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 / 333,875, filed April 22, 2022, which is incorporated herein 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. However, in many cases, pain persists beyond its usefulness, or patients benefit from suppressing pain. 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 injury indications include post-amputation pain, postoperative nerve injury pain and nerve entrapment injury 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 Na V1.8 Sodium Channels. Mol. Interv., 2007. 7(4): p. 192-5); England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin. Investig. Drugs) 17(12), pp. 1849-64 (2008); Krafte, DS and Bannon, AW, Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8(1), pp. 50-56 (2008). Na V Mediates the rapid rise of the action potential of many excitable cell types (e.g., neurons, skeletal muscle cells, cardiac muscle cells) and is therefore involved in the initiation of signal transduction in those cells (Hille, Bertil, Ion Channels of Excitable Membranes, 3rd Edition (Sinauer Associates, Inc., Sunderland, MA, 2001)). V Role in the initiation and propagation of neuronal signals, reducing Na V Antagonists of this current can prevent or reduce nerve signaling, and it has been suggested that Na V Channels are possible targets for reducing pain in situations 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 by antidepressant 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 includes 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 both the central and peripheral nervous systems. The nine subtypes have similar functional behaviors but differ in the characteristics of 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 V1.8 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, tetrodotoxin (TTX)-sensitive Na + Current, TTX resistance Na + Current and Ca 2+ Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons. Journal of Neuroscience (J. Neurosci.), 2002. 22(23): p. 10277-90. V 1.8 is involved in spontaneous firing in damaged neurons, such as those that drive neuropathic pain (Roza, C. et al., The tetrodotoxin-resistant Na + channel Na V 1.8 is essential for the expression ofspontaneous activity in damaged sensory axons of mice. J. Physiol., 2003.550 (Pt3): Page 921-6; Jarvis, MF et al., A-803467, a potent and selective Na V1.8 Sodium channel blocker attenuates neuropathic and inflammatory pain in the rat. Proc. Natl. Acad. Sci. U S A, 2007. 104(20): pp. 8520 - 5; Joshi, S.K. et al., Involvement of the TTX-resistant sodium channel Na V 1.8 in inflammatory and neuropathic, but not post-operative, pain states. Pain, 2006. 123(1 - 2): pp. 75 - 82; Lai, J. et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, Na V 1.8. Pain, 2002. 95(1 - 2): pp. 143 - 52; Dong, X.W. et al., Small interfering RNA-mediated selective knockdown of Na V1.8tetrodotoxin-resistant sodium channel reverses mechanical allodynia inneuropathic rats. Neuroscience, 2007.146(2): pages 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: page 33; Black, JA et al., Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann. Neurol., 2008.64(6): pages 644-53; Coward, K. et al., Immunolocalization of SNS / PN3 and NaN / SNS2 sodium channels in human pain states.Pain, 2000.85(1-2): pages 41-50; Yiangou, Y. et al., SNS / PN3 andSNS2 / NaN sodium channel-like immunoreactivity in human adult and neonateinjured sensory nerves. FEBS Lett., 2000.467(2-3): pages 249-52; Ruangsri, S. et al., Relationship of axonal voltage-gated sodium channel 1.8(Na V 1.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats. J. Biol. Chem. 286(46): p. 39836-47). Expression of Na V The small DRG neurons of 1.8 include nociceptors involved in pain signaling. V1.8 Mediating large-amplitude action potentials in small neurons of the dorsal root ganglion (Blair, NT and BPBean, Roles of tetrodotoxin (TTX)-sensitive Na + current,TTX-resistantNa + current, and Ca 2+ current in the action potentials of nociceptive sensoryneurons. J. Neurosci., 2002.22(23): pp. 10277-90). Na V 1.8 is required for rapid repetitive action potentials in nociceptors and spontaneous activity in injured neurons. (Choi, JS and SG Wixman, Physiological interactions between Na V 1.7 and Na V 1.8 sodium channels: acomputer simulationstudy.J.Neurophysiol.106(6): pp. 3173-84; Renganathan, M., TRCummins and SGWaxman, Contribution of Na( V )1.8sodium channels to action potentialelectrogenesis in DRG neurons.J.Neurophysiol., 2001.86(2): pp. 629-40; Roza, C. et al., The tetrodotoxin-resistant Na + channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550(Pt 3): p. 921-6). In depolarized or damaged DRG neurons, Na V1.8 appears to be a driving factor for hyperexcitability (Rush, AM et al., A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc. Natl. Acad. Sci. USA, 2006. 103(21): p. 8245-50). In some animal pain models, it has been shown that Na in DRG V 1.8 mRNA expression levels increased (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(Part 2): 359-75; Strickland, IT et al., Changes in the expression of Na V 1.7,Na V 1.8 and Na V 1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. Eur.J.Pain, 2008.12(5): pp. 564-72; Qiu, F. et al., Increased expression of tetrodotoxin-resistant sodium channels Na V 1.8 andNa V 1.9 within dorsal root ganglia in a rat model of bone cancerpain. Neurosci. Lett., 512(2): pp. 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 V1.8 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)

[0013]

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

[0015] A is

[0016] L is -O-, a single bond, -OC(R)2-, -C(R)2-, -C(R)2-O- or -N(R)-;

[0017] Each R is independently H, halo or C1-C6 alkyl;

[0018] X2 is N or CR2;

[0019] X4 is N or CR4;

[0020] X5 is N or CR5;

[0021] X6 is N or CR6;

[0022] X7 is N or CR7;

[0023] Y1 is N or CR 1a ;

[0024] Y2 is N, + NO - or CR 2a ;

[0025] Y3 is N or CR 3a ;

[0026] R2 is H, halo, C1-C6 alkyl, (C1-C6 alkylene)-NR8R9, C2-C6 alkenyl, C1-C6 alkoxy, (C1-C6 alkylene)-OH, C(O)OR8 or CH(OH)(CH2) m (CHOH) n (CH2) p H;

[0027] R4, R5, R6 and R7 are defined as follows:

[0028] (i) R4, R5, R6 and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl optionally substituted with one or more alkyl, halo or OH;

[0029] (ii) R4 and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with one or more halo; and R5 and R6 together with the carbon atoms to which they are attached form a ring of the formula:

[0030] or

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

[0032]

[0033] R8 and R9 are each independently H or C1-C6 alkyl;

[0034] Each R 10 are independently H or halo;

[0035] R 1a H, halo, CN, C1-C6 alkyl, OH, C(O)NR 12 R 13 、C1-C6 alkoxy、NR 12 R13 、NR8C(O)NR8R9、(C1-C6 alkylene)-C(O)NR8R9、(C1-C6 alkylene)-OH、C(O)OR 12 , OR 12 、CH(OH)(CH2) m (CHOH) n (CH2) p H, N=S(=O)(CH3)2, N=S(=O)R'R", 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the heterocyclyl or heteroaryl in the 5-10 membered heteroaryl or 4-10 membered heterocyclyl is optionally substituted with 1-4 substituents selected from the group consisting of OH, halo, oxo, C(O)NR8R9, NR8R9, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkylene)-OH, (C1-C6 alkylene)-O-(C1C6 alkyl) and (C1-C6 alkylene)-NR8R9;

[0036] R' and R" together with the S atom to which they are attached form a 4-7 membered heterocyclic group;

[0037] R 11 、R 2a and R 3a Each is independently H, halo, CN, C1-C6 alkyl, C(O)NR8R9 or C1-C6 alkoxy;

[0038] R 12 and R 13 Each is independently H, C(O)(C1-C6 alkyl), (C1-C6 alkylene)-NR8R9, CH2CH(OH)(CH2) m (CHOH) n (CH2) p H, C1-C6 alkyl optionally substituted with one or more OH; indanyl, (C1-C6 alkylene)-(C3-C6 cycloalkyl), (C1-C6 alkylene)-phenyl, (C1-C6 alkylene)-(5-membered heterocyclyl), C4-C7 cycloalkyl, C6-C 10 aryl, 5-6 membered heteroaryl or 4-7 membered heterocyclic group, wherein the indanyl, (C1-C6 alkylene)-(C3-C6 cycloalkyl), (C1-C6 alkylene)-phenyl, (C1-C6 alkylene)-(5 membered heterocyclic group), C4-C7 cycloalkyl, C6-C 10 Aryl, 5-6 membered heteroaryl or 4-7 membered heterocyclyl is optionally substituted with 1-4 substituents selected from the group consisting of OH, oxo, C1-C6 alkyl, (C1-C6 alkylene)-OH and C1-C6 alkoxy;

[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, CD3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, CH2OH, C(O)H, 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 X2 is N, then:

[0043] L is O, and Z1 is phenyl, wherein the phenyl is substituted with 2-4 substituents selected from the group consisting of halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy; or

[0044] L is a single bond, and Z1 is a 4-10 membered heterocyclyl, wherein the 4-10 membered heterocyclyl is substituted with 2-4 substituents selected from the group consisting of halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy; and

[0045] Wherein when X2, X4, X5, X6 and X7 are each CH, L is a single bond, and Z1 is phenyl, then the phenyl group is substituted with 1-4 substituents selected from the group consisting of halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

[0046] 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 incorporated herein by reference.

[0047] As used herein, the term "compounds of the present invention" refers to compounds of Formula (I), (II) and (III) as described herein and all embodiments thereof (e.g., Formula (IA-1) etc.), as well as the compounds identified in Table A and Table B.

[0048] As described herein, the compounds of the present invention include a number of variable groups (e.g., R1, X1, R 1a As will be appreciated by one 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 compounds that do not undergo substantial change when subjected to conditions that allow them to be produced, detected, and preferably recovered, purified, and used for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that does not undergo substantial change when stored at 40°C or less in the absence of moisture or other chemically reactive conditions for at least one week.

[0049] 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), (IA-1), (IA-2), (IB-1), (IC-1), and (IC-2), 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 atom labels in the chemical structure. Using different ChemDraw styles, Formula (I) can be drawn as follows to illustrate the bonds in question:

[0050]

[0051] 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.

[0052] As used herein, the term "halo" means F, Cl, Br, or I.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] As used herein, the term "alkoxy" refers to -OR a 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.

[0058] 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.

[0059] 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.

[0060] 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 ring atoms connected 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.

[0061] As used herein, the term "heterocyclyl" refers to a stable, non-aromatic, monocyclic, bicyclic or tricyclic (fused, bridged or spirocyclic) radical in which one or more ring atoms are heteroatoms (e.g., heteroatoms independently selected from N, O, P and S) having a specified 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 "heterocyclyl" group has a specified 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 heterocyclyl group comprises 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).

[0062] As used herein, the term "heteroaryl" refers to a stable monocyclic, bicyclic or tricyclic radical having a specified number of ring atoms, wherein at least one ring in the system is aromatic, and at least one aromatic ring in the system contains one or more heteroatoms (e.g., one or more heteroatoms independently selected from N, O, P and S). In some embodiments, each ring in the system contains 3 to 7 ring members. For example, a 6-membered heteroaryl group contains a total of 6 ring members, at least one of which is a heteroatom selected from N, S, O and P. The term "heteroaryl" can be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".

[0063] 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.

[0064] As used herein, labels such as "*5" and "*6," such as those shown in the structures below, designate the atom to which the corresponding R groups (in this case, the R5 and R6 groups, respectively) are attached.

[0065]

[0066] Similarly, the tokens "*8" and "*9" in the following structure specify R 8a and R 9a The atoms to which the groups are attached.

[0067]

[0068] Unless otherwise indicated, the compounds of the present invention, whether identified by chemical name or chemical structure, encompass 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.

[0069] As used herein, in any chemical structure or formula, a non-bold direct bond to a stereogenic center of a compound, such as in

[0070]

[0071] Indicates that the configuration of a stereocenter is unspecified. A compound may have any configuration or mixture of configurations at a stereocenter.

[0072] 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

[0073]

[0074] The relative stereochemistry of the stereocenter is indicated with respect to other stereocenters connected by bold or hashed direct bonds.

[0075] 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

[0076]

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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" encompasses 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.

[0081] 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.

[0082] 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 undefined in: VS Shirley and CM Lederer, Isotope Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0083] 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.

[0084] 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.

[0085] As used herein, "D", "d" and " 2 H" refers to deuterium.

[0086] In some embodiments, the compounds of the present invention and pharmaceutically acceptable salts thereof contain for each constituent atom approximately the natural abundance isotopic composition of a designated element.

[0087] In some embodiments, the compounds of the invention and pharmaceutically acceptable salts thereof contain one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the most abundant isotope of 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.

[0088] 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.

[0089] 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 in 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 may change significantly. For example, if deuterium is bonded to a carbon atom at 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.

[0090] 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.

[0091] 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).

[0092] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0093] A is

[0094] R 1a H, halo, CN, C1-C6 alkyl, OH, C(O)NR 12 R 13 、C1-C6 alkoxy、NR 12 R 13 、(C1-C6 alkylene)-C(O)NR8R9、(C1-C6 alkylene)-OH、C(O)OR 12 、CH(OH)(CH2) m (CHOH) n (CH2) p H or N═S(═O)(CH 3 ) 2 ; and

[0095] R 12 and R 13 Each is independently H, C(O)(C1-C6 alkyl), (C1-C6 alkylene)-NR8R9, CH2CH(OH)(CH2) m (CHOH) n (CH2) p H. C1-C6 alkyl optionally substituted with one or more OH.

[0096] In some embodiments, the present invention relates to compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein A is

[0097] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0098] L is a single bond or -C(R)2-;

[0099] X2 is CR2;

[0100] Z1 is a 4-10 membered cycloalkyl, a 3-10 membered cycloalkenyl, a phenyl or a 5-6 membered heteroaryl, wherein the 4-10 membered cycloalkyl, the 3-10 membered cycloalkenyl, the phenyl or the 5-6 membered heteroaryl may be unsubstituted or substituted by 1-4 substituents selected from the group consisting of halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

[0101] In some embodiments, the present invention relates to compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein R is H or C1-C6 alkyl.

[0102] In some embodiments, the present invention relates to compounds of formula (IA-1)

[0103]

[0104] or a pharmaceutically acceptable salt thereof, wherein L, X2, X4, X5, X6, X7, Y1, Y2, Y3 and Z1 are as defined above in conjunction with Formula (I) or any embodiment thereof.

[0105] In some embodiments, the present invention relates to compounds of formula (IA-2)

[0106]

[0107] or a pharmaceutically acceptable salt thereof, wherein L, X2, X4, X5, X6, X7, Y1, Y2 and Y3 are as defined above in conjunction with formula (I) or any embodiment thereof. 14 is selected from the group consisting of halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

[0108] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0109] L is a single bond;

[0110] X2 is CR2;

[0111] R 1a H, halogenated, CN, OH, C(O)NR 12 R 13 、C1-C6 alkoxy、-NR 12 R 13 、(C1-C6 alkylene)-C(O)NR8R9、(C1-C6 alkylene)-OH、C(O)OR 12 、CH(OH)(CH2)m (CHOH) n (CH2) p H or N=S(=O)(CH3)2;

[0112] Z1 is a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group may be unsubstituted or substituted by 1-4 substituents selected from the group consisting of 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 formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0114] L is a single bond;

[0115] X2 is CR2;

[0116] R 1a H, halogenated, CN, OH, C(O)NR 12 R 13 、C1-C6 alkoxy、-NR 12 R 13 、(C1-C6 alkylene)-C(O)NR8R9、(C1-C6 alkylene)-OH、C(O)OR 12 、CH(OH)(CH2) m (CHOH) n (CH2) p H or N=S(=O)(CH3)2;

[0117] Z1 is a 5-10 membered heterocyclic group, wherein the 5-10 membered heterocyclic group may be unsubstituted or substituted by 1-4 substituents selected from the group consisting of halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

[0118] In some embodiments, the present invention relates to compounds of formula (IA-1) or (IA-2), or pharmaceutically acceptable salts thereof, wherein R is H or C1-C6 alkyl.

[0119] In some embodiments, the present invention relates to compounds of formula (IB-1)

[0120]

[0121] or a pharmaceutically acceptable salt thereof, wherein X2, X4, X5, X6, X7, Y1, Y2, Y3 and Z1 are as defined above in conjunction with Formula (I) or any embodiment thereof.

[0122] In some embodiments, the present invention relates to compounds of formula (IB-2)

[0123]

[0124] or a pharmaceutically acceptable salt thereof, wherein X2, X4, X5, X6, X7, Y1, Y2, Y3 and Z1 are as defined above in conjunction with formula (I), including any embodiments thereof. 14 is selected from the group consisting of halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

[0125] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0126] L is O, -OC(R)2- or -C(R)2-O-;

[0127] Z1 is phenyl, 4-10 membered heterocyclyl or 5-6 membered heteroaryl, wherein the phenyl, 4-10 membered heterocyclyl or 5-6 membered heteroaryl may be unsubstituted or substituted by 1-4 substituents selected from the group consisting of halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, CH2OH, C(O)H and C1-C6 haloalkoxy.

[0128] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0129] L is O, -OC(R)2- or -C(R)2-O-;

[0130] Z1 is phenyl, 5-10 membered heterocyclyl or 5-6 membered heteroaryl, wherein the phenyl, the 5-10 membered heterocyclyl or the 5-6 membered heteroaryl may be unsubstituted or may be substituted by 1-4 substituents selected from the group consisting of halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, CH2OH, C(O)H and C1-C6 haloalkoxy.

[0131] In some embodiments, the present invention relates to compounds of formula (IC-1)

[0132]

[0133] or a pharmaceutically acceptable salt thereof, wherein X2, X4, X5, X6, X7, Y1, Y2, Y3 and Z1 are as defined above in conjunction with Formula (I) or any embodiment thereof.

[0134] In some embodiments, the present invention relates to compounds of formula (IC-2)

[0135]

[0136] or a pharmaceutically acceptable salt thereof, wherein X2, X4, X5, X6, X7, Y1, Y2 and Y3 are as defined above in conjunction with formula (I) or any embodiment thereof. 14 is selected from the group consisting of halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

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

[0138] L is -O- or a single bond;

[0139] X4 is CR4;

[0140] X6 is CR6;

[0141] R4, R5, R6 and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl optionally substituted with one or more halo;

[0142] Z1 is a 3-10 membered cycloalkyl or phenyl group, wherein the 3-10 membered cycloalkyl or phenyl group may be unsubstituted or substituted with 1-4 substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl.

[0143] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0144] A is

[0145] X2 is CR2;

[0146] Y1 is CR 1a ;

[0147] Y2 is N or CR 2a ;

[0148] Y3 is CR 3a ;

[0149] R 11 、R 2a and R 3a Each is H;

[0150] R 1a It is C(O)NR 12 R 13 NR 12 R 13 、NR8C(O)NR8R9、OR 12 、N=S(=O)R'R”、

[0151] 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the heterocyclyl or heteroaryl in the 5-10 membered heteroaryl or 4-10 membered heterocyclyl is optionally substituted with 1-4 substituents selected from the group consisting of OH, halo, oxo, C(O)NR8R9, NR8R9, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkylene)-OH, (C1-C6 alkylene)-O-(C1-C6 alkyl) and (C1-C6 alkylene)-NR8R9;

[0152] R' and R" together with the S atom to which they are attached form a 4-7 membered heterocyclic group; and

[0153] R 12 and R 13 Each is independently H, C(O)(C1-C6 alkyl), (C1-C6 alkylene)-NR8R9, CH2CH(OH)(CH2) m (CHOH) n (CH2) p H, C1-C6 alkyl optionally substituted with one or more OH; indanyl, (C1-C6 alkylene)-(C3-C6 cycloalkyl), (C1-C6 alkylene)-phenyl, (C1-C6 alkylene)-(5-membered heterocyclyl), C4-C7 cycloalkyl, C6-C 10 aryl, 5-6 membered heteroaryl or 4-7 membered heterocyclic group, wherein the indanyl, (C1-C6 alkylene)-(C3-C6 cycloalkyl), (C1-C6 alkylene)-phenyl, (C1-C6 alkylene)-(5 membered heterocyclic group), C4-C7 cycloalkyl, C6-C 10 The aryl, 5-6 membered heteroaryl or 4-7 membered heterocyclyl is optionally substituted with 1-4 substituents selected from OH, oxo, C1-C6 alkyl, (C1-C6 alkylene)-OH and C1-C6 alkoxy.

[0154] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0155] L is -O-;

[0156] A is

[0157] X2 is CR2;

[0158] X4 is CR4;

[0159] X5 is CR5;

[0160] X6 is CR6;

[0161] Y1 is CR 1a ;

[0162] Y3 is CR 3a ;

[0163] R2 is H;

[0164] R4, R5, R6 and R7 are each independently H, halo, C1-C6 alkyl or C1-C6 haloalkyl;

[0165] R8 and R9 are each independently H or C1-C6 alkyl;

[0166] R 1a It is C(O)NR 12 R 13 or NR8C(O)NR8R9;

[0167] R 12 and R 13 Each is H; and

[0168] Z1 is phenyl, wherein the phenyl group may be unsubstituted or substituted with 1-4 substituents selected from the group consisting of halo or C1-C6 alkyl. In some embodiments, the present invention relates to compounds of any one of Formula (I), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1) and (IC-2), or a pharmaceutically acceptable salt thereof, wherein Y2 is N. In other embodiments, Y2 is + NO - In some embodiments, Y2 is CR 2a ; and R 2a is H, halo, CN, C1-C6 alkyl, C(O)NR8R9 or C1-C6 alkoxy. 2a is H. In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a is a C1-C6 alkyl group. In some embodiments, R 2a is C(O)NR8R9. In some embodiments, R 2a It is a C1-C6 alkoxy group.

[0169] In some embodiments, the present invention relates to a compound of any one of Formula (I), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), and (IC-2), or a pharmaceutically acceptable salt thereof, wherein X4 is CR4; X5 is N; X6 is CR6; X7 is CR7. In some embodiments, X4 is CR4; X5 is N; X6 is CR6; X7 is N. In some embodiments, X4 is CR4; X5 is CR5; X6 is N; X7 is CR7. In some embodiments, X4 is CR4; X5 is CR5; X6 is CR6; X7 is N.

[0170] In some embodiments, the present invention relates to a compound of any one of Formula (I), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), and (IC-2), or a pharmaceutically acceptable salt thereof, wherein R4, R5, R6, and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with one or more alkyl, halo, or OH. In some embodiments, R4, R5, R6, and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl substituted with one or more halo. In some embodiments, R4, R5, R6, and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl substituted with one, two, or three halo. In some embodiments, R4 is H, halo, or C1-C6 alkyl. In some embodiments, R5 is H, halo or C1-C6 haloalkyl. In some embodiments, R5 is H or C1-C6 haloalkyl. In some embodiments, R5 is F. In some embodiments, R5 is -CF3. In some embodiments, R6 is H, C1-C6 alkyl, C1-C6 haloalkyl or a C3-C6 cycloalkyl substituted with two halo. In some embodiments, R6 is H. In some embodiments, R6 is -CF3. In some embodiments, R6 is a C4 cycloalkyl substituted with two F. In some embodiments, R7 is H.

[0171] In some embodiments, the present invention relates to a compound of any one of Formula (I), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1) and (IC-2), or a pharmaceutically acceptable salt thereof, wherein Y1 is CR 1a In some embodiments, R 1a It is C(O)NR 12 R 13 In some embodiments, R 1a is H. In some embodiments, R 1a In some embodiments, R1a In some embodiments, R 1a is a C1-C6 alkyl group. In some embodiments, R 1a In some embodiments, R 1a In some embodiments, R 1a It is NR 12 R 13 In some embodiments, R 1a is (C1-C6 alkylene)-C(O)NR8R9. In some embodiments, R 1a is (C1-C6 alkylene)-OH. In some embodiments, R 1a It is C(O)OR 12 In some embodiments, R 1a is OR 12 In some embodiments, R 1a is NR8C(O)NR8R9. In some embodiments, R 1a is N=S(=O)R'R", wherein R' and R" together with the S atom to which they are attached form a 4-7 membered heterocyclic group. In some embodiments, R 1a is a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with 1-4 substituents selected from the group consisting of OH, halo, oxo, C(O)NR8R9, NR8R9, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkylene)-OH, (C1-C6 alkylene)-O-(C1-C6 alkyl) and (C1-C6 alkylene)-NR8R9. In some embodiments, R 1a is a 4-10 membered heterocyclyl, wherein the 4-10 membered heterocyclyl is optionally substituted with 1-4 substituents selected from the group consisting of OH, halo, oxo, C(O)NR8R9, NR8R9, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkylene)-OH, (C1-C6 alkylene)-O-(C1C6 alkyl) and (C1-C6 alkylene)-NR8R 9。

[0172] In some embodiments, the present invention relates to a compound of any one of Formula (I), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), and (IC-2), or a pharmaceutically acceptable salt thereof, wherein X2 is CR2. In some embodiments, R2 is H. In some embodiments, R2 is halo. In some embodiments, R2 is C1-C6 alkyl. In some embodiments, R2 is (C1-C6 alkylene)-NR8R9. In some embodiments, R2 is C2-C6 alkenyl. In some embodiments, R2 is C1-C6 alkoxy. In some embodiments, R2 is (C1-C6 alkylene)-OH. In some embodiments, R2 is C(O)OR8. In some embodiments, R2 is CH(OH)(CH2) m (CHOH) n (CH2) p H.

[0173] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L is O, a single bond, OC(R)2, C(R)2, C(R)2-O, or N(R). In some embodiments, L is O. In some embodiments, L is a single bond. In some embodiments, L is OC(R)2. In some embodiments, L is C(R)2. In some embodiments, L is C(R)2-O. In some embodiments, L is N(R).

[0174] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L is O, a single bond, OC(R)2, C(R)2, C(R)2-O or N(R), and R is H or C1-C6 alkyl. In some embodiments, L is O. In some embodiments, L is a single bond. In some embodiments, L is OC(R)2, and R is H or C1-C6 alkyl. In some embodiments, L is C(R)2, and R is H or C1-C6 alkyl. In some embodiments, L is C(R)2-O, and R is H or C1-C6 alkyl. In some embodiments, L is N(R), and R is H or C1-C6 alkyl.

