Substituted tetrahydrofurans as modulators of sodium channels

Abstract

To provide substituted tetrahydrofurans as modulators of sodium channels.SOLUTION: In one aspect, the invention provides compounds of formula I, and pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels. Also provided are pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts, and methods of using the compounds, pharmaceutically acceptable salts and pharmaceutical compositions in the treatment of various disorders, including pain.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit of U.S. Provisional Application No. 62 / 944,869, filed Dec. 6, 2019, which is hereby incorporated by reference in its entirety.

Background Art

[0002] Pain is a defense mechanism that enables healthy animals to avoid tissue damage and prevent further damage to injured tissue. Nevertheless, there are many conditions in which pain persists beyond its usefulness, or in which patients would benefit from pain inhibition. Neuropathic pain is a form of chronic pain caused by injury to sensory nerves (Dieleman, J.P., 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 general metabolic damage to nerves and pain caused by isolated nerve injury. Examples of such metabolic neuropathies include post - herpetic neuropathy, diabetic neuropathy, and drug - induced neuropathy. Examples of isolated nerve injury indications include post - amputation pain, post - surgical neuropathic pain, and nerve entrapment - injury - like neuropathic back pain.

[0003] Voltage - dependent sodium channels (Na V ) are involved in pain signal transmission. Na Vis a biological mediator of electrical signal transmission, as it mediates the rapid rise of action potentials in many excitatory cell types (e.g., neurons, skeletal muscle cells, cardiomyocytes). Evidence regarding the role of these channels in normal physiology, pathological conditions arising from mutations in sodium channel genes, preclinical studies in animal models, and the clinical pharmacology of known sodium channel modulators all point to the central role of Na V in pain. (Rush, A.M. and T.R. Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Na V 1.8 Sodium Channels. Mol. Interv., 2007. 7(4): p. 192-5), England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin. Investig. Drugs 17 (12), p. 1849-64 (2008), Krafte, D. S. and Bannon, A. W., Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8 (1), p. 50-56 (2008)). Since Na V mediates the rapid rise of action potentials in many excitatory cell types (e.g., neurons, skeletal muscle cells, cardiomyocytes), it is involved in the initiation of signal transmission in those cells (Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). Due to the role that Na V plays in the initiation and propagation of neuronal signals, Na VAntagonists that decrease current can interfere with or reduce nerve signal transmission, and Na V channels are considered promising targets for reducing pain in states where hyperexcitability is observed. (Chahine, M., Chatelier, A., Babich, O. , and Krupp, J. J., Voltage-gated sodium channels in neurological disorders. CNS Neurol. Disord. Drug Targets 7 (2), p. 144-58 (2008)). Several clinically useful analgesics have been identified as inhibitors of Na V channels. Local anesthetics such as lidocaine block pain by inhibiting Na V channels, and other compounds, such as carbamazepine, lamotrigine, and tricyclic antidepressants that have been found to be effective in reducing pain, have also been suggested to act by sodium channel inhibition (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. Eur. J. Pain 6 Suppl. A, p. 3-9 (2002), Wang, G. K., Mitchell, J., and Wang, S. Y., Block of persistent late Na + currents by antidepressant sertraline and paroxetine. J. Membr. Biol. 222 (2), p. 79-90 (2008)).

[0004] Na V forms a subfamily of the voltage-dependent ion channel superfamily and includes nine isoforms called Na V 1.1 to Na V 1.9. The tissue localization of the nine isoforms is diverse. Na V1.4 is the major sodium channel in skeletal muscle, and Na V 1.5 is the major sodium channel in cardiomyocytes. Na V 1.7, 1.8, and 1.9 are mainly localized in the peripheral nervous system, and Na V 1.1, 1.2, 1.3, and 1.6 are nerve channels found in both the central and peripheral nervous systems. The functional behaviors of the nine isoforms are similar, but the characteristics of their voltage-dependence and kinetic behaviors are different (Catterall, W. A., Goldin, A. L., and Waxman, S. G., International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57 (4), p. 397 (2005)).

[0005] Upon their discovery, Na V 1.8 channel was identified as a promising target for analgesia (Akopian, A.N., L. Sivilotti, and J.N. Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562): p. 257-62). Since then, Na V 1.8 has been shown to be the carrier of the sodium current that sustains action potential firing in small dorsal root ganglion (DRG) neurons (Blair, N.T. and B.P. Bean, Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na + current, and Ca 2+ current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002. 22(23): p. 10277-90). Na V 1.8, like neurons that cause neuropathic pain, is involved in the spontaneous firing of damaged neurons (Roza, C., et al., The tetrodotoxin-resistant Na + channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550(Pt 3): p. 921-6; Jarvis, M.F., et al., A-803467, a potent and selective Na V 1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc. Natl. Acad. Sci. U S A, 2007. 104(20): p. 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 V1.8. Pain, 2002. 95(1-2): p. 143-52, Dong, X.W., et al., Small interfering RNA-mediated selective knockdown of Na V 1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. Neuroscience, 2007. 146(2): p. 812-21, Huang, H.L., et al., Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves. Mol. Pain, 2008. 4: p. 33, Black, J.A., et al., Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann. Neurol., 2008. 64(6): p. 644-53, Coward, K., et al., Immunolocalization of SNS / PN3 and NaN / SNS2 sodium channels in human pain states. Pain, 2000. 85(1-2): p. 41-50, Yiangou, Y., et al., SNS / PN3 and SNS2 / NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. FEBS Lett., 2000. 467(2-3): p. 249-52, Ruangsri, S., et al.,Relationship of axonal voltage-gated sodium channel 1.8 (NaV 1.8) mRNA accumulation in response to sciatic nerve injury-induced painful neuropathy in rats. J. Biol. Chem. 286(46): p. 39836 - 47). Na V Small - diameter DRG neurons that express 1.8 contain nociceptors involved in pain signal transmission. Na V 1.8 mediates large - amplitude action potentials in small - diameter neurons of the dorsal root ganglion (Blair, N.T. and B.P. Bean, Roles of tetrodotoxin (TTX) - sensitive Na + current, TTX - resistant Na + current, and Ca 2+ current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002. 22(23): p. 10277 - 90). Na V 1.8 is required for rapid repetitive action potentials in nociceptors and for the spontaneous activity of damaged neurons. (Choi, J.S. and S.G. Waxman, Physiological interactions between Na V 1.7 and Na V 1.8 sodium channels: a computer simulation study. J. Neurophysiol. 106(6): p. 3173 - 84, Renganathan, M., T.R. Cummins, and S.G. Waxman, Contribution of Na( V )1.8 sodium channels to action potential electrogenesis in DRG neurons. J. Neurophysiol., 2001. 86(2): p. 629 - 40, Roza, C., et al., The tetrodotoxin-resistant Na + channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550(Pt 3): p. 921-6). In depolarized or damaged DRG neurons, Na V 1.8 appears to be a driving factor for hyperexcitability (Rush, A.M., 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 several animal pain models, Na V 1.8 mRNA expression levels have been shown to increase in the DRG (Sun, W., et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats. Brain, 135(Pt 2): p. 359-75, Strickland, I.T., et al., Changes in the expression of Na V 1.7, Na V 1.8 and Na V 1.9 in a distinct population of dorsal Root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. Eur. J. Pain, 2008. 12(5): p. 564-72、Qiu, F., et al., Increased expression of tetrodotoxin-resistant sodium channels Na V 1.8 and Na V 1.9 within dorsal root ganglia in a rat model of bone cancer pain. Neurosci. Lett., 512(2): p. 61-6). Some of the major drawbacks of known Na V inhibitors are their inadequate therapeutic windows, which are probably the result of their lack of isoform selectivity. Since Na V 1.8 is mainly limited to neurons that sense pain, selective Na V 1.8 blockers are less likely to induce adverse events common to non-selective Na V blockers. Therefore, there remains a need to develop additional Na V channel modulators, preferably very potent and selective modulators for Na V 1.8. [[Prior Art Documents]] [[Non-Patent Documents]]

[0006] [[Non-Patent Document 1]] Dieleman, J.P., et al., Incidence rates and treatment of neuropathic pain conditions in the general population. Pain, 2008. 137(3): p. 681-8 [[Non-Patent Document 2]] Rush, A.M. and T.R. Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets NaV1.8 Sodium Channels. Mol. Interv., 2007. 7(4): p. 192-5

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Summary of the Invention

[0007] In one aspect, the present invention relates to the compounds described herein, or pharmaceutically acceptable salts thereof.

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

[0009] In yet another aspect, the present invention relates to a method of inhibiting a voltage-dependent sodium channel in a subject by administering a compound, a pharmaceutically acceptable salt, or a pharmaceutical composition thereto.

[0010] In yet another aspect, the present invention relates to a method of treating or reducing the severity of a subject having various diseases, disorders, or conditions, including but not limited to chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., pain after hysterectomy, hernia suture pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, and cardiac arrhythmia, by administering a compound, a pharmaceutically acceptable salt, or a pharmaceutical composition thereto. BRIEF DESCRIPTION OF THE DRAWINGS

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DETAILED DESCRIPTION OF THE INVENTION

[0037] In one aspect, the present invention provides a compound of formula (I) [Chemical] relates to a compound of formula (wherein, X 2a is N, N + -O - or C-R 2a ; X 4a is N, N + -O - or C-R 4a ; X 5a is N, N + -O - or C-R 5a ; X 6a is N, N + -O - or C-R 6a ; each R is independently H or C1-C6 alkyl; R 2a , R 4a , R 5a , and R 6a are each independently H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; R 5b1 and R 5b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; X 3c is N or C-R 3c ; X 4c is N or C-R 4c ; X 5c is N or C-R 5c ; X 6c is N or C-R 6c ; R 2cis H, OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), where the cycloalkyl is optionally substituted with 1 to 2 halos; L 1 is a bond or O; L 2 is a bond or C1-C6 alkylene; R 3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 4c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 5c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 6c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; provided that no more than two of X 2a , X 4a , X 5a , and X 6a are N or N + -O - ; and provided that no more than one of X X 3c , X 4c , X 5c and X 6c is N).

[0038] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 2a is C-R 2a ; X 5a is C-R 5a ; X 6a is C-R 6a ; R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl; R5b1 and R 5b2 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl; X 3c is C-R 3c ; X 4c is C-R 4c ; X 5c is C-R 5c ; X 6c is C-R 6c ; R 2c is H, OH, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0039] For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th th Ed. Further, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March’s Advanced Organic Chemistry," 5 th th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0040] As used herein, the term "compounds of the invention" refers to the compounds of formula (I), (I-A), (I-A-1), (I-B), (I-B-1), (I-C), and (I-C-1), and all embodiments thereof described herein, and the compounds identified in Tables A, B, and C.

[0041] As described herein, the compounds of the invention have a plurality of variable groups (e.g., R, X 4a , R 5bincluding, etc.). As will be recognized by those skilled in the art, the combinations of groups envisioned by the present invention are those that result in the formation of stable or chemically feasible compounds. The term "stable" in this context refers to a compound that does not substantially change when subjected to the conditions that allow for the generation, detection, and preferably the recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or a chemically feasible compound is one that does not substantially change when maintained at a temperature of 40 °C or lower for at least one week in the absence of moisture or other chemically reactive conditions.

[0042] The chemical structures shown herein are intended to be understood as would be understood by those skilled in the art. For example, with respect to Formulas (I), (I-A), (I-B), and (I-C), those skilled in the art will 5a and X 6a are connected by a double bond, and X 4c and X 5c are connected by a single bond, even if the bond between these groups is hidden by the atomic labels of the chemical structure. Further, those skilled in the art will understand that a substituent shown as "CF3" or "F3C" in a chemical structure refers to a trifluoromethyl substituent regardless of which depiction appears in the chemical structure.

[0043] As used herein, the term "halo" means F, Cl, Br, or I.

[0044] As used herein, the term "alkyl" refers to a straight-chain or branched-chain hydrocarbon radical group consisting only of carbon and hydrogen atoms, containing no unsaturation, having the specified number of carbon atoms, and bonded to the remainder of the molecule by a single bond. For example, a "C1-C6 alkyl" group is an alkyl group having 1 to 6 carbon atoms.

[0045] ​As used herein, the term "haloalkyl" refers to an alkyl group having the specified number of carbon atoms, wherein one or more of the hydrogen atoms of the alkyl group are replaced by halo groups. For example, a "C1-C6 haloalkyl" group is an alkyl group having 1 to 6 carbon atoms, wherein one or more of the hydrogen atoms of the alkyl group are replaced by halo groups.

[0046] As used herein, the term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon radical group consisting of only carbon and hydrogen atoms, containing one or more carbon-carbon double bonds, having the specified number of carbon atoms, and bonded to the remainder of the molecule by single bonds. For example, a "C2-C6 alkenyl" group is an alkenyl group having 2 to 6 carbon atoms.

[0047] As used herein, the term "cycloalkyl" refers to a stable, non-aromatic, monocyclic or bicyclic (fused, bridged, or spiro) saturated hydrocarbon radical consisting of only carbon and hydrogen atoms, having the specified number of carbon ring atoms, and bonded to the remainder of the molecule by single bonds. For example, a "C3-C8 cycloalkyl" group is a cycloalkyl group having 3 to 8 carbon atoms.

[0048] As used herein, the term "alkylene" refers to a divalent straight-chain or branched-chain hydrocarbon radical group consisting of only carbon and hydrogen atoms, containing no unsaturation, having the specified number of carbon atoms, and bonded to the remainder of the molecule by two single bonds. For example, a "C1-C6 alkylene" group is an alkylene group having 1 to 6 carbon atoms.

[0049] As used herein, the term "optionally substituted" refers to a group that is either unsubstituted or substituted with the substituents identified hereinafter. For example, a group "optionally substituted with 1 to 2 halos" is unsubstituted, substituted with one halo group, or substituted with two halo groups.

[0050] Unless otherwise specified, whether the compounds of the present invention are identified by chemical name or by chemical structure, all stereoisomers (e.g., enantiomers and diastereomers), double bond isomers (e.g., (Z) and (E)), conformational isomers, and tautomers of the compounds identified by the chemical names and chemical structures provided herein are included. Further, single stereoisomers, double bond isomers, conformational isomers, and tautomers, as well as mixtures of stereoisomers, double bond isomers, conformational isomers, and tautomers are within the scope of the present invention.

[0051] As used herein, in any chemical structure or formula, for example,

Chemical formula

Chemical formula

[0052] As used herein, in any chemical structure or formula, for example,

Chemical formula

Chemical formula

[0053] As used herein, when the prefix "rac-" is used in relation to a chiral compound, it refers to the racemic mixture of the compound. For a compound with the prefix "rac-", the (R)- and (S)-designators in the chemical name reflect the relative stereochemistry of the compound.

[0054] As used herein, when the prefix "rel-" is used in relation to a chiral compound, it refers to a single enantiomer of unknown absolute configuration. For a compound with the prefix "rel-", 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. For a compound with the prefix "rel-", 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.

[0055] As used herein, the term "compound", when referring to the compounds of the present invention, refers to a collection of molecules having the same chemical structure, except that there may be isotopic variations among the constituent atoms of the molecule. The term "compound" includes such a collection of molecules regardless of the purity of a given sample containing the collection of molecules. Thus, the term "compound" includes such a collection of molecules in pure form, in a mixture with one or more other substances (e.g., a solution, suspension, colloid, or pharmaceutical composition, or dosage form), or in the form of a hydrate, solvate, or co-crystal.

[0056] In this specification and the claims, unless otherwise specified, any atom in any compound of the present invention that is not specifically designated as a particular isotope represents any stable isotope of the designated element. In the examples, when no atom in any compound of the present invention is specifically designated as a particular isotope, no effort has been made to enrich that atom in a particular isotope, and thus one of ordinary skill in the art will understand that such atoms likely exist in an isotopic composition that is approximately the natural abundance ratio of the designated element.

[0057] As used herein, the term "stable", when referring to an isotope, means that the isotope is not known to undergo spontaneous radioactive decay. Stable isotopes include, but are not limited to, isotopes not identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0058] As used herein and in the claims, "H" refers to hydrogen and includes any stable isotope of hydrogen, i.e., 1 H and D. In the examples, when an atom is designated as "H", no effort has been made to enrich that atom in a particular isotope of hydrogen, and thus one of ordinary skill in the art will understand that such hydrogen atoms likely exist in an isotopic composition approximately that of natural abundance of hydrogen.

[0059] As used herein, " 1 H" refers to protium. When an atom in a compound of the invention, or in a pharmaceutically acceptable salt thereof, is referred to as protium, the protium is present at least at the position designated in the natural abundance of protium.

[0060] As used herein, "D", "d", and " 2 H" refer to deuterium.

[0061] In some embodiments, the compounds of the invention, and pharmaceutically acceptable salts thereof, contain each constituent atom in an isotopic composition approximately that of natural abundance of the designated element.

[0062] 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 designated element ( "isotopically labeled" compounds and salts). Examples of stable isotopes that are commercially available and suitable for use in the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, such as 2 H, 13 C, 15 N, 18 O, 17 O, and 31 P, but are not limited thereto.

[0063] Isotopically labeled compounds and salts can be used in a number of useful ways, including as pharmaceuticals. In some embodiments, the isotopically labeled compounds and salts are deuterium ( 2 H) labeled. Deuterium ( 2 H) labeled compounds and salts are therapeutically useful and have potential therapeutic advantages over non- 2 H labeled compounds. In general, deuterium ( 2 H) labeled compounds and salts can have higher metabolic stability compared to their non-isotopically labeled counterparts due to the kinetic isotope effects described below. Higher metabolic stability can be directly translated into increased in vivo half-life or lower dosages, which will represent a preferred embodiment of the present invention in most situations. Isotopically labeled compounds and salts can typically be prepared by carrying out the procedures disclosed in the synthetic schemes, examples, and associated descriptions and replacing the non-isotopically labeled reactants with readily available isotopically labeled reactants.

[0064] Deuterium ( 2H) The labeled compound and salt can manipulate the rate of oxidative metabolism of the compound by the primary kinetic isotope effect. The primary kinetic isotope effect is the change in the rate of a chemical reaction due to the exchange of isotopic nuclei, and this is caused by the change in the ground state energy of the covalent bond involved in the reaction. The exchange of a heavier isotope usually results in a decrease in the ground state energy of the chemical bond, which in turn causes a decrease in the rate-limiting bond cleavage. If the bond cleavage occurs at or near the saddle point region along the reaction coordinate of a multi-product reaction, the distribution ratio of the products can be substantially altered. For example, when deuterium is bonded to a carbon atom at a non-exchangeable position, the rate difference of k H / k D = 2 to 7 is typical. For further discussion, see S. L., which is hereby incorporated by reference in its entirety, Harbeson and R. D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403 - 417.

[0065] The concentration of an isotope (e.g., deuterium) incorporated at a given position of the isotopically labeled compound or a pharmaceutically acceptable salt thereof of the present invention can be defined by the isotope enrichment factor. The term "isotope enrichment factor" as used herein means the ratio between the abundance of an isotope at a given position in the isotopically labeled compound (or salt) and the natural abundance of that isotope.

[0066] When an atom in the compound of the present invention, or a pharmaceutically acceptable salt thereof, is designated as deuterium, such a compound (or salt) has an isotope enrichment factor of at least 3000 for such an atom (incorporation of about 45% deuterium). In some embodiments, the isotope enrichment factor is at least 3500 (incorporation of about 52.5% deuterium), at least 4000 (incorporation of about 60% deuterium), at least 4500 (incorporation of about 67.5% deuterium), at least 5000 (incorporation of about 75% deuterium), at least 5500 (incorporation of about 82.5% deuterium), at least 6000 (incorporation of about 90% deuterium), at least 6333.3 (incorporation of about 95% deuterium), at least 6466.7 (incorporation of about 97% deuterium), at least 6600 (incorporation of about 99% deuterium), or at least 6633.3 (incorporation of about 99.5% deuterium).

[0067] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently H or CH3. In other embodiments, N(R)2 is NHCH3.

[0068] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 2a is N. In other embodiments, X 2a is C-R 2a In some embodiments, R 2a is H, D, halo, or C1-C6 alkyl. In other embodiments, R 2a is H, D, F, or CH3. In some embodiments, X 2a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo. In other embodiments, X 2a is N, C-H, C-D, C-CH3, or C-F.

[0069] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 2a is C-R2a and R 2a is H.

[0070] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4a is N. In other embodiments, X 4a is N + -O - . In other embodiments, X 4a is C-R 4a . In some embodiments, R 4a is halo. In other embodiments, R 4a is H or halo. In other embodiments, R 4a is H or F. In other embodiments, X 4a is C-F. In some embodiments, X 4a is N, N + -O - , C-H, or C-halo. In other embodiments, X 4a is N, N + -O - , C-H, or C-F.

[0071] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4a is C-R 4a ; and R 4a is halo.

[0072] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 5a is N. In other embodiments, X 5a is C-R 5a . In some embodiments, R 5a is H, D, halo, or C1-C6 alkyl. In other embodiments, R 5a is H, D, F, or CH3. In some embodiments, X 5a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo. In other embodiments, X 5ais N, C-H, C-D, C-CH3, or C-F.

[0073] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 5a is C-R 5a and R 5a is H.

[0074] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 6a is N. In other embodiments, X 6a is C-R 6a In some embodiments, R 6a is H, D, halo, or C1-C6 alkyl. In other embodiments, R 6a is H, D, F, or CH3. In some embodiments, X 6a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo. In other embodiments, X 6a is N, C-H, C-D, C-CH3, or C-F.

[0075] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 6a is C-R 6a and R 6a is H.

[0076] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 4b1 and R 4b2 are each independently H or C1-C6 alkyl. In other embodiments, R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. In other embodiments, R 4b1 and R 4b2 are each independently H or CH3. In other embodiments, R 4b1 and R 4b2is independently H, CH3, CH2CH3, or cyclopropyl. In other embodiments, R 4b1 is C1-C6 alkyl and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is C1-C6 alkyl. In other embodiments, R 4b1 is CH3 and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is CH3.

[0077] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5b1 and R 5b2 are each independently C1-C6 alkyl or is C1-C6 haloalkyl. In other embodiments, R 5b1 and R 5b2 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl. In other embodiments, R 5b1 and R 5b2 are each independently H, CH3, or CF3. In other embodiments, R 5b1 and R 5b2 are each independently H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CHF2, CF2CH3, CH2CF3, or CF3. In other embodiments, R 5b1 is C1-C6 alkyl and R 5b2 is C1-C6 haloalkyl. In other embodiments, R 5b1 is C1-C6 haloalkyl and R 5b2 is C1-C6 alkyl. In other embodiments, R 5b1 is CH3 and R 5b2 is CF3. In other embodiments, R 5b1 is CF3 and R 5b2 is CH3.

