-gated sodium channels (Na V ) is involved in pain signal transduction. V Sodium channels are biological mediators of electrical signaling because they mediate the rapid rise of the action potential in many excitable cell types (e.g., neurons, skeletal muscle cells, and cardiac myocytes). Evidence for the role of these channels in normal physiology, pathological conditions caused by mutations in sodium channel genes, preclinical work in animal models, and clinical pharmacology of known sodium channel modulators all point to the role of sodium channels in normal physiology. V Central role in pain perception (Rush, AM and TR Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets NaV1.8 Sodium Channels) V1.8 Sodium Channels). Mol. Interv., 2007. 7(4): 192-5; England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin. Investig. Drugs 17(12), 1849-64 (2008); Krafte, DS and Bannon, AW, Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8(1), 50-56 (2008). Na V Mediates the rapid upstroke of the action potential of many excitable cell types (e.g., neurons, skeletal muscle cells, cardiac myocytes) and is therefore involved in the initiation of signal transduction in these cells (Hille, Bertil, Ion Channels of Excitable Membranes, 3rd ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). V The role played in the initiation and propagation of neuronal signals, reducing Na V Antagonists of this current can prevent or reduce nerve signaling, and Na V Channels have been considered as possible targets for alleviating pain under conditions where hyperexcitability is observed (Chahine, M., Chatelier, A., Babich, O., and Krupp, JJ. Voltage-gated sodium channels in neurological disorders. CNS Neurol. Disord. Drug Targets 7(2), pp. 144-58 (2008)). Several clinically useful analgesics have been identified as Na V Channel inhibitors. VChannel-blocking pain local anesthetics such as lidocaine and other compounds that have been shown to be effective in reducing pain such as carbamazepine, lamotrigine, and tricyclic antidepressants have also been suggested to act through sodium channel inhibition (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. Eur. J. Pain 6 Suppl A, pp. 3-9 (2002); Wang, GK, Mitchell, J. and Wang, SY, Block of persistent late Na+ current by the antidepressants sertraline and paroxetine. + currents byantidepressant sertraline and paroxetine). Journal of Membrane Biology (J.Membr.Biol.), 222(2), pp. 79-90 (2008).

[0005] Na V Forms a subfamily of the voltage-gated ion channel superfamily and contains nine isoforms named Na V 1.1-Na V 1.9. These nine subtypes have different tissue localizations. V 1.4 is the main sodium channel in skeletal muscle, and Na V 1.5 is the main sodium channel in myocardial cells. V 1.7, 1.8 and 1.9 are mainly located in the peripheral nervous system, while Na V 1.1, 1.2, 1.3, and 1.6 are neuronal channels found in the central and peripheral nervous systems. The functional behavior of the nine isoforms is similar but different 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)).

[0006] After its discovery, Na V 1.8 channel was identified as a possible analgesic target (Akopian, AN, L. Sivilotti and JN Wood, Atetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562): p. 257-62). V 1.8 has been shown to be a carrier of sodium currents that sustain action potential discharges in small dorsal root ganglion (DRG) neurons (Blair, NT and BPBean, Roles of tetrodotoxin (TTX)-sensitive Na+ currents, TTX-resistant Na+ currents, and Ca2+ currents in the action potential of nociceptive sensory neurons). + current,TTX-resistant Na + current, and Ca 2+ current in the action potentials of nociceptive sensoryneurons). Journal of Neuroscience (J. Neurosci.), 2002.22(23): p.10277-90). Na V 1.8 has been implicated in spontaneous firing in injured neurons, such as those that drive neuropathic pain (Roza, C. et al., The tetrodotoxin-resistant Na+ channel NaV1.8 is essential for the expression of spontaneous activity in injured sensory axons of mice (The tetrodotoxin-resistant Na + channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. Journal of Physiology, 2003. 550(Pt 3): p. 921-6; Jarvis, MF et al., A-803467, a potent and selective NaV1.8 sodium channel blocker, reduces neuropathic and inflammatory pain in rats. V1.8 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 NaV1.8 in inflammatory and neuropathic pain states, but not in postoperative pain states. V 1.8 in inflammatory and neuropathic, but not post-operative, pain states. Pain, 2006. 123(1-2): 75-82; Lai, J. et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8 V 1.8). Pain, 2002.95(1-2): p.143-52; Dong, XW et al., Small interfering RNA-mediated selective knockdown of NaV1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. V1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. Neuroscience, 2007. 146(2): 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: 33; Black, JA et al. Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Human neuromas. Ann. Neurol., 2008. 64(6): 644-53; Coward, K. et al. Immunolocalization of SNS / PN3 and NaN / SNS2 sodium channels in human pain states. Pain, 2000. 85(1-2): 41-50; Yiangou, Y. et al. SNS / PN3 and SNS2 / NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. FEBS Express. Lett.), 2000.467(2-3): p. 249-52; Ruangsri, S. et al., Axonal voltage-gated sodium channel 1.8 (NaV1.8) Relationship of axonal voltage-gatedsodium channel 1.8 (Na. V 1.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats. Journal of Biological Chemistry (J.Biol.Chem.) 286(46): p. 39836-47). Expression of Na V The small DRG neurons of 1.8 include nociceptors involved in pain signaling. V 1.8 Mediating large-amplitude action potentials in small neurons of the dorsal root ganglion (Blair, NT and BPBean, tetrodotoxin (TTX)-sensitive Na + Current, Anti-TTX Na + Current and Ca 2+ The role of current in the action potential of nociceptive sensory neurons. Journal of Neuroscience, 2002. 22(23): p. 10277-90). V 1.8 is necessary for the rapid repetitive action potentials in nociceptors and for the spontaneous activity of injured neurons. (Choi, JS and SG Wixman, Physiological interactions between NaV1.7 and NaV1.8 sodium channels: a computer simulation study) V 1.7 andNa V 1.8 sodium channels: a computer simulation study). J. Neurophysiol. 106(6): 3173-84; Renganathan, M., T. R. Cummins and S. G. Wixman. Contribution of NaV1.8 sodium channels to action potential generation in DRG neurons. V )1.8 sodium channels to action potential electrogenesis in DRG neurons). Journal of Neurophysiology., 2001.86(2): p. 629-40; Roza, C. et al., Tetrodotoxin-resistant Na + Channel Na V1.8 is essential for the expression of spontaneous activity in injured sensory axons of mice. Journal of Physiology., 2003. 550(Pt 3): p. 921-6). In depolarized or injured DRG neurons, Na V 1.8 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. Proceedings of the National Academy of Sciences of the United States of America, 2006. 103(21): p. 8245-50). In some animal pain models, Na V NaV1.8 mRNA expression levels have been shown to be increased 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): 359-75; Strickland, IT et al., Changes in the expression of NaV1.7, NaV1.8, and NaV1.9 in different dorsal root ganglion populations innervating the rat knee joint in a model of chronic inflammatory arthralgia). V 1.7,Na V 1.8and 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). European Journal of Pain, 2008. 12(5): p. 564-72; Qiu, F. et al. Increased expression of tetrodotoxin-resistant sodium channels NaV1.8 and NaV1.9 in dorsal root ganglia in a rat model of bone cancer pain.V 1.8 and Na V 1.9 within dorsal rootganglia in a rat model of bone cancer pain). Neurosci. Lett., 512(2): 61-6.

[0007] The present inventors have found that, due to, for example, a poor therapeutic window (e.g., due to lack of Na V Some voltage-gated sodium channel inhibitors have limitations as therapeutic agents due to isotype selectivity, low potency, and / or other reasons. Therefore, there is still a need to develop selective voltage-gated sodium channel inhibitors, such as selective Na V 1.8 Inhibitors. Summary of the Invention

[0008] In one aspect, the present invention relates to a compound described herein or a pharmaceutically acceptable salt thereof.

[0009] In another aspect, the present invention relates to a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or vehicles.

[0010] In still another aspect, the present invention relates to a method of inhibiting a voltage-gated sodium channel in a subject by administering to the subject the compound, pharmaceutically acceptable salt or pharmaceutical composition.

[0011] In yet another aspect, the present invention relates to a method of treating or lessening the severity of various diseases, disorders or conditions in a subject by administering to the subject the compound, pharmaceutically acceptable salt or pharmaceutical composition, including but not limited to chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., bunionectomy pain, hernia repair pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough and arrhythmia. DETAILED DESCRIPTION

[0012] In one aspect, the present invention relates to a compound of formula (I) or (II)

[0013]

[0014] or a pharmaceutically acceptable salt thereof, wherein:

[0015] L is O, a single bond, -OC(R)2-, -C(R)2- or -C(R)2-O-;

[0016] X2 is N or CR2;

[0017] X3 is N or CR3;

[0018] X4 is N or CR4;

[0019] X5 is N or CR5;

[0020] X6 is N or CR6;

[0021] X7 is N or CR7;

[0022] Each R is independently H or C1-C6 alkyl;

[0023] R1, R2, and R3 are defined as follows:

[0024] (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; and

[0025] 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)2NR8R9, 3-7 membered cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the cycloalkyl, heterocyclyl or heteroaryl in the 3-7 membered cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted with 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy and C(O)NR8R9; or

[0026] (ii) R2 is H; and

[0027] R1 and R3 together with the carbon atoms to which they are attached form a ring having the formula:

[0028]

[0029] R4, R5, R6 and R7 are defined as follows:

[0030] (i) R4, R5, R6 and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with halo;

[0031] (ii) R4 and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with halo; and R5 and R6, together with the carbon atoms to which they are attached, form a ring having the formula:

[0032] or

[0033] (iii) R4 and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with halo; and R5 and R6, together with the carbon atoms to which they are attached, form a ring having the formula:

[0034]

[0035] Each R8 and R9 is independently H or C1-C6 alkyl;

[0036] Each R 10 are independently C1-C4 alkyl;

[0037] Each R 11 are independently H, halo, C1-C4 alkyl or C1-C4 haloalkyl;

[0038] R 12 and R 13 Each is independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with halo;

[0039] Z1 is a 3-10 membered cycloalkyl, a 3-10 membered cycloalkenyl, a phenyl, a 4-10 membered heterocyclyl or a 5-6 membered heteroaryl, wherein the 3-10 membered cycloalkyl, the 3-10 membered cycloalkenyl, the phenyl, the 4-10 membered heterocyclyl or the 5-6 membered heteroaryl may be unsubstituted or substituted with 1-4 substituents selected from the group consisting of halo, OH, CH2OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy;

[0040] m, n and p are each independently 0 or 1; and

[0041] q is 1, 2, or 3;

[0042] When X3 is CR3 and R3 is C(O)OR8, then:

[0043] L is O, or

[0044] L is a bond, and X5 is N, or

[0045] L is a bond, and X7 is N;

[0046] When X2 or X3 is N, then:

[0047] L is O, and Z1 is phenyl, wherein the phenyl group may be unsubstituted or substituted with 1 to 4 substituents selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy, or

[0048] L is a single bond, and Z1 is a 4-10 membered heterocyclyl, wherein the 4-10 membered heterocyclyl may be unsubstituted or substituted by 1-4 substituents selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy; and

[0049] wherein the compound of formula (I) is not:

[0050]

[0051] For purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th ed. In addition, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th ed., eds.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0052] As used herein, the term "compounds of the present invention" refers to compounds of Formula (I) and (II) as described herein and all embodiments thereof (e.g., Formula (IA) etc.), as well as compounds identified in Table A and Table B.

[0053] As described herein, the compounds of the present invention comprise a plurality of variable groups (e.g., R1, X2, etc.). As will be appreciated by those of ordinary skill in the art, the combinations of groups contemplated by the present invention are those that result in the formation of stable or chemically feasible compounds. In this context, the term "stable" refers to a compound that does not substantially change when subjected to one or more conditions that allow it to be produced, detected, and preferably recovered, purified, and used for the purposes disclosed herein. In some embodiments, a stable compound or a chemically feasible compound refers to a compound that does not undergo substantial change when stored at 40° C. or lower for at least one week in the absence of moisture or other chemically reactive conditions.

[0054] The chemical structures depicted herein are intended to be understood as chemical structures that would be understood by one of ordinary skill in the art. For example, with respect to formulas (I) and (IA), X4 and X5 are connected by a single bond, X5 and X6 are connected by a double bond, and X6 and X7 are connected by a single bond, even though the bonds between these groups may be obscured by the atomic labels in the chemical structure. Using different ChemDraw styles, formula (I) can be drawn as follows to illustrate the bonds in question:

[0055]

[0056] Additionally, a substituent depicted in a chemical structure as "CF3" or "F3C" refers to a trifluoromethyl substituent, regardless of which depiction appears in the chemical structure.

[0057] As used herein, the term "halo" means F, Cl, Br, or I.

[0058] As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain radical radical consisting solely of carbon and hydrogen atoms, containing no unsaturation and having a specified number of carbon atoms attached to the remainder of the molecule by a single bond. For example, a "C1-C6 alkyl" is an alkyl group having from one to six carbon atoms.

[0059] As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon chain radical radical consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds and having a specified number of carbon atoms attached to the remainder of the molecule by a single bond. For example, "C2-C6 alkenyl" is an alkenyl group having from two to six carbon atoms.

[0060] As used herein, the term "alkynyl" refers to a straight or branched hydrocarbon chain radical radical consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon triple bonds and having a specified number of carbon atoms attached to the remainder of the molecule by a single bond. For example, a "C2-C6 alkynyl" is an alkynyl radical having from two to six carbon atoms.

[0061] As used herein, the term "cycloalkyl" refers to a stable, non-aromatic, monocyclic or bicyclic (fused, bridged or spirocyclic) saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, having the specified number of carbon atoms and attached to the remainder of the molecule by a single bond. For example, a "C3-C8 cycloalkyl" is a cycloalkyl radical having three to eight carbon atoms.

[0062] As used herein, the term "cycloalkenyl" refers to a stable, non-aromatic, monocyclic or bicyclic (fused, bridged or spirocyclic) hydrocarbon radical 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 "C3-C8 cycloalkenyl" is a cycloalkenyl radical having three to eight carbon atoms.

[0063] As used herein, the term "haloalkyl" refers to an alkyl group having a specified number of carbon atoms, wherein one or more of the alkyl group's hydrogen atoms are replaced by a halo group. For example, a "C1-C6 haloalkyl" is an alkyl group having from one to six carbon atoms, wherein one or more of the alkyl group's hydrogen atoms are replaced by a halo group.

[0064] As used herein, the term "alkoxy" refers to -ORa The free radical, R a is an alkyl group having the specified number of carbon atoms. For example, "C1-C6 alkoxy" is of the formula -OR a A group in which R a is an alkyl group having one to six carbon atoms.

[0065] As used herein, the term "haloalkoxy" refers to an alkoxy group having the specified number of carbon atoms in which one or more of the hydrogen atoms of the alkyl group are replaced by a halo group.

[0066] As used herein, the term "alkylene" refers to a divalent straight or branched hydrocarbon chain radical radical consisting solely of carbon and hydrogen atoms, containing no unsaturation and having a specified number of carbon atoms connected to the remainder of the molecule by two single bonds. For example, "C1-C6 alkylene" is an alkylene radical having from one to six carbon atoms.

[0067] As used herein, the term "heterocyclic radical" refers to a stable, non-aromatic, monocyclic, bicyclic or tricyclic (fused, bridged or spirocyclic) group, wherein one or more ring atoms are heteroatoms (e.g., heteroatoms independently selected from N, O, P and S), which have a specific number of ring atoms connected to the rest of the molecule by a single bond. The heterocycle can be saturated or can contain one or more double or triple bonds. In certain embodiments, a "heterocyclic radical" has an indicated number of ring members, wherein one or more ring members are heteroatoms independently selected from oxygen, sulphur, nitrogen and phosphorus, and each ring in the ring system contains 3 to 7 ring members. For example, a 6-membered heterocyclic radical includes a total of 6 ring members, at least one of which is a heteroatom (e.g., heteroatoms independently selected from N, O, P and S).

[0068] As used herein, the term "heteroaryl" refers to a stable monocyclic, bicyclic or tricyclic group having a specific 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 group includes a total of 6 ring members, at least one of which is a heteroatom selected from N, S, O and P. The term "heteroaryl" can be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".

[0069] As used herein, the term "optionally substituted" refers to a group that is unsubstituted or substituted with a subsequently identified substituent. For example, a group that is "optionally substituted with 1-2 halo" is unsubstituted, substituted with 1 halo group, or substituted with 2 halo groups.

[0070] As used herein, labels such as "*5" and "*6" designate the atoms to which the corresponding R groups (in this case, R5 and R6 groups, respectively) are attached, as shown in the structures below.

[0071]

[0072] Similarly, as shown in the structures below, labels such as "*3" and "*1" designate the atoms to which the corresponding R groups (in this case, the R3 and R1 groups, respectively) are attached.

[0073]

[0074] Unless otherwise indicated, the compounds of the present 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)), conformers, and tautomers of the compounds identified by the chemical names and chemical structures provided herein. In addition, single stereoisomers, double bond isomers, conformers, and tautomers, as well as mixtures of stereoisomers, double bond isomers, conformers, and tautomers, are within the scope of the present invention.

[0075] As used herein, in any chemical structure or formula, a non-bold direct bond to a stereogenic center of a compound, such as in

[0076]

[0077] Indicates that the configuration of a stereocenter is unspecified. A compound may have any configuration or mixture of configurations at a stereocenter.

[0078] As used herein, in any chemical structure or formula, a bold or hashed direct bond to a stereogenic center of a compound, such as in

[0079]

[0080] The relative stereochemistry of the stereocenter is indicated with respect to other stereocenters connected by bold or hashed direct bonds.

[0081] As used herein, in any chemical structure or formula, a bold or hashed wedge-shaped bond attached to a stereogenic center of a compound, such as in

[0082]

[0083] The absolute stereochemistry of the stereocenter and the relative stereochemistry of the stereocenter relative to other stereocenters connected by bold or hashed wedge-shaped bonds are indicated.

[0084] As used herein, the prefix "rac-" when used in conjunction with 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.

[0085] As used herein, the prefix "rel-" refers to a single enantiomer with unknown absolute configuration when used in conjunction with a chiral compound. In compounds with a "rel-" prefix, the (R)- and (S)-designators in the chemical name reflect the relative stereochemistry of the compound, but do not necessarily reflect the absolute stereochemistry of the compound. In the case where the relative stereochemistry of a given stereocenter is unknown, no stereochemical designator is provided. In some cases, the absolute configuration of some stereocenters is known, while only the relative configuration of other stereocenters is known. In these cases, the stereochemical designator associated with the stereocenter of known absolute configuration is marked with an asterisk (*), such as (R*)- and (S*)-, while the stereochemical identifier associated with the stereocenter of unknown absolute configuration is not marked as such. The unmarked stereochemical designator associated with the stereocenter of unknown absolute configuration reflects the relative stereochemistry of these stereocenters relative to other stereocenters of unknown absolute configuration, but does not necessarily reflect the relative stereochemistry relative to the stereocenter of known absolute configuration.

[0086] 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 there may be isotopic variations between the constituent atoms of the molecules. The term "compound" includes such a collection of molecules without regard to the purity of a given sample containing the collection of molecules. Thus, the term "compound" includes 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.

[0087] In the specification and claims, unless otherwise indicated, any atom in any compound of the present invention that is not specifically designated as a particular isotope is intended to represent any stable isotope of the specified element. In examples, where an atom in any compound of the present invention is not specifically designated as a particular isotope, no effort has been made to enrich such atom in that particular isotope, and thus, one of ordinary skill in the art will understand that such atom is likely to be present at approximately the natural abundance isotopic composition of the specified element.

[0088] As used herein, the term "stable" when referring to an isotope means that the isotope is not currently known to undergo spontaneous radioactive decay. Stable isotopes include, but are not limited to, isotopes for which the decay mode is undetermined in: VS Shirley and CM Lederer, Isotope Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0089] As used in this specification and claims, "H" means hydrogen and includes any stable isotope of hydrogen, i.e. 1 H and D. In instances where an atom is designated as "H," no effort has been made to enrich such atom in a particular isotope of hydrogen, and thus one of ordinary skill in the art will understand that such hydrogen atom is likely to be present at about the natural abundance isotopic composition of hydrogen.

[0090] As used herein, “ 1 H" refers to protium. When an atom in a compound of the present invention or a pharmaceutically acceptable salt thereof is designated as protium, the protium is present at least at the natural abundance concentration of protium at the specified position.

[0091] As used herein, "D", "d" and " 2 H” refers to deuterium.

[0092] In some embodiments, the compounds of the present invention and pharmaceutically acceptable salts thereof comprise approximately the natural abundance isotopic composition of a designated element for each constituent atom.

[0093] In some embodiments, the compounds of the present invention and pharmaceutically acceptable salts thereof include 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 a specified element ("isotopically labeled" compounds and salts). Examples of commercially available stable isotopes suitable for the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, for example, 2 H. 13 C. 15 N. 18 O. 17 O and 31 P.

[0094] Isotope-labeled compounds and salts can be used in a variety of beneficial ways, including as pharmaceuticals. In some embodiments, isotope-labeled compounds and salts are deuterated ( 2 H) labeling. Deuterium ( 2 H) The labeled compounds and salts are therapeutically useful and compared to non 2 H-labeled compounds have potential therapeutic advantages. In general, deuterium ( 2H) labeled compounds and salts can have higher metabolic stability due to the kinetic isotope effect described below. Higher metabolic stability directly translates into increased half-life in vivo or lower dosage, which in most cases will represent preferred embodiments of the present invention. Isotope-labeled compounds and salts can generally be prepared by carrying out the procedures disclosed in the synthetic schemes, examples, and related descriptions, substituting non-isotope-labeled reactants with readily available isotope-labeled reactants.

[0095] deuterium( 2 H) labeled compounds and salts can manipulate the oxidative metabolic rate of a compound through the primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction caused by the exchange of isotopic nuclei, which in turn is caused by a change in the ground state energy of the covalent bonds involved in the reaction. The exchange of heavier isotopes generally results in a decrease in the ground state energy of a chemical bond and, therefore, a reduction in rate-limiting bond breakage. If bond breakage occurs in or near a saddle point region along the coordinates of a multi-product reaction, the product distribution ratio can change significantly. For example, if deuterium is bonded to a carbon atom in a non-exchangeable position, then k H / k D Rate differences of 2-7 are typical. For further discussion, see SL Harbeson and RD Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417, which is incorporated herein by reference in its entirety.

[0096] The concentration of an isotope (e.g., deuterium) incorporated at a given position of an isotopically labeled compound of the invention, or a pharmaceutically acceptable salt thereof, can be defined by an 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.

[0097] Where 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 with respect to such atom of at least 3000 (approximately 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).

[0098] In some embodiments, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein 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 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)2NR8R9, 3-7 membered cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the cycloalkyl, heterocyclyl or heteroaryl in the 3-7 membered cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted with 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy and C(O)NR8R9.

[0099] In some embodiments, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein 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 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 Or S(O)2NR8R9.

[0100] In some embodiments, the present invention relates to compounds of formula (IA)

[0101]

[0102] or a pharmaceutically acceptable salt thereof, wherein R2, R3, X4, X5, X6 and X7 are as defined above with respect to formula (I);

[0103] R1 is H, halo, CN, OH, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkylene)-OH or NR8R9;

[0104] R4, R5, R6 and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with halo; and

[0105] Z1 is a 5-10 membered cycloalkyl, phenyl, 4-10 membered heterocyclyl or 5-6 membered heteroaryl, wherein the 5-10 membered cycloalkyl, phenyl, 4-10 membered heterocyclyl or 5-6 membered heteroaryl may be unsubstituted or substituted by 1-4 substituents selected from halo, CH2OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

[0106] 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.

[0107] 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 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.

[0108] In some embodiments, the present invention relates to compounds of any one of formula (I) and (IA), or pharmaceutically acceptable salts thereof, wherein X2 is CR2 and X3 is CR3. In some embodiments, X2 is N. In some embodiments, X3 is N.

[0109] 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 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, 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) pH, 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)2NR8R9. In some embodiments, R2 is H. In some embodiments, R2 is halo. In some embodiments, R2 is CN. In some embodiments, R2 is OH. In some embodiments, R2 is C1-C6 alkyl. In some embodiments, R2 is C2-C6 alkynyl. In some embodiments, R2 is C1-C6 haloalkyl. In some embodiments, R2 is C1-C6 alkoxy. In some embodiments, R2 is C1-C6 haloalkoxy. In some embodiments, R2 is (C1-C6 alkylene)-OH. In some embodiments, R2 is NR8R9. In some embodiments, R2 is (C1-C6 alkylene)-O-(C1-C6 alkyl). In some embodiments, R2 is C(O)NR8R9. In some embodiments, R2 is C(O)OR8. In some embodiments, R2 is CH(OR8)-C(O)OR9. In some embodiments, R2 is CH(OH)(CH2) m (CHOH) n (CH2) p 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.