[0175] In some embodiments, the present invention relates to a compound of any one of Formula (I), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1) and (IC-2), or a pharmaceutically acceptable salt thereof, wherein R 12 and R 13 Each is H. In some embodiments, R 12 and R 13 Each independently represents H or C1-C6 alkyl. In some embodiments, R 12 and R13 Each is independently H or C1-C6 alkyl optionally substituted with one or more OH.

[0176] In some embodiments, the present invention relates to a compound of any one of Formula (I), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1) and (IC-2), or a pharmaceutically acceptable salt thereof, wherein R 12 is C(O)(C1-C6 alkyl). In some embodiments, R 12 is (C1-C6 alkylene)-NR8R9. In some embodiments, R 12 is CH2CH(OH)(CH2) m (CHOH) n (CH2) p H. In some embodiments, R 12 is indanyl, wherein the indanyl is optionally substituted with 1-4 substituents selected from the group consisting of OH, oxo, C1-C6 alkyl, (C1-C6 alkylene)-OH, and C1-C6 alkoxy. 12 is (C1-C6 alkylene)-(C3-C6 cycloalkyl), wherein said (C1-C6 alkylene)-(C3-C6 cycloalkyl) is optionally substituted with 1-4 substituents selected from the group consisting of OH, oxo, C1-C6 alkyl, (C1-C6 alkylene)-OH, and C1-C6 alkoxy. In some embodiments, R 12 is (C1-C6 alkylene)-phenyl, wherein the (C1-C6 alkylene)-phenyl is optionally substituted with 1-4 substituents selected from the group consisting of OH, oxo, C1-C6 alkyl, (C1-C6 alkylene)-OH, and C1-C6 alkoxy. In some embodiments, R 12 is (C1-C6 alkylene)-(5-membered heterocyclyl), wherein said (C1-C6 alkylene)-(5-membered heterocyclyl) is optionally substituted with 1-4 substituents selected from the group consisting of OH, oxo, C1-C6 alkyl, (C1-C6 alkylene)-OH, and C1-C6 alkoxy. In some embodiments, R 12 is a C4-C7 cycloalkyl group, wherein the C4-C7 cycloalkyl group is optionally substituted by 1-4 substituents selected from the group consisting of OH, oxo, C1-C6 alkyl, (C1-C6 alkylene)-OH, and C1-C6 alkoxy. 12 It is C6-C 10 Aryl, wherein the C6-C 10 The aryl group is optionally substituted with 1-4 substituents selected from the group consisting of OH, oxo, C1-C6 alkyl, (C1-C6 alkylene)-OH, and C1-C6 alkoxy. 12is a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally substituted with 1-4 substituents selected from the group consisting of OH, oxo, C1-C6 alkyl, (C1-C6 alkylene)-OH, and C1-C6 alkoxy. 12 is a 4-7 membered heterocyclyl, wherein the 4-7 membered heterocyclyl is optionally substituted by 1-4 substituents selected from the group consisting of OH, oxo, C1-C6 alkyl, (C1-C6 alkylene)-OH, and C1-C6 alkoxy. 12 is a C3-C6 cycloalkyl group or a 5-6 membered heterocyclyl group, wherein the C3-C6 cycloalkyl group or the 5-6 membered heterocyclyl group is optionally substituted with 1 to 4 C1-C6 alkoxy substituents.

[0177] In some embodiments, the present invention relates to compounds of any one of formula (IA-2), (IB-2) and (IC-2), or a pharmaceutically acceptable salt thereof, wherein R 14 is halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 haloalkoxy. 14 In some embodiments, R 14 is a C1-C6 alkyl group. In some embodiments, R 14 is a C1-C6 haloalkyl group. In some embodiments, R 14 In some embodiments, R 14 In some embodiments, R 14 It is a C1-C6 alkoxy group.

[0178] In some embodiments, the present invention relates to a compound of any one of formula (I), (IA-1), (IB-1) and (IC-1), 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 the group consisting of halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, CH2OH, C(O)H and C1-C6 haloalkoxy. In some embodiments, the 3-10 membered cycloalkyl, the 3-10 membered cycloalkenyl, the phenyl, the 5-10 membered heterocyclyl or the 5-6 membered heteroaryl is substituted with D, OCD3 or CD3.

[0179] In some embodiments, the present invention relates to a compound of any one of Formula (I), (IA-1), (IB-1), and (IC-1), or a pharmaceutically acceptable salt thereof, wherein Z1 is a 4-10 membered cycloalkyl, a 3-10 membered cycloalkenyl, a phenyl, or a 5-6 membered heteroaryl. In some embodiments, Z1 is a 4-10 membered cycloalkyl. In some embodiments, Z1 is a 4-7 membered cycloalkyl. In some embodiments, Z1 is a 5-6 membered cycloalkyl. In some embodiments, Z1 is cyclohexane. In some embodiments, Z1 is phenyl. In some embodiments, Z1 is a 5-6 membered heteroaryl. In some embodiments, the 4-10 membered cycloalkyl, the 4-7 membered cycloalkyl, the 5-6 membered cycloalkyl, or the cyclohexane is substituted with 1, 2, 3, or 4 substituents selected from halo and C1-C6 haloalkyl. In some embodiments, the 4-10 membered cycloalkyl, the 4-7 membered cycloalkyl, the 5-6 membered cycloalkyl, or the cyclohexane is substituted with 1, 2, 3, or 4 halo substituents. In some embodiments, the 4-10 membered cycloalkyl, 4-7 membered cycloalkyl, 5-6 membered cycloalkyl, or cyclohexane is substituted with 1, 2, 3, or 4 C1-C6 haloalkyl groups.

[0180] In some embodiments, the present invention relates to a compound of any one of Formula (I), (IA-1), (IB-1), and (IC-1), or a pharmaceutically acceptable salt thereof, wherein Z1 is a 4-10 membered heterocyclyl. In some embodiments, Z1 is a 5-10 membered heterocyclyl. In some embodiments, Z1 is a 5-9 membered heterocyclyl. In some embodiments, Z1 is a 6-9 membered heterocyclyl. In some embodiments, Z1 is a 6-8 membered heterocyclyl. In some embodiments, Z1 is a 6-7 membered heterocyclyl. In some embodiments, Z1 is a 7-8 membered heterocyclyl. In some embodiments, Z1 is a 7 membered heterocyclyl.

[0181] In some embodiments, the present invention relates to a compound of any one of Formula (I), (IA-1), (IB-1), and (IC-1), or a pharmaceutically acceptable salt thereof, wherein Z1 is phenyl or a 4-10 membered heterocyclyl. In some embodiments, Z1 is phenyl or a 5-10 membered heterocyclyl. In some embodiments, Z1 is phenyl. In some embodiments, Z1 is a 4-10 membered heterocyclyl. In some embodiments, Z1 is a 5-10 membered heterocyclyl. In some embodiments, phenyl is substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, CH2OH, C(O)H, and C1-C6 haloalkoxy. In some embodiments, phenyl is substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 alkoxy, CH2OH, C(O)H, and C1-C6 haloalkyl. In some embodiments, the phenyl group is substituted with 2 substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 alkoxy, CH2OH, C(O)H, and C1-C6 haloalkyl.

[0182] In some embodiments, the present invention relates to compounds of any one of Formula (I), (IA-1), (IA-2), (IB-1), (IB-2), (IC-1), and (IC-2), or any embodiment thereof, i.e., in non-salt form.

[0183] In some embodiments, the present invention relates to compounds of formula (II) or (III)

[0184]

[0185] or a pharmaceutically acceptable salt thereof, wherein:

[0186] B is

[0187] L2 is a single bond or -CH2-;

[0188] X 12 is CH or N;

[0189] R 14 is H, halo or C1-C6 alkoxy;

[0190] R 8a and R 9a As defined below:

[0191] (i)R 8a and R 9aare each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1-4 substituents selected from C1-C6 alkyl, halo, and C1-C6 haloalkyl;

[0192] (ii)R 8a and R 9a Together with the carbon atoms to which they are attached, they form a ring of the formula:

[0193] wherein the ring is optionally substituted with 1-4 C1-C6 alkyl groups;

[0194] R 10a is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1-4 substituents selected from C1-C6 alkyl, halo, and C1-C6 haloalkyl;

[0195] R 11a is H or C1-C6 alkyl;

[0196] R 15 It is C(O)NR 16 R 17 or a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally substituted with 1-4 C1-C6 alkyl groups;

[0197] R 16 and R 17 Each independently is H or C1-C6 alkyl;

[0198] Z2 is C4-C6 cycloalkyl or phenyl, wherein said C4-C6 cycloalkyl or phenyl is optionally substituted with 1-4 substituents selected from halo and C1-C6 alkyl; and

[0199] q2 is 1, 2, or 3.

[0200] In some embodiments, the present invention relates to compounds of formula (II)

[0201]

[0202] or a pharmaceutically acceptable salt thereof, wherein R 14 、R 15 、R 8a 、R 9a , L2 and Z2 are as defined above in conjunction with Formula (II) or any embodiment thereof.

[0203] In some embodiments, the present invention relates to compounds of formula (III)

[0204]

[0205] or a pharmaceutically acceptable salt thereof, wherein R 14 、R 15 、R 10a 、R 11a , L2 and Z2 are as defined above in conjunction with formula (III) or any embodiment thereof.

[0206] In some embodiments, the present invention relates to compounds of any one of formula (II) and (III), or a pharmaceutically acceptable salt thereof, wherein L2 is a single bond. In some embodiments, L2 is -CH2-.

[0207] In some embodiments, the present invention relates to compounds of any one of formula (II) and (III), or a pharmaceutically acceptable salt thereof, wherein R 14 is H, halo or C1-C6 alkoxy. In some embodiments, R 14 is H. In some embodiments, R 14 In some embodiments, R 14 is Br. In some embodiments, R 14 In some embodiments, R 14 It's a methoxy group.

[0208] In some embodiments, the present invention relates to compounds of any one of formula (II) and (III), or a pharmaceutically acceptable salt thereof, wherein R 15 It is C(O)NR 16 R 17 or 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted with 1-4 C1-C6 alkyl groups. In some embodiments, R 15 It is C(O)NR 16 R 17 In some embodiments, R 15 is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally substituted with 1-4 C1-C6 alkyl groups. 15 is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally substituted with 1-2 methyl groups.

[0209] In some embodiments, the present invention relates to compounds of any one of formula (II) and (III), or a pharmaceutically acceptable salt thereof, wherein R 16 and R 17 Each independently represents H or C1-C6 alkyl. In some embodiments, R 16 and R 17 are each independently H. In some embodiments, R 16 and R 17 Each is independently a C1-C6 alkyl group.

[0210] In some embodiments, the present invention relates to compounds of any one of formula (II) and (III), or a pharmaceutically acceptable salt thereof, wherein R 8a is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1-4 substituents selected from C1-C6 alkyl, halo, and C1-C6 haloalkyl. 8a is H. In some embodiments, R 8a In some embodiments, R 8a is a C1-C6 alkyl group. In some embodiments, R 8a is a C1-C6 haloalkyl group. In some embodiments, R 8a is a C3-C6 cycloalkyl group optionally substituted with 1-4 substituents selected from C1-C6 alkyl, halo and C1-C6 haloalkyl. 8a is H. In some embodiments, R 8a is Br. In some embodiments, R 8a It's Cl.

[0211] In some embodiments, the present invention relates to compounds of any one of formula (II) and (III), or a pharmaceutically acceptable salt thereof, wherein R 9a is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1-4 substituents selected from C1-C6 alkyl, halo, and C1-C6 haloalkyl. 9a is a C1-C6 alkyl group. In some embodiments, R 9a is a C1-C6 haloalkyl group. In some embodiments, R 9a is a C3-C6 cycloalkyl group optionally substituted with 1-4 substituents selected from C1-C6 alkyl, halo and C1-C6 haloalkyl. 9a In some embodiments, R 9a In some embodiments, R 9a is a C3 cycloalkyl group optionally substituted with 1-4 substituents selected from C1-C6 alkyl, halo and C1-C6 haloalkyl. 9a is a C3 cycloalkyl group optionally substituted with one -CF3. 9a is a C4 cycloalkyl group optionally substituted with 1-4 substituents selected from C1-C6 alkyl, halo and C1-C6 haloalkyl. 9a is a C4 cycloalkyl group optionally substituted with a substituent -CF3. In some embodiments, R 9ais a C4 cycloalkyl optionally substituted with 1-2 F substituents. In some embodiments, R 9a is a C4 cycloalkyl optionally substituted with 1-2 C1-C6 alkyl substituents. In some embodiments, R 9a is a C4 cycloalkyl optionally substituted with 1-2 methyl substituents. In some embodiments, R 9a is a C4 cycloalkyl group optionally substituted by 1-2 substituents selected from halo and C1-C6 alkyl. 9a is a C4 cycloalkyl group optionally substituted by 1-2 substituents selected from F and methyl. In some embodiments, R 9a is a C5 cycloalkyl group optionally substituted with 1-4 substituents selected from C1-C6 alkyl, halo and C1-C6 haloalkyl. 9a is C5 cycloalkyl optionally substituted with one substituent -CF3.

[0212] In some embodiments, the present invention relates to compounds of any one of formula (II) and (III), or a pharmaceutically acceptable salt thereof, wherein R 10a is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1-4 substituents selected from C1-C6 alkyl, halo, and C1-C6 haloalkyl. 10a is H. In some embodiments, R 10a It is a C1-C6 alkyl group.

[0213] In some embodiments, the present invention relates to compounds of any one of formula (II) and (III), or a pharmaceutically acceptable salt thereof, wherein R 11a is H, halo or C1-C6 alkyl. In some embodiments, R 11a is H. In some embodiments, R 11a In some embodiments, the present invention relates to compounds of any one of formulas (II) and (III), or pharmaceutically acceptable salts thereof, wherein Z1 is a 4-10 membered cycloalkyl, a 3-10 membered cycloalkenyl, a phenyl, or a 5-6 membered heteroaryl. In some embodiments, Z1 is a 4-10 membered cycloalkyl.

[0214] In certain embodiments, the present invention relates to the compound of any one of formula (II) and (III), or its pharmaceutically acceptable salt, wherein Z2 is C1-C6 cycloalkyl or phenyl, wherein the C1-C6 cycloalkyl or phenyl is optionally substituted by 1-4 substituents selected from halo and C1-C6 alkyl. In certain embodiments, Z2 is C4 cycloalkyl, wherein the C4 cycloalkyl is optionally substituted by 1-4 substituents selected from halo and C1-C6 alkyl. In certain embodiments, Z2 is C4 cycloalkyl, wherein the C4 cycloalkyl is optionally substituted by 1-4 F substituents. In certain embodiments, Z2 is cyclohexane, wherein the cyclohexane is optionally substituted by 1-4 substituents selected from F and CF3. In certain embodiments, Z2 is phenyl, wherein the phenyl is optionally substituted by 1-4 substituents selected from F and methyl.

[0215] In some embodiments, the present invention relates to compounds of any one of formula (II) and (IIII) or any embodiment thereof, ie, in non-salt form.

[0216] 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, a compound in non-salt form.

[0217] Table A. Compound structures and names.

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257] 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.

[0258] Table B. Compound structures and names.

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285] In some embodiments, the present invention relates to compounds of the formula

[0286]

[0287] 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.

[0288] In some embodiments, the present invention relates to compounds of the formula

[0289]

[0290] 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.

[0291] In some embodiments, the present invention relates to compounds of the formula

[0292]

[0293] 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.

[0294] In some embodiments, the present invention relates to compounds of the formula

[0295]

[0296] 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.

[0297] In some embodiments, the present invention relates to compounds of the formula

[0298]

[0299] 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.

[0300] In some embodiments, the present invention relates to compounds of the formula

[0301]

[0302] 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.

[0303] In some embodiments, the present invention relates to compounds of the formula

[0304]

[0305] 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.

[0306] In some embodiments, the present invention relates to compounds of the formula

[0307]

[0308] 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.

[0309] In some embodiments, the present invention relates to compounds of the formula

[0310]

[0311] 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.

[0312] In some embodiments, the present invention relates to compounds of the formula

[0313]

[0314] 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.

[0315] In some embodiments, the present invention relates to compounds of the formula

[0316]

[0317] 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.

[0318] In some embodiments, the present invention relates to compounds of the formula

[0319]

[0320] 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.

[0321] In some embodiments, the present invention relates to compounds of the formula

[0322]

[0323] 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.

[0324] In some embodiments, the present invention relates to compounds of the formula

[0325]

[0326] 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.

[0327] In some embodiments, the present invention relates to compounds of the formula

[0328]

[0329] 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.

[0330] In some embodiments, the present invention relates to compounds of the formula

[0331]

[0332] 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.

[0333] In some embodiments, the present invention relates to compounds of the formula

[0334]

[0335] 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.

[0336] In some embodiments, the present invention relates to compounds of the formula

[0337]

[0338] 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.

[0339] In some embodiments, the present invention relates to compounds of the formula

[0340]

[0341] 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.

[0342] In some embodiments, the present invention relates to compounds of the formula

[0343]

[0344] 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.

[0345] In some embodiments, the present invention relates to compounds of the formula

[0346]

[0347] 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.

[0348] In some embodiments, the present invention relates to compounds of the formula

[0349]

[0350] 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.

[0351] In some embodiments, the present invention relates to compounds of the formula

[0352]

[0353] 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.

[0354] In some embodiments, the present invention relates to compounds of the formula

[0355]

[0356] 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.

[0357] In some embodiments, the present invention relates to compounds of the formula

[0358]

[0359] 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.

[0360] In some embodiments, the present invention relates to compounds of the formula

[0361]

[0362] 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.

[0363] In some embodiments, the present invention relates to compounds of the formula

[0364]

[0365] 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.

[0366] In some embodiments, the present invention relates to compounds of the formula

[0367]

[0368] 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.

[0369] In some embodiments, the present invention relates to compounds of the formula

[0370]

[0371] 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.

[0372] In some embodiments, the present invention relates to compounds of the formula

[0373]

[0374] 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.

[0375] In some embodiments, the present invention relates to compounds of the formula

[0376]

[0377] 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.

[0378] In some embodiments, the present invention relates to compounds of the formula

[0379]

[0380] 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.

[0381] In some embodiments, the present invention relates to compounds of the formula

[0382]

[0383] 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.

[0384] In some embodiments, the present invention relates to compounds of the formula

[0385]

[0386] 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.

[0387] In some embodiments, the present invention relates to compounds of the formula

[0388]

[0389] 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.

[0390] In some embodiments, the present invention relates to compounds of the formula

[0391]

[0392] 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.

[0393] In some embodiments, the present invention relates to compounds of the formula

[0394]

[0395] 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.

[0396] In some embodiments, the present invention relates to compounds of the formula

[0397]

[0398] 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.

[0399] In some embodiments, the present invention relates to compounds of the formula

[0400]

[0401] 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.

[0402] In some embodiments, the present invention relates to compounds of the formula

[0403]

[0404] 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.

[0405] In some embodiments, the present invention relates to compounds of the formula

[0406]

[0407] 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.

[0408] In some embodiments, the present invention relates to compounds of the formula

[0409]

[0410] 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.

[0411] In some embodiments, the present invention relates to compounds of the formula

[0412]

[0413] 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.

[0414] In some embodiments, the present invention relates to compounds of the formula

[0415]

[0416] 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.

[0417] In some embodiments, the present invention relates to compounds of the formula

[0418]

[0419] 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.

[0420] In some embodiments, the present invention relates to compounds of the formula

[0421]

[0422] 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.

[0423] In some embodiments, the present invention relates to compounds of the formula

[0424]

[0425] 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.

[0426] In some embodiments, the present invention relates to compounds of the formula

[0427]

[0428] 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.

[0429] In some embodiments, the present invention relates to compounds of the formula

[0430]

[0431] 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.

[0432] In some embodiments, the present invention relates to compounds of the formula

[0433]

[0434] 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.

[0435] In some embodiments, the present invention relates to compounds of the formula

[0436]

[0437] 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.

[0438] In some embodiments, the present invention relates to compounds of the formula

[0439]

[0440] 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.

[0441] In some embodiments, the present invention relates to compounds of the formula

[0442]

[0443] 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.

[0444] In some embodiments, the present invention relates to compounds of the formula

[0445]

[0446] 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.

[0447] In some embodiments, the present invention relates to compounds of the formula

[0448]

[0449] 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.

[0450] Salts, compositions, uses, formulations, administration and other pharmaceutical agents

[0451] Pharmaceutically acceptable salts and compositions

[0452] 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 include a compound as described herein or a pharmaceutically acceptable salt thereof and optionally include a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, these compositions optionally further include one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0453] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals, without undue toxicity, irritation, allergic response, etc., and 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.

[0454] Pharmaceutically acceptable salts are well known in the art. For example, S.M. 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 of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid; or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconate heptanoate, 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 1-4 Representative 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.

[0455] As described herein, the pharmaceutically acceptable compositions of the present invention additionally include pharmaceutically acceptable carriers, adjuvants or vehicles, as used herein, the carriers, adjuvants or vehicles include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., such as those suitable for the desired specific dosage form. Remington's Pharmaceutical Sciences, 16th edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers for the preparation of pharmaceutically acceptable compositions and the known technology thereof. Unless any conventional carrier medium is incompatible with the compound of the present invention, such as by producing any undesirable biological effect or interacting with any other component 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 carboxymethyl cellulose, ethyl cellulose and cellulose acetate. Cellulose; 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.

[0456] In another aspect, the invention features a pharmaceutical composition including a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0457] In another aspect, the invention features a pharmaceutical composition including a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or vehicles.

[0458] Uses of compounds, pharmaceutically acceptable salts, and compositions

[0459] 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.

[0460] 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.

[0461] 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.

[0462] 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 pain from inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, endometriosis, polycystic ovary disease, salpingitis, cervicitis, or interstitial cystitis, wherein the method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0463] 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.

[0464] 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 includes: post-herpetic neuralgia, diabetic neuropathy, 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 neuralgia; 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.

[0465] 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.

[0466] 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.

[0467] 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 comprises 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.

[0468] 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.

[0469] 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 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.

[0470] In yet another aspect, the invention features a method of treating or lessening the severity of idiopathic 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.

[0471] In yet another aspect, the invention features a method of treating or lessening the severity of pathological cough in a subject, the method comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0472] 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.

[0473] 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.

[0474] 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.

[0475] In yet another aspect, the invention features a method of treating or lessening the severity of shoulder replacement pain or arthroscopic shoulder 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.

[0476] 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.

[0477] 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.

[0478] 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.

[0479] In another aspect, the present invention is characterized in that a method for treating a neurodegenerative disease in a subject or alleviating its severity comprises 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).

[0480] 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.

[0481] 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.

[0482] 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 in a subject. , 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, hemorrhoidectomy 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.

[0483] 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.

[0484] 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.

[0485] Compounds, pharmaceutically acceptable salts, and compositions for use

[0486] 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.

[0487] 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.

[0488] 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.

[0489] 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.

[0490] 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, polycystic ovary disease, salpingitis, cervicitis, or interstitial cystitis.

[0491] 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.

[0492] 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 neuropathic pain in a subject, wherein the neuropathic pain includes: post-herpetic neuralgia, diabetic neuropathy, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, 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 neuralgia; pain after spinal cord injury, spinal stenosis pain, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic cephalus.

[0493] 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.

[0494] 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.

[0495] 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 comprises rheumatoid arthritis pain, ankylosing spondylitis, or vulvodynia.

[0496] 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.

[0497] 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.

[0498] 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 reflex sympathetic dystrophy pain.

[0499] 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.

[0500] 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.

[0501] 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.

[0502] 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.

[0503] 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 shoulder replacement pain or arthroscopic shoulder pain in a subject.

[0504] 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.

[0505] 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.

[0506] 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.

[0507] 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 is used to treat a neurodegenerative disease in a subject or to reduce its severity. In some aspects, neurodegenerative diseases include multiple sclerosis. In some aspects, neurodegenerative diseases include Pitt Hopkins Syndrome (PTHS).

[0508] 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.

[0509] 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.

[0510] 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 disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis and intestinal tract infections in a subject. Central neuropathic pain in irritable 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, hemorrhoidectomy pain, hernia repair pain, bunionectomy pain, or abdominoplasty pain), cancer pain, including chronic cancer pain and breakthrough cancer pain , stroke (e.g., post-stroke central neuropathic pain), whiplash-related conditions, fragility fractures, vertebral fractures, ankylosing spondylitis, pemphigus, Raynaud's 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 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 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, exercise-induced angina, palpitations, hypertension, or gastrointestinal dysmotility, or methods of reducing the severity thereof.

[0511] 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.

[0512] 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.

[0513] Preparation of medicine

[0514] 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.

[0515] 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.

[0516] 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.

[0517] 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.

[0518] In yet another aspect, the present invention provides 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 caused by inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, endometriosis, polycystic ovary disease, salpingitis, cervicitis, or interstitial cystitis.

[0519] 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).

[0520] 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 neuropathic pain in a subject or alleviating its severity, wherein the neuropathic pain includes: post-herpetic neuralgia, diabetic neuropathy, 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 neuralgia; pain after spinal cord injury, spinal stenosis pain, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic neuropathy.

[0521] 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.

[0522] 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.

[0523] 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 inflammatory pain in a subject or alleviating its severity, wherein the inflammatory pain includes rheumatoid arthritis pain, ankylosing spondylitis, or vulvodynia.

[0524] 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.

[0525] 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.

[0526] 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.

[0527] 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.

[0528] 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.

[0529] 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.

[0530] 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.

[0531] 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.

[0532] 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.

[0533] 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.

[0534] 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.

[0535] 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 is used to prepare a medicine for treating a neurodegenerative disease in a subject or reducing its severity. In some aspects, neurodegenerative diseases include multiple sclerosis. In some aspects, neurodegenerative diseases include Pitt Hopkins Syndrome (PTHS).

[0536] 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.

[0537] 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 disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis and irritable bowel syndrome. Central neuropathic pain with complications, 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, hemorrhoidectomy pain, hernia repair pain, bunionectomy pain, or abdominoplasty pain), cancer pain, including chronic cancer pain and breakthrough cancer pain, and stroke (e.g., central neuropathic pain after stroke), whiplash-related conditions, fragility fractures, vertebral 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, 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 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, exercise-induced angina, palpitations, hypertension, or gastrointestinal dysmotility, or agents to lessen their severity.

