RU2811402C2 - Pyridonamide prodrugs used as sodium channels modulators - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a process of the preparation of a compound of formula I, in which independently for each case R² and R³ independently represent hydrogen, halogen or C₁-C₆-alkyl, where the specified C₁-C₆-alkyl is substituted by 0–6 halogen atoms; R⁵ is hydrogen, halogen, OH or C₁-C₆-alkyl, where the specified C₁-C₆-alkyl is substituted by 0–6 halogen atoms and where up to two non-adjacent CH₂ units of the specified C₁-C₆-alkyl can be replaced by -O-; R⁷ is hydrogen, halogen or C₁-C₆-alkyl, where the specified C₁-C₆-alkyl is substituted by 0–6 halogen atoms and where up to two non-adjacent CH₂ units of the specified C₁-C₆-alkyl can be replaced on -O-; and X is -PO(OH)₂, -PO(OH)O^-M⁺, -PO(O^-)₂⋅2M⁺ or –PO(O^-)₂⋅D2⁺; M⁺ is a pharmaceutically acceptable monovalent cation; and D²⁺ is a pharmaceutically acceptable divalent cation; provided that R², R³, R⁵ and R⁷ are not simultaneously hydrogen; comprising processing a compound of formula BK(PG₁)₂PO₄ to obtain a compound of formula C; and deprotection of the compound of formula C to give a compound of formula I wherein X is P(O)(OH)₂ and PG₁ is t-butyl; and optionally treating a compound of formula I in which X is P(O)(OH)₂, M⁺OH^- or D²⁺(OH^-)₂ to give a compound of formula I in which X is P(O)(OH)(O^-)·M⁺, P(O)(O^-)₂·2M⁺ or P(O)(O^-)₂·D²⁺. The invention also relates to compounds of formula B and formula C.

EFFECT: technical result is the preparation of compounds used as inhibitors of voltage-gated sodium channels.

28 cl, 5 dwg, 9 tbl, 19 ex

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 USC 119 to US Provisional Application Serial No. 61/915937, filed December 13, 2013, the entire contents of which are incorporated herein by reference.

BACKGROUND OF THE ART

[0002] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and prevent further damage to damaged tissue. However, there are many conditions in which pain persists beyond its functional purpose or in which patients benefit from pain inhibition. Neuropathic pain is a form of chronic pain caused by damage to sensory nerves (Dieleman, JP, et al., Incidence rates and treatment of neuropathic pain conditions in the general population. Pain , 2008. 137 (3): p. 681-8) . Neuropathic pain can be divided into two categories, pain caused by generalized metabolic nerve damage and pain caused by discrete nerve damage. Metabolic neuropathies include postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Symptoms of discrete nerve injuries include pain after amputation, pain associated with postoperative nerve injury, and injuries related to nerve entrapment, such as neuropathic back pain.

[0003] Voltage-gated sodium channels (Na _V 's) play a critical role in the transmission of pain signals. Voltage-gated sodium channels are the major biological mediators of electrical signaling because they are the primary mediators of the rapid rise in action potential of many types of excitable cells (eg, neurons, skeletal myocytes, cardiomyocytes). Evidence for a role for 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 modulating agents all point to a central role for Na _V 's. in pain (Rush, AM and TR Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets NaV1.8 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)). Na _V are the primary mediators of the rapid rise in action potential of many types of excitable cells (e.g., neurons, skeletal myocytes, cardiomyocytes), and are thus critical for the initiation of signaling in these cells (Hille, Bertil, Ion Channels of Excitable Membranes . Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). Because Na _Vs play a role in the initiation and propagation of neural signals, antagonists that reduce Nav currents can prevent or reduce the transmission of neural signals, and Nav channels have long been considered as potential targets for reducing pain in conditions 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), pp. 144-58 (2008). Several clinically used analgesics have been identified as Nav channel inhibitors. Topical anesthetics such as lidocaine block pain by inhibiting Nav channels, and other compounds such as carbamazepine, lamotrigine and tricyclic antidepressants, which have been shown to be effective in reducing pain, have also been considered as agents that act by inhibiting sodium channels

[0004] Na _V form a subfamily of the voltage-gated ion channel superfamily and include 9 isoforms designated NaV1.1-NaV1.9. The tissue localizations of the nine isoforms vary widely. NaV1.4 is the major sodium channel in skeletal muscle, and NaV1.5 is the major sodium channel in cardiomyocytes. NaV 1.7, 1.8 and 1.9 are localized mainly in the peripheral nervous system, with Nav 1.1, 1.2, 1.3 and 1.6 being neuronal channels present in both the central and peripheral nervous systems. The functional behaviors of the nine isoforms are similar, but differ in the specificity of their voltage-gated and kinetic properties (Catterall, WA, Goldin, AL, and Waxman, SG, International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev 57 (4), p 397 (2005)).

[0005] Immediately after its discovery, NaV1.8 channels were identified as potential targets 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): pp. 257-62). NaV1.8 has since been shown to be the most significant carrier of the sodium current that supports action potential firing in small DRG (dorsal root) neurons (Blair, NT and BP Bean, Roles of tetrodotoxin (TT×) - 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). NaV1.8 is essential for spontaneous firing in damaged neurons, such as neurons that control neuropathic pain (Roza, C., et al., The tetrodotoxin-resistant Na ⁺ channel NaV1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice . J. Physiol ., 2003. 550 (Pt 3): p. 921-6; Jarvis, MF, et al., A-803467, a potent and selective NaV1.8 sodium channel blocker , attenuates neuropathic and inflammatory pain in the rat. Proc Natl Acad Sci. USA, 2007. 104 (20): p. 8520-5; Joshi, SK, et al., Involvement of the TTX-resistant sodium channel NaV1.8 in inflammatory and neuropathic, but not post-operative, pain states. Pain , 2006. 123 (1-2): pp. 75-82; Lai, J., et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin- sodiumresistant channel, NaV1.8. Pain , 2002. 95 (1-2): p. 143-52; Dong, XW, et al., Small interfering RNA-mediated selective knockdown of Na( _V )1,8 tetrodotoxin- sodiumresistant 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, JA, 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 (NaV1.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats . J Biol Chem . 286 (46): p. 39836-47). Small DRG neurons expressing NaV1.8 include nociceptors critical for pain signaling. NaV1.8 is a major channel that mediates large amplitude action potentials in small dorsal root ganglion neurons (Blair, NT and BP Bean, Roles of tetrodotoxin (TT×)-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). NaV1.8 is required for fast repetitive action potentials in nociceptors as well as spontaneous activity of damaged neurons. (Choi, JS and SG Waxman, Physiological interactions between NaV1.7 and NaV1.8 sodium channels: a computer simulation study . J Neurophysiol . 106 (6): p. 3173-84; Renganathan, M., TR Cummins, and SG 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 NaV1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice . J Physiol ., 2003. 550 (Pt 3): p. 921-6). In depolarized or damaged DRG neurons, NaV1.8 appears to be the primary driver of hyper-excitability (Rush, AM, et al., A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc Natl Acad Sci USA , 2006. 103 (21): p. 8245-50). In some animal models of pain, increased expression levels of NaV1.8 mRNA in the DRG have been shown (Sun, W., et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibres contributes to painful diabetic neuropathy in rats. Brain . 135 (Pt 2): pp. 359-75; Strickland, IT, et al., Changes in the expression of NaV1.7, NaV1.8 and NaV1.9 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 NaV1.8 and NaV1.9 within dorsal root ganglia in a rat model of bone cancer pain . Neurosci . Lett. 512 (2): p. 61-6).

[0006] The main disadvantage of known Nav inhibitors is their poor therapeutic window, which is likely a consequence of their lack of isoform selectivity. Because NaV1.8 is primarily restricted to neurons that perceive pain, it is unlikely that selective NaV1.8 blockers will cause the side effects common to nonselective Nav blockers. Accordingly, there is a need to provide other Nav antagonists, preferably antagonists that are more NaV1.8 selective and more effective, with increased metabolic stability, increased solubility and fewer side effects.

The essence of the invention

[0007] The compounds of the present invention and their pharmaceutically acceptable salts and compositions containing them have now been found to be useful as voltage-gated sodium channel inhibitors. These compounds have the general formula I:

I,

in which, independently for each case:

R ² and R ³ independently represent hydrogen, halogen or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms;

R ⁵ represents hydrogen, halogen, OH, or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms and wherein up to two non-adjacent CH ₂ units of said C ₁ -C ₆ -alkyl can be replaced by -O-;

R ⁷ represents hydrogen, halogen, or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms and wherein up to two non-adjacent CH ₂ units of said C ₁ -C ₆ -alkyl may be replaced by -O-; And

X represents -PO(OH) ₂ , –PO(OH)O ^- M ⁺ , –PO(O ^- ) ₂ ⋅2M ⁺ or -PO(O ^- ) ₂ ⋅D ²⁺ ; M ⁺ is a pharmaceutically acceptable monovalent cation; and D ²⁺ is a pharmaceutically acceptable divalent cation;

provided that R ² , R ³ , R ⁵ and R ⁷ are not both hydrogen.

[0008] The present invention also relates to novel solid forms of (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1( 2H )-yl)methyl dihydrogen phosphate (" connection 9"). In one embodiment, the present invention provides solid Form B of compound 9 characterized by an X-ray powder pattern (XRPD) containing at least three approximate peak positions (in degrees 2 theta [2θ]+0.2) when measured using Cu K _α radiation selected from the group including 4.4, 12.7, 13.3, 14.7, 15.2, 16.4, 18.0, 19.1, 19.3, 19.9, 20.2, 20.5, 21.0, 22.2, 23.5 24.2, 24.8, 26.3, 29.6, 30.1 and 31.3, with XPRD data collected in the range angles from about 4 to about 40 degrees are two theta (2θ). Solid Form B may be characterized by an X-ray powder diffraction pattern, when measured using Cu K _α radiation, substantially similar to that shown in FIG. 2, and an endothermic peak having an onset temperature of approximately 210° C., measured by differential scanning calorimetry, in which the temperature is scanned at a rate of approximately 10°C per minute. The present application also relates to a method for preparing crystalline Form B of Compound 9 by suspending a solid, free Compound 9, in a solvent system containing water, an organic solvent, or an organic solvent/water mixture, and isolating the solid. In another embodiment, the present invention provides an amorphous Form C of compound 9, characterized by an X-ray powder diffraction pattern (XRPD) substantially similar to that shown in Figure 5. In another embodiment, the present invention provides a spray-dried dispersion of amorphous Form C of compound 9, characterized by X-ray powder diffraction (XRPD) pattern substantially similar to that shown in Figure 6.

[0009] In addition to the compounds provided herein, the present invention also provides pharmaceutically acceptable compositions containing a compound of formula I and a pharmaceutically acceptable carrier, adjuvant or excipient.

[0010] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula I; a pharmaceutically acceptable carrier, adjuvant or excipient; and an additional therapeutic agent.

[0011] In another embodiment, the present invention provides a method of treating or reducing the severity of various diseases, disorders or conditions in a subject, including, but not limited to, chronic pain, bowel pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or cardiac arrhythmia, comprising administering to the subject a therapeutically effective amount of a compound of Formula I.

[0012] In another embodiment, the present invention provides a method of treating or reducing the severity of various diseases, disorders or conditions in a subject, including, but not limited to, chronic pain, bowel pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or cardiac arrhythmia, comprising administering to the subject a therapeutically effective amount of a compound of Formula I and an additional therapeutic agent.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] In FIG. Figure 1 shows the thermal ellipsoidal region of one symmetry-independent molecule of crystalline form B (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate.

[0014] Figure 2 shows the X-ray powder diffraction pattern of solid Form B (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate.

[0015] Figure 3 shows a DSC (differential scanning calorimetry) thermogram of solid Form B (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridine-1(2H) -yl)methyl dihydrogen phosphate.

[0016] Figure 4 shows a TGA (thermogravimetric analysis) thermogram of solid Form B (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridine-1(2H)- yl)methyl dihydrogen phosphate.

[0017] Figure 5 shows an X-ray powder diffraction pattern of solid transparent amorphous Form C (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl) methyl dihydrogen phosphate.

[0018] Figure 5 shows an X-ray powder diffraction pattern of amorphous Form C from a spray-dried dispersion of (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridine-1(2H)- yl)methyl dihydrogen phosphate.

DETAILED DESCRIPTION OF THE INVENTION

[0019] These compounds of Formula I are prodrugs of their respective parent compounds. Thus, the activity exhibited upon administration of the prodrug is due primarily to the presence of the parent compound, which results from cleavage of the prodrug.

[0020] The present invention also provides novel solid forms of (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1( 2H )-yl)methyl dihydrogen phosphate (“ connection 9"). In one embodiment, the present invention relates to the free crystalline form of compound 9 (Form B). In another embodiment, the present invention provides a method for preparing solid Form B of Compound 9. In another embodiment, the present invention provides an amorphous form of Compound 9 (Form C). In yet another embodiment, the present invention relates to a method for preparing amorphous Form C of compound 9.

[0021] The term “prodrug” refers to compounds that are precursors to drugs that, after administration and absorption, release the drug in vivo through certain metabolic processes. In general, a prodrug has less biological activity than its parent drug. The prodrug may also improve the physical properties of the parent drug and/or it may also improve the overall effectiveness of the drug, for example, by reducing the toxicity and unwanted effects of the drug by controlling its absorption, blood levels, metabolic distribution and cellular uptake.

[0022] The term “related compound” or “parent drug” refers to a biologically active compound that is released through the enzymatic action of a metabolic or catabolic process, or through a chemical process after administration of a prodrug. The parent compound may also be the starting material for the preparation of its corresponding prodrug.

[0023] Monovalent cations, defined as M ⁺ , include ammonium ions (for example, N( ^R9 ) ₄ , where ^R9 is H or _C1 - _C4 alkyl), alkali metal ions such as sodium, lithium and potassium ions , dicyclohexylamine ion and N-methyl-D-glucamine ion. These divalent cations, defined as D ²⁺ , include alkaline earth metal ions such as calcium and magnesium ions, as well as divalent aluminum ions. Also included are amino acid cations such as monovalent or divalent ions of arginine, lysine, ornithine, and so on. If M ⁺ is a monovalent cation, it is recognized that if the definition of 2M ⁺ is present, each M ⁺ may be the same or different. Additionally, likewise, it is recognized that if the definition of 2M ⁺ is present, the divalent cation D2 ⁺ may be present instead. In addition, basic nitrogen-containing groups can be quaternized with agents such as: lower alkyl halides, for example, methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as diethyl, dimethyl, dibutyl; diamyl sulfates; long-chain halides (such as decyl-, lauryl-, myristyl- and stearyl chlorides, bromides and iodides), aralkyl halides (such as benzyl and phenethyl bromides) and others.

[0024] The prodrugs and solid forms of the present invention are characterized by unexpectedly high solubility in water. This solubility facilitates the administration of higher doses of the prodrug, resulting in more drug content per unit dose.

[0025] For the purposes of the present invention, chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, ^75th Ed. Additionally, the general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry,” ^5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0026] It will be clear to any person skilled in the art that the combinations of substituents provided by the present invention are those combinations that lead to the formation of stable or chemically feasible compounds. The term “stable” as used herein refers to compounds that are substantially unchanged by conditions to enable their production, detection and, preferably, their isolation, purification and use for one or more of the purposes described herein. In some embodiments, a stable compound or chemically feasible compound is a compound that is substantially unchanged when stored at 40° C. or below, in the absence of humidity, or other chemically reactive conditions for at least one week.

[0027] The term “alkyl” as used herein means a straight (ie, straight) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or that contains one or more unsaturation units. Suitable alkyl groups include, but are not limited to, straight or branched and substituted or unsubstituted alkyl.

[0028] The term "halogen" or "halo" as used herein means F, Cl, Br or I.

[0029] The phrase "before" as used herein refers to zero or any integer that is equal to or less than the number following the phrase. For example, "up to 4" means any of the following numbers 0, 1, 2, 3, and 4.

[0030] Within the scope of the definition of a term, for example, R ⁷ , when a CH ₂ group or, interchangeably, a methylene group may be replaced by -O-, includes any CH ₂ group, including the CH ₂ at the terminal methyl group. For example, CH ₂ CH ₂ CH ₂ OH is included in the scope of the definition of C ₁ -C ₆ -alkyl, where up to two non-adjacent CH ₂ groups can be replaced by -O-, since the CH ₂ group in the terminal methyl group is replaced by -ABOUT-.

[0031] Unless otherwise indicated, structures presented herein are also intended to include all isomeric (eg, enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, (Z) and (E) isomers relative to the double bond, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers, as well as mixtures of enantiomeric, diastereomeric and geometric (or conformational) forms of the compounds of the present invention are included within the scope of the present invention. Thus, tautomers of the compounds of formula I are included within the scope of the present invention. Where appropriate, the structures also include zwitterionic forms of the compounds or salts of the formula.

[0032] In addition, unless otherwise indicated, the structures presented herein also include compounds that differ only in the presence of one or more isotopically enriched or isotopically labeled atoms. Isotopically labeled compounds may have one or more atoms replaced by an atom having an atomic mass or mass number commonly found in nature. Examples of isotopes that are present in compounds of formula I include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³⁵ S and ¹⁸ F. Certain isotopically labeled compounds of formula I, in addition to their use as therapeutic agents, can also be used in drug and/or substrate tissue distribution assays, as analytical tools or as samples in other biological research. In one aspect of the present invention, isotopes containing tritium (eg, ³ H) and carbon-14 (eg, ¹⁴ C) are used due to their ease of detection. In another aspect of the present invention, replacing one or more hydrogen atoms with heavier isotopes such as deuterium (eg, ² H) may provide certain therapeutic effects.

[0033] In one embodiment, the present invention provides a compound of Formula I and accompanying definitions, wherein R ² is H. In another embodiment, R ² is halogen. In another embodiment, R ² represents Cl. In another embodiment, R ² is F. In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ² is CF ₃ . In another embodiment, R ² is H, Cl or CF ₃ .

[0034] In another embodiment, the present invention provides a compound of Formula I and accompanying definitions, wherein R ³ is H. In another embodiment, R ³ is halogen. In another embodiment, R ³ represents Cl. In another embodiment, R ³ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ³ is CF ₃ . In another embodiment, R ³ is CF ₂ CF ₃ .

[0035] In another embodiment, the present invention provides a compound of Formula I and accompanying definitions, wherein R ⁵ is H. In another embodiment, R ⁵ is halogen. In another embodiment, R ⁵ represents Cl. In another embodiment, R ⁵ is F. In another embodiment, R ⁵ is C ₁ -C ₆ alkyl. In another embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ -alkyl is replaced by -O- . In another embodiment, R ⁵ is OCH ₃ . In another embodiment, R ⁵ represents OH. In another embodiment, R ⁵ is OCF ₃ .

[0036] In another embodiment, the present invention provides a compound of Formula I and accompanying definitions, wherein R ⁷ is H. In another embodiment, R ⁷ is halogen. In another embodiment, R ⁷ is F. In another embodiment, R ⁷ is C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms, wherein two non-adjacent CH ₂ units in said C ₁ -C ₆ -alkyl may be replaced by -O-. In another embodiment, R ⁷ is OCH ₃ . In another embodiment, R ⁷ is OCF ₃ .

[0037] In another embodiment, the present invention provides a compound of Formula I and accompanying definitions, wherein X is -PO(OH)O ^- M ⁺ , –PO(O ^- ) ₂ ⋅2M ⁺ ; or -PO(O ^- ) ₂ ⋅D ²⁺ ; M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ or N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group, and D ²⁺ represents Mg ²⁺ , Ca ²⁺ or Ba ²⁺ .

[0038] In another embodiment, the present invention provides a compound of Formula I and accompanying definitions, wherein X is -PO(OH)O ^- M ⁺ and M ⁺ is Li ⁺ . In one embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is Na ⁺ . In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is K ⁺ . In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group. In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ represents a CH ₃ group. In another embodiment, the present invention provides a compound of Formula I and accompanying definitions wherein X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is Li ⁺ . In one embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is Na ⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is K ⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group. In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ represents a CH ₃ group.

[0039] In another embodiment, the present invention provides a compound of Formula I and accompanying definitions wherein X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Mg ²⁺ , Ca ²⁺ or Ba ^{2 +} . In one embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Mg ²⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Ca ²⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Ba ²⁺ .

[0040] In another embodiment, the present invention provides a compound of Formula I and accompanying definitions, wherein X is -PO(OH) _2.

[0041] In another embodiment, the present invention provides a compound of formula I and accompanying definitions, wherein R ² is Cl, R ³ is Cl, R ⁵ is OCH ₃ , R ⁷ is F, and X is -PO (OH) ₂ .

[0042] In another embodiment, the present invention provides a compound of formula I and accompanying definitions, wherein R ² is Cl, R ³ is Cl, R ⁵ is OCH ₃ , R ⁷ is F, and X is -PO (O ^- ) ₂ ⋅2M ⁺ , M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ or N(R ⁹ ) ₄ ⁺ , where each R ⁹ independently represents H or a C ₁ -C ₄ -alkyl group.

[0043] In another embodiment, the present invention provides a compound of formula I and accompanying definitions wherein R ² is Cl, R ³ is Cl, R ⁵ is OCH ₃ , R ⁷ is F and X is –PO( OH)O ^- M ⁺ , M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ or N(R ⁹ ) ₄ ⁺ , where each R ⁹ independently represents H or a C ₁ -C ₄ -alkyl group.

[0044] In another embodiment, the present invention provides a compound of Formula I and accompanying definitions, wherein R ³ is CF ₂ CF ₃ , R ⁵ is OCH ₃ , R ⁷ is F, and X is -PO(OH) ₂ .

[0045] In another embodiment, the present invention provides a compound of Formula I and accompanying definitions wherein R ³ is CF ₂ CF ₃ , R ⁵ is OCH ₃ , R ⁷ is F, and X is -PO(O ^- ) ₂ ⋅2M ⁺ , M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ or N(R ⁹ ) ₄ ⁺ , where each R ⁹ independently represents H or a C ₁ -C ₄ -alkyl group.

[0046] In another embodiment, the present invention provides a compound of Formula I and accompanying definitions wherein R ³ is CF ₂ CF ₃ , R ⁵ is OCH ₃ , R ⁷ is F and X is -PO(OH)O ^- M ⁺ , M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ or N(R ⁹ ) ₄ ⁺ , where each R ⁹ independently represents H or a C ₁ -C ₄ -alkyl group.

[0047] In another embodiment, the present invention provides a compound of Formula I and accompanying definitions wherein R ³ is CF ₃ , R ⁵ is CH ₃ , R ⁷ is F, and X is -PO(OH) ₂ .

[0048] In another embodiment, the present invention provides a compound of formula I and accompanying definitions, wherein R ³ is CF ₃ , R ⁵ is CH ₃ , R ⁷ is F, X is -PO(O ^- ) ₂ ⋅ 2M ⁺ , M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ . In another embodiment, M ⁺ is Li ⁺ . In yet another embodiment, M ⁺ is Na ⁺ .

[0049] In another embodiment, the present invention provides a compound of formula I and accompanying definitions, wherein R ³ is CF ₃ , R ⁵ is CH ₃ , R ⁷ is F, X is -PO(O ^- ) ₂ ⋅ D ²⁺ , and D ²⁺ is Mg ²⁺ , Ca ²⁺ or Ba ²⁺ . In one embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Mg ²⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Ca ²⁺ .

[0050] In another embodiment, the present invention provides a compound of Formula I and accompanying definitions wherein R ² is CF ₃ , R ⁵ is CH ₃ , R ⁷ is F, and X is -PO(OH) ₂ .

[0051] In another embodiment, the present invention provides a compound of Formula I and accompanying definitions wherein R ² is CF ₃ , R ⁵ is CH ₃ , R ⁷ is F , X is -PO(O ^- ) ₂ ⋅ 2M ⁺ , M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ . In another embodiment, M ⁺ is Li ⁺ . In yet another embodiment, M ⁺ is Na ⁺ .

[0052] In another embodiment, the present invention provides a compound of Formula I and accompanying definitions wherein R ² is CF ₃ , R ⁵ is CH ₃ , R ⁷ is F , X is -PO(O ^- ) ₂ ⋅ D ²⁺ , and D ²⁺ is Mg ²⁺ , Ca ²⁺ or Ba ²⁺ . In one embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Mg ²⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Ca ²⁺ .

[0053] In another embodiment, the present invention provides a compound of Formula I and accompanying definitions wherein R ³ is Cl, R ⁵ is CH ₃ , R ⁷ is F, and X is -PO(OH) ₂ .

[0054] In another embodiment, the present invention provides a compound of Formula I and accompanying definitions wherein R ³ is Cl, R ⁵ is CH ₃ , R ⁷ is F, and X is -PO(O ^- ) ₂ ⋅ 2M ⁺ , M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ or N(R ⁹ ) ₄ ⁺ , where each R ⁹ independently represents H or a C ₁ -C ₄ -alkyl group.

[0055] In another embodiment, the present invention provides a compound of Formula I and accompanying definitions wherein R ³ is Cl, R ⁵ is CH ₃ , R ⁷ is F, and X is –PO(OH)O ^- M ⁺ , M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ or N(R ⁹ ) ₄ ⁺ , where each R ⁹ independently represents H or a C ₁ -C ₄ -alkyl group.

[0056] In another embodiment, the present invention provides a compound of Formula I and accompanying definitions wherein R ² is CF ₃ , R ⁵ is CH ₃ , R ⁷ is F, and X is -PO(OH) ₂ .

[0057] In another embodiment, the present invention provides a compound of Formula I and accompanying definitions, wherein R ² is CF ₃ , R ⁷ is F, X is -PO(O ^- ) ₂ ⋅2M ⁺ , M ⁺ is Li ⁺ , Na ⁺ , K ⁺ . In another embodiment, M ⁺ is Li ⁺ . In yet another embodiment, M ⁺ is Na ⁺ .

[0058] In another embodiment, the present invention provides a compound of Formula I and accompanying definitions wherein R ² is CF ₃ , R ⁷ is F, X is -PO(O ^- ) ₂ ⋅D ²⁺ , and D ^{2 +} is Mg ²⁺ , Ca ²⁺ or Ba ²⁺ . In one embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Mg ²⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Ca ²⁺ .

[0059] In another embodiment, the invention relates to a compound of formula IA

I.A.

in which, independently for each case:

R ² represents halogen or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms;

R ⁵ represents halogen, OH, or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms and wherein up to two non-adjacent CH ₂ units of said C ₁ -C ₆ -alkyl may be replaced by -O-;

R ⁷ represents halogen or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ -alkyl may be replaced by - ABOUT-; And

X represents -PO(OH) ₂ , –PO(OH)O ^- M ⁺ , –PO(O ^- ) ₂ ⋅2M ⁺ or -PO(O ^- ) ₂ ⋅D ²⁺ ; M ⁺ is a pharmaceutically acceptable monovalent cation; and D ²⁺ is a pharmaceutically acceptable divalent cation.