[0078] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy. In other embodiments, R 2c is OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), where the cycloalkyl is optionally substituted with 1 to 2 halos. In other embodiments, R 2c is H. In other embodiments, R 2c is C1-C6 alkoxy. In other embodiments, R 2c is C1-C6 haloalkoxy. In other embodiments, R 2c is -L 1 -L 2 -(C3-C6 cycloalkyl), where the cycloalkyl is optionally substituted with 1 to 2 halos. In other embodiments, R 2c is OH, OCH3, OCD3, OCH2CH3, or OCHF2. In other embodiments, R 2c is H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCHF2,

Chemical formula

[0079] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 3c is N. In other embodiments, X 3c is C-R 3c is as such. In other embodiments, R 3cis H, halo, C1-C6 alkyl, or C1-C6 haloalkyl. In other embodiments, R 3c is H, CH3, CH2CH3, CHF2, CF3, F, or Cl. In some embodiments, X 3c is N, C-H, C-CH3, C-CH2CH3, C-CHF2, C-CF3, C-F, or C-Cl.

[0080] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl. In other embodiments, R 3c [[ID=1--16]]is halo. In other embodiments, R 3c is C1-C6 alkyl. In other embodiments, R 3c is H, F, Cl, or CH3. In other embodiments, R 3c is H. In other embodiments, R 3c is F. In other embodiments, R 3c is C1. In other embodiments, R 3c is CH3.

[0081] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4c is N. In other embodiments, X 4c is C-R 4c ; In other embodiments, R 4c is H, halo, or C1-C6 haloalkyl. In other embodiments, R 4c is H, CHF2, CF3, or F. In some embodiments, X 4c is N, C-H, C-CHF2, C-CF3, or C-F.

[0082] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4c is C-R 4c ; R 4cis a halo. In other embodiments, R 4c is F.

[0083] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 5c is N. In other embodiments, X 5c is C-R 5c . In other embodiments, R 5c is H or a halo. In other embodiments, R 5c is H, D, or Cl. In some embodiments, X 5c is N, C-H, C-D, or C-Cl.

[0084] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 5c is C-R 5c ; R 5c is H.

[0085] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 6c is N. In other embodiments, X 6c is C-R 6c . In other embodiments, R 6c is H or a halo. In other embodiments, R 6c is H or F. In some embodiments, X 6c is N, C-H, or C-F.

[0086] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 6c is H.

[0087] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 2a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo; X 4a is N, N + -O- is C-H, or C-halo; X 5a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo; X 6a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo; each R is H or CH3; R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, or C3-C6 cycloalkyl; R 5b1 and R 5b2 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl; R 2c is OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), where the cycloalkyl is optionally substituted with 1 to 2 halos; X 3c is C-R 3c ; R 3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; X 4c is C-R 4c ; R 4c is H, halo, or C1-C6 haloalkyl; X 5c is C-R 5c ; R 5c is H or halo; X 6c is C-R 6c ; R 6c is H or halo.

[0088] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6aand R 6a is H; R 4b1 and R 4b2 are each independently H or C1-C6 alkyl; R 5b1 and R 5b2 are each independently C1-C6 alkyl or C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or is C1-C6 haloalkoxy; X 3c is C-R 3c and R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c and R 4c is halo; X 5c is C-R 5c and R 5c is H; X 6c is C-R 6c and R 6c is H.

[0089] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 2a is N, C-H, C-D, C-CH3, or C-F; X 4a is N, N + -O - , C-H, or C-F; X 5a is N, C-H, C-D, C-CH3 or C-F; X 6a is N, C-H, C-D, C-CH3 or C-F; each R is H or CH3; R 4b1 and R 4b2 are each independently H, CH3, CH2CH3, or cyclopropyl; R 5b1 and R 5b2 are each independently H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CHF2, CF2CH3, CH2CF3, or CF3; R 2c is H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCHF2, [Chemistry] is; X 3c is N, C-H, C-CH3, C-CH2CH3, C-CHF2, C-CF3, C-F, or C-Cl; X 4c is N, C-H, C-CHF2, C-CF3, or C-F; X 5c is N, C-H, C-D, or C-Cl; X 6c is N, C-H, or C-F.

[0090] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 4b1 and R 4b2 are each independently H or CH3; R 5b1 and R 5b2 are each independently H, CH3, or CF3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6c is H.

[0091] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 4b1 is C1-C6 alkyl; R 4b2 is H; R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6c is H.

[0092] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 4b1 is H; R 4b2 is C1-C6 alkyl; R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c wherein; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c wherein; R 4c is halo; X 5c is C-R 5c wherein; R 5c is H; X 6c is C-R 6c wherein; R 6c is H.

[0093] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a wherein; R 2a is H; X 5a is C-R 5a wherein; R 5a is H; X 6a is C-R 6a wherein; R 6a is H; R 4b1 is C1-C6 alkyl; R 4b2 is H; R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c wherein; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c wherein; R 4c is halo; X 5c is C-R 5c wherein; R 5c is H; X 6c is C-R 6c wherein; R 6c is H.

[0094] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 4b1 is H; R 4b2 is C1-C6 alkyl; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6c is H.

[0095] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 5b1 is CH3; R 5b2 is CF3; R 4b1is CH3; R 4b2 is H; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6c is H.

[0096] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 5b1 is CH3; R 5b2 is CF3; R 4b1 is H; R 4b2 is CH3; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6c is H.

[0097] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 5b1 is CF3; R 5b2 is CH3; R 4b1 is CH3; R 4b2 is H; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6c is H.

[0098] In some embodiments, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 5b1 is CF3; R 5b2 [[ID=8\6]]is CH3; R 4b1is H, and R 4b2 is CH3; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6c is H.

[0099] In some embodiments, the present invention relates to a compound of formula (I) (including any of the foregoing embodiments thereof), i.e., the compound in the non-salt form.

[0100] In some embodiments, the present invention relates to a compound of formula (I-A)

Chemical formula

[0101] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 2a is C-R 2a ; X 5a is C-R 5a ; X 6a is C-R 6a ; R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl; R 5b1 and R 5b2 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl; X 3c is C-R 3c ; X 4c is C-R 4c ; X 5c is C-R 5c ; X 6c is C-R 6c ; R 2c is H, OH, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy).

[0102] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently H or CH3. In other embodiments, N(R)2 is NHCH3).

[0103] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 2a is N. In other embodiments, X 2a is C-R 2a . In some embodiments, R 2a is H, D, halo, or C1-C6 alkyl. In other embodiments, R 2a is H, D, F, or CH3. In some embodiments, X 2a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo. In other embodiments, X 2a is N, C-H, C-D, C-CH3, or C-F.

[0104] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 2a is C-R 2a ; and R 2a is H.

[0105] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 4a is N. In other embodiments, X 4a is N + -O - . In other embodiments, X 4a is C-R 4a . In some embodiments, R 4a is halo. In other embodiments, R 4a is H or halo. In other embodiments, R 4a is H or F. In other embodiments, X 4a is C-F. In some embodiments, X 4a is N, N + -O - , C-H, or C-halo. In other embodiments, X 4a is N, N + -O - , C-H, or C-F.

[0106] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 4a is C-R 4a ; and R 4a is halo.

[0107] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 5a is N. In other embodiments, X 5a is C-R 5a . In some embodiments, R 5a is H, D, halo, or C1-C6 alkyl. In other embodiments, R 5a is H, D, F, or CH3. In some embodiments, X 5a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo. In other embodiments, X 5a is N, C-H, C-D, C-CH3, or C-F.

[0108] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 5a is C-R 5a ; and R 5a is H.

[0109] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 6a is N. In other embodiments, X 6a is C-R 6a . In some embodiments, R 6a is H, D, halo, or C1-C6 alkyl. In other embodiments, R 6a is H, D, F, or CH3. In some embodiments, X 6a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo. In other embodiments, X 6a is N, C-H, C-D, C-CH3, or C-F.

[0110] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 6a is C-R 6a and; R 6a is H.

[0111] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 4b1 and R 4b2 are each independently H or C1-C6 alkyl. In other embodiments, R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. In other embodiments, R 4b1 and R 4b2 are each independently H or CH3. In other embodiments, R 4b1 and R 4b2 are each independently H, CH3, CH2CH3, or cyclopropyl. In other embodiments, R 4b1 is C1-C6 alkyl and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is C1-C6 alkyl. In other embodiments, R 4b1 is CH3 and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is CH3.

[0112] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 5b1 and R 5b2 are each independently C1-C6 alkyl or C1-C6 haloalkyl. In other embodiments, R 5b1 and R 5b2 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl. In other embodiments, R 5b1 and R 5b2is independently H, CH3, or CF3. In other embodiments, R 5b1 and R 5b2 are independently H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CHF2, CF2CH3, CH2CF3, or CF3. In other embodiments, R 5b1 is C1-C6 alkyl, and R 5b2 is C1-C6 haloalkyl. In other embodiments, R 5b1 is C1-C6 haloalkyl, and R 5b2 is C1-C6 alkyl. In other embodiments, R 5b1 is CH3, and R 5b2 is CF3. In other embodiments, R 5b1 is CF3, and R 5b2 is CH3.

[0113] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy. In other embodiments, R 2c is OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 halo alkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halos. In other embodiments, R 2c is H. In other embodiments, R 2c is C1-C6 alkoxy. In other embodiments, R 2c is C1-C6 haloalkoxy. In other embodiments, R 2c is -L 1 -L 2 -(C3-C6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halos. In other embodiments, R 2c is OH, OCH3, OCD3, OCH2CH3, or OCHF2. In other embodiments, R 2cis H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCHF2,

Chem.

[0114] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 3c is N. In other embodiments, X 3c is C-R 3c and so on. In other embodiments, R 3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl. In other embodiments, R 3c is H, CH3, CH2CH3, CHF2, CF3, F, or Cl. In some embodiments, X 3c is N, C-H, C-CH3, C-CH2CH3, C-CHF2, C-CF3, C-F, or C-Cl.

[0115] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 3c is C-R 3c and; R 3c is H, halo, or C1-C6 alkyl. In other embodiments, R 3c is halo. In other embodiments, R 3c is C1-C6 alkyl. In other embodiments, R 3c is H, F, Cl, or CH3. In other embodiments, R 3c is H. In other embodiments, R 3c is F. In other embodiments, R 3cis C1. In other embodiments, R 3c is CH3.

[0116] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 4c is N. In other embodiments, X 4c is C-R 4c In other embodiments, R 4c is H, halo, or C1-C6 haloalkyl. In other embodiments, R 4c is H, CHF2, CF3, or F. In some embodiments, X 4c is N, C-H, C-CHF2, C-CF3, or C-F.

[0117] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 4c is C-R 4c and R 4c is halo. In other embodiments, R 4c is F.

[0118] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 5c is N. In other embodiments, X 5c is C-R 5c In other embodiments, R 5c is H or halo. In other embodiments, R 5c is H, D, or Cl. In some embodiments, X 5c is N, C-H, C-D, or C-Cl.

[0119] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 5c is C-R 5c and R 5c is H.

[0120] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 6c is N. In other embodiments, X 6c is C-R 6c . In other embodiments, R 6c is H or halo. In other embodiments, R 6c is H or F. In some embodiments, X 6c is N, C-H, or C-F.

[0121] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 6c is H.

[0122] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 2a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo; X 4a is N, N + -O - , C-H, or C-halo; X 5a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo; X 6a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo; each R is H or CH3; R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, or C3-C6 cycloalkyl; R 5b1 and R 5b2 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl; R 2c is OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halos; X 3c is C-R 3c ; R3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; X 4c is C-R 4c wherein; R 4c is H, halo, or C1-C6 haloalkyl; X 5c is C-R 5c wherein; R 5c is H or halo; X 6c is C-R 6c wherein; R 6c is H or halo.

[0123] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a wherein; R 2a is H; X 5a is C-R 5a wherein; R 5a is H; X 6a is C-R 6a wherein; R 6a is H; R 4b1 and R 4b2 are each independently H or C1-C6 alkyl; R 5b1 and R 5b2 are each independently C1-C6 alkyl or C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c wherein; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c wherein; R 4c is halo; X 5c is C-R 5c wherein; R 5c is H; X 6c is C-R 6c wherein; R 6c is H.

[0124] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 2a is N, C-H, C-D, C-CH3, or C-F; X 4a is N, N + -O - , C-H, or C-F; X 5a is N, C-H, C-D, C-CH3 or C-F; X 6a is N, C-H, C-D, C-CH3 or C-F; each R is H or CH3; R 4b1 and R 4b2 are each independently H, CH3, CH2CH3, or cyclopropyl; R 5b1 and R 5b2 are each independently H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CHF2, CF2CH3, CH2CF3, or CF3; R 2c is H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCHF2,

Chem.

[0125] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R6a and R 6a is H; R 4b1 and R 4b2 are each independently H or CH3; R 5b1 and R 5b2 are each independently H, CH3, or CF3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c and R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c and R 4c is halo; X 5c is C-R 5c and R 5c is H; X 6c is C-R 6c and R 6c is H.

[0126] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a and R 2a is H; X 5a is C-R 5a and R 5a is H; X 6a is C-R 6a and R 6a is H; R 4b1 is C1-C6 alkyl; R 4b2 is H; R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c and R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c and R 4cis a halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6c is H.

[0127] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 4b1 is H; R 4b2 is C1-C6 alkyl; R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6c is H.

[0128] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R5a and; R 5a is H; X 6a is C-R 6a and; R 6a is H; R 4b1 is C1-C6 alkyl; R 4b2 is H; R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy and; X 3c is C-R 3c and; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c and; R 4c is halo; X 5c is C-R 5c and; R 5c is H; X 6c is C-R 6c and; R 6c is H.

[0129] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a and; R 2a is H; X 5a is C-R 5a and; R 5a is H; X 6a is C-R 6a and; R 6a is H; R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 4b1 is H; R 4b2 is C1-C6 alkyl; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c and; R 3cis H, halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6c is H.

[0130] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 5b1 is CH3; R 5b2 is CF3; R 4b1 is CH3; R 4b2 is H; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6c is H.

[0131] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2aand R 2a is H; X 5a is C-R 5a and R 5a is H; X 6a is C-R 6a and R 6a is H; R 5b1 is CH3; R 5b2 is CF3; R 4b1 is H; R 4b2 is CH3; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c and R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c and R 4c is halo; X 5c is C-R 5c and R 5c is H; X 6c is C-R 6c and R 6c is H.

[0132] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a and R 2a is H; X 5a is C-R 5a and R 5a is H; X 6a is C-R 6a and R 6a is H; R 5b1 is CF3; R 5b2 is CH3; R 4b1 is CH3; R 4b2 is H; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c and R 3cis H, halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6c is H.

[0133] In some embodiments, the present invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 5b1 is CF3; R 5b2 is CH3; R 4b1 is H, and R 4b2 is CH3; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H , halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6c is H.

[0134] In some embodiments, the present invention relates to a compound of formula (I-A) (including any of the foregoing embodiments thereof), i.e., the compound in non-salt form.

[0135] In some embodiments, the present invention relates to a compound of formula (I-A-1)

Chemical formula

[0136] In some embodiments, the present invention relates to a compound of formula (I-A-1) or a pharmaceutically acceptable salt thereof, wherein X 4a is N. In other embodiments, X 4a is N + -O - . In other embodiments, X 4a is C-R 4a . In other embodiments, X 4a is C-F.

[0137] In some embodiments, the present invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently H or CH3. In other embodiments, N(R)2 is NHCH3.

[0138] In some embodiments, the present invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein R 4a is halo.

[0139] In some embodiments, the present invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein R 4b1 and R 4b2 are each independently H or C1-C6 alkyl. In other embodiments, R 4b1 and R 4b2 are each independently H or CH3. In other embodiments, R 4b1 is C1-C6 alkyl and R 4b 2 is H. In other embodiments, R 4b1 is H and R 4b2 is C1-C6 alkyl. In other embodiments, R 4b1 is CH3 and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is CH3.

[0140] In some embodiments, the present invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein R 5b1 and R 5b2 are each independently C1-C6 alkyl or C1-C6 haloalkyl. In other embodiments, R 5b1 and R 5b2 are each independently H, CH3, or CF3. In other embodiments, R 5b1 is C1-C6 alkyl and R 5b2 is C1-C6 haloalkyl. In other embodiments, R 5b1is C1-C6 haloalkyl, R 5b2 is C1-C6 alkyl. In other embodiments, R 5b1 is CH3, R 5b2 is CF3. In other embodiments, R 5b1 is CF3, R 5b2 is CH3.

[0141] In some embodiments, the present invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy. In other embodiments, R 2c is C1-C6 alkoxy. In other embodiments, R 2c is C1-C6 haloalkoxy. In other embodiments, R 2c is OH, OCH3, OCD3, OCH2CH3, or OCHF2. In other embodiments, R 2c is OH. In other embodiments, R 2c is OCH3. In other embodiments, R 2c is OCD3. In other embodiments, R 2c is OCH2CH3. In other embodiments, R 2c is OCHF2.

[0142] In some embodiments, the present invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein R 3c is H, halo, or C1-C6 alkyl. In other embodiments, R 3c is halo. In other embodiments, R 3c is C1-C6 alkyl. In other embodiments, R 3c is H, F, Cl, or CH3. In other embodiments, R 3c is H. In other embodiments, R 3c is F. In other embodiments, R 3c is C1. In other embodiments, R 3c is CH3.

[0143] In some embodiments, the present invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein R 4c is halo. In other embodiments, R 4c is F.

[0144] In some embodiments, the present invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 and R 4b2 are each independently H or C1-C6 alkyl; R 5b1 and R 5b2 are each independently C1-C6 alkyl or C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0145] In some embodiments, the present invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 and R 4b2 are each independently H or CH3; R 5b1 and R 5b2 are each independently H, CH3, or CF3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0146] In some embodiments, the present invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is C1-C6 alkyl; R 4b2 is H; R 5b1 is C1-C6 alkyl; R 5 b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0147] In some embodiments, the present invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H; R 4b2 is C1-C6 alkyl; R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0148] In some embodiments, the present invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is C1-C6 alkyl; R 4b2 is H; R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0149] In some embodiments, the present invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H; R 4b2 is C1-C6 alkyl; R 5b1is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0150] In some embodiments, the present invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is CH3; R 4b2 is H; R 5b1 is CH3; R 5b2 is CF3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0151] In some embodiments, the present invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H; R 4b2 is CH3; R 5b1 is CH3; R 5b2 is CF3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0152] In some embodiments, the present invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is CH3; R 4b2 is H; R 5b1 is CF3; R 5b2 is CH3; R 2cis OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0153] In some embodiments, the present invention relates to a compound of formula (I-A-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H; R 4b2 is CH3; R 5b1 is CF3; R 5b2 is CH3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0154] In some embodiments, the present invention relates to a compound of formula (I-A-1) (including any of the foregoing embodiments thereof), i.e., the compound in non-salt form.

[0155] In some embodiments, the present invention relates to formula (I-B)

Chemical formula

[0156] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 2a is CR 2a and X 5a is CR 5a and X 6a is CR 6a and;R 4b1 and R 4b2 are each independently H, C-C alkyl, or C-C haloalkyl; R 5b1 and R 5b2 are each unique X is independently H, C1-C6 alkyl, or C1-C6 haloalkyl; 3c is CR 3c and X 4c is CR 4c and X 5c is CR 5c and X 6c is CR 6c and;R 2c is H, OH, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0157] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently H or CH3. In other embodiments, N(R)2 is NHCH3.

[0158] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 2a is N. In other embodiments, X 2a is C-R 2a wherein. In some embodiments, R 2a is H, D, halo, or C1-C6 alkyl. In other embodiments, R 2a is H, D, F, or CH3. In some embodiments, X 2a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo. In other embodiments, X 2a is N, C-H, C-D, C-CH3, or C-F.

[0159] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 2a is C-R 2a wherein; R 2a is H.

[0160] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 4a is N. In other embodiments, X 4a is N + -O - wherein. In other embodiments, X 4a is C-R 4a wherein. In some embodiments, R 4a is halo. In other embodiments, R 4a is H or halo. In other embodiments, R 4a is H or F. In other embodiments, X 4a is C-F. In some embodiments, X 4a is N, N +-O - is C-H or C-halo. In other embodiments, X 4a is N, N + -O - is C-H or C-F.

[0161] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 4a is C-R 4a ; and R 4a is halo.

[0162] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 5a is N. In other embodiments, X 5a is C-R 5a . In some embodiments, R 5a is H, D, halo, or C1-C6 alkyl. In other embodiments, R 5a is H, D, F, or CH3. In some embodiments, X 5a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo. In other embodiments, X 5a is N, C-H, C-D, C-CH3, or C-F.

[0163] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 5a is C-R 5a ; and R 5a is H.

[0164] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 6a is N. In other embodiments, X 6a is C-R 6a . In some embodiments, R 6a is H, D, halo, or C1-C6 alkyl. In other embodiments, R 6ais H, D, F, or CH3. In some embodiments, X 6a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo. In other embodiments, X 6a is N, C-H, C-D, C-CH3, or C-F.

[0165] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 6a is C-R 6a and; R 6a is H.

[0166] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 4b1 and R 4b2 are each independently H or C1-C6 alkyl. In other embodiments, R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. In other embodiments, R 4b1 and R 4b2 are each independently H or CH3. In other embodiments, R 4b1 and R 4b2 are each independently H, CH3, CH2CH3, or cyclopropyl. In other embodiments, R 4b1 is C1-C6 alkyl and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is C1-C6 alkyl. In other embodiments, R 4b1 is CH3 and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is CH3.

[0167] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 5b1 and R 5b2is independently C1-C6 alkyl or C1-C6 haloalkyl. In other embodiments, R 5b1 and R 5b2 are independently H, C1-C6 alkyl, or C1-C6 haloalkyl. In other embodiments, R 5b1 and R 5b2 are independently H, CH3, or CF3. In other embodiments, R 5b1 and R 5b2 are independently H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CHF2, CF2CH3, CH2CF3, or CF3. In other embodiments, R 5b1 is C1-C6 alkyl and R 5b2 is C1-C6 haloalkyl. In other embodiments, R 5b1 is C1-C6 haloalkyl and R 5b2 is C1-C6 alkyl. In other embodiments, R 5b1 is CH3 and R 5b2 is CF3. In other embodiments, R 5b1 is CF3 and R 5b2 is CH3.

[0168] In some embodiments, the present invention relates to a compound of formula (I-B) or a pharmaceutically acceptable salt thereof, wherein R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy. In other embodiments, R 2c is OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), where the cycloalkyl is optionally substituted with 1 to 2 halos. In other embodiments, R 2c is H. In other embodiments, R 2c is C1-C6 alkoxy. In other embodiments, R 2c is C1-C6 haloalkoxy. In other embodiments, R 2c is -L 1 -L2 -(C3-C6 cycloalkyl), where the cycloalkyl is optionally substituted with 1 to 2 halos. In other embodiments, R 2c is OH, OCH3, OCD3, OCH2CH3, or OCHF2. In other embodiments, R 2c is H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCHF2,

Chemical formula

[0169] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 3c is N. In other embodiments, X 3c is C-R 3c is. In other embodiments, R 3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl. In other embodiments, R 3c is H, CH3, CH2CH3, CHF2, CF3, F, or Cl. In some embodiments, X 3c is N, C-H, C-CH3, C-CH2CH3, C-CHF2, C-CF3, C-F, or C-Cl.