[0538] On the other hand, 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 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 headache, migraine, tension headache, cluster headache, chronic and acute neuropathic pain, postherpetic neuralgia, diabetic neuropathy, HIV-related neuropathy, trigeminal nerve pain, pain, 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 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, vitiligo pain Use of pain caused by Silva's disease, adiposity dolorosa, phlebitis pain, Guillain-Barré syndrome pain, pain in the legs and moving toes, 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 an agent to reduce its severity.

[0539] 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.

[0540] Administration of compounds, pharmaceutically acceptable salts, and compositions

[0541] 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.

[0542] 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.

[0543] 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.

[0544] 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 compounds or salts, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, 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, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof. In addition to inert diluents, oral compositions can also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and aromatics.

[0545] 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 nontoxic parenteral acceptable 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. In addition, sterile fixed oils are conventionally used as solvents or suspension media. For this purpose, any gentle fixed oil can be employed, including synthetic monoglycerides or diglycerides. In addition, fatty acids, such as oleic acid, are used in the preparation of injectables.

[0546] 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 which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0547] 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 crystalline form. Alternatively, delayed absorption of the compound form administered parenterally can be achieved by dissolving or suspending the compound in an oily vehicle. Injectable reservoir-type (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 liposomes or microemulsions compatible with human tissues.

[0548] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compound or salt of the invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0549] 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 include a buffer.

[0550] 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.

[0551] 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, controlled release coatings and other coatings well known in the field of pharmaceutical preparations. 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. Such dosage forms can also conventionally contain other substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form can also include a buffer. 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 embedding compositions that can be used include polymeric substances and waxes.

[0552] The dosage form for topical or transdermal administration of the compound or salt of the present invention comprises an 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 required under aseptic conditions. Ophthalmic formulations, ear drops and eye drops are also considered to be within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches, which have the additional advantage of allowing the compound to be delivered to the body in a controlled manner. Such dosage forms are prepared by dissolving or being dispersed in an appropriate medium. Absorption enhancers can also be used to increase the flow 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 a gel.

[0553] 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 V 1.8 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 NaV 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". Therefore, in another aspect, the present invention provides a method for treating wherein Na V 1.8 Methods of activating or hyperactivating a disease, condition or disorder associated with a disease state or lessening its severity.

[0554] 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.

[0555] Additional therapeutic agents

[0556] 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 used to treat or prevent a specific 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.

[0557] In another embodiment, the additional suitable therapeutic agent is selected from the group consisting of:

[0558] (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;

[0559] (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) (e.g., )), meclofenamic acid, mefenamic acid, meloxicam, IV meloxicam (e.g., ), nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, or zomepirac;

[0560] (3) Barbiturate sedatives, such as amobarbital (amomobarbital), aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal, or thiopental;

[0561] (4) benzodiazepines with sedative effects, such as chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam;

[0562] (5) Histamine (H1) antagonists with sedative effects, such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine, or chlorcyclizine;

[0563] (6) Sedatives, such as glutethimide, meprobamate, methaqualone, or dichloralphenazone;

[0564] (7) skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphenadrine;

[0565] (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;

[0566] (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;

[0567] (10) tricyclic antidepressants, such as desipramine, imipramine, amitriptyline or nortriptyline;

[0568] (11) Anticonvulsants, such as carbamazepine Lamotrigine, topiramate, lacosamide or valproate;

[0569] (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);

[0570] (13) Muscarinic antagonists, such as oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

[0571] (14) COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib or lumiracoxib;

[0572] (15) Coal tar analgesics, especially paracetamol;

[0573] (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;

[0574] (17) Vanilloid receptor agonists (e.g., resinferatoxin or civamide) or antagonists (e.g., capsazepine, GRC-15300);

[0575] (18) β-adrenergic agents, such as propranolol;

[0576] (19) Local anesthetics, such as mexiletine;

[0577] (20) Corticosteroids, such as dexamethasone;

[0578] (21) 5-HT receptor agonists or antagonists, specifically 5-HT 1B / 1Dagonists, such as eletriptan, sumatriptan, naratriptan, zolmitriptan, or rizatriptan;

[0579] (22)5-HT 2A Receptor antagonists, such as R(+)-α-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinol (MDL-100907);

[0580] (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 (nicotine);

[0581] (twenty four) Tramadol ER(Ultram) ), IV Tramadol, Tapentadol ER

[0582] (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;

[0583] (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;

[0584] (27) Cannabinoids, such as KHK-6188;

[0585] (28) metabotropic glutamate subtype 1 receptor (mGluR1) antagonists;

[0586] (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;

[0587] (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;

[0588] (31) Dual serotonin-norepinephrine reuptake inhibitors, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, and duloxetine milnacipran and imipramine;

[0589] (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;

[0590] (33) Acetylcholinesterase inhibitors, such as donepezil;

[0591] (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;

[0592] (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;

[0593] (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);

[0594] (37) Sodium channel blockers, such as lidocaine, lidocaine plus tetracaine cream (ZRS-201), or eslicarbazepine acetate;

[0595] (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, for example, WO2011 / 140425 (US2011 / 306607); WO2012 / 106499 (US2012196869); WO2012 / 112743 (US2012245136); WO2012 / 125613 (US2012264749), WO2012 / 116440 (US2014 187533), WO2011026240 (US2012220605), US8883840, US8466188, WO2013 / 109521 (US2015005304), WO2020 / 117626, WO2021 / 252822, WO2021 / 252818, WO2021 / 252820, WO2014 / 201173, WO2012 / 125973, WO2013 / 086229, WO2013 / 134518, WO2014 / 201206, or WO2016 / 141035 and CN111217776, the entire contents of each of which are hereby incorporated by reference;

[0596] (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;

[0597] (39)Na V 1.8 Blockers, such as PF-04531083, PF-06372865 and those disclosed in the following applications: WO2008 / 135826 (US2009048306), WO2006 / 011050

[0598] (US2008312235), WO2013 / 061205 (US2014296313), US20130303535, WO2013131018, US8466188, WO201 3114250(US2013274243)、WO2014 / 120808(US2014213616)、WO2014 / 120815(US2014228371)WO2014 / 12 0820(US2014221435), WO2015 / 010065(US20160152561), WO2015 / 089361(US20150166589), WO2019 / 0 14352 (US20190016671), WO2018 / 213426, WO2020 / 146682, WO2020 / 146612, WO2020 / 014243, WO2020 / 01 4246, WO2020 / 092187, WO2020 / 092667 (US2020140411), WO2020 / 261114, WO2020 / 140959, WO2020 / 144 375. WO2020 / 151728, WO2021 / 032074, WO2021 / 257490, WO / 2021 / 257420, WO2021 / 257418, WO2022 / 2634 98, WO2022 / 235558, WO2022 / 235859, CN112390745, CN111808019, CN112225695, CN112457294, CN112300051, CN112300069, CN112441969, CN112479996 (WO2021 / 047622), and CN114591293, the entire contents of each of which are hereby incorporated by reference;

[0599] (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-(p-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]dihydrogen phosphate ) methyl ester, 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinic acid, 2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide, 2-(4-fluoro-2-methoxyphenoxy) quinoxaline-2-carboxamide, 3-(4-(trifluoromethoxy)phenoxy)-N-(3-sulfamoylphenyl)quinoxaline-3-carboxamide, 3-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoxaline-3-carboxamide, N-(3-sulfamoylphenyl)-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide, 3-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinic acid, 3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1H- quinoxaline-2-carboxamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4-yl)quinoxaline-2-carboxamide, 3-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, N-(4-carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)benzoic acid, N-(4-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 5-(2-(2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl) )benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)benzoic acid, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 4-(2-(2-chloro-4-fluorophenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 4-(2-(4-fluoro-2-methylphenoxy)- 4-(perfluoroethyl)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4-chloro-2-methylphenoxy)benzamido)benzoic acid, 5-(4-(tert-butyl)-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4 -fluoro-2-methylphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4-dimethoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(2-chloro-4-fluorophenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4-difluorophenoxy)benzamido)picolinic acid, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide , 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide )-4,6-bis(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3-sulfamoylphenyl)benzamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, N-(3-aminomethyl)benzamide benzoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteromethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteromethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide oxy)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]benzoyl]amino]pyridine-2-carboxamide amine, 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-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 1-[4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-pentafluoroethyl)benzamide, 4-[[4-(difluoromethoxy)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[4-cyclopropyl-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N- (3-Carbamoyl-4-fluoro-phenyl)-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide, 5-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzamide or 4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide;

[0600] (40) Combined Na V 1.7 and Na V1.8 Blockers, such as DSP-2230, Lohocla201 or BL-1021;

[0601] (41) 5-HT3 antagonists, such as ondansetron;

[0602] (42) TPRV1 receptor agonists, such as capsaicin and pharmaceutically acceptable salts and solvates thereof;

[0603] (43) Nicotinic receptor antagonists, such as varenicline;

[0604] (44) N-type calcium channel antagonists, such as Z-160;

[0605] (45) Nerve growth factor antagonists, such as tanezumab;

[0606] (46) Endopeptidase stimulators, such as senrebotase;

[0607] (47) Angiotensin II antagonists, such as EMA-401;

[0608] (48) Acetaminophen (including but not limited to intravenous acetaminophen (e.g., ));

[0609] (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

[0610] (50) Bupivacaine and meloxicam combination (e.g., HTX-011).

[0611] 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.

[0612] 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.

[0613] 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.

[0614] In another embodiment, the additional therapeutic agent is oliceridine or ropivacaine (TLC590).

[0615] In another embodiment, the additional therapeutic agent is Na V 1.7 Blockers, such as ST-2427 or ST-2578 and / or those disclosed in WO2010 / 129864, WO2015 / 157559, WO2017 / 059385, WO2018 / 183781, WO2018 / 183782, WO2020 / 072835 and WO2022 / 036297, the entire contents of each application are hereby incorporated by reference.

[0616] 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.

[0617] 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, R TA901, NRD1355-E1, MT-8554, LY3556050, AP-325, tetrodotoxin, Otenaproxesul, CFTX-1554, Funapide, iN1011-N17, JMKX000623 / ODM-111, ETX-801, OLP-1002, ANP-230 / DSP-2230, iN1011-N17, DSP-3905, or ACD440.

[0618] 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.

[0619] The amount of additional therapeutic agent present in the compositions of the present invention may be no more than the amount normally administered in a composition comprising the therapeutic agent as the sole active agent. The amount of additional therapeutic agent in the compositions disclosed herein may range from about 10% to 100% of the amount normally present in a composition comprising the agent as the sole therapeutically active agent.

[0620] 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 comprises a composition for coating an implantable device 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 comprises an implantable device 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.

[0621] 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.

[0622] 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.

[0623] Synthesis of the compounds of the present invention

[0624] 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).

[0625] Radiolabeled analogs of the compounds of the invention

[0626] 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.

[0627] 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, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0628] 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 C) Labeled compounds can be used in various types of assays, such as substrate tissue distribution assays, due to their relative ease of preparation and excellent detectability.

[0629] 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.

[0630] 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.

[0631] 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.

[0632] 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.

[0633] 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.

[0634] 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.

[0635] Examples

[0636] General Methods: Obtained as a solution in an appropriate deuterated solvent such as dimethyl sulfoxide-d6 (DMSO-d6) 1 H NMR spectroscopy.

[0637] Compound purity, retention times, and electrospray mass spectrometry (ESI-MS) data were determined by LC / MS analysis.

[0638] LC / MS Methods: LC / MS measurements were performed using one of the following chromatographic conditions: 1) Waters BEH C8 (1.7 μm, 2.1 × 50 mm), 2 to 98% acetonitrile in water (10 mM ammonium formate, pH 9) over 5.0 minutes at 45°C, flow rate 0.6 mL / min; 2) Kinetex EVO C18 (2.6 μm, 2.1 × 50 mm), 2 to 98% acetonitrile in water (10 mM ammonium formate, pH 9) over 4.0 minutes at 45°C, flow rate 0.7 mL / min; 3) Kinetex EVO C18 (2.6 μm, 2.1 × 50 mm), 2 to 98% acetonitrile in water (10 mM ammonium formate, pH 9) over 1.5 minutes at 45°C, flow rate 1.0 mL / min; 4) Waters Acquity UPLC BEH C18 (1.7 μm, 30×2.1 mm), 1 to 99% acetonitrile (0.035% TFA) in water (0.05% TFA) over 3 minutes, 60°C, flow rate = 1.5 mL / min; 6) Kinetex Polar C18 (2.6 μm, 3.0×50 mm), 5 to 95% acetonitrile in water (0.1% formic acid) over 6 minutes, flow rate 1.2 mL / min; 7) SunFire C18 (3.5 μm, 75×4.6 mm), 5 to 95% acetonitrile in water (0.1% formic acid) over 6 minutes, initially in 1 minute, then a linear gradient to 95% acetonitrile over 5 minutes, 45°C, flow rate 1.5 mL / min; 8) XBridge C18 (5 μm, 4.6 × 75 mm), initial gradient 5 to 95% acetonitrile (NH4HCO3) in 6 min run, 1 min equilibrium gradient, 95% acetonitrile from 0 to 3 min and hold for 3 min, flow rate 1.5 mL / min; 9) Waters CSH C18 (1.7 μm, 2.1 × 50 mm), 2 to 98% acetonitrile in water (0.1% TFA, pH 2) in 5.0 min, 45°C, flow rate 0.6 mL / min; 10) Waters CSH C18 (1.7 μm, 2.1 × 50 mm), 2 to 95% acetonitrile in water (0.1% formic acid) in 4.6 min, 40°C, flow rate 0.8 mL / min; 11) Waters BEH C18 (2.5 μm, 2.1 × 50 mm), 2 to 95% acetonitrile in water (0.1% TFA, pH 2) in 4.6 min, 40°C, flow rate 0.8 mL / min NH3), 2 to 95% acetonitrile in water (0.1% formic acid), 40°C, flow rate 0.8 mL / min; 13) Waters BEH C18 (3.5 μm, 75×4.6 mm), initial gradient from 5 to 95% acetonitrile in water (0.1% formic acid) over 6 minutes, then a linear gradient to 95% acetonitrile over 4 minutes, hold at 95% acetonitrile for 2 minutes, 45°C, flow rate 1.5 mL / min; 14) Waters BEH C18 (2.5 μm, 2.1×50 mm), 2 to 50% acetonitrile in water (0.1% NH3) in 4.6 minutes, 40°C, flow rate 0.8 mL / min; 15) Waters CSH C18 (1.7 μm, 2.1×50 mm), 2 to 98% acetonitrile in water (0.1% TFA) in 1.5 minutes, 45°C, flow rate 1.0 mL / min; 16) Waters CSH C18 (1.7 μm, 2.1×50 mm), 2 to 95% acetonitrile in water (0.1% formic acid) in 1.4 minutes, 40°C, flow rate 0.8 mL / min; 17) YMC Triart C18 (3 μm, 33×2.1 mm), 2 to 98% acetonitrile in water (5 mM NH4OAc) in 3 minutes, flow rate 1.0 mL / min; 18) Waters BEH C18 (2.5 μm, 2.1×50 mm), 2 to 95% acetonitrile in water (0.1% NH3) in 1.4 minutes, 40°C, flow rate 0.8 mL / min; 19) Waters Acquity UPLC BEH C18 (1.7 μm, 30×2.1 mm), 1 to 99% acetonitrile (0.035% TFA) in water (0.05% TFA) in 5 minutes, 60°C, flow rate = 1.5 mL / min; 20) Waters BEH C18 (2.5 μm, 2.1×50 mm), 20 to 70% acetonitrile in water (0.1% NH3) in 4.60 minutes, 40°C, flow rate 0.8 mL / min; 21) Kinetex Polar C18 column (2.6 μm, 3.0 × 50 mm), 5 to 95% acetonitrile in water (0.1% formic acid) in 3 minutes, flow rate 1.2 mL / min; 22) Waters Acquity UPLC BEH C18 column (1.7 μm, 30 × 2.1 mm), 1 to 99% acetonitrile in water (0.05% TFA) in 1 minute (0.035% TFA), 60°C, flow rate = 1.5 mL / min; 23) YMC Triart C18 column (3 μm, 33 × 2.1 mm), 2 to 98% acetonitrile in water (0.05% formic acid) in 3 minutes, flow rate 1.0 mL / min; 24) Waters Acquity UPLC BEH C18 (1.7 μm, 30 × 2.1 mm), 1 to 99% acetonitrile (0.05% ammonium formate) in water (0.05% ammonium formate) in 5 minutes, 60°C, flow rate = 1.5 mL / min; 25) Waters CSH C18 (1.7 μm, 2.1 × 50 mm), 2 to 98% acetonitrile in water (0.1% TFA) in 4.0 minutes, 45°C, flow rate 0.6 mL / min; 26) Acquity BEH C8 (1.7 μm, 50 × 2.1 mm), 2 to 98% 90:10 acetonitrile:water (0.05% formic acid), flow rate 0.8 mL / min; 27) XBridge C18 (5 μm, 50 × 4.6 mm), 10 to 90% acetonitrile in water (10 mM NH4OAc) over 6 minutes, flow rate 1.2 mL / min; 28) YMC Triart C18 (3 μm, 33 × 2.1 mm), 5 to 95% acetonitrile in water (0.05% formic acid) over 12 minutes, flow rate 1.0 mL / min; 29) Waters BEH C8 (1.7 μm, 2.1 × 50 mm), 50 to 95% acetonitrile in water (0.1% NH3) over 1.4 minutes, 40°C, flow rate 0.8 mL / min.

[0639] abbreviation

[0640] Unless otherwise stated or the context requires otherwise, the following abbreviations shall be understood to have the following meanings:

[0641] abbreviation meaning

[0642] NMR Nuclear Magnetic Resonance

[0643] ESI-MS electrospray mass spectrometry

[0644] LC / MS liquid chromatography-mass spectrometry

[0645] UPLC ultra-performance liquid chromatography

[0646] HPLC / MS / MS High-performance liquid chromatography / tandem mass spectrometry

[0647] IS internal standard

[0648] HPLC high-performance liquid chromatography

[0649] SFC Supercritical Fluid Chromatography

[0650] ESI electrospray ionization

[0651] g grams

[0652] mg milligrams

[0653] kg kilogram

[0654] L liter

[0655] mL milliliters

[0656] μL microliter

[0657] nL nanoliter

[0658] mol mole

[0659] mmol millimole

[0660] hr, h hours

[0661] min

[0662] ms milliseconds

[0663] mm millimeter

[0664] μm micrometer

[0665] nm nanometer

[0666] MHz Megahertz

[0667] Hz Hertz

[0668] N Normal (concentration)

[0669] M molar (concentration)

[0670] mM millimolar (concentration)

[0671] μM micromolar (concentration)

[0672] ppm parts per million

[0673] %w / v weight-volume concentration

[0674] abbreviation meaning

[0675] %w / w weight-weight concentration

[0676] t-BuOH tert-Butanol

[0677] CDI 1,1'-Carbonyldiimidazole

[0678] DAST Diethylaminosulfur trifluoride

[0679] DCM dichloromethane

[0680] DCE dichloroethane

[0681] DIEA, DIPEA N,N-diisopropylethylamine

[0682] DMA N,N-dimethylacetamide

[0683] DMAP N,N-dimethylaminopyridine

[0684] DMF N,N-dimethylformamide

[0685] DMSO dimethyl sulfoxide

[0686] DRG dorsal root ganglion

[0687] EDC.HCl Ethylcarbodiimide hydrochloride

[0688] EtOH

[0689] EtOAc

[0690] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine

[0691] Onium 3-hexafluorophosphate oxide

[0692] HOBt Hydroxybenzotriazole

[0693] EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0694] T3P Propylphosphonic anhydride, i.e., 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphine 2,

[0695] 4,6-trioxide

[0696] KOAc potassium acetate

[0697] m-CPBA m-chloroperbenzoic acid

[0698] MeOH methanol

[0699] MTBE methyl tert-butyl ether

[0700] NaOH sodium hydroxide

[0701] NBS N-bromosuccinimide

[0702] NMP N-Methylpyrrolidone

[0703] NMO N-Methylmorpholine N-oxide

[0704] PPTS Pyridinium p-toluenesulfonate

[0705] TBAB Tetra-n-butylammonium bromide

[0706] TBAF Tetra-n-butylammonium fluoride

[0707] TBSCl tert-Butyldimethylsilyl chloride

[0708] abbreviation meaning

[0709] TBSOTf tert-Butyldimethylsilyl trifluoromethanesulfonate

[0710] THF Tetrahydrofuran

[0711] TEA triethylamine

[0712] TFA trifluoroacetic acid

[0713] RB Round Bottom Flask

[0714] RT Room temperature

[0715] ca. approximately (circa)(approximately)

[0716] E-VIPR Electrically Stimulated Voltage Ion Probe Reader

[0717] HEK human embryonic kidney

[0718] KIR2.1 inward rectifier potassium channel 2.1

[0719] DMEM Dulbecco's Modified Eagle's Medium

[0720] FBS fetal bovine serum

[0721] NEAA non-essential amino acids

[0722] HEPES 2-[4-(2-Hydroxyethyl)piperazin-1-yl]ethanesulfonic acid

[0723] DiSBAC6(3) Bis-(1,3-dihexyl-thiobarbituric acid) trimethyloxanol

[0724] CC2-DMPE Chlorocoumarin-2-tetracosanoylphosphatidylethanolamine

[0725] VABSC-1 Voltage Assay Background Suppression Compound

[0726] HS human serum

[0727] BSA bovine serum albumin

[0728] Example 1

[0729] Intermediate A-1

[0730]

[0731] Step 1: 4-Benzyloxy-2-chloro-1,6-naphthyridine

[0732] To a mixture of 2,4-dichloro-1,6-naphthyridine (1.0 g, 4.9 mmol) and benzyl alcohol (0.5 mL, 4.8 mmol) in DMF (10 mL) and 2-MeTHF (10 mL) was added sodium hydride (60% in mineral oil, 208 mg, 5.20 mmol) in portions at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 hour, then gradually warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into a stirred mixture of 0.1M HCl aqueous solution (50 mL) and 2-MeTHF (50 mL). The layers were separated and the aqueous layer was extracted with 2-MeTHF (2 × 100 mL). The combined organic layers were washed with water (2 × 50 mL), 1: 1 water / brine (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. Purification by silica gel chromatography (0-35% ethyl acetate / heptane) gave 4-benzyloxy-2-chloro-1,6-naphthyridine (528 mg, 38%) as an off-white solid. ESI-MS m / z calculated 270.06, found 271.1 (M+1) + . 1 H NMR (400MHz, CDCl3) δ9.58 (s, 1H), 8.78 (d, J = 5.9 Hz, 1H), 7.75 (dd, J = 5.9, 0.6 Hz, 1H), 7.54-7.37 (m, 5H), 6.92 (s, 1H), 5.34 (s, 2H).

[0733] Step 2: 4-Benzyloxy-2-chloro-6-oxo-1,6-naphthyridin-6-ium

[0734] To a solution of 4-benzyloxy-2-chloro-1,6-naphthyridine (1.75 g, 6.46 mmol) in DCM (14 mL) was added mCPBA (1.6 g, 7.14 mmol) at 0 ° C. The resulting mixture was stirred at room temperature for 18 hours and then diluted with 2M aqueous sodium carbonate solution (60 mL) and water (90 mL). The aqueous layer was extracted with additional DCM (3 × 100 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4-benzyloxy-2-chloro-6-oxo-1,6-naphthyridine-6-ium (1.796 g, 97%) as an off-white solid. ESI-MS m / z calculated value 286.05, experimental value 287.1 (M + 1) + . 1 H NMR (400MHz, CDCl3) δ9.02-8.94(m,1H),8.30(dd,J=7.3,2.1Hz,1H),7.79-7.72(m,1H),7.44(d,J=2.6Hz,5H),6.93(s,1H),5.29(s,2H).

[0735] Step 3: 4-Benzyloxy-2-chloro-1,6-naphthyridine-5-carbonitrile

[0736] To a solution of 4-benzyloxy-2-chloro-6-oxo-1,6-naphthyridine-6-ium (1.0 g, 3.5 mmol) in DCM (10 mL) was added trimethylsilylcarbonitrile (1.3 mL, 9.8 mmol) under a nitrogen atmosphere, followed by TEA (1.25 mL, 8.97 mmol). The reaction mixture was stirred at room temperature for 20 hours. The mixture was quenched with water and the aqueous layer was extracted with DCM (3 times). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. Purified by silica gel chromatography (0-30% ethyl acetate / DCM) to give 4-benzyloxy-2-chloro-1,6-naphthyridine-5-carbonitrile (840 mg, 81%). ESI-MS m / z calculated value 295.05, experimental value 296.1 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ8.91(d,J=5.7Hz,1H),8.12(d,J=5.7Hz,1H),7.67-7.58(m,3H),7.50-7.34(m,3H),5.61(s,2H).

[0737] Intermediate A-2

[0738]

[0739] Step 1: 8-Benzyloxy-6-chloro-1-oxo-1,5-naphthyridin-1-ium

[0740] 8-Benzyloxy-6-chloro-1-oxo-1,5-naphthyridin-1-ium was prepared from 4-benzyloxy-2-chloro-1,5-naphthyridine (Intermediate A-31) using a procedure similar to that found in Intermediate A-4, Step 2. ESI-MS m / z Calcd. 286.05, Found 287.1 (M+1) + ; Retention time: 1.62min.

[0741] Step 2: 8-Benzyloxy-6-chloro-1,5-naphthyridine-2-carbonitrile

[0742] 8-Benzyloxy-6-chloro-1,5-naphthyridine-2-carbonitrile was prepared from 8-benzyloxy-6-chloro-1-oxo-1,5-naphthyridin-1-ium using a procedure analogous to that found in Intermediate A-4, Step 3. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 8.6 Hz, 1H), 8.34 (d, J = 8.7 Hz, 1H), 7.63 (s, 1H), 7.60-7.53 (m, 2H), 7.51-7.39 (m, 3H), 5.50 (s, 2H). ESI-MS m / z calculated value 295.05, found value 296.1 (M+1) + .