[0060] In another embodiment, the present invention provides a compound of formula IA and accompanying definitions, wherein R ² represents a halogen. In another embodiment, R ² represents Cl. In another embodiment, R ² is F. In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ² is CF ₃ . In another embodiment, R ² represents Cl or CF ₃ .

[0061] In another embodiment, the present invention provides a compound of formula IA and accompanying definitions, wherein R ⁵ represents a halogen. In another embodiment, R ⁵ represents Cl. In another embodiment, R ⁵ is F. In another embodiment, R ⁵ is C ₁ -C ₆ alkyl. In another embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ -alkyl is replaced by -O- . In another embodiment, R ⁵ is OCH ₃ . In another embodiment, R ⁵ represents OH. In another embodiment, R ⁵ is OCF ₃ . In another embodiment, R ⁵ is F, Cl, CH ₃ , OCH ₃ , OH or OCF ₃ .

[0062] In another embodiment, the present invention provides a compound of Formula IA and accompanying definitions, wherein R ⁷ is halogen. In another embodiment, R ⁷ is F. In another embodiment, R ⁷ is C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms, wherein two non-adjacent CH ₂ units in said C ₁ -C ₆ -alkyl may be replaced by -O-. In another embodiment, R ⁷ is OCH ₃ . In another embodiment, R ⁷ is OCF ₃ . In another embodiment, R ⁷ is F, OCH ₃ or OCF ₃ .

[0063] In another embodiment, the present invention provides a compound of Formula IA and accompanying definitions, wherein X is -PO(OH) ₂ , –PO(OH)O ^- M ⁺ ; –PO(O ^- ) ₂ ⋅2M ⁺ or -PO(O ^- ) ₂ ⋅D ²⁺ ; where M ⁺ represents Li ⁺ , Na ⁺ or K ⁺ and where D ²⁺ represents Mg ²⁺ or Ca ²⁺ .

[0064] In another embodiment, the present invention provides a compound of formula IA and accompanying definitions, wherein R ² is CF ₃ , R ⁵ is Cl, OCH ₃ or CH ₃ and R ⁷ is F. In one embodiment, R ² is CF ₃ , R ⁵ is Cl and R ⁷ is F. In another embodiment, R ² is CF ₃ , R ⁵ is OCH ₃ and R ⁷ is F. In another embodiment, R ² is CF ₃ , R ⁵ is CH ₃ and R ⁷ is F.

[0065] In another embodiment, the present invention provides a compound of Formula IA and accompanying definitions, wherein R ² is CF ₃ , R ⁵ is Cl, OCH ₃ or CH ₃ , R ⁷ is F, and X is -PO (OH) ₂ . In one embodiment, R ² is CF ₃ , R ⁵ is Cl, R ⁷ is F, and X is -PO(OH) ₂ . In another embodiment, R ² is CF ₃ , R ⁵ is OCH ₃ , R ⁷ is F, and X is -PO(OH) ₂ . In another embodiment, R ² is CF ₃ , R ⁵ is CH ₃ , R ⁷ is F, and X is -PO(OH) ₂ .

[0066] In another embodiment, the present invention provides a compound of Formula IA and accompanying definitions, wherein X is -PO(OH)O ^- M ⁺ , –PO(O ^- ) ₂ ⋅ 2M ⁺ ; or -PO(O ^- ) ₂ ⋅D ²⁺ ; M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ or N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group and D ²⁺ represents Mg ²⁺ , Ca ²⁺ or Ba ²⁺ .

[0067] In another embodiment, the present invention provides a compound of Formula IA and accompanying definitions, wherein X is -PO(OH)O ^- M ⁺ and M ⁺ is Li ⁺ . In one embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is Na ⁺ . In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is K ⁺ . In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group. In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ represents a CH ₃ group.

[0068] In another embodiment, the present invention provides a compound of Formula IA and accompanying definitions, wherein X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is Li ⁺ . In one embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is Na ⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is K ⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group. In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ represents a CH ₃ group.

[0069] In another embodiment, the present invention provides a compound of Formula IA and accompanying definitions wherein X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Mg ²⁺ , Ca ²⁺ or Ba ^{2 +} . In one embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Mg ²⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Ca ²⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Ba ²⁺ .

[0070] In another embodiment, the present invention provides a compound of Formula IA and accompanying definitions, wherein X is -PO(OH) ₂ .

[0071] In another embodiment, the present invention provides a compound of Formula IA and accompanying definitions wherein R ² is CF ₃ , R ⁵ is CH ₃ , R ⁷ is F, and X is -PO(OH) ₂ .

[0072] In another embodiment, the present invention provides a compound of formula IA and accompanying definitions, wherein R ² is CF ₃ , R ⁵ is CH ₃ , R ⁷ is F, X is -PO(O ^- ) ₂ ⋅ 2M ⁺ , M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ . In another embodiment, M ⁺ is Li ⁺ . In yet another embodiment, M ⁺ is Na ⁺ .

[0073] In another embodiment, the present invention provides a compound of formula IA and accompanying definitions, wherein R ² is CF ₃ , R ⁵ is CH ₃ , R ⁷ is F, X is -PO(O ^- ) ₂ ⋅ D ²⁺ , and D ²⁺ is Mg ²⁺ , Ca ²⁺ or Ba ²⁺ . In one embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Mg ²⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Ca ²⁺ .

[0074] In another embodiment, the invention relates to a compound of formula IB

I-B,

in which, independently for each case:

R ³ represents halogen or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms;

R ⁵ represents halogen, OH, or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms and wherein up to two non-adjacent CH ₂ units of said C ₁ -C ₆ -alkyl may be replaced by -O-;

R ⁷ represents halogen or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ -alkyl may be replaced by - ABOUT-; And

X represents -PO(OH) ₂ , –PO(OH)O ^- M ⁺ , –PO(O ^- ) ₂ ⋅2M ⁺ or -PO(O ^- ) ₂ ⋅D ²⁺ ; M ⁺ is a pharmaceutically acceptable monovalent cation; and D ²⁺ is a pharmaceutically acceptable divalent cation.

[0075] In another embodiment, the present invention provides a compound of Formula IB and accompanying definitions, wherein R ³ is halogen. In another embodiment, R ³ represents Cl. In another embodiment, R ³ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ³ is CF ₃ . In another embodiment, R ³ is CF ₂ CF ₃ .

[0076] In another embodiment, the present invention provides a compound of formula IB and accompanying definitions, wherein R ⁵ represents a halogen. In another embodiment, R ⁵ represents Cl. In another embodiment, R ⁵ is F. In another embodiment, R ⁵ is C ₁ -C ₆ alkyl. In another embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ -alkyl is replaced by -O- . In another embodiment, R ⁵ is OCH ₃ . In another embodiment, R ⁵ represents OH. In another embodiment, R ⁵ is OCF ₃ .

[0077] In another embodiment, the present invention provides a compound of Formula IB and accompanying definitions, wherein R ⁷ is halogen. In another embodiment, R ⁷ is F. In another embodiment, R ⁷ is C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms, wherein two non-adjacent CH ₂ units in said C ₁ -C ₆ -alkyl may be replaced by -O-. In another embodiment, R ⁷ is OCH ₃ . In another embodiment, R ⁷ is OCF ₃ .

[0078] In another embodiment, the present invention provides a compound of Formula IB and accompanying definitions, wherein X is -PO(OH) ₂ , –PO(OH)O ^- M ⁺ ; –PO(O ^- ) ₂ ⋅2M ⁺ or -PO(O ^- ) ₂ ⋅D ²⁺ ; where M ⁺ represents Li ⁺ , Na ⁺ or K ⁺ and where D ²⁺ represents Mg ²⁺ or Ca ²⁺ .

[0079] In another embodiment, the present invention provides a compound of Formula IB and accompanying definitions, wherein R ³ is CF ₃ , R ⁵ is F or CH ₃ , and R ⁷ is F. In one embodiment, R ³ is Cl, R ⁵ is CH ₃ and R ⁷ is F. In another embodiment, R ³ is CF ₂ CF ₃ , R ⁵ is OCH ₃ and R ⁷ is F.

[0080] In another embodiment, the present invention provides a compound of formula IB and accompanying definitions, wherein R ³ is CF ₃ , R ⁵ is F or CH ₃ , R ⁷ is F, and X is -PO(OH) ₂ . In one embodiment, R ³ is Cl, R ⁵ is CH ₃ , R ⁷ is F, and X is -PO(OH) ₂ . In another embodiment, R ³ is CF ₂ CF ₃ , R ⁵ is OCH ₃ , R ⁷ is F, and X is -PO(OH) ₂ .

[0081] In another embodiment, the present invention provides a compound of Formula IB and accompanying definitions, wherein X is -PO(OH)O ^- M ⁺ , –PO(O ^- ) ₂ ⋅ 2M ⁺ ; or -PO(O ^- ) ₂ ⋅D ²⁺ ; M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ or N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group and D ²⁺ represents Mg ²⁺ , Ca ²⁺ or Ba ²⁺ .

[0082] In another embodiment, the present invention provides a compound of Formula IB and accompanying definitions, wherein X is -PO(OH)O ^- M ⁺ and M ⁺ is Li ⁺ . In one embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is Na ⁺ . In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is K ⁺ . In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group. In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ represents a CH ₃ group.

[0083] In another embodiment, the present invention provides a compound of Formula IB and accompanying definitions, wherein X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is Li ⁺ . In one embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is Na ⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is K ⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group. In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ represents a CH ₃ group.

[0084] In another embodiment, the present invention provides a compound of Formula IB and accompanying definitions wherein X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Mg ²⁺ , Ca ²⁺ or Ba ^{2 +} . In one embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Mg ²⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Ca ²⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Ba ²⁺ .

[0085] In another embodiment, the present invention provides a compound of Formula IB and accompanying definitions, wherein X is -PO(OH) ₂ .

[0086] In another embodiment, the present invention provides a compound of Formula IB and accompanying definitions, wherein R ³ is CF ₂ CF ₃ , R ⁵ is OCH ₃ , R ⁷ is F, and X is -PO(OH) ₂ .

[0087] In another embodiment, the present invention provides a compound of Formula IB and accompanying definitions, wherein R ³ is CF ₂ CF ₃ , R ⁵ is OCH ₃ , R ⁷ is F, and X is -PO(O ^- ) ₂ ⋅2M ⁺ , M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ or N(R ⁹ ) ₄ ⁺ , where each R ⁹ independently represents H or a C ₁ -C ₄ -alkyl group.

[0088] In another embodiment, the present invention provides a compound of Formula IB and accompanying definitions, wherein R ³ is CF ₂ CF ₃ , R ⁵ is OCH ₃ , R ⁷ is F and X is -PO(OH)O ^- M ⁺ , M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ or N(R ⁹ ) ₄ ⁺ , where each R ⁹ independently represents H or a C ₁ -C ₄ -alkyl group.

[0089] In another embodiment, the present invention provides a compound of Formula IB and accompanying definitions, wherein R ³ is CF ₃ , R ⁵ is CH ₃ , R ⁷ is F, and X is -PO(OH) ₂ .

[0090] In another embodiment, the present invention provides a compound of Formula IB and accompanying definitions, wherein R ³ is CF ₃ , R ⁵ is CH ₃ , R ⁷ is F, X is -PO(O ^- ) ₂ ⋅ 2M ⁺ , M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ . In another embodiment, M ⁺ is Li ⁺ . In yet another embodiment, M ⁺ is Na ⁺ .

[0091] In another embodiment, the present invention provides a compound of formula IB and accompanying definitions, wherein R ³ is CF ₃ , R ⁵ is CH ₃ , R ⁷ is F, X is -PO(O ^- ) ₂ ⋅ D ²⁺ , and D ²⁺ is Mg ²⁺ , Ca ²⁺ or Ba ²⁺ . In one embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Mg ²⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Ca ²⁺ .

[0092] In another embodiment, the present invention provides a compound of Formula IB and accompanying definitions wherein R ³ is Cl, R ⁵ is CH ₃ , R ⁷ is F, and X is -PO(OH) ₂ .

[0093] In another embodiment, the present invention provides a compound of Formula IB and accompanying definitions, wherein R ³ is Cl, R ⁵ is CH ₃ , R ⁷ is F, and X is -PO(O ^- ) ₂ ⋅ 2M ⁺ , M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ or N(R ⁹ ) ₄ ⁺ , where each R ⁹ independently represents H or a C ₁ -C ₄ -alkyl group.

[0094] In another embodiment, the present invention provides a compound of Formula IB and accompanying definitions wherein R ³ is Cl, R ⁵ is CH ₃ , R ⁷ is F and X is -PO(OH)O ^- M ⁺ , M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ or N(R ⁹ ) ₄ ⁺ , where each R ⁹ independently represents H or a C ₁ -C ₄ -alkyl group.

[0095] In another embodiment, the invention relates to a compound of formula IC

I-C,

in which, independently for each case:

R ² represents halogen or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms;

R ⁷ represents halogen or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ -alkyl may be replaced by - ABOUT-; And

X represents -PO(OH) ₂ , –PO(OH)O ^- M ⁺ , –PO(O ^- ) ₂ ⋅2M ⁺ or -PO(O ^- ) ₂ ⋅D ²⁺ ; M ⁺ is a pharmaceutically acceptable monovalent cation; and D ²⁺ is a pharmaceutically acceptable divalent cation.

[0096] In another embodiment, the present invention provides a compound of formula IC and accompanying definitions, wherein R ² represents C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ² is CF ₃ .

[0097] In another embodiment, the present invention provides a compound of formula IC and accompanying definitions, wherein R ⁷ is halogen. In one embodiment, R ⁷ is F. In another embodiment, R ⁷ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and wherein up to two non-adjacent CH ₂ units the specified C ₁ -C ₆ -alkyl can be replaced by -O-. In one embodiment, R ⁷ is OCF ₃ .

[0098] In another embodiment, the present invention provides a compound of formula IC and accompanying definitions, wherein X is -PO(OH) ₂ , –PO(OH)O ^- M ⁺ ; –PO(O ^- ) ₂ ⋅2M ⁺ or -PO(O ^- ) ₂ ⋅D ²⁺ ; where M ⁺ represents Li ⁺ , Na ⁺ or K ⁺ and where D ²⁺ represents Mg ²⁺ or Ca ²⁺ .

[0099] In another embodiment, the present invention provides a compound of formula IC and accompanying definitions, wherein R ² is CF ₃ and R ⁷ is For OCF ₃ .

[00100] In another embodiment, the present invention provides a compound of formula IC and accompanying definitions, wherein R ² is CF ₃ , R ⁷ is F or OCF ₃ , and X is -PO(OH) ₂ .

[00101] In another embodiment, the present invention provides a compound of formula IC and accompanying definitions, wherein X is -PO(OH)O ^- M ⁺ , –PO(O ^- ) ₂ ⋅ 2M ⁺ ; or -PO(O ^- ) ₂ ⋅D ²⁺ ; M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ or N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group and D ²⁺ represents Mg ²⁺ , Ca ²⁺ or Ba ²⁺ .

[00102] In another embodiment, the present invention provides a compound of formula IC and accompanying definitions, wherein X is -PO(OH)O ^- M ⁺ and M ⁺ is Li ⁺ . In one embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is Na ⁺ . In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is K ⁺ . In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group. In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ represents a CH ₃ group.

[00103] In another embodiment, the present invention provides a compound of formula IC and accompanying definitions, where X is -PO(O ^- ) ₂ 2M ⁺ and M ⁺ is Li ⁺ . In one embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is Na ⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is K ⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group. In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ represents a CH ₃ group.

[00104] In another embodiment, the present invention provides a compound of formula IC and accompanying definitions, wherein X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Mg ²⁺ , Ca ²⁺ or Ba ^{2 +} . In one embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Mg ²⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Ca ²⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Ba ²⁺ .

[00105] In another embodiment, the present invention provides a compound of formula IC and accompanying definitions, wherein X is -PO(OH) ₂ .

[00106] In another embodiment, the present invention provides a compound of formula IC and accompanying definitions, wherein R ² is CF ₃ , R ⁵ is CH ₃ , R ⁷ is F, and X is -PO(OH) ₂ .

[00107] In another embodiment, the present invention provides a compound of formula IC and accompanying definitions, wherein R ² is CF ₃ , R ⁷ is F, X is -PO(O ^- ) ₂ ⋅2M ⁺ , M ⁺ is Li ⁺ , Na ⁺ , K ⁺ . In another embodiment, M ⁺ is Li ⁺ . In yet another embodiment, M ⁺ is Na ⁺ .

[00108] In another embodiment, the present invention provides a compound of formula IC and accompanying definitions, wherein R ² is CF ₃ , R ⁷ is F, X is -PO(O ^- ) ₂ ⋅D ²⁺ , and D ^{2 +} is Mg ²⁺ , Ca ²⁺ or Ba ²⁺ . In one embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Mg ²⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Ca ²⁺ .

[00109] In another embodiment, the invention provides a compound of formula ID

I-D,

in which, independently for each case:

R ³ represents halogen or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms;

R ⁷ represents halogen or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted by 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ -alkyl may be replaced by - ABOUT-; And

X represents -PO(OH) ₂ , –PO(OH)O ^- M ⁺ , –PO(O ^- ) ₂ ⋅2M ⁺ or -PO(O ^- ) ₂ ⋅D ²⁺ ; M ⁺ is a pharmaceutically acceptable monovalent cation; and D ²⁺ is a pharmaceutically acceptable divalent cation.

[00110] In another embodiment, the present invention provides a compound of formula ID and accompanying definitions, wherein R ³ represents C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ³ is CF ₃ . In another embodiment, R ³ is CF ₂ CF ₃ .

[00111] In another embodiment, the present invention provides a compound of Formula ID and accompanying definitions, wherein R ⁷ is halogen. In one embodiment, R ⁷ is F. In another embodiment, R ⁷ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and wherein up to two non-adjacent CH ₂ units the specified C ₁ -C ₆ -alkyl can be replaced by -O-. In one embodiment, R ⁷ is OCF ₃ .

[00112] In another embodiment, the present invention provides a compound of formula ID and accompanying definitions, wherein X is -PO(OH) ₂ , –PO(OH)O ^- M ⁺ ; –PO(O ^- ) ₂ ⋅2M ⁺ or -PO(O ^- ) ₂ ⋅D ²⁺ ; where M ⁺ represents Li ⁺ , Na ⁺ or K ⁺ and where D ²⁺ represents Mg ²⁺ or Ca ²⁺ .

[00113] In another embodiment, the present invention provides a compound of Formula ID and accompanying definitions, wherein R ³ is CF ₃ and R ⁷ is CF ₃ . In another embodiment, R ³ is CF ₂ CF ₃ and R ⁷ is F.

[00114] In another embodiment, the present invention provides a compound of Formula ID and accompanying definitions wherein R ³ is CF ₃ , R ⁷ is CF ₃ and X is -PO(OH) ₂ . In another embodiment, R ³ is CF ₂ CF ₃ , R ⁷ is F, and X is -PO(OH) ₂ .

[00115] In another embodiment, the present invention provides a compound of formula ID and accompanying definitions, wherein X is -PO(OH)O ^- M ⁺ , –PO(O ^- ) ₂ ⋅2M ⁺ ; or -PO(O ^- ) ₂ ⋅D ²⁺ ; M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ or N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group and D ²⁺ represents Mg ²⁺ , Ca ²⁺ or Ba ²⁺ .

[00116] In another embodiment, the present invention provides a compound of Formula ID and accompanying definitions, wherein X is -PO(OH)O ^- M ⁺ and M ⁺ is Li ⁺ . In one embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is Na ⁺ . In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is K ⁺ . In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group. In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ represents a CH ₃ group.

[00117] In another embodiment, the present invention provides a compound of formula ID and accompanying definitions, where X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is Li ⁺ . In one embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is Na ⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is K ⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group. In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ represents a CH ₃ group.

[00118] In another embodiment, the present invention provides a compound of formula ID and accompanying definitions wherein X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Mg ²⁺ , Ca ²⁺ or Ba ^{2 +} . In one embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Mg ²⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Ca ²⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Ba ²⁺ .

[00119] In another embodiment, the present invention provides a compound of formula ID and accompanying definitions, wherein X is -PO(OH) _2.

[00120] In another embodiment, the invention relates to a compound of formula IE

I-E,

in which, independently for each case:

R ² and R ³ independently represent halogen or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms;

R ⁷ represents halogen or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms; And

and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-;

X represents -PO(OH) ₂ , –PO(OH)O ^- M ⁺ , –PO(O ^- ) ₂ ⋅2M ⁺ or -PO(O ^- ) ₂ ⋅D ²⁺ ; M ⁺ is a pharmaceutically acceptable monovalent cation; and D ²⁺ is a pharmaceutically acceptable divalent cation.

[00121] In another embodiment, the present invention provides a compound of formula I-E and accompanying definitions, wherein R ² represents a halogen. In another embodiment, R ² represents Cl.

[00122] In another embodiment, the present invention provides a compound of Formula IE and accompanying definitions, wherein R ³ is halogen. In another embodiment, R ³ represents Cl.

[00123] In another embodiment, the present invention provides a compound of Formula IE and accompanying definitions, wherein R ⁷ is halogen. In one embodiment, R ⁷ is F.

[00124] In another embodiment, the present invention provides a compound of Formula IE and accompanying definitions, wherein X is -PO(OH) ₂ , –PO(OH)O ^- M ⁺ ; –PO(O ^- ) ₂ ⋅2M ⁺ or -PO(O ^- ) ₂ ⋅D ²⁺ ; where M ⁺ represents Li ⁺ , Na ⁺ or K ⁺ and where D ²⁺ represents Mg ²⁺ or Ca ²⁺ .

[00125] In another embodiment, the present invention provides a compound of formula IE and accompanying definitions, wherein R ² and R ³ are Cl and R ⁷ is F.

[00126] In another embodiment, the present invention provides a compound of formula IE and accompanying definitions, wherein R ² and R ³ are Cl, R ⁷ is F, and X is -PO(OH) ₂ .

[00127] In another embodiment, the present invention provides a compound of Formula IE and accompanying definitions, wherein X is -PO(OH)O ^- M ⁺ , –PO(O ^- ) ₂ ⋅ 2M ⁺ ; or -PO(O ^- ) ₂ ⋅D ²⁺ ; M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ or N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group, and D ²⁺ represents Mg ²⁺ , Ca ²⁺ or Ba ²⁺ .

[00128] In another embodiment, the present invention provides a compound of Formula IE and accompanying definitions, wherein X is -PO(OH)O ^- M ⁺ and M ⁺ is Li ⁺ . In one embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is Na ⁺ . In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is K ⁺ . In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group. In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ represents a CH ₃ group.

[00129] In another embodiment, the present invention provides a compound of formula IE and accompanying definitions, where X is -PO(O ^- ) ₂ 2M ⁺ and M ⁺ is Li ⁺ . In one embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is Na ⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is K ⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group. In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ represents a CH ₃ group.

[00130] In another embodiment, the present invention provides a compound of Formula IE and accompanying definitions wherein X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Mg ²⁺ , Ca ²⁺ or Ba ^{2 +} . In one embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Mg ²⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Ca ²⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Ba ²⁺ .

[00131] In another embodiment, the present invention provides a compound of Formula IE and accompanying definitions, wherein X is -PO(OH) _2.

[00132] In another embodiment, the invention relates to a compound of formula IF

I-F,

in which, independently for each case:

R ² represents halogen or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms;

R ⁵ represents halogen, OH, or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms and wherein up to two non-adjacent CH ₂ units of said C ₁ -C ₆ -alkyl may be replaced by -O-; And

X represents -PO(OH) ₂ , –PO(OH)O ^- M ⁺ , –PO(O ^- ) ₂ ⋅2M ⁺ or -PO(O ^- ) ₂ ⋅D ²⁺ ; M ⁺ is a pharmaceutically acceptable monovalent cation; and D ²⁺ is a pharmaceutically acceptable divalent cation.

[00133] In another embodiment, the present invention provides a compound of formula IF and accompanying definitions, wherein R ² represents C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ² is CF ₃ .

[00134] In another embodiment, the present invention provides a compound of formula IF and accompanying definitions, wherein R ⁵ represents a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and wherein up to two non-adjacent CH ₂ units of said C ₁ -C ₆ -alkyl may be replaced by -O-. In one embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is OCF ₃ .

[00135] In another embodiment, the present invention provides a compound of Formula IF and accompanying definitions, wherein X is -PO(OH) ₂ , –PO(OH)O ^- M ⁺ ; –PO(O ^- ) ₂ ⋅2M ⁺ or -PO(O ^- ) ₂ ⋅D ²⁺ ; where M ⁺ represents Li ⁺ , Na ⁺ or K ⁺ and where D ²⁺ represents Mg ²⁺ or Ca ²⁺ .

[00136] In another embodiment, the present invention provides a compound of Formula IF and accompanying definitions, wherein R ² is CF ₃ , R ⁷ is CH ₃ or OCF ₃ , and X is -PO(OH) ₂ .

[00137] In another embodiment, the present invention provides a compound of Formula IF and accompanying definitions, wherein X is -PO(OH)O ^- M ⁺ , –PO(O ^- ) ₂ ⋅ 2M ⁺ ; or -PO(O ^- ) ₂ ⋅D ²⁺ ; M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ or N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group and D ²⁺ represents Mg ²⁺ , Ca ²⁺ or Ba ²⁺ .

[00138] In another embodiment, the present invention provides a compound of Formula IF and accompanying definitions, wherein X is -PO(OH)O ^- M ⁺ and M ⁺ is Li ⁺ . In one embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is Na ⁺ . In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is K ⁺ . In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group. In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ represents a CH ₃ group.

[00139] In another embodiment, the present invention provides a compound of Formula IF and accompanying definitions, wherein X is -PO(O ^- ) ₂ 2M ⁺ and M ⁺ is Li ⁺ . In one embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is Na ⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is K ⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group. In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ represents a CH ₃ group.

[00140] In another embodiment, the present invention provides a compound of Formula IF and accompanying definitions wherein X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Mg ²⁺ , Ca ²⁺ or Ba ^{2 +} . In one embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Mg ²⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Ca ²⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Ba ²⁺ .

[00141] In another embodiment, the present invention provides a compound of Formula IF and accompanying definitions, wherein X is -PO(OH) _2.