[0170] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 3c is C-R 3c is; R 3c is H, halo, or C1-C6 alkyl. In other embodiments, R 3c is halo. In other embodiments, R3c is C1-C6 alkyl. In other embodiments, R 3c is H, F, Cl, or CH3. In other embodiments, R 3c is H. In other embodiments, R 3c is F. In other embodiments, R 3c is C1. In other embodiments, R 3c is CH3.

[0171] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 4c is N. In other embodiments, X 4c is C-R 4c . In other embodiments, R 4c is H, halo, or C1-C6 haloalkyl. In other embodiments, R 4c is H, CHF2, CF3, or F. In some embodiments, X 4c is N, C-H, C-CHF2, C-CF3, or C-F.

[0172] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 4c is C-R 4c ; and R 4c is halo. In other embodiments, R 4c is F.

[0173] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 5c is N. In other embodiments, X 5c is C-R 5c . In other embodiments, R 5c is H or halo. In other embodiments, R 5c is H, D, or Cl. In some embodiments, X 5c is N, C-H, C-D, or C-Cl.

[0174] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 5c is C-R 5c and; R 5c is H.

[0175] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 6c is N. In other embodiments, X 6c is C-R 6c and. In other embodiments, R 6c is H or halo. In other embodiments, R 6c is H or F. In some embodiments, X 6c is N, CH, or C-F.

[0176] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein R 6c is H.

[0177] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 2a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo; X 4a is N, N + -O - C-H, or C-halo; X 5a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo; X 6a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo; each R is H or CH3; R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, or C3-C6 cycloalkyl; R 5b1 and R 5b2 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl; R 2cis OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), where the cycloalkyl is optionally substituted with 1 to 2 halos; X 3c is C-R 3c ; R 3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; X 4c is C-R 4c ; R 4c is H, halo, or C1-C6 haloalkyl; X 5c is C-R 5c ; R 5c is H or halo; X 6c is C-R 6c ; R 6c is H or halo.

[0178] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 4b1 and R 4b2 are each independently H or C1-C6 alkyl; R 5b1 and R 5b2 are each independently C1-C6 alkyl or C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4cand R 4c is a halo; X 5c is C-R 5c and R 5c is H; X 6c is C-R 6c and R 6c is H.

[0179] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 2a is N, C-H, C-D, C-CH3, or C-F; X 4a is N, N + -O - C-H, or C-F; X 5a is N, C-H, C-D, C-CH3 or C-F; X 6a is N, C-H, C-D, C-CH3 or C-F; each R is H or CH₃; R 4b1 and R 4b2 are each independently H, CH₃, CH₂CH₃, or cyclopropyl; R 5b1 and R 5b2 are each independently H, CH₃, CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, CHF₂, CF₂CH₃, CH₂CF₃, or CF₃; R 2c is H, F, CH₃, CH=CH₂, OH, OCH₃, OCD₃, OCH₂CH₃, OCH(CH₃)₂, OCHF₂,

Chemical formula

[0180] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 4b1 and R 4b2 are each independently H or is CH3; R 5b1 and R 5b2 are each independently H, CH3, or CF3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6c is H.

[0181] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 4b1 is C1-C6 alkyl; R 4b2 is H; R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6c is H.

[0182] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 4b1 is H; R 4b2 is C1-C6 alkyl; R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6c is H.

[0183] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 4b1 is C1-C6 alkyl; R 4b2 is H;R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is CR 3c and;R 3c is H, halo, or C1-C6 alkyl; X 4c is CR 4c and;R 4c is a halo;X 5c is CR 5c and;R 5c is H;X 6c is CR 6c and;R 6c is H.

[0184] In some embodiments, the present invention relates to a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is CR 2a and;R 2a is H;X 5a is CR 5a and;R 5a is H;X 6a is CR 6a and;R 6a is H;R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R4b1 is H; R 4b2 is C1-C6 alkyl; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6c is H.

[0185] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 5b1 is CH3; R 5b2 is CF3 ; R 4b1 is CH3; R 4b2 is H; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6cIt is H.

[0186] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 5b1 is CH3; R 5b2 is CF3; R 4b1 is H; R 4b2 is CH3; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6c is H.

[0187] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 5b1 is CF3; R 5b2 is CH3; R4b1 is CH3; R 4b2 is H; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6c is H.

[0188] In some embodiments, the present invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 5b1 is CF3; R 5b2 is CH3; R 4b1 is H, and R 4b2 is CH3; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6c is H.

[0189] In some embodiments, the present invention relates to a compound of formula (I-B) (including any of the foregoing embodiments thereof), i.e., the compound in non-salt form.

[0190] In some embodiments, the present invention relates to a compound of formula (I-B-1)

Chemical formula

[0191] In some embodiments, the present invention relates to a compound of formula (I-B-1) or a pharmaceutically acceptable salt thereof, wherein X 4a is N. In other embodiments, X 4a is N + -O -It is. In other embodiments, X 4a is C-R 4a It is. In some embodiments, R 4a is a halo. In other embodiments, X 4a is C-F.

[0192] In some embodiments, the present invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently H or CH3. In other embodiments, N(R)2 is NHCH3.

[0193] In some embodiments, the present invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein R 4a is a halo.

[0194] In some embodiments, the present invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein R 4b1 and R 4b2 are each independently H or C1-C6 alkyl. In other embodiments, R 4b1 and R 4b2 are each independently H or CH3. In other embodiments, R 4b1 is C1-C6 alkyl and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is C1-C6 alkyl. In other embodiments, R 4b1 is CH3 and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is CH3.

[0195] In some embodiments, the present invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein R 5b1 and R 5b2 are each independently C1-C6 alkyl or C1-C6 haloalkyl. In other embodiments, R 5b1 and R 5b2is independently H, CH3, or CF3. In other embodiments, R 5b1 is C1-C6 alkyl and R 5b2 is C1-C6 haloalkyl. In other embodiments , R 5b1 is C1-C6 haloalkyl and R 5b2 is C1-C6 alkyl. In other embodiments, R 5b1 is CH3 and R 5b2 is CF3. In other embodiments, R 5b1 is CF3 and R 5b2 is CH3.

[0196] In some embodiments, the present invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy. In other embodiments, R 2c is C1-C6 alkoxy. In other embodiments, R 2c is C1-C6 haloalkoxy. In other embodiments, R 2c is OH, OCH3, OCD3, OCH2CH3, or OCHF2. In other embodiments, R 2c is OH. In other embodiments, R 2c is OCH3. In other embodiments, R 2c is OCD3. In other embodiments, R 2c is OCH2CH3. In other embodiments, R 2c is OCHF2.

[0197] In some embodiments, the present invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein R 3c is H, halo, or C1-C6 alkyl. In other embodiments, R 3c is halo. In other embodiments, R 3c is C1-C6 alkyl. In other embodiments, R 3c is H, F, Cl, or CH3. In other embodiments, R 3c is H. In other embodiments, R3c is F. In other embodiments, R 3c is C1. In other embodiments, R 3c is CH3.

[0198] In some embodiments, the present invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein R 4c is halo. In other embodiments, R 4c is F.

[0199] In some embodiments, the present invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 and R 4b2 are each independently H or C1-C6 alkyl; R 5b1 and R 5b2 are each independently C1-C6 alkyl or C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0200] In some embodiments, the present invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 and R 4b2 are each independently H or CH3; R 5b1 and R 5b2 are each independently H, CH3, or CF3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0201] In some embodiments, the present invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein X4a is N; each R is H; R 4b1 is C1-C6 alkyl; R 4b2 is H; R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0202] In some embodiments, the present invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H; R 4b2 is C1-C6 alkyl; R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl and; R 4c is halo.

[0203] In some embodiments, the present invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is C1-C6 alkyl; R 4b2 is H; R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0204] In some embodiments, the present invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H; R 4b2 is C1-C6 alkyl; R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0205] In some embodiments, the present invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is CH3; R 4b2 is H; R 5b1 is CH3; R 5b2 is CF3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0206] In some embodiments, the present invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H; R 4b2 is CH3; R 5b1 is CH3; R 5b2 is CF3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0207] In some embodiments, the present invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is CH3; R 4b2 is H; R 5b1 is CF3; R 5b2 is CH3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0208] In some embodiments, the present invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H; R 4b2 is CH3; R 5b1 is CF3; R 5b2 is CH3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0209] In some embodiments, the present invention relates to a compound of formula (I-B-1) (including any of the foregoing embodiments thereof), i.e., the compound in non-salt form.

[0210] In some embodiments, the present invention relates to a compound of formula (I-C)

Chemical formula

[0211] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 2a is C-R 2a ; X 5a is C-R 5a ; X 6a is C-R 6a ; R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl; R 5b1 and R 5b2 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl; X 3c is C-R 3c ; X 4c is C-R 4c ; X 5c is C-R 5c ; X 6c is C-R 6c ; R 2cis H, OH, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0212] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently H or CH3. In other embodiments, N(R)2 is NHCH3.

[0213] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 2a is N. In other embodiments, X 2a is C-R 2a In some embodiments, R 2a is H, D, halo, or C1-C6 alkyl. In other embodiments, R 2a is H, D, F, or CH3. In some embodiments, X 2a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo. In other embodiments, X 2a is N, C-H, C-D, C-CH3, or C-F.

[0214] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 2a is C-R 2a and R 2a is H.

[0215] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 4a is N. In other embodiments, X 4a is N + -O - In other embodiments, X 4a is C-R 4a In some embodiments, R 4a is halo. In other embodiments, R 4ais H or halo. In other embodiments, R 4a is H or F. In other embodiments, X 4a is C-F. In some embodiments, X 4a is N, N + -O - C-H, or C-halo. In other embodiments, X 4a is N, N + -O - C-H, or C-F.

[0216] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 4a is C-R 4a wherein; R 4a is halo.

[0217] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 5a is N. In other embodiments, X 5a is C-R 5a wherein. In some embodiments, R 5a is H, D, halo, or C1-C6 alkyl. In other embodiments, R 5a is H, D, F, or CH3. In some embodiments, X 5a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo. In other embodiments, X 5a is N, C-H, C-D, C-CH3, or C-F.

[0218] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 5a is C-R 5a wherein; R 5a is H.

[0219] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 6a is N. In other embodiments, X 6ais C-R 6a In some embodiments, R 6a is H, D, halo, or C1-C6 alkyl. In other embodiments, R 6a is H, D, F, or CH3. In some embodiments, X 6a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo. In other embodiments, X 6a is N, C-H, C-D, C-CH3, or C-F.

[0220] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 6a is C-R 6a and; R 6a is H.

[0221] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R 4b1 and R 4b2 are each independently H or C1-C6 alkyl. In other embodiments, R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. In other embodiments, R 4b1 and R 4b2 are each independently H or CH3. In other embodiments, R 4b1 and R 4b2 are each independently H, CH3, CH2CH3, or cyclopropyl. In other embodiments, R 4b1 is C1-C6 alkyl and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is C1-C6 alkyl. In other embodiments, R 4b1 is CH3 and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is CH3.

[0222] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R 5b1 and R 5b2 are each independently C1-C6 alkyl or C1-C6 haloalkyl. In other embodiments, R 5b1 and R 5b2 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl. In other embodiments, R 5b1 and R 5b2 are each independently H, CH3, or CF3. In other embodiments, R 5b1 and R 5b2 are each independently H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CHF2, CF2CH3, CH2CF3, or CF3. In other embodiments, R 5b1 is C1-C6 alkyl and R 5b2 is C1-C6 haloalkyl. In other embodiments, R 5b1 is C1-C6 haloalkyl and R 5b2 is C1-C6 alkyl. In other embodiments, R 5b1 is CH3 and R 5b2 is CF3. In other embodiments, R 5b1 is CF3 and R 5b2 is CH3.

[0223] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy. In other embodiments, R 2c is OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 2 halos. In other embodiments, R 2c is H. In other embodiments, R 2cis C1-C6 alkoxy. In other embodiments, R 2c is C1-C6 haloalkoxy. In other embodiments, R 2c is -L 1 -L 2 -(C3-C6 cycloalkyl), where the cycloalkyl is optionally substituted with 1 to 2 halos. In other embodiments, R 2c is OH, OCH3, OCD3, OCH2CH3, or OCHF2. In other embodiments, R 2c is H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCHF2,

Chemical formula

[0224] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 3c is N. In other embodiments, X 3c is C-R 3c . In other embodiments, R 3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl. In other embodiments, R 3c is H, CH3, CH2CH3, CHF2, CF3, F, or Cl. In some embodiments, X 3c is N, C-H, C-CH3, C-CH2CH3, C-CHF2, C-CF3, C-F, or C-Cl.

[0225] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 3cis CR 3c and;R 3c is H, halo, or C-C alkyl. In other embodiments, R 3c is halo. In other embodiments, R 3c is C1-C6 alkyl. In other embodiments, R 3c is H, F, Cl, or CH. In other embodiments, R 3c is H. In other embodiments, R 3c is F. In other embodiments, R 3c is C1. In other embodiments, R 3c is CH3.

[0226] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 4c is N. In other embodiments, X 4c is CR 4c In another embodiment, R 4c is H, halo, or C1-C6 haloalkyl. In other embodiments, R 4c is H, CHF2, CF3, or F. In some embodiments, X 4c is N, CH, C-CHF2, C-CF3, or CF.

[0227] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 4c is CR 4c and;R 4c is halo. In other embodiments, R 4c is F.

[0228] In some embodiments, the present invention relates to a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein X 5c is N. In other embodiments, X 5c is CR 5c In other embodiments, R 5c is H or halo. In other embodiments, R 5cis H, D, or Cl. In some embodiments, X 5c is N, C-H, C-D, or C-Cl.

[0229] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 5c is C-R 5c ; and R 5c is H.

[0230] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 6c is N. In other embodiments, X 6c is C-R 6c ; and in other embodiments, R 6c is H or halo. In other embodiments, R 6c is H or F. In some embodiments, X 6c is N, C-H, or C-F.

[0231] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R 6c is H.

[0232] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 2a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo; X 4a is N, N + -O - ; C-H, or C-halo; X 5a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo; X 6a is N, C-H, C-D, C-(C1-C6 alkyl), or C-halo; each R is H or CH3; R 4b1 and R 4b2 are each independently H, C1-C6 alkyl, or C3-C6 cycloalkyl; R 5b1 and R 5b2is independently H, C1-C6 alkyl, or C1-C6 haloalkyl; R 2c is O is H, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 is -(C3-C6 cycloalkyl), where the cycloalkyl is optionally substituted with 1 to 2 halos; X 3c is C-R 3c is; R 3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; X 4c is C-R 4c is; R 4c is H, halo, or C1-C6 haloalkyl; X 5c is C-R 5c is; R 5c is H or halo; X 6c is C-R 6c is; R 6c is H or halo.

[0233] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a is; R 2a is H; X 5a is C-R 5a is; R 5a is H; X 6a is C-R 6a is; R 6a is H; R 4b1 and R 4b2 are each independently H or C1-C6 alkyl; R 5b1 and R 5b2 are each independently C1-C6 alkyl or C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3cand R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c and R 4c is halo; X 5c is C-R 5c and R 5c is H; X 6c is C-R 6c and R 6c is H.

[0234] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 2a is N, C-H, C-D, C-CH3, or C-F; X 4a is N, N + -O - C-H, or C-F; X 5a is N, C-H, C-D, C-CH3 or C-F; X 6a is N, C-H, C-D, C-CH3 or C-F; each R is H or CH3; R 4b1 and R 4b2 are each independently H, CH3, CH2CH3, or cyclopropyl; R 5b1 and R 5b2 are each independently H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CHF2, CF2CH3, CH2CF3, or CF3; R 2c is H, F, CH3, CH=CH2, OH, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCHF2,

Chemical formula

[0235] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 4b1 and R 4b2 are each independently H or CH3; R 5b1 and R 5b2 are each independently H, CH3, or CF3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl ; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6c is H.

[0236] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 4b1 is C1-C6 alkyl; R4b2 is H; R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X 6c is C-R 6c ; R 6c is H.

[0237] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 4b1 is H; R 4b2 is C1-C6 alkyl; R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X6c is C-R 6c ; R 6c is H.

[0238] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6a ; R 6a is H; R 4b1 is C1-C6 alkyl; R 4b2 is H; R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c ; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c ; R 4c is halo; X 5c is C-R 5c ; R 5c is H; X<000231)]] 6c is C-R 6c ; R 6c is H.

[0239] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a ; R 2a is H; X 5a is C-R 5a ; R 5a is H; X 6a is C-R 6aand R 6a is H; R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 4b1 is H; R 4b2 is C1-C6 alkyl; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c and R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c and R 4c is halo; X 5c is C-R 5c and R 5c is H; X 6c is C-R 6c and R 6c is H.

[0240] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a and R 2a is H; X 5a is C-R 5a and R 5a is H; X 6a is C-R 6a and R 6a is H; R 5b1 is CH3; R 5b2 is CF3; R 4b1 is CH3; R 4b2 is H; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c and R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c and R 4c is halo ; X 5c is C-R5c and; R 5c is H; X 6c is C-R 6c and; R 6c is H.

[0241] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a and; R 2a is H; X 5a is C-R 5a and; R 5a is H; X 6a is C-R 6a and; R 6a is H; R 5b1 is CH3; R 5b2 is CF3; R 4b1 is H; R 4b2 is CH3; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c and; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c and; R 4c is halo; X 5c is C-R 5c and; R 5c is H; X 6c is C-R 6c and; R 6c is H.

[0242] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a and; R 2a is H; X 5a is C-R 5a and; R 5a is H; X 6a is C-R6a and; R 6a is H; R 5b1 is CF3; R 5b2 is CH3; R 4b1 is, CH3; R 4b2 is H; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c and; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c and; R 4c is halo; X 5c is C-R 5c and; R 5c is H; X 6c is C-R 6c and; R 6c is H.

[0243] In some embodiments, the present invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; X 2a is C-R 2a and; R 2a is H; X 5a is C-R 5a and; R 5a is H; X 6a is C-R 6a and; R 6a is H; R 5b1 is CF3; R 5b2 is CH3; R 4b1 is, H, and R 4b2 is, CH3; R 2c is C1-C6 alkoxy, or C1-C6 haloalkoxy; X 3c is C-R 3c and; R 3c is H, halo, or C1-C6 alkyl; X 4c is C-R 4c and; R 4c is halo; X 5c is C-R 5c and; R5c is H; X 6c is C-R 6c ; R 6c is H.

[0244] In some embodiments, the present invention relates to a compound of formula (I-C) (including any of the foregoing embodiments thereof), i.e., the compound in non-salt form.

[0245] In some embodiments, the present invention relates to a compound of formula (I-C-1)

Chemical formula

[0246] In some embodiments, the present invention relates to a compound of formula (I-C-1) or a pharmaceutically acceptable salt thereof, wherein X4a is N. In other embodiments, X 4a is N + -O - is. In other embodiments, X 4a is C-R 4a is. In some embodiments, R 4a is halo. In other embodiments, X 4a is C-F.

[0247] In some embodiments, the present invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently H or CH3. In other embodiments, N(R)2 is NHCH3.

[0248] In some embodiments, the present invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein R 4a is halo.

[0249] In some embodiments, the present invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein R 4b1 and R 4b2 are each independently H or C1-C6 alkyl. In other embodiments, R 4b1 and R 4b2 are each independently H or CH3. In other embodiments, R 4b1 is C1-C6 alkyl and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is C1-C6 alkyl. In other embodiments, R 4b1 is CH3 and R 4b2 is H. In other embodiments, R 4b1 is H and R 4b2 is CH3.

[0250] In some embodiments, the present invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein R 5b1 and R 5b2is independently C1-C6 alkyl or C1-C6 haloalkyl. In other embodiments, R 5b1 and R 5b2 are each independently H, CH3, or CF3. In other embodiments, R 5b1 is C1-C6 alkyl and R 5b2 is C1-C6 haloalkyl. In other embodiments, R 5b1 is C1-C6 haloalkyl and R 5b2 is C1-C6 alkyl. In other embodiments, R 5b1 is CH3 and R 5b2 is CF3. In other embodiments, R 5b1 is CF3 and R 5b2 is CH3.

[0251] In some embodiments, the present invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy. In other embodiments, R 2c is C1-C6 alkoxy. In other embodiments, R 2c is C1-C6 haloalkoxy. In other embodiments, R 2c is OH, OCH3, OCD3, OCH2CH3, or OCHF2. In other embodiments, R 2c is OH. In other embodiments, R 2c is OCH3. In other embodiments, R 2c is OCD3. In other embodiments, R 2c is OCH2CH3. In other embodiments, R 2c is OCHF2.

[0252] In some embodiments, the present invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein R 3c is H, halo, or C1-C6 alkyl. In other embodiments, R 3c is halo. In other embodiments, R 3c is C1-C6 alkyl. In other embodiments, R 3cis H, F, Cl, or CH3. In other embodiments, R 3c is H. In other embodiments, R 3c is F. In other embodiments, R 3c is C1. In other embodiments, R 3c is CH3.

[0253] In some embodiments, the present invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein R 4c is halo. In other embodiments, R 4c is F.

[0254] In some embodiments, the present invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 and R 4b2 are each independently H or C1-C6 alkyl; R 5b1 and R 5b2 are each independently C1-C6 alkyl or C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0255] In some embodiments, the present invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 and R 4b2 are each independently H or CH3; R 5b1 and R 5b2 are each independently H, CH3, or CF3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0256] In some embodiments, the present invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is C1-C6 alkyl; R 4b2 is H; R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0257] In some embodiments, the present invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H; R 4b2 is C1-C6 alkyl; R 5b1 is C1-C6 alkyl; R 5b2 is C1-C6 haloalkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0258] In some embodiments, the present invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is C1-C6 alkyl; R 4b2 is H; R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0259] In some embodiments, the present invention relates to a compound of formula (IC-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H;R 4b2 is C1-C6 alkyl; R 5b1 is C1-C6 haloalkyl; R 5b2 is C1-C6 alkyl; R 2c is OH, C1-C6 alkoxy, or is C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0260] In some embodiments, the present invention relates to a compound of formula (IC-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is CH3; R 4b2 is H;R 5b1 is CH3; R 5b2 is CF3; R 2c is OH, C-C alkoxy, or C-C haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0261] In some embodiments, the present invention relates to a compound of formula (IC-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H;R 4b2 is CH3; R 5b1 is CH3; R 5b2 is CF3; R 2c is OH, C-C alkoxy, or C-C haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is a halo.