[0743] Intermediate A-3

[0744] Step 1: 4-Benzyloxy-2-chloro-quinolin-5-ol

[0745]

[0746] A mixture of 4-benzyloxy-2-chloro-5-methoxy-quinoline (100 mg, 0.334 mmol), hydrogen bromide (2.0 mL 48% w / v, 11.7 mmol), and sodium iodide (50 mg, 0.33 mmol) was heated to 90°C for 18 hours. Purification by reverse phase chromatography (1-100% CH3CN / water) gave 4-benzyloxy-2-chloro-quinolin-5-ol (14 mg, 15%). ESI-MS m / z calculated: 285.06, found: 286.05 (M+1). + .

[0747] Intermediate A-4

[0748] Step 1: 4-Benzyloxy-2-chloro-quinoline

[0749]

[0750] At 0 ° C. under a nitrogen atmosphere, sodium hydride (16 mg, 0.68 mmol) was added portionwise to DMF (1 mL) containing 2-chloroquinoline-4-ol (102 mg, 0.570 mmol). The mixture was stirred at room temperature for 10 minutes and cooled again at 0 ° C., and benzyl bromide (75 μL, 0.63 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours and then distributed between brine (20 mL) and ethyl acetate (30 mL). The layers were separated, and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purified by silica gel chromatography (1-100% ethyl acetate / hexane) to obtain 4-benzyloxy-2-chloro-quinoline (139 mg, 90%) as a white solid. ESI-MS m / z calculated value 269.06, experimental value 270.11 (M+1) + .

[0751] Intermediate A-5

[0752]

[0753] Step 1: 4-Chloro-1-oxo-quinolin-1-ium-3-carboxylic acid ethyl ester

[0754] 4-Chloro-1-oxo-quinolin-1-ium-3-carboxylic acid ethyl ester was prepared from 4-chloroquinoline-3-carboxylic acid ethyl ester using a procedure similar to that found in Intermediate A-4, Step 2, using chloroform as solvent. 1 H NMR (300 MHz, CDCl3) δ 8.95 (s, 1H), 8.80 (d, J = 8.5 Hz, 1H), 8.52-8.42 (m, 1H), 7.97-7.89 (m, 1H), 7.88-7.80 (m, 1H), 4.49 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H). ESI-MS m / z calculated value 251.03, found value 252.1 (M+1) + .

[0755] Step 2: 2-Bromo-4-chloro-quinoline-3-carboxylic acid ethyl ester

[0756] POBr3 (1.20 g, 3.98 mmol) is added to a solution of 4- chloro-1-oxo-quinoline-3-formic acid ethyl ester (1.0 g, 3.5 mmol) in chloroform (15 mL). The reaction mixture is stirred at room temperature for 2 hours. Ice water (30 mL) is added to the reaction mixture and the layers are separated. The aqueous layer is extracted with DCM (2 × 25 mL), and the combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1.17 g of orange solids. The crude product is adsorbed on silica gel under vacuum and purified by silica gel chromatography (0-10% ethyl acetate / heptane) to give 2- bromo-4-chloro-quinoline-3-formic acid ethyl ester (771 mg, 69%) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 8.24 (dd, J = 8.4, 1.3 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.90-7.80 (m, 1H), 7.76-7.68 (m, 1H), 4.55 (q, J = 7.1 Hz, 2H), 1.48 (t, J = 7.2 Hz, 3H). ESI-MS m / z calculated value 312.95, found value 314.0 (M+1) + .

[0757] Step 3: 4-Benzyloxy-2-bromo-quinoline-3-carboxylic acid ethyl ester

[0758] 4-Benzyloxy-2-bromo-quinoline-3-carboxylic acid ethyl ester was prepared from 2-bromo-4-chloro-quinoline-3-carboxylic acid ethyl ester using a procedure similar to that found in Intermediate A-1, Step 1, using DMF as solvent. ESI-MS m / z calcd 385.03, found 386.0 (M+1) + .

[0759] Intermediate A-6

[0760]

[0761] Step 1: 3-[(3-Ethoxy-3-oxo-propionyl)amino]pyridine-2-carboxylic acid methyl ester

[0762] To 3-aminopyridine-2-carboxylic acid methyl ester (20.0 g, 132 mmol) in DCM (200 mL) was added 3-chloro-3-oxo-propionic acid ethyl ester (19.8 g, 132 mmol). The reaction was stirred at reflux for 45 minutes and then cooled to room temperature over 20 minutes. DCM (600 mL) was added and the organic solution was washed with saturated aqueous sodium bicarbonate solution (600 mL) and brine (400 mL), dried over magnesium sulfate, filtered and concentrated to give 3-[(3-ethoxy-3-oxo-propionyl)amino]pyridine-2-carboxylic acid methyl ester (26.16 g, 72%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 11.53 (s, 1H), 9.11 (d, 1H, J = 8.6 Hz), 8.46 (d, 1H, J = 2.3 Hz), 7.52 (m, 1H), 4.32-4.27 (m, 2H), 4.06 (d, 3H, J = 1.8 Hz), 3.57 (d, 2H, J = 1.1 Hz), 1.33 (td, 3H, J = 7.1, 1.8 Hz). ESI-MS m / z calcd 266.09, found 267.0 (M+1) + .

[0763] Step 2: Ethyl 4-hydroxy-2-oxo-1H-1,5-naphthyridine-3-carboxylate

[0764] To 3-[(3-ethoxy-3-oxo-propionyl)amino]pyridine-2-carboxylic acid methyl ester (24.16 g, 87.65 mmol) in ethanol (240 mL) was added sodium ethoxide (12.9 g, 190 mmol) in ethanol (120 mL) under argon at 5 ° C. for 5 minutes. The reaction was stirred at room temperature for 1 hour, then cooled to 0 ° C. and adjusted to pH 7 using 4M HCl. The solution was concentrated under reduced pressure to give crude 4-hydroxy-2-oxo-1H-1,5-naphthyridine-3-carboxylic acid ethyl ester (30.15 g, 147%) as a light yellow solid.1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.34 (d, 1H, J = 3.4 Hz), 7.66-7.64 (m, 1H), 7.51 (dd, 1H, J = 8.3, 4.4 Hz), 4.17 (q, 2H, J = 7.1 Hz), 1.23 (t, 3H, J = 7.1 Hz). ESI-MS m / z calculated value 234.06, found value 234.9 (M+1) + .

[0765] Step 3: Ethyl 2,4-dichloro-1,5-naphthyridine-3-carboxylate

[0766] To phosphorus oxychloride (33.5 g, 17 mL, 218 mmol) was added 4-hydroxy-2-oxo-1H-1,5-naphthyridine-3-carboxylic acid ethyl ester (1.75 g, 7.47 mmol). The reactants were heated at 120 ° C for 16 hours. The reactants were cooled to room temperature over 1 hour and then concentrated under reduced pressure. Toluene (2 × 50 mL) was used for the azeotropic residue. The solid was added to ice water (100 mL) and neutralized with sodium carbonate. The aqueous mixture was extracted with DCM (2 × 50 mL). The organic matter was combined, washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. Purified by silica gel chromatography (0-20% ethyl acetate / heptane) to give 2,4-dichloro-1,5-naphthyridine-3-carboxylic acid ethyl ester (1.05 g, 51%). 1 H NMR (400 MHz, CDCl3) δ 9.14 (dd, 1H, J = 4.2, 1.6 Hz), 8.39 (dd, 1H, J = 8.6, 1.6 Hz), 7.81 (dd, 1H, J = 8.5, 4.2 Hz), 4.59 (q, 2H, J = 7.1 Hz), 1.50 (t, 3H, J = 7.2 Hz). ESI-MS m / z calculated value 270.00, found value 270.88 (M+1) + .

[0767] Step 4: Ethyl 4-benzyloxy-2-chloro-1,5-naphthyridine-3-carboxylate

[0768] Ethyl 4-benzyloxy-2-chloro-1,5-naphthyridine-3-carboxylate was prepared from ethyl 2,4-dichloro-1,5-naphthyridine-3-carboxylate using a procedure analogous to that found in Intermediate A-1, Step 1.] 1H NMR (400 MHz, CDCl3) δ 8.99 (dd, 1H, J = 4.1, 1.7 Hz), 8.32 (dd, 1H, J = 8.6, 1.7 Hz), 7.71 (dd, 1H, J = 8.6, 4.0 Hz), 7.50-7.48 (m, 2H), 7.41-7.33 (m, 3H), 6.01 (s, 2H), 4.42 (q, 2H, J = 7.2 Hz), 1.34 (t, 3H, J = 7.1 Hz). ESI-MS m / z calcd 342.08, found 343.0 (M+1) + .

[0769] Intermediate A-7

[0770]

[0771] Step 1: 2-Chloro-4-[(4-methoxyphenyl)methoxy]-1,6-naphthyridine

[0772] To a mixture of 2,4-dichloro-1,6-naphthyridine (3.29 g, 16.5 mmol) and (4-methoxyphenyl)methanol (2.28 g, 2.05 mL, 16.47 mmol) in DMF (33 mL) and 2-MeTHF (33 mL) was added sodium hydride (715 mg, 60% in mineral oil, 17.88 mmol) in portions at 0 ° C. The mixture was stirred at 0 ° C for 1 hour, then slowly warmed to room temperature and stirred for 19.5 hours. The mixture was poured into a stirred mixture of 0.1M HCl aqueous solution (100 mL) and 2-MeTHF (100 mL). The layers were separated and the aqueous layer was extracted with additional 2-MeTHF (2×100 mL). The organic layers were combined and washed with water (2×50 mL), 1:1 water / brine (50 mL) and brine (50 mL). The solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (5-100% ethyl acetate / heptane) gave 2-chloro-4-[(4-methoxyphenoxy)methoxy]-1,6-naphthyridine (1.95 g, 39%) as a light yellow solid. ESI-MS m / z calculated value 300.06, found value 301.2 (M+1) + . 1 H NMR (400 MHz, CDCl3) δ 9.44 (s, 1H), 8.74 (d, J = 5.9 Hz, 1H), 7.72-7.67 (m, 1H), 7.48-7.42 (m, 2H), 7.09 (s, 1H), 6.97-6.88 (m, 2H), 5.50 (s, 2H), 3.83 (s, 3H). ESI-MS m / z calculated value 300.06, found value 301.2 (M+1) + .

[0773] Step 2: 2-chloro-4-[(4-methoxyphenyl)methoxy]-6-oxo-1,6-naphthyridin-6-ium

[0774] A solution of 2-chloro-4-[(4-methoxyphenoxy)methyl]-1,6-naphthyridine (5.0 g, 16.6 mmol) in DCM (100 mL) was cooled to 0 ° C and treated with solid 3-chloroperoxybenzoic acid (4.7 g, 21 mmol). The reactants were warmed to room temperature and stirred for 4 hours. The mixture was quenched with saturated aqueous sodium bicarbonate solution (100 mL) and the layers were separated. The aqueous layer was extracted with additional DCM (3×25 mL). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to obtain 2-chloro-4-[(4-methoxyphenyl)methoxy]-6-oxo-1,6-naphthyridine-6-ium (5.1 g, 97%). ESI-MS m / z calculated value 316.06, experimental value 317.2 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ8.66(d,J=2.1Hz,1H),8.40(dd,J=7.3,2.1Hz,1H),7.86(d,J=7 .3Hz,1H),7.53-7.47(m,2H),7.41(s,1H),7.05-6.95(m,2H),5.39(s,2H),3.78(s,3H).

[0775] Step 3: 2-Chloro-4-[(4-methoxyphenyl)methoxy]-1,6-naphthyridine-5-carbonitrile

[0776] To a solution of 2-chloro-4-[(4-methoxyphenyl)methoxy]-6-oxo-1,6-naphthyridine-6-ium (6.1 g, 19.3 mmol) in DCM (50 mL) was added trimethylsilyl cyanide (6.8 mL, 51 mmol) under a nitrogen atmosphere, followed by TEA (8 mL, 57.4 mmol). The mixture was stirred at room temperature for 20 hours. The reaction was quenched with water and the aqueous layer was extracted with DCM (3 times). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. Purified by silica gel chromatography (0-100% ethyl acetate / DCM) to give 2-chloro-4-[(4-methoxyphenyl)methoxy]-1,6-naphthyridine-5-carbonitrile (5.5 g, 88%). 1HNMR (400MHz, DMSO-d6) δ8.90(d,J=5.8Hz,1H),8.11(d,J=5.7Hz,1H),7.61(s,1H),7.60-7.52(m,2H),7.03-6.95(m,2H),5.52(s,2H),3.77(s,3H).

[0777] Intermediate A-8

[0778]

[0779] Step 1: 4-Chloro-1-oxo-quinolin-1-ium-5-carbonitrile

[0780] A mixture of 4-chloroquinoline-5-carbonitrile (840 mg, 4.45 mmol) and m-CPBA (1.36 g, 5.52 mmol) in DCM (12 mL) was stirred at room temperature for 2 hours. The mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM (3 times). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give 4-chloro-1-oxo-quinolin-1-ium-5-carbonitrile (910 mg, 100%). ESI-MS m / z calculated value 204.01, found value 205.0 (M+1) + .

[0781] Step 2: 2,4-Dichloroquinoline-5-carbonitrile

[0782] A vial containing 4-chloro-1-oxo-quinolin-1-ium-5-carbonitrile (900 mg, 4.40 mmol) and POCl3 (4.0 mL, 42.9 mmol) was heated at 50 ° C for 4 hours. The mixture was cooled to room temperature and poured onto ice. The resulting precipitate was filtered and washed with water. The solid was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution (2 times). The organic layer was dried over magnesium sulfate, filtered and concentrated. Purified by silica gel chromatography (0-20% ethyl acetate / hexane) to give 2,4-dichloroquinoline-5-carbonitrile (680 mg, 69%). ESI-MS m / z calculated value 221.97, experimental value 223.0 (M + 1) + .

[0783] Step 3: 4-Benzyloxy-2-chloro-quinoline-5-carbonitrile

[0784] To a solution of benzyl alcohol (232 μL, 2.24 mmol) in DMF (10 mL) was added sodium hydride (98 mg 60% w / w, 2.45 mmol) at 0 ° C and the mixture was warmed to room temperature and stirred for 30 minutes. The mixture was then cooled to -40 ° C and 2,4-dichloroquinoline-5-carbonitrile (500 mg, 2.24 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was cooled to 0 ° C, quenched with water and extracted with ethyl acetate (3 times). The organic phase was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Purified by silica gel chromatography (0-30% ethyl acetate / hexane) to obtain 4-benzyloxy-2-chloro-quinoline-5-carbonitrile (410 mg, 62%) as an off-white solid. ESI-MS m / z calculated value 294.05, experimental value 295.6 (M + 1) + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.23-8.15 (m, 2H), 7.92 (dd, J = 8.5, 7.4 Hz, 1H), 7.67-7.57 (m, 2H), 7.48 (s, 1H), 7.46-7.32 (m, 3H), 5.56 (s, 2H). Regioisomers of 2-benzyloxy-4-chloro-quinoline-5-carbonitrile were also isolated. ESI-MS m / z calculated: 294.06, found: 295.1 (M+1). + . 1 H NMR (400MHz, DMSO-d6) δ8.17(m,2H),7.90(dd,J=8.4,7.4Hz,1H),7.58(s,1H),7.55-7.50(m,2H),7.44-7.32(m,3H),5.53(s,2H).

[0785] General protocol for the preparation of intermediate A

[0786]

[0787] The intermediates in Table 1 were prepared using the corresponding dichloropyridine or dichloropyrimidine and a procedure similar to that found in Step 1 of Intermediate A-1. Dichloropyridine or dichloropyrimidine were obtained from commercial sources. Benzyl alcohol or substituted benzyl alcohols, such as 2-methoxybenzyl alcohol, may be used. DMF, THF, 2-MeTHF, or mixtures of these solvents may be used as reaction solvents.

[0788] Table 1

[0789]

[0790]

[0791]

[0792] Intermediate B-1

[0793]

[0794] Step 1: 3-Bromo-2-(3,4-difluoro-2-methyl-phenoxy)quinoline

[0795] To a mixture of 3-bromo-2-fluoro-quinoline (500mg, 2.21mmol) and 3,4-difluoro-2-methyl-phenol (478mg, 3.32mmol) in DMSO (12mL) was added cesium carbonate (1.8g, 5.5mmol). The resulting mixture was stirred at 55 ° C for 4 hours. The reactant was cooled to room temperature, diluted with ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0-20% ethyl acetate / hexane) gave 3-bromo-2- (3,4-difluoro-2-methyl-phenoxy) quinoline (596mg, 77%). 1 H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 7.95 (dd, J = 8.1, 1.4 Hz, 1H), 7.69 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.60 (dd, J = 8.1, 1.0 Hz, 1H), 7.54 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.40 (m, 1H), 7.17 (ddd, J = 9.1, 4.4, 2.1 Hz, 1H), 2.07 (d, J = 2.2 Hz, 3H). ESI-MS m / z calcd 348.99, found 350.0 (M+1) + .

[0796] Step 2: [2-(3,4-Difluoro-2-methyl-phenoxy)-3-quinolinyl]boronic acid

[0797] A solution of 3-bromo-2-(3,4-difluoro-2-methyl-phenoxy)quinoline (600mg, 1.71mmol) in THF (4mL) was treated dropwise with n-BuLi (750 μL 2.5M solution in hexane, 1.9mmol). The reaction mixture was stirred for 30 minutes and then treated dropwise with triisopropyl borate (550 μL, 2.40mmol). The mixture was stirred at -78 ° C for 30 minutes, then taken out from the cooling bath and quenched with saturated NH4Cl aqueous solution. The mixture was diluted with ether and the layers were separated. The aqueous layer was extracted with additional ether (3 times), and the combined organic layer was dried over magnesium sulfate, filtered and concentrated to give [2-(3,4-difluoro-2-methyl-phenoxy)-3-quinolyl] boronic acid (505mg, 94%). ESI-MS m / z calculated value 315.09, found value 316.2 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ8.51(d,J=4.8Hz,1H),8.36(s,2H),7.94(dd,J=8.1,1.5Hz,1H),7.66-7.57(m,1H),7.54 (d,J=8.7Hz,1H),7.46(ddd,J=8.1,6.8,1.4Hz,1H),7.41-7.28(m,1H),7.13(m,1H),2.06(dd,J=5.4,2.3Hz,3H).

[0798] Intermediate B-2

[0799]

[0800] Step 1: 3-Bromo-4,5-dimethyl-pyridin-2-ol

[0801] To a solution of 4,5-dimethylpyridin-2-ol (2.0 g, 16 mmol) in acetic acid (20 mL) was added bromine (2.8 g, 0.9 mL, 17.5 mmol). The reaction mixture was stirred at room temperature for 90 hours. It was poured onto a stirred 20% aqueous solution of potassium carbonate (250 mL) and then diluted with water (50 mL). The crushed solid was recovered by Büchner filtration and dried in vacuo to give 3-bromo-4,5-dimethyl-pyridin-2-ol (2.79 g, 82%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 13.45 (br.s, 1H), 7.21 (s, 1H), 2.36 (s, 3H), 2.10 (s, 3H). ESI-MS m / z calculated value 200.98, found value 202.1 (M+1) +.

[0802] Step 2: 3-Bromo-2-chloro-4,5-dimethyl-pyridine

[0803] A solution of 3-bromo-4,5-dimethyl-pyridin-2-ol (6.5 g, 29 mmol) in POCl3 (52.6 g, 32 mL, 343 mmol) was stirred at 110 ° C for 30 hours. Phosphorus oxychloride was removed under reduced pressure. The residue was dissolved in DCM (100 mL) and poured into a stirred saturated aqueous sodium bicarbonate solution (400 mL). The layers were separated and the aqueous layer was extracted with DCM (2 × 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was adsorbed on silica gel under vacuum and purified by silica gel chromatography (120 g silica, 0-10% ethyl acetate / heptane) to give 3-bromo-2-chloro-4,5-dimethyl-pyridine (6.06 g, 94%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 2.43 (s, 3H), 2.29 (s, 3H). ESI-MS m / z calculated value 218.95, found value 220.0 (M+1) + .

[0804] Step 3: 3-Bromo-2-(4-fluoro-2-methyl-phenoxy)-4,5-dimethyl-pyridine

[0805] 3-Bromo-2-(4-fluoro-2-methyl-phenoxy)-4,5-dimethyl-pyridine was prepared from 3-bromo-2-chloro-4,5-dimethyl-pyridine and 4-fluoro-2-methyl-phenol using a procedure analogous to that found in Intermediate B-1, Step 1. 1 H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.01 (dd, J = 8.7, 5.0 Hz, 1H), 6.96 (dd, J = 9.0, 2.9 Hz, 1H), 6.94-6.88 (m, 1H), 2.43 (s, 3H), 2.23 (s, 3H), 2.14 (s, 3H). ESI-MS m / z calculated value 309.02, found value 310.1 (M+1) + .

[0806] Step 4: 2-(4-Fluoro-2-methyl-phenoxy)-4,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0807] A mixture of 3-bromo-2-(4-fluoro-2-methyl-phenoxy)-4,5-dimethyl-pyridine (2.05 g, 6.60 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (3.3 g, 13 mmol), potassium acetate (1.9 g, 19.4 mmol) and Pd(dppf)Cl2.DCM (430 mg, 0.527 mmol) in DMSO (30 mL) was stirred at 110 °C for 4 hours. The reaction mixture was cooled to room temperature and partitioned between water (100 mL) and MTBE (500 mL). The biphasic mixture was purified by HPLC. The organic layer was washed with water (4 times) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was adsorbed on silica gel under vacuum and purified by silica chromatography (120 g silica, 0-10% ethyl acetate / heptane) to give 1.4 g of material. The solid was wet-ground in pentane (5 mL), filtered and the solid was vacuum-dried to give 2- (4-fluoro-2-methyl-phenoxy) -4,5-dimethyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) pyridine (749 mg, 31%) as a white solid. ESI-MS m / z calculated value 357.19, experimental value 358.2 (M + 1) + . 1 H NMR (400MHz, CDCl3) δ7.81 (s, 1H), 7.00 (dd, J = 8.8, 5.1 Hz, 1H), 6.92 (dd, J = 9.2, 2. 8Hz,1H),6.90-6.83(m,1H),2.31(s,3H),2.16(s,3H),2.13(s,3H),1.38(s,12H). 19 F NMR (377MHz, CDCl3) δ-119.47--119.80 (m, 1F).

[0808] Intermediate B-3

[0809]

[0810] Step 1: 3-Bromo-2-chloro-5,6-dimethyl-pyridine

[0811] A solution of 3-bromo-5,6-dimethyl-pyridin-2-ol (2.0 g, 9.9 mmol) in POCl3 (17.2 g, 10.5 mL, 112 mmol) was purged with nitrogen for 10 minutes and then heated at 110 ° C for 30 hours. Phosphorus oxychloride was removed under reduced pressure. The residue was dissolved in DCM (50 mL) and poured into a stirred saturated aqueous sodium bicarbonate solution (150 mL). The layers were separated and the aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a gray crude residue. The crude residue was purified by silica gel chromatography (40 g silica, 0-15% ethyl acetate / heptane) to obtain 3-bromo-2-chloro-5,6-dimethyl-pyridine (2.11 g, 97%) as a white solid. ESI-MS m / z calculated value 218.95, found value 220.0 (M+1) + . 1 H NMR (400MHz, CDCl3) δ7.66(s,1H),2.44(s,3H),2.26(s,3H).

[0812] Step 2: 3-Bromo-2-(4-fluoro-2-methyl-phenoxy)-5,6-dimethyl-pyridine

[0813] 3-Bromo-2-(4-fluoro-2-methyl-phenoxy)-5,6-dimethyl-pyridine was prepared from 3-bromo-2-chloro-5,6-dimethyl-pyridine and 4-fluoro-2-methyl-phenol using a procedure similar to that found in Intermediate B-1, Step 1. ESI-MS m / z calcd. 309.02, found 310.2 (M+1) + . 1 H NMR (400MHz, CDCl3) δ7.64(s,1H),6.99(dd,J=8.9,5.1Hz,1H),6.95(dd,J=9.0,3.1Hz,1H),6.91-6.85(m,1H),2.23(s,3H),2.21(s,3H),2.18(s,3H).

[0814] Step 3: [2-(4-Fluoro-2-methyl-phenoxy)-5,6-dimethyl-3-pyridyl]boronic acid

[0815] Under a nitrogen atmosphere, to a solution of 3-bromo-2-(4-fluoro-2-methyl-phenoxy)-5,6-dimethyl-pyridine (160 mg, 0.490 mmol) in diethyl ether (2.4 mL) was slowly added a solution of n-BuLi in hexane (210 μL 2.5 M, 0.53 mmol) at -78 ° C. The mixture was then stirred at this temperature for 1 hour, after which a solution of trimethyl borate (93 mg, 100 μL, 0.90 mmol) in diethyl ether (0.8 mL) was added dropwise. The resulting reaction mixture was allowed to warm to room temperature (1.5 hours) and stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (4 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 8 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude residue. Purification by reverse phase chromatography (C18, 5-100% CH3CN / 0.1% formic acid) gave [2-(4-fluoro-2-methyl-phenoxy)-5,6-dimethyl-3-pyridyl]boronic acid (98 mg, 72%) as a white solid. ESI-MS m / z calculated value 275.11, found value 276.1 (M+1) + . 1 H NMR (400MHz, CD3OD) δ7.54 (s, 1H), 6.99 (d, J = 8.8Hz, 1H), 6.89-6.86 (m, 2H), 2.28 (s, 3H), 2.24 (s, 3H), 2.16 (s, 3H).

[0816] Intermediate B-4

[0817]

[0818] Step 1: 4-tert-Butyl-2-methyl-aniline

[0819] To a solution of 2-bromo-4-tert-butyl-aniline (25 g, 110 mmol) in dioxane (750 mL) and water (85 mL) was added methylboric acid (32.8 g, 548 mmol), tricyclohexylphosphine (6.3 g, 22.5 mmol) and potassium phosphate (70 g, 330 mmol). The mixture was bubbled with nitrogen for 5 minutes, then palladium acetate (2.5 g, 11 mmol) was added. The mixture was heated at 110 ° C for 18 hours. The crude material was heated at 40 ° C for 18 hours. The mixture was filtered and washed with dichloromethane (300 mL). The filtrate was washed with brine (2×200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (330 g silica, 0-30% ethyl acetate / heptane) gave 4-tert-butyl-2-methyl-aniline (16.9 g, 94%) as a dark oil. ESI-MS m / z calculated value 163.14, found value 164.2 (M+1) + . 1 H NMR (400MHz, CDCl3) δ7.12-7.05 (m, 2H), 6.66 (d, J = 7.8Hz, 1H), 3.52 (br s, 2H), 2.21 (s, 3H), 1.31 (s, 9H).