[00142] In another embodiment, the invention relates to a compound of formula IG

I-G,

in which, independently for each case:

R ² and R ³ independently represent halogen or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms;

R ⁵ represents halogen, OH, or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms and wherein up to two non-adjacent CH ₂ units of said C ₁ -C ₆ -alkyl may be replaced by -O-;

R ⁷ represents halogen or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted by 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ -alkyl may be replaced by - ABOUT-; And

X represents -PO(OH) ₂ , –PO(OH)O ^- M ⁺ , –PO(O ^- ) ₂ ⋅2M ⁺ or -PO(O ^- ) ₂ ⋅D ²⁺ ; M ⁺ is a pharmaceutically acceptable monovalent cation; and D ²⁺ is a pharmaceutically acceptable divalent cation.

[00143] In another embodiment, the present invention provides a compound of formula IG and accompanying definitions, wherein R ² represents a halogen. In another embodiment, R ² represents Cl.

[00144] In another embodiment, the present invention provides a compound of formula IG and accompanying definitions, wherein R ³ is halogen. In another embodiment, R ³ represents Cl.

[00145] In another embodiment, the present invention provides a compound of formula IG and accompanying definitions, wherein R ⁵ represents a halogen. In another embodiment, R ⁵ represents Cl. In another embodiment, R ⁵ is F. In another embodiment, R ⁵ is C ₁ -C ₆ alkyl. In another embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ -alkyl is replaced by -O- . In another embodiment, R ⁵ is OCH ₃ . In another embodiment, R ⁵ represents OH. In another embodiment, R ⁵ is OCF ₃ .

[00146] In another embodiment, the present invention provides a compound of formula IG and accompanying definitions, wherein R ⁷ is halogen. In one embodiment, R ⁷ is F.

[00147] In another embodiment, the present invention provides a compound of formula IG and accompanying definitions, wherein X is -PO(OH) ₂ , –PO(OH)O ^- M ⁺ ; –PO(O ^- ) ₂ ⋅2M ⁺ or -PO(O ^- ) ₂ ⋅D ²⁺ ; where M ⁺ represents Li ⁺ , Na ⁺ or K ⁺ and where D ²⁺ represents Mg ²⁺ or Ca ²⁺ .

[00148] In another embodiment, the present invention provides a compound of formula IG and accompanying definitions, wherein R ² and R ³ are Cl, R ⁵ is OCH ₃ and R ⁷ is F.

[00149] In another embodiment, the present invention provides a compound of formula IG and accompanying definitions, wherein R ² and R ³ are Cl, R ⁷ is F, R ⁵ is OCH ₃ , and X is -PO(OH) ₂ .

[00150] In another embodiment, the present invention provides a compound of formula IG and accompanying definitions, wherein X is -PO(OH)O ^- M ⁺ , –PO(O ^- ) ₂ ⋅ 2M ⁺ ; or -PO(O ^- ) ₂ ⋅D ²⁺ ; M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ or N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group and D ²⁺ represents Mg ²⁺ , Ca ²⁺ or Ba ²⁺ .

[00151] In another embodiment, the present invention provides a compound of formula IG and accompanying definitions, where X is -PO(OH)O ^- M ⁺ and M ⁺ is Li ⁺ . In one embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is Na ⁺ . In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is K ⁺ . In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group. In another embodiment, X is -PO(OH)O ^- M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ represents a CH ₃ group.

[00152] In another embodiment, the present invention provides a compound of formula IG and accompanying definitions, where X is -PO(O ^- ) ₂ 2M ⁺ and M ⁺ is Li ⁺ . In one embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is Na ⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is K ⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ independently represents H or a C ₁ -C ₄ alkyl group. In another embodiment, X is -PO(O ^- ) ₂ ⋅2M ⁺ and M ⁺ is N(R ⁹ ) ₄ ⁺ ; where each R ⁹ represents a CH ₃ group.

[00153] In another embodiment, the present invention provides a compound of formula IG and accompanying definitions wherein X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Mg ²⁺ , Ca ²⁺ or Ba ^{2 +} . In one embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Mg ²⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Ca ²⁺ . In another embodiment, X is -PO(O ^- ) ₂ ⋅D ²⁺ and D ²⁺ is Ba ²⁺ .

[00154] In another embodiment, the present invention provides a compound of Formula IG and accompanying definitions, wherein X is -PO(OH) _2.

[00155] In another embodiment, the present invention provides a compound of formula IG and accompanying definitions, wherein R ² is Cl, R ³ is Cl, R ⁵ is OCH ₃ , R ⁷ is F, and X is -PO (OH) ₂ .

[00156] In another embodiment, the present invention provides a compound of formula IG and accompanying definitions, wherein R ² is Cl, R ³ is Cl, R ⁵ is OCH ₃ , R ⁷ is F, and X is -PO (O ^- ) ₂ ⋅2M ⁺ , M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ or N(R ⁹ ) ₄ ⁺ , where each R ⁹ independently represents H or a C ₁ -C ₄ -alkyl group.

[00157] In another embodiment, the present invention provides a compound of formula IG and accompanying definitions, wherein R ² is Cl, R ³ is Cl, R ⁵ is OCH ₃ , R ⁷ is F and X is -PO( OH)O ^- M ⁺ , M ⁺ represents Li ⁺ , Na ⁺ , K ⁺ or N(R ⁹ ) ₄ ⁺ , where each R ⁹ independently represents H or a C ₁ -C ₄ -alkyl group.

[00158] In another embodiment, the present invention provides a solid form of (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1( 2H )-yl)methyl dihydrogen phosphate .

[00159] In one embodiment, the present invention provides free crystalline Form B of Compound 9.

[00160] In one embodiment, the present invention provides crystalline Form B (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1( 2H )-yl )methyl dihydrogen phosphate.

[00161] In another embodiment, the present invention provides crystalline Form B (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1( 2H )-yl) methyl dihydrogen phosphate, which is characterized by an X-ray powder pattern (XRPD) containing at least three approximate peak positions (in degrees 2 theta + 0.2) when measured using Cu K _α radiation, selected from the group consisting of 4,4, 15, 2, 16.4, 18.0, 19.1, 19.3, 19.9, 20.2, 20.5, 21.0, 22.2, 23.5 24.2, 24.8, 26 ,3, 29.6, 30.1, and 31.3, with XPRD data collected over an angle range of approximately 4 to approximately 40 degrees 2 theta (2θ).

[00162] In another embodiment, the present invention provides crystalline Form B (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1( 2H )-yl) methyl dihydrogen phosphate, which is characterized by an X-ray powder pattern (XRPD) containing at least three approximate peak positions (in degrees 2 theta + 0.2), when measured using Cu K _α radiation, selected from the group consisting of 19.3, 22.2, 23.5, 26.3 and 30.1, with XPRD data collected over an angle range of approximately 4 to approximately 40 degrees 2 theta (2θ).

[00163] In another embodiment, the present invention provides crystalline Form B (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1( 2H )-yl) methyl dihydrogen phosphate, which is characterized by an X-ray powder pattern, when measured using Cu K _α radiation, substantially similar to that shown in FIG. 2.

[00164] In another embodiment, the present invention provides crystalline Form B (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1( 2H )-yl) methyl dihydrogen phosphate, further characterized by an endothermic peak having an initial temperature of about 210°C degrees, measured using differential scanning calorimetry, in which the temperature is scanned at a rate of approximately 10°C per minute.

[00165] In another embodiment, the present invention provides a method for preparing solid Form B of compound 9.

[00166] In another embodiment, the present invention provides a method for preparing crystalline Form B of Compound 9.

[00167] In one embodiment of the method of the present invention, substantially pure solid Form B of Compound 9 can be prepared from amorphous or crystalline Compound 9 by contacting the compound with an organic solvent, a mixture of organic solvents, or a mixture of an organic solvent and water , at a suitable temperature, stirring for up to 4 weeks and releasing a solid product.

[00168] In another embodiment of the method of the present invention, substantially pure solid Form B of Compound 9 can be prepared from amorphous or crystalline Compound 9 by contacting the compound with water at a suitable temperature, stirring for up to 4 weeks, and isolation of a solid product.

[00169] In another embodiment of the method of the present invention, substantially pure solid Form B of Compound 9 can be prepared from amorphous or crystalline Compound 9 by contacting the compound with an alcohol-based solvent at room temperature, stirring for up to 4- x weeks and isolation of a solid product. In another embodiment, the alcohol-based solvent is methanol, ethanol, or isopropanol.

[00170] In another embodiment of the method of the present invention, substantially pure solid Form B of Compound 9 can be prepared from amorphous or crystalline Compound 9 by contacting the compound with an organic ester solvent at room temperature, stirring for up to 4 -x weeks and isolation of a solid product. In one embodiment, the organic ester solvent is ethyl acetate or isopropyl acetate.

[00171] In another embodiment of the method of the present invention, substantially pure solid Form B of compound 9 can be prepared from amorphous or crystalline compound 9 by contacting the compound with an organic solvent at room temperature, with stirring for up to 4 weeks and isolation of a solid product. In one embodiment, the organic solvent is acetonitrile, acetone, tetrahydrofuran (THF), 2-methyl tetrahydrofuran, or methyl ethyl ketone.

[00172] In another embodiment, substantially pure solid Form B of Compound 9 can be prepared from amorphous or crystalline Compound 9 by contacting the compound with a mixture of organic solvent and water at room temperature, stirring for up to 4 weeks, and isolation of a solid product. In one embodiment, the organic solvent/water mixture refers to THF/water, acetone/water, or alcohol/water. In one embodiment, the alcohol in the alcohol/water mixture is methanol, ethanol, or isopropanol.

[00173] In another embodiment, substantially pure solid Form B of Compound 9 can be prepared from amorphous or crystalline Compound 9 by contacting the compound with a mixture of organic solvent and water at room temperature, stirring for up to 4 weeks, and isolating solid product.

[00174] In another embodiment, substantially pure solid Form B of Compound 9 can be prepared from amorphous or crystalline Compound 9 by contacting the compound with a mixture of an organic solvent and water at an elevated temperature, stirring for up to 4 weeks, and isolating solid product. In another embodiment, substantially pure solid Form B of compound 9 can be prepared from amorphous or crystalline compound 9 by contacting the compound with a mixture of an organic solvent and water under reflux with stirring for up to 24 hours and isolating a solid. In one embodiment, the organic solvent/water mixture refers to THF/water, acetone/water, or alcohol/water. In one embodiment, the organic solvent/water mixture refers to an acetone/water mixture. In another embodiment, the organic solvent/water mixture refers to a THF/water mixture.

[00175] In another embodiment, substantially pure solid Form B of compound 9 can be prepared from amorphous or crystalline compound 9 by exposing the compound to atmospheric conditions for up to 4 weeks and isolating a solid.

[00176] In one embodiment of the method of the present invention, substantially pure crystalline Form B of compound 9 can be prepared from amorphous or crystalline compound 9 by contacting the compound with an organic solvent, a mixture of organic solvents, or a mixture of an organic solvent and water, at suitable temperature, stirring for up to 4 weeks and releasing a crystalline solid.

[00177] In another embodiment of the method of the present invention, substantially pure crystalline Form B of Compound 9 can be prepared from amorphous or crystalline Compound 9 by contacting the compound with water at a suitable temperature, stirring for up to 4 weeks, and release of a crystalline solid.

[00178] In another embodiment of the method of the present invention, substantially pure crystalline Form B of Compound 9 can be prepared from amorphous or crystalline Compound 9 by bringing the compound into contact with an alcohol solvent at room temperature, stirring for up to 4 times weeks and release of a crystalline solid. In another embodiment, the alcohol-based solvent contains methanol, ethanol, or isopropanol.

[00179] In another embodiment of the method of the present invention, substantially pure crystalline Form B of Compound 9 can be prepared from amorphous or crystalline Compound 9 by contacting the compound with an organic ether solvent at room temperature, stirring for up to 4 -x weeks and release of a crystalline solid. In one embodiment, the organic ester solvent contains ethyl acetate or isopropyl acetate.

[00180] In another embodiment of the method of the present invention, substantially pure crystalline Form B of compound 9 can be prepared from amorphous or crystalline compound 9 by contacting the compound with an organic solvent at room temperature, with stirring for up to 4 weeks and liberation of a crystalline solid. In one embodiment, the organic solvent comprises acetonitrile, acetone, tetrahydrofuran (THF), 2-methyltetrahydrofuran, or methyl ethyl ketone.

[00181] In another embodiment, substantially pure crystalline Form B of Compound 9 can be prepared from amorphous or crystalline Compound 9 by contacting the compound with a mixture of organic solvent and water at room temperature, stirring for up to 4 weeks, and isolating crystalline solid. In one embodiment, the organic solvent/water mixture refers to THF/water, acetone/water, or alcohol/water mixtures. In one embodiment, the alcohol in the alcohol/water mixture is methanol, ethanol, or isopropanol.

[00182] In another embodiment, substantially pure crystalline Form B of Compound 9 can be prepared from amorphous or crystalline Compound 9 by contacting the compound with a mixture of organic solvent and water at room temperature, stirring for up to 4 weeks, and isolating crystalline solid.

[00183] In another embodiment, substantially pure crystalline Form B of Compound 9 can be prepared from amorphous or crystalline Compound 9 by contacting the compound with a mixture of an organic solvent and water at an elevated temperature, stirring for up to 4 weeks, and isolating solid product. In another embodiment, substantially pure crystalline Form B of Compound 9 can be prepared from amorphous or crystalline Compound 9 by contacting the compound with a mixture of an organic solvent and water under reflux with stirring for up to 24 hours and liberating a crystalline solid. In one embodiment, the organic solvent/water mixture refers to THF/water, acetone/water, or alcohol/water. In one embodiment, the organic solvent/water mixture contains acetone/water. In another embodiment, the organic solvent/water mixture contains THF/water.

[00184] In another embodiment, substantially pure crystalline Form B of compound 9 can be prepared from amorphous or crystalline compound 9 by exposing the compound to atmospheric conditions for up to 4 weeks and isolating a solid.

[00185] Crystalline Form B of Compound 9 can be identified by broad endothermicity at about 214°C, followed by an exothermic peak at about 217°C. The endothermic peak has an initial temperature of 210°C. One skilled in the art will recognize that the endothermic peak and endothermic onset temperatures may vary depending on the experimental conditions. Crystalline form B of compound 9 can also be identified by X-ray powder diffraction, mainly as shown in Table 1 and 2, where XRPD samples were measured using a powder diffractometer equipped with a Cu anode X-ray tube source. The sample was irradiated with Cu Kα ₁ radiation and XPRD data was collected over an angle range from approximately 4 to approximately 40 degrees 2 theta (2θ). One skilled in the art will appreciate that the relative intensities of the XPRD peaks may vary significantly depending on the orientation of the sample being examined and the type and setup of the instrument used, so that the intensities in the XPRD curves included in the present invention are illustrative to the extent character and are not intended for use in comparisons of absolute values.

[00186] Figure 2 shows an X-ray powder diffraction pattern of crystalline form B of compound 9 where data was collected over an angle range of about 4 to about 40 degrees 2θ. The peaks corresponding to the X-ray powder diffraction pattern having a relative intensity greater than or equal to 5% are shown in Table 1.

[00187] Figure 3 shows a DSC thermogram of crystalline form B of compound 9, showing a broad endothermic peak at approximately 214°C, followed by an exothermic peak at approximately 217°C. The endothermic peak has an initial temperature at 210°C. One skilled in the art will appreciate that the endothermic peak and endothermic onset temperatures may vary depending on the experimental conditions. The data presented in Figure 3 was collected as follows: approximately 1-2 mg of sample was placed in an aluminum cup, which was press-fitted with a single pin hole lid. The DSC sample was scanned from 25°C to the temperatures indicated in the graphs at a heating rate of 10°C/min in a nitrogen stream (50 ml/min). Samples were analyzed by modulated differential scanning calorimetry (MDSC), with temperature modulation with an amplitude of + and -1°C every 60 seconds at a ramp rate of 2 or 3°C/min. Data were collected and analyzed using TRIOS software (TA Instruments, New Castle, DE).

[00188] Figure 4 is a TGA thermogram of crystalline form B of compound 9 showing the onset of mass loss at approximately 218°C and scanned from room temperature to approximately 300°C at a heating rate of 10°C/min. .

[00189] In one embodiment, the present invention provides solid Form B (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1( 2H )-yl )methyl dihydrogen phosphate.

[00190] In one embodiment, the present invention provides crystalline Form B (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1( 2H )-yl )methyl dihydrogen phosphate.

[00191] In another embodiment, crystalline Form B of (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1( 2H )-yl)methyldihydrogen phosphate is characterized by powder X-ray diffraction pattern (XPRD) containing at least three approximate peak positions (in degrees 2 theta [2θ ] ± 0.2), when measured using Cu K _α radiation, selected from the group consisting of 4.4, 12, 7, 13.3, 14.7, 15.2, 16.4, 18.0, 19.1, 19.3, 19.9, 20.2, 20.5, 21.0, 22.2, 23.5 24.2, 24.8, 26.3, 29.6, 30.1 and 31.3, with XPRD data collected over an angle range of approximately 4 to approximately 40 in degrees 2 theta (2θ).

[00192] In another embodiment, crystalline Form B of (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1( 2H )-yl)methyldihydrogen phosphate is characterized by an X-ray powder diffraction pattern (XPRD) containing at least three approximate peak positions (in degrees 2 theta ± 0.2) when measured using Cu K _α radiation, selected from the group consisting of 4.4, 16.4, 19.3 , 22.2, 23.5, 26.3, 29.6, and 30.1, with XPRD data collected over a range of angles from approximately 4 to approximately 40 degrees 2θ.

[00193] In another embodiment, crystalline Form B of (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1( 2H )-yl)methyldihydrogen phosphate is characterized by an X-ray powder diffraction pattern , when measured using Cu K _α radiation, which is essentially the same as shown in Figure 2.

[00194] In another embodiment, crystalline Form B of (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1( 2H )-yl)methyldihydrogen phosphate is further characterized by an endothermic peak having an initial temperature of approximately 210°C, measured using differential scanning calorimetry, in which the temperature is scanned at a rate of 2-3°C per minute.

[00195] In another embodiment, the present invention relates to a method for preparing crystalline form B of compound 9, comprising suspending a solid in free form in a solvent system containing one or more organic solvents or a mixture of one or more organic solvents and water, and isolating the solid .

[00196] In another embodiment, the present invention provides a method for preparing solid Form B of Compound 9, comprising contacting Compound 9 with water, an organic solvent, a mixture of organic solvents, or a mixture of an organic solvent and water at a suitable temperature, with stirring for up to 4 -x weeks and isolation of a solid product.

[00197] In another embodiment, the present invention provides a method for preparing crystalline Form B of Compound 9, comprising direct crystallization from a reaction mixture with or without seeding Form B. In one embodiment, direct crystallization occurs in a final deprotection step where Compound 20 heated to the appropriate temperature in a suitable mixture of solvents with a suitable acidic reagent for an appropriate period of time. In one embodiment, a suitable mixture of organic solvents is water and acetonitrile, a suitable acid reagent is acetic acid, a suitable temperature is between 50°C and 100°C, and a suitable time is between 10 and 240 minutes.

[00198] In one embodiment, the direct crystallization method includes treating di-tert-butyl[4-[[2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1 -pyridyl]methylphosphate (123.2 g, 196 mmol) in a 3-liter vessel with acetonitrile (1.23 L), acetic acid (616 ml), water (616 ml) and heat with stirring at 70°C for 1. 1 hour, further treat the mixture with several seeds of 4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate Form B, leaving the mixture to stir at 70°C until cloudy and then turn off the heat and leave the mixture to cool to room temperature. After stirring overnight, the crystalline solids were collected by filtration and dried in a vacuum oven to constant weight to obtain 84.0 g of crystalline Form B 4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido) -2-oxopyridin-1(2H)-yl)methyl.

[00199] In another embodiment, crystalline Form B is physically and chemically stable for at least one month at 5°C/no humidity, 40°C/no humidity, 25°C with a relative humidity of up to 60 %; and at 40°C with relative humidity up to 75%. In another embodiment, crystalline Form B is physically and chemically stable for at least three months under any conditions, including, but not limited to, an open container at 40°C, at 40°C with relative humidity up to 75% , at 25°C with relative humidity up to 60%, and a closed vessel at 5°C with a desiccant. The phrase “chemically and physically stable” implies the absence of any change in the X-ray powder diffraction and HPLC impurity profiles (eg, less than 0.2% deviation) and implies no change in the physical properties of the samples.

[00200] Table 1. XRPD sample peaks for crystalline Form B of 4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1( 2H )-yl)methyl dihydrogen phosphate

Peak number Position
[°2θ] Relative intensity [%] 1 4.43 13.6 2 12.74 2.3 3 13.29 4.5 4 14.70 1.9 5 15.19 8.6 6 16.42 13.9 7 17.99 5.3 8 19.12 10.4 9 19.34 15.8 10 19.85 8.8 eleven 20.19 11.1 12 20.45 12.3 13 21.03 11.2 14 22.20 100.0 15 23.52 30.6 16 24.21 11.5 17 24.81 11.7 18 26.33 21.2 19 29.59 13.1 20 30.05 15.8 21 31.28 10.5

[00201] In one embodiment, the present invention provides an amorphous form of C (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1( 2H )-yl )methyl dihydrogen phosphate.

[00202] In another embodiment, amorphous Form C of compound 9, characterized by X-ray powder diffraction (XPRD) using Cu K _α radiation, is characterized by a broad halo without a distinct diffraction peak.

[00203] In yet another embodiment, the present invention provides a method for preparing amorphous Form C of Compound 9, comprising spray-drying a solution of Compound 9 with or without copolymer.

[00204] In one embodiment, the present application relates to a method for preparing solid Form C of compound 9. In some embodiments, the amorphous material is collected after it has precipitated from a solvent or from a solution after concentrating the solution by evaporating some of the water from the solution, for example , using a rotary evaporator. Alternatively, adding a second solvent to the mixture may cause Form C to precipitate.

[00205] Compound 9 can be converted to amorphous solid Form C using any method known to those skilled in the art. Amorphous compound 9 can be characterized by the absence of the diffraction pattern characteristic of the crystalline form. The X-ray powder diffraction pattern of the partially amorphous Form C may still not have the properties of the crystalline form, since the diffraction peaks of the crystalline portion of the sample may be too weak to be observed above the noise. Figure 5 shows the X-ray powder diffraction pattern of amorphous Form X of compound 9.

[00206] In one embodiment, amorphous Form C of Compound 9 can be prepared by spray-drying a solution of the compound in a suitable solvent. Spray drying is well known in the art and is often used for drying thermally sensitive substances such as pharmaceuticals. Spray drying also ensures an even distribution of particles that can be reproduced quite well. Any gas can be used to dry the powder, although air is usually used. If the substance is sensitive to air, an inert gas such as nitrogen or argon may be used. Any preparation method that converts a solution, slurry, suspension or emulsion of a compound into a solid powder may be suitable for amorphous Form C of Compound 9.

[00207] In one embodiment, a solution of compound 9 in a polar solvent can be spray dried using a nanospray dryer equipped with a condenser. The inlet temperature can be maintained between 70 and 120ºC.

[00208] It should be understood that the crystalline form B of compound 9 and the amorphous solid form C of compound 9, in addition to the XRPD, DSC, TGA and other characteristics described herein, may also have other characteristics that are not described, for example, but but not limited to, the presence of one or more molecules of water or solvent.

[00209] X-ray powder diffraction (XRPD) : X-ray powder diffraction measurements were performed using PANalytical's X-pert Pro diffractometer at room temperature with irradiation generated by a copper source (1.54060 A). The incident beam optical device included a slit with beam divergence control to provide a constant illumination length on the sample and on the side of the diffracted beam; used a fast linear solid state detector with an active length of 2.12 degrees 2 theta measured in scan mode. The powdered sample was packed onto the honeycomb surface of a silicon sample holder with zero background and centrifuged to obtain better statistics. The symmetric scan was measured from 4-40 degrees 2 theta (2θ) with a step size of 0.017 degrees and a scan step time of 15.5 sec.

[00210] Differential scanning calorimetry (DSC) :

[00211] Differential scanning calorimetry (DSC) was performed using a Discovery DSC differential scanning calorimeter (TA Instruments, New Castle, DE). The instrument was calibrated using indium. Approximately 1-2 mg of sample was placed in an aluminum cup, which was pressed with a lid with a single pinhole. DSC samples were scanned from 25°C to the temperatures indicated in the graphs at a heating rate of 10°C/min under a nitrogen stream (50 ml/min). Samples were analyzed by modulated differential scanning calorimetry (MDSC), with temperature modulation with an amplitude of + and -1°C every 60 seconds at a ramp rate of 2 or 3°C/min. Data were collected and analyzed using TRIOS software (TA Instruments, New Castle, DE).

[00212] Thermogravimetric analysis (TGA) :

[00213] For TGA measurements, a thermogravimetric analyzer, model Discovery TGA (TA Instruments, New Castle, DE) was used. A sample weighing approximately 2-5 mg was scanned from room temperature to the temperatures indicated in the curves at a heating rate of 10°C/min. Data were collected and analyzed using TRIOS software (TA Instruments, New Castle, DE).

[00214] The names of the compounds in the present invention were obtained using the ChemBioDrawUltra program, Cambridge Soft/Chem Office 2010 version.

[00215] Table 2 Compound Numbers, Structures, and Chemical Names

1
(4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate 10
(4-(2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate 2
(4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate eleven
(4-(2-(2-chloro-4-fluorophenoxy)-5-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate 3
(4-(4,5-dichloro-2-(4-fluorophenoxy)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate 12
(4-(5-chloro-2-(4-fluoro-2-methylphenoxy)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrophate 4
(4-(2-(4-fluoro-2-methoxyphenoxy)-5-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate 13
(4-(4-chloro-2-(4-fluoro-2-methylphenoxy)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate 5
(2-oxo-4-(2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamido)pyridin-1(2H)-yl)methyl dihydrogen phosphate 14
(4-(5-chloro-2-(2-chloro-4-fluorophenoxy)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate 6
(4-(2-(4-fluorophenoxy)-4-(perfluoroethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate 15
(2-oxo-4-(2-(o-tolyloxy)-5-(trifluoromethyl)benzamido)pyridin-1(2H)-yl)methyl dihydrogen phosphate 7
(4-(5-chloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate 16
(4-(2-(2,4-difluorophenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate 8
(2-oxo-4-(2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamido)pyridin-1(2H)-yl)methyl dihydrogen phosphate 17
(2-oxo-4-(2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamido)pyridin-1(2H)-yl)methyl dihydrogen phosphate 9
(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate 18
(4-(2-(4-fluorophenoxy)-5-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate

[00216] In one embodiment, the compound is (4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)-2-oxopyridin-1( 2H )-yl)methyl dihydrogen phosphate or thereof pharmaceutically acceptable salt.