[0262] In some embodiments, the present invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is CH3; R 4b2 is H; R 5b1 is CF3; R 5b2 is CH3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0263] In some embodiments, the present invention relates to a compound of formula (I-C-1), or a pharmaceutically acceptable salt thereof, wherein X 4a is N; each R is H; R 4b1 is H; R 4b2 is CH3; R 5b1 is CF3; R 5b2 is CH3; R 2c is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 3c is H, halo, or C1-C6 alkyl; R 4c is halo.

[0264] In some embodiments, the present invention relates to a compound of formula (I-C-1) (including any of the foregoing embodiments thereof), i.e., the compound in non-salt form.

[0265] 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 in non-salt form.

[0266]

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

[0267] 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 in non-salt form.

[0268]

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

[0269] In some embodiments, the present invention relates to a compound selected from Table C, or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to a compound selected from Table C in non-salt form.

[0270]

Table 3-1

Table 3-2

Table 3-3

Table 3-4

Table 3-5

Table 3-6

Table 3-7

Table 3-8

Table 3-9

Table 3-10

Table 3-11

Table 3-12

Table 3- (13)

Table 3-14

Table 3-15

Table 3-16

Table 3-17

Table 3-18

Table 3-19

Table 3-20

Table 3-21

Table 3-22

Table 3-23

Table 3-24

Table 3-25

Table 3-26

Table 3-27

Table 3-28

Table 3-29

Table 3-30

Table 3-31

Table 3-32

Table 3-33

Table 3-34

Table 3-35

Table 3-36

Table 3-37

Table 3-38

Table 3-39

Table 3-40

Table 3-41

Table 3-42

Table 3-43

Table 3-44

Table 3-45

Table 3-46

Table 3-47

Table 3-48

Table 3-49

Table 3-50

Table 3-51

Table 3-52

Table 3-53

Table 3-54

Table 3-55

Table 3-56

Table 3-57

Table 3-58

Table 3-59

Table 3-60

Table 3-61

Table 3-62

Table 3-63

Table 3-64

Table 3-65

Table 3-66

Table 3-67

Table 3-68

Table 3-69

Table 3-70

Table 3-71

Table 3-72

Table 3-73

Table 3-74

Table 3-75

Table 3-76

Table 3-77

Table 3-78

Table 3-79

Table 3-80

Table 3-81

[0271] In some embodiments, the present invention relates to a compound of the formula

Chemical formula

[0272] In some embodiments, the present invention relates to a compound of the formula

Chemical formula

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

Chemical formula

[0274] In some embodiments, the present invention relates to a compound of the formula

Chemical formula

[0275] In some embodiments, the present invention relates to a compound of the formula

Chemical formula

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

Chemical formula

[0277] In some embodiments, the present invention relates to a compound of the formula

Chemical formula

[0278] In some embodiments, the present invention relates to a compound of the formula

Chemical Formula

[0279] In some embodiments, the present invention relates to a compound of the formula

Chemical Formula

[0280] In some embodiments, the present invention relates to a compound of the formula

Chemical Formula

[0281] In some embodiments, the present invention relates to a compound of the formula

Chemical Formula

[0282] In some embodiments, the present invention relates to a compound of the formula

Chemical formula

[0283] In some embodiments, the present invention relates to a compound of the formula

Chemical formula

[0284] In some embodiments, the present invention relates to a compound of the formula

Chemical formula

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

Chemical formula

[0286] In some embodiments, the present invention relates to a compound of the formula [Chemical Formula] or a pharmaceutically acceptable salt thereof. Such compounds are considered to be "compounds of the present invention" when the term is used herein.

[0287] In some embodiments, the present invention relates to a compound of the formula [Chemical Formula] or a pharmaceutically acceptable salt thereof. Such compounds are considered to be "compounds of the present invention" when the term is used herein.

[0288] In some embodiments, the present invention relates to a compound of the formula [Chemical Formula] or a pharmaceutically acceptable salt thereof, and the compound has the absolute stereochemistry of the first eluting isomer when the racemic mixture of enantiomers is separated by SFC (Chiralpak AS-H column) as described in Example 1. Such compounds are considered to be "compounds of the present invention" when the term is used herein.

[0289] In some embodiments, the present invention relates to a compound of the formula [Chemical Formula] or a pharmaceutically acceptable salt thereof, and the compound has the absolute stereochemistry of the second eluting isomer when the racemic mixture of enantiomers is separated by SFC (Chiralpak AS-H column) as described in Example 1. Such compounds are considered to be "compounds of the present invention" when the term is used herein.

[0290] In some embodiments, the present invention relates to a compound of the formula [Chemical Formula] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry of the first eluting isomer when the racemic mixture of enantiomers is separated by SFC as described in Example 4, Step 4. Such compounds are considered to be "compounds of the present invention" when the term is used herein.

[0291] In some embodiments, the present invention relates to a compound of the formula [Chemical Formula] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry of the second eluting isomer when the racemic mixture of enantiomers is separated by SFC as described in Example 4, Step 4. Such compounds are considered to be "compounds of the present invention" when the term is used herein.

[0292] In some embodiments, the present invention relates to a compound of the formula [Chemical Formula] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry of the first eluting isomer when the racemic mixture of enantiomers is separated by SFC (Chiralpak AS-H column) as described in Example 4, Step 4. Such compounds are considered to be "compounds of the present invention" when the term is used herein.

[0293] In some embodiments, the present invention relates to a compound of the formula [Chemical Formula] Regarding the compound, or a pharmaceutically acceptable salt thereof, the compound has the absolute stereochemistry of the second eluted isomer when a racemic mixture of enantiomers is separated by SFC (Chiralpak AS-H column) as described in Example 4, Step 4. Such a compound is considered to be a "compound of the present invention" when the term is used herein.

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

Chemical formula

[0295] In some embodiments, the present invention relates to a compound of the formula

Chemical formula

[0296] In some embodiments, the present invention relates to a compound of the formula

Chemical formula

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

Chemical formula

[0298] In some embodiments, the present invention relates to a compound of the formula

Chemical formula

[0299] In some embodiments, the present invention relates to a compound of the formula

Chemical formula

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

Chemical formula

[0301] In some embodiments, the present invention relates to a compound of the formula [Chemistry] relates to a compound of , , or a pharmaceutically acceptable salt thereof. Such a compound is considered to be a "compound of the present invention" when the term is used herein.

[0302] In some embodiments, the present invention provides a compound of the formula [Chemistry] relates to a compound of , , or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry of the first eluting isomer when the racemic mixture of enantiomers is separated by SFC as described in Example 7, Step 11. Such a compound is considered to be a "compound of the present invention" when the term is used herein.

[0303] In some embodiments, the present invention provides a compound of the formula [Chemistry] relates to a compound of , , or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry of the second eluting isomer when the racemic mixture of enantiomers is separated by SFC as described in Example 7, Step 11. Such a compound is considered to be a "compound of the present invention" when the term is used herein.

[0304] In some embodiments, the present invention provides a compound of the formula [Chemistry] relates to a compound of , , or a pharmaceutically acceptable salt thereof. Such a compound is considered to be a "compound of the present invention" when the term is used herein.

[0305] Solid forms of the compounds of the present invention In another aspect, the present invention provides a solid form of a compound of the present invention or a pharmaceutically acceptable Relating to salts. In some embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, are in a crystalline solid form.

[0306] Solid form of Compound 7 In some embodiments, the invention relates to a compound of the formula

Chemical formula

[0307] In some embodiments, the crystalline solid form is Form A.

[0308] In some embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (2 theta ± 0.2 degrees) of 9.9, 13.9, 15.7, and 19.0. In other embodiments, Form A is characterized by an XRPD pattern having at least 1, at least 2, or at least 3 diffractions at angles (2 theta ± 0.2 degrees) of 9.9, 13.9, 15.7, and 19.0. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (2 theta ± 0.2 degrees) of 7.3, 9.9, 13.9, 15.7, 19.0, 20.1, 20.3, and 25.4. In other embodiments, Form A is characterized by an XRPD pattern having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, or at least 7 diffractions at angles (2 theta ± 0.2 degrees) of 7.3, 9.9, 13.9, 15.7, 19.0, 20.1, 20.3, and 25.4. In other embodiments, Form A is characterized by an XRPD pattern substantially the same as FIG. 1.

[0309] In some embodiments, Form A is characterized by a DSC thermogram with a melting onset at 186 °C and a peak at 187 °C.

[0310] In some embodiments, Form A can be obtained by crystallization from methanol at 60 °C.

[0311] In some embodiments, the crystalline solid form is Form B.

[0312] In some embodiments, Form B is characterized by an XRPD pattern having diffractions at angles (2 theta ± 0.2 degrees) of 12.8, 14.1, 15.2, 18.5, and 20.3. In other embodiments, Form B is characterized by an XRPD pattern having at least 1, at least 2, at least 3, or at least 4 diffractions at angles (2 theta ± 0.2 degrees) of 12.8, 14.1, 15.2, 18.5, and 20.3. In other embodiments, Form B has diffractions at angles (2 theta ± 0.2 degrees) of 12.0, 12.8, 14.1, 15.2, 16.9, 18.4, 18.5, 18.7, 19.3, and 20.3 It is characterized by an XRPD pattern. In other embodiments, Form B is characterized by an XRPD pattern having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or at least 9 diffractions at angles (2 theta ± 0.2 degrees) of 12.0, 12.8, 14.1, 15.2, 16.9, 18.4, 18.5, 18.7, 19.3, and 20.3. In other embodiments, Form B is characterized by an XRPD pattern having diffractions at angles (2 theta ± 0.2 degrees) of 7.6, 9.2, 12.0, 12.8, 14.1, 15.1, 15.2, 16.2, 16.9, 17.6, 18.4, 18.5, 18.7, 19.3, 20.3, 21.7, 22.0, 22.2, 22.9, 23.6, 24.0, 24.2, 25.2, 26.9, 27.0, 27.4, 28.6, and 28.9. In other embodiments, Form B is characterized by an XRPD pattern having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, or at least 27 diffractions at angles (2 theta ± 0.2 degrees) of 7.6, 9.2, 12.0, 12.8, 14.1, 15.1, 15.2, 16.2, 16.9, 17.6, 18.4, 18.5, 18.7, 19.3, 20.3, 21.7, 22.0, 22.2, 22.9, 23.6, 24.0, 24.2, 25.2, 26.9, 27.0, 27.4, 28.6, and 28.9. In other embodiments, Form B is characterized by an XRPD pattern substantially the same as FIG. 4.

[0313] In some embodiments, Form B is a solid having peaks at chemical shifts of 172.5, 172.1, 168.5, 168.3, 168.0, 151.5, 148.3, 147.8, 127.7, 122.7, 116.6, 115.1, 110.6, 86.5, 80.2, 63.2, 44.3, 23.0, and 13.1 ppm 13 characterized by a solid 13 13 C NMR spectrum. In some embodiments, Form B is characterized by a solid 13

[0314] C NMR spectrum substantially the same as FIG. 5. In some embodiments, Form B is a solid having peaks at chemical shifts of -137.1 and -152.8 ppm 19 characterized by a solid 19 19 F NMR spectrum. In some embodiments, Form B is characterized by a solid 19

[0315] F NMR spectrum substantially the same as FIG. 6. In some embodiments, Form B is characterized by a DSC thermogram with a melting onset at 182 °C and a peak at 183 °C

[0316] In some embodiments, Form B is characterized by an IR spectrum having peaks at 3501, 3356, 1684, 1565, 1505, and 1122 cm -1 In some embodiments, Form B is characterized by an IR spectrum substantially the same as FIG. 9. In some embodiments, Form B is orthorhombic, as determined by single crystal X-ray analysis. In other embodiments, Form B is characterized by the P212121 space group, as determined by single crystal X-ray analysis. In other embodiments, Form B is characterized by a unit cell of the following dimensions: a = 7.3929(2) Å; b = 14.5827(4) Å; c = 18.9312(6) Å; α = 90°; β = 90°; and γ = 90°, as determined by single crystal X-ray analysis

[0317] In some embodiments, Form B is orthorhombic, as determined by single crystal X-ray analysis. In other embodiments, Form B is characterized by the P212121 space group, as determined by single crystal X-ray analysis. In other embodiments, Form B is characterized by a unit cell of the following dimensions: a = 7.3929(2) Å; b = 14.5827(4) Å; c = 18.9312(6) Å; α = 90°; β = 90°; and γ = 90°, as determined by single crystal X-ray analysis

[0318] In some embodiments, Form B can be obtained by dissolving the compound in ethyl acetate and then crystallizing the compound by adding n-heptane as a poor solvent. In other embodiments, Form B can be obtained by the procedure described in Example 3.

[0319] In some embodiments, the present invention relates to a compound of the formula

Chemical formula

[0320] In some embodiments, the crystalline solid form is Form A.

[0321] In some embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (2 theta ± 0.2 degrees) of 9.9, 13.9, 15.7, and 19.0. In other embodiments, Form A is characterized by an XRPD pattern having at least 1, at least 2, or at least 3 diffractions at angles (2 theta ± 0.2 degrees) of 9.9, 13.9, 15.7, and 19.0. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (2 theta ± 0.2 degrees) of 7.3, 9.9, 13.9, 15.7, 19.0, 20.1, 20.3, and 25.4. In other embodiments, Form A is characterized by an XRPD pattern having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, or at least 7 diffractions at angles (2 theta ± 0.2 degrees) of 7.3, 9.9, 13.9, 15.7, 19.0, 20.1, 20.3, and 25.4. In other embodiments, Form A is characterized by an XRPD pattern substantially the same as that of Figure 1.

[0322] In some embodiments, Form A is characterized by a DSC thermogram with a melting onset at 186 °C and a peak at 187 °C.

[0323] In some embodiments, Form A can be obtained by crystallization from methanol at 60 °C.

[0324] In some embodiments, the crystalline solid form is Form B.

[0325] In some embodiments, Form B is characterized by an XRPD pattern having diffractions at angles (2 theta ± 0.2 degrees) of 12.8, 14.1, 15.2, 18.5, and 20.3. In other embodiments, Form B is characterized by an XRPD pattern having at least 1, at least 2, at least 3, or at least 4 diffractions at angles (2 theta ± 0.2 degrees) of 12.8, 14.1, 15.2, 18.5, and 20.3. In other embodiments, Form B is characterized by an XRPD pattern having diffractions at angles (2 theta ± 0.2 degrees) of 12.0, 12.8, 14.1, 15.2, 16.9, 18.4, 18.5, 18.7, 19.3, and 20.3. In other embodiments, Form B is characterized by an XRPD pattern having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or at least 9 diffractions at angles (2 theta ± 0.2 degrees) of 12.0, 12.8, 14.1, 15.2, 16.9, 18.4, 18.5, 18.7, 19.3, and 20.3. In other embodiments , Form B is characterized by an XRPD pattern having diffraction at angles of 7.6, 9.2, 12.0, 12.8, 14.1, 15.1, 15.2, 16.2, 16.9, 17.6, 18.4, 18.5, 18.7, 19.3, 20.3, 21.7, 22.0, 22.2, 22.9, 23.6, 24.0, 24.2, 25.2, 26.9, 27.0, 27.4, 28.6, and 28.9 (2 theta ± 0.2 degrees). In other embodiments, Form B is characterized by an XRPD pattern having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, or at least 27 diffractions at angles of 7.6, 9.2, 12.0, 12.8, 14.1, 15.1, 15.2, 16.2, 16.9, 17.6, 18.4, 18.5, 18.7, 19.3, 20.�, 21.7, 22.0, 22.2, 22.9, 23.6, 24.0, 24.2, 25.2, 26.9, 27.0, 27.4, 28.6, and 28.9 (2 theta ± 0.2 degrees). In other embodiments, Form B is characterized by an XRPD pattern substantially the same as FIG. 4.

[0326] In some embodiments, Form B is characterized by a solid 13C NMR spectrum having peaks at chemical shifts of 172.5, 172.1, 168.5, 168.3, 168.0, 151.5, 148.3, 147.8, 127.7, 122.7, 116.6, 115.1, 110.6, 86.5, 80.2, 63.2, 44.3, 23.0, and 13.1 ppm. 13 In other embodiments, Form B is characterized by a solid 13C NMR spectrum substantially the same as FIG. 5. 13 In other embodiments, Form B is characterized by a solid 13C NMR spectrum substantially the same as FIG. 5.

[0327] In some embodiments, Form B is characterized by a solid 13C NMR spectrum having peaks at chemical shifts of -137.1 and -152.8 ppm. 19It is characterized by an 19F NMR spectrum. In other embodiments, Form B is a solid substantially the same as that in FIG. 6 19 It is characterized by an 19F NMR spectrum.

[0328] In some embodiments, Form B is characterized by a DSC thermogram with a melting onset at 182 °C and a peak at 183 °C.

[0329] In some embodiments, Form B is characterized by an IR spectrum having peaks at 3501, 3356, 1684, 1565, 1505, and 1122 cm -1 In other embodiments, Form B is characterized by an IR spectrum substantially the same as that in FIG. 9.

[0330] In some embodiments, Form B is orthorhombic as determined by single crystal X-ray analysis. In other embodiments, Form B is characterized by the P212121 space group as determined by single crystal X-ray analysis. In other embodiments, Form B is characterized by a unit cell of the following dimensions as determined by single crystal X-ray analysis: a = 7.3929(2) Å; b = 14.5827(4) Å; c = 18.9312(6) Å; α = 90°; β = 90°; and γ = 90°.

[0331] In some embodiments, Form B can be obtained by dissolving the compound in ethyl acetate and then crystallizing the compound by adding n-heptane as a poor solvent. In other embodiments, Form B can be obtained by the procedure described in Example 3.

[0332] Solid form of Compound 9 In some embodiments, the present invention relates to a compound of the formula

Chemical formula

[0333] In some embodiments, the crystalline solid form is Form A.

[0334] In some embodiments, Form A is characterized by an orthorhombic crystal system as determined by single crystal X-ray analysis. In other embodiments, Form A is characterized by the I222 space group as determined by single crystal X-ray analysis. In other embodiments, Form A is characterized by a unit cell having the following dimensions as determined by single crystal X-ray analysis: a = 12.0172(5) Å; b = 15.6682(6) Å; c = 24.1406(11) Å; α = 90°; β = 90°; and γ = 90°.

[0335] In some embodiments, Form A can be obtained by dissolving the compound in a 10 / 90 dichloromethane / dichloroethane solution followed by vapor diffusion of pentane. In some embodiments, Form A can be obtained by the procedure described in Example 3.

[0336] Solid Forms of Compound 11 In some embodiments, the present invention relates to a compound of the formula

Chemical formula

[0337] In some embodiments, the crystalline solid form is Form A.

[0338] In some embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (2 theta ± 0.2 degrees) of 10.1, 13.7, 14.1, 16.3, and 20.0. In other embodiments, Form A is characterized by an XRPD pattern having at least 1, at least 2, at least 3, or at least 4 diffractions at angles (2 theta ± 0.2 degrees) of 10.1, 13.7, 14.1, 16.3, and 20.0. In other embodiments, Form A is characterized by an X-ray diffraction pattern having diffractions at angles (2 theta ± 0.2 degrees) of 7.3, 10.1, 13.7, 14.1, 16.0, 16.3, 20.0, 20.4, 23.7, and 24.8. It is characterized by an RPD pattern. In other embodiments, Form A is characterized by an XRPD pattern having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or at least 9 diffractions at angles (2 theta ± 0.2 degrees) of 7.3, 10.1, 13.7, 14.1, 16.0, 16.3, 20.0, 20.4, 23.7, and 24.8. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (2 theta ± 0.2 degrees) of 7.1, 7.3, 10.1, 13.7, 14.1, 16.0, 16.3, 17.6, 18.5, 18.9, 20.0, 20.4, 21.5, 23.7, 24.8, 25.7, and 26.1. In other embodiments, Form A is characterized by an XRPD pattern having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16 diffractions at angles (2 theta ± 0.2 degrees) of 7.1, 7.3, 10.1, 13.7, 14.1, 16.0, 16.3, 17.6, 18.5, 18.9, 20.0, 20.4, 21.5, 23.7, 24.8, 25.7, and 26.1. In other embodiments, Form A is characterized by an XRPD pattern substantially the same as that of Figure 12.

[0339] In some embodiments, Form A can be obtained by suspending the compound in water. In other embodiments, Form A can be obtained by the procedure described in Example 4.

[0340] In some embodiments, the crystalline solid form is Form B.

[0341] In some embodiments, Form B is characterized by an XRPD pattern having diffractions at angles of 6.8, 13.2, 16.1, 20.6, and 21.3 degrees (2 theta ± 0.2 degrees). In other embodiments, Form B is characterized by an XRPD pattern having at least 1, at least 2, at least 3, or at least 4 diffractions at angles of 6.8, 13.2, 16.1, 20.6, and 21.3 degrees (2 theta ± 0.2 degrees). In other embodiments, Form B is characterized by an XRPD pattern having diffractions at angles of 6.8, 11.5, 13.2, 13.6, 14.4, 16.1, 16.3, 18.8, 20.6, and 21.3 degrees (2 theta ± 0.2 degrees). In other embodiments, Form B is characterized by an XRPD pattern having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or at least 9 diffractions at angles of 6.8, 11.5, 13.2, 13.6, 14.4, 16.1, 16.3, 18.8, 20.6, and 21.3 degrees (2 theta ± 0.2 degrees). In other embodiments, Form B is characterized by an XRPD pattern having diffractions at angles of 6.8, 11.5, 13.2, 13.6, 14.4, 15.6, 16.1, 16.3, 17.6, 18.0, 18.8, 19.4, 20.6, 21.3, 22.3, 23.3, 24.2, and 27.4 degrees (2 theta ± 0.2 degrees). In other embodiments, Form B is characterized by an XRPD pattern having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, or at least 17 diffractions at angles of 6.8, 11.5, 13.2, 13.6, 14.4, 15.6, 16.1, 16.3, 17.6, 18.0, 18.8, 19.4, 20.6, 21.3, 22.3, 23.3, 24.2, and 27.4 degrees (2 theta ± 0.2 degrees). In other embodiments, Form B is characterized by an XRPD pattern substantially the same as FIG. 13.

[0342] In some embodiments, Form A is characterized by a monoclinic system as determined by single crystal X-ray analysis. In other embodiments, Form A is characterized by the P21 space group as determined by single crystal X-ray analysis. In other embodiments, Form A is characterized by a unit cell of the following dimensions as determined by single crystal X-ray analysis: a = 12.0863(2) Å; b = 7.48310(10) Å; c = 23.9904(4) Å; α = 90°; β = 90.0130(10)°; and γ = 90°. a = 12.0863(2) Å; b = 7.48310(10) Å; c = 23.9904(4) Å; α = 90°; β = 90.0130(10)°; and γ = 90°.

[0343] In some embodiments, Form B can be obtained by recrystallization from acetonitrile. In other embodiments, Form B can be obtained by the procedure described in Example 4.

