WO2020206119A1

WO2020206119A1 - Process for making pyridone amides and prodrugs thereof useful as modulators of sodium channels

Info

Publication number: WO2020206119A1
Application number: PCT/US2020/026384
Authority: WO
Inventors: Michael P. Ryan
Original assignee: Vertex Pharmaceuticals Incorporated
Priority date: 2019-04-02
Filing date: 2020-04-02
Publication date: 2020-10-08

Abstract

The present application is directed to a process of preparing compounds of formula I, and intermediates thereof as well as pharmaceutically acceptable salts, wherein R2, R3, R5, R7 and X are defined herein. The compounds formula I inhibit sodium channels are useful for treating disorders, e.g. pain.

Description

PROCESS FOR MAKING PYRIDONE AMIDES AND PRODRUGS THEREOF USEFUL AS MODULATORS OF SODIUM CHANNELS

BACKGROUND

[0001 ] This application claims the benefit of U.S. Provisional Application No.

62/828,353, filed April 2, 2019, the contents of which is incorporated by reference in its entirety.

[0002] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and to prevent further damage to injured tissue. Nonetheless, there are many conditions where pain persists beyond its usefulness, or where patients would benefit from inhibition of pain. Neuropathic pain is a form of chronic pain caused by an injury to the sensory nerves (Dieleman, J.P., et al., Incidence rates and treatment of neuropathic pain conditions in the general population. Pain, 2008. 137(3): p. 681-8). Neuropathic pain can be divided into two categories, pain caused by generalized metabolic damage to the nerve and pain caused by a discrete nerve injury. The metabolic neuropathies include post herpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Discrete nerve injuries indications include post amputation pain, post-surgical nerve injury pain, and nerve entrapment injuries like neuropathic back pain.

[0003] Voltage-gated sodium channels (Navs) play a critical role in pain signaling. Navs are key biological mediators of electrical signaling, as they are the primary mediators of the rapid upstroke of the action potential of many excitable cell types (e.g. neurons, skeletal myocytes, and cardiac myocytes). The evidence for the role of these channels in normal physiology, the pathological states arising from mutations in sodium channel genes, preclinical work in animal models, and the clinical pharmacology of known sodium channel modulating agents all point to the central role of Navs in pain sensation (Rush, A.M. and T.R. Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Navi -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)). Navs are the primary mediators of the rapid upstroke of the action potential of many excitable cell types (e.g. neurons, skeletal myocytes, cardiac myocytes), and thus are critical for the initiation of signaling in those cells (Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). Because of the role Nays play in the initiation and propagation of neuronal signals, antagonists that reduce Nav currents can prevent or reduce neural signaling and Nav channels have long been considered likely targets to reduce pain in conditions where hyper-excitability is observed (Chahine, M., Chatelier, A., Babich, O., and Krupp, J. J., Voltage-gated sodium channels in neurological disorders.

CNS Neurol Disord Drug Targets 7 (2), p. 144-58 (2008)). Several clinically useful analgesics have been identified as inhibitors of Nav channels. The local anesthetic drugs such as lidocaine block pain by inhibiting Nav channels, and other compounds, such as carbamazepine, lamotrigine, and tricyclic antidepressants that have proven effective at reducing pain have also been suggested to act by sodium channel inhibition (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. Eur J Pain 6 Suppl A, p. 3-9 (2002); Wang, G. K., Mitchell, J., and Wang, S. Y., Block of persistent late Na⁺ currents by antidepressant sertraline and paroxetine. J Membr Biol 222 (2), p. 79-90 (2008)).

[0004] The Navs form a subfamily of the voltage-gated ion channel super-family and comprises 9 isoforms, designated Navl.l - Navl.9. The tissue localizations of the nine isoforms vary greatly. Nav 1.4 is the primary sodium channel of skeletal muscle, and Navl.5 is primary sodium channel of cardiac myocytes. Navs 1.7, 1.8 and 1.9 are primarily localized to the peripheral nervous system, while Navs 1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the central and peripheral nervous systems. The functional behaviors of the nine isoforms are similar but distinct in the specifics of their voltage-dependent and kinetic behavior (Catterall, W. A., Goldin, A. L., and Waxman, S. G., International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev 57 (4), p. 397 (2005)).

[0005] Immediately upon their discovery, Navi.8 channels were identified as likely targets for analgesia (Akopian, A.N., L. Sivilotti, and J.N. Wood, A tetrodotox i n - resi stan t voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562): p. 257-62). Since then, Navi.8 has been shown to be the most significant carrier of the sodium current that maintains action potential firing in small DRG neurons (Blair, N.T. and B.P. Bean, Roles of tetrodotoxin (TTX)- sensitive Na-i- current, TTX-resistant Na⁺ current, and Ca²⁺ current in the action potentials of nociceptive sensory neurons. J Neurosci., 2002. 22(23): p. 10277-90). Navi.8 is essential for spontaneous firing in damaged neurons, like those that drive neuropathic pain (Roza, C., et ak, The tetrodotoxin- resistant Na⁺ channel Navi.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550(Pt 3): p. 921-6; Jarvis, M.F., et al.,

A-803467, a potent and selective Navi.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc Natl Acad Sci. U S A, 2007. 104(20): p. 8520-5;

Joshi, S.K., et al., Involvement of the TTX-resistant sodium channel Navi.8 in inflammatory and neuropathic, but not post-operative, pain states. Pain, 2006. 123(1-2): pp. 75-82; Lai, J., et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, Navi.8. Pain, 2002. 95(1-2): p. 143-52; Dong,

X.W., et al., Small interfering RNA-mediated selective knockdown of Navi.8

tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats.

Neuroscience, 2007. 146(2): p. 812-21; Huang, H.L., et al., Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper- excitable nerves. Mol Pain, 2008. 4: p. 33; Black, J.A., et al., Multiple sodium channel isoforms and mitogen- activated protein kinases are present in painful human neuromas.

Ann Neurol, 2008. 64(6): p. 644-53; Coward, K., et al., Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states. Pain, 2000. 85(1-2): p. 41-50;

Yiangou, Y., et al., SNS/PN3 and SNS2/NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. FEBS Lett, 2000. 467(2-3): p. 249-52;

Ruangsri, S., et al., Relationship of axonal voltage-gated sodium channel 1.8 (Navi.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats. J Biol

Chem. 286(46): p. 39836-47). The small DRG neurons where Navi.8 is expressed include the nociceptors critical for pain signaling. Navi.8 is the primary channel that mediates large amplitude action potentials in small neurons of the dorsal root ganglia (Blair, N.T. and B.P. Bean, Roles of tetrodotoxin (TTX)- sensitive Na⁺ current, TTX-resistant Na⁺ current, and Ca²⁺ current in the action potentials of nociceptive sensory neurons. J

Neurosci., 2002. 22(23): p. 10277-90). Navi.8 is necessary for rapid repetitive action potentials in nociceptors, and for spontaneous activity of damaged neurons. (Choi, J.S. and S.G. Waxman, Physiological interactions between Navi.7 and Navi.8 sodium channels: a computer simulation study. J Neurophysiol. 106(6): p. 3173-84; Renganathan,

M., T.R. Cummins, and S.G. Waxman, Contribution of Navi.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 Navi.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, Navi.8 appears to be the primary driver of hyper-excitablility (Rush, A.M., et al., A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc Natl Acad Sci USA, 2006. 103(21): p. 8245-50). In some animal pain models, Navi.8 mRNA expression levels have been shown to increase in the DRG (Sun, W., et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibres contributes to painful diabetic neuropathy in rats. Brain. 135(Pt 2): p. 359-75; Strickland, I.T., et al., Changes in the expression of Navl.7, Navi.8 and Navl.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 Navi.8 and Navl.9 within dorsal root ganglia in a rat model of bone cancer pain.

Neurosci. Lett. 512(2): p. 61-6).

[0006] The primary drawback to some known Nav inhibitors is their poor therapeutic window, and this is likely a consequence of their lack of isoform selectivity. Since Navi.8 is primarily restricted to the neurons that sense pain, selective Navi.8 blockers are unlikely to induce the adverse events common to non-selective Nav blockers.

Accordingly, there remains a need to develop additional Nav channel modulators preferably those that are highly potent and selective for Navi.8.

SUMMARY OF THE APPLICATION

[0007] In one embodiment, the invention features a method for preparing a compound of formula I,

I,

or a salt thereof, wherein, independently for each occurrence: R² and R³ are independently hydrogen, halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen;

R⁵ is hydrogen, halogen, OH, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent C¾ units of said C1-C6 alkyl may be replaced with -0-; R⁷ is hydrogen, halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -0-; and

X is -PO(OH)₂, -PO(OH)O M⁺, -P0(0 )_2*2M⁺, or -P0(0 )_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.

[0008] In one embodiment, the compound of formula I is a compound of formula I- A, I-B, I-C, I-D, I-E, I-F, or I-G as described herein.

[0009] In one embodiment, the method comprises reacting a compound of formula II,

with an acid to afford a compound of formula I wherein X is -PO(OH)₂. In another embodiment, the method comprises reacting the compound of formula II with a base to obtain a partially deprotected compound as a compound of formula Ila as described elsewhere in this application.

[0010] In a second embodiment, the method comprises reacting a compound of formula III,

or a salt thereof, wherein Z is halo (e.g., Cl, Br, I);

with K(tBu)₂P0₄ to afford a compound of formula II, or a salt thereof, to afford the compound of formula I, or a salt thereof. [0011 ] In a further embodiment, the present application provides a method for preparing a compound of formula III,

or a salt thereof, wherein R², R³, R⁵, R⁷, and Z are as defined herein.

[0012] The method comprises reacting a halogenating agent (e.g., a chlorinating agent such as thionyl chloride) with a compound of formula IV,

or a salt thereof, to afford the compound of formula III, or a salt thereof.

[0013] In a further embodiment, the present application provides a method for preparing a compound of formula IV,

or a salt thereof, wherein R², R³, R⁵, and R⁷ are as defined herein.

[0014] In another embodiment, the method comprises reacting formalin with a compound of formula V,

V,

to afford a compound of formula IV. In some embodiments, the reaction is conducted in an aprotic solvent. In some embodiments, the aprotic solvent is benzene, butyl acetate, tert-butyl methyl ether, chlorobenzene, chloroform, chloromethane, cyclohexane, dichloromethane (DCM), dichloroethane, di-tert-butyl ether, dimethyl ether, diethylene glycol, diethyl ether, diglyme, diisopropyl ether, ethyl tert-butyl ether, ethylene oxide, fluorobenzene, heptane, hexane, methyl tert-butyl ether, toluene, and combinations thereof. In another embodiment, the reaction is conducted in an ether such as tetrahydrofuran (THF). In another embodiment, the reaction is conducted in a non-polar solvent such as benzene, toluene, or cyclohexane.

[0015] In a further embodiment, the present application provides a method for preparing a compound of formula V.

[0016] In one embodiment, the method comprises comprising coupling a compound of formula VI,

VI,

or a salt thereof, wherein Y is a polar leaving group selected from halogen and nitro with a compound of formula VII,

or a salt thereof, to afford the compound of formula V, or a salt thereof. [0017] In a further embodiment, the present application provides a method for preparing a compound of formula VI,

VI,

or a salt thereof.