[0110] 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 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, NR8R9, (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)2NR8R9. 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) pH. 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.

[0111] 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 R4, R5, R6, and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with halo. In some embodiments, R4, R5, R6, and R7 are each independently H, halo, C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with halo. In some embodiments, R6 is a C3-C6 cycloalkyl substituted with halo. In some embodiments, R6 is a 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 a C3-C6 cycloalkyl substituted with halo; and R7 is H.

[0112] 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 Z1 is a 3-10 membered cycloalkyl, a 3-10 membered cycloalkenyl, a phenyl, a 5-10 membered heterocyclyl, or a 5-6 membered heteroaryl, wherein the 3-10 membered cycloalkyl, the 3-10 membered cycloalkenyl, the phenyl, the 5-10 membered heterocyclyl, or the 5-6 membered heteroaryl may be unsubstituted or substituted with 1-4 substituents selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy;

[0113] 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 Z1 is a 5-10 membered cycloalkyl group optionally substituted with 1-4 substituents selected from halo, CH2OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. In some embodiments, Z1 is a 5-10 membered cycloalkyl group 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 5-7 membered cycloalkyl group substituted with 1-4 substituents selected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. In certain embodiments, Z1 is optionally substituted by 1-4 substituents selected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy 6-membered cycloalkyl. In certain embodiments, Z1 is optionally substituted by 1-4 substituents selected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy 6-membered cycloalkyl. In certain embodiments, Z1 is optionally substituted by 5-10 yuan cycloalkyl of C1-C6 haloalkyl. In certain embodiments, Z1 is substituted by 5-10 yuan cycloalkyl of C1-C6 haloalkyl. In certain embodiments, Z1 is substituted by 6 yuan cycloalkyl of C1-C6 haloalkyl.

[0114] 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 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 by 1-2 halo; and Z1 is a 5-10 membered cycloalkyl substituted by C1-C6 haloalkyl.

[0115] 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 each R8 is C1-C6 alkyl. In some embodiments, R8 is C1-C6 alkyl, and R9 is H. In some embodiments, each R8 and R9 is H. In some embodiments, each R8 and R9 is C1-C6 alkyl.

[0116] In some embodiments, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0117] L is O, -OC(R)2- or -C(R)2-O-.

[0118] In some embodiments, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0119] L is O;

[0120] X2 is CR2;

[0121] X3 is CR3;

[0122] R1 is a C1-C6 alkyl group.

[0123] In some embodiments, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0124] L is 0; and

[0125] Z1 is phenyl, wherein the phenyl group may 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.

[0126] In some embodiments, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0127] L is -OC(R)2- or -C(R)2-O-;

[0128] X2 is CR2;

[0129] X3 is CR3; and

[0130] Z1 is a 3-membered cycloalkyl group or a 4-10-membered cycloalkyl group, wherein the 3-membered cycloalkyl group is substituted by 1-2 substituents selected from the group consisting of halo, CH2OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy, and the 4-10-membered cycloalkyl group may be unsubstituted or may be substituted by 1-4 substituents selected from the group consisting of halo, CH2OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

[0131] 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, 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 10In some embodiments, R2 and R3 are each independently H, halo, C(O)OR8, S(=O)(=NH)CH3, S(O)R8, or S(O)2NR8R9.

[0132] In some embodiments, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt 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 a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Z1 is phenyl substituted with 1-3 substituents selected from halo, CH2OH, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.

[0133] 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.

[0134] In some embodiments, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X5 is CR5; X6 is CR6; and R5 and R6 together with the carbon atoms to which they are attached form a ring having the following formula:

[0135]

[0136] In some embodiments, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 11 are independently H or halo.

[0137] In some embodiments, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0138] L is a single bond;

[0139] X2 is CR2;

[0140] X3 is CR3;

[0141] Z1 is a 4-10 membered heterocyclyl or a 5-6 membered heteroaryl, wherein the 4-10 membered heterocyclyl or the 5-6 membered heteroaryl may be unsubstituted or substituted by 1-4 substituents selected from halo, OH, CH2OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

[0142] In some embodiments, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0143] L is a single bond;

[0144] X2 is CR2;

[0145] X3 is CR3;

[0146] Z1 is a 5-10 membered heterocyclyl or a 5-6 membered heteroaryl, wherein the 5-10 membered heterocyclyl or the 5-6 membered heteroaryl may be unsubstituted or substituted by 1-4 substituents selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

[0147] In some embodiments, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0148] L is a single bond;

[0149] Z1 is a 7-membered heterocyclic radical, wherein the 7-membered heterocyclic radical may be unsubstituted or may be substituted by 1-4 substituents selected from halo, OH, CH2OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy. In certain embodiments, Z1 is an azepanyl optionally substituted by halo. In certain embodiments, Z1 is an azepanyl substituted by halo.

[0150] 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.

[0151] In some embodiments, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 is a 3-7 membered cycloalkyl, a 4-7 membered heterocyclyl or a 5-6 membered heteroaryl, wherein the cycloalkyl, heterocyclyl or heteroaryl in the 3-7 membered cycloalkyl, the 4-7 membered heterocyclyl or the 5-6 membered heteroaryl is optionally substituted with 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy and C(O)NR8R9; and R3 is H, halo, CN, OH, optionally C1-C6 alkyl, 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) substituted by C(O)OR8 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)2NR8R9. In other embodiments, R2 is a 4-7 membered heterocyclic group, wherein the heterocyclic group is 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 In other embodiments, R2 is a 5-6 membered heteroaryl, wherein the heteroaryl is 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 a 5-6 membered heteroaryl, wherein the heteroaryl is wherein said heteroaryl is optionally substituted with 1-4 C1-C6 alkyl substituents. In other embodiments, R2 is

[0152] In some embodiments, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R3 is H or C1-C6 alkyl.

[0153] 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, 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)2NR8R9; and R3 is a 3-7 membered cycloalkyl, a 4-7 membered heterocyclyl, or a 5-6 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, or heteroaryl in the 3-7 membered cycloalkyl, the 4-7 membered heterocyclyl, or the 5-6 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 other embodiments, R2 is H or C(O)OR8, wherein R8 is C1-C6 alkyl. In other embodiments, R3 is a 3-7 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 other embodiments, R3 is In other embodiments, 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 other embodiments, R3 is a 4-7 membered heterocyclyl, wherein the heterocyclyl is wherein the heterocyclic group is substituted with an oxo substituent. In other embodiments, R3 is In other embodiments, R3 is a 5-6 membered heteroaryl, wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, and C(O)NR8R9. In other embodiments, R3 is a 5-6 membered heteroaryl, wherein the heteroaryl is

[0154] wherein the heteroaryl is optionally substituted by 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy and C(O)NR8R9. In other embodiments, R3 is

[0155]

[0156] 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 5-6 membered heteroaryl, wherein the heteroaryl is optionally substituted with 1-4 C1-C6 alkyl substituents; R4 and R5 are each independently C1-C6 alkyl; and Z1 is a 3-10 membered cycloalkyl, wherein the 3-10 membered cycloalkyl may be unsubstituted or may be substituted with 1-4 C1-C6 alkyl substituents.

[0157] In some embodiments, the present invention relates to a compound of any one of Formula (I), (II), and (IA), or any embodiment thereof, ie, in non-salt form.

[0158] 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, ie, the compound in non-salt form.

[0159] Table A: Compound structures and names.

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218] 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, ie, a compound in non-salt form.

[0219] Table B: Compound structures and names.

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231] In some embodiments, the present invention relates to a compound of the formula

[0232]

[0233] or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the present invention" as that term is used herein.

[0234] In some embodiments, the present invention relates to a compound of the formula

[0235]

[0236] or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the present invention" as that term is used herein.

[0237] In some embodiments, the present invention relates to a compound of the formula

[0238]

[0239] or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the present invention" as that term is used herein.

[0240] In some embodiments, the present invention relates to a compound of the formula

[0241]

[0242] or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the present invention" as that term is used herein.

[0243] In some embodiments, the present invention relates to a compound of the formula

[0244]

[0245] or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the present invention" as that term is used herein.

[0246] In some embodiments, the present invention relates to a compound of the formula

[0247]

[0248] or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the present invention" as that term is used herein.

[0249] In some embodiments, the present invention relates to a compound of the formula

[0250]

[0251] or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the present invention" as that term is used herein.

[0252] In some embodiments, the present invention relates to a compound of the formula

[0253]

[0254] or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the present invention" as that term is used herein.

[0255] In some embodiments, the present invention relates to a compound of the formula

[0256]

[0257] or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the present invention" as that term is used herein.

[0258] In some embodiments, the present invention relates to a compound of the formula

[0259]

[0260] or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the present invention" as that term is used herein.

[0261] In some embodiments, the present invention relates to a compound of the formula

[0262]

[0263] or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the present invention" as that term is used herein.

[0264] In some embodiments, the present invention relates to a compound of the formula

[0265]

[0266] or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the present invention" as that term is used herein.

[0267] In some embodiments, the present invention relates to a compound of the formula

[0268]

[0269] or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the present invention" as that term is used herein.

[0270] In some embodiments, the present invention relates to a compound of the formula

[0271]

[0272] or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the present invention" as that term is used herein.

[0273] In some embodiments, the present invention relates to a compound of the formula

[0274]

[0275] or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the present invention" as that term is used herein.

[0276] In some embodiments, the present invention relates to a compound of the formula

[0277]

[0278] or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the present invention" as that term is used herein.

[0279] In some embodiments, the present invention relates to a compound selected from the group consisting of

[0280]

[0281] or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to the aforementioned compounds in non-salt form. Such compounds are considered "compounds of the present invention" as that term is used herein.

[0282] Salts, compositions, uses, formulations, administration and other pharmaceutical agents

[0283] Pharmaceutically acceptable salts and compositions

[0284] As discussed herein, the present invention provides compounds and pharmaceutically acceptable salts thereof that are voltage-gated sodium channel inhibitors, and thus the compounds of the present invention and pharmaceutically acceptable salts thereof can be used to treat 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, postoperative pain (e.g., bunionectomy pain, hernia repair pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or arrhythmia. Therefore, another aspect of the present invention provides pharmaceutical compositions, wherein these compositions comprise a compound as described herein or a pharmaceutically acceptable salt thereof and optionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0285] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for contact with the tissues of humans and lower animals, without undue toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. A "pharmaceutically acceptable salt" of a compound of the invention includes any non-toxic salt that, when administered to a recipient, is capable of directly or indirectly providing a compound of the invention or its inhibitory active metabolite or residue. The salt may be in pure form, in a mixture (e.g., solution, suspension, or colloid) containing one or more other substances, or in the form of a hydrate, solvate, or cocrystal. As used herein, the term "its inhibitory active metabolite or residue" means that its metabolite or residue is also a voltage-gated sodium channel inhibitor.

[0286] Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed of an amino group with an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or an organic acid (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), or salts formed 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, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconoheptate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other 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, as appropriate.

[0287] As described herein, the pharmaceutically acceptable compositions of the present invention additionally include pharmaceutically acceptable carriers, adjuvants or vehicles, as used herein, including any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., as applicable to the desired specific dosage form. Remington's Pharmaceutical Sciences, 16th edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation. Unless any conventional carrier medium is incompatible with the compounds of the present invention, such as by producing any undesirable biological effects or interacting with any other components of the pharmaceutically acceptable composition in other harmful ways, it is envisioned that it will be used within the scope of the present invention. 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 (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid or potassium sorbate), mixtures of saturated vegetable fatty acid partial glycerides, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, sugars such as Lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffer solutions and other nontoxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants, may also be present in the composition, according to the judgment of the formulator.

[0288] In another aspect, the invention features a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0289] In another aspect, the invention features a pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or vehicles.

[0290] Uses of compounds, pharmaceutically acceptable salts, and compositions

[0291] In another aspect, the invention features a method of inhibiting a voltage-gated sodium channel in a subject, the method comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another aspect, the voltage-gated sodium channel is Na V 1.8.

[0292] 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, postoperative pain (e.g., bunionectomy pain, hernia repair pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, and cardiac arrhythmia 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.

[0293] 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, postoperative pain, hernia repair 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 of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0294] In yet another aspect, the invention features a method of treating or lessening the severity of intestinal pain in a subject, wherein the intestinal pain comprises inflammatory bowel disease pain, Crohn's disease pain, irritable bowel syndrome, endometriosis, erythro-ovarian disease, salpingitis, cervicitis, or interstitial cystitis pain, wherein the method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0295] On the other hand, the present invention is characterized in that the neuropathic pain for treating subject or the method for alleviating its severity, methods described include applying an effective amount of the compound of the present invention, its pharmaceutically acceptable salt or its pharmaceutical composition.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 (for example, diabetic peripheral neuropathy).As used herein, phrase "idiopathic small fiber neuropathy" should be understood as including any small fiber neuropathy.

[0296] In yet another aspect, the invention features a method of treating or lessening the severity of neuropathic pain in a subject, wherein the neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom limb pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, drug therapy-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 cephalus, wherein the method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0297] In yet another aspect, the invention features a method of treating or lessening the severity of musculoskeletal pain 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. In some aspects, musculoskeletal pain includes osteoarthritis pain.

[0298] In yet another aspect, the invention features a method of treating or lessening the severity of musculoskeletal pain in a subject, wherein the musculoskeletal pain includes osteoarthritis pain, back pain, cold pain, burn pain, or dental pain, wherein the method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0299] In yet another aspect, the invention features a method of treating or lessening the severity of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain, ankylosing spondylitis, or vulvodynia, wherein the method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0300] In yet another aspect, the invention features a method of treating or lessening the severity of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain, wherein the method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0301] In yet another aspect, the invention features a method of treating or lessening the severity of idiopathic bone pain in a subject, wherein the idiopathic pain includes fibromyalgia, wherein the method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0302] In yet another aspect, the invention features a method of treating or lessening the severity of idiopathic skeletal pain in a subject, wherein the idiopathic pain includes reflex sympathetic dystrophy pain, wherein the method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0303] In yet another aspect, the invention features a method of treating or lessening the severity of pathological cough in a subject, wherein the method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0304] In yet another aspect, the invention features a method of treating acute pain in a subject or reducing its severity, the method comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, acute pain comprises acute postoperative pain.

[0305] In yet another aspect, the invention features a method of treating or lessening the severity of postoperative pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, hemorrhoidectomy pain, hernia repair pain, bunionectomy pain, or abdominoplasty pain) 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.

[0306] In yet another aspect, the invention features a method of treating or lessening the severity of bunionectomy pain 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.

[0307] In yet another aspect, the invention features a method of treating or lessening the severity of shoulder arthroplasty pain or shoulder arthroscopy pain 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.

[0308] In yet another aspect, the invention features a method of treating or lessening the severity of herniorrhaphy pain 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.

[0309] In yet another aspect, the invention features a method of treating or lessening the severity of abdominoplasty pain 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.

[0310] In yet another aspect, the invention features a method of treating or reducing the severity of visceral pain 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. In some aspects, the visceral pain comprises visceral pain induced by abdominoplasty.

[0311] In yet another aspect, the present invention features a method for treating a neurodegenerative disease in a subject or reducing its severity, the method comprising administering an effective amount of a compound of the present 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).

[0312] In yet another aspect, the invention features methods in which a subject is treated with one or more additional therapeutic agents that are administered concurrently with, prior to, or after treatment with an effective amount of the compound, pharmaceutically acceptable salt, or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0313] In another aspect, the invention features 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. In another aspect, the voltage-gated sodium channel is Na V 1.8.

[0314] In another aspect, the invention features a method of treating acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, nociplastic pain, arthritis, migraine, cluster headache, tension headache and all other forms of headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain of multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, nonspecific Chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (e.g., joint replacement pain, soft tissue surgery pain, thoracotomy pain, mastectomy pain, hernia repair pain, bunionectomy pain, or abdominoplasty pain), cancer pain, including chronic cancer pain and breakthrough cancer pain, stroke (e.g., central neuropathic pain after stroke), whiplash-related conditions, fragility fractures, vertebral fractures, ankylosing spondylitis, pemphigus, Raynaud's disease Disease), scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, ceroid bone disease, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperostosis, disc degeneration / herniation pain, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry's disease, mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolisthesis, spondylolisthesis, chemotherapy-induced oral mucositis, Charcot neuropathic osteoarthritis A method for treating or alleviating the severity of angina pectoris, osteoarthropathy, temporomandibular joint disorder, painful arthroplasty, non-cardiac chest pain, pudendal neuralgia, renal colic, biliary tract disease, vascular leg ulcers, Parkinson's disease pain, Alzheimer's disease pain, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina pectoris, exercise-induced angina pectoris, palpitations, hypertension or gastrointestinal motility disorders, which comprises administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0315] In another aspect, the invention features a method of treating, in a subject, 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, pancreatic pain, IBS pain, chronic and acute headaches, migraines, tension headaches, cluster headaches, chronic and acute neuropathic pain, postherpetic neuralgia, diabetic neuropathy, HIV-associated neuropathy, trigeminal neuralgia, Charcot-Marie-Tooth neuropathy, hereditary sensory neuropathies, peripheral nerve injury, painful neuromas, ectopic proximal and distal discharges, radiculopathy, chemotherapy-induced neuropathic pain, radiation therapy-induced neuropathic pain, persistent / chronic postoperative pain (e.g., post-amputation, post-thoracotomy, post-cardiac surgery), ), post-mastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, phantom limb pain (e.g., after lower limb, upper limb, or breast removal), intractable pain, acute pain, acute postoperative pain, acute musculoskeletal pain, joint pain, mechanical low back pain, neck pain, tendinitis, injury pain, movement pain, acute visceral pain, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, cardiac pain, pelvic pain, renal colic, acute labor pain, labor pain, cesarean section pain, acute inflammatory pain, burn pain, traumatic pain, acute intermittent pain, endometriosis, acute herpes zoster pain, sickle cell anemia, acute pancreatitis, breakthrough pain, oral and facial pain, sinusitis pain, toothache, multiple sclerosis (MS) pain, depression pain, leprosy pain, Behcet's disease A method for treating pain caused by idiopathic pain, adiposity pain, phlebitis pain, Guillain-Barre syndrome pain, leg and toe pain, Haglund syndrome, erythromelalgia, Fabry disease pain, bladder and genitourinary diseases, urinary incontinence, pathological cough, overactive bladder, painful bladder 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 pectoris, or reducing the severity thereof, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0316] In another aspect, the invention features a method of treating or lessening the severity of trigeminal neuralgia, botulinum toxin-treated migraine, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioglossal neuralgia, pudendal neuralgia, femoral neuropathy, meralgia paresthesia, saphenous neuropathy, sciatica, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain, or post-amputation pain 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.

[0317] Compounds, pharmaceutically acceptable salts, and compositions for use

[0318] 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.

[0319] 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. In another aspect, the voltage-gated sodium channel is Na V 1.8.

[0320] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., hernia repair pain, bunionectomy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, and arrhythmia in a subject.

[0321] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, hernia repair pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia in a subject.

[0322] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of intestinal pain in a subject, wherein the intestinal pain comprises pain from inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, endometriosis, erythro-ovarian disease, salpingitis, cervicitis, or interstitial cystitis.

[0323] On the other hand, the present invention is characterized in that the compound of the present invention or its pharmaceutically acceptable salt or pharmaceutical composition, it is used to treat the neuropathic pain of experimenter or the method for alleviating its severity.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 (for example, diabetic peripheral neuropathy).As used herein, phrase " idiopathic small fiber neuropathy " should be understood as including any small fiber neuropathy.

[0324] 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, wherein the neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom limb pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, drug therapy-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.

[0325] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of musculoskeletal pain in a subject. In some aspects, musculoskeletal pain includes osteoarthritis pain.

[0326] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of musculoskeletal pain in a subject, wherein the musculoskeletal pain includes osteoarthritis pain, back pain, cold pain, burn pain, or toothache.

[0327] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of inflammatory pain in a subject, wherein inflammatory pain includes rheumatoid arthritis pain, ankylosing spondylitis, and vulvodynia.

[0328] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain.

[0329] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of idiopathic pain in a subject, wherein the idiopathic pain includes fibromyalgia.

[0330] In yet another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of idiopathic pain in a subject, wherein the idiopathic pain includes reflex sympathetic dystrophy pain.

[0331] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of pathological cough in a subject.

[0332] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or reducing the severity of acute pain in a subject. In some aspects, acute pain includes acute postoperative pain.

[0333] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of postoperative pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, hemorrhoidectomy pain, hernia repair pain, bunionectomy pain, or abdominoplasty pain) in a subject.

[0334] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of bunionectomy pain in a subject.

[0335] In yet another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of shoulder replacement pain or shoulder arthroscopic pain in a subject.

[0336] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of herniorrhaphy pain in a subject.

[0337] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of abdominoplasty pain in a subject.

[0338] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or reducing the severity of visceral pain in a subject. In some aspects, the visceral pain includes visceral pain induced by abdominoplasty.

[0339] In another aspect, the present invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a neurodegenerative disease in a subject or a method of reducing its severity. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt-Hopkins syndrome (PTHS).

[0340] 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 wherein a subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or after treatment with an effective amount of the compound, pharmaceutically acceptable salt, or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0341] 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 biological sample, the method comprising contacting the biological sample with an effective amount of a compound of the invention, a pharmaceutically acceptable salt or pharmaceutical composition thereof. In another aspect, the voltage-gated sodium channel is Na V 1.8.

[0342] 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 treating acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, plastic pain, arthritis, migraine, cluster headache, tension headache, and all other forms of headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative diseases, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain of multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, nonspecific chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain) in a subject. pain, post-mastectomy pain, hernia repair pain, bunionectomy pain, or abdominoplasty pain), cancer pain, including chronic cancer pain and breakthrough cancer pain, stroke (e.g., central nervous system pain after stroke), whiplash-related conditions, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, oleoresinusitis, polymyalgia rheumatica, pyoderma gangrenosum, chronic myeloid leukemia, Generalized pain, diffuse idiopathic skeletal hyperostosis, disc degeneration / herniation pain, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolisthesis, spondylolisthesis, chemotherapy-induced oral mucositis, Charcot neuropathic osteoarthropathy, temporomandibular joint disorder, painful arthroplasty, non-cardiac chest pain, pudendal pain, renal colic, biliary 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 gastrointestinal dysmotility, or methods of reducing the severity thereof.

[0343] In another aspect, the invention features a compound of the invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in 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, pancreatic pain, IBS pain, chronic and acute headaches, migraines, tension headaches, cluster headaches, chronic and acute neuropathic pain, postherpetic neuralgia, diabetic neuropathy, HIV-associated neuropathy, trigeminal pain, spondylosis, schizophrenia, leukemia, leukemia, schizophrenia ... Geminid neuralgia, Charcot-Marie-Tooth neuropathy, hereditary sensory neuropathy, peripheral nerve injury, painful neuroma, ectopic proximal and distal discharges, radiculopathy, chemotherapy-induced neuropathic pain, radiation-induced neuropathic pain, persistent / chronic postoperative pain (e.g., post-amputation, post-thoracotomy, post-cardiac surgery), post-mastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, phantom limb pain (e.g., post-amputation, post-breastectomy), intractable pain, acute pain, acute postoperative pain, acute Musculoskeletal pain, joint pain, mechanical low back pain, neck pain, tendonitis, injury pain, exercise pain, acute visceral pain, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, cardiac pain, pelvic pain, renal colic, acute labor pain, labor pain, cesarean section pain, acute inflammatory pain, burn pain, traumatic pain, acute intermittent pain, endometriosis, acute herpes zoster pain, sickle cell anemia, acute pancreatitis, breakthrough pain, oral and facial pain, sinusitis pain, toothache, multiple sclerosis (MS) pain, depression pain, leprosy Pain, Behçet's disease pain, adiposity dolorosa, phlebitis pain, Guillain-Barré syndrome pain, leg and mobile toe pain, Haglund's syndrome, erythromelalgia, Fabry disease pain, bladder and genitourinary disorders, urinary incontinence, pathological cough, overactive bladder, painful bladder 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 or a method of reducing its severity.

[0344] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or reducing the severity of trigeminal neuralgia, botulinum toxin-treated migraine, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioglossal neuralgia, pudendal neuralgia, femoral neuropathy, meralgia paresthesia, saphenous neuropathy, sciatica, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain, or post-amputation pain in a subject.

[0345] Preparation of medicine

[0346] In another aspect, the present invention provides use of the compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof for preparing a medicament.