[0344] Solid Forms of Compound 19 In some embodiments, the present invention relates to a compound of the formula

Chemical formula

[0345] In some embodiments, the crystalline solid form is Form A.

[0346] In some embodiments, Form A is characterized by an XRPD pattern having diffractions at angles of 13.7, 15.2, and 18.2 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one, or at least two diffractions at angles of 13.7, 15.2, and 18.2 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles of 13.7, 15.2, 18.2, 18.3, 20.8, and 23.8 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, or at least five diffractions at angles of 13.7, 15.2, 18.2, 18.3, 20.8, and 23.8 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles of 13.7, 14.3, 15.2, 18.2, 18.3, 20.8, 22.5, 23.8, and 25.8 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight diffractions at angles of 13.7, 14.3, 15.2, 18.2, 18.3, 20.8, 22.5, 23.8, and 25.8 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles of 6.8, 13.7, 14.3, 15.2, 16.1, 18.2, 18.3, 19.1, 20.6, 20.8, 22.5, 23.8, 24.0, 25.8, 26.3, and 26.6 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 15 diffractions at angles of 6.8, 13.7, 14.3, 15.2, 16.1, 18.2, 18.3, 19.1, 20.6, 20.8, 22.5, 23.8, 24.0, 25.8, 26.3, and 26.6 (2 theta ± 0.2 degrees). It is characterized by turns. In other embodiments, Form A is characterized by an XRPD pattern substantially the same as that of FIG. 15.

[0347] In some embodiments, Form A is a solid having peaks at chemical shifts of 171.4, 141.6, 118.0, 112.2, 23.0, and 11.6 ppm 13 characterized by a solid 13C NMR spectrum. In other embodiments, Form A is a solid having peaks at chemical shifts of 171.4, 164.2, 151.8, 149.5, 148.4, 146.6, 144.0, 141.6, 138.7, 126.2, 123.8, 118.0, 112.2, 86.4, 78.8, 63.3, 47.6, 43.8, 23.0, and 11.6 ppm 13 characterized by a solid 13C NMR spectrum. In other embodiments, Form A is a solid 13 characterized by a 13C NMR spectrum substantially the same as that of FIG. 16.

[0348] In some embodiments, Form A is a solid having peaks at chemical shifts of -74.6, -141.5, and -154.6 ppm 19 characterized by a 19F NMR spectrum. In other embodiments, Form A is a solid 19 characterized by a 19F NMR spectrum substantially the same as that of FIG. 17.

[0349] In some embodiments, Form A is characterized by a monoclinic crystal system as determined by single crystal X-ray analysis. In other embodiments, Form A is characterized by the P21 space group as determined by single crystal X-ray analysis. In other embodiments, Form A is characterized by a unit cell of the following dimensions as determined by single crystal X-ray analysis: a = 11.2266(3) Å; b = 7.3948(2) Å; c = 13.1432(4) Å; α = 90°; β = 100.3980(1)°; and γ = 90°.

[0350] In some embodiments, Form A can be obtained by precipitation from methanol by adding a heptane-poor solvent. In other embodiments, Form A can be obtained by lyophilization from a suspension of the compound in ethanol, acetonitrile, and water. In other embodiments, Form A can be obtained by dissolving the compound in methanol and slowly diffusing a heptane-poor solvent. In other embodiments, Form A can be obtained by the procedure described in Example 5.

[0351] Solid form of Compound 22 In some embodiments, the present invention relates to a compound of the formula

Chemical formula

[0352] In some embodiments, the crystalline solid form is Form A.

[0353] In some embodiments, Form A is characterized by an XRPD pattern having diffractions at angles of 9.2, 10.4, and 15.7 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one, or at least two diffractions at angles of 9.2, 10.4, and 15.7 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles of 7.7, 9.2, 10.4, 12.9, 15.7, and 18.4 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, or at least five diffractions at angles of 7.7, 9.2, 10.4, 12.9, 15.7, and 18.4 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles of 7.7, 9.2, 10.4, 12.9, 15.7, 18.4, 19.8, 21.7, and 24.0 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight diffractions at angles of 7.7, 9.2, 10.4, 12.9, 15.7, 18.4, 19.8, 21.7, and 24.0 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles of 7.7, 9.2, 10.4, 12.9, 13.8, 14.7, 15.7, 16.1, 18.4, 19.8, 21.7, 22.3, and 24.0 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, or at least twelve diffractions at angles of 7.7, 9.2, 10.4, 12.9, 13.8, 14.7, 15.7, 16.1, 18.4, 19.8, 21.7, 22.3, and 24.0 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern substantially the same as that of Figure 19.

[0354] In some embodiments, Form A is a solid having peaks at chemical shifts of 167.7, 126.0, 115.9, 43.5, and 20.3 ppm 13 characterized by a 13C NMR spectrum. In other embodiments, Form A is a solid having peaks at chemical shifts of 172.6, 167.7, 158.7, 156.8, 151.8, 148.7, 128.6, 126.0, 115.9, 113.1, 112.3, 88.0, 85.5, 62.0, 60.5, 55.6, 43.5, 37.7, 29.6, 21.1, and 20.3 ppm 13 characterized by a 13C NMR spectrum. In other embodiments, Form A is a solid having a 13C NMR spectrum substantially the same as that of FIG. 20 13 characterized by a 13C NMR spectrum.

[0355] In some embodiments, Form A is a solid having peaks at chemical shifts of -82.2, -83.1, -111.7, and -114.4 ppm 19 characterized by a 19F NMR spectrum. In other embodiments, Form A is a solid having a 19F NMR spectrum substantially the same as that of FIG. 21 19 characterized by a 19F NMR spectrum.

[0356] In some embodiments, Form A can be obtained by slow evaporation of a 1:1 2-methyltetrahydrofuran / heptane solution. In other embodiments, Form A can be obtained by the procedure described in Example 6.

[0357] Solid form of Compound 23 In some embodiments, the present invention relates to a compound of the formula

Chemical formula

[0358] In some embodiments, the crystalline solid form is Form A.

[0359] In some embodiments, Form A is characterized by an XRPD pattern having diffractions at angles of 17.2, 19.3, and 22.3 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one, or at least two diffractions at angles of 17.2, 19.3, and 22.3 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles of 14.2, 15.8, 17.2, 19.3, 22.3, and 30.6 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, or at least five diffractions at angles of 14.2, 15.8, 17.2, 19.3, 22.3, and 30.6 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles of 12.2, 14.2, 15.8, 17.2, 19.3, 22.3, 25.0, 25.1, and 30.6 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight diffractions at angles of 12.2, 14.2, 15.8, 17.2, 19.3, 22.3, 25.0, 25.1, and 30.6 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles of 11.3, 12.2, 13.2, 14.2, 15.2, 15.8, 16.6, 17.2, 19.3, 21.1, 22.3, 22.8, 23.7, 24.6, 25.0, 25.1, 25.9, 27.1, 27.9, 30.6, 34.4, and 39.4 (2 theta ± 0.2 degrees).In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, or at least twenty-one diffractions at angles (2 theta ± 0.2 degrees) of 11.3, 12.2, 13.2, 14.2, 15.2, 15.8, 16.6, 17.2, 19.3, 21.1, 22.3, 22.8, 23.7, 24.6, 25.0, 25.1, 25.9, 27.1, 27.9, 30.6, 34.4, and 39.4. In other embodiments, Form A is characterized by an XRPD pattern substantially the same as FIG. 22.

[0360] In some embodiments, Form A is characterized by a solid 13 C NMR spectrum having peaks at chemical shifts of 171.1, 149.3, 123.3, 41.6, and 20.0 ppm. In other embodiments, Form A is characterized by a solid C NMR spectrum having peaks at chemical shifts of 171.1, 166.7, 156.8, 155.5, 151.9, 149.3, 147.3, 131.5, 123.3, 119.0, 114.2, 112.8, 86.0, 85.0, 61.7, 61.0, 44.4, 41.6 13 and 20.0 ppm. In other embodiments, Form A is characterized by a solid 13 C NMR spectrum substantially the same as FIG. 23.

[0361] In some embodiments, Form A is characterized by a solid 19 F NMR spectrum having peaks at chemical shifts of -78.2, -113.5, and -115.1 ppm. In other embodiments, Form A is characterized by a solid 19 F NMR spectrum substantially the same as FIG. 24.

[0362] In some embodiments, Form A is characterized by a monoclinic system as determined by single crystal X-ray analysis. In other embodiments, Form A is characterized by the P21 space group as determined by single crystal X-ray analysis. In other embodiments, Form A is characterized by a unit cell of the following dimensions as determined by single crystal X-ray analysis: a = 7.8661(3) Å; b = 7.9167(3) Å; c = 16.8777(7) Å; α = 90°; β = 98.487(2)°; and γ = 90°.

[0363] In some embodiments, Form A can be obtained by slow evaporation of a 1:1 2-methyltetrahydrofuran / heptane solution. In other embodiments, Form A can be obtained by dissolving the compound in methanol and slowly diffusing heptane vapor. In other embodiments, Form A can be obtained by the procedure described in Example 6.

[0364] Solid Forms of Compound 25 In some embodiments, the present invention relates to a compound of the formula

Chemical formula

[0365] In some embodiments, the crystalline solid form is Form A.

[0366] In some embodiments, Form A is characterized by an XRPD pattern having diffractions at angles of 6.8, 7.9, and 13.8 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one, or at least two diffractions at angles of 6.8, 7.9, and 13.8 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles of 6.8, 7.9, 11.0, 13.7, 13.8, and 27.4 (2 theta ± 0.2 degrees). In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, or at least five diffractions at angles of 6.8, 7.9, 11.0, 13.7, 13.8, and 27.4 (2 theta ± 0.2 degrees). In other embodiments, Form A is 6.8, 7.9, 11.0, 13.7, 13.8, 15.9, 16 .3, 23.2, and diffraction at an angle of 27.4 (2 theta ± 0.2 degrees), characterized by an XRPD pattern. In other embodiments, Form A has diffraction at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight angles of 6.8, 7.9, 11.0, 13.7, 13.8, 15.9, 16.3, 23.2, and 27.4 (2 theta ± 0.2 degrees), characterized by an XRPD pattern. In other embodiments, Form A has diffraction at angles of 3.2, 6.8, 7.9, 11.0, 11.8, 13.7, 13.8, 15.1, 15.9, 16.3, 17.5, 18.6, 19.0, 19.5, 21.6, 21.9, 23.2, 27.0, 27.4, 29.4, and 30.3 (2 theta ± 0.2 degrees), characterized by an XRPD pattern. In other embodiments, Form A has diffraction at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 angles of 3.2, 6.8, 7.9, 11.0, 11.8, 13.7, 13.8, 15.1, 15.9, 16.3, 17.5, 18.6, 19.0, 19.5, 21.6, 21.9, 23.2, 27.0, 27.4, 29.4, and 30.3 (2 theta ± 0.2 degrees), characterized by an XRPD pattern. In other embodiments, Form A has an XRPD pattern substantially the same as Figure 26.

[0367] In some embodiments, Form A can be obtained by slow evaporation of a 1:1 2-methyltetrahydrofuran / heptane solution. In other embodiments, Form A can be obtained by the procedure described in Example 7.

[0368] Salts, Compositions, Uses, Formulations, Administrations, and Additional Agents Pharmaceutically Acceptable Salts and Compositions As discussed herein, the present invention provides compounds which are inhibitors of voltage - dependent sodium channels and pharmaceutically acceptable salts thereof. Accordingly, the compounds of the present invention, and pharmaceutically acceptable salts thereof, are useful for the treatment of diseases, disorders, and conditions including, but not limited to, chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., pain after bunionectomy, pain after hernia suture, or pain after abdominoplasty), visceral pain, multiple sclerosis, Charcot - Marie - Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia. Accordingly, in another aspect of the present invention, pharmaceutical compositions are provided which comprise a compound or a pharmaceutically acceptable salt thereof as described herein and, optionally, a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, these compositions further comprise one or more additional therapeutic agents, optionally. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0369] As used herein, the term "pharmaceutically acceptable salt" refers to salts that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit / risk ratio. The "pharmaceutically acceptable salts" of the compounds of the present invention include any non - toxic salts that can provide, directly or indirectly, the compound of the present invention or an inhibitory active metabolite or a residue thereof upon administration to a recipient. The salts can be in pure form, in a mixture with one or more other substances (e.g., a solution, suspension, or colloid), or in the form of a hydrate, solvate, or co - crystal. As used herein, the term "inhibitory active metabolite or a residue thereof" means that the metabolite or the residue thereof is also an inhibitor of voltage - dependent sodium channels.

[0370] 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, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic acids, organic acids, and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are those 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 salts of amino groups formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, 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 suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1-4(alkyl)4 salts. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further non-limiting examples of pharmaceutically acceptable salts include, where appropriate, 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.

[0371] As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which includes, as used herein, any solvent, diluent, or other liquid vehicle, dispersing or suspending aid, surfactant, isotonic agent, thickening or emulsifying agent, preservative, solid binder, lubricant, etc. suitable for the particular dosage form desired. Remington’s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in the formulation of pharmaceutically acceptable compositions, and known techniques for their preparation. The use thereof is contemplated to be within the scope of the present invention, except where any conventional carrier medium is incompatible with the compounds of the present invention, such as by producing any undesirable biological effects or interacting in a detrimental manner with any other component(s) of the pharmaceutically acceptable composition. 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, buffering substances such as phosphates, glycine, sorbate or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, 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; powdered trag Gacanthus; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; 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; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer, and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, and coloring agents, release agents, coating agents, sweetening agents, flavoring agents and fragrances, preservatives and antioxidants may also, at the discretion of the formulator, be present in the composition.

[0372] In another aspect, the present invention features a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0373] In another aspect, the present invention features a pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

[0374] Use of the compound and pharmaceutically acceptable salts and compositions In another aspect, the present invention features a method of inhibiting a voltage-dependent sodium channel in a subject, 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-dependent sodium channel is Na V is 1.8.

[0375] In yet another aspect, the present invention features a method for treating a subject having chronic pain, visceral pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., pain from circumcision, hernia suture, or abdominoplasty), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia, 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.

[0376] In yet another aspect, the present invention features a method for treating a subject having chronic pain, visceral pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, pain from circumcision, hernia suture, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia, 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.

[0377] In yet another aspect, the present invention features a method for treating a subject having visceral pain or reducing the severity thereof, wherein the visceral pain includes pain from inflammatory bowel disease, Crohn's disease, or interstitial cystitis, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0378] In yet another aspect, the present invention features a method for treating a subject having neuropathic pain 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. In some aspects, the neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, or idiopathic small fiber neuropathy. As used herein, the term "idiopathic small fiber neuropathy" should be understood to include any small fiber neuropathy. In some aspects, the neuropathic pain includes diabetic neuropathy.

[0379] In yet another aspect, the present invention features a method for treating or reducing the severity of neuropathic pain, which includes postherpetic neuralgia, diabetic neuropathy, painful HIV-related sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-operative 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-induced neuropathy, cancer chemotherapy-induced neuropathy, antiretroviral therapy-induced neuropathy; pain after spinal cord injury, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia, and the method includes administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0380] In yet another aspect, the present invention features a method for treating or reducing the severity of musculoskeletal pain, which includes 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 musculoskeletal pain includes osteoarthritis pain.

[0381] In yet another aspect, the present invention features a method for treating or reducing the severity of musculoskeletal pain, which includes osteoarthritis pain, back pain, cold pain, burn pain or toothache, and the method includes administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0382] In yet another aspect, the present invention features a method for treating or reducing the severity of inflammatory pain, which includes rheumatoid arthritis pain or vulvodynia, and the method includes administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0383] In yet another aspect, the present invention features a method of treating or reducing the severity of inflammatory pain, which includes the pain of rheumatoid arthritis, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0384] In yet another aspect, the present invention features a method of treating or reducing the severity of idiopathic pain, which includes the pain of fibromyalgia, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0385] In yet another aspect, the present invention features a method of treating or reducing the severity of pathological cough, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0386] In yet another aspect, the present invention features a method of treating or reducing the severity of acute pain, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, acute pain includes acute postoperative pain.

[0387] In yet another aspect, the present invention features a method of treating or reducing the severity of postoperative pain (e.g., pain after hemorrhoidectomy, pain after hernia suture, or pain after abdominoplasty), the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof thereof.

[0388] In yet another aspect, the present invention features a method of treating or reducing the severity of pain after hemorrhoidectomy, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0389] In yet another aspect, the present invention is a method of treating a subject with hernia suture pain or reducing the severity thereof, comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0390] In yet another aspect, the present invention is a method of treating a subject with abdominal wall formation pain or reducing the severity thereof, comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0391] In yet another aspect, the present invention is a method of treating a subject with visceral pain or reducing the severity thereof, comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some aspects, the visceral pain includes visceral pain due to abdominal wall formation surgery.

[0392] In yet another aspect, the present invention is a method of treating a subject with a neurodegenerative disease or reducing the severity thereof, comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some aspects, the neurodegenerative disease includes multiple sclerosis. In some aspects, the neurodegenerative disease includes Pitt-Hopkins syndrome (PTHS).

[0393] In yet another aspect, the present invention features a method of treating a subject with one or more additional therapeutic agents administered before, during, or after treatment with an effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0394] In another aspect, the present invention is a method of inhibiting voltage-dependent sodium channels in a biological sample, comprising contacting the biological sample with an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another aspect, the voltage-dependent sodium channel is Na V 1.8.

[0395] In another aspect, the present invention is a method for treating or reducing the severity of a subject having acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpes neuralgia, general neuralgia, epilepsy, status epilepticus, neurodegenerative disorder, mental disorder, anxiety, depression, bipolar disorder, catatonia, arrhythmia, movement disorder, neuroendocrine disorder, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (e.g., pain after hemorrhoidectomy, pain after hernia suture or pain after abdominoplasty), cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal motility, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0396] In another aspect, the present invention is directed to 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, post-herpetic neuralgia; diabetic neuropathy; HIV-related neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuroma; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiotherapy-induced neuropathic pain; postmastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom limb pain; intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; arthralgia; mechanical low back pain; neck pain; tendinitis; pain of injury; pain of exercise; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, cardiac pain; pelvic pain, renal colic, acute obstetric pain, labor pains; cesarean section pain; acute inflammatory pain, burning pain, traumatic pain; acute intermittent pain, endometriosis; acute herpes pain; sickle cell anemia; acute pancreatitis; protrusion pain; orofacial pain; pain of rhinitis; toothache; pain in multiple sclerosis (MS); pain in depression; leprosy pain; Behçet's disease pain; painful lipodystrophy; phlebitis pain; Guillain-Barré pain; painful legs and moving toes; Haglund's syndrome; pain of erythromelalgia; Fabry disease pain; bladder and urogenital 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 extreme pain, itching, tinnitus, or a method for treating or reducing the severity of angina-induced pain, comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0397] Compounds, pharmaceutically acceptable salts and compositions for use In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use as a medicament.

[0398] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting voltage-dependent sodium channels in a subject. In another aspect, the voltage-dependent sodium channel is Na V is 1.8.

[0399] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a subject having chronic pain, visceral pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., pain from bunionectomy, hernia suture, or abdominoplasty), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia, or reducing the severity thereof.

[0400] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a subject having chronic pain, visceral pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, pain from bunionectomy, hernia suture, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia, or reducing the severity thereof.

[0401] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a subject having visceral pain or reducing the severity thereof, wherein the visceral pain includes inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain.

[0402] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a subject with neuropathic pain or reducing the severity thereof. In some aspects, the neuropathic pain includes post-herpetic neuralgia, small fiber neuropathy or idiopathic small fiber neuropathy. As used herein, the phrase "idiopathic small fiber neuropathy" is understood to include any small fiber neuropathy should be understood to include. In some aspects, the neuropathic pain includes diabetic neuropathy.

[0403] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a subject with neuropathic pain or reducing the severity thereof, wherein the neuropathic pain includes post-herpetic neuralgia, diabetic neuropathy, painful HIV-related 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 treatment-induced neuropathy, cancer chemotherapy-induced neuropathy, antiretroviral therapy-induced neuropathy; pain after spinal cord injury, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia.

[0404] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a subject with musculoskeletal pain or reducing the severity thereof. In some embodiments, the musculoskeletal pain includes osteoarthritis pain.

[0405] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or reducing the severity of skeletal muscle pain, which includes osteoarthritis pain, back pain, cold pain, burn pain or toothache.

[0406] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or reducing the severity of inflammatory pain, which includes rheumatoid arthritis pain or vulvar pain.

[0407] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or reducing the severity of inflammatory pain, which includes rheumatoid arthritis pain.

[0408] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or reducing the severity of idiopathic pain, which includes fibromyalgia pain.

[0409] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or reducing the severity of pathological cough.

[0410] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or reducing the severity of acute pain. In some aspects, acute pain includes acute postoperative pain.

[0411] In yet another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a subject having postoperative pain (e.g., pain after vasectomy, pain after hernia suture, or pain after abdominoplasty) or reducing the severity thereof.

[0412] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a subject having pain after vasectomy or reducing the severity thereof.

[0413] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a subject having pain after hernia suture or reducing the severity thereof.

[0414] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a subject having pain after abdominoplasty or reducing the severity thereof.

[0415] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a subject having visceral pain or reducing the severity thereof. In some aspects, the visceral pain includes visceral pain caused by abdominoplasty.

[0416] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a subject having a neurodegenerative disease or reducing the severity thereof. In some aspects, the neurodegenerative disease includes multiple sclerosis. In some aspects, the neurodegenerative disease includes Pitt-Hopkins syndrome (PTHS).

[0417] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a subject with one or more additional therapeutic agents administered before, during, or after treatment with a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0418] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting voltage-dependent sodium channels in a biological sample, the method comprising contacting the biological sample with a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In another aspect, the voltage-dependent sodium channel is Na V is 1.8.

[0419] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or reducing the severity of a subject having acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpes neuralgia, general neuralgia, epilepsy, status epilepticus, neurodegenerative disorder, mental disorder, anxiety, depression, bipolar disorder, catatonia, arrhythmia, movement disorder, neuroendocrine disorder, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (e.g., pain from hemorrhoidectomy, hernia suture, or abdominoplasty), cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal motility.

[0420] In another aspect, the present invention relates to 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 neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuroma; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiotherapy-induced neuropathic pain; postmastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom limb pain; intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendinitis; pain of injury; pain of exercise; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, angina; pelvic pain, nephroptosis; acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, burning pain, trauma pain; acute intermittent pain, endometriosis; acute herpes pain; sickle cell anemia; acute pancreatitis; protrusion pain; orofacial pain; pain of rhinitis; toothache; pain in multiple sclerosis (MS); pain in depression; leprosy pain; Behçet's disease pain; painful lipomatosis; phlebitis pain; Guillain-Barré pain; painful legs and moving toes; Haglund's syndrome; pain of erythromelalgia; Fabry disease pain; bladder and urogenital 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 extreme pain, itching, tinnitus, or angina-induced pain, and is characterized by the use of a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for treating or reducing the severity of such conditions.