[0018] In one embodiment, the method of preparing the compound of formula VI comprises dealkylating a compound of formula VIII. In some embodiments, the method comprises reacting a compound of formula VIII with an acid. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, p-toluene sulfonic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, and trifluoroborate etherate, or mixtures thereof.

[0019] In a further embodiment, the present application provides a method for preparing a compound of formula VIII,

In some embodiments, the compound of formula VIII may be prepared by coupling a compound of formula IX,

or an acid chloride thereof, wherein Y is a polar leaving group selected from halogen and nitro; with a compound of formula X,

wherein R is methoxy or chloro; to afford the compound of formula VIII, or a salt thereof.

[0020] In a further embodiment, the present application provides a method for preparing a compound of formula V comprising converting the compound of formula XI,

wherein R is methoxy or chloro; to the compound of formula V. In some embodiments, the converting comprises dealkylating the compound of formula XI. In some embodiments, the dealkylating reaction comprises reacting the compound of formula XI with an acid.

[0021 ] In a further embodiment, the present application provides a method for preparing a compound of formula XI,

wherein R is methoxy or chloro; or a salt thereof. The method comprises coupling a compound of formula VII,

with a compound of formula VIII,

wherein R is methoxy or chloro; to afford the compound of formula XI, or a salt thereof. DETAILED DESCRIPTION

[0022] The present application is directed to methods of preparing compounds, and salts and prodrugs thereof, useful as inhibitors of sodium channels. [0023] The compounds and salts of the present application may be represented by formula I,

I,

or a salt thereof, wherein or a salt thereof, wherein, independently for each occurrence:

R² and R³ are independently hydrogen, halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen;

R⁵ is hydrogen, halogen, OH, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with -0-;

R⁷ is hydrogen, halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with -0-; and

X is -P0(0H)₂, -PO(OH)O M⁺, -P0(0 )_2*2M⁺, or -P0(0 )_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.

[0024] In one embodiment, the invention provides a process for preparing compounds of formulae I, I-A, I-B, I-C, I-D, I-E, I-F, and I-G as described herein.

[0025] In one embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R² is H. In another embodiment, R² is halogen. In another embodiment, R² is Cl. In another embodiment, R² is F. In another embodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen.

In another embodiment, R² is CF₃. In another embodiment, R² is H, Cl or CF₃.

[0026] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R³ is H. In another embodiment, R³ is halogen. In another embodiment, R³ is Cl. In another embodiment, R³ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment, R³ is CF3. In another embodiment, R³ is CF2CF3.

[0027] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R⁵ is H. In another embodiment, R⁵ is halogen. In another embodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In another embodiment, R⁵ is C₁-C₆ alkyl. In another embodiment, R⁵ is CH₃. In another embodiment, R⁵ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CFF unit of said C₁-C₆ alkyl is replaced with -0-. In another embodiment, R⁵ is OCH₃. In another embodiment, R⁵ is OH. In another embodiment, R⁵ is OCF₃.

[0028] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R⁷ is H. In another embodiment, R⁷ is halogen. In another embodiment, R⁷ is F. In another embodiment, R⁷ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen wherein two non- adjacent C¾ units of said C1-C6 alkyl are replaced with -0-. In another embodiment, R⁷ is OCH3. In another embodiment, R⁷ is OCF3.

[0029] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein X is -PO(OH)0 M⁺, -P0(0 )_2*2M⁺, or -P0(0 )_2*D²⁺; M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺; wherein each R⁹ is independently H or a C1-C4 alkyl group and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺.

[0030] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein X is -PO(OH)0 M⁺ and M⁺ is Li⁺. In one embodiment, X is -PO(OH)0 M⁺ and M⁺ is Na⁺. In another embodiment, X is -PO(OH)0 M⁺ and M⁺ is K⁺. In another embodiment, X is -PO(OH)0 M⁺ and M⁺ is N(R⁹)₄ ⁺; wherein each R⁹ is independently H or a C1-C4 alkyl group. In another embodiment, X is -PO(OH)0 M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is a CH3 group. In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein X is -P0(0 )_2*2M⁺ and M⁺ is Li⁺. In one embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is Na⁺. In another embodiment, X is

-P0(0 )_2*2M⁺ and M⁺ is K⁺. In another embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is N(R⁹)₄ ⁺; wherein each R⁹ is independently H or a C1-C4 alkyl group. In another embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is N(R⁹)₄ ⁺; wherein each R⁹ is a CH3 group. [0031 ] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein X is -P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is -P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺. In another embodiment, X is -P0(0 )2*D²⁺ and D²⁺ is Ca²⁺. In another embodiment, X is

-P0(0 )_2*D²⁺ and D²⁺ is Ba²⁺.

[0032] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein X is -PO(OH)2_.

[0033] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R² is Cl, R³ is Cl, R⁵ is OCH₃, R⁷ is F and X is -PO(OH)₂.

[0034] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R² is Cl, R³ is Cl, R⁵ is OCH₃, R⁷ is F and X is -P0(0 )_2*2M⁺, M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)4⁺ wherein each R⁹ is independently H or a C₁-C₄ alkyl group.

[0035] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R² is Cl, R³ is Cl, R⁵ is OCH3, R⁷ is F and X is-PO(OH)0 M⁺, M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)4⁺ wherein each R⁹ is independently H or a C₁-C₄ alkyl group.

[0036] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R³ is CF₂CF₃, R⁵ is OCH₃, R⁷ is F and X is -PO(OH)₂.

[0037] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R³ is CF₂CF₃, R⁵ is OCH₃, R⁷ is F and X is -P0(0 )_2*2M⁺, M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺ wherein each R⁹ is independently H or a C₁-C₄ alkyl group.

[0038] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R³ is CF2CF3, R⁵ is OCH3, R⁷ is F and X is-PO(OH)O M⁺, M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺ wherein each R⁹ is independently H or a C₁-C₄ alkyl group.

[0039] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R³ is CF₃, R⁵ is CH₃, R⁷ is F and X is -PO(OH)₂. [0040] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R³ is CF3, R⁵ is CH3, R⁷ is F, X is -P0(0 )_2*2M⁺, M⁺ is Li⁺, Na⁺, K⁺. In another embodiment, M⁺ is Li⁺. In yet another embodiment, M⁺ is Na⁺.

[0041 ] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R³ is CF3, R⁵ is CH3, R⁷ is F, X is -P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is

-P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺. In another embodiment, X is -P0(0 )_2*D²⁺ and D²⁺ is Ca²⁺.

[0042] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R² is CF3, R⁵ is CH3, R⁷ is F and X is -PO(OH)₂.

[0043] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R² is CF3, R⁵ is CH3, R⁷ is F, X is -P0(0 )_2*2M⁺, M⁺ is Li⁺, Na⁺, K⁺. In another embodiment, M⁺ is Li⁺. In yet another embodiment, M⁺ is Na⁺.

[0044] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R² is CF3, R⁵ is CH3, R⁷ is F, X is -P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is

[0045] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R³ is Cl, R⁵ is CH3, R⁷ is F and X is -PO(OH)₂.

[0046] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R³ is Cl, R⁵ is CH3, R⁷ is F and X is -P0(0 )_2*2M⁺, M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)4⁺ wherein each R⁹ is independently H or a C1-C4 alkyl group.

[0047] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R³ is Cl, R⁵ is CFb, R⁷ is F and X is-PO(OH)0 M⁺, M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)4⁺ wherein each R⁹ is independently H or a C1-C4 alkyl group. [0048] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R² is CF₃, R⁵ is CH₃, R⁷ is F and X is -PO(OH)₂.

[0049] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R² is CF₃, R⁷ is F, X is -P0(0 )_2*2M⁺, M⁺ is Li⁺, Na⁺, K⁺. In another embodiment, M⁺ is Li⁺. In yet another embodiment, M⁺ is Na⁺.

[0050] In another embodiment, the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R² is CF₃, R⁷ is F, X is -P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is -P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺. In another embodiment, X is -P0(0 )_2*D²⁺ and D²⁺ is Ca²⁺.

[0051 ] In another embodiment, the invention provides a process for preparing a compound of formula I-A,

I-A,

wherein, independently for each occurrence:

R² is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen;

R⁵ is halogen, OH, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -0-;

R⁷ is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -0-; and

X is -PO(OH)₂, -PO(OH)O M⁺, -P0(0 )_2*2M⁺, or -P0(0 )_2*D²⁺; M⁺ is a

pharmaceutically acceptable monovalent cation; and D²⁺ is a pharmaceutically acceptable divalent cation. [0052] In one embodiment, the invention features a compound of formula I-A and the attendant definitions, wherein R² is halogen. In another embodiment, R² is Cl. In another embodiment, R² is F. In another embodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment, R² is CF₃. In another embodiment, R² is Cl or CF₃.

[0053] In another embodiment, the invention features a compound of formula I-A and the attendant definitions, wherein R⁵ is halogen. In another embodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In another embodiment, R⁵ is C₁-C₆ alkyl. In another embodiment, R⁵ is CH₃. In another embodiment, R⁵ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen wherein one C¾ unit of said C₁-C₆ alkyl is replaced with -0-. In another embodiment, R⁵ is OCH₃. In another embodiment, R⁵ is OH. In another embodiment, R⁵ is OCF₃. In another embodiment, R⁵ is F, Cl, CH₃, OCH₃, OH or OCF3.

[0054] In another embodiment, the invention features a compound of formula I-A and the attendant definitions, wherein R⁷ is halogen. In another embodiment, R⁷ is F. In another embodiment, R⁷ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen wherein two non-adjacent CH₂ units of said C₁-C₆ alkyl are replaced with -0-. In another embodiment, R⁷ is OCH₃. In another embodiment, R⁷ is OCF₃. In another embodiment, R⁷ is F, OCH₃ or OCF₃.

[0055] In another embodiment, the invention features a compound of formula I-A and the attendant definitions, wherein X is -PO(OH)₂, -PO(OH)0 M⁺; -P0(0 )2*2M⁺ or -P0(0 )2*D²⁺; wherein M⁺ is Li⁺, Na⁺ or K⁺ and wherein D²⁺ is Mg²⁺ or Ca²⁺.

[0056] In another embodiment, the invention features a compound of formula I-A and the attendant definitions, wherein R² is CF₃, R⁵ is Cl, OCH₃ or CH₃ and R⁷ is F. In one embodiment, R² is CF₃, R⁵ is Cl and R⁷ is F. In another embodiment, R² is CF₃, R⁵ is OCH₃ and R⁷ is F. In another embodiment, R² is CF₃, R⁵ is CH₃ and R⁷ is F.

[0057] In another embodiment, the invention features a compound of formula I-A and the attendant definitions, wherein R² is CF₃, R⁵ is Cl, OCH₃ or CH₃, R⁷ is F and X is -PO(OH)₂. In one embodiment, R² is CF₃, R⁵ is Cl, R⁷ is F and X is -PO(OH)₂. In another embodiment, R² is CF₃, R⁵ is OCH₃, R⁷ is F and X is -PO(OH)₂. In another embodiment, R² is CF3, R⁵ is CH3, R⁷ is F and X is -PO(OH)2.