[0820] Step 2: 2-Bromo-4-tert-butyl-6-methyl-aniline

[0821] N-Bromosuccinimide (20.5 g, 115 mmol) was slowly added to a cold (-30 ° C) solution of 4-tert-butyl-2-methyl-aniline (19.57 g, 119.9 mmol) in dichloromethane (1.2 L). The reaction mixture was stirred at -30 ° C for 3 hours, and then the reaction was quenched with water (700 mL). Once warmed to room temperature, the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give crude 2-bromo-4-tert-butyl-6-methyl-aniline (29.14 g, 96%) as a dark oil. The crude product was used in the next step without any further purification. ESI-MS m / z calculated value 241.05, experimental value 242.1 (M + 1) + . 1 H NMR (400MHz, CDCl3) δ7.32 (d, J = 2.2Hz, 1H), 7.06-7.02 (m, 1H), 4.05-3.89 (m, 2H), 2.24 (s, 3H), 1.29 (s, 9H).

[0822] Step 3: N-(2-Bromo-4-tert-butyl-6-methyl-phenyl)-2,2,2-trifluoro-acetamide

[0823] Trifluoroacetic anhydride (20 mL, 144 mmol) was added dropwise to a solution of 2-bromo-4-tert-butyl-6-methyl-aniline (29.14 g, 114.6 mmol) and triethylamine (24 mL, 172 mmol) in dichloromethane (300 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 3 hours, then water (200 mL) was added and the mixture was extracted with dichloromethane (3 × 100 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (2 × 150 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give N-(2-bromo-4-tert-butyl-6-methyl-phenyl)-2,2,2-trifluoro-acetamide (40.05 g, 100%) as a brown solid. The crude material was used in the next step without any further purification. ESI-MS m / z calculated value 337.03, experimental value 338.0 (M+1) + . 1 H NMR (400MHz, CDCl3) δ7.64-7.56 (m, 1H), 7.51 (d, J = 1.5Hz, 1H), 7.26 (s, 1H), 2.32 (s, 3H), 1.33 (s, 9H).

[0824] Step 4: N-[4-tert-Butyl-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-phenyl]-2,2,2-trifluoro-acetamide

[0825] A mixture of N-(2-bromo-4-tert-butyl-6-methyl-phenyl)-2,2,2-trifluoro-acetamide (87.8 g, 235 mmol), 4-fluoro-2-methoxy-phenol (39.9 g, 32 mL, 281 mmol), cesium carbonate (230 g, 706 mmol) and N,N-dimethylglycine (24.2 g, 235 mmol) in dioxane (920 mL) was degassed with argon for 10 minutes before copper (I) iodide (13.4 g, 70.4 mmol) was added. The reaction was warmed to 60° C. under argon for 20 hours and then allowed to cool. The reaction was carried out by Filter and concentrate. The product was washed with warm water (1.2 l) and ethyl acetate (600 mL), combined with the concentrate, and the phases were separated. The aqueous phase was extracted with ethyl acetate (3×400 mL). The combined organics were washed successively with water (3×400 mL) and brine (400 mL), dried over sodium sulfate and silica gel, filtered and concentrated. The crude material was boiled in heptane (200 mL), allowed to cool slowly to room temperature, and then cooled to 0°C. The solid was collected by filtration to give N-[4-tert-butyl-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-phenyl]-2,2,2-trifluoro-acetamide (70.3 g, 75%). ESI-MS m / z calculated value 399.15, experimental value 400.16 (M+1) + . 1 H NMR(301MHz,CDCl3)δ7.91(br s,1H),7.00(d,J=1.4Hz,1H),6.94(dd,J=8.9,5.4Hz,1H),6.73-6.69(m, 2H), 6.61 (td, J = 8.4, 2.9Hz, 1H), 3.80 (s, 3H), 2.27 (s, 3H), 1.21 (s, 9H).

[0826] Step 5: 4-tert-Butyl-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-aniline

[0827] To a solution of N-[4-tert-butyl-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-phenyl]-2,2,2-trifluoro-acetamide (70 g, 175 mmol) in ethanol (875 mL) was added NaOH (350 mL 2M, 700 mmol) and the mixture was stirred at reflux for 3 hours. The reaction was allowed to cool and then the ethanol was removed under reduced pressure. The residue was diluted with water (300 mL) and then extracted with CPME (3×250 mL). The combined organics were washed sequentially with 1N NaOH (200 mL) and brine (200 mL), dried over sodium sulfate, filtered and concentrated to give 4-tert-butyl-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-aniline (54.9 g, 100%). ESI-MS m / z calculated value 303.16, found value 304.14 (M+1) + . 1 H NMR (301MHz, CDCl3) δ6.87 (d, J = 1.7 Hz, 1H), 6.79-6.71 (m, 2H), 6.67 (d, J = 2.1 Hz, 1H), 6.59-6.52 (m, 1H), 3.87 (s, 3H), 2.22 (s, 3H), 1.20 (s, 9H).

[0828] Step 6: 2-Bromo-5-tert-butyl-1-(4-fluoro-2-methoxy-phenoxy)-3-methyl-benzene

[0829] To a slurry of copper (II) bromide (48.6 g, 218 mmol), lithium bromide (45.4 g, 523 mmol) and tert-butyl nitrite (19.7 g, 16 mL, 172 mmol) in CHCN (700 mL) was added a solution of 4-tert-butyl-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-aniline (54.9 g, 174 mmol) in CHCN (420 mL) at room temperature over 40 minutes. The reaction was warmed to 60° C. for 4 hours and then allowed to cool. The reaction was quenched with 1N HCl (800 mL) and extracted with CPME (3×300 mL). The combined organics were washed with water (2×300 mL) and brine (300 mL), dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0-2% ethyl acetate / heptane) gave 2-bromo-5-tert-butyl-1-(4-fluoro-2-methoxy-phenoxy)-3-methyl-benzene (41.3 g, 62%). 1 H NMR (400MHz, CDCl3) δ6.99 (d, J = 2.3 Hz, 1H), 6.79-6.72 (m, 2H), 6.63 (d, J = 2.3 Hz, 1H), 6.61-6.56 (m, 1H), 3.84 (s, 3H), 2.45 (s, 3H), 1.20 (s, 9H).

[0830] Step 7: 2-[4-tert-Butyl-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0831] n-BuLi (1.2mL 2.5M, 3.0mmol) was slowly added to a solution of 2-bromo-5-tert-butyl-1-(4-fluoro-2-methoxy-phenoxy)-3-methyl-benzene (1.0g, 2.7mmol) in THF (20mL) at -78°C. The reaction mixture was stirred for 15 minutes, and then a pre-cooled solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (684mg, 0.75mL, 3.68mmol) in THF (5mL) was slowly added. The reaction mixture was stirred for 1.5 hours at -78°C and then warmed to 0°C. The reaction mixture was quenched with water (20mL), poured into 1:1 saturated sodium chloride / water solution (50mL) and extracted with ethyl acetate (3×50mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% ethyl acetate / heptane) to give 2-[4-tert-butyl-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (890 mg, 79%) as a clear oil. 1 HNMR (400MHz, CDCl3) δ6.96 (d, J = 1.0Hz, 1H), 6.76-6.62 (m, 3H), 6.59-6.47 (m, 1H), 3.89 (s, 3H), 2.45 (s, 3H), 1.24 (s, 9H), 1.24 (s, 12H).

[0832] Intermediate B-5

[0833]

[0834] Step 1: 5-Bromo-4-(3,4-difluoro-2-methyl-phenoxy)-2-(trifluoromethyl)pyridine

[0835] 5-Bromo-4-(3,4-difluoro-2-methyl-phenoxy)-2-(trifluoromethyl)pyridine was prepared from 5-bromo-4-chloro-2-(trifluoromethyl)pyridine and 3,4-difluoro-2-methyl-phenol using a procedure similar to that found in Intermediate B-1, Step 1. ESI-MS m / z calcd 366.96, found 367.93 (M+1) + .

[0836] Step 2: 4-(3,4-Difluoro-2-methyl-phenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine

[0837] 4-(3,4-Difluoro-2-methyl-phenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine was prepared using a procedure similar to that found in Step 4 of Intermediate B-2. Purification by silica gel chromatography (40 g silica, 0-100% ethyl acetate / hexanes) gave 4-(3,4-difluoro-2-methyl-phenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (402 mg, 54%). ESI-MS m / z calcd 415.14, found 334.16 (M+1) + The product pinacol ester is believed to be hydrolyzed to the boronic acid under LC / MS conditions.

[0838] Intermediate B-6

[0839]

[0840] Step 1: 3-Bromo-2,5-dichloro-4-methyl-pyridine

[0841] A mixture of 3-bromo-5-chloro-4-methyl-pyridin-2-ol (10 g, 45 mmol) and POCl (65.8 g, 40 mL, 429 mmol) was heated at 90 ° C for 24 hours. The temperature was increased to 105 ° C and the reactants were stirred for 18 hours. It was then stirred at 120 ° C for 3 hours. It was cooled to room temperature and POCl was evaporated under reduced pressure. The residue was poured into a stirred mixture of water (400 mL), ethyl acetate (200 mL) and sodium carbonate (80 g). After 30 minutes, the layers were separated. The aqueous layer was extracted with ethyl acetate (200 mL). The organic layers were combined and washed with water (100 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 3-bromo-2,5-dichloro-4-methyl-pyridine (9.38 g, 87%) as a brown oil. ESI-MS m / z calculated value 238.89, found value 240.0 (M+1) + . 1 H NMR (400MHz, CDCl3) δ8.26 (s, 1H), 2.59 (s, 3H).

[0842] Step 2: 3-Bromo-5-chloro-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-pyridine

[0843] 3-Bromo-5-chloro-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-pyridine was prepared from 3-bromo-2,5-dichloro-4-methyl-pyridine and 4-fluoro-2-methyl-phenol using a procedure similar to that found in Intermediate B-1, Step 1. ESI-MS m / z calcd 328.96, found 329.9 (M+1) + . 1 H NMR (400MHz, CDCl3) δ7.94(s,1H),7.05-6.89(m,3H),2.58(s,3H),2.13(s,3H).

[0844] Step 3: [5-Chloro-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-3-pyridinyl]boronic acid

[0845] 5-Chloro-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-3-pyridyl]boronic acid was prepared from 3-bromo-5-chloro-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-pyridine using a procedure similar to that found in Intermediate B-3, Step 3. ESI-MS m / z Calcd. 295.06, Found 296.2 (M+1) + . 1 H NMR (400MHz, CDCl3) δ8.04(s,1H),7.05-6.86(m,3H),5.69(s,2H),2.67(s,3H),2.13(s,3H).

[0846] Intermediate B-7

[0847]

[0848] Step 1: 4-Methyl-5-(trifluoromethyl)pyridin-2-ol

[0849] A mixture of 2-chloro-4-methyl-5-(trifluoromethyl)pyridine (5.0 g, 25.6 mmol), aqueous hydrochloric acid solution (20 mL 37% w / v, 203 mmol), dioxane (40 mL) and water (20 mL) was stirred at 95 ° C for 48 hours and then stirred at 80 ° C for another 24 hours. The mixture was diluted with 2M aqueous sodium hydroxide solution (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL), then extracted with ethyl acetate (4×200 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to give 4-methyl-5-(trifluoromethyl)pyridin-2-ol (4.82 g, 98%) as a white solid. ESI-MS m / z calculated value 177.04, found value 178.2 (M+1) + .1 H NMR (400MHz, CDCl3) δ13.21(br.s,1H),7.70(s,1H),6.44(s,1H),2.35(s,3H). 19 F NMR (377MHz, CDCl3) δ-61.29 (s, 3F).

[0850] Step 2: 3-Bromo-4-methyl-5-(trifluoromethyl)pyridin-2-ol

[0851] Bromine (8.7g, 2.8mL, 54mmol) is added to a solution of 4-methyl-5-(trifluoromethyl)pyridin-2-ol (4.8g, 25mmol) in acetic acid (65mL). The mixture is stirred at room temperature for 65 hours and then poured into a mixture of stirred sodium carbonate (90g), water (400mL) and sodium thiosulfate pentahydrate (17g). The aqueous layer is extracted with ethyl acetate (3×250mL). The combined organic extracts are washed with water (100mL) and brine (100mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to give a beige solid (6.05g). The solid is wet-ground and filtered in 1:1MTBE / heptane (30mL). The solid is washed and dried with 1:1MTBE / heptane (15mL) to give 3-bromo-4-methyl-5-(trifluoromethyl)pyridin-2-ol (5.38g, 84%) as a white solid. ESI-MS m / z calculated value 254.95, found value 256.0 (M+1) + . 1 H NMR (400MHz, CDCl3) δ13.23(br.s,1H),7.83(s,1H),2.53(s,3H). 19 F NMR (377MHz, CDCl3) δ-60.81 (s, 3F).

[0852] Step 3: 3-Bromo-2-chloro-4-methyl-5-(trifluoromethyl)pyridine

[0853] A mixture of 3-bromo-4-methyl-5-(trifluoromethyl)pyridin-2-ol (4.09 g, 16.0 mmol) and POCl3 (65.8 g, 40 mL, 429 mmol) was stirred at 80 ° C for 23 hours. The mixture was cooled and slowly poured into a stirred mixture of sodium carbonate (160 g), water (400 mL) and ethyl acetate (100 mL). Ice was added during the addition to control the exotherm. The mixture was stirred at room temperature for 30 minutes and the layers were separated. The aqueous layer was extracted with additional ethyl acetate (3×100 mL). The combined extracts were washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to give 3-bromo-2-chloro-4-methyl-5-(trifluoromethyl)pyridine (3.87 g, 87%) as a light brown oil. ESI-MS m / z calculated value 272.92, found value 273.8 (M+1) + . 1 H NMR (400MHz, CDCl3) δ8.54 (s, 1H), 2.63 (s, 3H). 19 F NMR (377MHz, CDCl3) δ-61.06 (s, 3F).

[0854] Step 4: 3-Bromo-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine

[0855] A mixture of 3-bromo-2-chloro-4-methyl-5-(trifluoromethyl)pyridine (11.30 g, 41.17 mmol), 4-fluoro-2-methyl-phenol (5.710 g, 45.27 mmol) and cesium carbonate (26.83 g, 82.35 mmol) in DMSO (80 mL) was stirred at room temperature for 90 minutes. The mixture was partitioned between water and ether and the layers were separated. The aqueous layer was extracted with additional ether and the combined organic layers were washed with 1N NaOH (2 times) and brine, dried over MgSO, filtered and concentrated. Purified by silica gel chromatography (220 g silica, 0-20% ethyl acetate / hexane) to obtain 3-bromo-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine (14.22 g, 95%). ESI-MS m / z calculated value 362.99, found value 365.1 (M+1) + . 1 H NMR (400MHz, CD3OD) δ8.22 (s, 1H), 7.11-7.03 (m, 2H), 6.98 (td, J = 8.5, 3.4Hz, 1H), 2.63 (appd, J = 1.4Hz, 3H), 2.10 (s, 3H).

[0856] Step 5: [2-(4-Fluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)-3-pyridinyl]boronic acid

[0857] At -78 DEG C under argon, n-BuLi solution (4.7mL 1.6M solution in hexane, 7.5mmol) is slowly added to a solution of the bromo-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl) pyridine (2.56g, 6.82mmol) in diethyl ether (30mL) of stirring. The mixture is stirred at -78 DEG C for 1 hour. Then a solution of trimethyl borate (1.2g, 1.3mL, 11.7mmol) in diethyl ether (10mL) is added dropwise. The mixture is warmed to room temperature and then quenched with saturated aqueous ammonium chloride solution (50mL). The water layer is extracted with other diethyl ether (100mL). The combined organic extracts are washed with brine (50mL), dried over magnesium sulfate, filtered and concentrated. Trituration with hexanes and filtration gave [2-(4-fluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)-3-pyridinyl]boronic acid (1.91 g, 83%) as a light cream solid. 1 H NMR (400MHz, DMSO-d6) δ8.61(m,2H),8.26(s,1H),7.14-7.00(m,3H),2.42(s,3H),2.04(s,3H). 19 FNMR (376 MHz, DMSO-d6) δ -59.3--58.9 (3F), -118.3--117.9 (1F). ESI-MS m / z calculated value 329.09, found value 329.99 (M+1) + .

[0858] Intermediate B-8

[0859]

[0860] Step 1: 3-Bromo-2-(3,4-difluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine

[0861] A mixture of 3-bromo-2-chloro-4-methyl-5-(trifluoromethyl)pyridine (2.63 g, 9.58 mmol) and 3,4-difluoro-2-methyl-phenol (2.6 g, 18 mmol) was dissolved in DMSO (26 mL). Cesium carbonate (7.73 g, 23.7 mmol) was added to this solution and the mixture was stirred at 90 ° C for 2.5 hours. The mixture was cooled to room temperature and then diluted with ethyl acetate. The organic solution was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification using silica gel chromatography (120 g silica, 0-20% ethyl acetate / hexane) gave 3-bromo-2-(3,4-difluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine (3.340 g, 91%) as a light orange solid. ESI-MS m / z calculated value 380.98, experimental value 382.0 (M + 1) + . 1 H NMR (400MHz, DMSO-d6) δ 8.41 (s, 1H), 7.38 (q, J = 9.4Hz, 1H), 7.10 (ddd, J = 9.2, 4.4, 2.1Hz, 1H), 2.59 (d, J = 1.4Hz, 3H), 2.03 (d, J = 2.2Hz, 3H).

[0862] Step 2: [2-(3,4-Difluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)-3-pyridinyl]boronic acid

[0863] Under a nitrogen atmosphere, to a stirred solution of 3-bromo-2-(3,4-difluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine (2.0 g, 5.2 mmol) in diethyl ether (20 mL) was slowly added n-BuLi solution (2.5 mL of a 2.5 M solution in hexane, 6.25 mmol) at -78 ° C. The mixture was stirred at this temperature for 20 minutes, after which a solution of trimethyl borate (1 mL, 9 mmol) in diethyl ether (6 mL) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 90 minutes. The mixture was quenched with saturated aqueous ammonium chloride solution (150 mL) and extracted with ethyl acetate (3 × 100 mL). The combined extracts were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The material was purified by reverse phase chromatography (C18, 5-95% acetonitrile / water, containing 0.1% formic acid), and the product fractions were concentrated to remove acetonitrile. The resulting aqueous solution was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford [2-(3,4-difluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)-3-pyridinyl]boronic acid (1.64 g, 90%) as a white solid. 1H NMR (400MHz, CDCl3) δ8.32 (s, 1H), 7.06 (q, J = 9.0Hz, 1H), 6.85-6.80 (m, 1H), 5.45 (s, 2H), 2.71-2.67 (m, 3H), 2.10 (d, J = 2.0Hz, 3H). 19 FNMR (377 MHz, CDCl3) δ -60.66 (s, 3F), -137.75--137.88 (m, 1F), -140.42--140.54 (m, 1F). ESI-MS m / z calculated value 347.08, found value 348.2 (M+1) + .

[0864] Intermediate B-9

[0865]

[0866] Step 1: 3-Bromo-2-(4-fluoro-2-methoxy-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine

[0867] 3-Bromo-2-(4-fluoro-2-methoxy-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine was prepared from 3-bromo-2-chloro-4-methyl-5-(trifluoromethyl)pyridine and 4-fluoro-2-methoxy-phenol using a procedure similar to that found in Intermediate B-7, Step 4. ESI-MS m / z Calcd. 378.98, Found. 380.15 (M+1) + . 1 H NMR (400MHz, CD3OD) δ8.18 (s, 1H), 7.12 (dd, J = 8.8, 5.7Hz, 1H), 6.92 (dd, J = 10. 4, 2.9Hz, 1H), 6.72 (td, J = 8.3, 2.9Hz, 1H), 3.71 (s, 3H), 2.61 (d, J = 1.2Hz, 3H).

[0868] Step 2: [2-(4-Fluoro-2-methoxy-phenoxy)-4-methyl-5-(trifluoromethyl)-3-pyridinyl]boronic acid

[0869] [2-(4-Fluoro-2-methoxy-phenoxy)-4-methyl-5-(trifluoromethyl)-3-pyridinyl]boronic acid was prepared from 3-bromo-2-(4-fluoro-2-methoxy-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine using a procedure similar to that found in Intermediate B-1, Step 2, using diethyl ether as solvent. ESI-MS m / z calcd 345.08, found 346.1 (M+1) + . 1HNMR(400MHz,CD3OD)δ8.19(s,1H),7.09(dd,J=8.8,5.7Hz,1H),6.90(dd,J=10 .4, 2.9Hz, 1H), 6.71 (td, J = 8.4, 2.9Hz, 1H), 3.70 (s, 3H), 2.44 (d, J = 1.5Hz, 3H).

[0870] Intermediate B-10

[0871]

[0872] Step 1: 6-Chloro-2-methyl-3-(trifluoromethyl)pyridine

[0873] A mixture of Fe(acac)3 (140 mg, 0.394 mmol) and 2,6-dichloro-3-(trifluoromethyl)pyridine (2.0 g, 9.3 mmol) was evacuated in a sealed flask and placed under a nitrogen atmosphere. THF (40 mL) was added and the mixture was cooled to 0 ° C. Methylmagnesium bromide (3.6 mL 3M in diethyl ether, 10.8 mmol) was added dropwise and the mixture was stirred at 0 ° C for 3 hours. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 80 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give 6-chloro-2-methyl-3-(trifluoromethyl)pyridine (1.91 g, 95%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ7.90 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 2.63 (s, 3H).

[0874] Step 2: 6-Methyl-5-(trifluoromethyl)pyridin-2-ol

[0875] 6-Methyl-5-(trifluoromethyl)pyridin-2-ol was prepared from 6-chloro-2-methyl-3-(trifluoromethyl)pyridine using a procedure similar to that found in Intermediate B-7, Step 1. ESI-MS m / z calcd. 177.04, found 178.0 (M+1) + . 1 HNMR (400MHz, CDCl3) δ13.20 (s, 1H), 7.61 (d, J = 9.6Hz, 1H), 6.46 (d, J = 9.5Hz, 1H), 2.56-2.49 (m, 3H).

[0876] Step 3: 3-Bromo-6-methyl-5-(trifluoromethyl)pyridin-2-ol

[0877] 3-Bromo-6-methyl-5-(trifluoromethyl)pyridin-2-ol was prepared from 6-methyl-5-(trifluoromethyl)pyridin-2-ol using a procedure similar to that found in Intermediate B-7, Step 2. ESI-MS m / z Calcd. 254.95, Found 255.79 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ12.66(s,1H),7.99(s,1H),2.33-2.25(m,3H).

[0878] Step 4: 3-Bromo-2-chloro-6-methyl-5-(trifluoromethyl)pyridine

[0879] 3-Bromo-2-chloro-6-methyl-5-(trifluoromethyl)pyridine was prepared from 3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-ol using a procedure similar to that found in Step 1 of Intermediate B-6. 1 H NMR (400MHz, CDCl3) δ8.08 (s, 1H), 2.66-2.63 (m, 3H).

[0880] Step 5: 3-Bromo-2-(3,4-difluoro-2-methyl-phenoxy)-6-methyl-5-(trifluoromethyl)pyridine

[0881] 3-Bromo-2-(3,4-difluoro-2-methyl-phenoxy)-6-methyl-5-(trifluoromethyl)pyridine was prepared from 3-bromo-2-chloro-6-methyl-5-(trifluoromethyl)pyridine and 3,4-difluoro-2-methyl-phenol using a procedure similar to that found in Intermediate B-1, Step 1. ESI-MS m / z Calcd. 380.98, Found. 381.96 (M+1) + . 1 H NMR (400MHz, CDCl3) δ8.08 (s, 1H), 7.02 (q, J = 9.0Hz, 1H), 6.83 (m, 1H), 2.40 (q, J = 1.7Hz, 3H), 2.09 (d, J = 2.3Hz, 3H).

[0882] Step 6: [2-(3,4-Difluoro-2-methyl-phenoxy)-6-methyl-5-(trifluoromethyl)-3-pyridinyl]boronic acid

[0883] [2-(3,4-difluoro-2-methyl-phenoxy)-6-methyl-5-(trifluoromethyl)-3-pyridinyl]boronic acid was prepared from 3-bromo-2-(3,4-difluoro-2-methyl-phenoxy)-6-methyl-5-(trifluoromethyl)pyridine using trimethyl borate using a procedure analogous to that found in Intermediate B-3, Step 3. 1H NMR (400MHz, CD3OD) δ8.04 (s, 1H), 7.10 (q, J = 9.3Hz, 1H), 6.87-6.84 (m, 1H), 2.39 (d, J = 1.8Hz, 3H), 2.06 (d, J = 1.8Hz, 3H).

[0884] Intermediate B-11

[0885]

[0886] Step 1: Methyl 2-hydroxy-5-methyl-6-(trifluoromethyl)picolinate

[0887] To a solution of 3-amino-3-oxo-propionic acid methyl ester (9.6 g, 82 mmol) and 4-ethoxy-1,1,1-trifluoro-3-methyl-but-3-ene-2-one (15 g, 82 mmol) in methanol (120 mL) was added a methanol solution of sodium methoxide (23 mL 25% w / v, 106 mmol). The reaction mixture was heated under reflux for 1 hour and then cooled to room temperature. The precipitate was removed by filtration and washed with methanol (2 × 250 mL). The resulting solid was suspended in ethyl acetate (500 mL) and 2M hydrochloric acid (500 mL). The solid was filtered off and the filtrate was separated. The aqueous layer was extracted with ethyl acetate (500 mL). The combined organic extracts were washed with brine (500 mL), dried over magnesium sulfate and concentrated to give 2-hydroxy-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid methyl ester (11.4 g, 56%) as an off-white solid. ESI-MS m / z calculated value 235.04, found value 233.97 (M-1) - . 1 H NMR (400MHz, CDCl3) δ8.17 (s, 1H), 4.03 (s, 3H), 2.45 (m, 3H).