[0347] In another aspect, the present invention provides a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the preparation of a medicament for inhibiting voltage-gated sodium channels. In another aspect, the voltage-gated sodium channel is Na V 1.8.

[0348] 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 preparing a medicament for treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., hernia repair pain, bunionectomy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, and arrhythmia in a subject.

[0349] 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 preparing a medicament for treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, hernia repair pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or arrhythmia in a subject.

[0350] In yet another aspect, the present invention provides the use of a compound, pharmaceutically acceptable salt or pharmaceutical composition described herein for preparing a medicament for treating intestinal pain in a subject or alleviating its severity, wherein intestinal pain includes pain from inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, endometriosis, erythro-ovarian disease, salpingitis, cervicitis or interstitial cystitis.

[0351] On the other hand, the present invention provides compound of the present invention, its pharmaceutically acceptable salt or its pharmaceutical composition, it is used to prepare the neuropathic pain for treating experimenter or the medicine for alleviating its severity.In some respects, neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy or idiopathic small fiber neuropathy.In some respects, neuropathic pain includes diabetic neuropathy (for example, diabetic peripheral neuropathy).

[0352] In yet another aspect, the present invention provides a use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preparing a medicament for treating or alleviating the severity of neuropathic pain in a subject, wherein the neuropathic pain includes post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom limb pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, drug therapy-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 neuropathy.

[0353] In yet another aspect, the present invention provides a use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preparing a medicament for treating musculoskeletal pain in a subject or reducing its severity. In some aspects, musculoskeletal pain includes osteoarthritis pain.

[0354] 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 preparing a medicament for treating musculoskeletal pain in a subject or alleviating its severity, wherein the musculoskeletal pain includes osteoarthritis pain, back pain, cold pain, burn pain, or toothache.

[0355] 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 preparing a medicament for treating inflammatory pain in a subject or alleviating its severity, wherein the inflammatory pain includes rheumatoid arthritis pain, ankylosing spondylitis, or vulvodynia.

[0356] In yet another aspect, the present invention provides use of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preparing a medicament for treating inflammatory pain in a subject or alleviating its severity, wherein the inflammatory pain includes rheumatoid arthritis pain.

[0357] In yet another aspect, the present invention provides use of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preparing a medicament for treating idiopathic pain in a subject or alleviating its severity, wherein idiopathic pain includes fibromyalgia.

[0358] 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 preparing a medicament for treating idiopathic pain in a subject or alleviating its severity, wherein idiopathic pain includes reflex sympathetic dystrophy pain.

[0359] In yet another aspect, the present invention provides use of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preparing a medicament for treating pathological cough in a subject or alleviating its severity.

[0360] In another aspect, the present invention provides a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the preparation of a medicament for treating acute pain in a subject or alleviating the severity thereof. In some aspects, acute pain includes acute postoperative pain.

[0361] 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 preparing a medicament for treating postoperative pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, hemorrhoidectomy pain, hernia repair pain, bunionectomy pain, or abdominoplasty pain) in a subject or reducing its severity.

[0362] In yet another aspect, the present invention provides use of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preparing a medicament for treating or alleviating the severity of herniorrhaphy pain in a subject.

[0363] 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 preparing a medicament for treating or reducing the severity of bunionectomy pain in a subject.

[0364] In yet another aspect, the present invention provides use of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preparing a medicament for treating or alleviating the severity of shoulder arthroplasty pain or shoulder arthroscopic pain in a subject.

[0365] 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 preparing a medicament for treating or alleviating the severity of abdominoplasty pain in a subject.

[0366] In another aspect, the present invention provides a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the preparation of a medicament for treating visceral pain in a subject or reducing its severity. In some aspects, visceral pain includes visceral pain caused by abdominoplasty.

[0367] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the preparation of a medicament for treating a neurodegenerative disease in a subject or alleviating its severity. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt-Hopkins syndrome (PTHS).

[0368] 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 preparation of a medicament for use in combination with one or more additional therapeutic agents, the one or more additional therapeutic agents being administered concurrently with, prior to, or after treatment with the compound or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0369] In another aspect, the present invention provides a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the preparation of a preparation for treating acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, plastic pain, arthritis, migraine, cluster headache, tension headache and all other forms of headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative diseases, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis and irritable bowel Central neuropathic pain of irritability syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, nonspecific chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, hernia repair pain, bunionectomy pain, or abdominoplasty pain), cancer pain, including chronic cancer pain and breakthrough cancer pain, stroke (e.g., Central neuropathic pain after stroke), whiplash-related disorders, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, oleaginous bone disease, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperostosis, disc degeneration / herniation pain, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylitis, transverse myelitis, and Ehlers-Danlos syndrome Use of agents for the treatment of schizophrenia, Fabry disease, mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolisthesis, spondylolisthesis, chemotherapy-induced oral mucositis, Charcot neuropathic osteoarthropathy, temporomandibular joint disorder, painful arthroplasty, 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 gastrointestinal dysmotility, or agents to reduce their severity.

[0370] In another aspect, the present invention provides a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the preparation of a composition 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, pancreatic pain, IBS pain, chronic and acute headaches, migraines, tension headaches, cluster headaches, chronic and acute neuropathic pain, postherpetic neuralgia, diabetic neuropathy, HIV-related 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-induced neuropathic pain, persistent / chronic postoperative pain (e.g., post-amputation, post-thoracotomy, post-cardiac surgery), post-mastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, phantom limb pain (e.g., post-amputation, post-arm, post-breast amputation), refractory pain, acute pain, acute postoperative pain, acute musculoskeletal pain , joint pain, mechanical lower back pain, neck pain, tendonitis, injury pain, sports pain, acute visceral pain, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, heart pain, pelvic pain, renal colic, acute labor pain, labor pain, cesarean section pain, acute inflammatory pain, burn pain, trauma pain, acute intermittent pain, endometriosis, acute herpes zoster pain, sickle cell anemia, acute pancreatitis, breakthrough pain, oral and facial pain, sinusitis pain, toothache, multiple sclerosis (MS) pain, depression pain, leprosy pain, Behecet Use of drugs for pain in Teutz's disease, adiposity dolorosa, phlebitis pain, Guillain-Barré syndrome pain, leg and toe pain, Haglund's syndrome, erythromelalgia, Fabry disease pain, bladder and genitourinary system diseases, urinary incontinence, pathological cough, overactive bladder, painful bladder syndrome, interstitial cystitis (IC), prostatitis, complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II, widespread pain, paroxysmal severe pain, itching, tinnitus or angina-induced pain or to reduce its severity.

[0371] 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 preparing a medicament for treating trigeminal neuralgia, migraine treated with botulinum toxin, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioglossal neuralgia, pudendal neuralgia, femoral neuropathy, paresthesia meralgia, saphenous neuropathy, sciatica, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain, or post-amputation pain, or for alleviating the severity thereof.

[0372] Administration of compounds, pharmaceutically acceptable salts, and compositions

[0373] In certain embodiments of the present invention, an "effective amount" of the compound of the present invention, its pharmaceutically acceptable salt, or pharmaceutical composition thereof is an amount effective to treat one or more of the above-mentioned conditions or to lessen their severity.

[0374] According to the methods of the present invention, the compounds, salts, and compositions can be administered in any amount and by any route of administration that is effective for treating or alleviating the severity of one or more of the pain or non-pain conditions described herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition, the specific agent, the mode of administration, and the like. The compounds, salts, and compositions of the present invention are preferably formulated in dosage unit form for ease of administration and dosage uniformity. As used herein, the expression "dosage unit form" refers to a physically discrete dosage unit suitable for the subject to be treated. However, it should 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 condition being treated and the severity of the condition; the activity of the specific compound or salt employed; the specific composition employed; the age, weight, general health, sex, and diet of the subject; the time of administration, route of administration, and excretion rate of the specific compound or salt employed; the duration of treatment; the drugs used in combination with or concurrently with the specific compound or salt employed, and similar factors well known in the medical field. As used herein, the term "subject" or "patient" means an animal, preferably a mammal and most preferably a human.

[0375] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneal, topically (e.g., by powder, ointment, or drops), buccally, in the form of an oral spray or nasal spray, etc., depending on the severity of the condition being treated. In certain embodiments, the compounds, salts, and compositions of the present invention can be administered orally or parenterally at a dosage level of about 0.001 mg / kg to about 1000 mg / kg, once or more per day, to effectively achieve the desired therapeutic effect.

[0376] Liquid dosage forms for oral administration include but are not limited to pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to active compound or salt, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifying agents, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oil (particularly, cottonseed oil, peanuts, 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 can also include adjuvants, such as wetting agents, emulsifying agents and suspending agents, sweeteners, flavorings and aromatics.

[0377] Injectable preparations (e.g., sterile injectable aqueous or oily suspensions) can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in parenteral acceptable non-toxic diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be employed include 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 gentle fixed oil can be employed, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid are used to prepare injectables.

[0378] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

[0379] In order to prolong the effect of the compound of the present invention, it is generally desired to slow down the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. Thus, the absorption rate of the compound depends on its dissolution rate, which in turn can depend on crystal size and crystal form. Alternatively, delayed absorption of the compound form administered parenterally can be achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot-type injectable formulations are also prepared by trapping the compound in a liposome or microemulsion compatible with human tissue.

[0380] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compound or salt of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0381] 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, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents, such as paraffin; f) absorption promoters, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glycerol monostearate; h) adsorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer.

[0382] Solid compositions of similar types can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as other coatings well known in the field of enteric coatings and pharmaceutical formulations. The dosage form can optionally contain an emulsifier and its composition can also make the dosage form only or preferentially release the active ingredient in a delayed manner in a specific part of the intestinal tract. Examples of operable embedded compositions include polymeric substances and waxes. Solid compositions of similar types can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0383] The active compound or salt can also be in microencapsulated form together with one or more excipients as described above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells (such as enteric coatings, release-controlled coatings and other coatings well known in the field of pharmaceutical formulation). In such solid dosage forms, the active compound or salt can be mixed with at least one inert diluent such as sucrose, lactose or starch. Under normal circumstances, in addition to inert diluents, such dosage forms can also contain other substances, 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 form can also include a buffer. The dosage form can optionally contain an emulsifier and its composition can also make the dosage form release the active ingredient only or preferentially in a specific part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0384] The dosage form for topical or transdermal administration of the compound or salt of the present invention includes ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch. The active ingredient is mixed with a pharmaceutically acceptable carrier and any required preservative or buffer solution that may be needed under aseptic conditions. Ophthalmic formulations, ear drops and eye drops are also considered to be within the scope of the present invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of allowing the compound to be delivered to the body in a controlled manner. Such dosage forms are prepared by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. Rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0385] As generally described above, the compounds of the present invention can be used as voltage-gated sodium channel inhibitors. In one embodiment, the compound is Na V1.8 inhibitors and therefore, without wishing to be bound by any particular theory, the compounds, salts and compositions are particularly useful in treating conditions in which Na V 1.8 activation or hyperactivity of said disease, disorder or condition or lessening of its severity. V When activation or hyperactivity of 1.8 is associated with a particular disease, condition or disorder, the disease, condition or disorder may also be referred to as "Na V 1.8-mediated diseases, conditions or disorders". Thus, in another aspect, the present invention provides a method for treating a disease, condition or disorder wherein Na V 1.8 Methods of activating or hyperactivating a disease, condition or disorder associated with a disease state or lessening its severity.

[0386] In the present invention, Na V The activity of compounds that are inhibitors of 1.8 can be determined according to the methods generally described in International Publication No. WO 2014 / 120808 A9 and U.S. Publication No. 2014 / 0213616 A1, the methods described herein, and other methods known and available to those of ordinary skill in the art, both of which are incorporated herein by reference in their entireties.

[0387] Additional therapeutic agents

[0388] It should also be understood that the compounds, salts and pharmaceutically acceptable compositions of the present invention can be used in combination therapies, that is, the compounds, salts and pharmaceutically acceptable compositions can be used simultaneously with one or more other desired therapeutic agents or medical procedures, before or after them. The specific combination of the therapy (therapeutic agent or procedure) adopted in the combination regimen will take into account the compatibility of the desired therapeutic agent and / or procedure and the desired therapeutic effect to be achieved. It should also be understood that the therapy adopted can achieve the desired effect on the same disease (for example, the compound of the present invention can be used simultaneously with another medicament for the treatment of the same disease), or they can achieve different effects (for example, controlling any adverse reactions). As used herein, the additional therapeutic agent that is typically administered for the treatment or prevention of a particular disease or condition is referred to as "suitable for the disease or condition being treated".For example, exemplary additional therapeutic agents include, but are not limited to, non-opioid analgesics (indoles, such as Etodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones, such as Nabumetone; oxicams, such as Piroxicam; para-aminophenol derivatives, such as Acetaminophen; propionic acids, such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylates, such as Aspirin, Choline magnesium trisalicylate, trisalicylate, diflunisal; fenamates such as meclofenamic acid, mefenamic acid; and pyrazoles such as phenylbutazone); or opioid (narcotic) agonists (such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine). Additionally, non-drug analgesic approaches may be used in conjunction with the administration of one or more compounds of the invention. For example, anesthetic (intraspinal infusion, nerve block), neurosurgery (neurolysis of CNS pathways), neurostimulation (transcutaneous electrical nerve stimulation, dorsal column stimulation), physiological (physical therapy, orthopedic devices, diathermy) or psychological (cognitive approaches - hypnosis, biofeedback or behavioral approaches) approaches may also be utilized.Additional suitable therapeutic agents or approaches are generally described in The Merck Manual, 19th edition, ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and on the U.S. Food and Drug Administration website www.fda.gov, the entire contents of which are hereby incorporated by reference.

[0389] In another embodiment, the additional suitable therapeutic agent is selected from the group consisting of:

[0390] (1) Opioid analgesics, such as morphine, heroin, hydromorphone, oxymorphone, levonaphthol, levallorphan, methadone, pethidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, pentazocine, or difelikefalin;

[0391] (2) Nonsteroidal anti-inflammatory drugs (NSAIDs), e.g., aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen (including but not limited to intravenous ibuprofen (e.g., )), indomethacin, ketoprofen, ketorolac (including but not limited to ketorolac tromethamine (ketorolac tromethamine) (e.g., )), meclofenamic acid, mefenamic acid, meloxicam, IV meloxicam (e.g., ), nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, or zomepirac;

[0392] (3) Barbiturate sedatives, such as amobarbital (amomobarbital), aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal, or thiopental;

[0393] (4) benzodiazepines with sedative effects, such as chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam;

[0394] (5) Histamine (H1) antagonists with sedative effects, such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine, or chlorcyclizine;

[0395] (6) Sedatives, such as glutethimide, meprobamate, methaqualone, or dichloralphenazone;

[0396] (7) skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphenadrine;

[0397] (8) NMDA receptor antagonists, such as dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextromethorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinic acid, budipine, EN-3231 Combination formulations of morphine and dextromethorphan, topiramate, neramexane, or perzinfotel, including NR2B antagonists such as ifenprodil, traxoprodil, or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;

[0398] (9) α-adrenergic, such as doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonylamino-1,2,3,4-tetrahydroisoquinolin-2-yl)-5-(2-pyridyl)quinazoline;

[0399] (10) tricyclic antidepressants, such as desipramine, imipramine, amitriptyline or nortriptyline;

[0400] (11) Anticonvulsants, such as carbamazepine Lamotrigine, topiramate, lacosamide or valproate;

[0401] (12) Tachykinin (NK) antagonists, in particular NK-3, NK-2 or NK-1 antagonists, such as (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocinno[2,1-g][1,7]-naphthyridine-6-13-dione (TAK-637), 5-[[(2R,3S)-2-[(1R)-1- [3,5-Bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant, or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S);

[0402] (13) Muscarinic antagonists, such as oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

[0403] (14) COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib or lumiracoxib;

[0404] (15) Coal tar analgesics, especially paracetamol;

[0405] (16) Neuroleptics, such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, and aripiprazole , sonapiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, or sarizotan;

[0406] (17) Vanilloid receptor agonists (e.g., resinferatoxin or civamide) or antagonists (e.g., capsazepine, GRC-15300);

[0407] (18) β-adrenergic agents, such as propranolol;

[0408] (19) Local anesthetics, such as mexiletine;

[0409] (20) Corticosteroids, such as dexamethasone;

[0410] (21) 5-HT receptor agonists or antagonists, specifically 5-HT 1B / 1Dagonists, such as eletriptan, sumatriptan, naratriptan, zolmitriptan, or rizatriptan;

[0411] (22)5-HT 2A Receptor antagonists, such as R(+)-α-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinol (MDL-100907);

[0412] (23) Cholinergic (nicotinic) analgesics, such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), or nicotine;

[0413] (twenty four) Tramadol ER(Ultram ), IV Tramadol, Tapentadol ER

[0414] (25) PDE5 inhibitors, such as 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]-pyrimidin-7-one, Imido[3,4-b]indole-1,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridyl)-3-ethyl-2-(1-ethyl)- pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6 -dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;

[0415] (26) α-2-δ ligands, such as gabapentin Gabapentin GR Gabapentin enacarbil intermediate pregabalin 3-Methylgabapentin, (1[α],3[α],5[α])(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, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1-amino methyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(1-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;

[0416] (27) Cannabinoids, such as KHK-6188;

[0417] (28) metabotropic glutamate subtype 1 receptor (mGluR1) antagonists;

[0418] (29) Serotonin reuptake inhibitors, such as sertraline, (sertraline metabolite demethylsertraline), fluoxetine, norfluoxetine (fluoxetine demethyl metabolite), fluvoxamine, paroxetine, citalopram, (citalopram metabolite demethylcitalopram), escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine, and trazodone;

[0419] (30) Norepinephrine (NE) reuptake inhibitors, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, the bupropion metabolite hydroxybupropion, nomifensine, and viloxazine In particular, selective norepinephrine reuptake inhibitors such as reboxetine, specifically (S,S)-reboxetine;

[0420] (31) Dual serotonin-norepinephrine reuptake inhibitors, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, and duloxetine milnacipran and imipramine;

[0421] (32) Inducible nitric oxide synthase (iNOS) inhibitors, such as S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(1-iminoethyl)amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile, (3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolbutanol, 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-carboximidamide, NXN-462, or guanidine ethyl disulfide;

[0422] (33) Acetylcholinesterase inhibitors, such as donepezil;

[0423] (34) Prostaglandin E2 subtype 4 (EP4) antagonists, such as N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-toluenesulfonamide or 4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;

[0424] (35) Leukotriene B4 antagonists, such as 1-(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;

[0425] (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);

[0426] (37) Sodium channel blockers, such as lidocaine, lidocaine plus tetracaine cream (ZRS-201), or eslicarbazepine acetate;

[0427] (38)Na V1.7 Blockers, such as XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, and RG7893 BIIB-074 (Vixotrigine), BIIB-095, ASP-1807, DSP-3905, OLP-1002, RQ-00432979, FX-301, DWP-1706, DWP-17061, IMB-110, IMB-111, IMB-112 and WO2011 / 140425 (US2011 / 306607), WO2012 / 106499 (US2012196869), WO2012 / 112743 (US2012245136), WO2012 / 125613 (US2012264749), WO2012 / 116440 (US2012 14187533), WO2011026240 (US2012220605), US8883840, US8466188, WO2013 / 109521 (US2015005304), 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 of which are hereby incorporated by reference;

[0428] (38a)Na V1.7 Blockers, such as (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-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'-yl]-(4-isobutoxy-3-methoxy-phenyl)methanone, 1-(4-diphenylmethylpiperazin-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'-piperidin]-1'-yl]-(5-isopropoxy-6-methyl-2-pyridinyl)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'-piperidin]-1'-yl]methanone, 5-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone, -[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-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)-1-[1'-(5-isopropoxy)-1-[1'-(5-isopropoxy)-1-[1'-(5-isopropoxy)-1-[1'-(5-isopropoxy)-1-[1'-(5-isopropoxy)-1-[1'-(5-isopropoxy)-1-[1'-(5-isopropoxy)-1-[1'-(5-isopropoxy)-1-[1'-(5-isopropoxy)-1-[1'-(5-isopropoxy)-1-[1'-(5-isopropoxy)-1-[1'-(5-isopropoxy)-1-[1'-(5-isopropoxy)-1-[1'-(5-isopropoxy)-1- pyrrolo[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'-piperidin]-1'-yl]methanone, 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'-piperidin]-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'-piperidin]-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'-piperidin]-6-yl]-2,2,2-trifluoro-ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine oxazine-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]-6-yl]-2,2-dimethyl-propan-1-one 4'-piperidin]-1'-yl]-[4-(3,3,3-trifluoropropoxymethyl)phenyl]methanone, 4-bromo-N-(4-bromophenyl)-3-[(1-methyl-2-oxo-4-piperidinyl)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;

[0429] (39)Na V1.8 Blockers, such as PF-04531083, PF-06372865 and those disclosed in the following applications: WO2008 / 135826 (US2009048306), WO2006 / 011050 (US2008312235), WO2013 / 061205 (US2014296313), US20130303535, WO 2013131018, US8466188, WO 2013114250(US2013274243), WO2014 / 120808(US2014213616), WO2014 / 120815(US201422 8371), WO2014 / 120820 (US2014221435), WO2015 / 010065 (US20160152561), WO2015 / 089361 (US20150166589), WO2019 / 014352 (US20190016671), WO2018 / 213426, WO2020 / 146682, WO 2020 / 146612, WO2020 / 014243, WO2020 / 014246, WO2020 / 092187, WO2020 / 092667 (US202014 0411), WO2020 / 144375, WO2020 / 261114, WO2020 / 140959, WO2020 / 151728, WO2021 / 032074, WO2021 / 047622 (CN112479996), WO2021 / 257490, WO / 2021 / 257420, WO2021 / 257418, WO2021 / 032074 2 / 263498, WO2022 / 235558, WO2022 / 235859, CN112390745, CN111808019, CN112225695, CN112457294, CN112300051, CN112300069, CN112441969, and CN114591293, the entire contents of each of which are hereby incorporated by reference;

[0430] (39a)Na V1.8 Blockers, such as 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, -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 Benzamide, 2-((5-fluoro-2-hydroxybenzyl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide, 2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide,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-pyridinyl]methyl dihydrogen phosphate, 2-(4-fluoro-2-(methyl-d3)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, (4-(2-(4-fluoro-2-(methyl-d3)phenoxy)-4-(trifluoromethyl)benzamide)-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-sulfonylphenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-methoxyphenoxy)-N-(3-sulfonylphenyl)quinoxaline-2-carboxamide, 3-(4-chloro-2-methoxyphenoxy)-N-(3-sulfonylphenyl)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide)picolinic acid, 2-(2,4-difluorophenoxy)-N-(3-sulfonylphenyl)quinoline-3-carboxamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfonylphenyl)quinoline-3 -carboxamide, 3-(2,4-difluorophenoxy)-N-(3-sulfonylphenyl)quinoxaline-2-carboxamide, N-(3-sulfonylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoxaline-3-carboxamide, N-(3-sulfonylphenyl)-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide, 3-(4-chloro-2-methylphenoxy)-N-(3-sulfonylphenyl)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-methylphenoxy)-N-(3-sulfonylphenyl)quinoxaline-2-carboxamide quinoxaline-2-carboxamide, 3-(4-fluorophenoxy)-N-(3-sulfonylphenyl)quinoxaline-2-carboxamide, N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, N-(4-carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide)benzoic acid, N-(4-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamide)picolinic acid, 5-(2-(2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamide)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamide)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4,6-bis(trifluoromethyl)benzamide)picolinic acid, 4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamide)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy) -4-(perfluoroethyl)benzamide)picolinic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide)benzoic acid, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamide)picolinic acid, 4-(2-(2-chloro-4-fluorophenoxy)-4-(perfluoroethyl)benzamide)benzoic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(perfluoroethyl)benzamide)benzoic acid, 4- (4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamide)benzoic acid, 4-(4,5-dichloro-2-(4-chloro-2-methylphenoxy)benzamide)benzoic acid, 5-(4-(tert-butyl)-2-(4-fluoro-2-methoxyphenoxy)benzamide)picolinic acid, 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamide)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamide)benzoic acid )benzamide)benzoic acid, 5-(4,5-dichloro-2-(2,4-dimethoxyphenoxy)benzamide)picolinic acid, 5-(4,5-dichloro-2-(2-chloro-4-fluorophenoxy)benzamide)picolinic acid, 5-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamide)picolinic acid, 4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamide)benzoic acid, 5-(4,5-dichloro-2-(2,4-difluorophenoxy)benzamide)picolinic acid, 2-(4-fluorophenoxy)-N-(3-sulfonylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfonylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfonylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfonylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfonylphenyl)-4-(trifluoromethyl)benzamide -(3-sulfonylphenyl)-6-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfonylphenyl)benzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3-sulfonylphenyl)benzamide, 2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfonylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfonylphenyl)-5-(trifluoromethyl)benzamide, 5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfonylphenyl)benzamide, 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfonylphenyl)benzamide, 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfonylphenyl)benzamide, 2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3-sulfonylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfonylphenyl)benzamide -4,6-bis(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(3-sulfonylphenyl)-4,6-bis(trifluoromethyl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfonylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfonylphenyl)-4-(trifluoromethoxy)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfonylphenyl)-4-(trifluoromethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(3-sulfonylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfonylphenyl)benzamide, 5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfonylphenyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3-sulfonylphenyl)benzamide, N-(3-sulfonylphenyl)-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-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzamide, 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy] 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-(trideuteromethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2,3,4-Trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, N-(2-carbamoyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide, 4-[[6-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4- benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-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-aminomethoxy) acyl-4-fluoro-phenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-perfluoroethyl)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;

[0431] (40) Combined Na V 1.7 and Na V 1.8 Blockers, such as DSP-2230, Lohocla201 or BL-1021;

[0432] (41) 5-HT3 antagonists, such as ondansetron;

[0433] (42) TPRV1 receptor agonists, such as capsaicin and pharmaceutically acceptable salts and solvates thereof;

[0434] (43) Nicotinic receptor antagonists, such as varenicline;

[0435] (44) N-type calcium channel antagonists, such as Z-160;

[0436] (45) Nerve growth factor antagonists, such as tanezumab;

[0437] (46) Endopeptidase stimulators, such as senrebotase;

[0438] (47) Angiotensin II antagonists, such as EMA-401;

[0439] (48) Acetaminophen (including but not limited to intravenous acetaminophen (e.g., ));

[0440] (49) Bupivacaine (including but not limited to bupivacaine liposomal injectable suspension (e.g., ) Bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll), and transdermal bupivacaine );as well as

[0441] (50) Bupivacaine and meloxicam combination (e.g., HTX-011).