[0058] In another embodiment, the invention features a compound of formula I-A and the attendant definitions, wherein X is -P0(0H)0 M⁺, -P0(0 )2*2M⁺; or -P0(0 )2*D²⁺; M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)4⁺; wherein each R⁹ is independently H or a C₁-C₄ alkyl group and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺.

[0059] In another embodiment, the invention features a compound of formula I-A and the attendant definitions, wherein X is -PO(OH)0 M⁺ and M⁺ is Li⁺. In one embodiment, X is -PO(OH)0 M⁺ and M⁺ is Na⁺. In another embodiment, X is -P0(0H)0 M⁺ and M⁺ is K⁺. In another embodiment, X is -P0(0H)0 M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is independently H or a C₁-C₄ alkyl group. In another embodiment, X is -PO(OH)0 M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is a CH3 group.

[0060] In another embodiment, the invention features a compound of formula I-A and the attendant definitions, wherein X is -P0(0 )_2*2M⁺ and M⁺ is Li⁺. In one embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is Na⁺. In another embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is K⁺. In another embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is independently H or a C₁-C₄ alkyl group. In another embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is a CH₃ group.

[0061 ] In another embodiment, the invention features a compound of formula I-A and the attendant definitions, wherein X is -P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is -P0(0 )2*D²⁺ and D²⁺ is Mg²⁺. In another embodiment, X is -PO(0 )2»D²⁺ and D²⁺ is Ca²⁺. In another embodiment, X is -P0(0 )_2*D²⁺ and D²⁺ is Ba²⁺.

[0062] In another embodiment, the invention features a compound of formula I-A and the attendant definitions, wherein X is -PO(OH)2.

[0063] In another embodiment, the invention features a compound of formula I-A and the attendant definitions, wherein R² is CF3, R⁵ is CH3, R⁷ is F and X is -PO(OH)2.

[0064] In another embodiment, the invention features a compound of formula I-A and the attendant definitions, wherein R² is CF₃, R⁵ is CH₃, R⁷ is F, X is -P0(0 )_2*2M⁺, M⁺ is Li⁺, Na⁺, K⁺. In another embodiment, M⁺ is Li⁺. In yet another embodiment, M⁺ is Na⁺.

[0065] In another embodiment, the invention features a compound of formula I-A and the attendant definitions, wherein R² is CF₃, R⁵ is CFb, R⁷ is F, X is -P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is -P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺. In another embodiment, X is -P0(0 )_2*D²⁺ and D²⁺ is Ca²⁺.

[0066] In another embodiment, the invention provides a process for preparing a compound of formula I-B,

wherein, independently for each occurrence:

R³ is halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen;

R⁵ is halogen, OH, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with -0-;

R⁷ is halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with -0-; and

X is -PO(OH)₂, -PO(OH)O M⁺, -P0(0 )_2*2M⁺, or -P0(0 )_2*D²⁺; M⁺ is a

pharmaceutically acceptable monovalent cation; and D²⁺ is a pharmaceutically acceptable divalent cation.

[0067] In one embodiment, the invention features a compound of formula I-B and the attendant definitions, wherein R³ is halogen. In another embodiment, R³ is Cl. In another embodiment, R³ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen.

In another embodiment, R³ is CF₃. In another embodiment, R³ is CF₂CF₃.

[0068] In another embodiment, the invention features a compound of formula I-B and the attendant definitions, wherein R⁵ is halogen. In another embodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In another embodiment, R⁵ is C₁-C₆ alkyl. In another embodiment, R⁵ is CH₃. In another embodiment, R⁵ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with -0-. In another embodiment, R⁵ is OCH₃. In another embodiment, R⁵ is OH. In another embodiment, R⁵ is OCF₃.

[0069] In another embodiment, the invention features a compound of formula I-B and the attendant definitions, wherein R⁷ is halogen. In another embodiment, R⁷ is F. In another embodiment, R⁷ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen wherein two non-adjacent CH2 units of said C1-C6 alkyl are replaced with -0-. In another embodiment, R⁷ is OCH3. In another embodiment, R⁷ is OCF3.

[0070] In another embodiment, the invention features a compound of formula I-B and the attendant definitions, wherein X is X is -PO(OH)2, -PO(OH)0 M⁺; -P0(0 )_2*2M⁺ or -P0(0 )_2*D²⁺; wherein M⁺ is Li⁺, Na⁺ or K⁺ and wherein D²⁺ is Mg²⁺ or Ca²⁺.

[0071 ] In another embodiment, the invention features a compound of formula I-B and the attendant definitions, wherein R³ is CF3, R⁵ is F or CH3 and R⁷ is F. In one embodiment, R³ is Cl, R⁵ is CH3 and R⁷ is F. In another embodiment, R³ is CF2CF3, R⁵ is OCH3 and R⁷ is F.

[0072] In another embodiment, the invention features a compound of formula I-B and the attendant definitions, wherein R³ is CF3, R⁵ is F or CH3, R⁷ is F and X is -PO(OH)2.

In one embodiment, R³ is Cl, R⁵ is CFb, R⁷ is F and X is -PO(OH)2. In another embodiment, R³ is CF2CF3, R⁵ is OCH3, R⁷ is F and X is -PO(OH)2.

[0073] In another embodiment, the invention features a compound of formula I-B and the attendant definitions, wherein X is -P0(0H)0 M⁺, -P0(0 )_2*2M⁺; or -P0(0 )_2*D²⁺; M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)4⁺; wherein each R⁹ is independently H or a C1-C4 alkyl group and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺.

[0074] In another embodiment, the invention features a compound of formula I-B and the attendant definitions, wherein X is -P0(0H)0 M⁺ and M⁺ is Li⁺. In one embodiment, X is -PO(OH)0 M⁺ and M⁺ is Na⁺. In another embodiment, X is -P0(0H)0 M⁺ and M⁺ is K⁺. In another embodiment, X is -PO(OH)0 M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is independently H or a C1-C4 alkyl group. In another embodiment, X is -PO(OH)0 M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is a CH3 group.

[0075] In another embodiment, the invention features a compound of formula I-B and the attendant definitions, wherein X is -P0(0 )_2*2M⁺ and M⁺ is Li⁺. In one embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is Na⁺. In another embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is K⁺. In another embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is independently H or a C₁-C₄ alkyl group. In another embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is a CH₃ group.

[0076] In another embodiment, the invention features a compound of formula I-B and the attendant definitions, wherein X is -P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is -P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺. In another embodiment, X is -P0(0 )_2*D²⁺ and D²⁺ is Ca²⁺. In another embodiment, X is -P0(0 )_2*D²⁺ and D²⁺ is Ba²⁺.

[0077] In another embodiment, the invention features a compound of formula I-B and the attendant definitions, wherein X is -PO(OH)2.

[0078] In another embodiment, the invention features a compound of formula I-B and the attendant definitions, wherein R³ is CF₂CF₃, R⁵ is OCH₃, R⁷ is F and X is -PO(OH)₂.

[0079] In another embodiment, the invention features a compound of formula I-B and the attendant definitions, wherein R³ is CF₂CF₃, R⁵ is OCH₃, R⁷ is F and X is

-P0(0 )_2*2M⁺, M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)4⁺ wherein each R⁹ is independently H or a Ci- C₄ alkyl group.

[0080] In another embodiment, the invention features a compound of formula I-B and the attendant definitions, wherein R³ is CF2CF3, R⁵ is OCH3, R⁷ is F and X is

-PO(OH)0 M⁺, M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)4⁺ wherein each R⁹ is independently H or a Ci- C₄ alkyl group.

[0081 ] In another embodiment, the invention features a compound of formula I-B and the attendant definitions, wherein R³ is CF₃, R⁵ is CH₃, R⁷ is F and X is -PO(OH)₂.

[0082] In another embodiment, the invention features a compound of formula I-B and the attendant definitions, wherein R³ is CF₃, R⁵ is CH₃, R⁷ is F, X is -P0(0 )_2*2M⁺, M⁺ is Li⁺, Na⁺, K⁺. In another embodiment, M⁺ is Li⁺. In yet another embodiment, M⁺ is Na⁺.

[0083] In another embodiment, the invention features a compound of formula I-B and the attendant definitions, wherein R³ is CF₃, R⁵ is CH₃, R⁷ is F, X is -P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is -P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺. In another embodiment, X is -P0(0 )_2*D²⁺ and D²⁺ is Ca²⁺.

[0084] In another embodiment, the invention features a compound of formula I-B and the attendant definitions, wherein R³ is Cl, R⁵ is CFb, R⁷ is F and X is -PO(OH)2.

[0085] In another embodiment, the invention features a compound of formula I-B and the attendant definitions, wherein R³ is Cl, R⁵ is CH₃, R⁷ is F and X is -P0(0 )_2*2M⁺, M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)4⁺ wherein each R⁹ is independently H or a C₁-C₄ alkyl group.

[0086] In another embodiment, the invention features a compound of formula I-B and the attendant definitions, wherein R³ is Cl, R⁵ is CH₃, R⁷ is F and X is -PO(OH)0 M⁺, M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)4⁺ wherein each R⁹ is independently H or a C₁-C₄ alkyl group.

[0087] In another embodiment, the invention provides a process for preparing a compound of formula I-C,

I-C,

wherein, independently for each occurrence:

X is -PO(OH)₂, -PO(OH)O M⁺, -P0(0 )_2*2M⁺, or -P0(0 )_2*D²⁺; M⁺ is a

[0088] In one embodiment, the invention features a compound of formula I-C and the attendant definitions, wherein R² is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R² is CF3.

[0089] In another embodiment, the invention features a compound of formula I-C and the attendant definitions, wherein R⁷ is halogen. In one embodiment, R⁷ is F. In another embodiment, R⁷ is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH₂ units of said C1-C6 alkyl may be replaced with -0-. In one embodiment, R⁷ is OCF₃.

[0090] In another embodiment, the invention features a compound of formula I-C and the attendant definitions, wherein X is -PO(OH)₂, -P0(0H)0 M⁺; -R0(0 )₂·2M⁺ or -P0(0 )_2»D²⁺; wherein M⁺ is Li⁺, Na⁺ or K⁺ and wherein D²⁺ is Mg²⁺ or Ca²⁺.

[0091 ] In another embodiment, the invention features a compound of formula I-C and the attendant definitions, wherein R² is CF₃ and R⁷ is F or OCF₃.

[0092] In another embodiment, the invention features a compound of formula I-C and the attendant definitions, wherein R² is CF₃, R⁷ is F or OCF₃ and X is -PO(OH)₂.

[0093] In another embodiment, the invention features a compound of formula I-C and the attendant definitions, wherein X is -PO(OH)0 M⁺, -R0(0 )₂·2M⁺, or -P0(0 )_2»D²⁺; M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)4⁺; wherein each R⁹ is independently H or a C₁-C₄ alkyl group and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺.