[0421] Manufacture of medicaments In another aspect, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament.

[0422] In another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the manufacture of a medicament for use in inhibiting voltage-dependent sodium channels. In another aspect, the voltage-dependent sodium channel is Na V is 1.8.

[0423] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the manufacture of a medicament for treating or reducing the severity of a subject having chronic pain, visceral pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., pain after vasectomy, pain after hernia suture or pain after abdominoplasty), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia.

[0424] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the manufacture of a medicament for treating or reducing the severity of a subject having chronic pain, visceral pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, pain after vasectomy, pain after hernia suture, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia.

[0425] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the manufacture of a medicament for treating or reducing the severity of a subject having visceral pain, wherein the visceral pain includes inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis pain.

[0426] 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 manufacturing a medicament for treating a subject with neuropathic pain or reducing the severity thereof. In some aspects, the neuropathic pain includes postherpetic neuralgia, small fiber neuropathy or idiopathic small fiber neuropathy. In some aspects, the neuropathic pain includes diabetic neuropathy.

[0427] 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 manufacturing a medicament for treating a subject with neuropathic pain or reducing the severity thereof, wherein the neuropathic pain includes postherpetic neuralgia, diabetic neuralgia, painful HIV-related 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 neuropathy, cancer chemotherapy-induced neuropathy, antiretroviral therapy-induced neuropathy; pain after spinal cord injury, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic neuropathy.

[0428] 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 manufacturing a medicament for treating a subject with musculoskeletal pain or reducing the severity thereof. In some embodiments, the musculoskeletal pain includes osteoarthritis pain.

[0429] 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 manufacturing a medicament for treating a subject with musculoskeletal pain or reducing the severity thereof, wherein the musculoskeletal pain includes osteoarthritis pain, back pain, cold pain, burn pain, or toothache.

[0430] 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 manufacturing a medicament for treating a subject with inflammatory pain or reducing the severity thereof, wherein the inflammatory pain includes rheumatoid arthritis pain or vulvar pain.

[0431] 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 manufacturing a medicament for treating a subject with inflammatory pain or reducing the severity thereof, wherein the inflammatory pain includes rheumatoid arthritis pain.

[0432] 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 manufacturing a medicament for treating a subject with idiopathic pain or reducing the severity thereof, wherein the idiopathic pain includes fibromyalgia pain.

[0433] 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 manufacturing a medicament for treating a subject with pathological cough or reducing the severity thereof.

[0434] 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 manufacturing a medicament for treating a subject with acute pain or reducing the severity thereof. In some aspects, the acute pain includes acute postoperative pain.

[0435] 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 manufacturing a medicament for treating a subject with postoperative pain (e.g., pain after vasectomy, pain after hernia suture, or pain after abdominoplasty) or reducing the severity thereof.

[0436] 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 manufacturing a medicament for treating a subject with pain after vasectomy or reducing the severity thereof.

[0437] 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 manufacturing a medicament for treating a subject with pain after hernia suture or reducing the severity thereof.

[0438] 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 manufacturing a medicament for treating a subject with pain after abdominoplasty or reducing the severity thereof.

[0439] 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 manufacturing a medicament for treating a subject with visceral pain or reducing the severity thereof. In some aspects, the visceral pain includes visceral pain caused by abdominoplasty.

[0440] In another aspect, the present invention features a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for manufacturing a medicament for treating a subject with a neurodegenerative disease or reducing the severity thereof. In some aspects, the neurodegenerative disease includes multiple sclerosis. In some aspects, the neurodegenerative disease includes Pitt-Hopkins syndrome (PTHS).

[0441] In another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in combination with one or more additional therapeutic agents administered before, during, or after treatment with a compound or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0442] In another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating or reducing the severity of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpes neuralgia, systemic neuralgia, epilepsy, status epilepticus, neurodegenerative disorders, mental disorders, anxiety, depression, bipolar disorder, catatonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (e.g., pain after tonsillectomy, pain after hernia suture, or pain after abdominoplasty), cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal motility.

[0443] In another aspect, the present invention relates to 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 neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuroma; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiotherapy-induced neuropathic pain; postmastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom limb pain; intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendinitis; pain of injury; pain of exercise; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, cardiac pain; pelvic pain, renal colic; acute obstetric pain, labor pain; cesarean section pain ; acute inflammation, burning pain, trauma pain; acute intermittent pain, endometriosis; acute herpes pain; sickle cell anemia; acute pancreatitis; protruding pain; oral and facial pain; pain of rhinitis; toothache; pain in multiple sclerosis (MS); pain in depression; leprosy pain; Behcet's disease pain; painful lipomatosis; phlebitis pain; Guillain-Barré pain; painful legs and moving toes; Haglund's syndrome; pain of erythromelalgia; Fabry disease pain; bladder and urogenital 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 extreme pain, itching, tinnitus, or use of a compound of the present invention, its pharmaceutically acceptable salt or its pharmaceutical composition for manufacturing a medicament for treating or reducing the severity of angina-induced pain is provided.

[0444] Administration of pharmaceutically acceptable salts and compositions In certain embodiments of the present invention, an "effective amount" of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention is an amount effective to treat one or more of the above conditions or reduce their severity.

[0445] The compounds, salts, and compositions according to the methods of the present invention can be administered using any amount and any route of administration effective to treat or reduce the severity of one or more pain or non-pain diseases described herein. The exact amount required will vary for each subject depending on the species, age, and general condition of the subject, the severity of the condition, the specific agent, its mode of administration, etc. The compounds, salts, and compositions of the present invention are preferably formulated in unit dosage forms for ease of administration and uniformity of dosage. As used herein, the expression "unit dosage form" refers to physically discrete units suitable for the subject to be treated. However, it is understood that the total daily usage amount of the compounds, salts, and compositions of the present invention is determined by the attending physician within the scope of reasonable medical judgment. The specific effective dosage level for any particular subject or organism depends on a variety of factors including the disorder or severity of the disorder being treated; the activity of the specific compound or salt used; the specific composition used; the age, weight, health status, gender, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound or salt used; the duration of treatment; drugs used in combination with or simultaneously with the specific compound or salt used, as well as similar factors well known in the medical arts. As used herein, the terms "subject" or "patient" mean an animal, preferably a mammal, most preferably a human.

[0446] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intravesically, vaginally, intraperitoneally, topically (by powder, ointment, or droplet), orally or nasally as a spray, or in a similar manner, 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 100 mg / kg of subject body weight per day, or about 0.01 mg / kg to about 50 mg / kg of subject body weight, once or more than once a day, effective to obtain the desired therapeutic effect.

[0447] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound or salt, liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents, and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butylene glycol, dimethylformamide, oils (especially cottonseed oil, groundnut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof. In addition to the inert diluent, oral compositions may also contain adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0448] Injectable preparations, such as sterile aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3 - butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, non - volatile oils have been conventionally used as solvents or suspending media. For this purpose, any non - irritating non - volatile oil containing synthetic mono - or diglycerides can be used. Further, fatty acids such as oleic acid are used in the preparation of injectables.

[0449] Injectable formulations can be sterilized, for example, by filtration through a bacteria - retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0450] In order to prolong the effect of the compounds of the present invention, it is often desirable to delay the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a poorly water - soluble crystalline or amorphous material. In that case, the absorption rate of the compound depends on its dissolution rate, and the dissolution rate may depend on the crystal size and crystal form. Alternatively, a delay in the absorption of the parenterally administered compound form is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are prepared by forming a microcapsule matrix of the compound with a biodegradable polymer such as polylactide - polyglycolide. Depending on the ratio of the compound to the polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0451] The composition for rectal or vaginal administration is a suppository that is solid at room temperature but liquid at body temperature, and thus melts in the rectal or vaginal cavity and releases the active ingredient. It is preferably prepared by mixing a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, with the compound or salt of the present invention.

[0452] 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 bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retardants such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include buffering agents.

[0453] Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules using lactose or milk sugar, as well as high molecular weight polyethylene glycol, and similar excipients. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical field. These may optionally contain opacifying agents and may also be compositions that release the active compound(s) delayed, only in certain parts of the intestinal tract, or preferentially, as required. Examples of embedding compositions that can be used include polymeric substances and waxes. Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules using lactose or milk sugar, as well as high molecular weight polyethylene glycol, and similar excipients.

[0454] The active compound or salt can also be in microencapsulated form containing one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings, release control coatings, and other coatings well known in the pharmaceutical field. 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. According to conventional methods, such dosage forms can also contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form can also contain buffering agents. They may optionally contain opacifying agents and may also be compositions that release the active ingredient(s) delayed, only in certain parts of the intestinal tract, or preferentially, as required. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0455] Dosage forms for topical or transdermal administration of the compounds or salts of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under aseptic conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers as required. Ophthalmic formulations, ear drops, and eye drops are also contemplated to be within the scope of the present invention. Further, the present invention contemplates the use of transdermal patches which offer the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in a suitable medium. Penetration enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled either by providing a rate controlling membrane or by dispersing the compound in a polymeric matrix or gel.

[0456] As generally described above, the compounds of the present invention are useful as inhibitors of voltage-dependent sodium channels. In one embodiment, the compound is an inhibitor of Na V 1.8, and thus, without wishing to be bound by any particular theory, the compounds, salts, and compositions are particularly useful for treating or reducing the severity of a disease, condition, or disorder when activation or hyperexcitation of Na V 1.8 is associated with the disease, condition, or disorder. When activation or hyperexcitation of Na V 1.8 is associated with a particular disease, condition, or disorder, that disease, condition, or disorder may also be referred to as a "Na V 1.8-mediated disease, condition, or disorder". Thus, in another aspect, the present invention provides a method for treating or reducing the severity of a disease, condition, or disorder when activation or hyperexcitation of Na V 1.8 is associated with the medical condition.

[0457] Na VThe activity of the compounds utilized in the present invention as inhibitors of 1.8 can both be assayed according to the methods generally described in International Publication No. WO2014 / 120808A9 and US Publication No. 2014 / 0213616A1, which are incorporated by reference in their entirety, the methods described herein , and other methods known and available to those of skill in the art.

[0458] Additional therapeutic agents The compounds, salts, and pharmaceutically acceptable compositions of the present invention can be used in combination therapies, i.e., it will be understood that the compounds, salts, and pharmaceutically acceptable compositions can be administered simultaneously with, before, or after one or more other desired therapies or medical procedures. The particular combination of therapies (therapies or procedures) used in a given combination regimen will take into account the compatibility of the desired therapies and / or procedures and the desired therapeutic effect to be achieved. The therapies used can achieve the desired effect for the same disorder (e.g., the compounds of the present invention can be administered simultaneously with another agent used to treat the same disorder), or it will also be understood that they can achieve different effects (e.g., control of adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease or condition are known as "appropriate for the disease or condition being treated." For example, exemplary additional therapeutic agents include, but are not limited to, non-opioid analgesics (indoles 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, 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). Further, non-drug analgesic approaches can be utilized in conjunction with the administration of one or more of the compounds of the present invention.For example, an anesthesiological (intraspinal injection, nerve block), neurosurgical (nerve dissection of CNS pathways), neuromodulatory (transcutaneous electrical nerve stimulation, dorsal column spinal cord stimulation), physical therapy (physical therapy, orthotic devices, diathermy), or psychological (cognitive - hypnosis, biofeedback, or behavioral methods) approach may be utilized. Additional suitable therapeutic agents or approaches are outlined in The Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and on the website of the Food and Drug Administration, www.fda.gov, and the entire contents of these are hereby incorporated by reference into this specification.

[0459] In another embodiment, additional suitable therapeutic agents are selected from the following:

[0460] (1) Opioid analgesics, such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, pentazocine, or difelikefalin;

[0461] (2) Non - steroidal anti - inflammatory drugs (NSAIDs), such as aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen (including, but not limited to, intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketorolac (including ketorolac tromethamine (e.g., Toradol®)) (but not limited to), meclofenamic acid, mefenamic acid, meloxicam, IV meloxicam (e.g., Anjeso (registered trademark)), nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

[0462] (3) Barbiturate sedatives, such as amobarbital, aprobarbital, butabarbital, butarbital, mephobarbital, metalbarbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiopental or thiamylal;

[0463] (4) Benzodiazepines with sedative effects, such as chlordiazepoxide, chlorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;

[0464] (5) Histamine (H1) antagonists with sedative effects, such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;

[0465] (6) Sedatives, such as glutethimide, meprobamate, methocarbamol or dichloralphenazone;

[0466] (7) Skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine;

[0467] (8) NMDA receptor antagonists, such as dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrophan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinone, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), a combination preparation of morphine and dextromethorphan, topiramate, neramexane or perzinfotel; examples of 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;

[0468] (9) α-adrenergic agents, such as doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinolin-2-yl)-5-(2-pyridyl)quinazoline;

[0469] (10) Tricyclic antidepressants, such as desipramine, imipramine, amitriptyline or nortriptyline;

[0470] (11) Anticonvulsants, such as carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®) or valproate;

[0471] (12) Tachykinin (NK) antagonists, particularly NK-3 antagonists, NK-2 antagonists 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]diazocino[2,1-g][1 ,7]-Naphthyridin-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);

[0472] (13) Muscarinic antagonists, for example, oxybutynin, tolterodine, propiverine, tropium chloride, darifenacin, solifenacin, temiverine and ipratropium;

[0473] (14) COX-2 selective inhibitors, for example, celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

[0474] (15) Coal tar analgesics, especially, paracetamol;

[0475] (16) Neuroleptics, for example, droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonapiprazole, bromocriptine, iloperidone, perospirone, laclopropride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eprivanterol, osanetant, rimonabant, meclinertant, Miraxion (registered trademark) or sarizotan;

[0476] (17) Vanilloid receptor agonists (e.g., resiniferatoxin or civamide) or antagonists (e.g., capsazepine, GRC-15300);

[0477] (18) Beta-adrenergic agents, e.g., propranolol;

[0478] (19) Local anesthetics, e.g., mexiletine;

[0479] (20) Corticosteroids, e.g., dexamethasone;

[0480] (21) 5-HT receptor agonists or antagonists, particularly, 5-HT 1B / 1D agonists, e.g., eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

[0481] (22) 5-HT 2A receptor antagonists, e.g., R(+)-α-(2,3-dimethoxy-phenyl)-l-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);

[0482] (23) Cholinergic (nicotinic-like) analgesics, such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-l-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;

[0483] (24) Tramadol (registered trademark), Tramadol ER (Ultram E R (registered trademark)), IV Tramadol, tapentadol ER (Nucynta (registered trademark));

[0484] (25)PDE5 inhibitors, for example, 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2’,1’:6,1]-pyrido[3,4-b]indole-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-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]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;

[0485] (26) Alpha-2-delta ligands, such as gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methylgabapentin, (l[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, [(lR,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(l-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(l-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;

[0486] (27) Cannabinoids, such as KHK-6188;

[0487] (28) Metabotropic glutamate subtype 1 receptor (mGluR1) antagonists;

[0488] (29) Serotonin reuptake inhibitors, such as sertraline, demethylsertraline which is a metabolite of sertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, desmethylcitalopram which is a metabolite of citalopram, escitalopram, d,l-fenfluramine, femoxetine, iproxetine, cyanodothiepin, litoxetine, dapoxetine, ne fazodone, sericlamine and trazodone;

[0489] (30) Norepinephrine (noradrenaline) reuptake inhibitors, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, phenozolamine, tomoxetine, mianserin, bupropion, hydroxybupropion which is a metabolite of bupropion, nomifensine and viloxazine (Vivalan (registered trademark)), particularly, selective norepinephrine reuptake inhibitors, such as reboxetine, particularly, (S,S)-reboxetine;

[0490] (31) Dual serotonin-norepinephrine reuptake inhibitors, for example, venlafaxine, O-desmethylvenlafaxine which is a metabolite of venlafaxine, clomipramine, desmethylclomipramine which is a metabolite of clomipramine, duloxetine (Cymbalta (registered trademark)), milnacipran and imipramine;

[0491] (32) Inducible nitric oxide synthase (iNOS) inhibitors, such as S-[2-[(l-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(l-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(l-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(l-iminoethyl)amino]-5-heptenoic acid, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile; 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(lR,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamide, NXN-462 or guanidinoethyldisulfide;

[0492] (33) Acetylcholinesterase inhibitors, for example, donepezil;

[0493] (34) Prostaglandin E2 subtype 4 (EP4) antagonists, such as N-[({2-[4-(2-ethyl-4,6-dimethyl-lH-imidazo[4,5-c]pyridin-l-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[(15)-l-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;

[0494] (35) Leukotriene B4 antagonist; for example, l-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870;

[0495] (36) 5-Lipoxygenase inhibitor, for example, zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxymethyl]-l-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-l,4-benzoquinone (CV-6504);

[0496] (37) Sodium channel blocker, for example, lidocaine, lidocaine + tetracaine cream agent (ZRS-201) or eslicarbazepine acetate;

[0497] (38) Na V (39) Na1.7 blocker, for example, XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893, BIIB-074 (Vixotrigine), BIIB-095, ASP-1807, DSP-3905, OLP-1002, RQ-00432979, FX-301, DWP-17061, IMB-110, IMB-111, IMB-112 and, for example, the entire content of each application is incorporated herein by reference in WO2011 / 140425 (US2011 / 306607); WO2012 / 106499 (US2012196869); WO2012 / 112743 (US2012245136); WO2012 / 125613 (US2012264749), WO2012 / 116440 (US2014187533), WO2011026240 (US2012220605), US8883840, US8466188, or WO2013 / 109521 (US2015005304).

[0498] (38a)Na V1.7 Blocking agents, for example, (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-benzhydrylpiperazin-1-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy]propan-2-ol, (4-butoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]-(5-isopropoxy-6-methyl-2-pyridyl)methanone, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone, 5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-carbonyl]phenyl]pyridine-2-carbonitrile, (4-isopropoxy-3-methyl-phenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]ethanone, 2,2,2-Trifluoro-1-[1'-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-3,3-dimethyl-spiro[2,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, (4-isopropoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1'-yl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyra, [[(3S)-2,3-dimethyl-1'-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]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-1,4'-piperidin]-1'-yl]-[3-methoxy-4-[(1R)-1-methylpropoxy]phenyl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]ethanone, 1-[1'-[4-methoxy-3-(trifluoromethyl)benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]-2,2-dimethyl-propan-1-one, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone, [2-methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]-[4-(3,3,3-trifluoropropoxymethyl)phenyl]methanone, 4-bromo-N-(4-bromophenyl)-3-[(1-methyl-2-oxo-4-piperidyl)sulfamoyl]benzamide or (3-chloro-4-isopropoxy-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone.

[0499] (39)Na V1.8 Blocking agents, such as PF-04531083, PF-06372865, and the entire contents of each application are incorporated herein by reference: WO2008 / 135826 (US2009048306), WO2006 / 011050 (US2008312235), WO2013 / 061205 (US2014296313), US20130303535, WO2013131018, US8466188, WO2013114250 (US2013274243), WO2014 / 120808 (US2014213616), WO2014 / 120815 (US2014228371), WO2014 / 120820 (US2014221435), WO2015 / 010065 (US20160152561), WO2015 / 089361 (US20150166589), WO2019014352 (US20190016671), WO2018 / 213426, WO2020 / 146682, WO2020 / 146612, WO2020 / 014243, WO2020 / 014246, WO2020 / 092187, and WO2020 / 092667 (US2020140411).

[0500] (39a)Na V1.8 Blocking agents, for example, 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)-5-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide, 5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, N-(2-oxo -1,2-Dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-((5-fluoro-2-hydroxybenzyl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide, 2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide, [4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate, 2-(4-fluoro-2-(methyl-d3)phenoxy)-N-(2-oxo-1,(2-Dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, (4-(2-(4-Fluoro-2-(methyl-d3)phenoxy)-4-(trifluoromethyl)benzamide)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate, 3-(4-Fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide, 3-(2-Chloro-4-fluorophenoxy)-N-(3-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)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide, 3-(2,4-Difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-Sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoline-3-carboxamide, N-(3-Sulfamoylphenyl)-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide, 3-(4-Chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 5-(3-(4-(Trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinic acid, 3-(4-Fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-Dihydro-1H-benzo[d]imidazol-5-yl)quinoxaline-2-carboxamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4-yl)quinoxaline-2-carboxamide, 3-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, N-(4-carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenyl, Noxy)quinoxaline-2-carboxamide)benzoic acid, N-(4-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamide)picolinate, 5-(2-(2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamide)picolinate, 4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamide)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4,6-bis(trifluoromethyl)benzamide)picolinate, 4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamide)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamide)picolinate, 4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide)benzoic acid, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamide)picolinate, 4-(2-(2-chloro-4-fluorophenoxy)-4-(perfluoroethyl)benzamide)benzoic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(perfluoroethyl)benzamide)benzoic acid, 4-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamide)benzoic acid, 4-(4,5-dichloro-2-(4-chloro-2-methylphenoxy)benzamide)benzoic acid, 5-(4-(tert-butyl)-2-(4-fluoro-2-methoxyphenoxy)benzamide)picolinate, 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamide)picolinate, 4-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamide)benzoic acid, 5-(4,5-dichloro-2-(2,4-dimethoxyphenoxy)benzamide)picolinate, 5-(4,5-dichloro-2-(2-chloro-4-fluorophenoxy)benzamide)picolinate, 5-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamide)picolinate, 4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamide)benzoic acid, 5-(4,5-dichloro-2-(2,4-difluorophenoxy)benzamide picolinic acid, 2-(4-fluorophenoxy)-N-(3-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-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trif, (Ruo Luomethoxy)benzamide, 2-(4-Fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 4,5-Dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-Fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 5-Fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(2-Chloro-4-fluorophenoxy)-4-cyano-N-(3-sulfamoylphenyl)benzamide, N-(3-Sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, N-(3-Carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuterio-methoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-Carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-Carbamoyl-4-fluoro-p Rulo-phenyl)-2-fluoro-6-[2-(trideuterio methoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzamide, 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, 4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, 4-[[2-fluoro-6-[2-(trideuterio methoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, 4-[[2-fluoro-6-[2-(trideuterio methoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2,3,4-Trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, N-(2-carbamoyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide, 4-[[6-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(4-carbamoyl-3-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-pentafluoroethyl)benzamide, 4-[[4-(difluoromethoxy)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[4-cyclopropyl-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide, 5-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzamide, or 4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide;

[0501] (40)Combined Na V 1.7 and Na V 1.8 blockers, such as DSP-2230, Lohocla201 or BL-1021;

[0502] (41)5-HT3 antagonist, such as ondansetron;

[0503] (42)TRPV 1 receptor agonist (e.g., capsaicin (NeurogesX®, Qutenza®)); and pharmaceutically acceptable salts and solvates thereof;

[0504] (43) Nicotine receptor antagonists, such as varenicline;

[0505] (44) N-type calcium channel antagonists, such as Z-160;

[0506] (45) Nerve growth factor antagonists, such as tanezumab;

[0507] (46) Endopeptidase stimulants, such as cenreotide;

[0508] (47) Angiotensin II antagonists, such as EMA-401;

[0509] (48) Acetaminophen (including, but not limited to, intravenous acetaminophen (e.g., Ofirmev (registered trademark)));

[0510] (49) Bupivacaine (including, but not limited to, bupivacaine liposomal injection suspension (e.g., Exparel (registered trademark)), bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll), and transdermal bupivacaine (Eladur (registered trademark))); and

[0511] (50) A combination of bupivacaine and meloxicam (e.g., HTX-011).