[0888] Step 2: Methyl 2-chloro-5-methyl-6-(trifluoromethyl)picolinate

[0889] A solution of 2-hydroxy-5-methyl-6-(trifluoromethyl)pyridine-3-formic acid methyl ester (10g, 40.5mmol) in pure dichlorophenyl phosphate (56.5g, 40mL, 268mmol) is heated to 155 DEG C for 6 hours. The reaction mixture is cooled to room temperature and then quenched into a mixture of vigorously stirred ethyl acetate (1000mL), water (250mL) and sodium carbonate (60g) at a rate that keeps the temperature below 45 DEG C. The mixture is then stirred vigorously for 2 hours. Each layer is separated. The aqueous layer is extracted with ethyl acetate (200mL). The combined organic layer is washed with water (500mL), brine (500mL), dried over magnesium sulfate and concentrated. Purified by silica gel chromatography (0-20% ethyl acetate / heptane), 2-chloro-5-methyl-6-(trifluoromethyl)pyridine-3-formic acid methyl ester (6.15g, 56%) is obtained as a white solid. ESI-MS m / z calculated value 253.01, found value 253.96 (M+1) + . 1 HNMR (400MHz, CDCl3) δ8.11 (s, 1H), 3.99 (s, 3H), 2.53 (q, J = 1.7Hz, 3H).

[0890] Step 3: 2-(3,4-Difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid methyl ester

[0891] Methyl 2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)picolinate was prepared from methyl 2-chloro-5-methyl-6-(trifluoromethyl)picolinate and 3,4-difluoro-2-methylphenol using a procedure similar to that found in Intermediate B-1, Step 1. ESI-MS m / z calcd 361.07, found 362.06 (M+1) + . 1 H NMR (400MHz, CDCl3) δ8.19 (s, 1H), 6.99 (q, J = 9.2Hz, 1H), 6.84 (m, 1H), 3.97 (s, 3H), 2.45 (q, J = 1.8Hz, 3H), 2.11 (d, J = 2.3Hz, 3H).

[0892] Step 4: 2-(3,4-Difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid

[0893] To a mixture of 2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid methyl ester (30 g, 78.5 mmol) in methanol (60 mL), THF (120 mL) and water (60 mL) was added lithium hydroxide monohydrate (6.5 g, 155 mmol). The mixture was stirred at room temperature for 2 hours, and then the volatiles were removed under reduced pressure. The residue was acidified with 2M HCl (about pH 6). The resulting solid was collected by filtration and dried to give 2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid (27 g, 97%). ESI-MS m / z calculated value 347.06, experimental value 346.0 (M-1) - . 1 H NMR (400MHz, CDCl3) δ8.39(s,1H),7.07-6.99(m,1H),6.86(m,1H),2.48-2.44(m,3H),2.15-2.08(m,3H).

[0894] Step 5: tert-Butyl N-[2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)-3-pyridinyl]carbamate

[0895] To a solution of 2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid (27 g, 76 mmol) in toluene (240 mL) was added triethylamine (16 mL, 115 mmol) and DPPA (25.5 g, 20 mL, 93 mmol). The mixture was stirred at room temperature for 30 minutes and t-BuOH (45 mL) was added. The mixture was then heated at 110 ° C for 2 hours, cooled to room temperature and partitioned between ethyl acetate (400 mL) and water (200 mL). The aqueous layer was extracted with additional ethyl acetate (2×200 mL). The combined organics were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (heptane, then 10% ethyl acetate / heptane) gave tert-butyl N-[2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)-3-pyridinyl]carbamate (24 g, 74%). ESI-MS m / z calculated value 418.13, found value 417.05 (M-1) - . 1H NMR (400MHz, CDCl3) δ 8.43 (s, 1H), 7.18 (s, 1H), 7.00 (q, J = 9.0Hz, 1H), 6.81 (m, 1H), 2.40 (q, J = 2.0Hz, 3H), 2.09 (d, J = 2.3Hz, 3H), 1.56 (t, J = 5.0Hz, 9H).

[0896] Step 6: 2-(3,4-Difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridin-3-amine

[0897] A solution of tert-butyl N-[2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)-3-pyridinyl]carbamate (24 g, 56 mmol) in HCl in dioxane (150 mL 4M, 600 mmol) was stirred at room temperature overnight. The mixture was concentrated in vacuo to give 2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridin-3-amine (21.5 g, 97%). ESI-MS m / z calculated value 318.08, found value 318.93 (M+1) + . 1 H NMR (400MHz, CDCl3) δ6.98 (q, J = 9.2Hz, 1H), 6.88 (s, 1H), 6.84 (m, 1H), 2.33 (q, J = 2.0Hz, 3H), 2.11 (d, J = 2.3Hz, 3H).

[0898] Step 7: 3-Bromo-2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridine

[0899] Tert-butyl nitrite (208 mg, 0.24 mL, 2.02 mmol) was added dropwise to a stirred mixture of 2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridine-3-amine (300 mg, 0.823 mmol) and copper (II) bromide (420 mg, 1.88 mmol) in anhydrous CH3CN (6 mL) at 0 ° C under argon. After stirring at 0 ° C for 30 minutes, the mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (0-10% ethyl acetate in heptane) to give 3-bromo-2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridine (270 mg, 83%). 1H NMR (400MHz, CDCl3) δ7.92 (s, 1H), 7.07-6.98 (m, 1H), 6.91 (qd, J = 4.4, 2.0Hz, 1H), 2.44 (q, J = 1.9Hz, 3H), 2.15 (d, J = 2.4Hz, 3H).

[0900] Step 8: 2-(3,4-Difluoro-2-methyl-phenoxy)-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine

[0901] 2-(3,4-Difluoro-2-methyl-phenoxy)-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine was prepared from 3-bromo-2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridine using a procedure analogous to that found in Intermediate B-1, Step 2, using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolan. ESI-MS m / z calcd 429.15, found 346.0 (M-pinacol) - . 1 HNMR (400MHz, CDCl3) δ8.01(s,1H),6.94(t,J=8.9Hz,1H),6.87(qd,J=4.4,1.8Hz,1H),2.40(q,J=2.0Hz,3H),2.16(d,J=2.3Hz,3H),1.34(s,12H).

[0902] Intermediate B-12

[0903]

[0904] Step 1: 5-(3,4-Difluoro-2-methoxy-phenoxy)-2-(trifluoromethyl)picolinate Methyl 5-(3,4-difluoro-2-methoxy-phenoxy)-2-(trifluoromethyl)picolinate was prepared from methyl 5-bromo-2-(trifluoromethyl)picolinate and 3,4-difluoro-2-methoxy-phenol using a procedure similar to that found in Step 4 of Intermediate B-4, but without N,N-dimethylglycine. ESI-MS m / z calcd 363.05, found 364.0 (M+1) + . 1HNMR (500MHz, CDCl3) δ8.24 (s, 1H), 8.12 (s, 1H), 6.95 (td, J = 9.3, 7.9Hz, 1H), 6.88 (ddd, J = 9.3, 4.9, 2.2Hz, 1H), 3.99 (s, 3H), 3.95 (d, J = 1.8Hz, 3H).

[0905] Step 2: 5-(3,4-Difluoro-2-methoxy-phenoxy)-2-(trifluoromethyl)pyridine-4-carboxylic acid

[0906] 5-(3,4-Difluoro-2-methoxy-phenoxy)-2-(trifluoromethyl)picolinic acid was prepared from 5-(3,4-difluoro-2-methoxy-phenoxy)-2-(trifluoromethyl)picolinic acid methyl ester using a procedure similar to that found in Intermediate B-11, Step 4. ESI-MS m / z calcd 349.04, found 350.0 (M+1) + . 1 H NMR (500MHz, DMSO-d6) δ14.07(s,1H),8.43(s,1H),8.17(s,1H),7.25(td,J=9.7,8.4Hz,1H),7.12-7.08(m,1H),3.88(d,J=1.2Hz,3H).

[0907] Step 3: 5-(3,4-Difluoro-2-methoxy-phenoxy)-2-(trifluoromethyl)pyridin-4-amine

[0908] 5-(3,4-Difluoro-2-methoxy-phenoxy)-2-(trifluoromethyl)pyridin-4-amine was prepared from 5-(3,4-difluoro-2-methoxy-phenoxy)-2-(trifluoromethyl)pyridine-4-carboxylic acid using a procedure analogous to that found in Intermediate B-11, steps 5 to 7. ESI-MS m / z calcd 320.06, found 321.1 (M+1) + ;319.0(M-1) - . 1 H NMR (400MHz, CDCl3) δ7.91 (s, 1H), 7.06 (s, 1H), 6.90 (td, J = 9.3, 8.0Hz, 1H), 6.80 (ddd, J = 9.3, 4.9, 2.3Hz, 1H), 4.72 (s, 2H), 3.97 (d, J = 1.8Hz, 3H).

[0909] Step 4: 4-Bromo-5-(3,4-difluoro-2-methoxy-phenoxy)-2-(trifluoromethyl)pyridine

[0910] 4-Bromo-5-(3,4-difluoro-2-methoxy-phenoxy)-2-(trifluoromethyl)pyridine was prepared from 5-(3,4-difluoro-2-methoxy-phenoxy)-2-(trifluoromethyl)pyridin-4-amine using a procedure similar to that found in Intermediate B-4, Step 6. ESI-MS m / z calcd. 382.96, found 384.2 (M+1) + . 1 HNMR (400MHz, CDCl3) δ8.02 (s, 1H), 7.97 (s, 1H), 7.02-6.84 (m, 2H), 3.97 (d, J = 1.9Hz, 3H).

[0911] Step 5: 5-(3,4-Difluoro-2-methoxy-phenoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine

[0912] 5-(3,4-Difluoro-2-methoxy-phenoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine was prepared using a procedure similar to that found in Step 4 of Intermediate B-2 using PdCl2(PhP3)2 catalyst. ESI-MS m / z calcd 431.13, found 350.1 (M-pinacol) + .

[0913] Intermediate B-13

[0914]

[0915] Step 1: 5-Fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid

[0916] At -30 ° C, n-BuLi solution (62 mL of 2.5 M in hexane, 155 mmol) was added dropwise to a solution of diisopropylamine (16.3 g, 22.5 mL, 161 mmol) in THF (190 mL) and the reaction mixture was slowly warmed to 0 ° C over 30 minutes. The reaction mixture was cooled to -78 ° C and a solution of 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine (23.87 g, 122.6 mmol) in THF (50 mL) was added dropwise over 25 minutes. After 1 hour, solid carbon dioxide (55 g, 1.2497 mol) was added in one portion (exotherm = -74 to -60 ° C). After 10 minutes, the reaction mixture was slowly warmed to room temperature. After 1.5 hours, heptane (75 mL), tert-butyl methyl ether (100 mL), 1.5 M aqueous sodium hydroxide solution (200 mL, 8.4 volumes) and water (100 mL, 4.2 volumes) were added and the biphasic mixture was allowed to stand for 1 h. Filter. The organic layer was separated and extracted with water (150 mL). The aqueous layers were combined, washed with tert-butyl methyl ether (150 mL), acidified with 3.0 M aqueous hydrochloric acid (200 mL, 8.4 volumes), and extracted with tert-butyl methyl ether (2 x 200 mL, 16.7 volumes). The combined organic extracts were washed with 15% aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to a total weight of 42.6 g. This mixture was slowly cooled to 0°C over 30 minutes, then diluted with heptane (50 mL) and the mixture was stirred at 0°C for 15 minutes. The solid was filtered, washed with heptane (50 mL), and dried under vacuum to yield 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid (15.59 g). The mother liquor was concentrated under vacuum to dryness (9.04 g), then taken up in tert-butyl methyl ether (9 mL), and the mixture was heated at 55°C. After 10 minutes, heptane (20 mL, 2.2 volumes) was added over 25 minutes and the mixture was slowly cooled to room temperature overnight. The resulting solid was filtered, rinsed with heptane (25 mL), and dried under vacuum to give a second crop of 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid (3.97 g). The two crops were combined to give 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid (19.56 g, 70%). ESI-MS m / z calculated value 223.03, found value 222.1 (M-1) - . 1 H NMR (400MHz, DMSO-d6) δ14.74(brs,1H),8.73(s,1H),2.47-2.43(m,3H). 19 FNMR(377MHz,DMSO-d6)δ-62.99(s,1F),-125.50(s,1F).

[0917] Step 2: Methyl 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylate

[0918] To a stirred mixture of 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid (5.0 g, 22 mmol) in methanol (50.0 mL) was added dropwise H2SO4 (16 mL, 300 mmol) at room temperature. The reaction mixture was stirred at 80 ° C for 48 hours. After cooling to room temperature, the mixture was cooled to 0 ° C and 2M aqueous sodium hydroxide solution was added to adjust the solution to pH = 9. The solution was diluted with ethyl acetate (50 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give methyl 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylate (4.23 g, 80%). ESI-MS m / z calculated value 237.04, experimental value 238.0 (M+1) + . 1 H NMR (500MHz, CDCl3) δ8.45 (s, 1H), 4.01 (s, 3H), 2.50-2.48 (m, 3H).

[0919] Step 3: 5-(3,4-Difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid methyl ester

[0920] Methyl 5-(3,4-difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)picolinate was prepared from methyl 5-fluoro-3-methyl-2-(trifluoromethyl)picolinate and 3,4-difluoro-2-methyl-phenol using a procedure similar to that found in Step 1 of Intermediate B-1 using DMF as solvent. ESI-MS m / z calcd 361.07, found 362.2 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ8.13 (s, 1H), 7.37 (q, J = 9.4Hz, 1H), 7.03 (ddd, J = 9.2, 4.2, 2.0Hz, 1H), 3.93 (s, 3H), 2.44-2.38 (m, 3H), 2.13 (d, J = 2.2Hz, 3H).

[0921] Step 4: 5-(3,4-Difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid

[0922] A solution of 5-(3,4-difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid methyl ester (407 mg, 1.13 mmol) in ethanol (3 mL) was treated with NaOH (3 mL 2M, 6 mmol) and stirred at 70 ° C for 45 minutes. The reaction was cooled to room temperature and partitioned between 1M HCl (10 mL) and ethyl acetate (20 mL). The organic layer was separated and washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 5-(3,4-difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid (400 mg, quantitative yield). 1 H NMR (400MHz, DMSO-d6) δ8.09 (s, 1H), 7.36 (q, J = 9.4Hz, 1H), 6.99 (ddd, J = 9.3, 4.2, 2.0Hz, 1H), 2.46-2.41 (m, 3H), 2.15 (d, J = 2.1Hz, 3H).

[0923] Step 5: 5-(3,4-Difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridin-4-amine

[0924] A solution of DPPA (429 mg, 1.56 mmol) in 1,4-dioxane (1 mL) was added dropwise to a stirred mixture of 5-(3,4-difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid (391 mg, 1.13 mmol) and DIPEA (300 μL, 1.72 mmol) in 1,4-dioxane (6 mL) and tert-butanol (2 mL). The reaction mixture was stirred at 70 ° C for 21 hours. After cooling to room temperature, the reaction mixture was partitioned between water (10 mL) and ethyl acetate (10 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic extracts were dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (6 mL, 78 mmol) was added once at room temperature and stirred overnight. The solvent was removed under reduced pressure and the residue was neutralized using 2M sodium hydroxide. The aqueous layer was extracted with dichloromethane (3 times) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0-20% ethyl acetate / heptane) gave 5-(3,4-difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridin-4-amine (327 mg, 91%). ESI-MS m / z calculated value 318.08, found value 319.2 (M+1) + .

[0925] Step 6: 4-Bromo-5-(3,4-difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine

[0926] 4-Bromo-5-(3,4-difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine was prepared from 5-(3,4-difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridin-4-amine using a procedure similar to that found in Intermediate B-11, Step 7. ESI-MS m / z Calcd. 380.98, Found. 382.0 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ 8.05 (s, 1H), 7.35 (q, J = 9.4Hz, 1H), 6.94 (ddd, J = 9.2, 4.1, 2.0Hz, 1H), 2.57 (d, J = 1.8Hz, 3H), 2.19 (d, J = 2.2Hz, 3H).

[0927] Step 7: 5-(3,4-Difluoro-2-methyl-phenoxy)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine

[0928] To a solution of 4-bromo-5-(3,4-difluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine (125 mg, 0.3271 mmol) in 2-MeTHF (2 mL) at 0°C under nitrogen was added isopropylmagnesium chloride lithium chloride complex (400 μL 1.3 M in THF, 0.52 mmol). After 20 minutes at room temperature, the reaction mixture was cooled to 0°C and treated with a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (119 mg, 0.640 mmol) in 2-MeTHF (1.5 mL) at 0°C under nitrogen. After 2 hours at room temperature, saturated aqueous ammonium chloride (10 mL) was added, and the aqueous phase was separated and extracted with ethyl acetate (15 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (0-50% ethyl acetate / hexanes) gave 5-(3,4-difluoro-2-methyl-phenoxy)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (29.9 mg, 21%). ESI-MS m / z calculated: 429.15, found: 430.1 (M+1). + . 1H NMR (400MHz, DMSO-d6) δ 8.03 (s, 1H), 7.30 (q, J = 9.5Hz, 1H), 6.85-6.77 (m, 1H), 2.48 (d, J = 2.1Hz, 3H), 2.18 (d, J = 2.1Hz, 3H), 1.27 (s, 12H).

[0929] Intermediate B-14

[0930]

[0931] Step 1: 3-Bromo-2-(3,4-difluoro-2-methyl-phenoxy)-5-(trifluoromethyl)pyridine

[0932] 3-Bromo-2-(3,4-difluoro-2-methyl-phenoxy)-5-(trifluoromethyl)pyridine was prepared from 3-bromo-2-chloro-5-(trifluoromethyl)pyridine and 3,4-difluoro-2-methyl-phenol using a procedure similar to that found in Intermediate B-1, Step 1. ESI-MS m / z calcd 366.96, found 368.0 (M+1) + . 1 HNMR (400MHz, DMSO-d6) δ 8.74-8.67 (m, 1H), 8.57-8.44 (m, 1H), 7.39 (q, J = 9.4Hz, 1H), 7.19-7.05 (m, 1H), 2.04 (d, J = 2.1Hz, 3H).

[0933] Step 2: [2-(3,4-Difluoro-2-methyl-phenoxy)-5-(trifluoromethyl)-3-pyridinyl]boronic acid

[0934] [2-(3,4-Difluoro-2-methyl-phenoxy)-5-(trifluoromethyl)-3-pyridinyl]boronic acid was prepared from 3-bromo-2-(3,4-difluoro-2-methyl-phenoxy)-5-(trifluoromethyl)pyridine using a procedure similar to that found in Intermediate B-3, Step 3. ESI-MS m / z Calcd. 333.06, Found. 334.0 (M+1) + . 1 HNMR (400MHz, DMSO-d6) δ8.54 (s, 2H), 8.51-8.45 (m, 1H), 8.28-8.23 (m, 1H), 7.33 (q, J = 9.4Hz, 1H), 7.09-7.01 (m, 1H), 2.10-2.01 (m, 3H).

[0935] Intermediate B-15

[0936]

[0937] Step 1: 5-(4-Fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid methyl ester

[0938] 5-(4-Fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)picolinic acid methyl ester was prepared from 5-fluoro-3-methyl-2-(trifluoromethyl)picolinic acid methyl ester (Intermediate B-13 Step 2) and 4-fluoro-2-methyl-phenol using a procedure analogous to that found in Intermediate B-13 Step 3. 1 H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.04-6.88 (m, 3H), 3.98 (s, 3H), 2.48-2.42 (m, 3H), 2.19 (s, 3H). ESI-MS m / z calculated value 343.08, found value 344.1 (M+1) + .

[0939] Step 2: 5-(4-Fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid

[0940] 5-(4-Fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)picolinic acid was prepared from 5-(4-fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)picolinic acid methyl ester using a procedure analogous to that found in step 4 of intermediate B-13. 1 H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.07-6.88 (m, 3H), 2.56-2.52 (m, 3H), 2.20 (s, 3H). ESI-MS m / z calculated value 329.07, found value 330.2 (M+1) + .

[0941] Step 3: 5-(4-Fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridin-4-amine

[0942] 5-(4-Fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridin-4-amine was prepared from 5-(4-fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridin-4-carboxylic acid using a procedure analogous to that found in step 5 of intermediate B-13. 1H NMR (400 MHz, DMSO-d6) δ 7.51 (s, 1H), 7.22 (dd, J = 9.3, 3.2 Hz, 1H), 7.03 (td, J = 8.6, 3.2 Hz, 1H), 6.88 (dd, J = 8.9, 4.9 Hz, 1H), 6.29 (s, 2H), 2.24 (s, 3H), 2.22 (d, J = 1.7 Hz, 3H). ESI-MS m / z calcd 300.09, found 301.2 (M+1) + .

[0943] Step 4: 4-Bromo-5-(4-fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine

[0944] 4-Bromo-5-(4-fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine was prepared from 5-(4-fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridin-4-amine using a procedure analogous to that found in step 7 of intermediate B-11. 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.33-7.26 (m, 1H), 7.17-7.07 (m, 2H), 2.57 (d, J = 1.7 Hz, 3H), 2.20 (s, 3H). ESI-MS m / z calculated value 362.99, found value 364.1 (M+1) + .

[0945] Step 5: 5-(4-Fluoro-2-methyl-phenoxy)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine

[0946] 5-(4-Fluoro-2-methyl-phenoxy)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine was prepared from 4-bromo-5-(4-fluoro-2-methyl-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine using a procedure analogous to that found in step 7 of intermediate B-13. 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.24 (dd, J = 9.3, 3.1 Hz, 1H), 7.12-7.03 (m, 1H), 7.03-6.97 (m, 1H), 2.47 (d, J = 2.0 Hz, 3H), 2.20 (s, 3H), 1.29 (s, 12H). ESI-MS m / z calculated value 411.16, found value 412.1 (M+1) + .

[0947] Intermediate B-16

[0948]

[0949] Step 1: 5-Chloro-3-iodo-6-(trifluoromethyl)pyridin-2-ol

[0950] To a solution of 3-iodo-6-(trifluoromethyl)pyridin-2-ol (13.3 g, 45.2 mmol) in DMF (70 mL) was added 1,3-dichloro-5,5-dimethylhydantoin (15.960 g, 81.005 mmol). The reaction mixture was stirred at room temperature for 24 hours and then partitioned between ethyl acetate (500 mL) and water (200 mL). The biphasic mixture was cooled to 0-10 ° C, stirred vigorously and slowly treated with 10% sodium thiosulfate aqueous solution (200 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The pH of the aqueous layer was adjusted to 3 by adding 3M HCl aqueous solution (about 10 mL) and extracted with additional ethyl acetate (200 mL). The combined organic layers were washed with 50% saturated sodium chloride aqueous solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0-5% methanol / dichloromethane) gave 5-chloro-3-iodo-6-(trifluoromethyl)pyridin-2-ol (8.68 g, 57%). ESI-MS m / z calculated value 322.88, found value 323.9 (M+1) + . 1 H NMR (400MHz, CDCl3) δ9.45-8.67 (m, 1H), 8.22 (s, 1H). 19 F NMR (377MHz, CDCl3) δ-65.53--65.89 (m, 3F).

[0951] Step 2: Methyl 5-chloro-2-hydroxy-6-(trifluoromethyl)picolinate

[0952] Palladium (II) acetate (250 mg, 1.11 mmol) was added to a solution of 5-chloro-3-iodo-6-(trifluoromethyl)pyridin-2-ol (7.08 g, 20.8 mmol), triethylamine (6.5 g, 9.0 mL, 64.6 mmol) and 1,1′-ferrocenediyl-bis(diphenylphosphine) (1.2 g, 2.2 mmol) in methanol (100 mL) in a sealed tube. Carbon monoxide was bubbled into the solution for 5 minutes, then the tube was sealed and the reaction mixture was stirred at 60 ° C under a CO atmosphere for 5 hours. Additional CO was bubbled into the solution, and the reaction mixture was stirred at 60 ° C under a CO atmosphere overnight. The mixture was cooled to room temperature and dried over 40 ° C for 10 minutes. The product was filtered, washed with methanol and the filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane (150 mL) and washed with 1M HCl aqueous solution (100 mL), water (50 mL) and brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. Purification by silica gel chromatography (0-5% methanol / dichloromethane) gave methyl 5-chloro-2-hydroxy-6-(trifluoromethyl)pyridine-3-carboxylate (4.99 g, 94%). 1 H NMR (400MHz, CDCl3) δ11.30(br.s,1H),8.37(s,1H),4.08(s,3H). 19 F NMR (377 MHz, CDCl3) δ -66.91 (s, 3F). ESI-MS m / z calculated value 254.99, found value 256.0 (M+1) + .

[0953] Step 3: Methyl 5-chloro-6-(trifluoromethyl)-2-(trifluoromethylsulfonyloxy)pyridine-3-carboxylate

[0954] To a solution of 5-chloro-2-hydroxy-6-(trifluoromethyl)pyridine-3-carboxylic acid methyl ester (4.59 g, 17.96 mmol) in DCM (100 mL) was added DIPEA (10.2 g, 13.8 mL, 79.2 mmol) and trifluoromethanesulfonic anhydride (15.4 g, 9.2 mL, 54.7 mmol) at 0 ° C. The resulting mixture was stirred at room temperature for 3 hours, then diluted with saturated aqueous ammonium chloride solution (20 mL) and the layers were separated. The aqueous layer was extracted with DCM (3 × 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was adsorbed on silica gel under vacuum and purified by silica gel chromatography (120 g silica, 0-20% ethyl acetate / heptane) to give 5-chloro-6-(trifluoromethyl)-2-(trifluoromethylsulfonyloxy)pyridine-3-carboxylic acid methyl ester (6.36 g, 91%). 1 H NMR (400MHz, CDCl3) δ8.64 (s, 1H), 4.07 (s, 3H). 19 F NMR (377 MHz, CDCl3) δ -66.81 (s, 3F), -72.64 (s, 3F). ESI-MS m / z calculated value 386.94, found value 387.9 (M+1) + .