[0094] In another embodiment, the invention features a compound of formula I-C and the attendant definitions, wherein X is -PO(OH)0 M⁺ and M⁺ is Li⁺. In one embodiment, X is -PO(OH)0 M⁺ and M⁺ is Na⁺. In another embodiment, X is -P0(0H)0 M⁺ and M⁺ is K⁺. In another embodiment, X is -P0(0H)0 M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is independently H or a C₁-C₄ alkyl group. In another embodiment, X is -PO(OH)0 M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is a CH3 group.

[0095] In another embodiment, the invention features a compound of formula I-C and the attendant definitions, wherein X is -P0(0 )_2*2M⁺ and M⁺ is Li⁺. In one embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is Na⁺. In another embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is K⁺. In another embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is independently H or a C₁-C₄ alkyl group. In another embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is a CH₃ group.

[0096] In another embodiment, the invention features a compound of formula I-C and the attendant definitions, wherein X is -P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is -P0(0 )2*D²⁺ and D²⁺ is Mg²⁺. In another embodiment, X is

-P0(0 )_2*D²⁺ and D²⁺ is Ca²⁺. In another embodiment, X is -P0(0 )_2*D²⁺ and D²⁺ is Ba²⁺.

[0097] In another embodiment, the invention features a compound of formula I-C and the attendant definitions, wherein X is -PO(OH)2.

[0098] In another embodiment, the invention features a compound of formula I-C and the attendant definitions, wherein R² is CF₃, R⁵ is CH₃, R⁷ is F and X is -PO(OH)₂.

[0099] In another embodiment, the invention features a compound of formula I-C and the attendant definitions, wherein R² is CF₃, R⁷ is F, X is -P0(0 )_2*2M⁺, M⁺ is Li⁺, Na⁺, K⁺. In another embodiment, M⁺ is Li⁺. In yet another embodiment, M⁺ is Na⁺.

[00100] In another embodiment, the invention features a compound of formula I-C and the attendant definitions, wherein R² is CF₃, R⁷ is F, X is -P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is -P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺. In another embodiment, X is -P0(0 )2*D²⁺ and D²⁺ is Ca²⁺.

[00101 ] In another embodiment, the invention provides a process for preparing a compound of formula I-D,

wherein, independently for each occurrence:

R³ is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen;

R⁷ is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CFb units of said C1-C6 alkyl may be replaced with -0-; and

X is -PO(OH)₂, -PO(OH)O M⁺, -P0(0 )_2*2M⁺, or -P0(0 )_2*D²⁺; M⁺ is a

[00102] In one embodiment, the invention features a compound of formula I-D and the attendant definitions, wherein R³ is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R³ is CF3. In another embodiment, R³ is

CF₂CF₃.

[00103] In another embodiment, the invention features a compound of formula I-D and the attendant definitions, wherein R⁷ is halogen. In one embodiment, R⁷ is F. In another embodiment, R⁷ is Ci-G, alkyl wherein said Ci-G, alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CFF units of said Ci-Ce alkyl may be replaced with -0-. In one embodiment, R⁷ is OCF3.

[00104] In another embodiment, the invention features a compound of formula I-D and the attendant definitions, wherein X is -PO(OH)2, -PO(OH)0 M⁺; -P0(0 )_2*2M⁺ or - P0(0 )_2*D²⁺; wherein M⁺ is Li⁺, Na⁺ or K⁺ and wherein D²⁺ is Mg²⁺ or Ca²⁺.

[00105] In another embodiment, the invention features a compound of formula I-D and the attendant definitions, wherein R³ is CF3 and R⁷ is CF3. In another embodiment, R³ is CF2CF3 and R⁷ is F. [00106] In another embodiment, the invention features a compound of formula I-D and the attendant definitions, wherein R³ is CF3, R⁷ is CF3 and X is -PO(OH)2. In another embodiment, R³ is CF2CF3, R⁷ is F and X is -PO(OH)2.

[00107] In another embodiment, the invention features a compound of formula I-D and the attendant definitions, wherein X is -PO(OH)0 M⁺, -P0(0 )_2*2M⁺; or -P0(0 )_2*D²⁺; M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)4⁺; wherein each R⁹ is independently H or a C₁-C₄ alkyl group and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺.

[00108] In another embodiment, the invention features a compound of formula I-D and the attendant definitions, wherein X is -PO(OH)0 M⁺ and M⁺ is Li⁺. In one embodiment, X is -PO(OH)0 M⁺ and M⁺ is Na⁺. In another embodiment, X is -P0(0H)0 M⁺ and M⁺ is K⁺. In another embodiment, X is -P0(0H)0 M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is independently H or a C₁-C₄ alkyl group. In another embodiment, X is -PO(OH)0 M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is a CFb group.

[00109] In another embodiment, the invention features a compound of formula I-D and the attendant definitions, wherein X is -P0(0 )_2*2M⁺ and M⁺ is Li⁺. In one embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is Na⁺. In another embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is K⁺. In another embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is independently H or a C₁-C₄ alkyl group. In another embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is a CH₃ group.

[00110] In another embodiment, the invention features a compound of formula I-D and the attendant definitions, wherein X is -P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is -P0(0 )2*D²⁺ and D²⁺ is Mg²⁺. In another embodiment, X is

[00111] In another embodiment, the invention features a compound of formula I-D and the attendant definitions, wherein X is -PO(OH)2.

[00112] In another embodiment, the invention provides a process for preparing a compound of formula I-E,

I-E,

wherein, independently for each occurrence:

R² and R³ are independently halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is

substituted with 0-6 halogen;

X is -PO(OH)₂, -PO(OH)O M⁺, -PO(0)_2*2M⁺, or -P0(0 )_2*D²⁺; M⁺ is a

[00113] In one embodiment, the invention features a compound of formula I-E and the attendant definitions, wherein R² is halogen. In another embodiment, R² is Cl.

[00114] In another embodiment, the invention features a compound of formula I-E and the attendant definitions, wherein R³ is halogen. In another embodiment, R³ is Cl.

[00115] In another embodiment, the invention features a compound of formula I-E and the attendant definitions, wherein R⁷ is halogen. In one embodiment, R⁷ is F.

[00116] In another embodiment, the invention features a compound of formula I-E and the attendant definitions, wherein X is -PO(OH)₂, -PO(OH)0 M⁺, -R0(0 )₂·2M⁺ or -P0(0 )_2»D²⁺; wherein M⁺ is Li⁺, Na⁺ or K⁺ and wherein D²⁺ is Mg²⁺ or Ca²⁺.

[00117] In another embodiment, the invention features a compound of formula I-E and the attendant definitions, wherein R² and R³ are Cl and R⁷ is F.

[00118] In another embodiment, the invention features a compound of formula I-E and the attendant definitions, wherein R² and R³ are Cl, R⁷ is F and X is -PO(OH)₂.

[00119] In another embodiment, the invention features a compound of formula I-E and the attendant definitions, wherein X is -PO(OH)0 M⁺, -R0(0 )₂·2M⁺, or -P0(0 )_2»D²⁺; M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)4⁺; wherein each R⁹ is independently H or a C1-C4 alkyl group and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺.

[00120] In another embodiment, the invention features a compound of formula I-E and the attendant definitions, wherein X is -PO(OH)0 M⁺ and M⁺ is Li⁺. In one embodiment, X is -PO(OH)0 M⁺ and M⁺ is Na⁺. In another embodiment, X is -P0(0H)0 M⁺ and M⁺ is K⁺. In another embodiment, X is -P0(0H)0 M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is independently H or a C1-C4 alkyl group. In another embodiment, X is -PO(OH)0 M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is a CH3 group.

[00121 ] In another embodiment, the invention features a compound of formula I-E and the attendant definitions, wherein X is -P0(0 )_2*2M⁺ and M⁺ is Li⁺. In one embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is Na⁺. In another embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is K⁺. In another embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is independently H or a C1-C4 alkyl group. In another embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is a CH3 group.

[00122] In another embodiment, the invention features a compound of formula I-E and the attendant definitions, wherein X is -P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is -P0(0 )2*D²⁺ and D²⁺ is Mg²⁺. In another embodiment, X is

[00123] In another embodiment, the invention features a compound of formula I-E and the attendant definitions, wherein X is -PO(OH)2.

[00124] In another embodiment, the invention provides a process for preparing a compound of formula I-F,

wherein, independently for each occurrence:

R² is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen; R⁵ is halogen, OH, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -0-; and

X is -PO(OH)₂, -PO(OH)O M⁺, -P0(0 )_2*2M⁺, or -P0(0 )_2*D²⁺; M⁺ is a

[00125] In one embodiment, the invention features a compound of formula I-F and the attendant definitions, wherein R² is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R² is CF3.

[00126] In another embodiment, the invention features a compound of formula I-F and the attendant definitions, wherein R⁵ is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with -0-. In one embodiment, R⁵ is CH₃. In another embodiment, R⁵ is OCF3.

[00127] In another embodiment, the invention features a compound of formula I-F and the attendant definitions, wherein X is -PO(OH)₂, -PO(OH)0 M⁺, -R0(0 )₂·2M⁺ or -P0(0 )_2»D²⁺; wherein M⁺ is Li⁺, Na⁺ or K⁺ and wherein D²⁺ is Mg²⁺ or Ca²⁺.

[00128] In another embodiment, the invention features a compound of formula I-F and the attendant definitions, wherein R² is CF3, R⁷ is CH3 or OCF3 and X is -PO(OH)₂.

[00129] In another embodiment, the invention features a compound of formula I-F and the attendant definitions, wherein X is -PO(OH)0 M⁺, -R0(0 )₂·2M⁺ or -P0(0 )_2»D²⁺; M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)4⁺; wherein each R⁹ is independently H or a C1-C4 alkyl group and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺.

[00130] In another embodiment, the invention features a compound of formula I-F and the attendant definitions, wherein X is -P0(0H)0 M⁺ and M⁺ is Li⁺. In one embodiment, X is -PO(OH)0 M⁺ and M⁺ is Na⁺. In another embodiment, X is -PO(OH)0 M⁺ and M⁺ is K⁺. In another embodiment, X is -PO(OH)0 M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is independently H or a C1-C4 alkyl group. In another embodiment, X is -PO(OH)0 M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is a CH3 group.

[00131 ] In another embodiment, the invention features a compound of formula I-F and the attendant definitions, wherein X is -R0(0 )₂·2M⁺ and M⁺ is Li⁺. In one embodiment, X is -R0(0 )₂·2M⁺ and M⁺ is Na⁺. In another embodiment, X is -R0(0 )₂·2M⁺ and M⁺ is K⁺. In another embodiment, X is -R0(0 )₂·2M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is independently H or a C₁-C₄ alkyl group. In another embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is N(R⁹)₄ ⁺; wherein each R⁹ is a CH₃ group.

[00132] In another embodiment, the invention features a compound of formula I-F and the attendant definitions, wherein X is -P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is -P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺. In another embodiment, X is

[00133] In another embodiment, the invention features a compound of formula I-F and the attendant definitions, wherein X is -PO(OH)2.