[0442] In one embodiment, the additional suitable therapeutic agent is selected from V-116517, pregabalin, controlled release pregabalin, ezogabine Ketamine / amitriptyline topical cream AVP-923, Perampanel (E-2007), Ralfinamide, Transdermal Bupivacaine CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561, or ARC-4558.

[0443] 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.

[0444] In another embodiment, the additional therapeutic agent is selected from: a GlyT2 / 5HT2 inhibitor, such as Operanserin (VVZ149); a TRPV modulator, such as CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101, MDR16523, or MDR652; an EGR1 inhibitor, such as Brivoglide (AYX1); NG F inhibitors, such as tanezumab, fasinumab, ASP6294, and MEDI7352; Mu opioid agonists, such as cebranopadol and NKTR181 (oxycodegol); CB-1 agonists, such as NEO1940 (AZN1940); imidazoline 12 agonists, such as CR4056, or p75NTR-Fc modulators, such as LEVI-04.

[0445] In another embodiment, the additional therapeutic agent is oliceridine or ropivacaine (TLC590).

[0446] In another embodiment, the additional therapeutic agent is Na V 1.7 Blockers, such as ST-2427, 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 hereby incorporated by reference.

[0447] In another embodiment, the additional therapeutic agent is ASP18071, CC-8464, ANP-230, ANP-231, NOC-100, NTX-1175, ASN008, NW3509, AM-6120, AM-8145, AM-0422, BL-017881, NTM-006, Opiranserin (Unafra TM), brivoligide, 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.

[0448] In another embodiment, the additional therapeutic agent is Olinvyk, Zynrelef, Seglenits, Neumentum, Nevakar, HTX-034, CPL-01, ACP-044, HRS-4800, Tarlige, BAY2395840, LY3526318, Eliapixant, TRV045, RTA9 01, NRD1355-E1, MT-8554, LY3556050, AP-325, tetrodotoxin, octenaproxesul, CFTX-1554, furoate, iN1011-N17, JMKX000623 / ODM-111, ETX-801, OLP-1002, ANP-230 / DSP-2230, iN1011-N17, DSP-3905, or ACD440.

[0449] In another embodiment, the additional therapeutic agent is a sodium channel inhibitor (also known as a sodium channel blocker), such as Na identified above. V 1.7 and Na V 1.8 Blocker.

[0450] The amount of additional therapeutic agent present in the compositions of the present invention may be no more than the amount typically administered in a composition comprising the therapeutic agent as the only active agent. The amount of additional therapeutic agent in the compositions disclosed herein may range from about 10% to 100% of the amount typically present in a composition comprising the agent as the only therapeutically active agent.

[0451] The compounds and salts of the present invention, or pharmaceutically acceptable compositions thereof, can also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents, and catheters. Thus, in another aspect, the present invention includes compositions for coating implantable devices comprising a compound or salt of the present invention as generally described above, and classes and subclasses herein, and a carrier suitable for coating the implantable device. In still another aspect, the present invention includes implantable devices coated with a composition comprising a compound or salt of the present invention as generally described above, and 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. Patents 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 coating may optionally be further coated with a suitable topcoat of fluorosilicone, polysaccharide, polyethylene glycol, phospholipid or a combination thereof to impart controlled release properties to the composition.

[0452] Another aspect of the present invention relates to inhibiting Na V 1.8 activity, the method comprising administering to the subject a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, or contacting the biological sample therewith. As used herein, the term "biological sample" includes, but is not limited to: cell culture or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0453] Suppresses Na in biological samples V 1.8 Activity can be used for various purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, studying sodium channels in biological and pathological phenomena; and comparative evaluation of new sodium channel inhibitors.

[0454] Synthesis of the compounds of the present invention

[0455] Compounds of the present invention can be prepared by known materials by the method described in the examples, other similar methods and other methods known to those skilled in the art. As will be appreciated by those skilled in the art, the functional groups of the intermediate compounds in the methods described below may need to be protected by suitable blocking groups. Blocking groups can be added or removed according to standard techniques well known to those skilled in the art. The use of blocking groups is described in detail in the following literature: TGM Wuts et al., Greene's Protective Groups in Organic Synthesis (4th edition 2006).

[0456] Radiolabeled analogs of the compounds of the invention

[0457] In another aspect, the present invention relates to radiolabeled analogs of the compounds of the present invention. As used herein, the term "radiolabeled analog of a compound of the present invention" refers to a compound that is identical to a compound of the present invention as described herein, including all embodiments thereof, except that one or more atoms have been replaced by a radioactive isotope of an atom present in the compound of the present invention.

[0458] As used herein, the term "radioisotope" refers to an isotope of an element that is known to undergo spontaneous radioactive decay. Examples of radioisotopes include 3 H. 14 C. 32 P. 35 S. 18 F. 36 Cl et al., and the isotopes whose decay patterns are identified in: VS Shirley and CM Lederer, Isotope Program, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0459] Radiolabeled analogs can be used in a variety of beneficial ways, including in various types of assays, such as substrate tissue distribution assays. For example, tritium ( 3 H) and / or carbon-14 ( 14 )-labeled compounds can be used in various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detectability.

[0460] In another aspect, the invention relates to a pharmaceutically acceptable salt of a radiolabeled analog according to any of the embodiments described herein in conjunction with the compounds of the invention.

[0461] In another aspect, the invention relates to a pharmaceutical composition comprising a radiolabeled analogue or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle, according to any of the embodiments described herein in conjunction with the compounds of the invention.

[0462] 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 conditions, including pain, in a subject, comprising administering an effective amount of a radiolabeled analog, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof, according to any of the embodiments described herein in conjunction with the compounds of the present invention.

[0463] 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 conjunction with the compounds of the invention.

[0464] In another aspect, the invention relates to the use of a radiolabeled analogue or a pharmaceutically acceptable salt thereof and a pharmaceutical composition thereof for the preparation of a medicament according to any of the embodiments described herein in conjunction with the compounds of the invention.

[0465] In another aspect, according to any of the embodiments described herein in conjunction with the compounds of the invention, the radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, may be used in combination therapy.

[0466] Examples

[0467] abbreviation

[0468] Unless otherwise stated or the context requires otherwise, the following abbreviations shall be understood to have the following meanings:

[0469] abbreviation meaning

[0470] NMR Nuclear Magnetic Resonance

[0471] ESI-MS electrospray mass spectrometry

[0472] LC / MS liquid chromatography-mass spectrometry

[0473] UPLC ultra-performance liquid chromatography

[0474] HPLC / MS / MS High-performance liquid chromatography-tandem mass spectrometry

[0475] IS internal standard

[0476] HPLC high-performance liquid chromatography

[0477] SFC Supercritical Fluid Chromatography

[0478] ESI electrospray ionization

[0479] g grams

[0480] mg milligrams

[0481] kg kilogram

[0482] L liter

[0483] mL milliliters

[0484] μL microliter

[0485] nL nanoliter

[0486] mol mole

[0487] mmol millimole

[0488] hr,h hours

[0489] min

[0490] ms milliseconds

[0491] abbreviation meaning

[0492] mm millimeter

[0493] μm micrometer

[0494] nm nanometer

[0495] MHz Megahertz

[0496] Hz Hertz

[0497] N Normal (concentration)

[0498] M molar (concentration)

[0499] mM millimolar (concentration)

[0500] μM micromolar (concentration)

[0501] ppm parts per million

[0502] %w / v weight-volume concentration

[0503] %w / w weight-weight concentration

[0504] t-BuOH tert-Butanol

[0505] CDI 1,1'-Carbonyldiimidazole

[0506] DAST Diethylaminosulfur trifluoride

[0507] DCM dichloromethane

[0508] DCE dichloroethane

[0509] DIEA,DIPEA N,N-Diisopropylethylamine

[0510] DMA N,N-dimethylacetamide

[0511] DMAP N,N-dimethylaminopyridine

[0512] DMF N,N-dimethylformamide

[0513] DMSO dimethyl sulfoxide

[0514] DRG dorsal root ganglion

[0515] EDC.HCl Ethylcarbodiimide hydrochloride

[0516] EtOH

[0517] EtOAc

[0518] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide

[0519] HOBt Hydroxybenzotriazole

[0520] EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0521] T3P Propylphosphonic anhydride, i.e., 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphane 2,4,6-

[0522] trioxide

[0523] KOAc potassium acetate

[0524] abbreviation meaning

[0525] m-CPBA m-chloroperbenzoic acid

[0526] MeOH methanol

[0527] MTBE methyl tert-butyl ether

[0528] NaOH sodium hydroxide

[0529] NBS N-bromosuccinimide

[0530] NMP N-Methylpyrrolidone

[0531] NMO N-Methylmorpholine N-oxide

[0532] PdCl 2 (dtbpf) 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride

[0533] PPTS Pyridinium p-toluenesulfonate

[0534] TBAB Tetra-n-butylammonium bromide

[0535] TBAF Tetra-n-butylammonium fluoride

[0536] TBSCl tert-Butyldimethylsilyl chloride

[0537] TBSOTf tert-Butyldimethylsilyl trifluoromethanesulfonate

[0538] THF Tetrahydrofuran

[0539] TEA triethylamine

[0540] TFA trifluoroacetic acid

[0541] RB Round Bottom Flask

[0542] RT Room temperature

[0543] ca. approximately (circa)(approximately)

[0544] E-VIPR Electrically Stimulated Voltage Ion Probe Reader

[0545] HEK human embryonic kidney

[0546] KIR2.1 inward rectifier potassium channel 2.1

[0547] DMEM Dulbecco's Modified Eagle's Medium

[0548] FBS fetal bovine serum

[0549] NEAA non-essential amino acids

[0550] HEPES 2-[4-(2-Hydroxyethyl)piperazin-1-yl]ethanesulfonic acid

[0551] DiSBAC6(3) Bis-(1,3-dihexyl-thiobarbituric acid) trimethyloxanol

[0552] CC2-DMPE Chlorocoumarin-2-tetradecanoylphosphatidylethanolamine

[0553] VABSC-1 Voltage Assay Background Suppression Compound

[0554] HS human serum

[0555] BSA bovine serum albumin

[0556] General Methods. Obtained as a solution in an appropriate deuterated solvent, such as dimethyl sulfoxide-d6 (DMSO-d6) 1 H NMR spectroscopy.

[0557] Compound purity, retention times, and electrospray mass spectrometry (ESI-MS) data were determined by LC / MS analysis.

[0558] LC / MS method

[0559] Unless otherwise stated, LC / MS determinations were performed using one of the following chromatographic conditions:

[0560] 1) Waters BEH C8 (1.7 μm, 2.1 x 50 mm) 2 to 98% acetonitrile / water (10 mM ammonium formate, pH 9), 45°C, flow rate 0.6 ml / min over 5.0 min;

[0561] 2) Kinetex EVO C18 (2.6 μm, 2.1 x 50 mm) 2 to 98% acetonitrile / water (10 mM ammonium formate, pH 9), 45°C, flow rate 0.7 ml / min over 4.0 min;

[0562] 3) Kinetex EVO C18 (2.6 μm, 2.1 x 50 mm) 2 to 98% acetonitrile / water (10 mM ammonium formate, pH 9), 45°C, flow rate 1.0 ml / min in 1.5 min;

[0563] 4) Waters Acquity UPLC BEH C18 (1.7 μm, 30 x 2.1 mm) 1 to 99% acetonitrile (0.035% TFA) / water (0.05% TFA), 60° C., flow rate = 1.5 mL / min over 3 minutes;

[0564] 5) Kinetex Polar C18 (2.6 μm, 3.0 x 50 mm) 5 to 95% acetonitrile / water (0.1% formic acid) at a flow rate of 1.2 ml / min over 6 minutes;

[0565] 6) SunFire C18 (3.5 μm, 75 x 4.6 mm): Initial 5 to 95% acetonitrile / water (0.1% formic acid) over 1 minute, followed by a linear gradient to 95% acetonitrile over 5 minutes. 45°C, flow rate: 1.5 mL / min over 6 minutes.

[0566] 7) XBridge C18 (5 μm, 4.6 x 75 mm) with an initial gradient of 5 to 95% acetonitrile (NH4HCO3) for 6 minutes and an equilibrium gradient of 95% acetonitrile for 1 minute from 0 to 3 minutes and held for 3 minutes, at a flow rate of 1.5 ml / min;

[0567] 8) Waters CSH C18 (1.7 μm, 2.1 x 50 mm) 2 to 98% acetonitrile / water (0.1% TFA, pH 2), 45°C, flow rate 0.6 ml / min in 5.0 min;

[0568] 9) Waters CSH C18 (1.7 μm, 2.1 x 50 mm) 2 to 95% acetonitrile / water (0.1% formic acid), 40°C, flow rate 0.8 ml / min in 4.6 min;

[0569] 10) Waters BEH C18 (2.5 μm, 2.1 x 50 mm) 2 to 95% acetonitrile / water (0.1% NH 3 ), 40° C., flow rate 0.8 mL / min in 4.6 min;

[0570] 11) Waters BEH C18 (3.5 μm, 75 x 4.6 mm) initial gradient 5 to 95% acetonitrile / water (0.1% formic acid), then linear gradient to 95% acetonitrile for 4 minutes, hold at 95% acetonitrile for 2 minutes, 45°C, flow rate 1.5 ml / min over 6 minutes;

[0571] 12) Waters BEH C18 (2.5 μm, 2.1 x 50 mm) 2 to 50% acetonitrile / water (0.1% NH 3 ), 40° C., flow rate 0.8 mL / min in 4.6 min;

[0572] 13) Waters CSH C18 (1.7 μm, 2.1 x 50 mm) 2 to 98% acetonitrile / water (0.1% TFA), 45°C, flow rate 1.0 ml / min in 1.5 min;

[0573] 14) Waters CSH C18 (1.7 μm, 2.1 x 50 mm) 2 to 95% acetonitrile / water (0.1% formic acid), 40°C, flow rate 0.8 ml / min in 1.4 min;

[0574] 15) YMC Triart C18 (3 μm, 33 x 2.1 mm) 2 to 98% acetonitrile / water (5 mM NH4OAc) at a flow rate of 1.0 ml / min over 3 min;

[0575] 16) Waters BEH C18 (2.5 μm, 2.1 x 50 mm) 2 to 95% acetonitrile / water (0.1% NH 3 ), 40° C., flow rate 0.8 ml / min in 1.4 min;

[0576] 17) Waters Acquity UPLC BEH C18 (1.7 μm, 30 x 2.1 mm) 1 to 99% acetonitrile (0.035% TFA) / water (0.05% TFA), 60° C., flow rate = 1.5 ml / min over 5 min;

[0577] 18) Waters BEH C18 (2.5 μm, 2.1 x 50 mm), 20 to 70% acetonitrile / water (0.1% NH 3 ), 40° C., flow rate: 0.8 mL / min over 4.60 min;

[0578] 19) Kinetex Polar C18 (2.6 μm, 3.0 x 50 mm) 5 to 95% acetonitrile / water (0.1% formic acid) at a flow rate of 1.2 ml / min over 3 minutes;

[0579] 20) Waters Acquity UPLC BEH C18 column (1.7 μm, 30×2.1 mm) 1 to 99% acetonitrile (0.035% TFA) / water (0.05% TFA), 60° C., flow rate = 1.5 mL / min in 1 min;

[0580] 21) YMC Triart C18 (3 μm, 33 x 2.1 mm) 2 to 98% acetonitrile / water (0.05% formic acid) at a flow rate of 1.0 mL / min over 3 minutes;

[0581] 22) Waters Acquity UPLC BEH C18 (1.7 μm, 30 x 2.1 mm) 1 to 99% acetonitrile (0.05% ammonium formate) / water (0.05% ammonium formate), 60° C., flow rate = 1.5 mL / min over 5 min;

[0582] 23) Waters CSH C18 (1.7 μm, 2.1 x 50 mm) 2 to 98% acetonitrile / water (0.1% TFA), 45°C, flow rate 0.6 ml / min in 4.0 min;

[0583] 24) Acquity BEH C8 (1.7 μm, 50 x 2.1 mm) 2 to 98% 90:10 acetonitrile:water (0.05% formic acid), flow rate 0.8 mL / min over 3 minutes;

[0584] 25) XBridge C18 (5 μm, 50 x 4.6 mm) 10 to 90% acetonitrile / water (10 mM NH4OAc), flow rate 1.2 ml / min over 6 min;

[0585] 26) YMC Triart C18 (3 μm, 33 x 2.1 mm) 5 to 95% acetonitrile / water (0.05% formic acid) at a flow rate of 1.0 mL / min over 12 minutes;

[0586] 27) Waters BEH C8 (1.7 μm, 2.1 x 50 mm), 50 to 95% acetonitrile / water (0.1% NH 3 ), 40° C., flow rate 0.8 ml / min in 1.4 min.

[0587] Example 1

[0588] Preparation 1

[0589] 4-Benzyloxy-2-chloro-5-iodo-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0590]

[0591] Step 1: Ethyl 2-hydroxy-5-iodo-6-methyl-4-oxo-1H-pyridine-3-carboxylate

[0592] 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 in portions over 10 minutes. After 30 minutes, the reaction solution was cooled to room temperature and a KHSO4 aqueous solution was added. The resulting solid was collected by suction filtration and washed with 1: 1 Et2O / acetonitrile to obtain 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, found value 323.84 (M+1) + .

[0593] Step 2: 2,4-Dichloro-5-iodo-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0594] By 2-hydroxy-5-iodo-6-methyl-4-oxo-1H-pyridine-3-carboxylic acid ethyl ester (1.434g, 4.217mmol) in POCl3(16.5g, 10mL, 107mmol) in suspension was heated at 120 DEG C for 2 hours, concentrated and azeotroped twice with toluene.The residue was neutralized with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (2x).The combined organic matter was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0-10% ethyl acetate / heptane) gave 2,4-dichloro-5-iodo-6-methyl-pyridine-3-carboxylic acid ethyl ester (1.15g, 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, found value 359.79 (M+1) + .

[0595] Step 3: 4-Benzyloxy-2-chloro-5-iodo-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0596] To a solution of benzyl alcohol (2.4 mL, 23 mmol) in THF (80 mL) and DMF (4 mL) was added sodium hydride (972 mg, 60% dispersion in mineral oil, 24.3 mmol) at 0 ° C., and the reaction mixture was stirred at room temperature for 30 minutes. 2,4-dichloro-5-iodo-6-methyl-pyridine-3-carboxylic acid ethyl ester (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 4-benzyloxy-2-chloro-5-iodo-6-methyl-pyridine-3-carboxylic acid ethyl ester (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, found value 432.0 (M+1) + .

[0597] Preparation 2

[0598] 4-Benzyloxy-6-chloro-3-iodo-2-methyl-pyridine

[0599]

[0600] Step 1: 4-Benzyloxy-6-chloro-pyridine-3-carboxylic acid

[0601] At 0 DEG C under argon, sodium hydride (50.0g, 60% dispersion in mineral oil, 1.25mol) is added in batches to a stirred solution of benzyl alcohol (140g, 135mL, 1.30mol) in THF (500mL). After 90 minutes at room temperature, the reaction is cooled to 10 DEG C, and a solution of 4,6-dichloropyridine-3-carboxylic acid (100g, 469mmol) in THF (500mL) is added within 30 minutes while keeping the reaction temperature below 30 DEG C. After addition, the reaction solution is stirred at room temperature for 4 hours, and then it is quenched by dropwise addition of water (1L) at 0 DEG C. The mixture is adjusted to pH 4 with 2N HCl aqueous solution and extracted with ethyl acetate (2 × 500mL). The combined organic extracts are concentrated and merged with toluene (500mL). The mixture was filtered, and the collected solid was washed sequentially with toluene (500 mL), then 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, found value 263.9 (M+1) + .

[0602] Step 2: tert-Butyl N-(4-benzyloxy-6-chloro-3-pyridyl)carbamate

[0603] DPPA (691g, 540mL, 2.51mol) is added to a stirred suspension of 4-benzyloxy-6-chloro-pyridine-3-carboxylic acid (568g, 2.05mol), TEA (598g, 823mL, 5.91mol) and tert-butyl alcohol (726g, 937mL, 9.80mol) in toluene (8.5L). The reaction solution is heated at 100 DEG C for 4 hours, then concentrated. The residue is distributed between ethyl acetate (7.5L) and saturated sodium bicarbonate solution (5L). Some insoluble materials are removed by filtration, and the organic phase is separated and concentrated to obtain tert-butyl N-(4-benzyloxy-6-chloro-3-pyridyl)carbamate (710g, 93%) as a tan solid. 1 HNMR (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, found value 335.02 (M+1) +.

[0604] Step 3: 4-Benzyloxy-6-chloro-pyridin-3-amine

[0605] To a suspension of tert-butyl N-(4-benzyloxy-6-chloro-3-pyridyl)carbamate (10.9g, 29.3mmol) in dichloromethane (25mL) is added trifluoroacetic acid (37g, 25mL, 325mmol). The resulting solution is stirred for 2.5 hours, then added in batches to a saturated aqueous sodium carbonate solution (200mL). The mixture is filtered, and the solid is washed with dichloromethane (50mL). The organic phase is separated, dried over sodium sulfate, and concentrated into a light brown solid. It is boiled in TBME (250mL) and then allowed to cool to room temperature. The mixture is filtered, and the filtrate is concentrated into a light brown solid. It is stirred with heptane (50mL), filtered, washed with heptane (50mL), and dried in air to obtain 4-benzyloxy-6-chloro-pyridine-3-amine (6g, 84%) as a light brown solid. 1 H 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, found value 233.0 (M-1) - .

[0606] Step 4: 4-Benzyloxy-2-bromo-6-chloro-pyridin-3-amine

[0607] At 15-20 DEG C, NBS (84.3g, 474mmol) is added in batches to a cooling solution of 4-benzyloxy-6-chloro-pyridine-3-amine (103.8g, 437.9mmol) in DCM (2L). The mixture is stirred at room temperature for 30 minutes, then the solution is washed with water (2×1L) and dried over sodium sulfate. The reaction is repeated twice, and all organics are combined and concentrated into a red solid. It is stirred for 1 hour in 1:4 ethyl acetate-heptane (1.5L), and the solid is filtered, washed with 1:4 ethyl acetate-heptane (500mL), then washed with heptane (500mL), and dried in air to obtain 4-benzyloxy-2-bromo-6-chloro-pyridine-3-amine (411.6g, 100%) as an orange solid. 1H 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, found value 312.8 (M+1) + .