[00217] In another embodiment, the compound is (4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)-2-oxopyridin-1( 2H )-yl)methyl dihydrogen phosphate or pharmaceutical thereof acceptable salt.

[00218] In another embodiment, the compound is (4-(4,5-dichloro-2-(4-fluorophenoxy)benzamido)-2-oxopyridin-1( 2H )-yl)methyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof.

[00219] In another embodiment, the compound is (4-(2-(4-fluoro-2-methoxyphenoxy)-5-(trifluoromethyl)benzamido)-2-oxopyridin-1( 2H )-yl)methyl dihydrogen phosphate or pharmaceutical grade thereof acceptable salt.

[00220] In another embodiment, the compound is (2-oxo-4-(2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamido)pyridin-1( 2H )-yl)methyl dihydrogen phosphate, or a pharmaceutical grade thereof acceptable salt.

[00221] In another embodiment, the compound is (4-(2-(4-fluorophenoxy)-4-(perfluoroethyl)benzamido)-2-oxopyridin-1( 2H )-yl)methyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof.

[00222] In another embodiment, the compound is (4-(5-chloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)-2-oxopyridin-1( 2H )-yl)methyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof .

[00223] In another embodiment, the compound is (2-oxo-4-(2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamido)pyridin-1( 2H )-yl)methyl dihydrogen phosphate, or a pharmaceutical grade thereof acceptable salt.

[00224] In another embodiment, the compound is (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1( 2H )-yl)methyl dihydrogen phosphate or pharmaceutical thereof acceptable salt.

[00225] In another embodiment, the compound is (4-(2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamido)-2-oxopyridin-1( 2H )-yl)methyl dihydrogen phosphate or pharmaceutical thereof acceptable salt.

[00226] In another embodiment, the compound is (4-(2-(2-chloro-4-fluorophenoxy)-5-(trifluoromethyl)benzamido)-2-oxopyridin-1( 2H )-yl)methyl dihydrogen phosphate or pharmaceutical grade thereof acceptable salt.

[00227] In another embodiment, the compound is (4-(5-chloro-2-(4-fluoro-2-methylphenoxy)benzamido)-2-oxopyridin-1( 2H )-yl)methyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof .

[00228] In another embodiment, the compound is (4-(4-chloro-2-(4-fluoro-2-methylphenoxy)benzamido)-2-oxopyridin-1( 2H )-yl)methyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof .

[00229] In another embodiment, the compound is (4-(5-chloro-2-(2-chloro-4-fluorophenoxy)benzamido)-2-oxopyridin-1( 2H )-yl)methyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof .

[00230] In another embodiment, the compound is (2-oxo-4-(2-(o-tolyloxy)-5-(trifluoromethyl)benzamido)pyridin-1( 2H )-yl)methyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof.

[00231] In another embodiment, the compound is (4-(2-(2,4-difluorophenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1( 2H )-yl)methyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof .

[00232] In another embodiment, the compound is (2-oxo-4-(2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamido)pyridin-1( 2H )-yl)methyl dihydrogen phosphate, or a pharmaceutical grade thereof acceptable salt.

[00233] In another embodiment, the compound is (4-(2-(4-fluorophenoxy)-5-(trifluoromethyl)benzamido)-2-oxopyridin-1( 2H )-yl)methyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof.

Compositions, uses, dosage form, administration and additional agents

Pharmaceutically acceptable compositions

[00234] As described herein, the present invention relates to compounds that are voltage-gated sodium channel inhibitors, and thus, the compounds of the present invention are used for the treatment of diseases, disorders and conditions, including, but not limited to, chronic pain, bowel pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or cardiac arrhythmia. Accordingly, in another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein said compositions contain any of the compounds described herein and optionally include a pharmaceutically acceptable carrier, adjuvant or excipient. In some embodiments, these compositions optionally further include one or more additional therapeutic agents.

[00235] The term "pharmaceutically acceptable salt" refers to salts that, within the bounds of sound medical judgment, are suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and are reasonable benefit/risk ratio. The term "pharmaceutically acceptable salt" means any non-toxic salt of the present invention which, when administered to a recipient, is capable of providing, directly or indirectly, a compound of the present invention or an inhibitory active metabolite or residue thereof. As used herein, the term “inhibitory active metabolite or residue” means that its metabolite or residue is also a voltage-gated sodium channel inhibitor.

[00236] Pharmaceutically acceptable salts are known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the invention include salts prepared with suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzulfulfonate, benzoate, bisulfate, borat, butyrate, campforates, campfordfonet, citrate, cyclopentanpropionate, diglukonate, pre -deucyl sulfate, ethangent, format, fumarat, glucogheptanoathane, claws Rofosphate, gluconate, hemysufate, heptanoate , hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate , phosphate, picrinate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts prepared with suitable bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 -alkyl) ₄ salts. The present invention also provides for the quaternization of any basic nitrogen atom-containing groups in the compounds described herein. Water-soluble or fat-soluble or dispersible products can be obtained by such quaternization. Examples of alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts and the like. Other pharmaceutically acceptable salts include, as appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using a counterion such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate.

[00237] As described herein, pharmaceutically acceptable compositions of the present invention further include a pharmaceutically acceptable carrier, adjuvant or vehicle, which, as used herein, includes any and all solvents, diluents or other liquid carriers, dispersing or suspending excipients , surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., suitable for the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) describes various carriers used in the preparation of pharmaceutically acceptable compositions and known methods for their preparation. Unless the normal carrier environment is incompatible with the compounds of the present invention, for example, producing any undesirable biological effect or otherwise interacting in an undesirable manner with any other component(s) of the pharmaceutically acceptable composition, its use is within the scope of the present invention. Some examples of substances that may be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffers such as phosphates, aminoacetic acid, sorbic potassium acid or sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon oxide, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene - block polymers, lanolin, sugars such as lactose, glucose and sucrose; starch such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline solution; Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colors, release agents, coating agents, sweeteners, flavors and fragrances, preservatives and antioxidants may also be present in the composition at the discretion of the formulator.

[00238] In another aspect, the present invention relates to a pharmaceutical composition containing a compound of the invention and a pharmaceutically acceptable carrier.

[00239] In another aspect, the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of compounds of formula I and one or more pharmaceutically acceptable carriers or excipients.

Use of Compounds and Pharmaceutically Acceptable Compositions

[00240] In another aspect, the present invention provides a method of inhibiting a voltage-gated sodium channel in a subject, comprising administering to the subject a compound of Formula I or a pharmaceutical composition thereof. In another aspect, the voltage-gated sodium channel is NaV1.8.

[00241] In yet another aspect, the present invention provides a method for treating or alleviating chronic pain, bowel pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis in a subject. , Charcot-Marie-Tooth syndrome, incontinence, pathological cough or cardiac arrhythmia, comprising administering to a subject an effective amount of a compound or pharmaceutical composition of a compound of Formula I.

[00242] In yet another aspect, the present invention provides a method of treating or reducing the severity of bowel pain in a subject, wherein the bowel pain includes inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain, wherein the method includes administering an effective amount compounds or pharmaceutical compositions of compounds of formula I.

[00243] In yet another aspect, the present invention provides a method for treating or alleviating neuropathic pain in a subject, wherein the neuropathic pain includes postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, pain after amputations, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma, pinched nerves, spinal stenosis, carpal tunnel syndrome, sciatica, sciatica pain; nerve avulsion, brachial plexus avulsion, complex regional pain syndrome, drug therapy-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, pain after spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia wherein the method comprises administering an effective amount of a compound or pharmaceutical composition of a compound of Formula I.

[00244] In yet another aspect, the present invention provides a method for treating or alleviating the severity of musculoskeletal pain in a subject, wherein the musculoskeletal pain includes osteoarthritic pain, back pain, cold pain, burn pain, or dental pain, wherein said method comprising administering an effective amount of a compound or pharmaceutical composition of a compound of formula I.

[00245] In yet another aspect, the present invention provides a method of treating or reducing the severity of inflammatory pain in a subject, wherein the inflammatory pain includes pain associated with rheumatoid arthritis or vulvodynia, the method comprising administering an effective amount of a compound or pharmaceutical composition of a compound of Formula I.

[00246] In yet another aspect, the present invention provides a method of treating or reducing the severity of inflammatory pain in a subject, wherein the inflammatory pain includes pain associated with rheumatoid arthritis, the method comprising administering an effective amount of a compound or pharmaceutical composition of a compound of Formula I.

[00247] In yet another aspect, the present invention provides a method of treating or reducing the severity of idiopathic pain in a subject, wherein the idiopathic pain includes fibromyalgia pain, the method comprising administering an effective amount of a compound or pharmaceutical composition of a compound of Formula I.

[00248] In yet another aspect, the present invention provides a method of treating or alleviating the severity of a subject's cough, wherein the method comprises administering an effective amount of a compound or pharmaceutical composition of a compound of Formula I.

[00249] In yet another aspect, the present invention provides a method in which a subject is treated with one or more additional therapeutic agents administered simultaneously with, before, or after treatment with an effective amount of a compound or pharmaceutical composition of a compound of Formula I.

[00250] In another aspect, the present invention provides a method of inhibiting a voltage-gated sodium channel in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutical composition of a compound of formula I. In another aspect, the voltage-gated sodium channel is NaV1.8.

[00251] In another aspect, the present invention provides a method of inhibiting a voltage-gated sodium channel in a biological sample, comprising contacting the biological sample with an effective amount of a compound or pharmaceutical composition of a compound of Formula I. In another aspect, the voltage-gated sodium channel is NAV1.8.

[00252] In another aspect, the present invention relates to a method of treating or reducing the severity of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, in a subject, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety disorders, depression, dipolar disorder, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritic pain, postherpetic neuralgia, diabetic neuropathy, sciatica, sciatica, back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain, cancer pain, stroke, cerebral ischemia, cranial injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, elevated blood pressure, or abnormal gastrointestinal motility, comprising administering an effective amount of a compound or pharmaceutical composition of a compound of Formula I.

[00253] In another aspect, the present invention relates to a method of treating or reducing the severity of a subject's pain from malignant tumor of the femur, chronic pain from benign bone tumor, rheumatoid arthritis, osteoarthritis, spinal stenosis, neuropathic lumbar back pain, myofascial pain syndrome ; fibromyalgia, pain in the temporomandibular joint, chronic visceral pain, abdominal pain, pain in the pancreas, pain in irritable bowel syndrome, chronic and acute headaches; migraine, tension headaches, cluster headaches, chronic and acute neuropathic pain, postherpetic neuralgia, diabetic neuropathy, HIV-associated neuropathy, trigeminal neuralgia, Charcot-Marie-Tooth neuropathy, hereditary sensory neuropathy, peripheral nerve damage, painful neuromas, ectopic proximal and distal secretions; radiculopathy, chemotherapy-induced neuropathic pain, radiation therapy-induced neuropathic pain, post-mastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, complex regional pain syndrome, phantom pain, unrelieved pain, acute pain, acute post-operative pain , acute musculoskeletal pain, joint pain, mechanical lumbar pain, neck pain, tendonitis, traumatic pain, pain on exercise, acute visceral pain, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, heart pain ; pain in the pelvic area, pain with renal colic, acute obstetric pain, pain during labor; cesarean section pain, acute inflammatory pain, burn pain, traumatic pain, acute periodic pain, endometriosis, acute herpes zoster pain, sickle cell anemia, acute pancreatitis, breakthrough pain, orofacial pain, sinus pain, toothache , pain in multiple sclerosis (MS), pain in depression, pain in leprosy, pain in Behçet's disease, pain in morbid obesity, phlebitis pain, pain in Guillain-Barré syndrome, pain in the case of painful legs and toes when walking; Haglund syndrome, erythromelalgia pain, Fabry disease pain, bladder and genitourinary disease, stress urinary incontinence, pathological cough, overactive bladder, bladder pain syndrome, interstitial cystitis (IC), prostatitis, complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II, general pain, severe paroxysmal pain, pruritis, tinnitus or pain caused by angina pectoris, comprising administering an effective amount of a compound or pharmaceutical composition of a compound of Formula I.

[00254] In another aspect, the present invention provides a method of treating or reducing the severity of neuropathic pain in a subject, comprising administering an effective amount of a compound or pharmaceutical composition, a compound of Formula I. In one aspect, the neuropathic pain is selected from postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma, entrapped nerves, spinal stenosis, carpal tunnel syndrome, sciatica, sciatica pain, nerve avulsion, brachial plexus avulsion, complex regional pain syndrome, drug therapy-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, pain after spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalgia.

Production of medicines

[00255] In one aspect, the present invention relates to the use of a compound or pharmaceutical composition of Formula I for the preparation of a medicament for use in voltage-gated sodium channel inhibition. In another aspect, the voltage-gated sodium channel is NaV1.8.

[00256] In yet another aspect, the present invention relates to the use of a compound or pharmaceutical composition of Formula I for the preparation of a medicament for use in the treatment or reduction of severity in a subject of chronic pain, bowel pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, pain associated with a malignant tumor, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or cardiac arrhythmia.

[00257] In yet another aspect, the present invention relates to the use of a compound or pharmaceutical composition of Formula I for the preparation of a medicament for use in treating or reducing the severity of bowel pain in a subject, wherein bowel pain refers to pain associated with inflammatory bowel disease, pain associated with Crohn's disease or pain due to interstitial cystitis.

[00258] In yet another aspect, the present invention relates to the use of a compound or pharmaceutical composition of Formula I for the preparation of a medicament for use in treating or reducing the severity of neuropathic pain in a subject, wherein the neuropathic pain includes postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory pain neuropathy, trigeminal neuralgia, burning mouth syndrome, pain after amputation, phantom pain, painful neuroma; traumatic neuroma, Morton's neuroma, nerve entrapment, spinal stenosis, carpal tunnel syndrome, sciatica, sciatica pain, nerve avulsion, brachial plexus avulsion, complex regional pain syndrome, drug therapy-induced neuralgia, cancer chemotherapy-induced neuralgia, neuralgia, induced by antiretroviral therapy, pain after spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic neuropathy.

[00259] In yet another aspect, the present invention relates to the use of a compound or pharmaceutical composition of Formula I for the preparation of a medicament for use in treating or reducing the severity of musculoskeletal pain in a subject, wherein the musculoskeletal pain includes osteoarthritic pain, back pain, pain pain caused by cold, pain from burns or toothache.

[00260] In yet another aspect, the present invention relates to the use of a compound or pharmaceutical composition of Formula I for the preparation of a medicament for use in treating or reducing the severity of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain or vulvodynia.

[00261] In yet another aspect, the present invention relates to the use of a compound or pharmaceutical composition of Formula I for the preparation of a medicament for use in treating or reducing the severity of inflammatory pain in a subject, wherein the inflammatory pain includes pain associated with rheumatoid arthritis.

[00262] In yet another aspect, the present invention relates to the use of a compound or pharmaceutical composition of Formula I for the preparation of a medicament for use in treating or reducing the severity of idiopathic pain in a subject, wherein the idiopathic pain includes fibromyalgia pain.

[00263] In yet another aspect, the present invention relates to the use of a compound or pharmaceutical composition of Formula I for the preparation of a medicament for use in treating or reducing the severity of a subject having a pathological cough.

[00264] In yet another aspect, the present invention relates to the use of a compound or pharmaceutical composition of Formula I for the preparation of a drug in combination with one or more additional therapeutic agents administered simultaneously with, before, or after treatment with the compound or pharmaceutical composition.

[00265] In another aspect, the present invention relates to the use of a compound or pharmaceutical composition of Formula I for the preparation of a medicament for use in treating or reducing the severity of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headaches, neuralgia trigeminal nerve, herpetic neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, mental disorders, anxiety disorders, depression, dipolar disorder, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritic pain, postherpetic neuralgia, diabetic neuropathy, sciatica, sciatica, back pain, headache, neck pain, severe pain, unrelenting pain, nociceptive pain, breakthrough pain, post-operative pain, cancer pain , stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, rapid heartbeat, elevated blood pressure, or abnormal gastrointestinal motility.

[00266] In another aspect, the present invention relates to the use of a compound or pharmaceutical composition of Formula I for the preparation of a medicament for use in treating or reducing the severity of pain due to malignant tumor of the femur, benign chronic bone pain, rheumatoid arthritis, osteoarthritis, spinal stenosis , neuropathic pain in the lumbar back, myofascial pain syndrome, fibromyalgia, pain in the temporomandibular joint, chronic visceral pain, abdominal pain, pain in the pancreas, pain in irritable bowel syndrome, chronic and acute headaches, migraines, tension headaches, cluster headaches, chronic and acute neuropathic pain, postherpetic neuralgia, diabetic neuropathy, HIV-associated neuropathy, trigeminal neuralgia, Charcot-Marie-Tooth neuropathy, hereditary sensory neuropathy, peripheral nerve damage, painful neuroma, ectopic proximal and distal discharge, radiculopathy, chemotherapy-induced neuropathic pain, radiation therapy-induced neuropathic pain, post-mastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, complex regional pain syndrome, phantom pain, unrelieved pain, acute pain, acute post-operative pain, acute musculoskeletal pain, joint pain, mechanical lumbar pain, neck pain, tendinitis, traumatic pain, pain on exercise, acute visceral pain, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain , heart pain, pain in the pelvic area, renal colic, acute obstetric pain, pain during labor, pain during caesarean section, acute inflammatory pain, pain from burns, traumatic pain, acute periodic pain, endometriosis, acute pain from herpes zoster, sickle cell anemia, acute pancreatitis, breakthrough pain, orofacial pain, sinus pain, dental pain, multiple sclerosis (MS) pain, depression pain, leprosy pain, Behçet's disease pain, morbid obesity pain, phlebitis pain, pain in Guillain-Barré syndrome, pain in the case of painful legs and toes when walking, Haglund's syndrome, pain in erythromelalgia, pain in Fabry disease, diseased bladder and genitourinary diseases, stress urinary incontinence, pathological cough, overactive bladder, bladder pain syndrome, interstitial cystitis (IC), prostatitis, complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II, widespread pain, severe paroxysmal pain, pruritis, tinnitus or pain caused by angina pectoris .

[00267] In another aspect, the present invention relates to the use of a compound or pharmaceutical composition of Formula I for the preparation of a medicament for use in treating or reducing the severity of neuropathic pain. In one aspect, the neuropathic pain is selected from postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment, spinal stenosis, carpal tunnel syndrome, sciatica, sciatica pain, nerve avulsion, brachial plexus avulsion, complex regional pain syndrome, drug therapy-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, pain after spinal cord injury , idiopathic sensory neuropathy or trigeminal autonomic cephalgia.

Administration of pharmaceutically acceptable compositions.

[00268] In some embodiments of the present invention, an "effective amount" of a compound or pharmaceutically acceptable composition is an amount effective to treat or reduce the severity of one or more conditions: chronic pain, bowel pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, pain associated with a malignant tumor, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or cardiac arrhythmia.

[00269] The compounds and compositions, in accordance with 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 painful or non-painful diseases described herein. The exact amount required will vary depending on the subject, depending on the species, age and general condition of the subject, the severity of the infection, the specific agent, its route of administration, and the like. The compounds of the present invention are preferably prepared in unit dosage form for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically discrete unit of agent suitable for the patient being treated. However, it will be appreciated that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the bounds of sound medical judgment. The specific effective dose level for any particular subject or organism will depend on various factors, including the disorder being treated and the severity of the disease; the activity of the particular compound used; the specific composition used; age, body weight, general health, gender, and diet of the subject; timing of administration, route of administration, and rate of elimination of the particular compound used; duration of treatment; drugs used in combination or in conjunction with the particular compound used, and similar factors well known in the medical fields. The term "subject" or "patient" as used herein refers to an animal, preferably a mammal, and most preferably a human.

[00270] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (in the form of powders, ointments or drops), buccally, as an oral or nasal spray, or the like. etc., depending on the severity of the infection to be treated. In some embodiments, the compounds of the present invention may be administered orally or parenterally in doses ranging from about 0.01 mg/kg to about 50 mg/kg, and preferably from about 1 mg/kg to about 25 mg/kg of the subject's body weight per day, one or several times a day to obtain the desired therapeutic effect.

[00271] 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 compounds, liquid dosage forms may contain excipients commonly used in the art, such as water or other solvents, solubility enhancing agents, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol , 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, wheat germ, olive, castor and sesame oils), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitol fatty acid esters, and mixtures thereof. In addition to excipients, adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances may be added to oral compositions.

[00272] Injectable preparations, for example, sterile aqueous or oleaginous injectable suspensions, can be prepared using suitable dispersing or wetting agents, as well as suspending agents, known in the art. Sterile injectable preparations may also be a sterile injectable solution, suspension or emulsion in a non-toxic, parenterally acceptable vehicle or diluent, for example a solution in 1,3-butanediol. Acceptable carriers and solvents that may be used are water, Ringer's solution, USP solution and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as the dissolution or suspension medium. Any soft, fixed oil can be used for this purpose, including synthetic mono- and diglycerides. In addition, fatty acids such as oleic acid are used to produce injectable drugs.

[00273] Injectable formulations may be sterilized, for example, by filtration through bacterial filters or by adding sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable media prior to administration.

[00274] In order to prolong the effect of the compound of the present invention, it is generally desirable to delay the absorption of the compound from the site of subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous substances that are poorly soluble in water. The rate of absorption of the compound in this case will depend on the rate of its dissolution, which, in turn, depends on the size of the crystals and crystal structure. Alternatively, delayed absorption of a parenterally administered compound is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are prepared by forming microcapsule matrices of the compound on biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer, as well as the nature of the particular polymer used, the rate of release of the compound can be adjusted. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot forms are also prepared by enclosing the compound in liposomes or microemulsions that are compatible with body tissues.

[00275] Compositions for rectal or vaginal administration are advantageously suppositories, which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or suppository wax, which are solid at room temperature. temperature, but become liquid at body temperature and, as a result, melt in the rectum or vaginal cavity, and release the active compound.

[00276] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In said solid forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as citrate or dicalcium phosphate and/or a) excipients or dry diluents such as starch, lactose, glucose, mannitol and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) humectants such as glycerin, d) disintegrants such as agar-agar, calcium carbonate, potato starch or tapioca starch , alginic acid, some silicates and sodium carbonate, e) dissolution retarding agents such as paraffin, f) absorption accelerating agents such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h ) adsorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.

[00277] Solid compositions of a similar type can also be enclosed in soft and hard gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms, such as tablets, dragees, capsules, pills and granules, can be prepared using coatings and coatings, such as enteric coatings and other coatings well known to those skilled in the art of pharmacy. They may optionally contain opalescent agents and also include compositions which release the active component(s) only or preferentially in a specific part of the gastrointestinal tract, optionally in a delayed manner. Examples of "embedded" compositions that can be used include polymeric substances and waxes. Solid compositions of this type can also be enclosed in soft and hard gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[00278] The active compounds may also be in the form of microcapsules with 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 coatings, such as enteric coatings, controlled release coatings, and other coatings well known to those skilled in the art of preparing pharmaceutical compositions. In these solid dosage forms, the active compound may be mixed with at least one excipient such as sucrose, lactose or starch. These dosage forms, in addition to excipients, may also typically contain additional substances, for example tablet lubricants and other tablet excipients such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, dosage forms may also contain buffering agents. They may optionally contain opalescent agents and also include compositions which release the active component(s) only or preferentially in a specific part of the gastrointestinal tract, optionally in a delayed manner. Examples of "embedded" compositions that can be used include polymeric substances and waxes.

[00279] Dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, if required. Ophthalmic preparations, ear drops and eye drops are also included within the scope of the present invention. In addition, the present invention includes the use of transdermal patches, which have the additional effect of providing controlled delivery of the drug to tissues. Said dosage forms can be prepared by dissolving and dispersing the compound in an appropriate medium. Absorption accelerators can be used to increase penetration of the compound through the skin. The rate can be controlled either by rate-controlling membranes or by distributing the compound in a polymer matrix or gel.

[00280] As described generally above, the compounds of the present invention are useful as inhibitors of voltage-gated sodium channels. In one embodiment, the compounds and compositions of the present invention are inhibitors of NaV1.8 and, thus, without wishing to be bound by any particular theory, the compounds and compositions are used, in particular, for treating or reducing the severity of a disease, condition or disorder , where activation or hyperactivity of NaV1.8 is involved in the development of this disease, condition or disorder. When activation or hyperactivity of NaV1.8 is present in a particular disease, condition or disorder, the disease, condition or disorder may also be referred to as a “NaV1.8-mediated disease, condition or disorder”. Accordingly, in another aspect, the present invention relates to a method of treating or reducing the severity of a disease, condition or disorder in which NaV1.8 activation or hyperactivity is present during the course of the disease.

[00281] The activity of the compound used in the present invention as an inhibitor of NaV1.8 can be tested in accordance with the methods described generally herein in the Examples, or in accordance with methods available to one of ordinary skill in the art technology.

Additional therapeutic agents

[00282] It should also be understood that the compounds and pharmaceutically acceptable compositions of the present invention may be used in combination therapy, that is, the compounds and pharmaceutically acceptable compositions may be administered simultaneously with, before, or after the administration of one or more other desired therapeutic agents or medical procedures. The specific combination of therapeutic agents (therapeutic agents or procedures) to be used in a combination regimen will take into account the compatibility of the desired therapeutic agents and/or procedures and the desired therapeutic effect achieved. It should also be appreciated that the treatments used may provide the desired effect for a similar disorder (e.g., a compound of the present invention may be administered concomitantly with another agent used to treat a similar disorder), or they may provide other effects (e.g., control of any adverse effects). effects). As used herein, additional therapeutic agents that are typically administered to treat or prevent a particular disease or condition are known as "suitable for the disease or condition being treated." For example, typical adjunctive 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 asprin, choline magnesium trisalicylate, diflunisal; fenamates such as meclofenamic acid, mefenamic acid; and pyrazoles such as phenylbutazone); or opioid agonists (narcotic analgesics) (such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine). In addition, non-drug methods of analgesia can be used in combination with the administration of one or more compounds of the present invention. For example, anesthetic (intraspinal infusion, neuronal blockade), neurosurgical (neurolysis of central nervous system pathways), neurostimulatory (transcutaneous electrical nerve stimulation, spinal cord stimulation), physiotherapeutic (physical therapy, orthopedic devices, diathermy) or psychological ( cognitive methods - hypnosis, biofeedback or behavioral methods) methods. Additional appropriate therapeutic agents or techniques are described primarily in The Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and the Food and Drug Administration website, www.fda.gov, the entire contents of which are incorporated herein by reference.