[00134] In another embodiment, the invention provides a process for preparing a compound of formula I-G,

wherein, independently for each occurrence:

substituted with 0-6 halogen;

X is -PO(OH)₂, -PO(OH)O M⁺, -P0(0 )_2*2M⁺, or -P0(0 )_2*D²⁺; M⁺ is a

[00135] In one embodiment, the invention features a compound of formula I-G and the attendant definitions, wherein R² is halogen. In another embodiment, R² is Cl. [00136] In another embodiment, the invention features a compound of formula I-G and the attendant definitions, wherein R³ is halogen. In another embodiment, R³ is Cl.

[00137] In another embodiment, the invention features a compound of formula I-G and the attendant definitions, wherein R⁵ is halogen. In another embodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In another embodiment, R⁵ is C1-C6 alkyl. In another embodiment, R⁵ is CH3. In another embodiment, R⁵ is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -0-. In another embodiment, R⁵ is OCH3. In another embodiment, R⁵ is OH. In another embodiment, R⁵ is OCF3.

[00138] In another embodiment, the invention features a compound of formula I-G and the attendant definitions, wherein R⁷ is halogen. In one embodiment, R⁷ is F.

[00139] In another embodiment, the invention features a compound of formula I-G and the attendant definitions, wherein X is -PO(OH)2, -PO(OH)0 M⁺, -P0(0 )_2*2M⁺ or -P0(0 )_2*D²⁺; wherein M⁺ is Li⁺, Na⁺ or K⁺ and wherein D²⁺ is Mg²⁺ or Ca²⁺.

[00140] In another embodiment, the invention features a compound of formula I-G and the attendant definitions, wherein R² and R³ are Cl, R⁵ is OCH3 and R⁷ is F.

[00141 ] In another embodiment, the invention features a compound of formula I-G and the attendant definitions, wherein R² and R³ are Cl, R⁷ is F, R⁵ is OCH3 and X is

-PO(OH)₂.

[00142] In another embodiment, the invention features a compound of formula I-G and the attendant definitions, wherein X is -P0(0H)0 M⁺, -P0(0 )_2*2M⁺ or -P0(0 )_2*D²⁺; M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)4⁺; wherein each R⁹ is independently H or a C1-C4 alkyl group and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺.

[00143] In another embodiment, the invention features a compound of formula I-G and the attendant definitions, wherein X is -PO(OH)0 M⁺ and M⁺ is Li⁺. In one embodiment, X is -PO(OH)0 M⁺ and M⁺ is Na⁺. In another embodiment, X is

-PO(OH)0 M⁺ and M⁺ is K⁺. In another embodiment, X is -P0(0H)0 M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is independently H or a C1-C4 alkyl group. In another embodiment, X is -PO(OH)0 M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is a CH3 group.

[00144] In another embodiment, the invention features a compound of formula I-G and the attendant definitions, wherein X is -P0(0 )_2*2M⁺ and M⁺ is Li⁺. In one embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is Na⁺. In another embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is K⁺. In another embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is N(R⁹)4⁺; wherein each R⁹ is independently H or a C₁-C₄ alkyl group. In another embodiment, X is -P0(0 )_2*2M⁺ and M⁺ is N(R⁹)₄ ⁺; wherein each R⁹ is a CH₃ group.

[00145] In another embodiment, the invention features a compound of formula I-G and the attendant definitions, wherein X is -P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is -P0(0 )_2*D²⁺ and D²⁺ is Mg²⁺. In another embodiment, X is

[00146] In another embodiment, the invention features a compound of formula I-G and the attendant definitions, wherein X is -PO(OH)2.

[00147] In another embodiment, the invention features a compound of formula I-G and the attendant definitions, wherein R² is Cl, R³ is Cl, R⁵ is OCH3, R⁷ is F and X is

-P0(0H)₂.

[00148] In another embodiment, the invention features a compound of formula I-G and the attendant definitions, wherein R² is Cl, R³ is Cl, R⁵ is OCH₃, R⁷ is F, X is

-P0(0 )_2*2M⁺ and M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)4⁺ wherein each R⁹ is independently H or a C₁-C₄ alkyl group.

[00149] In another embodiment, the invention features a compound of formula I-G and the attendant definitions, wherein R² is Cl, R³ is Cl, R⁵ is OCH₃, R⁷ is F, X is -PO(OH)0 M⁺ and M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)4⁺ wherein each R⁹ is independently H or a C₁-C₄ alkyl group.

[00150] In still yet other embodiments, the compounds prepared in accordance with the methods of the present application may be selected from the following group (or a salt thereof):

[00151 ] The application provides for a method for preparing a compound of formula I,

I,

or a salt thereof, wherein, R², R³, R⁵, and R⁷ are as defined in any of embodiments above; comprising deprotecting a compound of formula II,

to afford a compound of formula I wherein X is -PO(OH)2.

[00152] The compound of formula II, or a salt thereof, may be obtained from any source or prepared in accordance with the reaction steps described in the present application.

[00153] In some embodiments, the deprotection step comprises reacting the compound of formula II with an acid. In other embodiments, the acid is selected from the group consisting of sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, p-toluene sulfonic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, and trifluoroborate etherate. In certain embodiments, the acid is acetic acid or propionic acid. In some embodiments, the deprotection step may comprises keeping the compound of formula II at between about 10 °C and about 70 °C for 30 minutes to one week. Further, the compound of formula I, or a salt thereof, may be obtained without chromatographic purification. The compound of formula I may also be converted to a pharmaceutically acceptable salt of the compound of formula I such that the compound of formula I is obtained as a salt of the compound of formula I, wherein said salt of the compound of formula I is a pharmaceutically acceptable salt of the compound of formula I wherein the pharmaceutically acceptable salt of the compound of formula I may be obtained without chromatographic purification. In one embodiment, the compound of formula I may be recrystallized from a solvent system comprising DMSO to afford a DMSO-solvate of the compound of formula I in which X is -PO(OH)₂. In some embodiments, the solvent system comprises DMSO and ethyl acetate. In other embodiments, the DMSO-solvate of the compound of formula I is recrystallized from a solvent mixture comprising water, THF and ethyl acetate. In some embodiments, the DMSO-solvate of the compound of formula I is recrystallized from a solvent mixture comprising water and THF.

[00154] The present application provides for a method in which the deprotecting step comprises reacting the compound of formula II with a base to afford a compound of formula Ila,

which is then further deprotected by reacting the compound of formula Ila with an acid. Any combination of suitable base and reaction conditions may be used to convert the compound of formula II to the compound of formula Ila. For example, when a strong base is used to convert the compound of formula II to the compound of formula Ila, mild reaction conditions and/or short reaction period may be used. When a weaker base is used to partially deprotect the compound of formula II, higher temperature and/or longer reaction time may be used.

[00155] To further deprotect the compound of formula Ila, any suitable acid may be used. Suitable acids include sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, p-toluene sulfonic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, and trifluoroborate etherate, and mixtures thereof. For example, the acid may be acetic acid or propionic acid. In some embodiments, the deprotection step comprises keeping the compound of formula Ila at between about 10 °C and about 70 °C for about 30 minutes to about one day, about two days, about three days, or about four days. In some embodiments, the deprotection step comprises keeping the compound of formula Ila at between about 10 °C and about 70 °C for about 30 minutes to about 72 hours.

[00156] The present application also provides for a method of preparing the compound of formula II comprising reacting a compound of formula III,

with K(tBu)₂P0₄ to afford the compound of formula II.

[00157] In one embodiment, the compound of formula III is a compound of formula Ilia:

Ilia.

[00158] The compound of formula II, or a salt thereof, may be obtained from any source or prepared in accordance with the reaction steps described in the present application.

[00159] In some embodiments, the reaction between the compound of formula III, or a salt thereof, and KitBujiPCU may be conducted in the presence of a base. Any suitable base may be used. Suitable bases include potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium ieri-butoxide, sodium ieri-butoxide, 2-t -butyl-l, 1,3,3- tetramethylguanidine, or l,8-diazabicyclo[5.4.0]undec-7-ene. In some embodiments, the reaction between the compound of formula III, or a salt thereof, and K(tBu)₂P0₄ may be conducted at a temperature of no more than about 90 °C. In other embodiments, the reaction between the compound of formula III, or a salt thereof, and K(tBu)₂P0₄ may be conducted at a temperature of no more than about 60 °C, about 70 °C, or about 80 °C. In further embodiments, the reaction between the compound of formula III, or a salt thereof, and K(tBu)₂P0₄ may be conducted at a temperature of no more than about 70 °C. In some embodiments, the reaction between the compound of formula III, or a salt thereof, and K(tBu)₂P0₄ may be conducted in a solvent comprising one or more of benzene, toluene, NMP, DMF, DMSO, acetonitrile, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, 2-methyltetrahydrofuran, dichloromethane, chloroform, and tetrachloroethylene, including any mixture thereof. In some embodiments, the reaction between the compound of formula III, or a salt thereof, and K(tBu)₂P0₄ may be conducted in the presence of Nal.

[00160] The present application provides for a method of preparing a compound of formula

III,

comprising reacting a compound of formula IV,

with a halogenating agent to afford the compound of formula III.

[00161 ] In one embodiment, the halogenating agent is a chlorinating agent. In such an embodiment, the compound of formula III is a compound of formula Ilia:

Ilia.

[00162] The compound of formula IV, or a salt thereof, may be obtained from any source or prepared in accordance with the reaction steps described in the present application.

[00163] Any chlorinating agent suitable for chlorinating the compound of formula IV may be used. In some embodiments, the chlorinating agent is thionyl chloride, methanesulfonyl chloride, phosphorus oxychloride or phosphorus pentachloride. In some embodiments, the chlorinating agent is methanesulfonyl chloride. In some embodiments, the chlorinating agent is thionyl chloride. In some embodiments, the chlorinating agent is phosphorus oxychloride or phosphorus pentachloride. The reaction between the compound of formula IV and the chlorinating agent may be conducted in the presence of a non-nucleophilic base. Any suitable non-nucleophilic base may be used to scavenge the HC1 generated by the chlorinating reaction. Suitable non-nucleophilic bases include triethylamine, diisopropyl ethylamine (Hunig’s base), N- methylmorpholine, l,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, butylamine, or 1,5- diazabicyclo(4.3.0)non-5-ene, or a mixture thereof. In some embodiments, the reaction between the compound of formula IV and the chlorinating agent is conducted at a

temperature of no more than about 90 °C. In other embodiments, the reaction between the compound of formula III, or a salt thereof, and compound of formula IV may be conducted at a temperature of no more than about 60 °C, about 70 °C, or about 80 °C. In further embodiments, the reaction between the compound of formula III, or a salt thereof, and compound of formula IV may be conducted at a temperature of no more than about 70 °C. [00164] The present application provides for a method of preparing a compound of formula IV,

comprising reacting a compound of formula V,

with formaldehyde to afford the compound of formula IV.

[00165] The compound of formula V, or a salt thereof, may be obtained from any source or prepared in accordance with the reaction steps described in the present application.