[0955] Step 4: 5-Chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)picolinate

[0956] 5-Chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)picolinic acid methyl ester was prepared from 5-chloro-6-(trifluoromethyl)-2-(trifluoromethylsulfonyloxy)picolinic acid methyl ester and 3,4-difluoro-2-methyl-phenol using a procedure similar to that found in Intermediate B-1, Step 1, using DIPEA as base and DMF as solvent. 1 H NMR (400MHz, CDCl3) δ8.41 (s, 1H), 7.05 (dd, J = 18.1, 10.0Hz, 1H), 6.93-6.83 (m, 1H), 4.03 (s, 3H), 2.14 (d, J = 2.0Hz, 3H). 19 FNMR (377 MHz, CDCl3) δ -66.69 (s, 3F), -138.33 (d, J = 20.4 Hz, 1F), -140.88 (d, J = 21.8 Hz, 1F). ESI-MS m / z calculated value 381.02, found value 382.0 (M+1) + .

[0957] Step 5: 5-Chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxylic acid

[0958] 5-Chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)picolinic acid was prepared from 5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)picolinic acid methyl ester using a procedure similar to that found in Intermediate B-11, Step 4. ESI-MS m / z Calcd. 367.00, Found. 367.9 (M+1) + . 1 H NMR (400MHz, CDCl3) δ8.58 (s, 1H), 7.08 (dd, J = 18.6, 9.3Hz, 1H), 6.93-6.86 (m, 1H), 2.15 (d, J = 2.0Hz, 3H).

[0959] Step 6: tert-Butyl N-[5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)-3-pyridinyl]carbamate

[0960] Tert-butyl N-[5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)-3-pyridinyl]carbamate was prepared from 5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxylic acid using a procedure similar to that found in step 5 of intermediate B-11 using tert-butanol as solvent. ESI-MS m / z calcd 438.08, found 439.1 (M+1) + .

[0961] Step 7: 5-Chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridin-3-amine

[0962] 5-Chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridin-3-amine was prepared from tert-butyl N-[5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)-3-pyridinyl]carbamate using a procedure analogous to that found in Intermediate B-11, Step 6. ESI-MS m / z calcd. 338.02, found 339.0 (M+1) + . 1 H NMR (400MHz, CDCl3) δ7.07 (s, 1H), 7.06-6.98 (m, 1H), 6.93-6.84 (m, 1H), 4.42 (br.s, 2H), 2.13 (d, J = 2.2Hz, 3H). 19 FNMR (377MHz, CDCl3) δ -64.18 (s, 3F), -138.52 (d, J = 20.4Hz, 1F), -141.43 (d, J = 20.4Hz, 1F).

[0963] Step 8: 5-Chloro-2-(3,4-difluoro-2-methyl-phenoxy)-3-iodo-6-(trifluoromethyl)pyridine

[0964] To a suspension of 5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridin-3-amine (683 mg, 1.88 mmol) and p-toluenesulfonic acid monohydrate (462 mg, 2.43 mmol) in acetonitrile (20 mL) cooled at 0 ° C. isoamyl nitrite (305 mg, 0.35 mL, 2.6 mmol) is slowly added dropwise. The resulting mixture is stirred at 0 ° C. for 90 minutes. Potassium iodide (400 mg, 2.41 mmol) is added to the mixture at 0 ° C. and stirred at this temperature for 2 hours. The mixture is allowed to warm to room temperature within 1 hour, and the resulting suspension is concentrated under reduced pressure. The mixture is dissolved in ethyl acetate (50 mL), and sodium bicarbonate aqueous solution (25 mL) is added, followed by water (25 mL). The phases were separated and the organic layer was washed with aqueous sodium bicarbonate (25 mL), then with aqueous sodium thiosulfate (2×25) and brine (25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0-10% ethyl acetate / heptane) gave 5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-3-iodo-6-(trifluoromethyl)pyridine (363 mg, 43%). ESI-MS m / z calculated value 448.91, found value 450.2 (M+1) + . 1 H NMR (400MHz, CDCl3) δ8.32 (s, 1H), 7.06 (dd, J = 19.6, 9.2Hz, 1H), 6.95-6.85 (m, 1H), 2.14 (d, J = 2.0Hz, 3H). 19 F NMR (377MHz, CDCl3) δ -66.31 (s, 3F), -138.21 (d, J = 21.8Hz, 1F), -140.67 (d, J = 23.2Hz, 1F).

[0965] Step 9: [5-Chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)-3-pyridinyl]boronic acid

[0966] [5-Chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)-3-pyridinyl]boronic acid was prepared from 5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-3-iodo-6-(trifluoromethyl)pyridine using a procedure analogous to that found in Intermediate B-13, Step 7. ESI-MS m / z calcd 367.02, found 368.1 (M+1)+.

[0967] Intermediate B-17

[0968]

[0969] Step 1: 5-Fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid

[0970] 5-Fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid was prepared from 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine using a procedure similar to that found in Intermediate B-13, Step 1. ESI-MS m / z Calcd. 223.03, Found. 222.1 (M-1) - . 1 H NMR (400MHz, DMSO-d6) δ14.74(br s,1H),8.73(s,1H),2.47-2.43(m,3H). 19 F NMR(377MHz, DMSO-d6)δ-62.99(s,1F),-125.50(s,1F).

[0971] Step 2: Methyl 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylate

[0972] To a stirred mixture of 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid (8.20 g, 36.8 mmol) in methanol (75 mL) was added thionyl chloride (4.9 g, 3 mL, 41 mmol) dropwise at 0 ° C. The reaction mixture was heated to 70 ° C and stirred for 24 hours. The reaction mixture was cooled to room temperature and partitioned between water and dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution (2 times) and brine, dried over sodium sulfate, and then concentrated in vacuo. Purified by silica gel chromatography (0-20% ethyl acetate / heptane) to obtain 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid methyl ester (1.085 g, 8%) as a clear, colorless oil. ESI-MS m / z calculated value 237.04, found value 238.03 (M + 1) + . 1 H NMR (400MHz, CDCl3) δ8.45 (s, 1H), 4.00 (s, 3H), 2.50-2.48 (m, 3H). 19 F NMR (376MHz, CDCl3) δ-64.4 (s, 3F), -124.2 (s, 1F).

[0973] Step 3: Methyl 5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)picolinate

[0974] Methyl 5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)picolinate was prepared from methyl 5-fluoro-3-methyl-2-(trifluoromethyl)picolinate and 2-methoxy-4-(trifluoromethoxy)phenol using a procedure similar to that found in Step 1 of Intermediate B-1 and using toluene as solvent. ESI-MS m / z calcd 425.07, found 426.04 (M+1) + . 1 H NMR (400MHz, CDCl3) δ7.86(s,1H),7.13(d,1H),6.87-6.83(m,2H),3.97(s,3H),3.79(s,3H),2.44-2.44(m,3H). 19 F NMR (376MHz, CDCl3) δ-57.9--58.0(m,3F),-64.0--64.0(m,3F).

[0975] Step 4: 5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid

[0976] 5-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)picolinic acid was prepared from methyl 5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)picolinate using a procedure analogous to that found in Intermediate B-13, Step 4. ESI-MS m / z calcd 411.05, found 411.98 (M+1) + .

[0977] Step 5: 5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridin-4-amine

[0978] 5-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridin-4-amine was prepared from 5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid using a procedure analogous to that found in Intermediate B-13, Step 5. ESI-MS m / z calcd 382.08, found 383.02 (M+1) + . 1HNMR (400MHz, CDCl3) δ7.69 (s, 1H), 7.22 (dd, J = 8.7, 7.3Hz, 1H), 7.02-6.99 (m, 1H), 6.86-6.78 (m, 3H), 3.83 (s, 3H), 2.28 (d, J = 1.4Hz, 3H). 19 F NMR (376MHz, CDCl3) δ-57.9--58.0 (m, 3F), -63.3 (d, J=18.8Hz, 3F).

[0979] Step 6: 4-Bromo-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine

[0980] 4-Bromo-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine was prepared from 5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridin-4-amine using a procedure similar to that found in Intermediate B-4, Step 6. ESI-MS m / z calcd 444.98, found 445.89 (M+1) + .

[0981] Step 7: 5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine

[0982] 5-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine was prepared from 4-bromo-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine using a procedure analogous to that found in Intermediate B-13, Step 7. ESI-MS m / z calcd 493.15, found 494.06 (M+1) + . 1 H NMR (400MHz, CDCl3) δ7.82 (s, 1H), 7.02 (d, J = 8.2Hz, 1H), 6.84-6.79 (m, 2H), 3.80 (s, 3H), 2.52 (d, J = 1.8Hz, 3H), 1.34 (s, 12H). 19 F NMR (376MHz, CDCl3) δ -58.0 (s, 3F), -64.0 (d, J = 1.6Hz, 3F).

[0983] Intermediate B-18

[0984]

[0985] Step 1: 2-Fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoic acid

[0986] 2-Fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoic acid was prepared using a procedure similar to that found in Intermediate B-4, Step 4, without N,N-dimethylglycine and using toluene as solvent. 1 H NMR (400MHz, CDCl3) δ9.40 (br.s, 1H), 7.54 (t, J = 8.5Hz, 1H), 7.04-6.99 (m, 2H), 6.98-6.92 (m, 1H), 6.45 (d, J = 8.9Hz, 1H), 2.19 (s, 3H). 19 F NMR (376MHz, CDCl3) δ-60.8 (d, J = 12.3Hz, 3F), -112.1--112.2 (m, 1F), -116.3 (s, 1F).

[0987] Step 2: 2-Fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)aniline

[0988] 2-Fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)aniline was prepared from 2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoic acid using a procedure similar to that found in Intermediate B-13, Step 5. ESI-MS m / z Calcd. 303.07, Found. 303.94 (M+1) + . 1 H NMR (400MHz, CDCl3) δ7.23-7.18(m,1H),6.93-6.89(m,2H),6.83-6.76(m,1H),6.31-6.26(m,1H),2.19(s,3H). 19 F NMR (376MHz, CDCl3) δ -60.6 (d, J = 12.3Hz, 3F), -117.7 (s, 1F), -135.6 (q, J = 12.5Hz, 1F).

[0989] Step 3: 2-Bromo-3-fluoro-1-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzene

[0990] 2-Bromo-3-fluoro-1-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzene was prepared from 2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)aniline using a procedure analogous to that found in Intermediate B-4, Step 6. 1 HNMR (400MHz, CDCl3) δ7.43-7.37(m,1H),7.04-6.92(m,3H),6.43-6.37(m,1H),2.17(s,3H). 19 FNMR (376MHz, CDCl3) δ-60.9 (d, J = 12.3Hz, 3F), -103.9--104.0 (m, 1F), -116.6 (s, 1F).

[0991] Step 4: 2-[2-Fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0992] 2-[2-Fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was prepared from 2-bromo-3-fluoro-1-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzene using a procedure analogous to that found in step 7 of intermediate B-13. 1 H NMR (400MHz, CDCl3) δ7.45 (t, J = 8.5 Hz, 1H), 6.99-6.84 (m, 3H), 6.39 (d, J = 8.8 Hz, 1H), 2.18 (s, 3H), 1.35 (s, 12H). 19 F NMR (376MHz, CDCl3) δ-60.8 (d, J = 12.2Hz, 3F), -103.6--103.8 (m, 1F), -118.0 (s, 1F).

[0993] Intermediate B-19

[0994]

[0995] Step 1: 5-Chloro-2-(4-fluoro-2-methyl-phenoxy)-4,6-dimethyl-pyridine-3-carbonitrile

[0996] 5-Chloro-2-(4-fluoro-2-methyl-phenoxy)-4,6-dimethyl-pyridine-3-carbonitrile was prepared from 2,5-dichloro-4,6-dimethyl-pyridine-3-carbonitrile and 4-fluoro-2-methyl-phenol using a procedure similar to that found in Intermediate B-1, Step 1, using potassium carbonate as the base and NMP as the solvent. ESI-MS m / z calcd 290.06, found 291.2 (M+1) + . 1 HNMR (400MHz, CDCl3) δ7.04 (dd, J = 8.8, 4.9 Hz, 1H), 6.97 (dd, J = 8.9, 2.8 Hz, 1H), 6.95-6.88 (m, 1H), 2.63 (s, 3H), 2.45 (s, 3H), 2.16 (s, 3H). 19 F NMR (377MHz, CDCl3) δ-117.65 (s, 1F).

[0997] Step 2: 5-Chloro-2-(4-fluoro-2-methyl-phenoxy)-4,6-dimethyl-pyridine-3-carbonitrile

[0998] To a solution of 5-chloro-2-(4-fluoro-2-methyl-phenoxy)-4,6-dimethyl-pyridine-3-carbonitrile (1.09 g, 3.75 mmol) in DMSO (25 mL) was added hydrogen peroxide (35% in water) (2.6 mL, 10.394 mmol) and NaOH (2.7 g, 67.5 mmol) at room temperature. The resulting mixture was stirred at 50 ° C for 4 hours. The mixture was cooled to 0 ° C, and then 10% aqueous sodium thiosulfate solution (50 mL) and 5% aqueous citric acid solution (50 mL) were slowly added over 5 minutes. The resulting mixture was stirred for 10 minutes and then extracted with ethyl acetate (3×75 mL). The organic layers were combined, washed with brine (75 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (10-80% ethyl acetate / heptane) gave 5-chloro-2-(4-fluoro-2-methyl-phenoxy)-4,6-dimethyl-pyridine-3-carboxamide (952 mg, 82%) as a white solid. ESI-MS m / z calculated value 308.07, found value 309.2 (M+1) + . 1 H NMR (400MHz, CDCl3) δ7.02-6.86(m,3H),6.13-5.82(m,2H),2.51(s,3H),2.40(s,3H),2.15(s,3H). 19 F NMR (377MHz, CDCl3) δ-118.51 (s, 1F).

[0999] Step 3: 5-Chloro-2-(4-fluoro-2-methyl-phenoxy)-4,6-dimethyl-pyridine-3-carboxylic acid

[1000] Sulfuric acid (10 g, 5.5 mL, 103 mmol) and 5-chloro-2-(4-fluoro-2-methyl-phenoxy)-4,6-dimethyl-pyridine-3-carboxamide (900 mg, 2.91 mmol) were stirred until dissolution was complete. The solution was cooled to 0 ° C and a solution of sodium nitrite (500 mg, 7.25 mmol) in water (2.5 mL) was added dropwise over 5 minutes. The resulting mixture was allowed to reach room temperature and stirred for 5 hours. 1 M aqueous sodium hydroxide solution was added to the reaction mixture until pH 4-5, and the resulting suspension was extracted with ethyl acetate (2 × 100 mL). The combined organic layer was washed with brine (75 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by reverse phase chromatography (5-80% acetonitrile / 0.1% formic acid) gave 5-chloro-2-(4-fluoro-2-methyl-phenoxy)-4,6-dimethyl-pyridine-3-carboxylic acid (792 mg, 79%) as a white solid. ESI-MS m / z calculated value 309.06, found value 310.2 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ13.78 (br s, 1H), 7.16 (dd, J = 9.4, 2.6Hz, 1H), 7.11-7.00 (m, 2H), 2.36 (s, 3H), 2.32 (s, 3H), 2.07 (s, 3H). 19 F NMR(377MHz,DMSO-d6)δ-118.27--118.47(m,1F).

[1001] Step 4: 5-Chloro-2-(4-fluoro-2-methyl-phenoxy)-3-iodo-4,6-dimethyl-pyridine

[1002] 5-Chloro-2-(4-fluoro-2-methyl-phenoxy)-3-iodo-4,6-dimethyl-pyridine was prepared from 5-chloro-2-(4-fluoro-2-methyl-phenoxy)-3-iodo-4,6-dimethyl-pyridine using a procedure similar to that found in Intermediate B-26, Step 2. ESI-MS m / z Calcd. 390.97, Found. 392.0 (M+1) + . 1 H NMR (400MHz, CDCl3) δ7.02-6.97(m,1H),6.95(dd,J=9.2,2.9Hz,1H),6.93-6.86(m,1H),2.67(s,3H),2.36(s,3H),2.15(s,3H). 19F NMR (377MHz, CDCl3) δ-118.77 (s, 1F).

[1003] Step 5: 5-Chloro-2-(4-fluoro-2-methyl-phenoxy)-4,6-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[1004] 5-Chloro-2-(4-fluoro-2-methyl-phenoxy)-4,6-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was prepared from 5-chloro-2-(4-fluoro-2-methyl-phenoxy)-3-iodo-4,6-dimethyl-pyridine using a procedure similar to that found in Intermediate B-2, Step 4. ESI-MS m / z Calcd. 391.15, Found. 392.2 (M+1) + . 1 H NMR (400MHz, CDCl3) δ6.99-6.89(m,2H),6.88-6.82(m,1H),2.43(s,3H),2.38(s,3H),2.18(s,3H),1.37(s,12H). 19 F NMR (377MHz, CDCl3) δ-119.98 (s, 3F).

[1005] Intermediate B-20

[1006]

[1007] Step 1: 3-Bromo-2-(4,4-difluoroazepan-1-yl)quinoline

[1008] A solution of 2,3-dibromoquinoline (8.16 g, 28.4 mmol) and 4,4-difluoroazepane hydrochloride (5.0 g, 29 mmol) in NMP (65 mL) was treated with KCO (7.9 g, 57.16 mmol) and heated at 80-85 ° C for 2 hours. Additional 4,4-difluoroazepane hydrochloride (0.5 g, 2.9 mmol) was added and the mixture was stirred at 80-85 ° C for another 19 hours. Additional 4,4-difluoroazepane hydrochloride (0.5 g, 2.9 mmol) was added and the mixture was stirred at 80-85 ° C for another 6 hours. The mixture was extracted with MTBE (250 mL) / water (500 mL) and the organic phase was washed with water (500 mL) and brine (200 mL). The aqueous layer was extracted with additional MTBE (100 mL) and the combined organic phases were dried, filtered and evaporated to give 3-bromo-2-(4,4-difluoroazepan-1-yl)quinoline (9.48 g, 94%). ESI-MS m / z calcd 340.04, found 341.0 (M+1) + . 1 H NMR(400MHz, CDCl3)δ8.26(s,1H),7.84-7.70(m,1H),7.66-7.52(m,2H),7.34(td,J=7.2,1 .2Hz,1H),3.86-3.61(m,4H),2.58-2.38(m,2H),2.35-2.13(m,2H),2.08-1.92(m,2H)ppm; 19 F NMR (376MHz, CDCl3) δ-88.51.

[1009] Step 2: [2-(4,4-difluoroazepan-1-yl)-3-quinolinyl]boronic acid

[1010] n-BuLi (16mL in hexane 1.6M, 25.6mmol) was slowly added to a stirred solution of 3-bromo-2-(4,4-difluoroazepan-1-yl)quinoline (7.42g, 20.95mmol) in diethyl ether (95mL) at -78°C under argon. The mixture was stirred at -78°C for 1 hour and then treated dropwise with a solution of trimethyl borate (3.3g, 3.5mL, 31mmol) in diethyl ether (35mL). The reaction was warmed to room temperature and stirred for 18 hours. The mixture was diluted with saturated aqueous ammonium chloride solution (200mL) and extracted with ethyl acetate (200mL). The organic extract was washed with brine (200mL), dried over magnesium sulfate, filtered and concentrated. The solid was triturated with 10% ethyl acetate in heptane (10 vol), filtered and dried to give [2-(4,4-difluoroazepan-1-yl)-3-quinolinyl]boronic acid (2.6 g, 32%) as a white solid. ESI-MS m / z calculated 306.14, found 307.15 (M+1) + . 1 H NMR (400MHz, CD3OD) δ8.00 (s, 1H) 7.64 (t, J = 7.1Hz, 2H), 7.54-7.50 (m, 1H), 7.24-7.19 ( m,1H),3.85-3.82(m,2H),3.67(t,J=5.5Hz,2H),2.45-2.35(m,2H),2.08-2.00(m,4H). 19 F NMR (376MHz, CD3OD) δ-92.0--92.1 (m, 2F).

[1011] Intermediate B-21

[1012]

[1013] Step 1: Methyl 2-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylate

[1014] Methyl 2-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)picolinate was prepared from methyl 2-chloro-5-methyl-6-(trifluoromethyl)picolinate (Intermediate B-11, Step 2) and 4,4-difluoroazepane using a procedure similar to that found in Intermediate B-20, Step 1, using cesium carbonate as the base and DMF as the solvent. ESI-MS m / z calcd. 352.12, found 353.15 (M+1). + . 1H NMR (400MHz, CDCl3) δ7.79(s,1H),3.89(s,3H),3.74-3.67(m,2H),3.31-3.24(m,2H),2.44-2.28(m,5H),2.02-1.89(m,4H).

[1015] Step 2: 2-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid

[1016] 2-(4,4-Difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)picolinic acid was prepared from methyl 2-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)picolinate using a procedure similar to that found in Intermediate B-11, Step 4. ESI-MS m / z calcd 338.11, found 338.99 (M+1) + . 1 H NMR (400MHz, CDCl3) δ8.09 (s, 1H), 3.57-3.50 (m, 2H), 3.32 (t, J = 6.0Hz, 2H), 2.43-2.30 (m, 5H), 2.13-2.04 (m, 2H), 1.97-1.90 (m, 2H).

[1017] Step 3: 1-[3-Bromo-5-methyl-6-(trifluoromethyl)-2-pyridinyl]-4,4-difluoro-azepane

[1018] The vial was loaded with 2- (4,4-difluoroazepane-1-yl) -5-methyl -6- (trifluoromethyl) pyridine -3- carboxylic acid (1.5 g, 4.4 mmol), potassium phosphate (941 mg, 4.43 mmol) and tetrabutylammonium tribromide (3.2 g, 6.6 mmol). The vial was capped and purged with nitrogen. Acetonitrile (22 mL) was added via a syringe, and the reactants were stirred at 90 ° C for 1.5 hours. The reactants were cooled and concentrated under reduced pressure. Purified by reverse phase chromatography (C18, 1-99% acetonitrile / 5 mM HCl) to obtain 1- [3- bromo -5- methyl -6- (trifluoromethyl) -2- pyridyl] -4,4- difluoro - azepane (1.3 g, 79%) as a yellow oil. ESI-MS m / z calculated value 372.03, experimental value 372.9 (M + 1) + . 1H NMR (400MHz, CDCl3) δ7.70(s,1H),3.73-3.62(m,2H),3.64-3.56(m,2H),2.50-2.36(m,2H),2.34(s,3H),2.26-2.06(m,2H),2.06-1.86(m,2H).

[1019] Step 4: 4,4-difluoro-1-[5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-2-pyridinyl]azepane

[1020] 4,4-Difluoro-1-[5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-2-pyridyl]azepane was prepared from 1-[3-bromo-5-methyl-6-(trifluoromethyl)-2-pyridyl]-4,4-difluoro-azepane using a procedure analogous to that found in Intermediate B-20, Step 2, and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolan. ESI-MS m / z calcd 420.21, found 339.12 (M-pinacol) + ; Mass of the corresponding boronic acid observed by LC / MS. 1 H NMR (400MHz, CDCl3) δ7.66 (s, 1H), 3.73-3.70 (m, 2H), 3.52 (t, J = 5.5Hz, 2H), 2.37-2.26 (m, 5H), 2.01-1.91 (m, 4H), 1.34 (s, 12H).

[1021] Intermediate B-22

[1022]

[1023] Step 1: 3-Bromo-2-(4,4-difluoro-1-piperidinyl)-5-(trifluoromethyl)pyridine

[1024] To a solution of 3-bromo-2-fluoro-5-(trifluoromethyl)pyridine (1.224 g, 5.017 mmol) in THF (6 mL) was added a solution of 4,4-difluoropiperidine (1.22 g, 10.1 mmol) in THF (2 mL) dropwise at 0 ° C. The mixture was removed from the ice bath and allowed to reach room temperature within 1 hour and then heated at 50 ° C for 24 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was separated and washed with 50% saturated NH4Cl aqueous solution, dried over sodium sulfate, filtered and concentrated in vacuo. Purified by silica gel chromatography (40 g silica, 10-100% ethyl acetate / hexane) to give 3-bromo-2-(4,4-difluoro-1-piperidinyl)-5-(trifluoromethyl)pyridine (1.68 g, 97%). ESI-MS m / z calculated value 343.99, experimental value 345.0 (M + 1) + . 1 HNMR (400MHz, DMSO-d6) δ8.62 (dd, J = 2.2, 1.1Hz, 1H), 8.40-8.35 (m, 1H), 3.58-3.51 (m, 4H), 2.19-2.06 (m, 4H).

[1025] Step 2: [2-(4,4-difluoro-1-piperidinyl)-5-(trifluoromethyl)-3-pyridinyl]boronic acid

[1026] [2-(4,4-difluoro-1-piperidinyl)-5-(trifluoromethyl)-3-pyridinyl]boronic acid was prepared from 3-bromo-2-(4,4-difluoro-1-piperidinyl)-5-(trifluoromethyl)pyridine using a procedure similar to that found in Intermediate B-3, Step 3, and triisopropyl borate. ESI-MS m / z calcd 310.09, found 311.0 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ8.42 (dd, J=2.6, 1.2Hz, 1H), 7.79 (d, J=2.6Hz, 1H), 3.66-3.55 (m, 4H), 2.16-1.98 (m, 4H).

[1027] Intermediate B-23

[1028]

[1029] Step 1: 1-[3-Bromo-6-(trifluoromethyl)-2-pyridinyl]-4,4-difluoro-azepane

[1030] 1-[3-Bromo-6-(trifluoromethyl)-2-pyridinyl]-4,4-difluoro-azepane was prepared from 3-bromo-2-fluoro-6-(trifluoromethyl)pyridine using a procedure similar to that found in Intermediate B-20, Step 1, using DMSO as solvent and DIEA as base. ESI-MS m / z calcd 358.01, found 359.0 (M+1) + . 1 H NMR (400MHz, CDCl3) δ7.87 (dd, J=7.8, 0.9Hz, 1H), 6.97 (d, J=7.9Hz, 1H), 3.77-3.65 (m, 4H), 2.49-2.34 (m, 2H), 2.23-2.08 (m, 2H), 2.03-1.92 (m, 2H).