[0608] Step 5: 4-Benzyloxy-6-chloro-2-methyl-pyridin-3-amine

[0609] By 4-benzyloxy-2-bromo-6-chloro-pyridine-3-amine (10.0g, 31.8mmol), trimethylboroxane (4.8g, 38mmol), potassium carbonate (8.80g, 63.7mmol) in 1,4-dioxane (100mL) and water (10mL) degassed with argon, then treated with Pd (PPh3) 4 (1.8g, 1.6mmol). The reaction mixture was heated under reflux for 7 hours, then cooled to room temperature and distributed between ethyl acetate (300mL) and water (100mL). The organic phase was dried over sodium sulfate and concentrated into a dark oil. Purified by silica gel chromatography (0-25% ethyl acetate / heptane), 4-benzyloxy-6-chloro-2-methyl-pyridine-3-amine (5g, 63%) was obtained 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, found value 248.97 (M+1) + .

[0610] Step 6: 4-Benzyloxy-6-chloro-3-iodo-2-methyl-pyridine

[0611] At 0-2 DEG C, to the cooling solution of 4-benzyloxy-6-chloro-2-methyl-pyridine-3-amine (25.0g, 94.8mmol) in 16% aqueous hydrochloric acid solution (250mL), a solution of sodium nitrite (9.80g, 142mmol) in water (40mL) is added dropwise. After stirring at 0-2 DEG C for 1 minute, the solution is added to a mixture of sodium iodide (71.1g, 474mmol), water (250mL) and dichloromethane (250mL) at 0 DEG C. After stirring at 0-2 DEG C for 10 minutes, the mixture is warmed to room temperature in 30 minutes. The organic phase is separated, dried over sodium sulfate and concentrated. Purified by silica gel chromatography (0-20% ethyl acetate / heptane), subsequently ground with heptane, 4-benzyloxy-6-chloro-3-iodo-2-methyl-pyridine (13.0g, 35%) is obtained. ESI-MS m / z calculated value 358.96, found value 359.95 (M+1) + . 1 H NMR (400MHz, CDCl3) δ7.47-7.34(m,5H),6.61(s,1H),5.23-5.19(m,2H),2.77-2.73(m,3H).

[0612] Preparation 3

[0613] 4-Benzyloxy-6-chloro-2-methyl-pyridine-3-carboxylic acid

[0614]

[0615] Step 1: 4-Benzyloxy-6-chloro-2-methyl-pyridine-3-carboxylic acid ethyl ester

[0616] A mixture of 4,6-dichloro-2-methyl-pyridine-3-formic acid ethyl ester (20.0g, 85.4mmol) and benzyl alcohol (10.0g, 92.5mmol) in DMF (200mL) is treated with potassium tert-butoxide (12.0g, 107mmol) and stirred at room temperature for 16 hours. The mixture is diluted with water (500mL) and extracted with ethyl acetate (2×400mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (5-8% ethyl acetate / hexane) gives 4-benzyloxy-6-chloro-2-methyl-pyridine-3-formic acid ethyl ester (12g, 26%). 1H 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, found value 306.14 (M+1) + .

[0617] Step 2: 4-Benzyloxy-6-chloro-2-methyl-pyridine-3-carboxylic acid

[0618] To a solution of 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carboxylic acid ethyl ester (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, then heated at 50 ° C for 2 hours. Another 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 1M HCl aqueous solution until pH 3-4. The precipitate was filtered and rinsed with water (50 mL). The solid was dried under high vacuum to obtain 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carboxylic acid (1 g, 104%) as a white solid. 1 H 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, found value 278.2 (M+1) + .

[0619] Intermediate A-1

[0620] 4-Benzyloxy-2-bromo-3,5,6-trimethyl-pyridine

[0621]

[0622] Step 1: 4-Hydroxy-3,5,6-trimethyl-1H-pyridin-2-one

[0623] 2-methylpropane dioic acid diethyl ester (21.90g, 125.7mmol) is dissolved in toluene (5mL), and adds the ethanolic solution of sodium ethoxide (40.7mL 21%w / v, 126mmol).Reaction solution was at room temperature stirred 1 hour.Add 3-amino-2-methyl-but-2-enoic acid ethyl ester (18.0g, 126mmol), and reaction solution is heated to reflux, continues 18 hours.Make condenser open other 6 hours to air under reflux.

[0624] The reaction solution was then cooled to room temperature, diluted with water (100 mL) and stirred for 1 hour. The mixture was distributed between water and toluene. The aqueous layer was washed with toluene (2 × 50 mL), and the aqueous layer pH was adjusted to pH 5. The resulting precipitate was filtered and dried under vacuum to obtain 4-hydroxy-3,5,6-trimethyl-1H-pyridin-2-one (3 g, 16%) as an off-white solid.

[0625] 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),9.11(s,1H),2.08(s,3H),1.85(s,3H),1.82(s,3H).

[0626] Step 2: 2,4-Dibromo-3,5,6-trimethyl-pyridine

[0627] 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, found value 279.9 (M+1) + .

[0628] Step 3: 4-Benzyloxy-2-bromo-3,5,6-trimethyl-pyridine

[0629] 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. 1H 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, found value 306.0 (M+1) + .

[0630] Intermediate A-2

[0631] 4-(Benzyloxy)-2-bromo-3-methoxy-6-methylpyridine

[0632]

[0633] Step 1: 2,4-Dibromo-3-methoxy-6-methylpyridine

[0634] In a 2L round-bottom flask immersed in a water bath, iodomethane (37.61g, 16.50mL, 265mmol) is slowly added to a stirred suspension of 2,4-dibromo-6-methylpyridine-3-ol (50g, 178.0mmol) and potassium carbonate (36.90g, 267mmol) in acetone (1.24L) via a syringe (no exotherm). The suspension was stirred at room temperature for the entire weekend. The reaction mixture was filtered, and the filter cake was washed with acetone. The brown filtrate was collected and concentrated in a vacuum at 40°C. The residue was distributed between MTBE (400mL) and water (400mL), and stirred at room temperature. The solid was filtered and rinsed with water (200mL) to give 2,4-dibromo-3-methoxy-6-methylpyridine (49.72g, 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, found value 279.8 (M+1) + .

[0635] Step 2: 4-(Benzyloxy)-2-bromo-3-methoxy-6-methylpyridine

[0636] 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 hour. 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 hour and then warmed to room temperature within 30 minutes. The mixture was stirred at room temperature for another 1 hour. The mixture was distributed 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 to 40% ethyl acetate / heptane) provided 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, found value 308.0 (M+1) + .

[0637] The following intermediate was prepared using a procedure similar to that found in intermediate A-2 using 2-iodopropane and 2-bromoethyl methyl ether in step 1.

[0638]

[0639] Intermediate A-5

[0640] 4-(Benzyloxy)-2-chloro-5-methoxy-6-methylnicotinate

[0641]

[0642] Step 1: 4-(Benzyloxy)-2-chloro-5-hydroxy-6-methylnicotinate

[0643] At -11 to -5 ° C, iPrMgCl solution (544mL, 2.0M solution in Et2O, 1.1mol) was added to a stirred solution of ethyl 4-(benzyloxy)-2-chloro-5-iodo-6-methylnicotinate (preparation 1, 414g, 906mmol) in Et2O (5L) within 40 minutes. The reaction mixture was stirred at -10 ° C for 10 minutes. At -10 ° C, trimethyl borate (188g, 1.81mol) was added within 10 minutes. The reaction solution was warmed to room temperature and stirred for 1 hour. The mixture was quenched by adding a mixture of ammonium chloride (2M, 1.5L) and brine (1.5L). 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 (395g, 94%) as a light yellow solid.

[0644] Crude boronic acid is suspended in acetonitrile (4L), and a solution of Oxone (418g, 680mmol) in water (2L) is added at 0°C. The reaction mixture is warmed to room temperature and stirred for 16 hours. Additional Oxone (60g, 98mmol) is added, and the reaction solution is stirred at room temperature for another 20 hours. The mixture is filtered, and the solid is rinsed with acetonitrile (2×250mL). The solid is distributed between brine (1L) and ethyl acetate (2L). The organic phase is separated, dried over sodium sulfate and concentrated in a vacuum. Heptane (3L) is added, and the mixture is concentrated to about 1.5kg weight, then cooled to room temperature and filtered. The solid is dissolved in MTBE (4L) and washed with 1M NaOH (2×1L). The combined aqueous extracts are acidified to pH 2 by adding 3N HCl and extracted with ethyl acetate (2×1L). The organic extracts are combined, dried over sodium sulfate, filtered and concentrated in a vacuum to about 750g. Add heptane (1.5L), and the mixture is concentrated to about 1.5kg, induced product crystallization. Add heptane (1.5L), and the mixture is concentrated to about 1.5kg. Solid is filtered, rinsed with heptane (200mL), and dried in a vacuum to obtain 4-(benzyloxy)-2-chloro-5-hydroxy-6-methylnicotinic acid ethyl ester (209g, 69%). 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 7.42-7.31 (m, 5H), 5.16 (s, 2H), 4.23 (q, J = 7.1 Hz, 2H), 2.38 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H). ESI-MS m / z calculated value 321.08, found value 322.1 (M+1) + .

[0645] Step 2: Ethyl 4-(benzyloxy)-2-chloro-5-methoxy-6-methylnicotinate

[0646] At room temperature, cesium carbonate (125g, 384mmol) and iodomethane (43g, 18.9mL, 303mmol) are added successively to a solution of 4-(benzyloxy)-2-chloro-5-hydroxy-6-methylnicotinate (83g, 255mmol) in acetonitrile (415mL). The reaction mixture is stirred for 1 hour, and then filtered. The filter cake is rinsed with acetonitrile (2×100mL), and the filtrate is concentrated in a vacuum. The residue is dissolved in DCM (100mL), filtered through a silica gel plug (75g), and rinsed with DCM (1.5L). The filtrate is concentrated in a vacuum to obtain 4-(benzyloxy)-2-chloro-5-methoxy-6-methylnicotinate (81.4g, 94%). 1 HNMR (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, found value 336.1 (M+1) + .

[0647] Intermediate A-6

[0648] 4-Benzyloxy-2-chloro-5-methoxy-6-methyl-pyridine-3-carboxylic acid methyl ester

[0649]

[0650] Step 1: 4-Benzyloxy-2-chloro-5-methoxy-6-methyl-pyridine-3-carboxylic acid

[0651] The chloro-5-methoxy-6-methyl-pyridine-3-formic acid ethyl ester (490mg, 1.39mmol) of 4-benzyloxy-2- is processed with the NaOH aqueous solution (3mL 1M, 3mmol) in methanol (5mL) and THF (3mL), and is stirred at 65 DEG C for 12 hours.Mixture is quenched with 1N HCl solution, diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution and salt water.The organic layer is dried over magnesium sulfate, filtered and concentrated under reduced pressure.Gained solid is ground in 1:2 dichloromethane / hexane, and filtered, to obtain 4-benzyloxy-2-chloro-5-methoxy-6-methyl-pyridine-3-formic acid. 1H NMR (400 MHz, DMSO-d6) δ 13.88 (brs, 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, found value 308.2 (M+1) + .

[0652] Step 2: 4-Benzyloxy-2-chloro-5-methoxy-6-methyl-pyridine-3-carbonyl chloride

[0653] 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 2M, 3 mmol) was added, followed by DMF (10 μL, 0.13 mmol). The resulting mixture was stirred at 0°C for 30 minutes and then concentrated to give 4-benzyloxy-2-chloro-5-methoxy-6-methyl-pyridine-3-carbonyl chloride. ESI-MS m / z calculated value 325.03, found value 326.2 (M+1) + .

[0654] Step 3: 4-Benzyloxy-2-chloro-5-methoxy-6-methyl-pyridine-3-carboxylic acid methyl ester

[0655] The 4-benzyloxy-2-chloro-5-methoxy-6-methyl-pyridine-3-carbonyl chloride from step 2 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 minutes, then diluted with dichloromethane, washed with saturated aqueous ammonium chloride solution, and then washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0-70% ethyl acetate / hexane in 20 minutes) gave 4-benzyloxy-2-chloro-5-methoxy-6-methyl-pyridine-3-carboxylic acid methyl ester (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, found value 322.256 (M+1) + .

[0656] Intermediate A-7

[0657] 6-Bromo-4-((4-methoxybenzyl)oxy)-2,5-dimethylnicotinonitrile

[0658]

[0659] Step 1: 4-Hydroxy-2,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonitrile

[0660] 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 minutes. 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 value 164.06, found value 165.2 (M + 1) + .

[0661] Step 2: 4,6-Dibromo-2,5-dimethylnicotinonitrile

[0662] 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 obtain the first batch of product (250 mg). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to obtain the second batch of product. The two batches were combined to obtain 4,6-dibromo-2,5-dimethylnicotinonitrile (1.54 g, 67%). ESI-MS m / z calculated value 287.89, experimental value 288.8 (M+1) + .

[0663] Step 3: 6-Bromo-4-((4-methoxybenzyl)oxy)-2,5-dimethylnicotinonitrile

[0664] 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 the solvent. ESI-MS m / z calcd 346.03, found 224.9 (M-PMB) + .

[0665] Intermediate A-8

[0666] 4-(Benzyloxy)-2-chloropyridine

[0667]

[0668] Cesium carbonate (1.89g, 5.80mmol) and benzyl bromide (700 μ L, 5.89mmol) are added successively to a solution of 2-chloropyridine-4-ol (500mg, 3.86mmol) in acetonitrile (8mL). The reaction mixture is stirred at room temperature for 1 hour. The mixture is diluted with ethyl acetate (15mL) and poured onto saturated sodium bicarbonate aqueous solution (20mL). The water layer is separated and extracted with ethyl acetate (2×20mL). The combined organic extracts are washed with brine (30mL), dried over magnesium sulfate, and concentrated in vacuo. Purified by silica gel chromatography (24g silica, 0-100% ethyl acetate / heptane) to obtain 4-(benzyloxy)-2-chloropyridine (601mg, 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, found value 220.3 (M+1) + ;218.1(M-1) - .

[0669] Intermediate A-9

[0670] 4-Benzyloxy-6-chloro-N,N-dimethyl-pyridin-2-amine

[0671]

[0672] Step 1: 4,6-Dichloro-N,N-dimethyl-pyridin-2-amine

[0673] 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. Iodomethane (732 mg, 5.16 mmol) was then added, and the mixture was stirred at room temperature overnight. The reaction mixture 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 obtain 4,6-dichloro-N, N-dimethyl-pyridin-2-amine (220 mg, 63%). ESI-MS m / z calculated value 190.01, experimental value 191.1 (M+1) + .1 H NMR (400MHz, CDCl3) δ6.55 (d, J = 1.3 Hz, 1H), 6.34 (d, J = 1.3 Hz, 1H), 3.07 (s, 6H).

[0674] Step 2: 4-Benzyloxy-6-chloro-N,N-dimethyl-pyridin-2-amine

[0675] 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 Calcd. 262.09, Found 263.3 (M+1) + . 1 H NMR (400MHz, CDCl3) δ7.41-7.32 (m, 5H), 6.26 (d, J = 1.7Hz, 1H), 5.89 (d, J = 1.8Hz, 1H), 5.05 (s, 2H), 3.03 (s, 6H).

[0676] Intermediate A-10

[0677] 4-Benzyloxy-2-chloro-N,N,6-trimethyl-pyridin-3-amine

[0678]

[0679] Step 1: 2,4-Dichloro-6-methyl-3-nitro-pyridine

[0680] 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 POCl (39.5 g, 24.5 mL, 252 mmol) was stirred at room temperature for 10 minutes and then stirred at 120 ° C for 12 hours. The mixture was cooled, diluted with ice-cold 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 obtain 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, found value 206.80 (M+1) + .

[0681] Step 2: 2,4-Dichloro-6-methyl-pyridin-3-amine

[0682] At 0 ° C, to a mixture of 2,4-dichloro-6-methyl-3-nitro-pyridine (3.0g, 13.9mmol) and iron (20g, 350mmol) in methanol (60mL) and water (15mL), ammonium chloride (743mg, 13.6mmol) was added 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 obtain 2,4-dichloro-6-methyl-pyridine-3-amine (2.2g, 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, found value 177.0 (M+1) + .

[0683] Step 3: 2,4-Dichloro-N,N,6-trimethyl-pyridin-3-amine

[0684] At 0 ° C, to a solution of 2,4-dichloro-6-methyl-pyridine-3-amine (1.02g, 5.76mmol) in THF (28mL), a THF solution of potassium tert-butoxide (17.3mL 1.0M, 17.3mmol) was added and the mixture was stirred for 30 minutes. Methyl iodide (4.1g, 1.8mL, 29mmol) was added dropwise, and the reaction solution was warmed to room temperature and stirred for 1 hour. The reaction solution was quenched with half-saturated brine (50mL), and the mixture was extracted with ethyl acetate (2×50mL). The combined extracts were washed with brine (50mL), dried over sodium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (5-20% ethyl acetate / heptane) gave 2,4-dichloro-N, N, 6-trimethyl-pyridine-3-amine (668mg, 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, found value 205.07 (M+1) + .

[0685] Step 4: 4-Benzyloxy-2-chloro-N,N,6-trimethyl-pyridin-3-amine

[0686] 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 analogous to that found in Preparation 1, Step 3. 1H 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, found value 276.95 (M+1) + .

[0687] Intermediate A-11

[0688] 4-Benzyloxy-6-chloro-5-(dimethylamino)-2-methyl-pyridine-3-carboxylic acid ethyl ester

[0689]

[0690] Step 1: 4,6-Dihydroxy-2-methyl-5-nitro-pyridine-3-carboxylic acid ethyl ester

[0691] At 0 ° C, nitric acid (4.2 g, 3.0 mL, 67 mmol) was added dropwise to a solution of 4,6-dihydroxy-2-methyl-pyridine-3-carboxylic acid ethyl ester (10.0 g, 48.9 mmol) in sulfuric acid (75 mL) 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), air-dried, to obtain 4,6-dihydroxy-2-methyl-5-nitro-pyridine-3-carboxylic acid ethyl ester (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, found value 243.2 (M+1) + .

[0692] Step 2: 4,6-Dichloro-2-methyl-5-nitro-pyridine-3-carboxylic acid ethyl ester

[0693] 4,6-Dichloro-2-methyl-5-nitro-pyridine-3-carboxylic acid ethyl ester was prepared from 4,6-dihydroxy-2-methyl-5-nitro-pyridine-3-carboxylic acid ethyl ester using a procedure analogous 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, found value 279.0 (M+1) + .

[0694] Step 3: 5-Amino-4,6-dichloro-2-methyl-pyridine-3-carboxylic acid ethyl ester

[0695] 5-Amino-4,6-dichloro-2-methyl-pyridine-3-carboxylic acid ethyl ester was prepared from 4,6-dichloro-2-methyl-5-nitro-pyridine-3-carboxylic acid ethyl ester using a procedure analogous 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, found value 249.2 (M+1) + .

[0696] Step 4: 4,6-Dichloro-5-(dimethylamino)-2-methyl-pyridine-3-carboxylic acid ethyl ester

[0697] To a solution of 5-amino-4,6-dichloro-2-methyl-pyridine-3-carboxylic acid ethyl ester (200 mg, 0.794 mmol) and sodium cyanoborohydride (300 mg, 4.77 mmol) in THF (4 mL) at 0°C was added a solution of formaldehyde in water (0.30 mL 37% w / w, 4.0 mmol), followed by dropwise addition of sulfuric acid (0.25 mL, 4.7 mmol) over 5 minutes. The mixture was allowed to warm to room temperature and stirred for 2.75 hours. A second portion of aqueous formaldehyde solution (0.30 mL 37% w / w, 4.0 mmol) and sodium cyanoborohydride (150 mg, 2.39 mmol) were added to the mixture, and the mixture was stirred at room temperature for 1 hour. Formalin (328mg, 0.30mL 37% w / w, 4.0mmol) and sodium cyanoborohydride (150mg, 2.39mmol) were added for the third time, and the mixture was stirred at room temperature for 2 hours. The mixture was distributed between water (50mL) and ethyl acetate (30mL), and the water layer was extracted with other ethyl acetate (2×30mL). The combined organic layer was washed with salt water (40mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (24g silica, 0-5% ethyl acetate / heptane) gave 4,6-dichloro-5-(dimethylamino)-2-methyl-pyridine-3-ethyl formate (178mg, 81%) as a light yellow oil. 1H 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, found value 277.2 (M+1) + .

[0698] Step 5: 4-Benzyloxy-6-chloro-5-(dimethylamino)-2-methyl-pyridine-3-carboxylic acid ethyl ester

[0699] 4-Benzyloxy-6-chloro-5-(dimethylamino)-2-methyl-pyridine-3-carboxylic acid ethyl ester was prepared from 4,6-dichloro-5-(dimethylamino)-2-methyl-pyridine-3-carboxylic acid ethyl ester and benzyl alcohol using a procedure analogous to that found in Preparation 1, Step 3. 1 HNMR (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, found value 349.1 (M+1) + .

[0700] Intermediate A-12

[0701] 4-Benzyloxy-2-chloro-6-vinyl-pyridine

[0702]

[0703] Step 1: 4-Benzyloxy-2,6-dichloro-pyridine

[0704] 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 hour and then filtered. Filter and concentrate in vacuo. Purification by silica gel chromatography (0-35% ethyl acetate / heptane) provided 4-benzyloxy-2,6-dichloro-pyridine (6.91 g, 85%) as a white solid. ESI-MS m / z calculated value 253.01, found value 254.0 (M+1) + . 1 H NMR (400MHz, CDCl3) δ7.48-7.33(m,5H),6.86(s,2H),5.11(s,2H).

[0705] Step 2: 4-Benzyloxy-2-chloro-6-vinyl-pyridine

[0706] To a solution of 4-benzyloxy-2,6-dichloropyridine (4.6 g, 18 mmol) in 1,4-dioxane (100 mL) and water (20 mL) was added potassium vinyl trifluoroborate (2.5 g, 19 mmol) and sodium carbonate (5.7 g, 54 mmol). The solution was bubbled with nitrogen, 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 distributed 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-vinylpyridine (2.55 g, 57%) as a clear oil. 1 H 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, found value 246.0 (M+1) + .

[0707] Following Suzuki coupling of 4-benzyloxy-2-chloro-6-vinylpyridine with Intermediate-B, the olefin can be reduced using standard hydrogenation conditions to afford the corresponding ethyl analog.

[0708] Intermediate A-13

[0709] (4-Benzyloxy-2-chloro-6-methyl-3-pyridyl)methanol

[0710]

[0711] 4-Benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylic acid ethyl ester (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 a THF solution of LAH (490 μL 1.0 M in THF, 0.49 mmol) was added, and the resulting solution was stirred at 0 ° C. for 4 hours and allowed to warm to room temperature. The resulting solution was diluted with ethyl acetate (20 mL), washed with saturated potassium sodium tartrate (Rochelle salt) solution 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 give (4-benzyloxy-2-chloro-6-methyl-3-pyridyl) methanol (126.3 mg, 98%) as a white solid. ESI-MS m / z calculated value 263.07, found value 164.12 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ7.49(d,J=7.0Hz,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).

[0712] Intermediate A-14

[0713] 4-Benzyloxy-2-chloro-3-(ethoxymethyl)-6-methyl-pyridine

[0714]

[0715] A stirred solution of (4-benzyloxy-2-chloro-6-methyl-3-pyridyl)methanol (188 mg, 0.713 mmol) in THF (3 mL) at 0°C was treated with sodium hydride (53.6 mg, 60% dispersion in mineral oil, 1.34 mmol) and 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 distributed between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with additional ethyl acetate (2x). The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (0-30% ethyl acetate / hexane) gave 4-benzyloxy-2-chloro-3-(ethoxymethyl)-6-methyl-pyridine (140.9 mg, 68%). 1H 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, found value 292.2 (M+1) + .

[0716] Intermediate A-15

[0717] 4-Benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylic acid ethyl ester

[0718]

[0719] Step 1: 2,4-Dichloro-5,6-dimethyl-pyridine-3-carboxylic acid ethyl ester

[0720] 4-Hydroxy-5,6-dimethyl-2-oxo-1H-pyridine-3-carboxylic acid ethyl ester (500mg, 2.37mmol) was dissolved in POCl3 (1.5mL, 16mmol), and the solution was heated at 105 ° C for 14 hours. After cooling to room temperature, the mixture was poured onto ice and stirred for 30 minutes. The residue was dissolved in ethyl acetate and carefully washed with saturated sodium bicarbonate solution (3×5mL), filtered and concentrated in vacuo. Purification by silica gel chromatography (0-30% ethyl acetate / hexane) gave 2,4-dichloro-5,6-dimethyl-pyridine-3-carboxylic acid ethyl ester (494mg, 83%) as a white solid. ESI-MS m / z calculated value 247.02, experimental value 248.1 (M+1) + .