[00166] Any source of formaldehyde may be used in converting the compound of formula V to the compound of formula IV. Suitable sources of formaldehyde include paraformaldehyde, formalin solution, trioxane, and monomeric formaldehyde. In some embodiments, the source of formaldehyde is a formalin solution. In some embodiments, the formalin solution comprises methanol and/or water. In further embodiments, the reaction between formalin and the compound of formula V may be conducted in the presence of toluene, THF, 2-Me-THF, and/or EtOAc. In some embodiments, the compound of formula V is reacted with formaldehyde at between about room temperature and about 80°C.

[00167] The present application provides for a method of preparing a compound of formula V,

comprising reacting a compound of formula VI,

with a compound of formula VII,

wherein Y is a leaving group; to afford the compound of formula V.

[00168] The compounds of formulae VI, or a salt thereof, and VII, or a salt thereof, may be obtained from any source or prepared in accordance with the reaction steps described in the present application.

[00169] Any suitable leaving group may be used. In some embodiments, the leaving group is N₂ ⁺, NO, NOi, S0₂R\ NMe₃ ⁺, CF₃, CHO, COR, COOH, S0₃ , Br, Cl, I, COO , or F wherein R’ is an alkyl group with 1-4 carbon atoms. In some embodiments, the leaving group is CF₃, S0₃ , Br, Cl, I, COO , or F. In some embodiments, the leaving group may be CF₃, Cl, or F. In some embodiments, the leaving group is CF₃ or F. In a further embodiment, the leaving group is F. In some embodiment, the compound of formula VI is reacted with the compound of formula VII at between about 50 °C and about 110 °C. In other embodiments, the compound of formula VI is reacted with the compound of formula VII at between about 70 °C and about 100 °C. In a further embodiment, the compound of formula VI is reacted with the compound of formula VII at between about 80 °C and about 90 °C.

[00170] The present application provides for a method of preparing a compound of formula VI,

comprising converting a compound of formula VIII,

wherein R is Cl or methoxy; to the compound of formula VI.

[00171 ] The compound of formula VIII, or a salt thereof, may be obtained from any source or prepared in accordance with the reaction steps described in the present application.

[00172] Where R is an alkoxy (such as methoxy), any dealkylating agent may be suitable to dealkylate the compound of formula VIII to afford the compound of formula VI. In some embodiments, the dealkylating agent is an acid. Any suitable acid may be used to dealkylate the compound of formula VIII to afford a compound of formula VI. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, p-toluene sulfonic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, trifluoroborate etherate, or mixtures thereof. In other embodiments, the acid is hydrochloric acid, hydrobromic acid, acetic acid, propionic acid, or mixtures thereof. In some embodiments, the acid is hydrobromic acid, acetic acid, propionic acid, or mixtures thereof.

[00173] Where R is a halo, such as chloro, reacting the compound of formula VIII with formic acid affords the compound of formula VI.

[00174] The present application provides for a method of preparing a compound of formula VIII,

comprising reacting a compound of formula IX,

or an acid chloride thereof, with a compound of formula XI,

wherein R is Cl or methoxy, to afford the compound of formula VIII.

[00175] The compounds of formulae IX, or a salt thereof, and X, or a salt thereof, may be obtained from any source.

[00176] In some embodiments, the reaction between the compounds of formulae IX and X is conducted in the presence of a coupling reagent. Any coupling reagent suitable for coupling a carboxylic acid and amine to afford an amide may be suitable in the preparing the compound of formula VIII. In some embodiments, the coupling reagent is diethyl chlorophosphate, diphenyl chlorophosphate, propylphosphonic anhydride (T3P), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), N-(3-dimethylaminopropyl)-N’ -ethylcarbodiimide

hydrochloride (EDAC-HC1), diphenyl phosphoryl chloride (DPPC1), propylphosphonic anhydride, thionyl chloride, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt). In one embodiment, the coupling reagent is diphenyl phosphoryl chloride (DPPC1) or propylphosphonic anhydride (T3P).

[00177] The present application provides for a method of preparing a compound of formula V,

comprising converting a compound of formula XI,

wherein R is Cl or methoxy; to the compound of formula V. Where R is an alkoxy group (such as methoxy), the conversion reaction is a dealkylation reaction. Where R is alkoxy, reacting the compound of formula XI with a dealkylating agent affords the compound of formula V.

[00178] The compound of formula XI, or a salt thereof, may be obtained from any source or prepared in accordance with the reaction steps described in the present application.

[00179] Where R is alkoxy group, any dealkylating agent may be suitable to dealkylate the compound of formula XI, or a salt thereof, to afford the compound of formula V. In some embodiments, the dealkylating agent is an acid. Any suitable acid may be used to dealkylate the compound of formula XI to afford a compound of formula V. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, p-toluene sulfonic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, trifluoroborate etherate, or mixtures thereof. In other embodiments, the acid is hydrochloric acid, hydrobromic acid, acetic acid, propionic acid, or mixtures thereof. In some embodiments, the acid is hydrobromic acid, acetic acid, propionic acid, or mixtures thereof. In a further embodiment, the dealkylating agent is a mixture of hydrobormic acid and acetic acid. [00180] In some embodiments, the dealkylating agent is p-toluene sulfonic acid in combination with a Lewis acid. In some embodiments, the Lewis acid is lithium chloride or lithium bromide.

[00181 ] Where R is a halo, such as chloro, reacting the compound of formula XI with formic acid affords the compound of formula V.

[00182] The present application provides for a method of preparing a compound of formula

XI,

wherein R is Cl or methoxy; comprising reacting a compound of formula VIII,

wherein Y is a leaving group; to afford the compound of formula XI.

[00183] The compounds of formula VIII, or a salt thereof, may be obtained from any source or prepared in accordance with the reaction steps described in the present application. The compounds of formula VII, or a salt thereof, may be obtained from any source.

[00184] In some embodiments, the leaving group is N₂ ⁺, NO, NO₂, SO₂R’, NMe₃ ⁺, CF₃, CHO, COR’, COOH, SOT, Br, Cl, I, COO , or F wherein R’ is an alkyl group with 1-4 carbon atoms. In some embodiments, the leaving group is CF3, SO3 , Br, Cl, I, COO , or F. In some embodiments, the leaving group is CF3, SO3 , Br, Cl, I, COO , or F. In other embodiments, the leaving group is N2⁺, NO, NO2, CF3, Cl, or F. In other embodiments, the leaving group is N2⁺, NO, or NO2. In other embodiments, the leaving group is NO2. In some embodiments, the compound of formula VII is reacted with the compound of formula VIII at between about 50 °C and about 110 °C. In other embodiments, the compound of formula VII is reacted with the compound of formula VIII at between about 70 °C and about 100 °C. In a further embodiment, the compound of formula VII is reacted with the compound of formula VIII at between about 80 °C and about 90 °C.

[00185] The present application provides for a method of preparing a compound of formula

VIII,

wherein R is Cl or methoxy, comprising reacting a compound of formula IX,

or its acid chloride, with a compound of formula

to afford the compound of formula VIII.

[00186] The compounds of formulae IX, or a salt thereof, and X, or a salt thereof, may be obtained from any source.

[00187] In some embodiments, the reaction between the compounds of formulae IX and X is conducted in the presence of a coupling reagent. Any coupling reagent suitable for coupling a carboxylic acid and an amine to afford an amide may be suitable in the preparing the compound of formula VIII. In some embodiments, the coupling reagent is diethyl chlorophosphate, diphenyl chlorophosphate, propylphosphonic anhydride (T3P), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (ED AC HC1), diphenyl phosphoryl chloride (DPPC1), propylphosphonic anhydride, thionyl chloride, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt). In one embodiment, the coupling reagent is diphenyl phosphoryl chloride (DPPC1) or propylphosphonic anhydride (T3P).

[00188] In some embodiments, the acid chloride of the compound of formula IX is reacted with a compound of formula X in the presence of a base to afford a compound of formula VIII.

[00189] The present application provides for a method of preparing a compound of formula III,

comprising reacting a compound of formula V,

with formaldehyde to afford the compound of formula IV,

and reacting the compound of formula IV with a halogenating agent to afford the compound of formula III.

[00190] In one embodiment, the halogenating agent is a chlorinating agent. In such an embodiment, the compound of formula III is a compound of formula Ilia:

Ilia.

[00191 ] The compound of formula V, or a salt thereof, may be obtained from any source or prepared in accordance with the reaction steps described in the present application.

[00192] In converting the compound of formula V to the compound of formula IV, any source of formaldehyde may be used. Suitable sources of formaldehyde include

paraformaldehyde, formalin solution, trioxane, and monomeric formaldehyde. In some embodiments, the source of formaldehyde is a formalin solution. In some embodiments, the formalin solution comprises methanol and/or water. In further embodiments, the reaction between formalin and the compound of formula V may be conducted in the presence of toluene, THF, 2-Me-THF, and/or EtOAc. In some embodiments, the compound of formula V is reacted with formaldehyde at between about room temperature and about 80 °C.

[00193] In converting the compound of formula IV to the compound of formula III, any chlorinating agent suitable for chlorinating the compound of formula IV may be used. In some embodiments, the chlorinating agent is thionyl chloride, methanesulfonyl chloride, phosphorus oxychloride or phosphorus pentachloride. The reaction between the compound of formula IV and the chlorinating agent may be conducted in the presence of non-nucleophilic base. Any suitable non-nucleophilic agent may be used to scavenge the HC1 generated by the chlorinating reaction. Suitable non-nucleophilic base include triethylamine, diisopropyl ethylamine, N- methylmorpholine, l,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, butylamine, 1,5- diazabicyclo(4.3.0)non-5-ene, and mixtures thereof. In some embodiments, the non-nucleophilic base is triethylamine or diisopropyl ethylamine. In some embodiments, the non-nucleophilic base is diisopropyl ethylamine. In some embodiments, the reaction between the compound of formula IV and the chlorinating agent is conducted at a temperature of no more than about 60 °C.

[00194] The present application provides for a method of preparing a compound of formula V,

comprising reacting a compound of formula IX,

with a compound of formula XI,

wherein R is Cl or methoxy; to a afford the compound of formula VIII,

converting a compound of formula VIII to the compound of formula VI,

and reacting a compound of formula VI with a compound of formula VII,

wherein Y is a leaving group; to afford the compound of formula V.

[00195] In some embodiments, the reaction between the compounds of formulae IX and X is conducted in the presence of a coupling reagent. Any coupling reagent suitable for coupling a carboxylic acid and an amine to afford an amide may be suitable in the preparing the compound of formula VIII. In some embodiments, the coupling reagent is diethyl chlorophosphate, diphenyl chlorophosphate, propylphosphonic anhydride (T3P), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (ED AC HC1), diphenyl phosphoryl chloride (DPPC1), propylphosphonic anhydride, thionyl chloride, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt). In one embodiment, the coupling reagent is diphenyl phosphoryl chloride (DPPC1) or propylphosphonic anhydride (T3P).

[00196] Any dealkylating agent may be suitable to dealkylate the compound of formula VIII to afford the compound of formula VI. In some embodiments, the dealkylating agent is an acid.

In some embodiments, the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, p-toluene sulfonic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, trifluoroborate etherate, or a mixture thereof. In other

embodiments, the acid is hydrochloric acid, hydrobromic acid, acetic acid, propionic acid, or a mixture thereof. In some embodiments, the acid is hydrobromic acid, acetic acid, propionic acid, or a mixture thereof.