[00283] In another embodiment, additional appropriate therapeutic agents are selected from the following:

[00284] (1) opioid analgesic, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine , butorphanol, nalbuphine or pentazocine;

[00285] (2) non-steroidal anti-inflammatory drugs (NSAIDs), for example, aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, meloxicam, naproxen , nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

[00286] (3) a barbiturate sedative, for example, amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metatarbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal, or thiopental;

[00287] (4) a benzodiazepine having a sedative effect, for example, chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;

[00288] (5) a histamine (H ₁ ) antagonist having a sedative effect, for example, diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;

[00289] (6) a sedative such as glutethimide, meprobamate, methaqualone, or dichloralphenazone;

[00290] (7) a musculoskeletal relaxant, for example, baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadine;

[00291] (8) NMDA receptor antagonist, e.g. dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine , cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), a combination drug of morphine and dextromethorphan), topiramate, neramexane or perzinfotel, including an NR2B antagonist such as ifenprodil, traxoprodil or (-) -(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;

[00292] (9) an alpha-adrenergic agent, for example, doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3, 4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline;

[00293] (10) a tricyclic antidepressant, for example, desipramine, imipramine, amitriptyline or nortriptyline;

[00294] (11) an anticonvulsant, for example, carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®) or valproate;

[00295] (12) a tachykinin (NK) antagonist, in particular an NK-3, NK-2 or NK-1 antagonist, for example (alpha-R,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]-naphthyridine-6-13 -dione (TAK-637), 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4- morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5-(trifluoromethoxy) phenyl]-methylamino]-2-phenylpiperidine (2S,3S);

[00296] (13) a muscarinic receptor antagonist, for example, oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

[00297] (14) a selective COX-2 inhibitor, for example, celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib or lumiracoxib;

[00298] (15) a coal tar analgesic, in particular paracetamol;

[00299] (16) an antipsychotic agent such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone , raclopride , zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindor, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan;

[00300] (17) a vanilloid receptor agonist (eg, resinferatoxin or civamide) or a vanilloid receptor antagonist (eg, capsazepine, GRC-15300);

[00301] (18) a beta-adrenergic agent such as propranolol;

[00302] (19) a local anesthetic such as mexiletine;

[00303] (20) a corticosteroid such as dexamethasone;

[00304] (21) a 5-HT receptor agonist or antagonist, in particular a 5-HT _1B/1D agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

[00305] (22) 5-HT _2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL -100907);

[00306] (23) a cholinergic (nicotinic) analgesic such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-butene-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;

[00307] (24) Tramadol®, tramadol ER (Ultram ER®), tapentadol ER (Nucynta®);

[00308] (25) a PDE5 inhibitor such as 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro- 7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4- methylenedioxyphenyl)-pyrazino[2',1':6,1]-pyrido[3,4-b]indole-l,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4 -ethyl-piperazin-1-yl-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,lf][1,2,4]triazin-4-one (vardenafil), 5 -(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azatidinyl)-2,6-dihydro- 7H -pyrazolo[4,3- d ]pyrimidin- 7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azatidinyl)-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)pyrimidin-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;

[00309] (26) alpha 2-delta ligand such as gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methylgabapentin, (1[alpha] ,3[alpha],5[alpha])(3-aminomethylbicyclo[3.2.0]hept-3-yl)acetic acid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid, (3S,5R )-3-amino-5-methylheptanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-( 3-fluorobenzyl)proline, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3,2,0]hept-6-yl]acetic acid, 3-(1-aminomethylcyclohexylmethyl)-4H-[1, 2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)cycloheptyl]methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethylcyclopentyl)acetic acid, (3S ,5R)-3-aminomethyl-5-methyloctanoic acid, (3S,5R)-3-amino-5-methylnonanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (3R,4R,5R) -3-amino-4,5-dimethylheptanoic acid and (3R,4R,5R)-3-amino-4,5-dimethyloctanoic acid;

[00310] (27) a cannabinoid such as KHK-6188;

[00311] (28) metabotropic glutamate receptor subtype 1 (mGluR1) antagonist;

[00312] (29) a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (desmethylfluoxetine metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine , ifoxetine, cyanodothiepine , litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;

[00313] (30) a norepinephrine (norepinephrine) reuptake inhibitor such as maprotiline, lofepramine, mirtazepine, oxaprotiline, phesolamine, tomoxetine, mianserin, bupropyrone, the bupropyrone metabolite hydroxybupropyrone, nomifensine and viloxazine (Vivalan®), in particular a selective reuptake inhibitor norepinephrine capture, such as reboxetine, in particular (S,S)-reboxetine;

[00314] (31) a dual-acting serotonin-norepinephrine reuptake inhibitor such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran and imipramine;

[00315] (32) an inhibitor of inducible nitric oxide synthase (iNOS), such as S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(1-iminoethyl)amino] ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl -7-[(1-iminoethyl)amino]-5-heptenoic acid, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chloro -3-pyridinecarbonitrile; 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2- chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolbutanol, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl )-3-pyridinecarbonitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3 -chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN-462 or guanidinoethyl disulfide;

[00316] (33) an acetylcholinesterase inhibitor such as donepenesil;

[00317] (34) a prostaglandin E2 subtype 4 (EP4) antagonist such as N -[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridinium- 1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide or 4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino) ethyl]benzoic acid;

[00318] (35) leukotriene B4 antagonist; such as 1-(3-biphenyl-4-ylmethyl-4-hydroxychroman-7-yl)cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl) -5E-hexenyl]oxyphenoxy]valeric acid (ONO-4057) or DPC-11870,

[00319] (36) 5-lipoxygenase inhibitor such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxymethyl ]-1-methyl-2-quinolone (ZD-2138) or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504);

[00320] (37) a sodium channel blocker such as lidocaine, lidocaine and tetracaine cream (ZRS-201), or eslicarbazepine acetate;

[00321] (38) a NaV1.7 blocker such as XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893, and such as described in WO2011/140425; WO2012/106499; WO2012/112743; WO2012/125613, WO2012/116440, WO2011026240, US8883840, US8466188 or PCT/US2013/21535, the entire contents of each of which are incorporated herein by reference.

[00322] (38a) NaV1.7 blocker such as (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidin]-1'-yl)-(4-isopropoxy -3-methylphenyl)methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethyl-spiro[3,4 -dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidin]-6-yl]ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2 -a]pyrazin-1,4'-piperidin]-1'-yl]-(4-isobutoxy-3-methoxyphenyl)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]pyrazin- 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-methylphenyl)-[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'-piperidine]-1'-carbonyl]phenyl]pyridine-2-carbonitrile, (4- isopropoxy-3-methylphenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1,4'-piperidin]-1'-yl]methanone, 2, 2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1, 4'-piperidin]-6-yl]ethanone, 2,2,2-trifluoro-1-[1'-(5-isopropoxy-6-methylpyridin-2-carbonyl)-3,3-dimethylspiro[2,4- dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidin]-6-yl]ethanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridin-2-carbonyl)-2- methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidin]-6-yl]ethanone, (4-isopropoxy-3-methoxy-phenyl)-[2-methyl-6 -(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone, 2,2,2-trifluoro-1-[1'-( 5-isopentyloxypyridin-2-carbonyl)-2,4-dimethylspiro[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]pyrazin-1,4'-piperidin]-6-yl ]-2,2,2-trifluoroethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1' -yl]-[3-methoxy-4-[(1R)-1-methylpropoxy]phenyl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopropoxy-6-methylpyridin-2-carbonyl )-2,4-dimethylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]ethanone, 1-[1'-[4-methoxy-3-( trifluoromethyl)benzoyl]-2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidin]-6-yl]-2,2-dimethylpropan-1-one, (4-isopropoxy -3-methylphenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazin-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-isopropoxyphenyl)-[2- methyl 6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidin]-1'-yl]methanone.

[00323] (39) NaV1.8 blocker such as PF-04531083, PF-06372865, and such as described in WO2008/135826, WO2006/011050, WO2013/061205, US20130303535, WO2013131018, US84661 88, WO2013114250, WO2014/1280808, WO2014/120815 and WO2014/120820, the entire contents of each of which are incorporated herein by reference.

[00324] (39a) a NaV1.8 blocker such as 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy) -N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridine -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-dihydropyridine -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. In one embodiment, the compound is 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)phenoxy)quinoxaline-2-carboxamido)benzoic acid, N-(4-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 5-(4,5-dichloro-2-( 4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 5-(2-(2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid, 4-(4,5-dichloro-2- (4-fluoro-2-methoxyphenoxy)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid, 4-(2-(4- fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)picolinic acid, 4-(2-(4- fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)benzoic acid, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 4-(2-(2- chloro-4-fluorophenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 4-(4,5-dichloro) -2-(4-(trifluoromethoxy)phenoxy)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4-chloro-2-methylphenoxy)benzamido)benzoic acid, 5-(4-(tert-butyl )-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)picolinic acid, 4-(4,5-dichloro) -2-(4-fluoro-2-methylphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4-dimethoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2 -(2-chloro-4-fluorophenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2 -(4-chloro-2-methoxyphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4-difluorophenoxy)benzamido)picolinic acid, 2-(4-fluorophenoxy)-N-(3 -sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3 -sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3 -sulfamoylphenyl)-6-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl )-N-(3-sulfamoylphenyl)benzamide, 2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)- N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 4,5-dichloro-2-(4 -fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-dichloro- 6-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide , 2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-( 3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3- sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl) -N-(3-sulfamoylphenyl)benzamide, 5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-4-cyano -N-(3-sulfamoylphenyl)benzamide or N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide.

[00325] (40) a combined NaV1.7 and NaV1.8 blocker such as DSP-2230 or BL-1021;

[00326] (41) a 5-HT3 antagonist such as ondansetron;

[00327] (42) a TPRV1 receptor agonist such as capsaicin (NeurogesX®, Qutenza®); and pharmaceutically acceptable salts and solvates thereof;

[00328] (43) a nicotinic receptor antagonist such as varenicline;

[00329] (44) an N-type calcium channel antagonist such as Z-160;

[00330] (45) a nerve growth factor antagonist such as tanezumab;

[00331] (46) an endopeptidase stimulator such as senrebotaz;

[00332] (47) Angiotensin II antagonist such as EMA401

[00333] In one embodiment, additional appropriate therapeutic agents are selected from V-116517, pregabalin, controlled-release pregabalin, ezogabine (Potiga®), topical cream containing ketamine and amitriptyline (Amiket®), AVP-923, perampanel (E-2007), ralfinamide, transdermally administered bupivacaine, (Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561, or ARK-4558.

[00334] In another embodiment, additional suitable therapeutic agents are selected from N-(6-amino-5-(2,3,5-trichlorophenyl)pyridin-2-yl)acetamide; N-(6-amino-5-(2-chloro-5-methoxyphenyl)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; or 3-((4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)methyl)oxetan-3-amine.

[00335] The amount of additional therapeutic agent present in the compositions of the present invention will be no greater than the amount that would normally be administered in a composition containing only the active agent as a therapeutic agent. The amount of additional therapeutic agent in the described composition of the present invention will range from about 50% to 100% of the amount typically present in a composition containing only the therapeutically active agent as a therapeutic agent.

[00336] The compounds of the present invention or pharmaceutically acceptable compositions thereof may also be included in compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the present invention in yet another aspect includes a composition for coating an implantable device, comprising a compound of the present invention described generally above and in the classes and subclasses described herein, and a carrier suitable for coating said implantable device. In yet another aspect, the present invention includes an implantable device coated having a composition comprising a compound of the present invention described generally above and in the classes and subclasses described herein, and a carrier suitable for coating said implantable device. Suitable coatings and a general description of the preparation of coated implantable devices can be found in US Pat. No. 6,099,562; 5886026 and 5304121. Coatings are typically biocompatible polymeric substances such as polymer hydrogels, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate and mixtures thereof. The coatings may optionally be further coated with a suitable top layer of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids, or combinations thereof to impart controlled release characteristics to the composition.

[00337] Another aspect of the present invention relates to inhibiting NaV1.8 activity in a subject, the method comprising administering to the subject a compound of Formula I or a composition containing the compound. Another aspect of the present invention relates to the inhibition of NaV1.8 activity in a biological sample, said method comprising contacting said biological sample with a compound of Formula I or a composition containing said compound. The term "biological sample" as used herein includes, without limitation, cell cultures or extracts thereof; biopsy material obtained from a mammal, or extracts thereof; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

[00338] Inhibition of NaV1.8 activity in a biological sample is used for various purposes that are known to one skilled in the art. Examples of such purposes include, but are not limited to, the study of sodium channels in biological and pathological processes; and comparative evaluation of new sodium channel inhibitors.

DIAGRAMS AND EXAMPLES

[00339] The compounds of the present invention can be easily prepared using the following methods. Scheme 1 below presents a general method for preparing the compounds of the present invention.

[00340] Scheme 1: Preparation of compounds of formula I in which X is P(O)(OH) ₂ :

[00341] a) Alkoxy pyridin-4-amine (i.e. 2-methoxypyridin-4-amine), condensing agent (i.e. HATU, EDCI, HOBT), base (i.e. N-methylmorpholine, Et ₃ N, solvent (i.e. i.e., DMF, dichloromethane); (b) SO ₂ Cl ₂ , DMF in solvent (i.e., dichloromethane); (c) 2-Methoxypyridin-4-amine, base (i.e., pyridine, solvent (i.e., dichloromethane, DMF); (d) TMSI or HBr, solvent (i.e., acetonitrile or acetic acid); (e) base (i.e., Cs ₂ CO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ , solvent (i.e. is, DMF, NMP, dioxane), heat; (f) ClCO ₂ CH ₂ Cl, solvent (i.e., CH ₂ Cl ₂ , DMF); (g) phosphorylating reagent (i.e., K(PG ₁ ) ₂ PO ₄ , including K( t -Bu) ₂ PO ₄ and the like), ( n -Bu) ₄ NI, solvent (ie, DMF), base (eg, DIPEA), heat (ie, 70°C); (h ) HOAc, H ₂ O, solvent (eg CH ₃ CN), heat (ie 70°C).

[00342] One skilled in the art will appreciate that steps (e) and (g) shown in Scheme 1 above can be combined into a single step without isolating the chloride intermediate.

[00343] Scheme 1A: Preparation of compounds of formula I in which X is P(O)(O ^- ) ₂ 2M ⁺ , X is P(O)(O ^- ) ₂ D ²⁺ or X is P(O )(OH)O ^- M ⁺ :

[00344] (i) M ⁺ OH ^- or D ²⁺ (OH ^- ) ₂ , 2-MeTHF; (j) aq. H ⁺ ; (k) aq. M ^{+ OH-}

[00345] Salts of compounds of Formula I can be prepared by the method shown in Scheme 1A. In step (i), a solution of compound I is treated with M ⁺ OH ^- or D ²⁺ (OH ^- ) ₂ to obtain the dianionic form of the compound (X = –PO(O-)2⋅2M ⁺ or -PO(O ^- ) ₂ D ²⁺ ). The free acid form of the compound (X=PO(OH) ₂ ) can be prepared by treating the dianionic form with an aqueous acid solution. The monoanionic form of the compound (X=PO(OH)O ^- M ⁺ ) can be prepared by treating the free acid form with one equivalent of M ⁺ OH ^- .

EXAMPLES

[00346] General methods. ¹ H NMR (400 MHz) and ³¹ P NMR (162 MHz) spectra were obtained as solutions in an appropriate deuterated solvent such as dimethyl sulfoxide-d ₆ (DMSO-d6). Mass spectra (MS) were obtained using an Applied Biosystems API-EX LC/MS system. Compound purity and retention time were determined by reverse phase HPLC using a Kinetix C18 column (50 x 2.1 mm, 1.7 µm particle size) from Phenomenex (Pn: 00B-4475-AN)) and eluting with mobile phase B with double gradient 1-99% for 3 minutes. Mobile phase A=H ₂ O (0.05% CF ₃ CO ₂ H). Mobile phase B=CH ₃ CN (0.05% CF ₃ CO ₂ H). Flow rate = 2 mL/min, injection volume = 3 μL, and column temperature = 50°C. Silica gel chromatography was performed using silica gel-60 with a particle size of 230-400 mesh. Pyridine, dichloromethane (CH ₂ Cl ₂ ) and tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile (ACN), methanol (MeOH) and 1,4-dioxane were purchased from Baker or Aldrich and, in some cases, the reagents were stored in Aldrich Sure-Seal vessels under a dry nitrogen atmosphere. All reaction mixtures were stirred using a magnetic stirrer unless otherwise indicated. HATU is (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate).

Example 1

Preparation of 4-chloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide

[00347] Solution of 4-chloro-2-fluorobenzoic acid (7.0 g, 40.10 mmol), HATU (15.25 g, 40.10 mmol), 2-methoxypyridin-4-amine (4.98 g, 40.10 mmol) and Et ₃ N (22.4 ml, 160.4 mmol) in dichloromethane (63.0 ml) were stirred at room temperature overnight. The crude mixture was purified by column chromatography, eluting with a gradient of ethyl acetate in hexanes (0-50%) to give 4-chloro-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (4.35 g, 39%), in as a white solid. ESI-MS m/z calculated: 280.04, determined: 281.3 (M+1) ⁺ ; Retention time: 1.31 minutes (assay time was 3 minutes). ¹ H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.09 (m, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.66 ( dd, J=10.1, 1.9 Hz, 1H), 7.46 (dd, J=8.3, 1.9 Hz, 1H), 7.21 (m, 2H), 3.84 (s , 3H) ppm

[00348] To 4-chloro-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (4.35 g, 15.50 mmol) in acetonitrile (145.0 mL) was added TMSI (8.8 mL , 62.0 mmol). The reaction mixture was stirred at 50°C overnight. The acetonitrile was evaporated and the crude solid was triturated with ethyl acetate. The solid was collected by filtration and washed with ethyl acetate to give 4-chloro-2-fluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (3.8 g, 92%). ESI-MS m/z calculated: 266.02, determined: 267.1 (M+1)+; Retention time: 1.23 minutes (assay time was 3 minutes). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.86 (s, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.68 (dd, J=10.1, 1.9 Hz, 1H), 7.60 (d, J=7.1 Hz, 1H), 7.47 (dd, J=8.3, 2.0 Hz, 1H), 7.11 (d, J=2.0 Hz, 1H), 6.71 (dd, J=7.1, 2.1 Hz, 1H) ppm.

Example 2

Preparation of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide

[00349] A solution of 4-bromo-2-fluoro-benzoyl chloride (2 g, 8.42 mmol) in dichloromethane (10.0 mL) was added dropwise to a mixture of 2-methoxypyridin-4-amine (1.0 g, 8. 42 mmol), pyridine (2.0 ml, 25.27 mmol) and dichloromethane (40.0 ml) at 0°C. The mixture was allowed to warm to room temperature and stirred at this temperature overnight. The mixture was poured into 1N HCl (200 ml) and dichloromethane (200 ml). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4-bromo-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (1.2 g, 44%) as a solid. cream-colored substances. ESI-MS m/z calculated: 323.99, determined: 325.1 (M+1) ⁺ ; Retention time: 1.37 minutes (assay time was 3 minutes). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.80 (s, 1H), 8.11-8.06 (m, 1H), 7.79 (dd, J=9.8, 1.7 Hz, 1H), 7.68-7.62 (m, 1H), 7.59 (dd, J=8.3, 1.7 Hz, 1H), 7.23-7.18 (m, 2H) , 3.84 (s, 3H) ppm

[00350] Into a stirred solution of 4-bromo-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (800 mg, 2.46 mmol) and copper (1.6 g, 24.61 mmol) in DMSO (15 ml) 1,1,1,2,2-pentafluoro-2-iodoethane (4.1 g, 16.47 mmol) was bubbled into a pressure vessel. The vessel was hermetically sealed and heated at 120°C for 16 hours. The reaction mixture was diluted with water and filtered through a pad of silica and then extracted with ethyl acetate (4×). The organics were combined, washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated to dryness to give a crude mixture, which was purified by column chromatography using a gradient of ethyl acetate in hexane (0-40%) to give 2-fluoro-N -(2-methoxy-4-pyridyl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide (200 mg, 22%) as a cream-colored solid. ESI-MS m/z calculated: 364.06, determined: 365.3 (M+1)+; Retention time: 1.39 minutes (assay time was 3 minutes). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 8.11 (d, J=6.3 Hz, 1H), 7.95 (dd, J=7.4 Hz , 1H), 7.89 (d, J=9.9 Hz, 1H), 7.72 (d, J=9.1 Hz, 1H), 7.23-7.19 (m, 2H), 3 .85 (s, 3H) ppm

[00351] 2-Fluoro-N-(2-methoxy-4-pyridyl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide (200 mg, 0.55 mmol) in HBr in acetic acid ( 1.3 ml of 33% w/v, 5.49 mmol) was stirred at 100°C for 2 hours, while 1 ml of HBr in acetic acid (33% w/v) was added and the mixture was stirred at 100°C for 4 hours, then cooled to room temperature. The reaction mixture was diluted with water and a precipitate formed. The precipitate was filtered off, washed with water (2×), cooled methyl tert- butyl ether and dried in vacuo to give 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(1,1, 2,2,2-pentafluoroethyl)benzamide (138 mg, 72%) as a light gray solid. ESI-MS m/z calculated: 350.05, determined: 351.3 (M+1)+; Retention time: 1.3 minutes (assay time was 3 minutes).

EXAMPLE 3

Preparation of 4,5-dichloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide

[00352] Solution of 2-methoxypyridin-4-amine (186.2 mg, 1.5 mmol), 4,5-dichloro-2-fluorobenzoic acid (285.1 mg, 1.36 mmol), HATU (622.4 mg, 1.64 mmol) and N-methylmorpholine (299.9 µl, 2.73 mmol) in DMF (3 ml) were stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The organics were combined, washed with water (3×), brine and dried over Na ₂ SO ₄ , filtered through a thin layer of silica and evaporated to dryness. The material was treated with HBr (in acetic acid) (6.689 ml 33% w/v, 27.28 mmol) and stirred at 95°C for 16 hours. The solution was cooled to room temperature, filtered and the solid was washed with water (2×) and then with ether (2×) and dried in vacuo to give 4,5-dichloro-2-fluoro-N-(2-oxo-1H-pyridinium- 4-yl)benzamide (250 mg, 61%) as a cream-colored solid. ESI-MS m/z calculated: 299.99, determined: 301.3 (M+1) ⁺ ; Retention time: 1.16 minutes (assay time was 3 minutes).

EXAMPLE 4

Preparation of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide ( 19 )

[00353] A solution of 2-fluoro-4-(trifluoromethyl)benzoyl chloride (25.0 g, 110.3 mmol) in dichloromethane (125.0 mL) was added dropwise to a mixture of 2-methoxypyridin-4-amine (13.7 g , 110.3 mmol), pyridine (26.8 ml, 330.9 mmol) and dichloromethane (500.0 ml) at 0 °C. The mixture was allowed to warm to room temperature and stirred at this temperature overnight. The mixture was poured into 1N HCl (200 ml) and dichloromethane (200 ml). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was suspended in hexane, the hexane was decanted and the product was dried under reduced pressure to give 2-fluoro-N-(2-methoxy-4-pyridyl)-4-(trifluoromethyl)benzamide (25.7 g, 74%) as a solid. cream color. ESI-MS m/z calculated: 314.07, determined: 315.3 (M+1) ⁺ ; Retention time: 1.49 minutes (assay time was 3 minutes). ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.96 (s, 1H), 8.15-8.04 (m, 1H), 8.00-7.85 (m, 2H), 7. 76 (d, J=8.1 Hz, 1H), 7.26-7.15 (m, 2H), 3.85 (s, 3H) ppm.

[00354] To 2-fluoro-N-(2-methoxy-4-pyridyl)-4-(trifluoromethyl)benzamide (1.00 g, 3.18 mmol) in acetic acid (6.0 ml) was added HBr (33 % in acetic acid) (3.9 ml 33% w/v, 15.91 mmol) and the mixture was stirred at 100ºC for 6 hours. Additional HBr (2 mL, 33% in acetic acid) was added and the mixture was stirred at room temperature overnight. The mixture was then heated at 100°C for 2 hours before cooling the mixture to room temperature. The mixture was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with water and brine (2×), dried over sodium sulfate, filtered and concentrated under reduced pressure. The solid was suspended in methyl tert-butyl ether and filtered to give 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide ( 19 ) (731 mg, 76%) . ESI-MS m/z calculated: 301.05, determined: 301.3 (M+1) ⁺ ; Retention time: 1.35 minutes (assay time was 3 minutes). ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.33 (s, 1H), 10.70 (s, 1H), 7.96-7.85 (m, 2H), 7.75 (d, J=8.2 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 6.81 (d, J=1.9 Hz, 1H), 6.41 (dd, J= 7.2, 2.1 Hz, 1H) ppm

EXAMPLE 5

Preparation of N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide ( 5a )

[00355] Cs ₂ CO ₃ (651.6 mg, 2 mmol) was added to a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (60, 0 mg, 0.2 mmol) and 4-(trifluoromethoxy)phenol (259.1 μl, 2 mmol) in DMF (1 ml), and the reaction mixture was stirred at 100°C for 1 hour. The reaction mixture was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as modifier to give N-(2-oxo-1,2-dihydropyridin-4-yl)-2- (4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide ( 5a ) (25.7 mg, 28%). ESI-MS m/z calculated: 458.07, determined: 459.5 (M+1) ⁺ ; Retention time: 1.80 minutes (assay time was 3 minutes)

EXAMPLE 6

Preparation of 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide ( 9a )

[00356] A mixture of 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (13.6 g, 45.30 mmol), 4-fluoro-2-methylphenol ( 17.1 g, 135.9 mmol), Cs ₂ CO ₃ (44.28 g, 135.9 mmol) and DMF (340.0 ml) were heated at 100°C for 1.5 hours. The mixture was cooled to room temperature and poured into water (500 ml). The mixture was stirred vigorously for 30 minutes, then filtered. The solid was washed with water (250 ml) and suspended in methyl tert-butyl ether (200 ml). The mixture was filtered and the solid was suspended in hexane (2 x 400 ml) and the filtrate was dried in vacuo to give 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4 -(trifluoromethyl)benzamide ( 9a ) (13.1 g, 70%) as a solid. ESI-MS m/z calculated: 406.09, determined: 407.5 (M+1) ⁺ ; Retention time: 1.73 minutes (assay time was 3 minutes). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.28 (s, 1H), 10.63 (s, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.60 (d, J=7.1 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.26-7.20 (m, 1H), 7.14-7.06 ( m, 2H), 7.00-6.95 (m, 1H), 6.75 (d, J=1.8 Hz, 1H), 6.38 (dd, J=7.2, 2.1 Hz , 1H), 2.16 (s, 3H) ppm

EXAMPLE 7

Preparation of 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide (4a)

[00357] Cs ₂ CO ₃ (651.6 mg, 2.0 mmol) was added to a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide ( 60.0 mg, 0.2 mmol) and 4-fluoro-3-methoxyphenol (228 μl, 2.0 mmol) in DMF (1 ml) and the reaction mixture was stirred at 100°C for 1 hour. The reaction mixture was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as modifier to give 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1 ,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide ( 4a ) (67.9 mg, 80%). ESI-MS m/z calculated: 422.09, determined: 423.2 (M+1) ⁺ ; Retention time: 1.56 minutes (assay time was 3 minutes).