[0721] Step 2: 4-Benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylic acid ethyl ester

[0722] 4-Benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylic acid ethyl ester was prepared from 2,4-dichloro-5,6-dimethyl-pyridine-3-carboxylic acid ethyl ester and benzyl alcohol using a procedure similar to that found in Preparation 1, Step 3. ESI-MS m / z calcd. 319.1, found 320.0 (M+1) + .

[0723] Intermediate A-16

[0724] 4-Benzyloxy-6-chloro-2,5-dimethyl-pyridine-3-carboxylic acid ethyl ester

[0725]

[0726] Step 1: 4,6-Dihydroxy-2,5-dimethyl-pyridine-3-carboxylic acid ethyl ester

[0727] A mixture of (Z)-3-aminobut-2-enoic acid ethyl ester (32.7 g, 32.0 mL, 253 mmol) and 2-methylpropane dioic 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 the mixture was cooled. The resulting solid was collected by filtration, washed with ethyl acetate (100 mL) and dried to give 4,6-dihydroxy-2,5-dimethyl-pyridine-3-carboxylic acid ethyl ester (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, found value 212.02 (M+1) + .

[0728] Step 2: 4,6-Dichloro-2,5-dimethyl-pyridine-3-carboxylic acid ethyl ester

[0729] A mixture of 4,6-dihydroxy-2,5-dimethyl-pyridine-3-carboxylic acid ethyl ester (20.15 g, 95.15 mmol) and tetramethylammonium chloride (11.5 g, 105 mmol) in POCl (146 g, 89 mL, 955 mmol) was heated under 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 × 200 mL). The combined extracts were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated to obtain 4,6-dichloro-2,5-dimethyl-pyridine-3-carboxylic acid ethyl ester (24.13 grams, 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, found value 247.91 (M+1) + .

[0730] Step 3: 4-Benzyloxy-6-chloro-2,5-dimethyl-pyridine-3-carboxylic acid ethyl ester

[0731] 4-Benzyloxy-6-chloro-2,5-dimethyl-pyridine-3-carboxylic acid ethyl ester was prepared from 4,6-dichloro-2,5-dimethyl-pyridine-3-carboxylic acid ethyl ester and benzyl alcohol using a procedure analogous 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, found value 320.01 (M+1) + .

[0732] Intermediate A-17

[0733] [6-Chloro-4-[(4-methoxyphenyl)methoxy]-2-methyl-3-pyridyl]methanol

[0734]

[0735] To a stirred solution of 6-chloro-4-[(4-methoxyphenyl)methoxy]-2-methyl-pyridine-3-carboxylic acid ethyl ester (Intermediate A-39, 375 mg, 1.12 mmol) in THF (5 mL) was added LAH (0.8 mL 2.0 M in THF, 1.6 mmol) in portions at 0°C. The mixture was stirred at 0°C for 30 minutes and then at room temperature for 4 hours. The mixture was cooled to 0°C and quenched with saturated sodium sulfate solution by Filter and extract 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-pyridinyl]methanol (350 mg, 107%). ESI-MS m / z calculated value 293.08, found value 294.0 (M+1) + .

[0736] Intermediate A-18

[0737] 1-[6-chloro-4-[(4-methoxyphenyl)methoxy]-2-methyl-3-pyridyl]ethanone

[0738]

[0739] At -5 ° C, to a solution of 6-chloro-4-[(4-methoxyphenyl)methoxy]-2-methyl-pyridine-3-carboxylic acid ethyl ester (100 mg, 0.294 mmol) in THF (2 mL) was slowly added methylmagnesium bromide solution (0.25 mL 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 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 (400MHz, CDCl3) δ7.27 (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).

[0740] Intermediate A-19

[0741] 4-Benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylic acid benzyl ester

[0742]

[0743] Step 1: 4-Benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylic acid

[0744] By 4-benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylic acid ethyl ester (intermediate A-15, 400mg, 1.23mmol) in methanol (6mL) and THF (4mL) solution with NaOH aqueous solution (7mL1M, 7mmol) treatment, and stirred at 65 DEG C overnight.The mixture is quenched with 1N HCl aqueous solution, diluted with ethyl acetate, and washed with saturated ammonium chloride aqueous solution and brine.The organic layer is dried over magnesium sulfate, filtered and concentrated under reduced pressure.The solid is ground in dichloromethane / hexane (2: 1), then filtered, to obtain 4-benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylic acid (318mg, 89%). 1H 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, found value 292.2 (M+1) + .

[0745] Step 2: 4-Benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylic acid benzyl ester

[0746] 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 hours. The mixture was quenched with 1N HCl solution, diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution 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 / hexane in 20 minutes) gave 4-benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylic acid benzyl ester (64.1 mg, 77%) as a clear thick oil, which crystallized after standing. 1 H 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, found value 382.36 (M+1) + .

[0747] Intermediate A-20

[0748] 4-Benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylic acid isopropyl ester

[0749]

[0750] 4-Benzyloxy-2-chloro-5,6-dimethyl-pyridine-3-carboxylic acid isopropyl ester 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. 1H NMR (400 MHz, DMSO-d6) δ 7.47-7.33 (m, 5H), 5.16 (heptane, 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, found value 334.645 (M+1) + .

[0751] Intermediate A-21

[0752] 4-Benzyloxy-2-chloro-5-cyano-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0753]

[0754] Step 1: 2,4-Dichloro-5-cyano-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0755] A mixture of 2,4-dichloro-5-iodo-6-methyl-pyridine-3-carboxylic acid ethyl ester (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 hours. 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 / hexane) gave 2,4-dichloro-5-cyano-6-methyl-pyridine-3-carboxylic acid ethyl ester (49 mg, 68%). ESI-MS m / z calculated value 258.0, experimental value 259.1 (M + 1) + . 1 H NMR (400MHz, DMSO-d6) δ4.46 (q, J = 7.1Hz, 2H), 2.71 (s, 3H), 1.34 (t, J = 7.1Hz, 3H). 13 C NMR (101MHz, DMSO-d6) δ165.17,162.35,149.23,144.89,127.34,114.01,110.57,63.79,24.26,14.24.

[0756] Step 2: 4-Benzyloxy-2-chloro-5-cyano-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0757] 4-Benzyloxy-2-chloro-5-cyano-6-methyl-pyridine-3-carboxylic acid ethyl ester was prepared from 2,4-dichloro-5-cyano-6-methyl-pyridine-3-carboxylic acid ethyl ester and benzyl alcohol using a procedure similar to that found in Preparation 1, Step 3. ESI-MS m / z calcd. 330.08, found 331.2 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ7.51-7.37 (m, 5H), 5.47 (s, 2H), 4.33 (d, J = 7.2Hz, 2H), 3.29 (s, 3H), 1.22 (t, J = 7.1Hz, 3H).

[0758] Intermediate A-22

[0759] 4-Benzyloxy-2-chloro-5-ethynyl-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0760]

[0761] Step 1: 4-Benzyloxy-2-chloro-6-methyl-5-(2-trimethylsilylethynyl)pyridine-3-carboxylic acid ethyl ester

[0762] 4-Benzyloxy-2-chloro-5-iodo-6-methyl-pyridine-3-carboxylic acid ethyl ester (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-carboxylic acid ethyl ester was obtained by purification by silica gel chromatography (0-40% ethyl acetate / hexane in 15 minutes). ESI-MS m / z calculated value 401.12, experimental value 402.5 (M+1) + .

[0763] Step 2: 4-Benzyloxy-2-chloro-5-ethynyl-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0764] The 4-benzyloxy-2-chloro-6-methyl-5-(2-trimethylsilylethynyl)pyridine-3-carboxylic acid ethyl ester from step 1 was dissolved in methanol (2 mL) and potassium carbonate (33.5 mg, 0.242 mmol) was added. 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 (0-30% ethyl acetate / heptane over 15 minutes) gave 4-benzyloxy-2-chloro-5-ethynyl-6-methyl-pyridine-3-carboxylic acid ethyl ester (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, found value 330.3 (M+1) + .

[0765] Intermediate A-23

[0766] 4-(Benzyloxy)-6-chloro-2-methyl-3-(methylthio)pyridine

[0767]

[0768] Step 1: 4-Chloro-3-iodo-2-methylpyridine 1-oxide

[0769] At 0 ° C, mCPBA solution (23.4g, 70-75% w / w in water, 101.7mmol) was added in batches to a solution of 4-chloro-3-iodo-2-methylpyridine (17.2g, 67.9mmol) in DCM (250mL). The reaction mixture was warmed to room temperature and stirred overnight. The mixture was diluted with DCM (250mL) and washed with water (250mL). The aqueous layer was separated and extracted with DCM (200mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was ground in methanol (2 × 30mL), filtered and dried to give 4-chloro-3-iodo-2-methylpyridine 1-oxide (15g, 82%) as a white solid. 1 H 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, found value 269.78 (M+1) + .

[0770] Step 2: 4,6-Dichloro-3-iodo-2-methylpyridine

[0771] 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 hours. The reaction mixture was cooled to room temperature 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 (2×20 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 value 286.88, experimental value 287.73 (M+1) + .

[0772] Step 3: 4,6-Dichloro-2-methyl-3-(methylthio)pyridine

[0773] A mixture of 4,6-dichloro-3-iodo-2-methylpyridine (212 mg, 0.710 mmol), sodium thiomethoxide (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 for 1 hour under microwave irradiation. The mixture was distributed 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, found value 207.94 (M+1) + .

[0774] Step 4: 4-(Benzyloxy)-6-chloro-2-methyl-3-(methylthio)pyridine

[0775] 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 analogous to that found in step 3 of Preparation 1 and NMP as solvent. 1H 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, found value 280.4 (M+1) + .

[0776] Intermediate A-24

[0777] (4-Benzyloxy-6-chloro-2-methyl-3-pyridyl)-imino-methyl-oxo-λ6-sulfane

[0778]

[0779] 4- (benzyloxy) -6- chloro- 2- methyl -3- (methylthio) pyridine (2.0g, 7.2mmol) is dissolved in DCM (20mL) and methanol (20mL), and the solution is cooled to 0 DEG C. Ammonium carbamate (837mg, 10.7mmol) and (diacetoxy iodine) benzene (4.61g, 14.3mmol) are added, and the mixture is warmed to room temperature and stirred for 2 hours. Additional (diacetoxy iodine) benzene (1.15g, 3.57mmol) and ammonium carbamate (223mg, 2.86mmol) are added, and the resulting mixture is stirred at room temperature for 1.5 hours. The reaction mixture is concentrated in a vacuum and purified by silica gel column chromatography (0-100% ethyl acetate / heptane), to obtain (4- benzyloxy -6- chloro- 2- methyl -3- pyridyl) -imino- methyl -oxo -λ 6- sulfane (1.314g, 59%) as a white solid. ESI-MS m / z calculated value 310.05, found value 311.2 (M+1) + . 1 H NMR(500MHz,DMSO-d6)δ7.56-7.54(m,2H),7.45-7.40(m,2H),7.39-7.35(m, 2H), 5.39 (d, J = 2.0Hz, 2H), 4.59 (s, 1H), 3.17 (d, J = 1.2Hz, 3H), 2.74 (s, 3H).

[0780] The enantiomers were separated by chiral SFC at 40°C using a Nexera UC Prep (Shimadzu) using a ChiralPak IC (250 x 20 mm), 5 μm, (Daicel Corp.) column. 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. Detection was at 215 nm. The retention time of peak 1 was 4.380 minutes, and the retention time of peak 2 was 5.468 minutes.

[0781] Peak 1: (4-Benzyloxy-6-chloro-2-methyl-3-pyridyl)-imino-methyl-oxo-λ6-sulfane (561 mg, 51%), ESI-MS m / z calculated value 310.05, found value 311.1 (M+1) + ; Retention time: 2.19 minutes, 98.1% ee.

[0782] Peak 2: (4-Benzyloxy-6-chloro-2-methyl-3-pyridyl)-imino-methyl-oxo-λ6-sulfane (523 mg, 47%), ESI-MS m / z calculated value 310.05, found value 311.1 (M+1) + ; Retention time: 2.19 minutes, 91.1% ee.

[0783] Intermediate A-25

[0784] 4,5-Dibenzyloxy-2-chloro-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0785]

[0786] Step 1: (4-Benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridinyl)boronic acid

[0787] Step 1: (4-Benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridinyl)boronic acid

[0788] 4-Benzyloxy-2-chloro-5-iodo-6-methyl-pyridine-3-carboxylic acid ethyl ester (preparation 1, 236 mg, 0.547 mmol) was dissolved in Et2O (5 mL). The resulting mixture was cooled to -78 ° C. Then n-BuLi (250 μL 2.5M, 0.63 mmol) was added dropwise over 5 minutes, and the resulting mixture was stirred at -78 ° C for 15 minutes. (MeO) 3B (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 solution was quenched with saturated aqueous ammonium chloride solution, diluted with ethyl acetate, and washed with salt water. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a mixture of (4-benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridinyl)boronic acid, ESI-MS m / z calculated value 349.09, found value 350.2 (M+1) + ; and 4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylic acid ethyl ester, ESI-MS m / z calculated value 305.08, found value 306.2 (M+1) + .

[0789] Step 2: 4-Benzyloxy-2-chloro-5-hydroxy-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0790] The (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), cooled to 0°C, and then HO (200 μL 35% w / w, 2.34 mmol) was added dropwise, followed by aqueous NaOH (150 μL 1 M, 0.15 mmol). The mixture was stirred at room temperature for 4 hours, then cooled to 0°C and quenched with saturated aqueous sodium thiosulfate solution (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 minutes) provided a 3:2 mixture of 4-benzyloxy-2-chloro-5-hydroxy-6-methyl-pyridine-3-carboxylic acid ethyl ester, ESI-MS m / z calcd 321.08, found 322.256 (M+1) + ; and 4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylic acid ethyl ester, ESI-MS m / z calculated value 305.08, found value 306.2 (M+1) + .

[0791] Step 3: 4,5-Dibenzyloxy-2-chloro-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0792] The mixture obtained from step 2 was dissolved in DMF (2mL) and cooled to 0 ° C. Benzyl bromide (30 μL, 0.25mmol) and cesium carbonate (89mg, 0.27mmol) were added, and the mixture was stirred for 30 minutes. The mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification was carried out by silica gel chromatography (0-30% ethyl acetate / hexane in 15 minutes) to obtain 4,5-dibenzyloxy-2-chloro-6-methyl-pyridine-3-ethyl formate (74.6mg, 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, found value 412.4 (M+1) + .

[0793] Intermediate A-26

[0794] 2-(4-Benzyloxy-6-chloro-2-methyl-3-pyridyl)acetamide

[0795]

[0796] Step 1: 4-Benzyloxy-6-chloro-3-[(E)-2-ethoxyvinyl]-2-methyl-pyridine

[0797] By 4-benzyloxy-6-chloro-3-iodo-2-methyl-pyridine (314mg, 0.87mmol) (preparation 2, step 2), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (173mg, 0.87mmol), PdCl2(dtbpf) (66mg, 0.1mmol), potassium phosphate (550mg, 2.6mmol) in 1,4-dioxane (3mL) and water (1mL) degassing, continue for 5 minutes, and under nitrogen at 110 DEG C in a sealed vial for 20 hours. The mixture is cooled and diluted with ethyl acetate. The organic layer is washed with saturated aqueous ammonium chloride solution 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 value 303.10, found value 304.3 (M+1) + . 1H NMR (400MHz, CDCl3) δ7.46-7.32(m,5H),7.13(d,J=12.7Hz,1H),6.76(s,1H),5.73(d, J=12.7Hz,1H),5.11(s,2H),3.81(q,J=7.0Hz,2H),2.51(s,3H),1.26(t,J=7.0Hz,3H). 1 H NMR (400MHz, CD3OD) δ7.54-7.32(m,5H),7.16(d,J=12.7Hz,1H),7.02(s,1H),5.70(d, J=12.7Hz,1H),5.20(s,2H),3.80(q,J=7.0Hz,2H),2.44(s,3H),1.21(t,J=7.1Hz,3H).

[0798] Step 2: 2-(4-Benzyloxy-6-chloro-2-methyl-3-pyridyl)acetaldehyde

[0799] 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 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 saturated aqueous 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.

[0800] Step 3: 2-(4-Benzyloxy-6-chloro-2-methyl-3-pyridyl)acetic acid

[0801] 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 hour. The mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution 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 value 291.07, found value 292.3 (M+1) + . 1H NMR (400MHz, DMSO-d6) δ12.45(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).

[0802] Step 4: 2-(4-Benzyloxy-6-chloro-2-methyl-3-pyridyl)acetamide

[0803] 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 (150 μL 7M, 1.0 mmol) in methanol and stirred for 30 minutes. The mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution 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 value 290.08, found value 291.3 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ7.50-7.28(m,6H),7.05(s,1H),6.94(br s,1H),5.23(s,2H),3.47(s,2H),2.34(s,3H).

[0804] Intermediate A-27

[0805] 4-Benzyloxy-2-chloro-6-methyl-pyridine-3,5-dicarboxylic acid diethyl ester

[0806]

[0807] 4-benzyloxy-2-chloro-5-iodo-6-methyl-pyridine-3-ethyl formate (preparation 1,265mg, 0.6139mmol) is dissolved in Et o (6mL). The resulting mixture is cooled to -78 ℃ and placed under a nitrogen atmosphere. n-BuLi (300 μ L 2.5M, 0.75mmol) is added dropwise over 5 minutes, and the resulting mixture is stirred at -78 ℃ for 15 minutes. Ethyl chloroformate (200 μ L, 2.09mmol) is added dropwise, and the mixture is stirred at -78 ℃ for 60 minutes. After 60 minutes, the reaction solution is placed in 0 ℃ of baths, and quenched with saturated aqueous ammonium chloride solution (5mL). The mixture is diluted with ethyl acetate and washed with salt water. The organic layer is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0-40% ethyl acetate / hexanes over 20 minutes) provided 4-benzyloxy-2-chloro-6-methyl-pyridine-3,5-dicarboxylic acid diethyl ester (145 mg, 63%). 1 HNMR (400 MHz, DMSO-d6) δ 7.46-7.31 (m, 5H), 5.10 (s, 2H), 4.34 (q, J = 7.1 Hz, 2H) overlapped 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 value 377.10, found value 378.4 (M+1) + .

[0808] Intermediate A-28

[0809] 4-Benzyloxy-2-chloro-6-methyl-5-oxalamido-pyridine-3-carboxylic acid ethyl ester

[0810]

[0811] Step 1: 4-Benzyloxy-2-chloro-5-(2-ethoxy-2-oxo-acetyl)-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0812] 4-benzyloxy-2-chloro-5-iodo-6-methyl-pyridine-3-ethyl formate (preparation 1,408mg, 0.945mmol) is dissolved in Et o (7mL). The resulting mixture is cooled to -78 ℃. In 5 minutes, n-BuLi (500 μ L 2.5M, 1.3mmol) is added dropwise, and the resulting mixture is stirred at -78 ℃ for 25 minutes. 2-chloro-2-oxo-ethyl acetate (340 μ L, 3.04mmol) is added dropwise, and the resulting mixture is stirred at -78 ℃ for 30 minutes. After 30 minutes, the reaction solution is placed in 0 ℃ of baths, and quenched with saturated aqueous ammonium chloride solution (5mL). The mixture is diluted with ethyl acetate, and then washed with salt water. The organic layer is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. Purification by silica gel chromatography (0-40% ethyl acetate / hexanes over 20 minutes) provided 4-benzyloxy-2-chloro-5-(2-ethoxy-2-oxo-acetyl)-6-methyl-pyridine-3-carboxylic acid ethyl ester (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, found value 406.4 (M+1) + .

[0813] Step 2: 4-Benzyloxy-2-chloro-6-methyl-5-oxalamido-pyridine-3-carboxylic acid ethyl ester

[0814] A solution of 4-benzyloxy-2-chloro-5-(2-ethoxy-2-oxo-acetyl)-6-methyl-pyridine-3-carboxylic acid ethyl ester (200 mg, 0.468 mmol) in ethanol (1 mL) at 0° C. was treated dropwise with ammonia in methanol (550 μL 2.0 M, 1.1 mmol) and then stirred at room temperature for 3 hours. The solvent was removed in vacuo to give 4-benzyloxy-2-chloro-6-methyl-5-oxalamido-pyridine-3-carboxylic acid ethyl ester (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, found value 377.4 (M+1) + .

[0815] Intermediate A-29

[0816] 5-(2-Amino-1-hydroxy-2-oxo-ethyl)-4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0817]

[0818] By 4-benzyloxy-2-chloro-6-methyl-5-oxalyl-pyridine-3-carboxylic acid ethyl ester (135mg, 0.340mmol) at 0 DEG C in ethanol (1mL) and THF (1mL) solution with sodium borohydride (14mg, 0.37mmol), and stirred at room temperature for 10 minutes.The mixture is quenched with saturated aqueous ammonium chloride solution (5mL), diluted with ethyl acetate, and then washed with brine.The organic layer is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain 5-(2-amino-1-hydroxy-2-oxo-ethyl)-4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylic acid ethyl ester (128mg, 99%). 1 H 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) overlapped with DMSO, 1.25 (t, J = 7.1 Hz, 3H). ESI-MS m / z calcd 378.10, found 379.3 (M+1) + .

[0819] Intermediate A-30

[0820] 5-(2-Amino-1-methoxy-2-oxo-ethyl)-4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0821]

[0822] Step 1: 4-Benzyloxy-2-chloro-5-(2-methoxy-2-oxo-acetyl)-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0823] 4-benzyloxy-2-chloro-5-iodo-6-methyl-pyridine-3-ethyl formate (preparation 1,539mg, 1.25mmol) is dissolved in Et o (8mL).The resulting mixture is cooled to -78 ℃.In 5 minutes, n-BuLi (650 μ L 2.5M, 1.63mmol) is added dropwise, and the resulting mixture is stirred at -78 ℃ for 25 minutes.Then 2-chloro-2-oxo-methyl acetate (350 μ L, 3.80mmol) is added dropwise, and the resulting mixture is stirred at -78 ℃ for 30 minutes. After 30 minutes, the reaction solution is placed in 0 ℃ of baths, and quenched with saturated ammonium chloride aqueous solution (5mL), diluted with ethyl acetate, and then washed with salt water.The organic layer is dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. Purification by silica gel chromatography (0-40% ethyl acetate / hexanes over 20 minutes) provided 4-benzyloxy-2-chloro-5-(2-methoxy-2-oxo-acetyl)-6-methyl-pyridine-3-carboxylic acid ethyl ester (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, found value 392.3 (M+1) + .

[0824] Step 2: 4-Benzyloxy-2-chloro-5-(2-ethoxy-1-hydroxy-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylic acid ethyl ester and 4-Benzyloxy-2-chloro-5-(1-hydroxy-2-methoxy-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0825] 4-Benzyloxy-2-chloro-5-(2-methoxy-2-oxo-acetyl)-6-methyl-pyridine-3-carboxylic acid ethyl ester (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 solution (5 mL), diluted with ethyl acetate, and then washed with brine. The organic layer was dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to give a mixture of the following two: the main ethyl ester transesterification product 4-benzyloxy-2-chloro-5-(2-ethoxy-1-hydroxy-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylic acid ethyl ester, ESI-MS m / z calculated value 407.11, experimental value 408.55 (M+1) + and the minor methyl ester product 4-benzyloxy-2-chloro-5-(1-hydroxy-2-methoxy-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylic acid ethyl ester, ESI-MS m / z calculated value 393.10, experimental value 394.46 (M+1) + .

[0826] 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 minutes. Iodomethane (150 μL, 2.41 mmol) was then added, and the reaction solution was gradually warmed to room temperature and stirred for 30 minutes. The mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, and then washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a mixture of the following two: the main product 4-benzyloxy-2-chloro-5-(2-ethoxy-1-methoxy-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylic acid ethyl ester, ESI-MS m / z calculated value 421.13, experimental value 422.58 (M + 1) + ; and the minor product 4-benzyloxy-2-chloro-5-(1,2-dimethoxy-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylic acid ethyl ester, ESI-MS m / z calculated value 407.11, experimental value 408.38 (M+1) + .