[1031] Step 2: [2-(4,4-Difluoroazepan-1-yl)-6-(trifluoromethyl)-3-pyridinyl]boronic acid [2-(4,4-Difluoroazepan-1-yl)-6-(trifluoromethyl)-3-pyridinyl]boronic acid was prepared from 1-[3-bromo-6-(trifluoromethyl)-2-pyridinyl]-4,4-difluoro-azepane using a procedure analogous to that found in Intermediate B-20, Step 2, and triisopropyl borate. ESI-MS m / z calcd 324.11, found 325.2 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ7.72-7.62(m,1H),7.00(dd,J=7.3,1.3Hz,1H),3.71-3.60(m,2H),3.54-3.46(m,3H),2.39-2.18(m,2H),2.13-1.83(m,5H).

[1032] Intermediate B-24

[1033]

[1034] Step 1: 4,4-difluoro-1-[6-methyl-5-(trifluoromethyl)-2-pyridinyl]azepane

[1035] 4,4-Difluoro-1-[6-methyl-5-(trifluoromethyl)-2-pyridinyl]azepane was prepared from 6-chloro-2-methyl-3-(trifluoromethyl)pyridine using a procedure similar to that found in Intermediate B-20, Step 1, using DMSO as solvent. ESI-MS m / z calcd 294.12, found 295.5 (M+1) + . 1H NMR(400MHz, CDCl3) δ7.60(d,J=8.9Hz,1H),6.30(d,J=8.9Hz,1H),3.81-3.76(m,2 H), 3.65 (t, J = 6.1Hz, 2H), 2.54-2.49 (m, 3H), 2.30-2.16 (m, 2H), 2.11-1.94 (m, 4H).

[1036] Step 2: 1-[3-Bromo-6-methyl-5-(trifluoromethyl)-2-pyridinyl]-4,4-difluoro-azepane

[1037] 4,4-difluoro-1-[6-methyl-5-(trifluoromethyl)-2-pyridinyl]azepane (1.29 g, 4.38 mmol) and NBS (786 mg, 4.42 mmol) were combined in DCM (25 mL) and stirred at room temperature for 16 hours. The reaction was evaporated and the resulting material was purified by silica gel chromatography (0-20% ethyl acetate / hexanes) to give 1-[3-bromo-6-methyl-5-(trifluoromethyl)-2-pyridinyl]-4,4-difluoro-azepane (1.34 g, 82%) as a clear oil. ESI-MS m / z calculated value 372.03, found value 373.2 (M+1) + . 1 H NMR (400MHz, CDCl3) δ7.86 (s, 1H), 3.77 (t, J = 6.3Hz, 2H), 3.74-3.69 (m, 2H), 2.50-2.46(m,3H),2.46-2.33(m,2H),2.19-2.06(m,2H),2.01-1.93(m,2H).

[1038] Step 3: [2-(4,4-Difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)-3-pyridinyl]boronic acid

[1039] [2-(4,4-Difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)-3-pyridinyl]boronic acid was prepared from 1-[3-bromo-6-methyl-5-(trifluoromethyl)-2-pyridinyl]-4,4-difluoro-azepane using a procedure analogous to that found in Intermediate B-20, Step 2. ESI-MS m / z calcd 338.12, found 339.3 (M+1) + . 1 H NMR (400MHz, CD3OD) δ7.62(s,1H),3.80-3.75(m,2H),3.54-3.48(m,2H),2.48(s,3H),2.36-2.21(m,2H),2.00-1.92(m,4H).

[1040] Intermediate B-25

[1041]

[1042] Step 1: [5-chloro-3-iodo-6-(trifluoromethyl)-2-pyridinyl] trifluoromethanesulfonate

[1043] [5-Chloro-3-iodo-6-(trifluoromethyl)-2-pyridinyl] trifluoromethanesulfonate was prepared from 5-chloro-3-iodo-6-(trifluoromethyl)pyridin-2-ol (Intermediate B-16, Step 1) using a procedure similar to that found in Intermediate B-16, Step 3. ESI-MS m / z calcd. 454.83, found 456.0 (M+1) + . 1 HNMR (400MHz, CDCl3) δ8.45 (s, 1H). 19 FNMR(377MHz, CDCl3)δ-66.56(s,3F),-71.85(s,3F).

[1044] Step 2: 1-[5-chloro-3-iodo-6-(trifluoromethyl)-2-pyridinyl]-4,4-difluoro-azepane

[1045] 1-[5-Chloro-3-iodo-6-(trifluoromethyl)-2-pyridinyl]-4,4-difluoro-azepane was prepared from [5-chloro-3-iodo-6-(trifluoromethyl)-2-pyridinyl] trifluoromethanesulfonate using a procedure similar to that found in Intermediate B-20, Step 1, using DIPEA as the base and DMF as the solvent. ESI-MS m / z calcd 439.96, found 441.2 (M+1) + . 1 H NMR (400MHz, CDCl3) δ8.17(s,1H),3.71-3.57(m,4H),2.47-2.33(m,2H),2.24-2.09(m,2H),2.02-1.92(m,2H). 19 F NMR (377MHz, CDCl3) δ -66.38 (s, 3F), -89.34 (quin, J = 15.0Hz, 2F).

[1046] Step 3: [5-Chloro-2-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)-3-pyridinyl]boronic acid

[1047] [5-Chloro-2-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)-3-pyridinyl]boronic acid was prepared from 1-[5-chloro-3-iodo-6-(trifluoromethyl)-2-pyridinyl]-4,4-difluoro-azepane using a procedure similar to that found in Intermediate B-20, Step 2, using triisopropyl borate and THF as solvent. ESI-MS m / z calcd 358.07, found 359.1 (M+1) + . 1 H NMR (400MHz, CDCl3) δ7.14 (s, 1H), 5.35 (s, 2H), 3.80-3.72 (m, 2H), 3.66 (t, J = 6.2Hz, 2H), 2.31-2.17 (m, 2H), 2.12-1.94 (m, 4H). 19 F NMR (377MHz, CDCl3) δ -65.93 (s, 3F), -91.23 (quin, J = 14.3Hz, 2F).

[1048] Intermediate B-26

[1049]

[1050] Step 1: 5-Chloro-2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-pyridine-3-carboxylic acid

[1051] 5-Chloro-2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-pyridine-3-carboxylic acid was prepared from 2,5-dichloro-4,6-dimethyl-pyridine-3-carboxylic acid and 4,4-difluoroazepane hydrochloride using a procedure similar to that found in Intermediate B-20, Step 1. ESI-MS m / z calcd 318.09, found 319.2 (M+1) + . 1 H NMR (400MHz, CDCl3) δ3.50-3.43 (m, 2H), 3.36 (t, J = 6.0Hz, 2H), 2.74 (s, 3H), 2. 61(s,3H),2.51-2.37(m,2H),2.31-2.16(m,2H),2.02(dt,J=11.7,6.0Hz,2H). 19 F NMR (377MHz, CDCl3) δ-88.93 (brs, 2F).

[1052] Step 2: 1-(5-chloro-3-iodo-4,6-dimethyl-2-pyridyl)-4,4-difluoro-azepane

[1053] A solution of 5-chloro-2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-pyridine-3-carboxylic acid (1.0 g, 3.1 mmol), potassium phosphate (670 mg, 3.16 mmol) and iodine (2.42 g, 9.54 mmol) in acetonitrile (15 mL) was purged with nitrogen for 5 minutes. The reaction vessel was sealed and the mixture was stirred at 100 ° C for 3 hours. The reaction mixture was cooled to room temperature, diluted with 10% sodium thiosulfate aqueous solution (50 mL) and saturated sodium bicarbonate aqueous solution (50 mL), and extracted with dichloromethane (3 × 75 mL). The combined extracts were washed with 10% sodium thiosulfate (2 × 50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was adsorbed onto silica gel under vacuum and purified by silica gel chromatography (0-10% ethyl acetate / heptane) to give 1-(5-chloro-3-iodo-4,6-dimethyl-2-pyridinyl)-4,4-difluoro-azepane (1.03 g, 82%...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: A is L is -O-, a single bond, -OC(R)2-, -C(R)2-, -C(R)2-O- or -N(R)-; Each R is independently H, halo or C1-C6 alkyl; X2 is N or CR2; X4 is N or CR4; X5 is N or CR5; X6 is N or CR6; X7 is N or CR7; Y1 is N or CR 1a ; Y2 is N, + NO - or CR 2a ; Y3 is N or CR 3a ; R2 is H, halo, C1-C6 alkyl, (C1-C6 alkylene)-NR8R9, C2-C6 alkenyl, C1-C6 alkoxy, (C1-C6 alkylene)-OH, C(O)OR8 or CH(OH)(CH2) m (CHOH) n (CH2) p H; R4, R5, R6 and R7 are 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 one or more alkyl, halo or OH; (ii) R4 and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl optionally substituted with one or more halo; and R5 and R6 together with the carbon atoms to which they are attached form a ring of the formula: (iii) R4 and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl substituted with one or more halo; and R5 and R6 together with the carbon atoms to which they are attached form a ring of the formula: R8 and R9 are each independently H or C1-C6 alkyl; Each R 10 are independently H or halo; R 1a H, halo, CN, C1-C6 alkyl, OH, C(O)NR 12 R 13 、C1-C6 alkoxy、NR 12 R 13 、NR8C(O)NR8R9、(C1-C6 alkylene)-C(O)NR8R9、(C1-C6 alkylene)-OH、C(O)OR 12 , OR 12 、CH(OH)(CH2) m (CHOH) n (CH2) p H, N=S(=O)(CH3)2, N=S(=O)R'R", 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the heterocyclyl or heteroaryl in the 5-10 membered heteroaryl or 4-10 membered heterocyclyl is optionally substituted with 1-4 substituents selected from the group consisting of OH, halo, oxo, C(O)NR8R9, NR8R9, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkylene)-OH, (C1-C6 alkylene)-O-(C1C6 alkyl) and (C1-C6 alkylene)-NR8R9; R' and R" together with the S atom to which they are attached form a 4-7 membered heterocyclic group; R 11 , R 2a and R 3a Each is independently H, halo, CN, C1-C6 alkyl, C(O)NR8R9 or C1-C6 alkoxy; R 12 and R 13 Each independently represents H, C(O)(C1-C6 alkyl), (C1-C6 alkylene)-NR8R9, CH2CH(OH)(CH2) m (CHOH) n (CH2) p H, C1-C6 alkyl, indanyl, (C1-C6 alkylene)-(C3-C6 cycloalkyl), (C1-C6 alkylene)-phenyl, (C1-C6 alkylene)-(5-membered heterocyclyl), C4-C7 cycloalkyl, C6-C 10 The indanyl, (C1-C6 alkylene)-(C3-C6 cycloalkyl), (C1-C6 alkylene)-phenyl, (C1-C6 alkylene)-(5-membered heterocyclyl), C4-C7 cycloalkyl, C6-C 10 Aryl, 5-6 membered heteroaryl or 4-7 membered heterocyclyl is optionally substituted with 1-4 substituents selected from the group consisting of OH, oxo, C1-C6 alkyl, (C1-C6 alkylene)-OH and C1-C6 alkoxy; 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 by 1-4 substituents selected from the group consisting of halo, OH, CD3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, CH2OH, C(O)H, and C1-C6 haloalkoxy; m, n and p are each independently 0 or 1; and q is 1, 2, or 3, When X2 is N, then: L is O, and Z1 is phenyl, wherein the phenyl is substituted with 2-4 substituents selected from the group consisting of halo, OH, 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 heterocyclic group, wherein the 4-10 membered heterocyclic group is substituted with 2-4 substituents selected from the group consisting of halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy; and Wherein when X2, X4, X5, X6 and X7 are each CH, L is a single bond, and Z1 is phenyl, then the phenyl is substituted by 1-4 substituents selected from the following: halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: A is R 1a H, halo, CN, C1-C6 alkyl, OH, C(O)NR 12 R 13 、C1-C6 alkoxy、NR 12 R 13 、(C1-C6 alkylene)-C(O)NR8R9、(C1-C6 alkylene)-OH、C(O)OR 12 、CH(OH)(CH2) m (CHOH) n (CH2) p H or N=S(=O)(CH3)2; and R 12 and R 13 Each independently represents H, C(O)(C1-C6 alkyl), (C1-C6 alkylene)-NR8R9, CH2CH(OH)(CH2) m (CHOH) n (CH2) p H. C1-C6 alkyl optionally substituted by one or more OH.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: L is a single bond or -C(R)2-; X2 is CR2; Z1 is a 4-10 membered cycloalkyl, a 3-10 membered cycloalkenyl, a phenyl or a 5-6 membered heteroaryl, wherein the 4-10 membered cycloalkyl, the 3-10 membered cycloalkenyl, the phenyl or the 5-6 membered heteroaryl may be unsubstituted or may be substituted by 1-4 substituents selected from the group consisting of halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

4. The compound according to any one of claims 1 to 3, wherein the compound has formula (IA-1) or a pharmaceutically acceptable salt thereof.

5. A compound according to any one of claims 1 to 3, wherein the compound has formula (IA-2) or a pharmaceutically acceptable salt thereof, wherein: Each R 14 Selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

6. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein each R 14 It is halogenated or C1-C6 halogenated alkyl.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Y2 is N.

8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R4, R5, R6 and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl optionally substituted with one or more alkyl, halo or OH.

9. The compound according to any one of claims 4 to 8, or a pharmaceutically acceptable salt thereof, wherein Y1 is CR 1a .

10. The compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein R 1a It is C(O)NR 12 R 13 .

11. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein R 12 and R 13 Each is H.

12. A compound according to any one of claims 3 to 11, or a pharmaceutically acceptable salt thereof, wherein R2 is H.

13. The compound according to any one of claims 3 to 11, or a pharmaceutically acceptable salt thereof, wherein L is a single bond.

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

15. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: L is a single bond; X2 is CR2; R 1a H, halogenated, CN, OH, C(O)NR 12 R 13 、C1-C6 alkoxy、-NR 12 R 13 、(C1-C6 alkylene)-C(O)NR8R9、(C1-C6 alkylene)-OH、C(O)OR 12 , CH(OH)(CH2) m (CHOH) n (CH2) p H or N=S(=O)(CH3)2; and Z1 is a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group may be unsubstituted or may be substituted by 1-4 substituents selected from the group consisting of halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

16. The compound according to claim 15, wherein the compound has the formula (IB-1) or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 15, wherein the compound has the formula (IB-2) or a pharmaceutically acceptable salt thereof, wherein: Each R 14 Selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

18. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein each R 14 It is halogenated.

19. The compound according to any one of claims 15 to 18, or a pharmaceutically acceptable salt thereof, wherein Y2 is N.

20. A compound according to any one of claims 15 to 19, or a pharmaceutically acceptable salt thereof, wherein R4, R5, R6 and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with one or more alkyl, halo or OH.

21. A compound according to any one of claims 16 to 20, or a pharmaceutically acceptable salt thereof, wherein Y1 is CR 1a .

22. The compound according to claim 21, or a pharmaceutically acceptable salt thereof, wherein R 1a It is C(O)NR 12 R 13 .

23. The compound according to claim 22, or a pharmaceutically acceptable salt thereof, wherein R 12 and R 13 Each is H.

24. The compound according to any one of claims 15 to 23, or a pharmaceutically acceptable salt thereof, wherein R2 is C1-C6 alkoxy.

25. A compound according to any one of claims 15 to 24, wherein the compound is or a pharmaceutically acceptable salt thereof.

26. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: L is O, -OC(R)2- or -C(R)2-O-; Z1 is phenyl, 4-10 membered heterocyclyl or 5-6 membered heteroaryl, wherein the phenyl, 4-10 membered heterocyclyl or 5-6 membered heteroaryl may be unsubstituted or may be substituted by 1-4 substituents selected from the following: halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, CH2OH, C(O)H and C1-C6 haloalkoxy.

27. The compound according to claim 26, wherein the compound has the formula (IC-1) or a pharmaceutically acceptable salt thereof.

28. The compound according to claim 26, wherein the compound has the formula (IC-2) or a pharmaceutically acceptable salt thereof, wherein each R 14 Selected from halo, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

29. A compound according to any one of claims 26 to 28, or a pharmaceutically acceptable salt thereof, wherein Y2 is N.

30. A compound according to any one of claims 26 to 29, or a pharmaceutically acceptable salt thereof, wherein R4, R5, R6 and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with one or more alkyl, halo or OH.

31. A compound according to any one of claims 27 to 30, or a pharmaceutically acceptable salt thereof, wherein Y1 is CR 1a .

32. The compound according to claim 31, or a pharmaceutically acceptable salt thereof, wherein R 1a It is C(O)NR 12 R 13 .

33. The compound according to claim 32, or a pharmaceutically acceptable salt thereof, wherein R 12 and R 13 Each is H.

34. A compound according to any one of claims 26 to 33, or a pharmaceutically acceptable salt thereof, wherein X2 is CR2 and R2 is H.

35. according to the compound described in any one of claims 26 to 34, wherein said compound is or a pharmaceutically acceptable salt thereof.

36. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: L is -O- or a single bond; X4 is CR4; X6 is CR6; R4, R5, R6 and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl optionally substituted with one or more halo; Z1 is a 3-10 membered cycloalkyl or phenyl group, wherein the 3-10 membered cycloalkyl or phenyl group may be unsubstituted or substituted with 1-4 substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl.

37. The compound according to claim 36, or a pharmaceutically acceptable salt thereof, wherein: A is X2 is CR2; Y1 is CR 1a ; Y2 is N or CR 2a ; Y3 is CR 3a ; R 11 , R 2a and R 3a Each is H; R 1a It is C(O)NR 12 R 13 NR 12 R 13 、NR8C(O)NR8R9、OR 12 , N=S(=O)R'R", 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the heterocyclyl or heteroaryl in the 5-10 membered heteroaryl or 4-10 membered heterocyclyl is optionally substituted by 1-4 substituents selected from the group consisting of OH, halo, oxo, C(O)NR8R9, NR8R9, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkylene)-OH, (C1-C6 alkylene)-O-(C1C6 alkyl) and (C1-C6 alkylene)-NR8R9; R' and R" together with the S atom to which they are attached form a 4-7 membered heterocyclic group; and R 12 and R 13 Each independently represents H, C(O)(C1-C6 alkyl), (C1-C6 alkylene)-NR8R9, CH2CH(OH)(CH2) m (CHOH) n (CH2) p H, C1-C6 alkyl, indanyl, (C1-C6 alkylene)-(C3-C6 cycloalkyl), (C1-C6 alkylene)-phenyl, (C1-C6 alkylene)-(5-membered heterocyclyl), C4-C7 cycloalkyl, C6-C 10 The indanyl, (C1-C6 alkylene)-(C3-C6 cycloalkyl), (C1-C6 alkylene)-phenyl, (C1-C6 alkylene)-(5-membered heterocyclyl), C4-C7 cycloalkyl, C6-C 10 The aryl, 5-6 membered heteroaryl or 4-7 membered heterocyclyl is optionally substituted with 1-4 substituents selected from the group consisting of OH, oxo, C1-C6 alkyl, (C1-C6 alkylene)-OH and C1-C6 alkoxy.

38. The compound according to claim 37, or a pharmaceutically acceptable salt thereof, wherein: R 1a It is C(O)NR 12 R 13 ;and R 12 and R 13 each independently represents H, C1-C6 alkyl optionally substituted with one or more OH, (C1-C6 alkylene)-(C3-C6 cycloalkyl), (C1-C6 alkylene)-phenyl, (C1-C6 alkylene)-(5-membered heterocyclyl), C4-C7 cycloalkyl, C6-C 10 aryl, 5-6 membered heteroaryl or 4-7 membered heterocyclic group, wherein said (C1-C6 alkylene)-(C3-C6 cycloalkyl), (C1-C6 alkylene)-phenyl, (C1-C6 alkylene)-(5 membered heterocyclic group), C4-C7 cycloalkyl, C6-C 10 The aryl, 5-6 membered heteroaryl or 4-7 membered heterocyclyl is optionally substituted with 1-4 substituents selected from the group consisting of OH, oxo, C1-C6 alkyl, (C1-C6 alkylene)-OH and C1-C6 alkoxy.

39. The compound according to claim 37, or a pharmaceutically acceptable salt thereof, wherein: R 1a It is a 4-10 membered heterocyclic group, wherein the heterocyclic group in the 4-10 membered heterocyclic group is optionally substituted by 1-4 substituents selected from the group consisting of OH, oxo, C(O)NR8R9, NR8R9, C1-C6 alkyl and C1-C6 alkoxy.

40. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein: R 1a It is a 5-10 membered heteroaryl, wherein the heteroaryl in the 5-10 membered heteroaryl is optionally substituted by 1-4 substituents selected from the following: halo, oxo, C(O)NR8R9, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkylene)-OH, C1-C6 alkylene)-O-(C1C6 alkyl) and (C1-C6 alkylene)-NR8R9.

41. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein: R 1a YesNR 12 R 13 ; R 12 is H; and R 13 is (C1-C6 alkylene)-(5-membered heterocyclic group), C4-C7 cycloalkyl, C6-C 10 aryl, 5-6 membered heteroaryl or 4-7 membered heterocyclic group, wherein the (C1-C6 alkylene)-(5 membered heterocyclic group), C4-C7 cycloalkyl, C6-C 10 The aryl, 5-6 membered heteroaryl or 4-7 membered heterocyclyl is optionally substituted with 1-4 substituents selected from OH, oxo, C1-C6 alkyl and (C1-C6 alkylene)-OH.

42. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein: R 1a Yes OR 12 ;and R 12 is a C3-C6 cycloalkyl or a 5-6 membered heterocyclyl, wherein the C3-C6 cycloalkyl or the 5-6 membered heterocyclyl is optionally substituted by 1 to 4 C1-C6 alkoxy substituents.

43. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein: R 1a YesNR 12 R 13 ;and R 12 and R 13 Each is independently H, C(O)(C1-C6 alkyl) or (C1-C6 alkylene)-NR8R9.

44. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein: R 1a is N=S(=O)R'R"; and R' and R" together with the S atom to which they are attached form a 4-7 membered heterocyclic group.

45. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: L is -O-; A is X2 is CR2; X4 is CR4; X5 is CR5; X6 is CR6; Y1 is CR 1a ; Y3 is CR 3a ; R2 is H; R4, R5, R6 and R7 are each independently H, halo, C1-C6 alkyl or C1-C6 haloalkyl; R8 and R9 are each independently H or C1-C6 alkyl; R 1a It is C(O)NR 12 R 13 or NR8C(O)NR8R9; R 12 and R 13 each is H; and Z1 is phenyl, wherein the phenyl group may be unsubstituted or substituted with 1 to 4 substituents selected from the group consisting of halo or C1-C6 alkyl.

46. ​​The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein: A is R 1a It's NR8C(O)NR8R9.

47. The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein: A is and R 1a It is C(O)NR 12 R 13 .

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

49. A compound of formula (II) or a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein: B is L2 is a single bond or -CH2-; X 12 is CH or N; R 14 is H, halo or C1-C6 alkoxy; R 8a and R 9a As defined below: (i)R 8a and R 9a Each is independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1-4 substituents selected from C1-C6 alkyl, halo and C1-C6 haloalkyl; (ii) R 8a and R 9a Together with the carbon atoms to which they are attached, they form a ring of the formula: wherein the ring is optionally substituted with 1-4 C1-C6 alkyl groups; R 10a is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1-4 substituents selected from C1-C6 alkyl, halo and C1-C6 haloalkyl; R 11a is H or C1-C6 alkyl; R 15 It is C(O)NR 16 R 17 or a 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted with 1-4 C1-C6 alkyl groups; R 16 and R 17 Each independently is H or C1-C6 alkyl; Z2 is C4-C6 cycloalkyl or phenyl, wherein the C4-C6 cycloalkyl or phenyl is optionally substituted with 1-4 substituents selected from halo and C1-C6 alkyl; and q2 is 1, 2, or 3.

50. The compound of formula (II) according to claim 49, or a pharmaceutically acceptable salt thereof.

51. The compound of formula (II) according to claim 50, or a pharmaceutically acceptable salt thereof, wherein R 8a and R 9a Each is independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl optionally substituted with 1-4 substituents selected from C1-C6 alkyl, halo and C1-C6 haloalkyl.

52. A compound of formula (II) according to claim 51, or a pharmaceutically acceptable salt thereof, wherein: R 8a is H, halo, C1-C6 alkyl or C1-C6 haloalkyl; R 9a is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted by 1 to 4 substituents selected from C1-C6 alkyl, halo and C1-C6 haloalkyl; R 15 It is C(O)NR 16 R 17 ;and R 16 and R 17 Each is H.

53. A compound of formula (II) according to claim 52, or a pharmaceutically acceptable salt thereof, wherein: R 8a is H, Br, Cl, -CF3 or methyl; and R 9a It is tert-butyl, -CH2CF3 or C3-C6 cycloalkyl optionally substituted by 1 to 4 substituents selected from C1-C6 alkyl, halo and C1-C6 haloalkyl.

54. A compound of formula (II) according to claim 50, or a pharmaceutically acceptable salt thereof, wherein: L2 is a single bond; R 14 It is H; R 8a and R 9a Each is independently a C1-C6 alkyl group; R 15 is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally substituted with 1-4 C1-C6 alkyl groups; Z2 is a C4-C6 cycloalkyl group, wherein the C4-C6 cycloalkyl group is optionally substituted with 1 to 4 halo substituents.

55. A compound of formula (III) according to claim 49, or a pharmaceutically acceptable salt thereof, wherein: L2 is a single bond; R 14 It is H; R 10a It is H; R 11a is a C1-C6 alkyl group; R 15 It is C(O)NR 16 R 17 ; R 16 and R 17 each is H; and Z2 is a C4-C6 cycloalkyl group, wherein the C4-C6 cycloalkyl group is optionally substituted with 1 to 4 halo substituents.

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

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

58. A compound selected from: or a pharmaceutically acceptable salt thereof.

59. The compound according to claim 58, 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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