[00358] According to the method described above for starting compound 4a, the following compounds were prepared starting from 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide and the following alcohols.

Connection No. Product Alcohol 18a 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 4-fluorophenol 15a N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide 2-methylphenol 11a 2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 2-chloro-4-fluorophenol 10a 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 4-fluoro-2-methylphenol 8a N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide 4-(trifluoromethoxy)phenol 17a N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide 2-(trifluoromethoxy)phenol

EXAMPLE 8

Preparation of 5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (7a)

[00359] Cs ₂ CO ₃ (879.9 mg, 2.7 mmol) was added to a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-chlorobenzamide (72.0 mg, 0.27 mmol) and 4-fluoro-3-methoxyphenol (307.7 µl, 2.7 mmol) in DMF (1 ml) and the reaction mixture was stirred at 100°C for 1 hour. The reaction mixture was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl modifier to give 5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2 -oxo-1,2-dihydropyridin-4-yl)benzamide (7a) (31.8 mg, 30%). ESI-MS m/z calculated: 388.06, determined: 389.10 (M+1) ⁺ ; Retention time: 1.52 minutes (assay time was 3 minutes).

[00360] According to the method described above for starting compound 7a, the following compounds were prepared starting from 5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridine- 4-yl)benzamide and the following alcohols.

Connection No. Product Alcohol 12a 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 4-fluoro-2-methylphenol 14a 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 2-chloro-4-fluorophenol

EXAMPLE 9

Preparation of 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (1a)

[00361] Cs ₂ CO ₃ (97.7 mg, 0.3 mmol) was added to a solution of 4,5-dichloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide ( 30.1 mg, 0.1 mmol) and 4-fluoro-3-methoxyphenol (42.6 mg, 0.3 mmol) in NMP (0.5 ml) and the reaction mixture was stirred at 90°C for 2 hours. The reaction mixture was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (1-99%) and HCl as modifier to give 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N- (2-oxo-1,2-dihydropyridin-4-yl)benzamide ( 1a ) (13.2 mg, 30%). ESI-MS m/z calculated: 422.02, determined: 423.3 (M+1) ⁺ ; Retention time: 1.57 minutes (assay time was 3 minutes).

[00362] In accordance with the method described above for starting compound 1a, the following compounds were prepared starting from 4,5-dichloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide and the following alcohols.

Connection No. Product Alcohol 3a 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 4-fluorophenol

EXAMPLE 10

Preparation of 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide ( 2a )

[00363] Cs ₂ CO ₃ (69.8 mg, 0.21 mmol) was added to a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide ( 25 mg, 0.07 mmol) and 4-fluoro-2-methoxyphenol (24.4 μl, 0.2 mmol) in NMP (0.3 ml) and the reaction mixture was stirred at 100°C for 45 minutes. The reaction mixture was poured into water:ethyl acetate (9:1). The mixture was shaken and the solid was filtered, washed with ether, then triturated with ethyl acetate and dried to obtain the desired product. The mother liquors were filtered and washed with ethyl acetate to obtain a second batch of the substance. Both solids were combined and dried in vacuo to give 2-(4-fluoro-2-methoxy-phenoxy)-N-(2-oxo- 1H- pyridin-4-yl)-4-(1,1,2, 2,2-pentafluoroethyl)benzamide (2a) (15.4 mg, 45%) as a white solid. ESI-MS m/z calculated: 472.08, determined: 473.3 (M+1)+; Retention time: 1.62 minutes. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.32 (s, 1H), 10.62 (s, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.39-7.27 (m, 2H), 7.17 (dd, J=10.7, 2.8 Hz, 1H), 6.88 ( dd, J=11.3, 5.7 Hz, 1H), 6.81 (s, 1H), 6.75 (s, 1H), 6.43 (d, J=7.1 Hz, 1H), 3.73 (s, 3H) ppm

EXAMPLE 11

Preparation of 4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (13a)

[00364] To a solution of 4-chloro-2-fluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (500 mg, 1.87 mmol) in NMP (5 ml) was added 4-fluoro-2 -methylphenol (709.5 mg, 5.62 mmol) and Cs ₂ CO ₃ (1.83 g, 5.62 mmol) and the reaction mixture was stirred at 90°C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The organics were combined, washed with 3N NaOH (3×), water, brine, dried (Na ₂ SO ₄ ) and evaporated to dryness. Purification by silica gel column chromatography gave 4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo- 1H- pyridin-4-yl)benzamide (13a) (300 mg, 43 %) in the form of a brown solid. ESI-MS m/z calculated: 372.07, determined: 373.1 (M+1) ⁺ ; Retention time: 1.5 minutes (assay time was 3 minutes). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.25 (s, 1H), 10.48 (s, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.30 (dd, J=7.9, 1.6 Hz, 2H), 7.21 (d, J=8.7 Hz, 1H), 7.09 (d, J=5.5 Hz, 2H), 6 .75 (dd, J=5.1, 1.8 Hz, 2H), 6.38 (dd, J=7.2, 2.0 Hz, 1H), 2.16 (s, 3H) ppm .

EXAMPLE 12

Preparation of 2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (16a)

[00365] To a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (30 mg, 0.1 mmol) in DMF (1 ml) was added 2 ,4-difluorophenol (130 mg, 1.0 mmol) and Cs ₂ CO ₃ (325.8 mg, 1.0 mmol) and the reaction mixture was stirred at 100°C for 1 hour. The reaction mixture was cooled to 25 °C, filtered and purified by reverse phase chromatography using a gradient of acetonitrile in water (10-99%) and HCl modifier to give 2-(2,4-difluorophenoxy)-N-(2 -oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (16). ESI-MS m/z calculated: 410.07, determined: 411.2 (M+1)+; Retention time: 1.55 minutes (assay time was 3 minutes).

EXAMPLE 13

Preparation of N-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (20)

[00366] 2-(4-Fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide solution ( 9a ) (406.3 mg, 1 .0 mmol) and chloromethylchloroformate (106.7 μl, 1.2 mmol) in dichloromethane (3.5 ml) and N,N-dimethylformamide (0.3 ml) were stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine, dried over Na ₂ SO ₄ , filtered and evaporated to dryness to give N-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-( 4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide, which was used in the next step without further purification. ESI-MS m/z calculated: 454.07, determined: 455 (M+1) ⁺ ; Retention time: 0.73 minutes (assay time 1 minute).

[00367] The crude N-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide from the previous step was dissolved in N,N-dimethylformamide (5 ml). Di-tert-butoxyphosphoryloxypotassium (496.6 mg, 2.0 mmol) and tetrabutylammonium iodide (36.94 mg, 0.10 mmol) were added and the reaction mixture was stirred at 70°C for 4 hours. The reaction mixture was then diluted with ethyl acetate and washed with water, then brine, dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The material was purified by column chromatography (40 g silica gel, 50-100% EtOAc in hexane) and product containing fractions were combined and evaporated to give di-tert-butyl[4-[[2-(4-fluoro-2-methylphenoxy)- 4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate ( 20 ) (280 mg, 45%) as a yellow oil, which was used in the next step without further purification. ESI-MS m/z calculated: 628.20, determined: 629 (M+1) ⁺ ; Retention time: 0.76 minutes (assay time 1 minute).

EXAMPLE 14

Preparation of [4-[[2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate ( 9 )

[00368] Di-tert-Butyl[4-[[2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate solution ( 20 ) (50 mg, 0.080 mmol) in acetonitrile (1 ml), H ₂ O (1 ml) and acetic acid (1 ml) were stirred at 70°C for 3 hours, then evaporated to dryness. The substance was then co-evaporated with acetonitrile (3×), triturated with acetonitrile, filtered, washed with acetonitrile and dried to obtain [4-[[2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoyl]amino]- 2-oxo-1-pyridyl]methyl dihydrogen phosphate ( 9 ) (20 mg, 49%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.49 (s, 2H), 10.77 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.61 (d, J=7.6 Hz, 2H), 7.27-7.19 (m, 1H), 7.11 (dd, J=10.9, 7.6 Hz, 2H), 6.98 ( s, 1H), 6.90 (d, J=2.0 Hz, 1H), 6.43 (dd, J=7.5, 2.1 Hz, 1H), 5.53 (d, J=9 .7 Hz, 2H), 2.16 (s, 3H) ppm. ³¹ P NMR (162 MHz, DMSO-d ₆ -85% aq. H ₃ PO ₄ as internal standard - 0 ppm) δ-1.76 (t, J=9.6 Hz, 1H).

[00369] The substance was further purified according to the following procedure. To a stirred suspension of [4-[[2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate (9) (30.00 mg, 0. 05810 mmol) in isopropanol (600.0 μl), methanol (300.0 μl) was added, causing the substance to go into solution. NaOH (14.52 μl of 4 M, 0.058 mmol) was added, which caused the formation of a white precipitate, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then cooled to 0°C, filtered, washed with chilled isopropanol and dried in vacuo to give [4-[[2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo -1-pyridyl]methyl dihydrogen phosphate ( 9 ) as a white solid. ESI-MS m/z calculated: 516.07, determined: 517.0 (M+1)+; Retention time: 0.57 minutes (UHPLC analysis time is 1 minute).

EXAMPLE 15

Alternative preparation of [4-[[2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate (9)

[00370] Sample 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide monohydrate (9a) (6.0 g, 14 .7 mmol) was dehydrated in vacuum at 65°C. Anhydrous 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide solution (9a) (5.0 g, 12.31 mmol) and N,N-dimethylformamide (10.0 ml) in dichloromethane (50.0 ml) were stirred at room temperature, chloromethyl chloroformate (1.64 ml, 18.46 mmol) was added and the solution was stirred at room temperature for one hour . The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine, dried with anhydrous sodium sulfate, filtered and evaporated to dryness. The resulting oil was purified by column chromatography (40 g silica gel, 20-100% EtOAc in hexanes) and product fractions were combined and evaporated to give N-[1-(chloromethyl)-2-oxo-4-pyridyl]-2 -(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (3.26 g, 7.168 mmol), which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.83 (s, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.76 (d, J=7.6 Hz , 1H), 7.66-7.58 (m, 1H), 7.28-7.19 (m, 1H), 7.10 (dd, J=7.7, 2.0 Hz, 2H), 6.98 (s, 1H), 6.92 (d, J=2.1 Hz, 1H), 6.50 (dd, J=7.6, 2.3 Hz, 1H), 5.79 (s , 2H), 2.16 (s, 3H) ppm.

[00371] A mixture of N-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (500 mg, 1.1 mmol), potassium di-tert-butoxyphosphoryloxy (409.2 mg, 1.65 mmol), tetrabutylammonium iodide (20.3 mg, 0.05 mmol) and diisopropylethylamine (191.4 μl, 1.1 mmol) in acetonitrile (10.0 ml) was stirred at 70°C for one hour. The reaction mixture was then diluted with ethyl acetate and washed with water and brine, and the organic layer was evaporated to dryness. The crude product was purified by column chromatography (4 g silica gel, 25-100% EtOAc in hexanes), product containing fractions were combined and evaporated to give di-tert-butyl[4-[[2-(4-fluoro-2- methylphenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate ( 20 ) (390 mg, 56%) as a light amber solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.83 (s, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.76 (d, J=7.6 Hz , 1H), 7.66-7.58 (m, 1H), 7.28-7.19 (m, 1H), 7.10 (dd, J=7.7, 2.0 Hz, 2H), 6.98 (s, 1H), 6.92 (d, J=2.1 Hz, 1H), 6.50 (dd, J=7.6, 2.3 Hz, 1H), 5.79 (s , 2H), 2.16 (s, 3H) ppm.

[00372] Di-tert-Butyl[4-[[2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate solution ( 20 ) (350 mg, 0.557 mmol) in acetonitrile (7 ml), acetic acid (7 ml) and H ₂ O (7 ml) were stirred at 70°C and the deprotection reaction was carried out, followed by HPLC. Removal of the protecting groups was completed after 1.5 hours. The reaction mixture was partially concentrated to remove most of the toluene, then acetonitrile (100 ml) was added and the mixture was evaporated azeotropically to remove water and acetic acid. Heptane (10 ml) was added to the resulting suspension and the suspension was distilled to 2-3 volumes (1 ml). Heptane (2 ml) was added and the resulting suspension was stirred at room temperature and filtered. The collected solid was dried in vacuo to give [4-[[2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate (9) (254 mg , 88.4%) as a cream-colored crystalline solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.52 (s, 2H), 10.77 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.60 (d, J=7.6 Hz, 2H), 7.26-7.19 (m, 1H), 7.09 (dd, J=10.9, 7.6 Hz, 2H), 6.98 ( s, 1H), 6.90 (d, J=2.0 Hz, 1H), 6.43 (dd, J=7.5, 2.1 Hz, 1H), 5.53 (d, J=9 .7 Hz, 2H), 2.16 (s, 3H) ppm. ³¹ P NMR (162 MHz, DMSO-d ₆ ) δ -2.35 (t, J=9.6 Hz, 1H) ppm.

EXAMPLE 15A

Preparation of 2-fluoro-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide

[00373] A 50-L jacketed glass reactor was equipped with an N ₂ inlet valve, a mechanical stirrer, and a condenser. 2-Me-THF (6,000 L, 3.0 vol), 2-fluoro-4- (trifluoromethyl)benzoic acid (2000 g, 9.610 mol), 2-methoxypyridin-4-amine (1.278 kg, 10.09 mol) and TEA (2.917 kg, 4.018 L, 28.83 mol) to give a slightly cloudy solution of light amber color. The reactor was switched to the reaction control position and heated to 35°C. To the resulting solution was added T3P in 2-Me-THF (9.176 kg, 9.176 L 50% w/w, 14.42 mol) over 30-45 min to obtain a light yellow solution. After 2 hours, the reaction was assessed as complete (<2% residual 1) by HPLC analysis. The reaction was quenched with water (1000 L, 0.5 vol), which was added using a dropping funnel over 10 minutes to control the exothermic quench reaction. The mixture was then diluted with 2-Me-THF (8000 L, 4.0 vol.) and water (8000 L, 4.0 vol.), and stirred for 30 minutes at 30-40°C. After mixing was complete, the layers were allowed to separate and the aqueous layer was removed. The organic layer was washed with 10% NaOH aqueous solution (6,000 L, 3.0 vol.), stirred to form an emulsion. Saturated saline (500.0 mL, 0.25 vol) was added and the mixture was stirred for about 5 minutes. The layers were separated and the aqueous layer was removed. The organic layer was washed again with brine (10.00 L, 5.0 vol) and the aqueous layer was discarded. The organic layer was dried over Na ₂ SO ₄ and filtered through diatomite (celite). The filter cake was washed with 2-Me-THF (4,000 L, 2.0 vol) and recovered dry. The filtrate was transferred to a rotary vacuum evaporator and partial distillation of the solvent was started at a bath temperature of 40°C and a pressure of 150 mbar, resulting in the formation of solids in the mixture. Cyclohexane (10.00 L, 5.0 vol.) was added in portions while partially distilling. The distillation was stopped, the reaction mixture (~8 L) was transferred to a slurry on a rotary evaporator, and the bath temperature was reduced to room temperature. The mixture was filtered and the filter cake was washed with cyclohexane (2,000 L, 1.0 vol) and dried under nitrogen to give a light yellow solid. The solid was removed from the funnel and dried under vacuum (40°C, <30 mbar, evaporated on rotation) to give 2-fluoro-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide (2.501 g, 7.959 mol, 83%) as a fine-grained, cream-colored solid.

EXAMPLE 15B

Preparation of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide hydrobromide

[00374] AcOH (17.50 L, 7.0 vol) and 2-fluoro-N-(2-methoxypyridin-4-yl) were added to a 50 L jacketed glass reactor equipped with an N2 inlet valve and a mechanical stirrer. -4-(trifluoromethyl)benzamide (2500 g, 7.956 mol) and the resulting mixture was stirred. A solution of HBr in HOAc (5.853 kg, 3.928 L 33% w/w, 23.87 mol) was added which was moderately exothermic and produced a light yellow solution. As a result of adding additional HBr, the solution acquired a darker amber color. The temperature of the reaction mixture was raised to moderate condensation temperature (internal temperature 70°C) for ~30 min, which resulted in the evolution of a significant amount of gas (MeBr, HBr). The internal temperature of the reaction mixture was then raised to 85°C over 1.5 hours and stirring was continued overnight at 85°C. Until completion of the reaction, which was achieved after 16 hours, the progress of the reaction was monitored by HPLC analysis, (<1% residual 2-fluoro-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide relative to product 2 -fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide hydrobromide). The internal temperature of the reaction mixture was lowered from 85 to 50°C over 30 minutes, and then toluene (7,500 L, 3.0 vol.) was added. Stirring was continued for 10-15 minutes. The internal temperature of the reaction mixture was then lowered to 20°C, and the mixture was stirred at this temperature for 1-2 hours. The reaction mixture was then filtered and the wet filter cake was washed with toluene (7,500 L, 3.0 vol) and recovered dry. The solid was removed from the filter and dried under vacuum (40°C, 10-25 mbar, rotary vacuum evaporator) to give 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-( trifluoromethyl)benzamide hydrobromide (2609 g, 6.846 mol, 86%) as a white crystalline solid.

EXAMPLE 15C

Preparation of 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide ( 9a )

[00375] 1-methyl-2-pyrrolidinone (NMP) (3.75 liters) was added to a 50-liter jacketed glass reactor equipped with an _N2 inlet valve and a mechanical stirrer. The solution was stirred and 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide hydrobromide salt (1500.2 g, 3.94 mol, 1.0 eq.) was added. and diluted with NMP (1 liter), and the jacket temperature was brought to 35°C. Potassium carbonate (1631.9 g, 11.8 mol, 3.0 eq, 325 mesh) was then added in portions over 10 minutes, during which time the reaction temperature was raised to 40°C. The resulting suspension was treated with a solution of 4-Fluoro-2-methylphenol (5, 546.1 g, 4.33 mol, 1.1 equiv, AK Scientific) in NMP (2.25 liters) with stirring, and then the addition funnel was rinsed with NMP ( 0.75 liters) to obtain an orange suspension. The jacket temperature was raised to 61° C. over 30 minutes and the suspension was stirred overnight under nitrogen while reaction completion was determined by HPLC analysis. 2-methyltetrahydrofuran (15 liters) and water (15 liters) were added to the reaction mixture, and the mixture was stirred until the solids dissolved. Stirring was completed, the orange aqueous layer was drained, and the organic layer was washed with water (7.5 liters) with stirring and a jacket temperature of ~52 ^o C. The water washing procedure was repeated 4 times (washed with 3x7.5 liters of water, then 1x4 .5 liters of water). The resulting organic slurry was stirred at a jacket temperature of 50.8°C and isopropyl acetate (6 liters, Sigma Aldrich) was added. The jacket temperature was raised to 20°C over 30 minutes and the slurry was stirred overnight, then the precipitated solids were collected by filtration. The collected solid was returned to the reactor, suspended in isopropyl acetate with stirring for about 2 hours, then filtered, washed with isopropyl acetate (1.5 liters) and dried in vacuum at 65°C to obtain 1253.1 g (78%) 2-( 4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (9a) as a cream-colored solid.

EXAMPLE 15D

Preparation of N-(1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide

[00376] 2-(4-Fluoro-2-methylphenoxy)-N- ₍ 2 -oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (9a, 2482.0 g, 6.11 mol, 1.0 eq.) under nitrogen. While stirring at 100 rpm, ethyl acetate (25 liters) was added, then 1,4-diazabicyclo[2,2,2]octane (DABCO) (342.6 g, 3.05 mol, 0.5 eq.) and DMF (1.25 liters, Sigma-Aldrich). Chloromethyl chloroformate (815 mL, 9.16 mol, 1.5 eq.) was then added over 30 minutes. After the addition of chloromethylchloroformate was completed, the jacket temperature was raised to 60°C for 30 minutes. The resulting yellow suspension was stirred for 3 hours at a temperature of about 60°C, and the completion of the reaction was determined by HPLC analysis. The jacket temperature was raised to 15°C for 20 minutes before quenching the reaction by slowly adding water (500 ml) over 10 minutes. Additional water was added and the mixture was stirred at 115 rpm for 15 minutes. Stirring was stopped, the aqueous layer was removed, and the organic layer was washed with water (5 liters) and then with a saturated solution of NaHCO ₃ (137 g) in water (620 ml). 5 g of N-(1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (7) were sown into the organic layer ), and the resulting slurry was partially concentrated (18.5 liters of organic matter removed) on a rotary vacuum evaporator (40°C, vacuum). The resulting suspension was stored at room temperature under a nitrogen atmosphere overnight, during which time additional amounts of the substance crystallized from the solution. The remaining solvent was diluted with heptane, adding additional heptane if necessary to maintain the volume at 10 liters. The thick suspension was stirred on a rotary vacuum evaporator at room temperature for 45 minutes, and then the solid was collected by filtration. The cream-colored solid was washed with heptane (2.5 liters) then dried in vacuo (40°C, full vacuum) to obtain 2409 g (87%) N-(1-(chloromethyl)-2-oxo-1,2- dihydropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide as a cream-colored crystalline solid.

EXAMPLE 15E

Preparation of di-tert-butyl-((4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl)phosphate (20)

[00377]

N-( _1- (chloromethyl)-2-oxo-1,2-dihydropyridine- 4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (1199.5 g, 2.64 mol, 1.0 eq.) under nitrogen. Ethyl acetate (12 liters) was added with stirring to form a slurry. Potassium di-tert-butyl phosphate (792.7 g, 95% purity, 3.03 mol, 1.15 eq.) was added to the mixture, followed by TBAI (9.7 g, 0.026 mol, 0.01 eq.) and temperature shirts were raised to 71°C for 20 minutes. The resulting jelly-like suspension was stirred for 4.5 hours, as a result of which HPLC analysis showed the completion of the reaction. The jacket temperature was raised to 30°C for 15 minutes, and then water (6 liters) was added while stirring. The aqueous layer was discarded and then the organic layer was washed twice with water (1 x 3.6 liters, then 1 x 2.4 liters). The organic layer was concentrated to 3.0-3.5 volumes at 40°C using a rotary vacuum evaporator. Heptane (1.8 liters) was added as an antisolvent and the rotary vacuum evaporator bath heater was then turned off and the mixture was allowed to cool to room temperature and stirred at 40 rpm overnight. The solid was collected by filtration, washed with heptane (1.2 liters), and then dried in vacuo at 45°C to obtain 1417.7 g (88%) di-tert-butyl-((4-(2-(4-fluoro -2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl) phosphate ( 20 ) as a light yellow crystalline solid.

EXAMPLE 15F

Preparation of (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate ( 9 )

[ ₀₀₃₇₈ ] Di-tert-butyl-((4-(2-(4- fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl)phosphate (20, 2820.9 g, 4.49 mol, 1.0 eq.) and isopropyl alcohol (25.4 liters, 9.0 volumes). The mixture was stirred at 200 rpm and acetic acid (14.1 liters, 5.0 volumes) was added to obtain a clear solution. The clear solution was filtered using a barrier filter and transferred to a 50-L jacketed glass reactor system while stirring at 100 rpm. Water (5.6 liters) was added and the jacket temperature was raised to 71°C over 20 minutes. After stirring and heating for 4.5 hours, HPLC analysis indicated completion of the reaction. The jacket temperature was raised to 19°C over 3 hours and the product began to crystallize from solution. The solid was collected by filtration and washed with acetone (5 liters). The solid was added back to the reaction vessel, acetone (8.5 liters) was added, the reactor jacket temperature was raised to 45°C for 10 minutes, and the suspension was stirred. After 40 minutes, the reactor jacket temperature was raised to 20°C over 30 minutes and the crystalline solid was collected by filtration, washed with acetone (5 liters) and dried in vacuo at 50°C to give 1917.7 g (83%) (4- (2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate (9) as a white crystalline solid.

EXAMPLE 15G

Preparation of N-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide ( 21 )

[00379] 2-(4-Fluoro-2-methoxyphenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide (2a) solution ) (99.9 mg, 0.2115 mmol) and chloromethyl chloroformate (32.73 mg, 22.04 μL, 0.2538 mmol) in DCM (900 μL) and DMF (100 μL) were stirred at room temperature for 4 hours (gas release). The reaction mixture was diluted with EtOAc, the organic phase was washed with saturated aqueous NaHCO ₃ solution, saturated saline solution, dried over Na ₂ SO ₄ and evaporated to dryness. The residue was dissolved in DMF (999 μl), di-tert-butoxyphosphoryloxypotassium (105.0 mg, 0.4230 mmol) and tetrabutylammonium iodide (7.81 mg, 0.021 mmol) were added and the reaction mixture was stirred at 70°C for 4 hours . The reaction mixture was cooled, diluted with water and extracted with EtOAc (3×). The organics were combined, washed with water, then with brine, dried over Na ₂ SO ₄ and evaporated to dryness. Purification by column chromatography (4 g silica gel; 0-100% EtOAc in hexanes) gave di-tert-butyl[4-[[2-(4-fluoro-2-methoxy-phenoxy)-4-(1,1, 2,2,2-pentafluoroethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate ( 21 ) (35 mg, 0.05039 mmol, 23.8%) as a clear oil. ESI-MS m/z calculated: 694.18787, determined: 695.4 (M+1) ⁺ ; Retention time: 0.78.