[0827] Step 4: 2-(4-Benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridinyl)-2-methoxy-acetic acid

[0828] To be dissolved in ethanol (5mL) from the mixture of step 3, and with the NaOH aqueous solution (1.5mL 1M, 1.5mmol) process, and under nitrogen, stirred 40 minutes at 25 ℃.Mixture is acidified to pH<5 with the 1M HCl aqueous solution, and dilute with ethyl acetate.With saturated aqueous ammonium chloride solution and salt water washing for organic phase.With organic layer dried over magnesium sulfate, filter, and under reduced pressure concentrate, to obtain 2-(4-benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridyl)-2-methoxy-acetic acid (250mg, 77%). 1 H 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) overlapping 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) overlapping with HOH, 2.51 (s, 3H) overlapping with DMSO, 1.24 (t, J = 7.1 Hz, 3H). ESI-MS m / z calcd 393.10, found 394.18 (M+1) + .

[0829] Step 5: 5-(2-Amino-1-methoxy-2-oxo-ethyl)-4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0830] 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 NH3 (200 μL 7M, 1.4 mmol) in methanol and stirred for 20 minutes. The mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution and 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 / heptane in 25 minutes) gave 5-(2-amino-1-methoxy-2-oxo-ethyl)-4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylic acid ethyl ester (187 mg, 81%). 1H 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, found value 393.4 (M+1) + .

[0831] Intermediate A-31

[0832] 2-(4-Benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridyl)acetic acid

[0833]

[0834] Step 1: 4-Benzyloxy-2-chloro-5-[(Z)-2-ethoxyvinyl]-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0835] By 4-benzyloxy-2-chloro-5-iodo-6-methyl-pyridine-3-carboxylic acid ethyl ester (preparation 1,573mg, 1.327mmol), tributyl-[(Z)-2-ethoxyvinyl] stannane (593mg, 1.642mmol) and PdCl2(PPh3)2(182mg, 0.260mmol) in toluene (5mL) degassing, continue 5 minutes, and be placed under nitrogen atmosphere. The tube is sealed and stirred at 110 ℃ for 20 hours. The mixture is diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution and brine. The organic layer is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. Purification by silica gel chromatography (0-50% ethyl acetate / heptane in 15 minutes) gives 4-benzyloxy-2-chloro-5-[(Z)-2-ethoxyvinyl]-6-methyl-pyridine-3-carboxylic acid ethyl ester (235mg, 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 calcd 375.12, found 376.1 (M+1) + .

[0836] Step 2: Ethyl 4-benzyloxy-2-chloro-6-methyl-5-(2-oxoethyl)pyridine-3-carboxylate

[0837] To a solution of 4-benzyloxy-2-chloro-5-[(Z)-2-ethoxyvinyl]-6-methyl-pyridine-3-carboxylic acid ethyl ester from step 1 in acetone (4 mL) was added aqueous HCl (2.5 mL 1 M, 2.500 mmol) and the mixture was stirred at 50° C. for 3 hours. The mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution and brine. The organic layer was dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to give 4-benzyloxy-2-chloro-6-methyl-5-(2-oxoethyl)pyridine-3-carboxylic acid ethyl ester, which was used directly in step 3.

[0838] Step 3: 2-(4-Benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridyl)acetic acid

[0839] The crude product 4-benzyloxy-2-chloro-6-methyl-5-(2-oxoethyl) pyridine-3-carboxylic acid ethyl ester from step 2 is treated with OXONE (813mg, 1.32mmol) in DMF (3mL) and stirred at room temperature for 1 hour. The mixture is diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution and salt water. The organic layer is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. Purification by silica gel chromatography (0-50% ethyl acetate / heptane in 20 minutes) gave 2-(4-benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridyl) acetic acid (285mg, 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, found value 364.4 (M+1) + .

[0840] Intermediate A-32

[0841] 4-Benzyloxy-2-chloro-5-(2-methoxy-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0842]

[0843] 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) at 0 ° C was treated with oxalyl chloride (600 μL 2M in DCM, 1.2 mmol) and subsequently treated with DMF (6 μL, 0.08 mmol). The resulting mixture was stirred at 0 ° C for 30 minutes, then slowly treated with DIPEA (150 μL, 0.861 mmol) and subsequently treated with 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 solution 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) provided 4-benzyloxy-2-chloro-5-(2-methoxy-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylic acid ethyl ester (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, found value 379.3 (M+1) + .

[0844] Intermediate A-33

[0845] 4-Benzyloxy-2-chloro-5-(2-methoxy-1-methyl-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0846]

[0847] A solution of 4-benzyloxy-2-chloro-5-(2-methoxy-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylic acid ethyl ester (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 minutes. MeI (150 μL, 2.41 mmol) was added, and the reaction solution was gradually warmed to room temperature and stirred for 30 minutes. The mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 4-benzyloxy-2-chloro-5-(2-methoxy-1-methyl-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylic acid ethyl ester. ESI-MS m / z calculated value 391.12, experimental value 392.53 (M + 1) + .

[0848] Intermediate A-34

[0849] 5-(2-Amino-1-methyl-2-oxo-ethyl)-4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0850]

[0851] Step 1: 2-(4-Benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridyl)propanoic acid

[0852] A solution of 4-benzyloxy-2-chloro-5-(2-methoxy-1-methyl-2-oxo-ethyl)-6-methyl-pyridine-3-carboxylic acid ethyl ester (210 mg, 0.536 mmol) in ethanol (6 mL) was treated with an aqueous NaOH solution (1 mL 1M, 1.0 mmol) and stirred at 45 ° C under a nitrogen atmosphere for 6 hours. The mixture was acidified to pH <5 with a 1M aqueous HCl solution and diluted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution 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) propionic acid. ESI-MS m / z calculated value 377.10, found value 378.4 (M+1) + .

[0853] Step 2: 5-(2-Amino-1-methyl-2-oxo-ethyl)-4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0854] A solution of 2-(4-benzyloxy-6-chloro-5-ethoxycarbonyl-2-methyl-3-pyridinyl)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 NH3 in methanol (150 μL 7M, 1.1 mmol) and 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 (0-100% ethyl acetate / heptane over 25 minutes) gave 5-(2-amino-1-methyl-2-oxo-ethyl)-4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylic acid ethyl ester (214 mg, 99%). 1H 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) overlapped with 1.25 (t, J = 7.1 Hz, 3H). ESI-MS m / z calcd 376.12, found 377.23 (M+1) + .

[0855] Intermediate A-35

[0856] 2-(4-Benzyloxy-6-chloro-2-methyl-3-pyridyl)-N-methyl-acetamide

[0857] Step 1: 2-(4-Benzyloxy-6-chloro-2-methyl-3-pyridinyl)-N-methyl-acetamide

[0858]

[0859] 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), followed by the addition of HATU (110 mg, 0.29 mmol), DIPEA (65 μL, 0.37 mmol), and MeNH2 in ethanol (120 μL 33% w / v, 1.28 mmol), and the resulting mixture was stirred for 30 minutes. The resulting mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride, 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 (0-100% ethyl acetate / hexanes) provided 2-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-N-methyl-acetamide (70.1 mg, 92%). ESI-MS m / z calculated value 304.1, found value 305.3 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ7.79(q,J=4.8Hz,1H),7.45-7.29(m,5H),7.06(s,1H),5.22(s,2H),3.46(s,2H),2.56(d,J=4.6Hz,3H),2.34(s,3H).

[0860] Intermediate A-36

[0861] 4-Benzyloxy-2-chloro-6-methyl-3-methylsulfanyl-pyridine

[0862]

[0863] Step 1: 2,4-Dichloro-3-iodo-6-methyl-pyridine

[0864] 2,4-dichloro-6-methyl-pyridine-3-amine (250mg, 1.41mmol) and p-TsOH hydrate (806mg, 4.24mmol) are suspended in acetonitrile (5.6mL) and cooled to 0 DEG C. In a separate flask, sodium nitrite (195mg, 2.83mmol) and potassium iodide (586mg, 3.53mmol) are dissolved in water (0.84mL). At 0 DEG C, NaNO2 aqueous solution / KI mixture is added dropwise to amine / p-TsOH mixture. The resulting mixture is warmed to room temperature and stirred for 2 hours. The mixture is poured over water (20mL) and diluted with TBME (20mL). The organic layer is separated, and the water layer is extracted with TBME (2×10mL). The combined organic extracts are washed with salt water (20mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (24 g silica, 0-20% ethyl acetate / heptane) provided 2,4-dichloro-3-iodo-6-methyl-pyridine (223 mg, 55%) as a light yellow oil. ESI-MS m / z calculated 286.88, found 288.2 (M+1) + . 1 HNMR (400MHz, CDCl3) δ7.16 (d, J=0.6Hz, 1H), 1.56 (s, 3H).

[0865] Step 2: 2,4-Dichloro-6-methyl-3-methylsulfanyl-pyridine

[0866] 2,4-dichloro-3-iodo-6-methyl-pyridine (200mg, 0.695mmol), Pd2(dba)3(16mg, 0.018mmol) and Xantphos (20mg, 0.035mmol) are added to a vial purged with N2. 1,4-dioxane (2.5mL), DIPEA (250μL, 1.44mmol) and sodium thiomethoxide (230μL 21% w / v in water, 0.6891mmol) are added and the resulting mixture is stirred at 100°C for 45 minutes. The mixture is poured onto water (20mL) and diluted with TBME (20mL). The organic layer is separated and the aqueous layer is extracted with TBME (20mL). The combined organic extracts are washed with brine, dried over magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (24 g silica, 0-20% ethyl acetate / heptane) provided 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 (400MHz, CDCl3) δ7.21 (d, J = 0.5Hz, 1H), 2.50 (d, J = 0.5Hz, 3H), 2.44 (s, 3H).

[0867] Step 3: 4-Benzyloxy-2-chloro-6-methyl-3-methylsulfanyl-pyridine

[0868] 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 step 3 of preparation 1 and NMP as solvent. ESI-MS m / z calcd 279.05, found 280.4 (M+1) + . 1 H NMR (400MHz, CDCl3) δ7.46-7.35 (m, 5H), 6.67 (s, 1H), 5.20 (s, 2H), 2.47 (d, J = 0.5Hz, 3H), 2.38 (s, 3H).

[0869] Intermediate A-37

[0870] N-Benzyl-4-benzyloxy-6-chloro-N,2-dimethyl-pyridine-3-sulfonamide

[0871]

[0872] Step 1: 4-Benzyloxy-3-benzylsulfanyl-6-chloro-2-methyl-pyridine

[0873] 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 phenylmethyl mercaptan (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 Pd2(dba)3 (190 mg, 0.208 mmol) and then heated at 80 ° C for 2 hours. The mixture was passed through Filter through a pad of 4-[ ... + .

[0874] Step 2: 4-Benzyloxy-6-chloro-2-methyl-pyridine-3-sulfonyl chloride

[0875] At 0 ° C, 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (900 mg, 4.57 mmol) was added in batches 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). The mixture was stirred at 0-5 ° C for 2 hours and then concentrated under vacuum. The residue was diluted with DCM (30 mL), and the solution was cooled to 0 ° C. 5% saturated sodium bicarbonate aqueous solution (30 mL) was slowly added (maintaining temperature < 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 obtain 4-benzyloxy-6-chloro-2-methyl-pyridine-3-sulfonyl chloride (520 mg, 70%) as a white solid.

[0876] Step 3: N-Benzyl-4-benzyloxy-6-chloro-N,2-dimethyl-pyridine-3-sulfonamide

[0877] 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 layer was washed with brine (20 mL), dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (5-8% ethyl acetate / hexane) gave N-benzyl-4-benzyloxy-6-chloro-N, 2-dimethyl-pyridine-3-sulfonamide (142 mg, 43%). 1 H NMR (400 MHz, CDCl3) δ7.48–7.35 (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 is missing, possibly due to insufficient solvent signal). ESI-MS m / z calculated value 416.09, found value 417.33 (M+1) + .

[0878] Intermediate A-38

[0879] N,N-Dibenzyl-4-benzyloxy-6-chloro-2-methyl-pyridine-3-sulfonamide

[0880]

[0881] 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 analogous 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, found value 493.33 (M+1) + .

[0882] General protocol for the preparation of intermediate A

[0883]

[0884] The intermediates in Table 1 were prepared using the corresponding dichloro-pyridine or -pyrimidine and a procedure similar to that found in Preparation 1, Step 3. Dichloro-pyridine or -pyrimidine was obtained from commercial sources. Benzyl alcohol or substituted benzyl alcohol, such as 2-methoxybenzyl alcohol, may be used. DMF, THF, 2-MeTHF, or mixtures of these solvents may be used as reaction solvents.

[0885] Table 1

[0886]

[0887]

[0888]

[0889] Intermediate A-52

[0890]

[0891] Step 1: tert-Butyl N-[(4-benzyloxy-6-chloro-2-methyl-pyridine-3-carbonyl)amino]carbamate

[0892] 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) was added oxalyl chloride (1.5 g, 1.0 mL, 11.5 mmol) dropwise at 0°C. 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 carbamate (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 Hunin's base (1.1 g, 1.5 mL, 8.6 mmol) and tert-butyl carbamate (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 1M 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 value 391.13, found value 392.15 (M+1) + . 1H NMR (400MHz, CDCl3) δ7.66(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).

[0893] Step 2: 4-Benzyloxy-6-chloro-2-methyl-pyridine-3-carbohydrazide

[0894] A solution of tert-butyl N-[(4-benzyloxy-6-chloro-2-methyl-pyridine-3-carbonyl)amino]carbamate (808 mg, 1.98 mmol) in HCl / 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) (722 mg, 95%) as a light yellow solid. ESI-MS m / z calculated value 291.07, found value 292.04 (M+1) + . 1 HNMR (400MHz, DMSO-d6) δ11.72(s,1H),7.44-7.33(m,5H),7.27(s,1H),5.29(s,2H),2.37(s,3H).

[0895] Step 3: 2-(4-Benzyloxy-6-chloro-2-methyl-3-pyridyl)-5-methyl-1,3,4-oxadiazole

[0896] 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 hour. The reaction mixture was cooled and distributed between ethyl acetate (10 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The organic layer was separated and 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 value 315.07, experimental value 316.04 (M + 1) + . 1 H NMR (400MHz, CDCl3) δ7.39-7.30(m,5H),6.86(s,1H),5.15(s,2H),2.58(s,3H),2.52(s,3H).

[0897] Intermediate A-53

[0898] 2-(4-Benzyloxy-6-chloro-2-methyl-3-pyridyl)-1,3,4-oxadiazole

[0899]

[0900] Step 1: tert-Butyl N-[(4,6-dichloro-2-methyl-pyridine-3-carbonyl)amino]carbamate

[0901] A mixture of 4,6-dichloro-2-methyl-pyridine-3-carboxylic acid (7.0 g, 34 mmol) and SOCl2 (24.5 g, 15.0 mL, 206 mmol) was refluxed for 2 hours. The mixture was concentrated under vacuum, then dissolved in toluene, and evaporated under reduced pressure to give 9 g of corresponding acyl chloride. At 0 ° C, a solution of the above-mentioned acyl 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). After stirring for 2 hours, 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 layer was dried over magnesium sulfate and concentrated by filtration. Purification by silica gel column chromatography (16-20% ethyl acetate / hexane) gave tert-butyl N-[(4,6-dichloro-2-methyl-pyridine-3-carbonyl)amino]carbamate (7 g, 64%). ESI-MS m / z calculated value 319.05, found value 320.1 (M+1) + .

[0902] Step 2: 4,6-Dichloro-2-methyl-pyridine-3-carbohydrazide

[0903] A mixture of tert-butyl N-[(4,6-dichloro-2-methyl-pyridine-3-carbonyl)amino]carbamate (7.0 g, 22 mmol) and a hydrochloric acid solution in dioxane (120 mL 4.0 M, 480 mmol) was stirred at room temperature for 3 hours. The solvent was evaporated to afford 4,6-dichloro-2-methyl-pyridine-3-carbohydrazide (5 g, 98%). ESI-MS m / z calculated value 218.99, found value 220.07 (M+1) + .

[0904] Step 3: 2-(4,6-dichloro-2-methyl-3-pyridyl)-1,3,4-oxadiazole

[0905] 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 hours. 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 value 228.98, experimental value 230.14 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ9.60(s,1H),7.99(s,1H),2.43(s,3H).

[0906] Step 4: 2-(4-Benzyloxy-6-chloro-2-methyl-3-pyridyl)-1,3,4-oxadiazole

[0907] 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 hours. 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 value 301.06, experimental value 302.27 (M+1) + . 1 HNMR (400MHz, DMSO-d6) δ9.48(s,1H),7.44–7.28(m,6H),5.34(s,2H),2.37(s,3H).

[0908] Intermediate A-54

[0909] 3-(4-Benzyloxy-6-chloro-2-methyl-3-pyridyl)-5-methyl-1,2,4-oxadiazole

[0910]

[0911] Step 1: 4-Benzyloxy-6-chloro-2-methyl-pyridine-3-carboxamide

[0912] To a stirred solution of 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carboxylic acid (1.0 g, 2.9 mmol) and Hunin'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, 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), Hunin'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. Purification by silica gel chromatography (0-100% ethyl acetate / heptane) gave 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, found value 277.05 (M+1) + .

[0913] Step 2: 4-Benzyloxy-6-chloro-2-methyl-pyridine-3-carbonitrile

[0914] 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 oxalyl chloride (0.39 mL, 4.5 mmol) dropwise at 0 ° C. The mixture was warmed 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 1M 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%). 1H 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, found value 259.08 (M+1) + .

[0915] Step 3: 4-Benzyloxy-6-chloro-N'-hydroxy-2-methyl-pyridine-3-carboximidamide

[0916] 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-carboximidamide (371 mg, 58%). ESI-MS m / z calculated value 291.08, found value 292.05 (M + 1) + .

[0917] Step 4: 3-(4-Benzyloxy-6-chloro-2-methyl-3-pyridyl)-5-methyl-1,2,4-oxadiazole

[0918] At 0 ° C, acetyl chloride (99 mg, 90 μ L, 1.3 mmol) was added to a solution of 4-benzyloxy-6-chloro-N'-hydroxy-2-methyl-pyridine-3-formamidine (371 mg, 0.983 mmol) and triethylamine (0.35 mL, 2.5 mmol) in acetone (5 mL). The reaction solution was warmed 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 μ L, 1.3 mmol) were added. The mixture was warmed to room temperature and stirred for 20 hours. The mixture was distributed 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. The reaction mixture was directly purified by reverse phase chromatography (C18, 5-95% acetonitrile / water, 0.1% v / v ammonia) to give 3-(4-benzyloxy-6-chloro-2-methyl-3-pyridinyl)-5-methyl-1,2,4-oxadiazole (55 mg, 17%) as a white solid. 1H 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, found value 316.04 (M+1) + .

[0919] Intermediate A-55

[0920] 5-(4-Benzyloxy-6-chloro-2-methyl-3-pyridyl)-3-methyl-1,2,4-oxadiazole

[0921]

[0922] Step 1: 4-Benzyloxy-6-chloro-2-methyl-pyridine-3-carbonyl chloride

[0923] 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 warmed to room temperature for 4 hours. 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%).

[0924] Step 2: 5-(4-Benzyloxy-6-chloro-2-methyl-3-pyridyl)-3-methyl-1,2,4-oxadiazole

[0925] 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 solution was stirred at 100 ° C for 3 hours. The mixture was cooled to room temperature and distributed between ethyl acetate (100 mL) and water (100 mL). Each layer was 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 / water, each 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 (400MHz, CDCl3) δ7.41-7.32(m,5H),6.87(s,1H),5.19(s,2H),2.52(s,3H),2.51(s,3H).

[0926] Intermediate A-56

[0927] 4-Benzyloxy-6-chloro-2-methyl-3-(2-methyltetrazol-5-yl)pyridine

[0928]

[0929] 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, washed with saturated aqueous ammonium chloride solution, and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (0-70% ethyl acetate / hexane over 20 minutes) gave 4-benzyloxy-6-chloro-2-methyl-3-(2-methyltetrazol-5-yl)pyridine (172.5 mg, 91%). 1H 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, found value 316.2 (M+1) + .

[0930] The intermediates in Table 2 were prepared from 4-benzyloxy-6-chloro-3-iodo-2-methyl-pyridine and the appropriate stannane using procedures analogous to those described for intermediate A-56 (4-benzyloxy-6-chloro-2-methyl-3-(2-methyltetrazol-5-yl)pyridine).

[0931] Table 2

[0932]

[0933]

[0934] Intermediate A-65

[0935] 4-Benzyloxy-6-chloro-2-methyl-3-(1-methylpyrazol-4-yl)pyridine

[0936]

[0937] By 4-benzyloxy-6-chloro-3-iodo-2-methyl-pyridine (107mg, 0.298mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (76mg, 0.37mmol), PdCl2(dtbpf) (32.5mg, 0.0499mmol) and potassium phosphate (275mg, 1.29mmol) in dioxane (2mL) and water (500μL) in a microwave vial, nitrogen degassed for 5 minutes, then stirred at 45°C for 1 hour. The mixture is diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution and brine. The organic layer is dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (0-75% ethyl acetate / hexanes over 20 minutes) provided 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, found value 314.26 (M+1) + .

[0938] The intermediates in Table 3 were prepared from 4-benzyloxy-6-chloro-3-iodo-2-methyl-pyridine or 4-benzyloxy-2-chloro-5-iodo-6-methyl-pyridine-3-carboxylic acid ethyl ester and the appropriate boronic acid or boronic acid ester using procedures analogous to those described for intermediate A-65 (4-benzyloxy-6-chloro-2-methyl-3-(1-methylpyrazol-4-yl)pyridine).

[0939] Table 3

[0940]

[0941]

[0942] Intermediate A-77

[0943] 5-(4-Benzyloxy-6-chloro-2-methyl-3-pyridyl)oxazolidin-2-one

[0944]

[0945] Step 1: 1-(4-Benzyloxy-6-chloro-2-methyl-3-pyridinyl)-2-chloro-ethanone

[0946] A solution of 4-benzyloxy-6-chloro-2-methyl-pyridine-3-carbonyl chloride (10.9 g, 35.0 mmol) in THF (200 mL) at 0 ° C was treated dropwise with diazomethylene (trimethyl) silane (35 mL 2.0 M in hexane, 70 mmol). The mixture was allowed to warm to room temperature and stirred overnight. Additional (trimethylsilyl) diazomethane) (17.5 mL 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 a 1,4-dioxane solution of hydrochloric acid (17.5 mL 4.0 M, 70 mmol) was added dropwise. The mixture was stirred at 0 ° C for 30 minutes and then stirred at room temperature for 1 hour. The mixture was added into saturated sodium bicarbonate aqueous solution (600 mL) and extracted with ethyl acetate (1 L). The organic phase was washed with brine (250 mL), dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (0-20% EtOAc / heptane) provided 1-(4-benzyloxy-6-chloro-2-methyl-3-pyridinyl)-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, found value 309.97 (M+1) + .

[0947] Step 2: 2-[2-(4-Benzyloxy-6-chloro-2-methyl-3-pyridyl)-2-oxo-ethyl]isoindoline-1,3-dione

[0948] A mixture of 1-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)-2-chloro-ethanone (9.18 g, 28.1 mmol) and potassium phthalimide (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 ground in diethyl ether (2 × 100 mL). The resulting solid was separated 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, found value 421.12 (M+1) + .

[0949] Step 3: 2-[2-(4-Benzyloxy-6-chloro-2-methyl-3-pyridyl)-2-hydroxy-ethyl]isoindoline-1,3-dione

[0950] 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. Another 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 solution (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) provided 2-[2-(4-benzyloxy-6-chloro-2-methyl-3-pyridinyl)-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, found value 423.13 (M+1) + .

[0951] Step 4: 2-amino-1-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)ethanol

[0952] 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 hours. 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%). 1H 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, found value 293.05 (M+1) +。

[0953] Step 5: 5-(4-Benzyloxy-6-chloro-2-methyl-3-pyridyl)oxazolidin-2-one

[0954] To a solution of 2-amino-1-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)ethanol (1.55g, 4.43mmol) in DCM (25mL) was added CDI (755mg, 4.66mmol), and the mixture was stirred at room temperature overnight. The mixture was distributed between DCM (250mL) and water (100mL), and each phase was separated. The organic phase was washed with salt water, 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 (762mg, 53%). 1 H 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, found value 319.03 (M+1) + .

[0955] Intermediate A-78

[0956] 4-(4-Benzyloxy-6-chloro-2-methyl-3-pyridyl)oxazolidin-2-one

[0957]

[0958] Step 1: 4-Benzyloxy-6-chloro-2-methyl-3-vinyl-pyridine

[0959] Under argon at 70 ℃, 4-benzyloxy-6-chloro-3-iodo-2-methyl-pyridine (7.13g, 19.4mmol), vinylboronic acid pinacol ester (3.6g, 4.0mL, 24mmol), Pd (dppf) Cl2 (1.43g, 1.95mmol) and sodium carbonate aqueous solution (30mL of 2.0M, 60mmol) in dioxane (60mL) were stirred for 20 hours. The mixture was cooled and distributed between ethyl acetate (200mL) and water (200mL). The aqueous layer was extracted with additional ethyl acetate (100mL), 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-vinylpyridine (4.79g, 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, found value 260.03 (M+1) + .