[0512] In one embodiment, additional suitable therapeutic agents are selected from: V-116517, pregabalin, controlled release pregabalin, ezogabine (Potiga (registered trademark)). Ketamine / amitriptyline topical cream (Amiket (registered trademark)), AVP-923,

[0513] perampanel (E-2007), ralfinamide, transdermal bupivacaine (Eladur (registered trademark)), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561 or ARC-4558.In another embodiment, the additional suitable therapeutic agent is selected from the following: 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.

[0514] In another embodiment, the additional therapeutic agent is selected from a GlyT2 / 5HT2 inhibitor, such as operanserin (VVZ149), a TRPV regulator, such as CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101, MDR16523, or MDR652, an EGR1 inhibitor such as Brivoglide (AYX1), an NGF inhibitor, such as tanezumab, fasinumab, ASP6294, MEDI7352, a Mu opioid agonist, such as sebranopadol, NKTR181 (oxycodegol), a CB-1 agonist, such as NEO1940 (AZN1940), an imidazoline 12 agonist such as CR4056, or a p75NTR-Fc regulator such as LEVI-04.

[0515] In another embodiment, the additional therapeutic agent is oriselidine or ropivacaine (TLC590).

[0516] In another embodiment, the additional therapeutic agent is a Na V 1.7 blocker, such as ST-2427, and all the contents of each application are those disclosed in WO2010129864, WO2015157559, WO2017059385, WO2018183781, WO2018183782, and WO2020072835 which are incorporated herein by reference.

[0517] 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™), brivolidide, SR419, NRD.E1, LX9211, LY3016859, ISC-17536, NFX-88, LAT-8881, AP-235, NYX2925, CNTX-6016, S-600918, S-637880, RQ-00434739, KLS-2031, MEDI 7352, or XT-150.

[0518] In another embodiment, the additional therapeutic agent is a sodium channel inhibitor (also known as a sodium channel blocker) such as the Na V 1.7 and Na V 1.8 blockers.

[0519] The amount of additional therapeutic agent present in the compositions of the invention will not normally be more than the amount that would be administered in a composition containing that therapeutic agent as the sole active agent. The amount of additional therapeutic agent in the compositions of the present disclosure can be in the range of about 10% to 100% of the amount normally present in a composition containing that therapeutic agent as the sole therapeutic active agent.

[0520] The compounds and salts of the invention or their pharmaceutically acceptable compositions may also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, artificial blood vessels, stents and catheters. Thus, in another aspect, the present invention is directed to the compositions described herein for coating implantable medical devices. A composition for coating an implantable device comprising a compound or salt of the invention generally described above in the classes and subclasses, and a carrier suitable for coating the implantable device. In yet another aspect, the invention provides an implantable device coated with a composition comprising a compound or salt of the invention generally described above in the classes and subclasses herein, and a carrier suitable for coating the implantable device. General preparation of suitable coatings and coated implantable devices is described in U.S. Patent Nos. 6,099,562; 5,886,026; and 5,304,121. Coatings are typically biocompatible polymeric materials such as hydrogel polymers, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coating can optionally be further covered with a suitable topcoat of fluorosilicone, polysaccharide, polyethylene glycol, phospholipid, or combinations thereof to impart controlled release properties to the composition.

[0521] Another aspect of the invention relates to inhibition of Nav1.8 activity in a biological sample or subject, the method comprising administering to the subject a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, or contacting the biological sample with a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy materials or extracts thereof obtained from mammals; and blood, saliva, urine, feces, sperm, tears, or other body fluids or extracts thereof.

[0522] Inhibition of Na V 1.8 activity in a biological sample is useful for a variety of purposes known to those of skill in the art. Examples of such purposes include sodium ion channel research in biological and pathological phenomena, as well as comparative evaluation of novel sodium ion channel inhibitors, but are not limited thereto.

[0523] Synthesis of Compounds of the Invention The compounds of the present invention can be prepared from known materials by the methods described in the Examples, other analogous methods, and other methods known to those skilled in the art. As will be appreciated by those skilled in the art, functional groups of intermediate compounds may need to be protected by suitable protecting groups. Protecting groups can be added or removed according to standard techniques well known to those skilled in the art. For information on the use of protecting groups, see TGM Wuts et al., Greene's Protective Groups in Organic Synthesis (4th ed.). 2006) is explained in detail.

[0524] Radiolabeled Analogs of the Compounds of the Invention In another aspect, the present invention relates to radiolabeled analogs of the compounds of the present invention. As used herein, the term "radiolabeled analogs of the compounds of the present invention" refers to one or more "Radioactive isotopes" refers to compounds that are identical to the compounds of the invention described herein (including all embodiments thereof) except that more atoms are replaced with radioactive isotopes of atoms present in the compounds of the invention.

[0525] 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, etc., and isotopes whose decay modes are identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0526] Radioactive label analogs can be used in a plurality of useful ways, including various types of assays such as substrate tissue distribution assays. For example, tritium ( 3 H) labeled compounds and / or carbon-14 ( 14 C) labeled compounds are useful for various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detectability.

[0527] In another aspect, the invention relates to a pharmaceutically acceptable salt of a radioactive label analog according to any of the embodiments described herein in relation to the compounds of the invention.

[0528] In another aspect, the invention relates to a pharmaceutical composition comprising a radioactive label analog or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle, according to any of the embodiments described herein in relation to the compounds of the invention.

[0529] In another aspect, the invention relates to a method of inhibiting a voltage-dependent sodium channel and a method of treating or reducing the severity of various diseases and disorders including pain in a subject, according to any of the embodiments described herein in relation to the compounds of the invention, comprising administering an effective amount of a radioactive label analog, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof.

[0530] In another aspect, the invention relates to a radioactive label analog, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof for use, according to any of the embodiments described herein in relation to the compounds of the invention.

[0531] In another aspect, the invention relates to the use of a radioactive label analog, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof for the manufacture of a medicament, according to any of the embodiments described herein in relation to the compounds of the invention.

[0532] In another aspect, the radiolabeled analogs, their pharmaceutically acceptable salts, and their pharmaceutical compositions can be used in combination therapy in accordance with any of the embodiments described herein in relation to the compounds of the present invention.

Examples

[0533] General method. 1 The 1H NMR (400 MHz) spectrum was obtained as a solution in a suitable deuterated solvent such as dimethyl sulfoxide-d6 (DMSO-d6).

[0534] Analytical supercritical fluid chromatography (SFC) separation of various isomer mixtures was achieved using a Waters UPC2-SFC instrument composed of a convergence manager, a sample manager, a binary solvent manager, a column manager-30S, a PDA detector, an isocratic solvent manager, and a QDa detector. The columns used include those manufactured by Regis Technologies (for example, R’R Whelk 0-1, 3.5 μm particle size, 5.0 cm × 3.0 mm size), solvent A: liquid CO2 (58-60 bar / 40 °C), solvent B: 20 mM The mobile phase of HPLC grade methanol containing NH3 was accompanied at a flow rate of 2 ml / min and an injection volume of 2 μl. Gradient: 0 min (95:5) A:B, 3.5 min (50:50) A:B, 3.55 min (40:60) A:B, 3.95 min (40:60) A:B, and 4.0 min (95:5) A:B. The sample for analytical SFC was dissolved in methanol at a concentration of about 0.5 mg / ml.

[0535] Preparative SFC used the same stationary and mobile phases as described above for analytical SFC, but the sample was purified using different equipment and gradient methods as follows. Preparative SFC separation of various isomer mixtures was performed using a back pressure regulator, a 2767 sample manager, 25 Achieved using a Waters Prep-100 SFC instrument composed of a 45 Quaternary Gradient Module, Column Oven, 2998 PDA Detector, Isocratic Solvent Manager, P-200 CO2 Pump, SFC Flow Splitter-100, three Heat Exchangers, Series III LC Pump, and QDa Detector. The columns used included those manufactured by Regis Technologies (e.g., R’R Whelk 0-1, particle size 5.0 μm, size 25.0 cm × 21.1 mm), with mobile phase of Solvent A: liquid CO2 (58 - 60 bar / 40 °C) and Solvent B: HPLC grade methanol containing 20 mM NH3. A flow rate of 100 ml / min and injection volume of 500 μl (crude loading 50 mg) were used. For solubilization of the crude compound and SFC injection, a 2:1 ratio of methanol to dichloroethane was used. For 500 μl / 50 mg loading injections, the following method was used: Isocratic: 0 min - 7.6 min (80:20) A:B, Gradient: 8.1 min (75:25) A:B, Isocratic 8.2 - 10.6 min (75:25) (A:B), Gradient: 10.7 min (80:20) A:B, and Isocratic: 11 min (80:20) (A:B). For 1500 μl / 150 mg loading injections, the following method was used: Isocratic: 0 min - 7.5 min (80:20) A:B, Gradient: 7.6 min (75:25) A:B, Gradient: 8.1 min (60:40) A:B, Isocratic: 8.7 min - 10.6 min (60:40) A:B, Gradient: 10.7 min (80:20) A:B and Isocratic: 12 min (80:20) A:B.

[0536] LC / MS method: LC / MS analysis was performed using a Waters Acquity UPLC BEH C8 column (50 × 2.1 mm, 1.7 μm particles) (pn: 186002877) with a guard column (2.1 × 5 mm, 1.7 μm particles) (pn: 186003978) attached. A dual gradient was run with mobile phase B from 2 - 98% over 4.45 minutes. Mobile phase A = H2O (10 mM ammonium formate containing 0.05% ammonium hydroxide). Mobile phase B = acetonitrile. Flow rate = 0.6 mL / min, injection volume = 2 μL, and column temperature = 45 °C.

[0537] X-ray powder diffraction (XRPD) analysis was performed at room temperature in transmission mode using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel 1D Medipix-3 detector (Malvern PANalytical Inc, Westborough, Massachusetts). The X-ray generator was operated at a voltage of 45 kV and a current of 40 mA, using a copper wire (1.54060 Å). The powder sample was placed in a 96-well sample holder with a Mylar film and loaded into the instrument. The sample was scanned in the range of about 3° to about 40° 2θ with a step size of 0.0131303° and 49 seconds per step.

[0538] Solid-state NMR analysis was carried out on a Bruker-Biospin 400 MHz wide-bore spectrometer equipped with a Bruker-Biospin 4 mm HFX probe. The sample was packed into a 4 mm ZrO2 rotor and rotated at a rotation speed usually set at 12.5 kHz under magic angle spinning (MAS) conditions. The proton relaxation time was 1 measured using the H MAS T1 saturation recovery relaxation experiment, 13 and the appropriate recycle delay for the 13C cross-polarization (CP) MAS experiment was set. The fluorine relaxation time was 19 measured using the 19F MAS T1 saturation recovery relaxation experiment, 19 and the appropriate recycle delay for the 19F MAS experiment was set. The CP contact time for the carbon CPMAS experiment was set to 2 ms. A linear gradient (50% - 100%) CP proton pulse was used. The carbon Hartmann-Hahn match was optimized with an external reference sample (glycine). Both the carbon spectrum and the fluorine spectrum were recorded by proton decoupling using a TPPM15 decoupling sequence with an electric field strength of approximately 100 kHz.

[0539] Thermogravimetric analysis (TGA) data was obtained using a TA Discovery thermogravimetric analyzer or equivalent Collected with the equipment. Samples weighing approximately 1 - 5 mg were scanned from 25°C to 350°C at a heating rate of 10°C / min. Data were collected by Thermal Advantage Q Series (trademark) software and analyzed by Trios and / or Universal Analysis software (TA Instruments, New Castle, DE).

[0540] Differential scanning calorimetry (DSC) data were obtained using a TA Instruments Q2000 or equivalent instrument. Samples weighing 1 - 10 mg were weighed into aluminum pans. The pans were placed in the sample position of the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a nitrogen flow was passed through the cell. The heating program was set to heat the sample to a temperature of 300°C at a heating rate of 10°C / min. When the execution was completed, the data were analyzed by Trios and / or Universal Analysis software (TA Instruments, New Castle, DE).

[0541] Infrared (IR) spectra were collected using a Thermo Scientific Nicolet iS50 spectrometer equipped with a diamond ATR sampling accessory.

[0542] X-ray diffraction data were obtained with a Bruker diffractometer equipped with Cu K α radiation (λ = 1.5478 Å) and a CCD detector. The structure was analyzed and refined using the SHELX program (Sheldrick, G.M., Acta Cryst., (2008) A64, 112 - 122)).

[0543] Abbreviations Unless otherwise specified or indicated otherwise by the context, the following abbreviations are understood to have the following meanings. Abbreviation Meaning NMR Nuclear magnetic resonance ESI-MS Electrospray mass spectrometry LC / MS Liquid Chromatography-Mass Spectrometry UPLC Ultra Performance Liquid Chromatography HPLC / MS / MS High Performance Liquid Chromatography / Tandem Mass Spectrometry IS Internal Standard HPLC High Performance Liquid Chromatography SFC Supercritical Fluid Chromatography MDAP Mass Directed Automated Purification ESI Electrospray Ionization LED Light Emitting Diode g Gram mg Milligram L Liter(s) mL Milliliter μL Microliter nL Nanoliter mmol Millimole hr, h Hour min Minute ms Millisecond mm Millimeter μm Micrometer nm Nanometer MHz Megahertz Hz Hertz N Normality M Mole (concentration) mM mmol (concentration) μm Micromole (concentration) ppm Parts per million % w / v Weight - volume concentration ArBPin 2-[2-(Difluoromethoxy)-4-fluoro-phenyl -4,4,5,5-tetramethyl-1,3,2-dioxabor olane t-BuOH tert-Butyl alcohol DAST Diethylaminosulfur trifluoride DCM Dichloromethane DCE Dichloroethane DIEA, DIPEA N,N-Diisopropylethylamine DMA N,N-Dimethylacetamide DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DRG Dorsal root ganglion EtOH Ethanol EtOAc Ethyl acetate HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3 -Triazolo[4,5-b]pyridinium 3-oxide hexa fluorophosphate EDCI 1-Ethyl-3-(3-dimethylpropyl)carbodiimide T3P Propylphosphonic anhydride, i.e., 2,4,6-tripro pyl-1,3,5,2,4,6-trioxatriphosphinan 2,4,6-trioxide TCFH N,N,N’,N’-Tetramethylchloroformamidinium hexafluorophosphate MeOH Methanol MTBE Methyl tert-butyl ether NMP N-Methylpyrrolidone THF Tetrahydrofuran TEA Triethylamine RB Round bottom (flask) RT Room temperature ca. Approximately E-VIPR Electrical stimulation voltage ion probe reader HEK Human embryonic kidney KIR2.1 Inwardly rectifying potassium ion channel 2.1 DMEM Dulbecco's modified Eagle medium FBS Fetal bovine serum NEAA Non-essential amino acids HEPES 2-[4-(2-Hydroxyethyl)piperazin-1-yl] ethanesulfonic acid DiSBAC6(3) Bis-(1,3-dihexyl-thiobarbituric acid) Trimethine oxonol CC2-DMPE chlorocoumarin-2-dimyristoyl phosphatidyl Ethanolamine VABSC-1 Potential assay background suppression compound HS Human serum BSA Bovine serum albumin

[0544] Example 1 rel-(2S,3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (1) and rel-(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (2)

Chemical formula

[0545] A mixture of ethyl rac-(2S,3R)-2,3-dimethyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (3.0 g, 7.77 mmol), 2-[2-(difluoromethoxy)-4-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (“ArBPin”, 2.33 g, 8.09 mmol), Pd(PPh3)4 (380 mg, 0.33 mmol), and sodium carbonate (2 M 16 mL, 32.00 mmol) in dioxane (60 mL) was heated at 100 °C for 1 h. The solution was diluted with EtOAc and water, the layers were separated, the organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography (220 g of SiO2, 0 - 30% EtOAc in petroleum ether) gave ethyl rac-(2S,3R)-4-[2-(difluoromethoxy)-4-fluorophenyl]-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (2.0 g, 65%). 1 H NMR (500 MHz, chloroform-d) δ 7.19 (dd, J = 8.5, 6.4 Hz, 1H), 6.99 - 6.89 (m, 2H), 6.44 (t, J = 73.3 Hz, 1H), 4.14 (qd, J = 7.1, 1.7 Hz, 2H), 3.45 (q, J = 7.4 Hz, 1H), 1.72 - 1.65 (m, 3H), 1.14 (t, J = 7 .1 Hz, 3H), 1.12 - 1.08 (m, 3H) ppm. ESI-MS m / z calcd for 398.09528, found 399.0 (M+1) + .

[0546] Step 2:

[0547] Magnesium shavings (3.5 g, 144.0 mmol) were pulverized in a mortar and added to a solution of ethyl rac-(2S,3R)-4-[2-(difluoromethoxy)-4-fluoro-phenyl]-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (2.0 g, 5.02 mmol) in MeOH (60 mL). The flask was purged with nitrogen and the reaction was stirred at ambient temperature until the observed exotherm had ceased (30 minutes). The reaction was then heated at 90 °C for 3 hours, cooled to 0 °C and quenched and acidified by careful addition of 2 M HCl. The mixture was concentrated under reduced pressure and extracted with DCM (3 x 100 mL). The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to give methyl rac-(3R,4R,5S)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.7 g, 88%) as a mixture of epimers at the position adjacent to the ester (stereochemical assignment is tentative). ESI-MS m / z calcd for 386.09528, found 387.0 (M+1) + 。

[0548] Step 3:

[0549] To a solution of methyl rac-(3R,4R,5S)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (3.2 g, 8.28 mmol) in t-BuOH (80 mL) was added KOt-Bu (4.25 g, 37.87 mmol). The reaction was stirred at ambient temperature overnight, then quenched by addition of saturated aqueous NH4Cl and diluted with EtOAc. The aqueous layer was separated, extracted with EtOAc, the combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was dissolved in EtOH (20 mL) and LiOH (2 M 15 mL, 30.00 mmol) and the mixture was stirred at 110 °C for 1 h. The reaction was quenched by addition of saturated aqueous NH4Cl and diluted with EtOAc. The aqueous layer was separated, extracted with EtOAc, the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (80 g of SiO2, 0 - 100% EtOAc in heptane) gave rac-(3R,4R,5S)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (2.2 g, 71%) as a mixture of epimers at the position adjacent to the ester (stereochemical assignment tentative). ESI-MS m / z calcd for 372.07962, found 371.2 (M-1) - .

[0550] Step 4:

[0551] A solution of rac-(3R,4R,5S)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (650 mg, 1.75 mmol) in DCM (24 mL) stirred at 0 °C was treated with DMF (50 μL, 0.65 mmol) and oxalyl chloride (400 μL, 4.59 mmol). The reaction was warmed to ambient temperature over 30 min and then concentrated under reduced pressure. The residue was dried in a high vacuum apparatus for a further 5 min to afford a white foam, which was dissolved in DCM (24 mL) and added dropwise to a solution of methyl 4-aminopyridine-2-carboxylate (305 mg, 2.01 mmol) and NEt3 (800 μL, 5.74 mmol) in DCM (9 mL) stirred at 0 °C. The reaction was warmed to ambient temperature over 4 h, then quenched by addition of MeOH (2 mL) and concentrated under reduced pressure. Purification by flash chromatography (1 2 g of SiO2, eluting with 0 - 70% EtOAc in heptane, DCM) gave methyl rac-(3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (840 mg, 95%) as an 85:15 mixture of epimers at the position adjacent to the amide (stereochemical assignment provisional). ESI-MS m / z calcd for 506.12766, found 507.9 (M + 1) + .

[0552] Step 5:

[0553] A solution of methyl rac-(3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluorophenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (740 mg, 1.46 mmol) in methanol ammonia (7M 15 mL, 105.0 mmol) was stirred at 100 °C for 16 h in a sealed vessel. The solution was concentrated under reduced pressure to give rac-(3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluorophenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (700 mg, 98%) as a mixture of epimers at the position adjacent to the amide (stereochemical assignment is provisional). ESI-MS m / z calcd for 491.12796, found 491.7 (M+1) + 。

[0554] Step 6:

[0555] Purification of rac-(3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluorophenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (400 mg, 0.81 mmol) by chiral SFC using a Daicel Chiralpak IC column, 5um particle size, 25 cm × 20 mm gave the following:

[0556] First eluted isomer (rt = 3.40 min): rel-(2S,3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluorophenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (1, 150 mg, 74%) (stereochemical assignment is provisional). 1 H NMR (500 MHz, methanol-d4) δ 8.48 (d, J = 5.5 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.90 (dd, J = 5.5, 2.2 Hz, 1H), 7.49 (dd, J = 9.0, 6.3 Hz, 1H), 7.01 (dd, J = 9.0, 6.7 Hz, 2H), 7.14 - 6.74 (m, 1H), 5.14 (d, J = 10.3 Hz, 1H), 4.33 (dd, J = 10.3, 7.9 Hz, 1H), 2.83 (p, J = 7.6 Hz, 1H), 1.66 (s, 3H), 0.83 (dd, J = 7.7, 2.3 Hz, 3H) ppm. ESI-MS m / z calculated value 491.12796, measured value 492.2 (M+1) + ;490.3 (M-1) - .

[0557] The second elution isomer (rt = 4.28 min): The second elution isomer was further purified by reverse-phase preparative HPLC (basic eluent) to obtain rel-(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-4-fluorophenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (2, 100 mg, 50%) (the stereochemical assignment is provisional). 1 H NMR (500 MHz, methanol-d4) δ 8.49 (d, J = 5.5 Hz, 1H), 8.27 - 8.23 (m, 1H), 7.90 (dd, J = 5.5, 2.2 Hz, 1H), 7.49 (dd, J = 9.1, 6.4 Hz, 1H), 7.06 - 6.99 (m, 2H), 7.16 - 6.69 (m, 1H), 5.14 (d, J = 10.3 Hz, 1H), 4.33 (dd, J = 10.3, 7.9 Hz, 1H), 2.83 (p, J = 7.6 Hz, 1H), 1.66 (d, J = 1.3 Hz, 3H), 0.83 (dd, J = 7.6, 2.3 Hz, 3H) ppm. Calculated value of ESI-MS m / z is 491.12796, measured value is 492.1 (M+1)+.

[0558] The following compounds were prepared using the same method as described in Example 1, but the SFC separation step 6 was not performed at the end of the synthesis, and the compounds were isolated as racemates.