EXAMPLE 15H

Preparation of N-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide ( 2 )

[00380] A solution of ditert-butyl[4-[[2-(4-fluoro-2-methoxy-phenoxy)-4-(1,1,2,2,2-pentafluoroethyl)benzoyl]amino]-2-oxo- 1-pyridyl]methylphosphate ( 21 ) (35 mg, 0.05039 mmol) in CH ₃ CN (700.0 µl), water (700.0 µl) and AcOH (700.0 µl) was refluxed for 1 hours, then evaporated to dryness. The substance was then co-evaporated with CH ₃ CN (3×), triturated with CH ₃ CN, filtered, washed with CH ₃ CN and dried to give [4-[[2-(4-fluoro-2-methoxyphenoxy)-4-(1 ,1,2,2,2-pentafluoroethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate ( 2 ) (13 mg, 0.02210 mmol, 43.9%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.72 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.63 (d, J=7.6 Hz , 1H), 7.51 (d, J=8.2 Hz, 1H), 7.31 (dd, J=8.9, 5.9 Hz, 1H), 7.16 (dd, J=10, 7, 2.9 Hz, 1H), 6.94 (d, J=1.9 Hz, 1H), 6.91-6.84 (m, 1H), 6.77 (s, 1H), 6, 47 (dd, J=7.6, 2.2 Hz, 1H), 5.54 (d, J=9.7 Hz, 2H), 3.74 (s, 3H) ppm. ³¹ P NMR (162 MHz, DMSO-d ₆ - 85% aq. H ₃ PO ₄ as internal standard - 0 ppm) δ-1.93 (t, J=9.7 Hz, 1H) m. d.

EXAMPLE 15I

Di-tert-butyl[4-[[2-(4-fluorophenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate ( 22 )

[00381] A solution of 2-(4-fluorophenoxy)-N-(2-oxo-1H-pyridin-4-yl)-5-(trifluoromethyl)benzamide ( 18a ) (98 mg, 0.2498 mmol) and chloromethyl chloroformate (38 .66 mg, 26.39 µl, 0.2998 mmol) in CH ₂ Cl ₂ (1 ml) and DMF (100 µl) were stirred at room temperature for 4 hours (gas evolution). The reaction mixture was diluted with EtOAc and the organic phase was washed with saturated aqueous NaHCO ₃ solution, brine, dried over Na ₂ SO ₄ and evaporated to dryness. The residue was dissolved in DMF (1 ml), di-tert-butoxyphosphoryloxypotassium (124.0 mg, 0.4996 mmol) and tetrabutylammonium iodide (9.227 mg, 0.02498 mmol) were added and the reaction mixture was stirred at 70°C for 4 hours . The reaction mixture was cooled, diluted with water and extracted with EtOAc (3×). The organic layers were combined, washed with water, then with brine, dried over Na ₂ SO ₄ and evaporated to dryness. Purification by column chromatography (4 g silica gel; 0-100% EtOAc in hexanes) gave di-tert-butyl[4-[[2-(4-fluorophenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo -1-pyridyl]methylphosphate ( 22 ) (67 mg, 0.1090 mmol, 43.7%) as a clear oil. ESI-MS m/z calculated: 614.1805, determined: 615.5 (M+1)+; Retention time: 0.73 minutes.

EXAMPLE 15J

[4-[[2-(4-Fluorophenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate ( 18 )

[00382] Di-tert-Butyl[4-[[2-(4-fluorophenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate solution ( 22 ) (67 mg, 0. 1090 mmol) in CH ₃ CN (1.340 ml), water (1.340 ml) and AcOH (1.340 ml) were heated at reflux for 1 hour, then evaporated to dryness. The material was then co-evaporated with CH ₃ CN (3×), triturated with CH ₃ CN, filtered, washed with CH ₃ CN and dried to give [4-[[2-(4-fluorophenoxy)-5-(trifluoromethyl)benzoyl]amino ]-2-oxo-1-pyridyl]methyl dihydrogen phosphate ( 18 ) (32 mg, 0.06052 mmol, 55.5%) as a white solid. ESI-MS m/z calculated: 502.0553, determined: 503.4 (M+1)+; Retention time: 1.39 minutes. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.83 (dd, J=8.8, 2.4 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.35-7.23 (m, 4H), 7.00 (d, J=8.7 Hz, 1H), 6.91 (d, J=2.2 Hz, 1H), 6.45 (dd, J=7.6, 2.3 Hz, 1H), 5.53 (d, J=9.7 Hz, 2H) ppm ³¹ P NMR (162 MHz, DMSO-d ₆ - 85% aq. H ₃ PO ₄ as internal standard - 0 ppm) δ -2.11 (t, J=9.6 Hz) ppm

EXAMPLE 15K

Di-tert-butyl[4-[[4-chloro-2-(4-fluoro-2-methylphenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate ( 23 )

[00383] A solution of 4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1H-pyridin-4-yl)benzamide (13a) (99 mg, 0.2656 mmol) and chloromethyl chloroformate (82.19 mg, 55.35 µl, 0.6374 mmol) in THF (2 ml) was added DMF (0.2 ml) and CH ₂ Cl ₂ (0.5 ml) and stirred at room temperature for 2 hours . The reaction mixture was diluted with EtOAc and the organic phase was washed with saturated aqueous NaHCO ₃ solution, brine, dried over Na ₂ SO ₄ and evaporated to dryness. The residue was dissolved in DMF (1 ml), di-tert-butoxyphosphoryloxypotassium (263.7 mg, 1.062 mmol) and tetrabutylammonium iodide (9.810 mg, 0.02656 mmol) were added and the reaction mixture was stirred at 70°C for 4 hours. The reaction mixture was cooled, diluted with water and extracted with EtOAc (3×). The organic phases were combined, washed with water, then with brine, dried over Na ₂ SO ₄ and evaporated to dryness. Purification by column chromatography (12 g silica gel; 0-100% EtOAc in hexanes) gave di-tert-butyl[4-[[4-chloro-2-(4-fluoro-2-methylphenoxy)benzoyl]amino]-2 -oxo-1-pyridyl]methylphosphate ( 23 ) (35 mg, 0.05882 mmol, 22.2%) as a pure foam. ESI-MS m/z calculated: 594.1698, determined: 595.5 (M+1)+; Retention time: 0.77 minutes.

EXAMPLE 15L

[4-[[4-Chloro-2-(4-fluoro-2-methylphenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate ( 13 )

[00384] Di-tert-Butyl[4-[[4-chloro-2-(4-fluoro-2-methylphenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate solution ( 23 ) (35 mg, 0.05882 mmol) in CH ₃ CN (700.0 μl), water (700.0 μl) and AcOH (0.7 ml, 12.31 mmol) were heated at 90°C for 20 min, then evaporated and co evaporated with CH ₃ CN (3×). The material was triturated with CH ₃ CN, filtered, washed with CH ₃ CN and dried to give [4-[[4-chloro-2-(4-fluoro-2-methylphenoxy)benzoyl]amino]-2-oxo-1-pyridyl] methyl dihydrogen phosphate ( 13 ) (13 mg, 0.02558 mmol, 43.5%) as a white solid. ESI-MS m/z calculated: 482.0446, determined: 483.4 (M+1)+; Retention time: 1.41 minutes. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.59 (s, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.60 (d, J=7.5 Hz , 1H), 7.30 (dd, J=8.2, 2.0 Hz, 1H), 7.21 (d, J=9.3 Hz, 1H), 7.16-7.05 (m, 2H), 6.89 (d, J=2.3 Hz, 1H), 6.74 (d, J=2.0 Hz, 1H), 6.44 (dd, J=7.6, 2.3 Hz, 1H), 5.51 (d, J=9.7 Hz, 2H), 2.16 (s, 3H) ppm. ³¹ P NMR (162 MHz, DMSO-d ₆ - 85% H3PO4 aq as internal standard - 0 ppm) δ -2.15 (t, J=9.7 Hz) ppm

EXAMPLE 15M

Di-tert-butyl[4-[[2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate (24)

[00385] To a solution of 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1H-pyridin-4-yl)-5-(trifluoromethyl)benzamide (10a) (102 mg, 0.2510 mmol ) and chloromethylchloroformate (77.67 mg, 52.30 µl, 0.6024 mmol) in CH ₂ Cl ₂ (2 ml), DMF (200 µl) was added and the reaction mixture was stirred at room temperature for 1 hour. Additional chloromethylchloroformate (77.67 mg, 52.30 μL, 0.6024 mmol) was added and the reaction mixture was heated to 70°C for 25 minutes. The reaction mixture was diluted with EtOAc, the organic phase was washed with saturated aqueous NaHCO ₃ solution, saturated saline solution, dried over Na ₂ SO ₄ and evaporated to dryness. The residue was dissolved in DMF (3 ml), di-tert-butoxyphosphoryloxypotassium (249.3 mg, 1.004 mmol) and tetrabutylammonium iodide (9.271 mg, 0.02510 mmol) were added and the reaction mixture was stirred at 70°C for 4 hours. The reaction mixture was cooled, diluted with water and extracted with EtOAc (3×). The organic layers were combined, washed with water, then with brine, dried over Na ₂ SO ₄ and evaporated to dryness. Purification by column chromatography (12 g silica gel; 0-100% EtOAc in hexanes) gave di-tert-butyl[4-[[2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzoyl]amino] -2-oxo-1-pyridyl]methylphosphate (24) (23 mg, 0.03659 mmol, 14.6%) as a clear glassy substance. ESI-MS m/z calculated: 628.19617, determined: 629.5 (M+1)+; Retention time: 0.78 minutes

EXAMPLE 15N

[4-[[2-(4-Fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate ( 10 )

[00386] Di-tert-Butyl[4-[[2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate solution (24) (23 mg, 0.03659 mmol) in CH ₃ CN (460.0 µl), water (460.0 µl) and AcOH (460.0 µl) were heated at 90°C for 15 min, then evaporated and co-evaporated with CH ₃ CN (3×). The material was triturated with CH ₃ CN, filtered, washed with CH ₃ CN and dried to give [4-[[2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1- pyridyl]methyl dihydrogen phosphate (10) (6 mg, 0.01104 mmol, 30.2%) as a white solid. ESI-MS m/z calculated: 516.0709, determined: 517.4 (M+1)+; Retention time: 1.45 minutes. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.14 (s, 1H), 8.42 (d, J=2.4 Hz, 1H), 8.22 (dd, J=8.8, 2.2 Hz, 1H), 8.05 (d, J=7.6 Hz, 1H), 7.67 (dd, J=9.5, 3.1 Hz, 1H), 7.65-7, 50 (m, 2H), 7.35 (d, J=2.3 Hz, 1H), 7.26 (d, J=8.7 Hz, 1H), 6.88 (dd, J=7.6 , 2.4 Hz, 1H), 5.95 (d, J=9.8 Hz, 2H), 2.57 (s, 3H) ppm. ³¹ P NMR (162 MHz, DMSO-d ₆ - 85% aq. H ₃ PO ₄ as internal standard - 0 ppm) δ-2.17 (t, J=9.7 Hz) ppm

Example 15O

Di-tert-butyl[4-[[4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate ( 25 )

[00387] To a solution of 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1H-pyridin-4-yl)benzamide (1a) (101 mg, 0.2386 mmol ) and chloromethylchloroformate (36.92 mg, 24.86 μl, 0.2863 mmol) in CH ₂ Cl ₂ (2 ml), DMF (200 μl) was added and the reaction mixture was stirred at room temperature for 1 hour. THF (1 mL) was added followed by additional chloromethyl chloroformate (36.92 mg, 24.86 μL, 0.2863 mmol) and the reaction mixture was stirred at room temperature for 1 hour. Additional DMF (1 mL) and chloromethylchloroformate (36.92 mg, 24.86 μL, 0.2863 mmol) were added and the reaction mixture was heated to 70°C for 15 min. The reaction mixture was diluted with EtOAc and the organic phase was washed with saturated aqueous NaHCO ₃ solution, brine, dried over Na ₂ SO ₄ and evaporated to dryness. The residue was dissolved in DMF (1.010 ml), di-tert-butoxyphosphoryloxypotassium (118.5 mg, 0.4772 mmol) and tetrabutylammonium iodide (8.813 mg, 0.02386 mmol) were added and the reaction mixture was stirred at 70°C for 4 hours. The reaction mixture was cooled, diluted with water and extracted with EtOAc (3×). The organic layers were combined, washed with water, then brine, dried over Na ₂ SO ₄ and evaporated to dryness. Purification by column chromatography (12 g silica gel; 0-100% EtOAc in hexanes) gave di-tert-butyl[4-[[4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzoyl]amino] -2-oxo-1-pyridyl]methylphosphate ( 25 ) (40 mg, 0.06197 mmol, 26.0%) as a clear glassy substance. ESI-MS m/z calculated: 644.12573, determined: 647.3 (M+1)+; Retention time: 0.81 minutes

EXAMPLE 15P

[4-[[4,5-Dichloro-2-(4-fluoro-2-methoxyphenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate ( 1 )

[00388] Di-tert-Butyl[4-[[4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate solution (40 mg , 0.06197 mmol) in CH ₃ CN (800.0 µl), water (800.0 µl) and AcOH (800 µl, 14.07 mmol) heated at 90°C for 15 min, then evaporated and co-evaporated with CH ₃ CN (3×). The material was triturated with CH ₃ CN, filtered, washed with CH ₃ CN and dried to give [4-[[4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzoyl]amino]-2-oxo-1- pyridyl]methyl dihydrogen phosphate (1) (19 mg, 0.03385 mmol, 54.6%) as a white solid. ESI-MS m/z calculated: 532.00055, determined: 533.3 (M+1)+; Retention time: 1.5 minutes. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.58 (s, 1H), 7.91 (s, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.27 (dd, J=8.9, 5.8 Hz, 1H), 7.13 (dd, J=10.7, 3.0 Hz, 1H), 6.90 (d, J=2.3 Hz, 1H), 6.86 (s, 1H), 6.86-6.81 (m, 1H), 6.44 (dd, J=7.6, 2.4 Hz, 1H), 5.52 (d , J=9.7 Hz, 2H), 3.76 (s, 3H) ppm. ³¹ P NMR (162 MHz, DMSO-d ₆ -85% H ₃ PO ₄ aq as internal standard - 0 ppm) δ -2.12 (t, J=9.4 Hz) ppm

[00389] Compounds 3-8, 11, 12 and 14-17 can be prepared using similar procedures described above for the preparation of compounds 1, 2, 9, 10, 13 and 18.

EXAMPLE 15Q

[00390] A spray-dried dispersion of compound 9 with 50% HPMCAS was prepared as follows. Compound 9 (14 g) was added to a laboratory vessel (1000 ml), followed by 400 ml THF/H ₂ 0 (95:5) and 100 ml MeOH. The substance was stirred for 1 hour to obtain a slightly cloudy solution. In a separate container, 14 g of hydroxypropyl methylcellulose, HF grade acetate succinate (HPMCAS-HF) was dissolved in 100 ml of THF and the resulting mixture was stirred for 15 minutes. Both solutions were combined and continuously mixed, while spray drying was carried out using a Buchi Mini Spray Dryer with the following parameters:

[00391] T inlet (set point) 78°C

[00392] T output (start) 38°C

[00393] T output (end) 3°C

[00394] Nitrogen pressure 75 psi. inch (517106.77 Pa)

[00395] Aspirator 100%

[00396] Pump 20%

[00397] Rotameter 60 mm

[00398] Filtration pressure -50 mbar

[00399] Condenser temperature -5°C

[00400] Operating time 3 hours

[00401] Approximately 18.2 g of amorphous Form C of Compound 9 was obtained as a spray-dried dispersion (65% yield). The amorphous C form of compound 9 in the spray-dried dispersion was confirmed by XRPD (Figure 5) and DSC, showing a glass transition temperature of 96 °C.

[00402] Pure amorphous Form C of Compound 9 was prepared by spray-dried dispersion according to the conditions discussed above except that HPMCAS polymer was not added. Pure amorphous Form C of compound 9 in the spray-dried dispersion was confirmed by XRPD (Figure 6).

[00403] The structure of crystalline form B of compound 9 was confirmed by X-ray diffraction analysis (Figure 1). Single crystal diffraction data were obtained using a Bruker Apex II diffractometer equipped with a Cu K alpha radiation source in a sealed tube (Cu K _α radiation, γ = 1.54178 ) and a CCD Apex II detector. A colorless flat crystal with dimensions of 0.01×0.05×0.05 mm was selected for data collection. To determine the orientation matrix and initial cell parameters, three batches of 40 frames were obtained, separated in reciprocal space. The final cell parameters were obtained and refined after completion of data collection based on the complete data set.

[00404] The reciprocal space diffraction data set was acquired at a resolution of 0.84 in 1.0° increments, using 60 second exposures for each low angle frame and 120 second exposures for each high angle frame. Observation of the crystal after data collection did not show any signs of decomposition.

[00405] Data was collected, corrected and processed using Bruker Apex software. Structure was determined using SHELXS97 (Sheldrick, 1990); the program(s) and structure were refined using the SHELXL97 program (Sheldrick, 1997). The crystal shows a monoclinic cell with space group P2 ₁ /c. The lattice parameters are as follows: a=20.194(9) , b=9.205(4) , c=11.956(5) , β=95.213(8)°. Volume=2213.4(17) ³ . High angle reflections were weak, resulting in a high R-factor of 9.8%. However, the structure was determined, and the structure had one symmetry of an independent molecule.

[00406]

Table 3
Analytical data for compounds and intermediates Connection No. LCMS
Retention time in min MS
(M+1) ¹ H-NMR (400 MHz) 1 1.50 533.3 (DMSO-d ₆ ) δ 10.58 (s, 1H), 7.91 (s, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.27 (dd, J=8 ,9, 5.8 Hz, 1H), 7.13 (dd, J=10.7, 3.0 Hz, 1H), 6.90 (d, J=2.3 Hz, 1H), 6.86 (s, 1H), 6.86-6.81 (m, 1H), 6.44 (dd, J=7.6, 2.4 Hz, 1H), 5.52 (d, J=9.7 Hz, 2H), 3.76 (s, 3H) ppm 1a 1.57 423.3 (DMSO-d ₆ ) δ 11.27 (s, 1H), 10.49 (s, 1H), 7.90 (br s, 1H), 7.32 (d, J=7.2 Hz, 1H) , 7.28 (dd, J=8.9, 5.8 Hz, 1H), 7.14 (dd, J=10.7, 2.9 Hz, 1H), 6.89-6.82 (m , 2H), 6.77 (s, 1H), 6.39 (dd, J=7.2, 2.1 Hz, 1H), 3.76 (s, 3H) ppm. 2 1.54 583.4 (DMSO-d ₆ ) δ 10.72 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H), 7, 51 (d, J=8.2 Hz, 1H), 7.31 (dd, J=8.9, 5.9 Hz, 1H), 7.16 (dd, J=10.7, 2.9 Hz , 1H), 6.94 (d, J=1.9 Hz, 1H), 6.91-6.84 (m, 1H), 6.77 (s, 1H), 6.47 (dd, J= 7.6, 2.2 Hz, 1H), 5.54 (d, J=9.7 Hz, 2H), 3.74 (s, 3H) ppm. 2a 1.62 473.3 (DMSO-d ₆ ) δ 11.32 (s, 1H), 10.62 (s, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.51 (d, J=7 .9 Hz, 1H), 7.39-7.27 (m, 2H), 7.17 (dd, J=10.7, 2.8 Hz, 1H), 6.88 (dd, J=11, 3, 5.7 Hz, 1H), 6.81 (s, 1H), 6.75 (s, 1H), 6.43 (d, J=7.1 Hz, 1H), 3.73 (s, 3H) ppm 3a 1.53 393.1 (DMSO- _d6 ) δ 11.32 (s, 1H), 10.57 (s, 1H), 7.95 (s, 1H), 7.34-7.24 (m, 3H), 7.22 -7.15 (m, 3H), 6.74 (s, 1H), 6.38 (d, J=7.2 Hz, 1H) ppm 4a 1.56 423.2 5a 1.8 459.5 6a 1.59 443.5 (DMSO-d ₆ ) δ 7.87 (d, J=7.9 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.37-7.25 (m, 3H ), 7.24-7.16 (m, 2H), 7.07 (s, 1H), 6.73 (s, 1H), 6.37 (d, J=6.9 Hz, 1H) m. d. 7a 1.52 389.1 8a 1.93 459.3 (DMSO-d ₆ ) δ 11.29 (s, 1H), 10.62 (s, 1H), 8.02 (d, J=2.3 Hz, 1H), 7.86 (dd, J=8 ,7, 2.4 Hz, 1H), 7.58-7.40 (m, 2H), 7.40-7.21 (m, 3H), 7.11 (d, J=8.7 Hz, 1H), 6.76 (d, J=2.1 Hz, 1H), 6.38 (dd, J=7.2, 2.1 Hz, 1H) ppm. 9 1.79 407.1 (DMSO-d ₆ ) δ 11.27 (s, 1H), 10.63 (s, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.60 (d, J=7 .8 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.23 (m, 1H), 7.10 (m, 2H), 6.97 (s, 1H), 6.76 (d, J=1.6 Hz, 1H), 6.38 (dd, J=7.2, 2.0 Hz, 1H), 2.16 (s, 3H) ppm. 9a 1.79 407.1 (DMSO-d ₆ ) δ 11.27 (s, 1H), 10.63 (s, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.60 (d, J=7 .8 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.23 (m, 1H), 7.10 (m, 2H), 6.97 (s, 1H), 6.76 (d, J=1.6 Hz, 1H), 6.38 (dd, J=7.2, 2.0 Hz, 1H), 2.16 (s, 3H) ppm. 10 1.45 517.4 (DMSO-d ₆ ) δ 11.14 (s, 1H), 8.42 (d, J=2.4 Hz, 1H), 8.22 (dd, J=8.8, 2.2 Hz, 1H ), 8.05 (d, J=7.6 Hz, 1H), 7.67 (dd, J=9.5, 3.1 Hz, 1H), 7.65-7.50 (m, 2H) , 7.35 (d, J=2.3 Hz, 1H), 7.26 (d, J=8.7 Hz, 1H), 6.88 (dd, J=7.6, 2.4 Hz, 1H), 5.95 (d, J=9.8 Hz, 2H), 2.57 (s, 3H) ppm. 10a 1.6 407.2 (DMSO-d ₆ ) δ 11.77 (s, 1H), 10.79 (s, 1H), 8.00 (d, J=2.2 Hz, 1H), 7.80 (dd, J=8 ,8, 2.3 Hz, 1H), 7.45 (d, J=7.2 Hz, 1H), 7.25 (dd, J=9.3, 3.0 Hz, 1H), 7.16 (m, 2H), 6.95 (d, J=1.9 Hz, 1H), 6.83 (d, J=8.7 Hz, 1H), 6.56 (dd, J=7.2, 2.0 Hz, 1H), 2.14 (s, 3H) ppm. 11a 1.57 427.2 (DMSO-d ₆ ) δ 11.29 (s, 1H), 10.62 (s, 1H), 8.02 (d, J=2.2 Hz, 1H), 7.83 (dd, J=8 ,8, 2.2 Hz, 1H), 7.69 (dd, J=8.4, 3.0 Hz, 1H), 7.45 (dd, J=9.1, 5.3 Hz, 1H) , 7.40-7.30 (m, 2H), 6.92 (d, J=8.7 Hz, 1H), 6.79 (d, J=1.9 Hz, 1H), 6.42 ( dd, J=7.2, 2.1 Hz, 1H) ppm 12a 1.57 373.1 13 1.41 483.4 (DMSO-d ₆ ) δ 10.59 (s, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.60 (d, J=7.5 Hz, 1H), 7, 30 (dd, J=8.2, 2.0 Hz, 1H), 7.21 (d, J=9.3 Hz, 1H), 7.16-7.05 (m, 2H), 6.89 (d, J=2.3 Hz, 1H), 6.74 (d, J=2.0 Hz, 1H), 6.44 (dd, J=7.6, 2.3 Hz, 1H), 5 .51 (d, J=9.7 Hz, 2H), 2.16 (s, 3H) ppm. 13a 1.57 373.2 (DMSO-d ₆ ) δ 11.48 (s, 1H), 10.57 (s, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.36 (d, J=7 .2 Hz, 1H), 7.30 (dd, J=8.2, 1.9 Hz, 1H), 7.21 (d, J=9.3 Hz, 1H), 7.10 (m, 2H ), 6.83 (d, J=1.9 Hz, 1H), 6.74 (d, J=1.9 Hz, 1H), 6.45 (dd, J=7.2, 2.1 Hz , 1H), 2.16 (s, 3H) ppm 14a 1.64 393.1 15a 1.48 359.2 (DMSO-d ₆ ) δ 11.25 (s, 1H), 10.48 (s, 1H), 7.65 (t, J=8.5 Hz, 1H), 7.29 (m, 4H), 7.19 (m, 2H), 6.91 (d, J=1.9 Hz, 1H), 6.75 (d, J=1.9 Hz, 1H), 6.38 (dd, J=7 ,2, 2.1 Hz, 1H) ppm 16a 1.55 411.17 17a 1.83 459.3 (DMSO-d ₆ ) δ 11.28 (s, 1H), 10.63 (s, 1H), 8.04 (d, J=2.3 Hz, 1H), 7.86 (dd, J=8 ,7, 2.4 Hz, 1H), 7.60-7.54 (m, 1H), 7.54-7.43 (m, 1H), 7.43-7.34 (m, 1H), 7.34-7.28 (m, 2H), 7.05 (d, J=8.7 Hz, 1H), 6.75 (d, J=2.0 Hz, 1H), 6.38 (dd , J=7.2, 2.1 Hz, 1H) ppm 18 1.39 503.4 (DMSO-d ₆ ) δ 10.70 (s, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.83 (dd, J=8.8, 2.4 Hz, 1H ), 7.61 (d, J=7.6 Hz, 1H), 7.35-7.23 (m, 4H), 7.00 (d, J=8.7 Hz, 1H), 6.91 (d, J=2.2 Hz, 1H), 6.45 (dd, J=7.6, 2.3 Hz, 1H), 5.53 (d, J=9.7 Hz, 2H) m. d. 18a 1.72 393.1 (DMSO-d ₆ ) δ 11.40 (s, 1H), 10.64 (s, 1H), 8.00 (d, J=2.2 Hz, 1H), 7.83 (dd, J=8 ,8, 2.3 Hz, 1H), 7.30 (tdd, J=6.9, 5.9, 3.4 Hz, 5H), 6.99 (d, J=8.8 Hz, 1H) , 6.82 (d, J=1.8 Hz, 1H), 6.43 (dd, J=7.2, 2.0 Hz, 1H) ppm.

Example 16

STUDIES TO IDENTIFY AND MEASURE THE INHIBITORY PROPERTIES OF COMPOUNDS IN RELATION TO Nav

Method for optical analysis of membrane potential E-VIPR with electrical stimulation

[00407] Sodium channels are voltage-gated proteins that can be activated by inducing changes in membrane voltage under the influence of an electric field. The electrical stimulation instrument and method of use thereof are described in ION Channel Assay Methods PCT/US01/21652, which is incorporated herein by reference and referred to as E-VIPR. The instrument includes a microtiter plate holder, an optical system for exciting the coumarin dye while simultaneously recording the emission of coumarin and oxonol, a wave signal generator, a controlled current or potential amplifier, and a device for introducing electrodes into the well. Under the integral control of a computer, this device carries out electrical stimulation of cells in the wells of a microtiter plate programmed by the user according to the protocol. The E-VIPR assay is performed according to the following procedure (including reagents and solutions, assay protocol, and data analysis). The procedure, for simplicity, is described in the past tense, but it should be understood that the specified procedure applies to specified tests performed in the past (if required) and to specified tests performed in the future (if required).