[00197] Any suitable leaving group may be used. In some embodiments, the leaving group is

N₂ ⁺, NO, NO2, S0₂R\ NMe₃ ⁺, CF₃, CHO, COR’, COOH, S0₃ , Br, Cl, I, COO , or F wherein R’ is an alkyl group with 1-4 carbon atoms. In some embodiments, the leaving group is CF₃, S0₃ , Br, Cl, I, COO , or F. In other embodiments, the leaving group may be CF₃, Cl, or F. In some embodiments, the leaving group is CF₃ or F. In a further embodiment, the leaving group is F. In some embodiments, the compound of formula VI is reacted with the compound of formula VII at between about 50 °C and about 110 °C. In other embodiments, the compound of formula VI is reacted with the compound of formula VII at between about 70 °C and about 100 °C. In a further embodiment, the compound of formula VI is reacted with the compound of formula VII at between about 80 °C and about 90 °C.

[00198] The present application provides for a method of preparing a compound of formula V,

comprising reacting a compound of formula IX,

with a compound of formula XI,

wherein R is Cl or methoxy, to afford the compound of formula VIII,

reacting a compound of formula VIII with a compound of formula VII,

wherein Y is a leaving group, to afford the compound of formula XI,

converting the compound of formula XI to the compound of formula V.

[00199] In some embodiments, the reaction between the compounds of formulae IX and X is conducted in the presence of a coupling reagent. Any coupling reagent suitable for coupling a carboxylic acid and an amine to afford an amide may be suitable in the preparing the compound of formula VIII. In some embodiments, the coupling reagent is diethyl chlorophosphate, diphenyl chlorophosphate, propylphosphonic anhydride (T3P), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (ED AC HC1), diphenyl phosphoryl chloride (DPPC1), propylphosphonic anhydride, thionyl chloride, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt). In one embodiment, the coupling reagent is diphenyl phosphoryl chloride (DPPC1) or propylphosphonic anhydride (T3P).

[00200] In some embodiments, the leaving group is N2⁺, NO, NO2, SO2R’, NMe3⁺, CF3, CHO, COR’, COOH, SO3 , Br, Cl, I, COO , or F wherein R’ is an alkyl group with 1-4 carbon atoms.

In some embodiments, the leaving group is CF3, SO3 , Br, Cl, I, COO , or F. In some

embodiments, the leaving group is CF3, SO3 , Br, Cl, I, COO , or F. In other embodiments, the leaving group is N2⁺, NO, NO2, CF3, Cl, or F. In other embodiments, the leaving group is N2⁺, NO, or NO2. In other embodiments, the leaving group is NO2. In some embodiments, the compound of formula VII is reacted with the compound of formula VIII at between about 50 °C and about 110 °C. In other embodiments, the compound of formula VII is reacted with the compound of formula VIII at between about 70 °C and about 100 °C. In a further embodiment, the compound of formula VII is reacted with the compound of formula VIII at between about 80 °C and about 90 °C.

[00201] In some embodiments, the converting reaction is a dealkylating reaction. Any dealkylating agent may be suitable to dealkylate the compound of formula VIII to afford the compound of formula VI. In some embodiments, the dealkylating agent is an acid. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, p-toluene sulfonic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, and trifluoroborate etherate, or mixtures thereof. In other

embodiments, the acid is hydrochloric acid, hydrobromic acid, acetic acid, and propionic acid, or mixtures thereof. In some embodiments, the acid is hydrobromic acid, acetic acid, and propionic acid, or mixtures thereof.

[00202] The method of preparing the compound of formula I can be carried out as a batch process or as a continuous process. In one aspect, the reaction steps for converting a compound of formula II, a compound of formula III, a compound of formula IV, a compound of formula V, a compound of formula VI, a compound of formula VIII, a compound of formula IX, or a compound of formula XI to the compopund of formula I are performed in reaction vessels customary for such reactions, the reactions being carried out in a continuous, semi-continuous or batchwise manner. The skilled artisan could adapt any batch process for making the compound of formula I in continuous process in which the starting point is preparation of a compound of formula II, a compound of formula III, a compound of formula IV, a compound of formula V, a compound of formula VI, a compound of formula VIII, a compound of formula IX, or a compound of formula XI.

[00203] In one embodiment, the compound of formula I prepared in accordance with the methods of the present application is (4-(4,5-dichloro-2-(4-fluoro-2- methoxyphenoxy)benzamido)-2-oxopyridin-l(2 /)-yl)methyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof.

[00204] In another embodiment, the compound of formula I prepared in accordance with the methods of the present application is (4-(2-(4-fluoro-2-methoxyphenoxy)-4- (perfluoroethyl)benzamido)-2-oxopyridin-l(2 )-yl)methyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof.

[00205] In another embodiment, the compound of formula I prepared in accordance with the methods of the present application is (4-(4,5-dichloro-2-(4-fluorophenoxy)benzamido)-2- oxopyridin-l (2 /)-yl)mcthyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof.

[00206] In another embodiment, the compound of formula I prepared in accordance with the methods of the present application is (4-(2-(4-fluoro-2-methoxyphenoxy)-5- (trifluoromethyl)benzamido)-2-oxopyridin-l(2 )-yl)methyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof.

[00207] In another embodiment, the compound of formula I prepared in accordance with the methods of the present application is (2-oxo-4-(2-(4-(trifluoromethoxy)phenoxy)-4- (trifluoromethyl)benzamido)pyridin-l(2 )-yl)methyl dihydrogen phosphate or a

pharmaceutically acceptable salt thereof.

[00208] In another embodiment, the compound of formula I prepared in accordance with the methods of the present application is (4-(2-(4-fluorophenoxy)-4-(perfluoroethyl)benzamido)-2- oxopyridin-l (2 /)-yl)mcthyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof.

[00209] In another embodiment, the compound of formula I prepared in accordance with the methods of the present application is (4-(5-chloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)-2- oxopyridin-1 (2//)-yl)mcthyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof. [00210] In another embodiment, the compound of formula I prepared in accordance with the methods of the present application is (2-oxo-4-(2-(4-(trifluoromethoxy)phenoxy)-5- (trifluoromethyl)benzamido)pyridin-l(2//)-yl)methyl dihydrogen phosphate or a

pharmaceutically acceptable salt thereof.

[00211 ] In another embodiment, the compound of formula I prepared in accordance with the methods of the present application is (4-(2-(4-fluoro-2-methylphenoxy)-4- (trifluoromethyl)benzamido)-2-oxopyridin-l(2 )-yl)methyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof.

[00212] In another embodiment, the compound of formula I prepared in accordance with the methods of the present application is (4-(2-(4-fluoro-2-methylphenoxy)-5- (trifluoromethyl)benzamido)-2-oxopyridin-l(2 )-yl)methyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof.

[00213] In another embodiment, the compound of formula I prepared in accordance with the methods of the present application is (4-(2-(2-chloro-4-fluorophenoxy)-5- (trifluoromethyl)benzamido)-2-oxopyridin-l(2 )-yl)methyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof.

[00214] In another embodiment, the compound of formula I prepared in accordance with the methods of the present application is (4-(5-chloro-2-(4-fluoro-2-methylphenoxy)benzamido)-2- oxopyridin-l (2 /)-yl)mcthyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof.

[00215] In another embodiment, the compound of formula I prepared in accordance with the methods of the present application is (4-(4-chloro-2-(4-fluoro-2-methylphenoxy)benzamido)-2- oxopyridin-l (2 /)-yl)mcthyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof.

[00216] In another embodiment, the compound of formula I prepared in accordance with the methods of the present application is (4-(5-chloro-2-(2-chloro-4-fluorophenoxy)benzamido)-2- oxopyridin-l (2//)-yl)mcthyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof.

[00217] In another embodiment, the compound of formula I prepared in accordance with the methods of the present application is (2-oxo-4-(2-(o-tolyloxy)-5- (trifluoromethyl)benzamido)pyridin-l(2 )-yl)methyl dihydrogen phosphate or a

pharmaceutically acceptable salt thereof. [00218] In another embodiment, the compound of formula I prepared in accordance with the methods of the present application is (4-(2-(2,4-difluorophenoxy)-4- (trifluoromethyl)benzamido)-2-oxopyridin-l(2 )-yl)methyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof.

[00219] In another embodiment, the compound of formula I prepared in accordance with the methods of the present application is (2-oxo-4-(2-(2-(trifluoromethoxy)phenoxy)-5- (trifluoromethyl)benzamido)pyridin-l(2 )-yl)methyl dihydrogen phosphate or a

pharmaceutically acceptable salt thereof.

[00220] In another embodiment, the compound of formula I prepared in accordance with the methods of the present application is (4-(2-(4-fluorophenoxy)-5-(trifluoromethyl)benzamido)-2- oxopyridin-l (2 /)-yl)mcthyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof.