[0960] Step 2: 4-(4-Benzyloxy-6-chloro-2-methyl-3-pyridyl)oxazolidin-2-one

[0961] To a solution of diphenyl diselenide (120 mg, 0.385 mmol), ammonium persulfate (105 mg, 0.460 mmol) and trifluoromethanesulfonic 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 trifluoromethanesulfonic 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 another 18 hours. Ammonium persulfate (105mg, 0.4601mmol) was added and the reaction solution was stirred for 3 hours. The mixture was cooled to room temperature and distributed between ethyl acetate (20mL) and water (20mL). The organic phase was separated, washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase chromatography (5-80% acetonitrile / water, 0.1% v / v formic acid) gave 4-(4-benzyloxy-6-chloro-2-methyl-3-pyridyl)oxazolidin-2-one (20mg, 14%). Not observed 1 HNMR (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 value 318.08, found value 319.07 (M+1) + .

[0962] Intermediate A-79

[0963] 4-Benzyloxy-2-chloro-3-(2,5-dihydrofuran-3-yl)-5,6-dimethyl-pyridine

[0964]

[0965] Step 1: 3-Bromo-5,6-dimethyl-pyridine-2,4-diol

[0966] At 0 ° C, to a solution of 5,6-dimethylpyridine-2,4-diol (15.0 g, 108 mmol) in dichloromethane (1 L) 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 hour. 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 minutes. 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 value 216.97, experimental value 218.0 (M + 1) + .

[0967] Step 2: 3-Bromo-2,4-dichloro-5,6-dimethyl-pyridine

[0968] 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 hours. The mixture was quenched with ice water (200 mL), then quenched with saturated sodium bicarbonate aqueous solution (200 mL), and extracted with ethyl acetate (2 × 500 mL). The combined organic layer was washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (0-3% ethyl acetate / hexane) 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), the additional 3H was obscured by the solvent peak. ESI-MS m / z calculated value 252.91, found value 254.0 (M+1) + .

[0969] Step 3: 2,4-Dichloro-3-(2,5-dihydrofuran-3-yl)-5,6-dimethyl-pyridine

[0970] 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-furyl)-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 hours. The mixture was filtered, and the filter 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) provided 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), the additional 3H was obscured by the solvent peak. ESI-MS m / z calculated value 243.02, found value 244.08 (M+1) + .

[0971] Step 4: 4-Benzyloxy-2-chloro-3-(2,5-dihydrofuran-3-yl)-5,6-dimethyl-pyridine

[0972] At 0 ° C, potassium tert-butoxide (500 mg, 4.46 mmol) was added in batches to a solution of benzyl alcohol (0.4 mL, 3.8 mmol) in DMSO (8 mL), 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 layer was 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 / hexane) gave 4-benzyloxy-2-chloro-3-(2,5-dihydrofuran-3-yl)-5,6-dimethyl-pyridine (776 mg, 70%). 1H 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, found value 316.15 (M+1) + .

[0973] Following Suzuki coupling of 4-benzyloxy-2-chloro-3-(2,5-dihydrofuran-3-yl)-5,6-dimethyl-pyridine with Intermediate-B, the olefin can be reduced using standard hydrogenation conditions to afford the corresponding tetrahydrofuran analog.

[0974] Intermediate A-80

[0975] 4-Benzyloxy-2-chloro-3-(3,6-dihydro-2H-pyran-4-yl)-5,6-dimethyl-pyridine

[0976]

[0977] 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-dimethylpyridine 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, found value 330.23 (M+1) + .

[0978] Following Suzuki coupling of 4-benzyloxy-2-chloro-3-(3,6-dihydro-2H-pyran-4-yl)-5,6-dimethyl-pyridine with Intermediate-B, the olefin can be reduced using standard hydrogenation conditions to afford the corresponding tetrahydropyran analog.

[0979] Intermediate A-81

[0980] 4-(4-Benzyloxy-2-chloro-6-methyl-3-pyridyl)morpholine

[0981]

[0982] Step 1: Diethyl 2-morpholinopropionate

[0983] To a solution of diethyl 2-bromomalonate (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 hours. The mixture was filtered, concentrated, and purified by silica gel chromatography (10-15% ethyl acetate / hexane) to give diethyl 2-morpholinopropionate (22.53 g, 88%). 1 H 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, found value 246.23 (M+1) + .

[0984] Step 2: 4-Hydroxy-6-methyl-3-morpholino-1H-pyridin-2-one

[0985] The mixture of (E)-3-aminobut-2-enoic acid ethyl ester (5.0g, 39mmol) and 2-morpholino diethyl propionate (10.0g, 40.8mmol) was heated at 220 ℃ for 45 minutes.Then resistates was dissolved in the NaOH aqueous solution (200mL 2M, 400mmol), and heated at 130 ℃ for 24 hours.Mixture is cooled and acidified with 1N HCl aqueous solution.Precipitated solid is collected by filtration, and dried in a vacuum, to obtain crude product 4-hydroxyl-6-methyl-3-morpholino-1H-pyridine-2-one (3.12g, 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, found value 211.39 (M+1) + .

[0986] Step 3: 4-(2,4-dichloro-6-methyl-3-pyridyl)morpholine

[0987] A solution of 4-hydroxy-6-methyl-3-morpholino-1H-pyridine-2-one (3.0g, 14mmol) and phenyl dichlorophosphate (28.2g, 20.0mL, 134mmol) was heated at 180°C for 1 hour. The mixture was quenched with ice water (50mL), then quenched with saturated sodium bicarbonate aqueous solution (50mL), and extracted with ethyl acetate (2×100mL). The combined organic layer was washed with brine (100mL), dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (5-8% ethyl acetate / hexane) gave 4-(2,4-dichloro-6-methyl-3-pyridyl)morpholine (1.56g, 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, found value 247.31 (M+1) + .

[0988] Step 4: 4-(4-Benzyloxy-2-chloro-6-methyl-3-pyridyl)morpholine

[0989] At 0 ° C, potassium tert-butoxide (902 mg, 8.04 mmol) was added in batches to a solution of benzyl alcohol (800 mg, 7.40 mmol) in DMSO (15 mL) and stirred at 0 ° C for 30 minutes. 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 hours. The mixture was quenched with ice-cold water (50 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layer was 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 / hexane) gave 4- (4-benzyloxy-2-chloro-6-methyl-3-pyridyl) morpholine (1.03 g, 53%). 1 H 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, found value 319.28 (M+1) + .

[0990] Intermediate A-82

[0991] 2-(4-(Benzyloxy)-2-chloro-6-methylpyridin-3-yl)-1,3,4-oxadiazole

[0992]

[0993] Step 1: 2,4-Dichloro-6-methyl-pyridine-3-carboxylic acid

[0994] To a solution of 2,4-dichloro-6-methyl-pyridine-3-carboxylic acid ethyl ester (1.0 g, 4.3 mmol) in ethanol (10 mL) was added LiOH (6.5 mL 2M, 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 2M, 10 mmol) was added and the mixture was heated at 80 ° C for 3 hours. The mixture was cooled and concentrated and then acidified with 2M HCl. The mixture was extracted with ethyl acetate (× 3), then dried and filtered using Whatman 1PS hydrophobic phase separator filter paper. The filtrate was concentrated to obtain 2,4-dichloro-6-methyl-pyridine-3-carboxylic acid (823 mg, 94%). 1 HNMR (400MHz, CD3OD) δ7.44 (d, J = 0.7 Hz, 1H), 2.53 (d, J = 0.6 Hz, 3H).

[0995] Step 2: tert-Butyl N-[(2,4-dichloro-6-methyl-pyridine-3-carbonyl)amino]carbamate

[0996] A mixture of 2,4-dichloro-6-methyl-pyridine-3-carboxylic acid (7.0 g, 34 mmol) and SOCl2 (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 acyl chloride (9 g). At 0 ° C, a solution of acyl 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). 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 sodium bicarbonate aqueous solution (100 mL) and brine (100 mL), dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (25-30% ethyl acetate / hexanes) provided tert-butyl N-[(2,4-dichloro-6-methyl-pyridine-3-carbonyl)amino]carbamate (6.3 g, 54%). 1H 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, found value 320.2 (M+1) + .

[0997] Step 3: 2,4-Dichloro-6-methyl-pyridine-3-carbohydrazide

[0998] Hydrochloric acid (in dioxane) (34 mL 4M, 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, found value 219.9 (M+1) + .

[0999] Step 4: 2-(2,4-dichloro-6-methyl-3-pyridyl)-1,3,4-oxadiazole

[1000] 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 to 140 ° C for 17 hours. After cooling to room temperature, the mixture was poured into water (10 mL) and extracted with ethyl acetate (× 3). The combined organic layer was 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, found value 229.85 (M+1) + .

[1001] Step 5: 2-(4-(Benzyloxy)-2-chloro-6-methylpyridin-3-yl)-1,3,4-oxadiazole

[1002] Under argon, a solution of benzyl alcohol (350 mg, 0.34 mL, 3.3 mmol) in 2-MeTHF (15 mL) was cooled to 0 ° C, and NaH (155 mg, 60% w / w, 3.9 mmol) in mineral oil was added in one go. 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 solution was stirred at room temperature for 3 hours. The mixture was distributed between water and ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate (× 3). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (0-40% ethyl acetate / heptane) first gave 2-(2-benzyloxy-4-chloro-6-methyl-3-pyridyl)-1,3,4-oxadiazole (276 mg, 25%) as a clear oil. 1 HNMR (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, found value 302.05 (M+1) + , followed by the desired 2-(4-benzyloxy-2-chloro-6-methyl-3-pyridinyl)-1,3,4-oxadiazole (644 mg, 66%) 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, found value 302.04 (M+1) + .

[1003] Intermediate A-83

[1004] 4-Benzyloxy-2-chloro-6-methyl-3-(1-methylpyrazol-3-yl)pyridine

[1005]

[1006] Step 1: 4-Benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylic acid

[1007] 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 solution (4.9 mL 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 1N HCl, water and brine. The organic layer was then dried over sodium sulfate, filtered and concentrated. Purification by reverse phase HPLC (C18, 1-99% acetonitrile / water / 5mM HCl) gave 4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylic acid (203 mg, 75%). ESI-MS m / z calculated value 277.05, found value 278.1 (M + 1) + .

[1008] Step 2: 4-Benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylic acid triazolo[4,5-b]pyridin-3-yl ester

[1009] 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 for 16 hours under an argon atmosphere 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 4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylic acid triazolo[4,5-b]pyridin-3-yl ester (623 mg, 88%). ESI-MS m / z calculated value 395.08, experimental value 394.1 (M-1) - . 1 H NMR (400MHz, DMSO-d6) δ8.88(d,J=3.9Hz,1H),8.77(d,J=7.8Hz,1H),7.70(dd,J=8 .4Hz,4.3Hz,1H),7.60-7.54(m,3H),7.46-7.36(m,3H),5.50(s,2H),2.57(s,3H).

[1010] Step 3: 1-(4-Benzyloxy-2-chloro-6-methyl-3-pyridyl)ethanone

[1011] At -40 ° C, over a period of 5 minutes, MeLi (in THF solution) (1.2 mL 1.6 M, 1.9 mmol) was added dropwise to a stirred solution of 4-benzyloxy-2-chloro-6-methyl-pyridine-3-carboxylic acid triazolo [4,5-b] pyridin-3-yl ester (330 mg, 0.628 mmol) in THF (6 mL). The mixture was stirred at the same temperature for 30 minutes and then quenched with saturate...

Claims

1. A compound of formula (I) or (II) 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 defined 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; and 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 by 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、3-7 3-7 membered cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the cycloalkyl, heterocyclyl or heteroaryl in the 3-7 membered cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted with 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy and C(O)NR8R9; or (ii) R2 is H; and R1 and R3 together with the carbon atoms to which they are attached form a ring having the following formula: R4, R5, R6 and R7 are defined as follows: (i) R4, R5, R6 and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or 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 by halo; and R5 and R6 together with the carbon atoms to which they are attached form a ring having the formula: or (iii) R4 and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted by halo; and R5 and R6 together with the carbon atoms to which they are attached form a ring having the formula: Each R8 and R9 is independently H or C1-C6 alkyl; Each R 10 are independently C1-C4 alkyl; Each R 11 are independently H, halo, C1-C4 alkyl or C1-C4 haloalkyl; R 12 and R 13 Each is independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with halo; Z1 is a 3-10 membered cycloalkyl, a 3-10 membered cycloalkenyl, a phenyl, a 4-10 membered heterocyclyl or a 5-6 membered heteroaryl, wherein the 3-10 membered cycloalkyl, the 3-10 membered cycloalkenyl, the phenyl, the 4-10 membered heterocyclyl or the 5-6 membered heteroaryl may be unsubstituted or may be substituted by 1-4 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; and q is 1, 2, or 3; When X3 is CR3 and R3 is C(O)OR8, then: 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, then: L is O, and Z1 is phenyl, wherein the phenyl group may be unsubstituted or may be substituted by 1-4 substituents selected from halo, OH, CH2OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy, or L is a single bond, and Z1 is a 4-10 membered heterocyclyl, wherein the 4-10 membered heterocyclyl may be unsubstituted or may be substituted by 1-4 substituents selected from halo, OH, CH2OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy; and Wherein the compound of formula (I) is not:

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: 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; and 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 by 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, 3-7 membered cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the cycloalkyl, heterocyclyl or heteroaryl in the 3-7 membered cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted with 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy and C(O)NR8R9.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: 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; and 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 by 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)2NR8R9.

4. A compound of formula (I) according to any one of claims 1 to 3, wherein the compound has formula (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; R4, R5, R6 and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with halo; and Z1 is a 5-10 membered cycloalkyl, phenyl, 4-10 membered heterocyclyl or 5-6 membered heteroaryl, wherein the 5-10 membered cycloalkyl, phenyl, 4-10 membered heterocyclyl or 5-6 membered heteroaryl may be unsubstituted or may be substituted by 1-4 substituents selected from CH2OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein at least one of X4, X5, X6 or X7 is N.

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein X5 is N.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R1 is a C1-C6 alkyl group.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R2 and R3 are each independently 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)2NR8R9.

9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 8, wherein R4, R5, R6 and R7 are each independently H, halo, C1-C6 haloalkyl or C3-C6 cycloalkyl substituted with 1-4 halo.

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein Z1 is a 5-10 membered cycloalkyl group optionally substituted by 1-4 substituents selected from CH2OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein: R1 is a C1-C6 alkyl group; 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 by 1-2 halogen groups; and Z1 is a 5-10 membered cycloalkyl group substituted by a C1-C6 haloalkyl group.

12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R8 is C1-C6 alkyl.

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein X4 is CR4, and X7 is CR7.

14. A compound of formula (I) according to any one of claims 1 to 13, wherein the compound is or a pharmaceutically acceptable salt thereof.

15. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: L is O; X2 is CR2; X3 is CR3; and R1 is a C1-C6 alkyl group.

16. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 3 and 15, wherein: L is 0; and Z1 is phenyl, wherein the phenyl group may be unsubstituted or substituted with 1-4 substituents selected from CH2OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

17. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: L is -OC(R)2- or -C(R)2-O-; X2 is CR2; X3 is CR3; and Z1 is a 3-membered cycloalkyl group or a 4-10-membered cycloalkyl group, wherein the 3-membered cycloalkyl group is substituted by 1-2 substituents selected from the group consisting of halo, CH2OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy, and the 4-10-membered cycloalkyl group may be unsubstituted or may be substituted by 1-4 substituents selected from the group consisting of CH2OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

18. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 3 and 15 to 17, wherein: X2 is CR2; X3 is CR3; and R2 and R3 are each independently 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)2NR8R9.

19. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 3 and 15 to 18, wherein R2 and R3 are each independently H, halo, C(O)OR8, S(=O)(=NH)CH3, S(O)R8 or S(O)2NR8R9.

20. A compound of formula (I) according to any one of claims 1, 2, 3, 15 and 17 to 19, or a pharmaceutically acceptable salt thereof, wherein Z1 is phenyl substituted with 1-3 substituents selected from CH2OH, halo, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkoxy.

21. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 3 and 15 to 20, wherein: X2 is CR2; X3 is CR3; X4 is CR4; X5 is CR5; X6 is CR6; and X7 is CR7.

22. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 21, wherein R4, R5, R6 and R7 are each independently H, halo, C1-C6 alkyl or C1-C6 haloalkyl.

23. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 21, wherein R5 and R6 together with the carbon atoms to which they are attached form a ring having the following formula:

24. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 23, wherein each R 11 are independently H or halo.

25. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 3 and 15 to 20, wherein X7 is N.

26. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 3 and 15 to 20, wherein X6 is N.

27. A compound of formula (I) according to any one of claims 1, 2, 3, 15, 16 and 18 to 20, wherein the compound is or a pharmaceutically acceptable salt thereof.

28. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: L is a single bond; X2 is CR2; X3 is CR3; and Z1 is a 4-10 membered heterocyclyl or a 5-6 membered heteroaryl, wherein the 4-10 membered heterocyclyl or the 5-6 membered heteroaryl may be unsubstituted or may be substituted by 1-4 substituents selected from halo, OH, CH2OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

29. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 28, wherein: Z1 is a 7-membered heterocyclic group, wherein the 7-membered heterocyclic group may be unsubstituted or may be substituted by 1-4 substituents selected from halo, OH, CH2OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

30. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 29, wherein X5 is CR5; X6 is CR6; and R5 and R6 together with the carbon atoms to which they are attached form a ring having the formula:

31. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 30, wherein each R 11 are independently H or halo.

32. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 29 to 31, wherein X2 is CR2; X3 is CR3; and R2 and R3 are each independently H, C1-C6 alkoxy or C(O)OR8.

33. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 32, wherein R2 and R3 are each independently C1-C6 alkoxy or C(O)OR8.

34. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 28 to 33, wherein R1 is C1-C6 alkyl.

35. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 3 and 27 to 34, wherein Z1 is azepanyl optionally substituted by halogen.

36. A compound of formula (I) according to any one of claims 1, 2, 3 and 28 to 35, wherein the compound is or a pharmaceutically acceptable salt thereof.

37. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, 9, 10, 12, 13, 15 to 17, 20 to 26, 28 to 31, 34 and 35, wherein: R2 is a 3-7 membered cycloalkyl, a 4-7 membered heterocyclyl, or a 5-6 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, or heteroaryl in the 3-7 membered cycloalkyl, the 4-7 membered heterocyclyl, or the 5-6 membered heteroaryl is optionally substituted with 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, and C(O)NR8R9; and 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, 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 by 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)2NR8R9.

38. A compound of formula (I) according to claim 37, or a pharmaceutically acceptable salt thereof, wherein R2 is a 4-7 membered heterocyclic radical, wherein the heterocyclic radical is optionally substituted with 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy and C(O)NR8R9.

39. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 38, wherein R2 is 40. A compound of formula (I) according to claim 37, or a pharmaceutically acceptable salt thereof, wherein R2 is a 5-6 membered heteroaryl, wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy and C(O)NR8R9.

41. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 40, wherein the heteroaryl group is wherein the heteroaryl group is optionally substituted with 1-4 C1-C6 alkyl substituents.

42. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 40, wherein R2 is 43. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 37 to 42, wherein R3 is H or C1-C6 alkyl.

44. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, 9, 10, 12, 13, 15 to 17, 20 to 26, 28 to 31, 34 and 35, 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, 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 by 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)2NR8R9; and R3 is a 3-7 membered cycloalkyl, a 4-7 membered heterocyclyl or a 5-6 membered heteroaryl, wherein the cycloalkyl, heterocyclyl or heteroaryl in the 3-7 membered cycloalkyl, the 4-7 membered heterocyclyl or the 5-6 membered heteroaryl is optionally substituted with 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy and C(O)NR8R9.

45. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 44, wherein R2 is H or C(O)OR8, wherein R8 is C1-C6 alkyl.

46. ​​A compound of formula (I) according to claim 44 or claim 45, or a pharmaceutically acceptable salt thereof, wherein R3 is a 3-7 membered cycloalkyl group, wherein the cycloalkyl group is optionally substituted with 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy and C(O)NR8R9.

47. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 46, wherein R3 is 48. A compound of formula (I) according to claim 44 or claim 45, or a pharmaceutically acceptable salt thereof, wherein R3 is a 4-7 membered heterocyclic radical, wherein the heterocyclic radical is optionally substituted with 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy and C(O)NR8R9.

49. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 48, wherein the heterocyclic group is wherein the heterocyclyl is substituted with an oxo substituent.

50. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 48, wherein R3 is 51. A compound of formula (I) according to claim 44 or claim 45, or a pharmaceutically acceptable salt thereof, wherein R3 is a 5-6 membered heteroaryl, wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy and C(O)NR8R9.

52. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 51, wherein the heteroaryl group is wherein the heteroaryl group is optionally substituted with 1-4 substituents independently selected from oxo, OH, C1-C6 alkyl, C1-C6 alkoxy and C(O)NR8R9.

53. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 51, wherein R3 is 54. A compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: L is a single bond; X2 is CH; X3 is CR3; R1 is a C1-C6 alkyl group; R3 is a 5-6 membered heteroaryl, wherein the heteroaryl is optionally substituted with 1-4 C1-C6 alkyl substituents; R4 and R5 are each independently C1-C6 alkyl; and Z1 is a 3-10 membered cycloalkyl group, wherein the 3-10 membered cycloalkyl group may be unsubstituted or substituted with 1-4 C1-C6 alkyl substituents.

55. A compound selected from Table A or a pharmaceutically acceptable salt thereof.

56. The compound according to claim 55, wherein the compound is or a pharmaceutically acceptable salt thereof.

57. A compound selected from Table B or a pharmaceutically acceptable salt thereof.

58. The compound according to claim 57, wherein the compound is or a pharmaceutically acceptable salt thereof.

59. The compound according to claim 1, wherein the compound is selected from or a pharmaceutically acceptable salt thereof.

60. A compound according to any one of claims 1 to 59 in non-salt form.

61. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt thereof or a compound according to claim 60 and one or more pharmaceutically acceptable carriers or vehicles.

62. A pharmaceutical composition comprising a compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt thereof or a compound according to claim 60 and one or more pharmaceutically acceptable carriers or vehicles.

63. A method of inhibiting a voltage-gated sodium channel in a subject, the method comprising administering to the subject a compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt thereof, a compound according to claim 60, or a pharmaceutical composition according to claim 61 or 62.

64. The method of claim 63, wherein the voltage-gated sodium channel is Na V 1.

8.

65. A method of treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or arrhythmia in a subject, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt thereof, a compound according to claim 60, or a pharmaceutical composition according to claim 61 or 62.

66. The method of claim 65, wherein the method comprises treating or reducing the severity of neuropathic pain in the subject.

67. The method of claim 66, wherein the neuropathic pain comprises post-herpetic neuralgia.

68. The method of claim 66, wherein the neuropathic pain comprises small fiber neuropathy.

69. The method of claim 66, wherein the neuropathic pain comprises idiopathic small fiber neuropathy.

70. The method of claim 66, wherein the neuropathic pain comprises diabetic neuropathy.

71. The method of claim 70, wherein the diabetic neuropathy comprises diabetic peripheral neuropathy.

72. The method of claim 65, wherein the method comprises treating or reducing the severity of musculoskeletal pain in the subject.

73. The method of claim 72, wherein the musculoskeletal pain comprises osteoarthritis pain.

74. The method of claim 65, wherein the method comprises treating or reducing the severity of acute pain in the subject.

75. The method of claim 74, wherein the acute pain comprises acute postoperative pain.

76. The method of claim 65, wherein the method comprises treating or reducing the severity of postoperative pain in the subject.

77. The method of claim 76, wherein the post-operative pain comprises bunionectomy pain.

78. The method of claim 76, wherein the post-operative pain comprises abdominoplasty pain.

79. The method of claim 76, wherein the post-operative pain comprises herniorrhaphy pain.

80. The method of claim 65, wherein the method comprises treating or reducing the severity of visceral pain in the subject.

81. The method of any one of claims 63 to 80, wherein the subject is treated with one or more additional therapeutic agents that are administered concurrently with, prior to, or subsequent to treatment with the compound, pharmaceutically acceptable salt, or pharmaceutical composition.

82. Use of a compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt thereof, a compound according to claim 60, or a pharmaceutical composition according to claim 61 or 62 as a medicament.

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