[00408] 24 hours prior to E-VIPR assay, HEK cells expressing human NaV1.8 were seeded into 384-well polylysine-coated plates at a concentration of 15,000-20,000 cells per well. HEK cells were grown in media (the exact composition is specific to each cell type and NaV subtype) supplemented with 10% FBS (fetal bovine serum, grade appropriate; GibcoBRL #16140-071) and 1% Pen-Strep (penicillin-streptomycin; GibcoBRL # 15140-122). Cells were grown in vessels with perforated lids, at 90% humidity and in an atmosphere of 5% CO ₂ .

Reagents and solutions:

[00409] 100 mg/ml Pluronic F-127 (Sigma #P2443) in dry DMSO

[00410] Compound Application Plates: 384-well round bottom plates, such as Corning 384-well Polypropylene Round Bottom #3656

[00411] Cell culture plates: 384-well tissue culture-treated plates, e.g. Greiner #781091-1B

[00412] 10 mM DiSBAC6 (3) (Aurora #00-100-010) in dry DMSO

[00413] 10 mM CC2-DMPE (Aurora #00-100-008) in dry DMSO

[00414] 200 mM ABSC1 in H ₂ O

[00415] Bath1 Buffer: Glucose 10 mM (1.8 g/L), Magnesium Chloride (Anhydrous) 1 mM (0.095 g/L), Calcium Chloride 2 mM (0.222 g/L), HEPES 10 mM ( 2.38 g/l), potassium chloride, 4.5 mmol (0.335 g/l), sodium chloride 160 mmol (9.35 g/l).

[00416] Hexyl Dye Solution: Bath1 buffer + 0.5% β-cyclodextrin (prepared before use, Sigma #C4767), 8 µM CC2-DMPE + 2.5 µM DiSBAC ₆ (3). To obtain a solution, a volume of a stock solution of 10% Pluronic F127 was added equal to the volume of CC2-DMPE+DiSBAC ₆ (3). The order of preparation was as follows: first mix Pluronic and CC2-DMPE, then add DiSBAC ₆ (3) with vortex mixing and then add Bath1+β-cyclodextrin.

Study protocol :

[00417] 1) Pre-coat compounds (in pure DMSO) onto compound application plates. Vehicle control (straight DMSO), positive control (20 mM DMSO original tetracaine, 125 μM assay final), and test compounds were added to each well at 160x the desired final concentration in neat DMSO. The final volume of compound in the plate was 80 μl (80-fold intermediate dilution of 1 μl DMSO sample; 160-fold final dilution after transfer to the cell culture plate). The final DMSO concentration for all wells in the assay was 0.625%.

[00418] 2) Hexyl Dye Solution was prepared.

[00419] 3) Cell culture plates were prepared. On the day of the assay, the medium was aspirated and the cells were washed three times with 100 μl Bath1 solution, maintaining a 25 μl residual volume in each well.

[00420] 4) Dispense 25 μl of Hexyl Dye Solution per well into cell culture plates. Incubate for 20-35 minutes at room temperature or ambient conditions.

[00421] 5) 80 μl per well of Bath1 was dispensed into the loading plates. Acid Yellow-17 (1 mM) was added and potassium chloride was changed from 4.5 to 20 mM depending on NaV subtype and assay sensitivity.

[00422] 6) Cell culture plates were washed three times with 100 μl per well of Bath1, leaving 25 μl of residual volume. 25 μl per well was then transferred from the junction plates to the cell plates. Incubate for 20-35 minutes at room temperature/ambient conditions.

[00423] 7) The plates were read on the E-VIPR. A current-controlled amplifier was used to deliver stimulating waveforms for 10 seconds at a scanning frequency of 200 Hz. To obtain initial values of unstimulated intensities, recording was performed for 0.5 seconds before stimulation. The stimulus signal followed the post-stimulation recording for 0.5 s to examine resting state relaxation.

[00424] Data are analyzed as normalized intensity ratios measured in the 460 nm and 580 nm channels. The answer, as a function of time, is presented as a ratio calculated using the following formula:

[00425] The data is further minimized by calculating the ratio of the initial indicators (R _i ) and the final indicators (R _f ). They represent the average of the ratios during the partial or full period before stimulation and at sampling time points during the stimulation period. Then the response to the stimulus R=R _f /R _i is calculated.

[00426] Response control values are obtained by performing assays in the presence of a compound with the desired properties (positive control), such as tetracaine, and in the absence of pharmacological agents (negative control). Negative (N) and positive (P) control responses were calculated as above. The activity index (A) of antagonist compound A is determined as follows:

$$A=\frac{R-P}{N-P}*100.$$ , where R is the relative response of the test compound

EXAMPLE 17

ELECTROPHYSIOLOGICAL ANALYSIS TO DETERMINE THE ACTIVITY OF NAV CHANNELS AND THE INHIBITORY ACTIVITY OF TEST COMPOUNDS

[00427] An electrophysiological voltage clamp method was used to evaluate the efficacy and selectivity of sodium channel blockers in dorsal root ganglion neurons. Rat neurons were isolated from the dorsal root ganglia and maintained in culture for 2 to 10 days in the presence of NGF (50 ng/ml) (culture medium consisted of NeurobasalA supplemented with B27, glutamine and antibiotics). Small diameter neurons (8–12 μm diameter nociceptors) were identified visually and probed with fine glass electrode tips connected to an amplifier (Axon Instruments). Voltage clamp mode was used to evaluate the IC ₅₀ of compounds while holding cells at a potential level of 60 mV. In addition, a “current clamp” mode was used to test how effective the test compounds were in blocking action potentials arising in response to current stimulation. The experimental results contributed to the determination of the effectiveness profile of the compounds.

[00428] Herein, selected compounds and intermediates of the present invention are active on NaV1.8 sodium channels, as determined using the assays described herein and presented in Table 4 below.

[00429]

Table 4
IC ₅₀ - activity against NaV1.8 Connection no. IC ₅₀ (µM) NaV1.8 1 0.004 1a 0.001 2 0.028 2a 0.003 3a 0.006 4a 0.011 5a 0.011 6a 0.012 7a 0.013 8a 0.013 9 0.33 9a 0.014 10 0.086 10a 0.017 11a 0.028 12a 0.03 13 0.329 13a 0.03 14a 0.037 15a 0.044 16a 0.05 17a 0.051 18 0.457 18a 0.054

EXAMPLE 18

[00430] IonWorks Assays. This assay is performed to determine the activity of the compounds of the present invention on NaV1.8 channels. This analysis is carried out according to the following procedure. The procedure, for simplicity, is described in the past tense, however it will be understood that this procedure applies to specified analyzes performed in the past (if any) and to specified analyzes performed in the future (if any). Sodium channels were monitored using an IonWorks voltage clamp automation system (Molecular Devices Corporation, Inc.). Cells expressing Nav subtypes were collected from tissue culture and placed in a suspension of 0.5-4 million cells per ml Bath1. The IonWorks instrument measured changes in sodium currents in response to the voltage clamp assay, similar to the traditional voltage clamp assay, except in the 384-well format. IonWorks was used to determine the voltage-clamp dose-response relationship by depolarizing the cell from the specific baseline potential in the experiment to an analytical potential of approximately 0 mV before and after addition of the test compound. The effect of the connection on the currents was measured at analytical potential.

EXAMPLE 19

[00431] WATER SOLUBILITY TEST

[00432] The water solubility of compounds 9 and 9a was determined in accordance with the following procedure. Solubility data were determined under ambient conditions by equilibrating the compound with water on a rocking bed for 24 hours, followed by centrifugation and separation of the saturated solutions. Before centrifugation, the pH of each media was measured, and the saturated solutions were analyzed by HPLC. The aqueous solubility of compound 9a was low (<0.001 mg/mL at pH 6.0), whereas the aqueous solubility of compound 9 in water was approximately 0.3 mg/mL.

[00433]

Table 5
Water solubility of compounds 9 and 9a Compound Solid form pH Solubility (mg/ml) 9a crystalline 6.0 <0.001 9a crystalline 1.2 <0.001 9 crystalline 1 0.002 9 crystalline 3 0.11 9 crystalline 3.3 0.24 9 crystalline 5 0.42 9 crystalline 7 0.50 9 crystalline 8 2.24

EXAMPLE 20

[00434] PHARMACOKINETIC STUDIES

[00435] The pharmacokinetic parameters of selected compounds of the present invention were determined in the experiments described below. General analytical procedures and specific experimental protocols were used as follows:

[00436] General analytical procedures

[00437] The following general analytical procedures were used in the pharmacokinetic experiments described below:

[00438] Sample analysis. Plasma concentrations of compound 9 and compound 9a were determined using tandem high-performance liquid chromatography-mass spectrometry (HPLC/MS/MS). Before extraction, plasma samples were diluted using null plasma with an appropriate dilution factor, if necessary, depending on the dose level. Compound 9a and compound 9 along with internal standard (IS) were extracted from (diluted) plasma, 20 μl each, by direct protein precipitation with acetonitrile (1:25 plasma/acetonitrile ratio). After centrifugation, the supernatant of the extract (10 μL) was injected into the LC/MS/MS system. The HPLC system included a Phenomenex Synergy Kinetix C8 column (2.6 μm, 2.0 mm diameter x 75 mm length) with a gradient elution with a mobile phase consisting of 0.1% formic acid in water or acetonitrile.

[00439] Test substances were detected using electrospray ionization (ESI) tandem mass spectrometry (MS/MS) in multiple reaction monitoring (MRM) mode. The lower limit of quantitation (LLOQ) was 1 to 10 ng/mL for compound 9a, and 2.5 to 25 ng/mL for compound 9. The linear range of the assay was 1 or 10 to 10,000 ng/mL for compound 9a. and 2.5 or 25 to 10,000 ng/ml for compound 9. The intraday and interday analysis errors were within 20% of the nominal values. Intraday and interday variability was ≤20%.

[00440] Pharmacokinetic data analysis . The plasma concentration-time profiles of compound 9a and compound 9 were analyzed by non-compartmental pharmacokinetic methods using Watson LIMS version 7.4 SP3 (Thermo Fisher Scientific, Inc., Philadelphia, Philadelphia, PA)

[00441] The main pharmacokinetic parameters were determined, such as AUC _all , AUC _extra , C _max , t _max , Cl, Vss and t _1/2 .

[00442] Statistical data analysis.We calculated a quantitative indicator of the distribution of pharmacokinetic parameters, including mean, standard deviation (SD) using Watson LIMS version 7.4 SP3 or Microsoft Excel 2000.

[00443] Study of oral administration of the compound to monkeys

Male or female cynomolgus monkeys (n=3 per dose group) were administered orally by gavage to single nominal doses of compound 9 corresponding to 10, 40, 100, 300, 500, 750 and 1000 mg/kg. Compound 9 contained 30% PEG400 and 10% TPGS in water or 5% TPGS, 5% PVP-K30 in 50 mM citrate (pH 5). Animals were fasted overnight before dosing and fed two hours after dosing. Water was available before and after dosing.

[00444] Blood samples (approximately 0.25 ml each) were collected using a carotid catheter before dosing and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72 hours after dosing. Each blood sample was collected in a tube, which was stored on “natural” ice and which contained potassium EDTA as an anticoagulant. Plasma was separated and stored at approximately 70°C until analysis.

[00445] Plasma samples were analyzed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) to determine the concentration of compound 9a and compound 9 with a lower limit of detection (LLOQ) of 1.00 to 10.0 ng/ml for compound 9a, and from 10.0 to 25.0 ng/ml for compound 9. Compound 9a plasma concentration-time data were subjected to non-compartmental pharmacokinetic (PK) analysis. The results of this analysis are presented in Table 7. For compound 9, plasma concentrations were below the LLOQ for most samples and PK analysis could not be performed.

[00446]

Table 7
Pharmacokinetic data from an oral administration study in monkeys Nominal dose
(mg/kg) Composition Test substance AUC _extra
(µg∙h/ml) C _max
(µg/ml) _Tmax
(h) T _1/2
(h) 10 30%PEG400/10%TPGS/60% water Compound
9a 21.5±13.7 1.13±0.187 4.67±3.06 8.57±2.75 40 5% TPGS/5%PVP-K30/50 mM Citrate pH5 Compound
9a 62.4±23.8 4.50±0.51 3.33±1.15 9.58±3.91 100 5% TPGS/5%PVP-K30/50 mM Citrate pH5 Compound
9a 49.6±10.7 3.34±0.34 4.00±0.00 7.04±0.36 300 5% TPGS/5%PVP-K30/50 mM Citrate pH5 Compound
9a 93.4±22.7 5.77±1.46 2.67±1.15 11.6±2.3 500 5% TPGS/5%PVP-K30/50 mM Citrate pH5 Compound
9a 124±6.0 5.76±1.69 6.00±3.46 9.80±1.08 750 5% TPGS/5%PVP-K30/50 mM Citrate pH5 Compound
9a 138±47.3 7.49±3.13 6.67±4.62 13.1±3.1 N=3 monkeys per dose, mean ± standard deviation

[00447] Study of oral administration of the compound to rats

[00448] Groups of male and female Sprague Dawley rats (n=3 per dose group) were administered orally by gavage to single nominal doses of Compound 9 corresponding to 10, 40, 100, 300, 500, 750 and 1000 mg/kg (for males) and 30, 100, 300, 640, 1000 mg/kg (for females). Compound 9 contained 30% PEG400 and 10% TPGS in water or 5% TPGS, 5% PVP-K30 in 50 mM citrate (pH 5). Animals had free access to food and water before and after dosing. Blood samples (approximately 0.25 ml each) were collected using a carotid catheter before dosing and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, and 72 hours after. administration of doses. Each blood sample was collected in a tube, which was stored on “natural” ice and which contained potassium EDTA as an anticoagulant. Plasma was separated and stored at approximately 70°C until analysis.

[00449] Plasma samples were analyzed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) to determine the concentration of compound 9a and compound 9 with a lower limit of detection (LLOQ), from 1 to 25 ng/ml for compound 9a, and from 2.5 to 25 ng/ml for compound 9. Compound 9a plasma concentration-time data were subjected to non-compartmental pharmacokinetic (PK) analysis. The results of this analysis are presented in Table 8. For compound 9, plasma concentrations were below the LLOQ for most samples and PK analysis could not be performed.

[00450]

Table 8
Pharmacokinetic data from an oral administration study in rats Floor Nominal dose
(mg/kg) Composition Test substance AUC _extra
(µg∙h/ml) _Cmax
(µg/ml) _Tmax
(h) T _1/2
(h) Male 10 5% TPGS/5%PVP-K30/50 mM Citrate pH5 Connection 9a 3.6±0.24 0.29±0.05 5.33±2.31 3.80±0.73 100 5% TPGS/5%PVP-K30/50 mM Citrate pH5 Connection 9a 24.8±4.6 1.67±0.19 8.00±0.00 5.36±2.37 400 5% TPGS/5%PVP-K30/50 mM Citrate pH5 Connection 9a 68.6±25.7 3.74±1.25 5.67±4.04 5.20±1.96 640 5% TPGS/5%PVP-K30/50 mM Citrate pH5 Connection 9a 74.9±24.1 4.76±0.98 6.00±3.46 6.91±1.84 1000 5% TPGS/5%PVP-K30/50 mM Citrate pH5 Connection 9a 88.5±41.0 4.54±0.91 6.67±2.31 7.95±2.24 Female thirty 5% TPGS/5%PVP-K30/50 mM Citrate pH5 Connection 9a 99.2±6.88 3.33±0.43 6.67±2.31 10.8±1.60 100 5% TPGS/5%PVP-K30/50 mM Citrate pH5 Connection 9a 187±17.5 5.82±0.58 12.0±0.00 9.15±0.44 300 5% TPGS/5%PVP-K30/50 mM Citrate pH5 Connection 9a 282±74.2 7.90±1.30 10.7±2.31 13.1±2.65 640 5% TPGS/5%PVP-K30/50 mM Citrate pH5 Connection 9a 324±32.8 10.0±1.45 9.33±2.31 7.51±1.86 1000 5% TPGS/5%PVP-K30/50 mM Citrate pH5 Connection 9a 345±69.6 10.6±3.58 13.3±9.24 7.90±3.37 N=3 rats per dose, mean ± standard deviation

[00451] Rat research IV

[00452] Male Sprague Dawley rats (n=3) were used and administered intravenously a single nominal bolus dose of Compound 9 of 1 mg/kg via a jugular vein cannula. Compound 9, containing 35% PEG 400, 15% ethanol, 10% dimethyl isosorbide and 40% (5% dextran in water), was prepared in DMI carrier. Animals had free access to food and water before and after dosing. Blood samples (approximately 0.25 ml each) were collected through a carotid catheter before dosing and after 5 min, 10 min, 0.25, 0.5, 1, 2, 4, 8, 12, 24 hours after dosing. Each blood sample was collected in a tube, which was stored on “natural” ice and which contained potassium EDTA as an anticoagulant. Plasma was separated and stored at approximately 70°C until analysis.

[00453] Plasma samples were analyzed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) to determine the concentration of compound 9a and compound 9 with a lower limit of detection (LLOQ) of 1 for compound 9a and 2.5 ng/ml for compound 9. Plasma concentration-time data were subjected to non-compartmental pharmacokinetic (PK) analysis. The results of this analysis are presented in Table 9. For compound 9, plasma concentrations were below the LLOQ for most samples and PK analysis could not be performed.

[00454]

Table 9
Pharmacokinetic data from IV rat study Dose (mg/kg) Composition Analyte C0 (µg/ml) AUC _all (µg*h/ml) AUC _extra (µg*h/ml) t1/2 (h) Cl (ml/min/kg) Vss (l/kg) 1 DMI Connection 9a 0.259 0.592 0.611 2.43 18.7 3.77

[00455] The studies described above show that compound 9 is converted in vivo to compound 9a, at least in rats and monkeys.

[00456] Many modifications and embodiments described herein can be made without departing from the scope of the present invention, as will be apparent to those skilled in the art. The specific embodiments described herein are offered by way of example only.

ton; metpldihydrophosphate.

[1] in fig. 4 shows the TGA thermogram

fhermot'-Raviterkie analysis) of solid form B ( 4 - (2 - (4 - fluorine - 2 –

methylphenoxy> -4- i orifluoromethyl 5 benzamido) - 2-oxopyridine -1 (2 H) -

id)methylditchydrophosphate.

[2] Figure 5 shows a powder X-ray diffraction pattern of a solid
transparent amorphous form C (4 -{2-(4-fluoro-2-motylphenoxy) -4 -(triftsrmethyl)benzamido)-2-oxopyridine-1 (2K) -

id)methylhydrogen phosphate.

GO 113] ti. .5'f>a powder X-ray diffractionamorphous

sawing the dispersion (4- (2- (4-fluoro-2-
i)benzamido)-2-oxopyridine-1 (2 H)-

DETAILED DESCRIPTION OF THE INVENTION

[00X9] these compounds of formula I are pro-drug
their corresponding parent compounds. Thus,
the activity demonstrated upon administration of the prodrug,
conditioned, “thus, by the presence of the parent compound,
Xyoroe occurs as a result of the cleavage of a prodrug.

[1] The present invention also relates to new

Solid Forms (4-(2-(4-fluoro-2-methylfexkey)-4-

N'oiFtsrmethyl)benzamido)-2-oxopyridine-1(2d)-

il) met'/.lld.g'l, ^1g , rsFssphata ("compound 9"), In one of the variants
and implementation, the present invention relates to free
crystalline form of compound 9 (form B). 3 other option

implementation of the present invention relates to a method
obtain, solid Form 3 compounds 9. In another charge
implementation of the present invention relates to an amorphous form
compounds 9 (form C). In yet another embodiment
The present invention relates to a method for producing amorphous
Form C of connection 9.

[2] The term "prodrug" refers to compounds that
which are precursors to drugs.,
which, after administration and absorption, release the drug
agent in vivo through certain metabolic processes.
In general, a prodrug has less biological

Claims (147)

1. Method for preparing the compound of formula I I, in which, independently for each case: R ² and R ³ independently represent hydrogen, halogen or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms; R ⁵ represents hydrogen, halogen, OH or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms and wherein up to two non-adjacent CH ₂ units of said C ₁ -C ₆ -alkyl may be replaced by -O-; R ⁷ represents hydrogen, halogen or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted by 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ -alkyl may be replaced on -O-; And X represents –PO(OH) ₂ , –PO(OH)O ^- M ⁺ , –PO(O ^- ) ₂ ⋅2M ⁺ or –PO(O ^- ) ₂ ⋅D ²⁺ ; M ⁺ is a pharmaceutically acceptable monovalent cation; and D ²⁺ is a pharmaceutically acceptable divalent cation; with the proviso that R ² , R ³ , R ⁵ and R ⁷ are not both hydrogen; including: processing of a compound of formula B B K(PG ₁ ) ₂ PO ₄ to obtain a compound of formula C C; And removing the protecting groups in a compound of formula C to obtain a compound of formula I in which X is P(O)(OH) ₂ and PG ₁ is tert -butyl; And optionally, treating a compound of formula I in which X is P(O)(OH) ₂ , M ⁺ OH ^- or D ²⁺ (OH ^- ) ₂ to obtain a compound of formula I in which X is P(O) (OH)(O ^- )⋅M ⁺ , P(O)(O ^- ) ₂ ⋅2M ⁺ or P(O)(O ^- ) ₂ ⋅D ²⁺ . 2. The method of claim 1, further comprising treating a compound of formula A A chloromethyl chloroformate to give the compound of formula B. 3. Method according to claim 1, where: R ² represents H; R ³ represents CF ₃ ; R ⁵ represents CH ₃ ; R ⁷ represents F; And X represents -PO(OH) ₂ . 4. Method according to claim 2, where: R ² represents H; R ³ represents CF ₃ ; R ⁵ represents CH ₃ ; And R ⁷ represents F. 5. The method according to claim 4, where X represents -PO(OH) ₂ . 6. Method according to claim 1, where: R ² represents H; R ³ represents CF ₂ CF ₃ ; R ⁵ represents OCH ₃ ; R ⁷ represents F; And X represents -PO(OH) ₂ . 7. Method according to claim 2, where: R ² represents H; R ³ represents CF ₂ CF ₃ ; R ⁵ represents OCH ₃ ; And R ⁷ represents F. 8. Method according to claim 7, where X represents -PO(OH) ₂ . 9. Method according to claim 1, where: R ² represents H; R ³ represents Cl; R ⁵ represents CH ₃ ; R ⁷ represents F; And X represents -PO(OH) ₂ . 10. Method according to claim 2, where: R ² represents H; R ³ represents Cl; R ⁵ represents CH ₃ ; And R ⁷ represents F. 11. The method according to claim 10, where X represents -PO(OH) ₂ . 12. Method according to claim 1, where: R ² represents CF ₃ ; R ³ represents H; R ⁵ represents CH ₃ ; R ⁷ represents F; And X represents -PO(OH) ₂ . 13. Method according to claim 2, where: R ² represents CF ₃ ; R ³ represents H; R ⁵ represents CH ₃ ; And R ⁷ represents F. 14. The method according to claim 13, where X represents -PO(OH) ₂ . 15. Method according to claim 1, where: R ² represents CF ₃ ; R ³ represents H; R ⁵ represents H; R ⁷ represents F; And X represents -PO(OH) ₂ . 16. Method according to claim 2, where: R ² represents CF ₃ ; R ³ represents H; R ⁵ represents H; And R ⁷ represents F. 17. The method according to claim 16, where X represents -PO(OH) ₂ . 18. Method according to claim 1, where: R ² represents Cl; R ³ represents Cl; R ⁵ represents OCH ₃ ; R ⁷ represents F; And X represents -PO(OH) ₂ . 19. Method according to claim 2, where: R ² represents Cl; R ³ represents Cl; R ⁵ represents OCH ₃ ; And R ⁷ represents F. 20. The method according to claim 19, where X represents -PO(OH) ₂ . 21. Compound of formula B B, in which, independently for each case: R ² and R ³ independently represent hydrogen, halogen or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms; R ⁵ represents hydrogen, halogen, OH or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms and wherein up to two non-adjacent CH ₂ units of said C ₁ -C ₆ -alkyl may be replaced by -O-; And R ⁷ represents hydrogen, halogen or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted by 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ -alkyl may be replaced on -O-. 22. The compound according to claim 21, where the compound is selected from the group consisting of: N-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide; N-(1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamide; N-(1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-fluorophenoxy)-5-(trifluoromethyl)benzamide; 4-chloro-N-(1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)benzamide; N-(1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamide; And 4,5-dichloro-N-(1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methoxyphenoxy)benzamide. 23. The connection according to claim 21, where the connection is N-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide. 24. The connection according to claim 21, where the connection is N-(1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamide. 25. Compound of formula C C, in which, independently for each case: R ² and R ³ independently represent hydrogen, halogen or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms; R ⁵ represents hydrogen, halogen, OH or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted with 0-6 halogen atoms and wherein up to two non-adjacent CH ₂ units of said C ₁ -C ₆ -alkyl may be replaced by -O-; R ⁷ represents hydrogen, halogen or C ₁ -C ₆ -alkyl, wherein said C ₁ -C ₆ -alkyl is substituted by 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ -alkyl may be replaced on -O-; And PG ₁ is tert -butyl. 26. The compound according to claim 25, where the compound is selected from the group consisting of: di-tert-butyl[4-[[2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate; di-tert-butyl[4-[[2-(4-fluoro-2-methoxyphenoxy)-4-(1,1,2,2,2-pentafluoroethyl)benzoyl]amino]-2-oxo-1-pyridyl] methyl phosphate; di-tert-butyl[4-[[2-(4-fluorophenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate; di-tert-butyl[4-[[4-chloro-2-(4-fluoro-2-methylphenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate; di-tert-butyl[4-[[2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate; And di-tert-butyl[4-[[4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate. 27. The connection according to claim 25, where the connection is di-tert-butyl[4-[[2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate. 28. The connection according to claim 25, where the connection is di-tert-butyl[4-[[2-(4-fluoro-2-methoxyphenoxy)-4-(1,1,2,2,2-pentafluoroethyl)benzoyl]amino]-2-oxo-1-pyridyl] methyl phosphate.