Table 4

[0559] The following compounds were prepared using the same method as described in Example 1, but methylamine was used at 40 °C in step 5. The conditions used in the epimerization / hydrolysis step 3 followed the conditions described in step 5 of Example 11. The purification in step 6 was carried out by chiral SFC using a Chiralpak AS-H column manufactured by Daicel, 5 μm particle size, 25 cm × 10 mm, on a Minigram SFC instrument manufactured by Berger Instruments.

Table 5

[0560] The following compounds were prepared using the same method as described in Example 1, except that 5-amino-2-fluorobenzamide was used as the coupling partner in step 4 and step 5 was omitted. The conditions used in the epimerization / hydrolysis step 3 followed the conditions described in step 5 of Example 11. The purification in step 6 was carried out by chiral SFC using a Chiralpak AS-H column manufactured by Daicel, 5 um particle size, 25 cm × 10 mm, on a Minigram SFC instrument manufactured by Berger Instruments.

Table 6

[0561] The following compounds were prepared using a method similar to that described in Example 1, but using catalytic 1,2-dibromoethane to activate magnesium in Step 2 and prepared without separation of the racemate by chiral SFC in Step 6.

Table 7-1

Table 7-2

[0562] The following compounds were prepared using a method similar to that described in Example 1, but using catalytic 1,2-dibromoethane to activate magnesium in Step 2 and not adding LiOH / EtOH in Step 3. Purification in Step 6 was carried out by SFC using a DEAP column, 5 μm particle size, 25 cm × 21.2 mm, manufactured by Princeton Chromatography Inc. on a Waters Corp. SFC 100 instrument, followed by chiral SFC using a Chiralpak AS-H column, 5 μm particle size, 25 cm × 10 mm, manufactured by Daicel on a Minigram SFC instrument manufactured by Berger Instruments. Compound 3a was further purified by chiral SFC using a Chiralpak OD-H column, 5 μm particle size, 25 cm × 10 mm, manufactured by Daicel on a Minigram SFC instrument manufactured by Berger Instruments. Compounds 38 and 39 were separated by chiral SFC using an (R,R)-Whelk-O1 column, 5 μm particle size, 25 cm × 21.2 mm, manufactured by Regis Technologies.

Table 8-1

Table 8-2

Table 8-3

Table 8-4

[0563] The following compounds were prepared using the same method as described in Example 1, except that catalytic 1,2-dibromoethane was used to activate magnesium in Step 2 and LiOH / EtOH was not added in Step 3. The purification in Step 6 was carried out by SFC using a Lux Cellulose-2 column, 5 μm particle size, 25 cm × 10 mm, manufactured by Phenomenex, on an SFC 100 instrument manufactured by Waters Corp. and a Minigram SFC instrument manufactured by Berger Instruments.

Table 9

[0564] The following compounds were prepared using the same method as described in Example 1, except that LiOH / EtOH was not added in Step 3. The amide coupling Step 4 was carried out using T3P as the activator instead of oxalyl chloride. The purification in Step 6 was carried out by SFC using a Lux i-Cellulose-5 column, 5 μm particle size, 25 cm × 10 mm, manufactured by Phenomenex, on an SFC 100 instrument manufactured by Waters Corp. and a Minigram SFC instrument manufactured by Berger Instruments.

Table 10

[0565] The following compounds were prepared using the same method as described in Example 1, except that methylamine was used instead of ammonia in Step 5. The purification in Step 6 was carried out by chiral SFC using a Chiralpak AS-H column, 5 μm particle size, 25 cm × 10 mm, manufactured by Daicel, on a Minigram SFC instrument manufactured by Berger Instruments.

Table 11

[0566] Example 2 rel-(2S,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (4) and rel-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (5)

Chemical formula

[0567] Triethylamine (8.05 g, 11.2 mL, 78.8 mmol) was added to a solution of ethyl 2-diazo-3-oxo-butanoate (5.0 g, 31.4 mmol) in DCM (50 mL) stirred at 0 °C. TBSOTf (9.24 g, 8.2 mL, 34.3 mmol) was added slowly and the reaction mixture was stirred at 0 °C for 30 minutes. The reaction mixture was washed with 30% NaHCO3 solution (200 mL). The organic layer was separated, washed with water (500 mL), and then dried over MgSO4. The solvent was evaporated to give ethyl 3-[tert-butyl(dimethyl)silyl]oxy-2-diazo-but-3-enoate (8.22 g, 97%), which was used in the next step without further purification.

[0568] Step 2:

[0569] A solution of 1,1,1-trifluoropropan-2-one (33.8 g, 27 mL, 301.2 mmol) in DCM (150 mL) was stirred at -78 °C, and TiCl4 (56.8 g, 33 mL, 299.2 mmol) was added dropwise. After keeping the reaction mixture at -78 °C for 10 minutes, a solution of ethyl 3-[tert-butyl(dimethyl)silyl]oxy-2-diazo-but-3-enoate (64 g, 236.7 mmol) in DCM (150 mL) was added dropwise. The reaction was maintained at -78 °C for 1 hour, then saturated solution of NaHCO3 was added and the mixture was diluted with DCM. The organic layer was dried over MgSO4 and concentrated under reduced pressure, and the residue was purified by column chromatography (0 - 30% EtOAc in hexane) to give ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-5-methyl-3-oxo-hexanoate (39 g, 61%) as a pale yellow liquid. 1 H NMR (400 MHz, chloroform-d) δ 4.92 (s, 1H), 4.32 (q, J = 7.1 H z, 2H), 3.63 (d, J = 15.5 Hz, 1H), 2.84 (d, J = 15.5 Hz, 1H), 1.41 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H) ppm.

[0570] Step 3:

[0571] Oven-dried two-necked flask was charged with rhodium(II) acetate (643 mg, 1.45 mmol). Toluene (970 mL) was added and the solution was stirred at 100 °C for 10 minutes. While lifting the solution from the oil bath briefly, a solution of ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-5-methyl-3-oxo-hexanoate (39 g, 145.4 mmol) in toluene (200 mL) was added dropwise and the reaction was heated to reflux for 1 hour. The reaction mixture was filtered through filter paper and the filtrate was concentrated under reduced pressure to give ethyl 5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (30.89 g, 88%). 11H NMR (400 MHz, chloroform-d) δ 4.68 (s, 1H), 4.35 - 4.17 (m, 2H), 2.89 (d, J = 18.8, 1H), 2.58 (d, J = 18.8, 1H), 1.70 (s, 3H), 1.30 (t, J = 7.2, Hz, 3H) ppm。

[0572] Step 4:

[0573] Trifluoromethanesulfonic anhydride (6.0 mL, 35.7 mmol) was added dropwise to a solution of ethyl 5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (6.5 g, 27.1 mmol) and DIPEA (14 mL, 80.4 mmol) in DCM (150 mL) at -78 °C. After stirring the reaction mixture for 2.5 h, saturated aqueous NH4Cl (75 mL) was added. The mixture was warmed to ambient temperature, the layers were separated, and the aqueous layer was extracted with DCM (2 × 30 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure to give ethyl 2-methyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (10.1 g, 100%), which was used directly in the next reaction.

[0574] Step 5:

[0575] To a stirred solution of (3,4-difluoro-2-methoxyphenyl)boronic acid (2.0 g, 10.6 mmol) and ethyl 2-methyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (3 g, 7.90 mmol) in toluene (80 mL) was added K3PO4 (13 mL of 2 M aqueous solution, 26.0 mmol). The mixture was degassed with N2 for 20 minutes, then Pd(PPh3)4 (466 mg, 0.40 mmol) was added and the mixture was then heated at 100 °C for 1 hour. The mixture was filtered through a pad of celite, the filtrate was diluted with water (50 mL) and the aqueous layer was extracted with EtOAc (50 × 2 mL). The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (SiO2, 0 - 2% EtOAc in hexane) to give ethyl 4-(3,4-difluoro-2-methoxyphenyl)-2-methyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (2.5 g, 85%) as a pale yellow liquid. 1 H NMR (400 MHz, chloroform-d) δ 6.87 (pd, J = 8.8, 6.2 Hz, 2H), 4.15 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.42 (d, J = 17.4 Hz, 1H), 2.93 (d, J = 17.4 Hz, 1H), 1.65 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H) ppm. ESI-MS m / z calcd for 366.089, found 367.2 (M+1) + 。

[0576] Step 6:

[0577] EtOH (200 mL) was added to ethyl 4-(3,4-difluoro-2-methoxyphenyl)-2-methyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (5.51 g, 15.0 mmol) and Pd / C (10 wt.% loaded, 2.2 g, 2.067 mmol). The mixture was degassed and stirred under a balloon of H2 for 96 h. The catalyst was removed by filtration, the solid was washed with EtOH (50 mL), and the filtrate was concentrated under reduced pressure. A further portion of Pd / C (10 wt.% loaded, 2.2 g, 2.07 mmol) was added to the residue, followed by EtOH (200 mL), and the reaction mixture was stirred at ambient temperature under a balloon of H2 for 24 h. The catalyst was removed by filtration, the solid was washed with EtOH (50 mL), and the filtrate was concentrated under reduced pressure. A further portion of Pd / C (10 wt.% loaded, 2.2 g, 2.07 mmol) was added to the residue, followed by EtOH (200 mL), and the reaction mixture was stirred at ambient temperature under a balloon of H2 for 4 days. The catalyst was removed by filtration, the solid was washed with EtOH (50 mL), and the filtrate was concentrated under reduced pressure to give ethyl rac-(2S,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (5.19 g, 94%) as a white solid and as a single diastereomer. 1 1H NMR (500 MHz, chloroform-d) δ 6.89 - 6.86 (m, 1H), 6.82 - 6.77 (m, 1H), 4.93 (d, J = 8.9 Hz, 1H), 4.23 (dt, J = 13.0, 7.6 Hz, 1H), 4.08 (d, J = 2.9 Hz, 3H), 3.85 - 3.71 (m, 2H), 2.82 (t, J = 12.5 Hz, 1H), 2.04 (dd, J = 12.0, 6.7 Hz, 1H), 1.53 (s, 3H), 0.94 (t, J = 7.1 Hz, 3H) ppm; 19 19F NMR (471 MHz, chloroform-d) δ -80.15, -136.84 (d, J = 19.4 Hz), -154.77 (d, J = 19.6 Hz) ppm。

[0578] Step 7:

[0579] Ethyl rac-(2S,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (5.19 g, 14.09 mmol) was dissolved in ethanol (100 mL). Cesium carbonate (7.1 g, 21.8 mmol) was added and the suspension was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure and then the residue was partitioned between 1 M HCl and MTBE. The layers were separated and the aqueous layer was extracted twice with MTBE. The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to give rac-(2R,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (5.11 g, 96%) as a colorless oil and as a single diastereomer. 1 H NMR (500 MHz, chloroform-d) δ 6.99 - 6.96 (m, 1H), 6.92 - 6.87 (m, 1H), 4.68 (d, J = 10.5 Hz, 1H), 4.00 (d, J = 2.7 Hz, 3H), 3.90 (ddd, J = 12.0, 10.6, 8.2 Hz, 1H), 2.58 (t, J = 12.5 Hz, 1H), 2.31 (dd, J = 13.0, 8.2 Hz, 1H), 1.60 (s, 3H) ppm; 19 F NMR (471 MHz, chloroform-d) δ -81.56, -136.40 (d, J = 19.6 Hz), -153.60 (d, J = 19.5 Hz) ppm. ESI-MS m / z calcd for 340.0734, found 339.5 (M-1) - 。

[0580] Step 8:

[0581] A solution of rac-(2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1.5 g, 4.41 mmol) in DCM (30 mL) cooled to -10 °C was added with DMF (5 μL, 0.065 mmol), followed by oxalyl chloride (620 μL, 7.11 mmol). The reaction mixture was stirred for 4 h, warmed to ambient temperature, and then further added with oxalyl chloride (300 μL, 3.55 mmol). After the reaction mixture was stirred for an additional 1 h, it was concentrated under reduced pressure. The residue was dissolved in DCM (30 mL), and the solution was cooled in an ice bath. TEA (600 μL, 4.31 mmol) and methyl 4-aminopyridine-2-carboxylate (663.7 mg, 4.36 mmol) were sequentially added. The resulting mixture was stirred for 30 min, quenched with MeOH, and concentrated under reduced pressure. Purification by flash chromatography (40 g of SiO2, packed with 0 - 60% ethyl acetate in heptane, DCM) gave methyl rac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (827.6 mg, 74%). 1 H NMR (500 MHz, chloroform-d) δ 8.63 (d, J = 5.5 Hz, 1H), 8.46 (s, 1H), 8.07 (d, J = 2.1 Hz, 1H), 7.94 (dd, J = 5.5, 2.2 Hz, 1H), 7.00 (ddd, J = 8.0, 5.5, 2.1 Hz, 1H), 6.90 (td, J = 9.1, 7.3 Hz, 1H), 4.75 (d, J = 10.7 Hz, 1H), 4.01 (s, 3H), 3.99 (d, J = 2.6 Hz, 3H), 3.83 (td, J = 11.4, 8.3 Hz, 1H), 2.61 (t, J = 12.5 Hz, 1H), 2.34 (dd, J = 13.1, 8.2 Hz, 1H), 1.65 (s, 3H) ppm. ESI-MS m / z calculated value 474.1214, measured value 474.7 (M+1) + and 473.2 (M-1) - .

[0582] Step 9:

[0583] Methyl rac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (1.9 g, 4.01 mmol) was dissolved in methanolic ammonia (7M 20 mL, 140.0 mmol), and the reaction mixture was stirred at ambient temperature overnight. Additional methanolic ammonia (7M 5 mL, 35.0 mmol) was added, and the reaction mixture was stirred at ambient temperature for an additional 3 hours and then concentrated under reduced pressure to give rac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (1.94 g, 99%). 1 H NMR (500 MHz, methanol-d4) δ 8.49 (dd, J = 5.5, 0.6 Hz, 1H), 8.26 (dd, J = 2.2, 0.6 Hz, 1H), 7.88 (dd, J = 5.5, 2.2 Hz, 1H), 7.14 (ddd, J = 8.3, 5.7, 2.3 Hz, 1H), 6.99 (ddd, J = 9.9, 8.9, 7.5 Hz, 1H), 4.67 (d, J = 10.3 Hz, 1H), 4.10 - 4.01 (m, 1H), 3.92 (d, J = 2.3 Hz, 3H), 3.35 (s, 3H), 2.62 (t, J = 12.4 Hz, 1H), 2.40 (dd, J = 12.8, 8.2 Hz, 1H), 1.63 (s, 3H) ppm. ESI-MS m / z calculated value 459.12173, measured value 460.2 (M+1) + and 458.3 (M-1)- .

[0584] Step 10:

[0585] rac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (1.9 g, 3.89 mmol) was separated by chiral SFC using a Regis Technologies (R,R)-Whelk-O1 column, 5 μm particle size, 25 cm × 21.2 mm, to obtain two single isomers of unknown absolute configuration:

[0586] The first eluted isomer (rt = 5.05 min): rel-(2S,3R,5S)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (4,724 mg, 38%); ESI-MS m / z calculated 459.12173, found 460.2 (M+1) + and 458.3 (M-1) - . 1 H NMR (500 MHz, methanol-d4) δ 8.36 (d, J = 5.5 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 7.75 (dd, J = 5.5, 2.2 Hz, 1H), 7.00 (ddd, J = 8.2, 5.6, 2.2 Hz, 1H), 6.86 (td, J = 9.3, 7.5 Hz, 1H), 4.55 (d, J = 10.3 Hz, 1H), 3.92 (ddd, J = 12.2, 10.4, 8.2 Hz, 1H), 3.79 (d, J = 2.3 Hz, 3H), 3.22 (s, 1H), 2.49 (t, J = 12.4 Hz, 1H), 2.27 (dd, J = 12.8, 8.2 Hz, 1H), 1.50 (s, 3H) ppm.

[0587] Second elution isomer (rt = 7.36 minutes): rel-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (5,749 mg, 39%); ESI-MS m / z calculated value 459.12173, measured value 460.2 (M+1) + and 458.3 (M-1) - 。 1 H NMR (500 MHz, methanol-d4) δ 8.36 (d, J = 5.5 Hz, 1H), 8.13 (d, J = 2.2 Hz, 1H), 7.75 (dd, J = 5.5, 2.2 Hz, 1H), 7.01 (ddd, J = 8.3, 5.6, 2.2 Hz, 1H), 6.86 (td, J = 9.4, 7.5 Hz, 1H), 4.55 (d, J = 10.2 Hz, 1H), 3.92 (ddd, J = 12.0, 10.4, 8.2 Hz, 1H), 3.79 (d, J = 2.3 Hz, 3H), 3.22 (s, 3H), 2.49 (t, J = 12.4 Hz, 1H), 2.27 (dd, J = 12.9, 8.2 Hz, 1H), 1.50 (s, 3H) ppm。

[0588] The following compounds were prepared using the same method as described in Example 2, except that 5-amino-2-fluorobenzamide was used as the coupling partner in Step 8 and Step 9 was omitted.

Table 12

[0589] Example 3 (2S,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (6) and (2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (7)

Chem.

[0590] NEt3 (7.7 mL, 55.2 mmol) was added to a solution of ethyl 2-diazo-3-oxo-pentanoate (6.69 g, 39.3 mmol) in DCM (80 mL) stirred at 0 °C under nitrogen. Trimethylsilyl trifluoromethanesulfonate (8.5 mL, 47.0 mmol) was added dropwise over 5 minutes and the mixture was stirred at 0 °C for a further 30 minutes. The reaction mixture was diluted with pentane (100 mL), the layers were separated and the organic phase was washed with dilute aqueous sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to give ethyl (Z)-2-diazo-3-trimethylsilyloxy-penta-3-enoate (9.4 g, 99%) as a red oil. 1 1H NMR (500 MHz, chloroform-d) δ 5.33 (q, J = 7.0 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 1.67 (d, J = 7.0 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 0.22 (s, 9H) ppm.

[0591] Step 2:

[0592] A solution of 1,1,1-trifluoropropan-2-one (8 mL, 89.4 mmol) in DCM (80 mL) stirred at -78 °C was added with TiCl4 (1 M 70 mL in DCM, 70.00 mmol) via a cannula. To the resulting solution was added dropwise a solution of ethyl (Z)-2-diazo-3-trimethylsilyloxy-penta-3-enoate (31.3% w / w 36.1 g, 46.6 mmol) in 40 mL of DCM over 15 minutes. After 100 minutes, the reaction was carefully quenched with water, the temperature was slowly raised, and then extracted with DCM. The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography (330 g of SiO2, 0 - 20% EtOAc in heptane) gave ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxo-hexanoate (8.82 g, 67%), which was stored as a toluene solution. 1 1H NMR (500 MHz, chloroform-d) δ 4.33 (q, J = 7.1 Hz, 2H), 4.14 (q, J = 7.0 Hz, 1H), 3.98 (s, 1H), 1.43 (q, J = 1.2 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H), 1.31 (dq, J = 7.0, 1.4 Hz, 3H) ppm. ESI-MS m / z calculated 282.08273, found 283.1 (M+1) + ; 281.0 (M-1) - .

[0593] Step 3:

[0594] A solution of rhodium(III) acetate (245 mg, 0.55 mmol) in benzene (32 mL) was heated under reflux for 10 minutes, and then a solution of ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxo-hexanoate (10 g, 35.4 mmol) in benzene (13 mL) was slowly added via an addition funnel while refluxing for 60 minutes. Next, the mixture was concentrated under reduced pressure to give ethyl rac-(4R,5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (9.0 g, 100%) as a green residue containing residual catalyst and as a mixture of epimers at the position adjacent to the ester. This material was used without further purification. 1 H NMR (500 MHz, chloroform-d) δ 4.83 - 4.57 (m, 1H), 4.38 - 4.16 (m, 2H), 2.60 (dddd, J = 9.3, 8.2, 5.6, 1.4 Hz, 1H), 1.73 - 1.63 (m, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.24 (ddq, J = 6.4, 4.1, 1.9 Hz, 3H) ppm.

[0595] Step 4:

[0596] To a stirred solution of ethyl rac-(4R,5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (48 g, 188.83 mmol) in DCM (400 mL) stirred at -78 °C was added DIPEA (29.680 g, 40 mL, 229.64 mmol). A solution of trifluoromethylsulfonyl trifluoromethanesulfonate (53.440 g, 32 mL, 189.41 mmol) in DCM (200 mL) was added to the reaction mixture at the same temperature over 1 hour. The reaction mixture was stirred at 0 °C for 30 minutes and then quenched with 100 mL of saturated aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with DCM (160 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to afford ethyl rac-(4R,5R)-2,3-dimethyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (71 g, 97%). 1 H NMR (400 MHz, chloroform-d) δ 4.38-4.32 (m, 2H), 3.29-3. 23 (m, 1H), 1.64 (s, 3H), 1.37-1.33 (m, 6H) ppm。

[0597] Step 5:

[0598] To a stirred solution of ethyl rac-(4R,5R)-2,3-dimethyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (26 g, 67.311 mmol) in toluene (130.00 mL), (3,4-difluoro-2-methoxy-phenyl)boronic acid (14 g, 74.5 mmol) was added, followed by the addition of K3PO4 (2 M 100 mL, 200.00 mmol) under an argon atmosphere. After degassing the reaction mixture, tetrakis(triphenylphosphine)palladium(0) (4 g, 3.46 mmol) was added. After further degassing, the reaction mixture was heated at 100 °C for 2 h. The reaction mixture was diluted with water and the aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were concentrated under reduced pressure. Purification by flash chromatography (SiO2, 0 - 10% EtOAc in heptane) gave ethyl 4-(3,4-difluoro-2-methoxy-phenyl)-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (24.4 g, 93%) as a 6:1 diastereomer mixture, the major isomer being ethyl rac-(4R,5R)-4-(3,4-difluoro-2-methoxy-phenyl)-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate. Major isomer: 1 H NMR (400 MHz, chloroform-d) δ 6.88 - 6.79 (m, 2H), 4.17 - 4.09 (m, 2H), 3.90 (s, 3H), 3.46 (q, J = 7.4 Hz, 1H), 1.67 (s, 3H), 1.12 (t, J = 7.4 Hz, 3H), 1.06 (dd, J = 5.4, 2.7 Hz, 3H) ppm. Minor isomer 11H NMR (400 MHz, chloroform-d) δ 6.88 - 6.79 (m, 2H), 4.17 - 4.09 (m, 2H), 3.88 (s, 3H), 3.76 - 3.71 (m, 1H), 1.51 (s, 3H), 1.12 (t, J = 7.4 Hz, 3H), 0.99 (dd, J = 5.4, 2.7 Hz, 3H) ppm. ESI-MS m / z calculated value 380.1047, measured value 381.02 (M+1) + .

[0599] Step 6:

[0600] ...

Claims

【Claim 1】 The invention described in the specification.

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