[00221 ] In one embodiment, the application provides for a method for treating, amelioration of, reducing the symptoms of, prophylaxis of, or lessening the severity of any type of pain in a subject in need thereof comprising administering an effective amount of the compound of formula I prepared in accordance with the methods of the present application. In another embodiment, the pain comprises one or more of abdominal pain, abnormal gastrointestinal motility pain, acute herpes zoster pain, acute inflammatory pain, acute intermittent pain, acute musculoskeletal pain, acute obstetric pain, acute pain, acute post-operative pain (e.g., bunionectomy pain; abdominoplasty pain; knee pain from a total knee replacement; hip pain from a total hip replacement; pain from a laminectomy; pain from a hernia repair; or hemorrhoid removal pain), acute tendonitis pain, acute visceral pain, adiposis dolorosa pain, amyotrophic lateral sclerosis pain, angina-induced pain, anti-retroviral therapy induced neuralgia, anxiety pain, appendicitis pain, arrhythmia pain, arthritis pain, ataxia pain, back pain, Behcet’s disease pain, bipolar disorder pain, bladder and urogenital disease pain, bone pain, brachial plexus avulsion injury pain, breakthrough pain, bum pain, burning mouth syndrome pain, bursitis pain, cancer chemotherapy induced neuralgia, cancer pain, cardiac arrhythmia pain, cardiac pain, carpal tunnel syndrome pain, central pain, cerebral ischemia, Cesarean-section pain, Charcot- Marie Tooth neuropathic pain, chemotherapy induced neuropathic pain, chest pain, cholecystitis pain, chronic and acute headache pain, chronic and acute neuropathic pain, chronic arthritis, chronic pain, chronic visceral pain, cluster headache pain, cold pain, complex regional pain syndrome, Crohn’s disease pain, dental pain (e.g., third molar extraction), depression pain, diabetic neuralgia, diabetic neuropathic pain, diabetic peripheral neuropathic pain, drug therapy induced neuralgia, ectopic proximal and distal discharge pain, endometriosis pain, epilepsy pain, erythromelalgia pain, exercise induced angina pain, exercise induced pain, exercise pain, Fabry’s disease pain, femur cancer pain, fibromyalgia pain, general neuralgias, granuloma annulare pain, Guillain-Barre pain, gut pain, Haglund syndrome pain, head pain, headache pain, hereditary sensory neuropathic pain, hernia pain, herpetic neuralgia pain, HIV-associated neuropathic pain, HIV-associated sensory neuropathic pain, hyperactivity bladder pain, hypertension pain, idiopathic pain, idiopathic sensory neuropathic pain, idiopathic small-fiber neuropathic pain, incontinence pain, inflammatory bowel disease pain, inflammatory pain, injury pain, interstitial cystitis (IC) pain, intestinal obstruction pain, intractable pain, irritable bowel syndrome pain, joint pain, labor pain, leprosy pain, lipoidica pain, malignancy pain, mechanical low back pain, migraine pain, Morton’s neuroma pain, movement disorder pain, multiple sclerosis (MS) pain, musculoskeletal pain, myofascial pain syndrome pain, myotonia pain, neck pain, necrobiosis pain, nerve avulsion injury pain, nerve entrapment injury pain, neurodegenerative disorder pain, neuroendocrine disorder pain, neuropathic low back pain, neuropathic pain, nociceptive pain, non-malignant chronic bone pain, orofacial pain, osteoarthritis pain, painful bladder syndrome, painful legs, painful moving toes, painful neuromas, palpitations, pancreatic pain, paroxysmal extreme pain, pathological cough pain, pelvic pain, peripheral nerve injury pain, phantom pain, phlebitic pain, post spinal cord injury pain, post- amputation pain, post-herpetic neuralgia, post mastectomy pain, post-stroke pain, postsurgical pain, premenstrual pain, prostatitis pain, pmritis pain, psychiatric disorder associated pain, pyelonephritis pain, radicular pain, radiculopathy, radiotherapy-induced neuropathic pain, renal colic pain, rheumatoid arthritis pain, sarcoidosis pain, sciatica pain, severe pain, shingles pain, sickle cell anemia pain, sinusitis pain, spinal cord injury pain, spinal stenosis pain, sports injury pain, stress-induced angina pain, stress-induced pain, stroke pain, temporomandibular joint pain, tendonitis pain, tension headache pain, thalamic pain, tinnitus pain, trauma pain, traumatic brain injury pain, traumatic neuroma, trigeminal autonomic cephalalgia, trigeminal neuralgia, urinary incontinence pain, visceral pain, widespread pain, or other types of pain.

[00222] In one embodiment the pain comprises acute pain including bunionectomy pain, abdominoplasty pain, orthopedic procedure pain (e.g., total knee replacement, total hip replacement and laminectomy), hernia pain, hemorrhoid pain, or dental pain (e.g., third molar extractions).

[00223] In another embodiment the pain comprises chronic pain including diabetic peripheral neuropathy pain, trigeminal neuralgia, rheumatoid or osteoarthritis pain, chronic lower back pain, post-herpetic neuralgia, or radiculopathy pain.

[00224] In another embodiment the pain comprises acute pain, chronic pain, gut 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.

[00225] In another embodiment the pain comprises gut pain, including inflammatory bowel disease pain, Crohn’s disease pain or interstitial cystitis pain.

[00226] In another embodiment the pain comprises neuropathic pain, wherein neuropathic pain comprises post-herpetic 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 injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia, post spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia.

[00227] In another embodiment the pain comprises musculoskeletal pain, such as

osteoarthritis pain, back pain, cold pain, bum pain or dental pain.

[00228] In another embodiment the pain comprises inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain or vulvodynia. [00229] In another embodiment the pain comprises inflammatory pain, such as rheumatoid arthritis pain.

[00230] In another embodiment the pain comprises idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.

[00231 ] In another embodiment the method comprises treating pathological cough.

[00232] In another embodiment the method comprises treating trigeminal neuralgia or herpetic neuralgia.

[00233] In some embodiments, the pain comprises musculoskeletal pain. In some

embodiments, the musculoskeletal pain comprises osteoarthritis pain. In some embodiments, the pain comprises neuropathic pain. In some embodiments, the neuropathic pain comprises idiopathic small-fiber neuropathy. As used herein, the phrase“idiopathic small-fiber neuropathy” includes any small fiber neuropathy. In some embodiments, the neuropathic pain comprises small-fiber neuropathy.

[00234] In some embodiments, the pain comprises acute pain. In some embodiments, the acute pain comprises acute post-operative pain. In some embodiments, the pain comprises postsurgical pain.

[00235] In another embodiment, the application provides for a method for treating, amelioration of, reducing the symptoms of, prophylaxis of, or lessening the severity of neurodegenerative diseases comprising administering an effective amount of the compound of formula I prepared in accordance with the methods of the present application. In one embodiment, the neurodegenerative disease is multiple sclerosis. In another embodiment, the neurodegenerative disease is a genetic form of autism called Pitt Hopkins Syndrome (PTHS).

[00236] A process for preparing the compounds of formula I, and salts thereof, and the prodrug compounds of formula VII, and salts thereof, is set forth in Scheme 1. Scheme 1

[00237] In Scheme 1, each occurrence of the following variables independently has the following definition: R², R³, R⁵, R⁷, X and Y are as defined above. R is a leaving group (such as a halogen) or OPG wherein PG is an alcohol protecting group. For example, R may be Cl or F. Where R is Cl, the compound of formula VIII may be reacted with formic acid in the presence of NH4OAC to afford the compound of formula VI, which can then be converted to the compound of formula V using Step E as described below. Where R is Cl, the compound of formula XI may be reacted with formic acid in the presence of NH4OAC to afford the compound of formula V.

[00238] Alternatively, where R is OPG, PG may be methyl, ethyl, isopropyl, benzyl, 2- tetrahydropyranyl, acetyl, trifluoroacetyl, trialkylsilyl, aryldialkylsilyl, alkyldiarylsilyl, or triarylsilyl. In some embodiments, PG is methyl. Where R is a leaving group, Steps C and D may include a step in which the leaving group corresponding to R is replaced by OPG (as defined above) or OH. It would be understood that where R is OPG, converting OPG to OH will involve a deprotection step.

[00239] In order that this application be more fully understood, the following general and specific examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the application in any way.

Step A

X VI II

IX

[00240] In Step A, a compound of formula IX, or an acid chloride thereof, is coupled with a compound of formula X, or a salt thereof, wherein Y is a leaving group, to afford a compound of formula VIII, or a salt thereof. Where R is a leaving group, Steps C and D may include a step in which the leaving group corresponding to R is replaced by OPG (as defined above) or OH. It would be understood that where R is OPG, converting OPG to OH will involve a deprotection step. [00241] In some embodiments, the leaving group is N2⁺, NO, NO2, SO2R’, NMe3⁺, CF3, CHO, COR’, COOH, SO3-, Br, Cl, I, COO , or F, wherein R is an alkyl group with 1-4 carbon atoms.

In other embodiments, Y is F or NO2.

[00242] The coupling of the compound of formula IX, or a salt thereof, with the compound of formula X, or a salt thereof, may be accomplished by reacting a mixture of the compound of formula IX, or a salt thereof, and the compound of formula X, or a salt thereof, with a coupling reagent. Alternatively, the coupling may be accomplished by reacting the compound of formula IX, or a salt thereof, with a coupling reagent, and then reacting the compound of formula X, or a salt thereof, with the resulting mixture. In some embodiments, the coupling reagent is propylphosphonic anhydride (T3P), diethyl chlorophosphate, diphenyl chlorophosphate, thionyl chloride, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), N, N’- dicyclohexylcarbodiimide (DCC) , 1 - [bis(dimethylamino)methylene] - 1 H- 1 ,2,3 -triazolo [4,5- b]pyridinium 3-oxid hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt). In other embodiments, the coupling reagent is propylphosphonic anhydride. In still other embodiments, the coupling reagent is propylphosphonic anhydride and is reacted with a mixture of the compound of formula IX, or a salt thereof, and the compound of formula X, or a salt thereof. In yet other embodiments, the coupling reagent is thionyl chloride and is reacted with the compound of formula X, or a salt thereof, to afford an acid chloride derivative of the compound of formula X, and then the compound of formula IX is reacted with the acid chloride derivative. In some embodiments, the coupling of the compound of formula IX, or a salt thereof, with the compound of formula X, or a salt thereof, is conducted in the presence of N,N- dimethylaminopyridine (DMAP).

[00243] Alternatively, the coupling of the compound of formula IX, or a salt thereof, with the compound of formula X, or a salt thereof, may be accomplished by reacting the compound of formula IX, or a salt thereof, and the compound of formula X, or a salt thereof.

[00244] The coupling of the compound of formula IX, or a salt thereof, with the compound of formula X, or a salt thereof, may be conducted in the presence of a base. In some embodiments, the base is a neutral organic base. In other embodiments, the base is triethylamine, diisopropyl ethylamine, N-methylmorpholine, l,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, butylamine, or l,5-diazabicyclo(4.3.0)non-5-ene. In still other embodiments, the base is triethylamine. In other embodiments, the coupling reagent is propylphosphonic anhydride, and the base is triethylamine,

[00245] The coupling of the compound of formula IX, or a salt thereof, with the compound of formula X, or a salt thereof, may be conducted in any of a wide variety of organic solvents. In some embodiments, the solvent is N-methyl-2-pyrrolidinone, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, isopropyl acetate, methyl isobutyl ketone, 2- methyltetrahydrofuran, tetrahydrofuran, dichloromethane, chloroform, or tetrachloroethylene. In other embodiments, the solvent is 2-methyltetrahydrofuran or tetrahydrofuran. In still other embodiments, the solvent is 2-methyltetrahydrofuran. In yet other embodiments, the solvent is a ketone solvent, such as methyl isobutyl ketone, methyl ethyl ketone, or acetone. In still yet other embodiments, the solvent is an ethereal solvent, such as tetrahydrofuran, 2- methyltetrahydrofuran, or methyl tert- butyl ether. In other embodiments, the solvent is an ester solvent, such as ethyl acetate or isopropyl acetate. In still other embodiments, the solvent is a halogenated solvent, such as tetrachloroethylene, dichloroethane, chloroform, carbon

tetrachloride, or dichloromethane. In yet other embodiments, the solvent is a polar aprotic solvent, such as acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or N-methyl-2- pyrrolidinone. In still yet other embodiments, the solvent is an aromatic solvent, such as toluene, benzene, or xylene. In still other embodiments, the solvent is 2-methyltetrahydrofuran, tetrahydrofuran, methylene chloride, or ethyl acetate.

[00246] The coupling of the compound of formula IX, or a salt thereof, with the compound of formula X, or a salt thereof, may be conducted at any suitable temperature. In some

embodiments, the temperature is between about 0 °C and about 150 °C. In other embodiments, the temperature is between about 20 °C and about 100 °C. In still other embodiments, the temperature is between about 30 °C and about 80 °C.

[00247] General Procedure

[00248] To a vessel containing the compounds of formulae IX and X is charged 2- methyltetrahydrofuran and triethylamine. The reaction is heated and a 50% w/w solution of T3P in 2-methyltetrahydrofuran is added. The mixture is stirred and once the reaction is complete, the mixture is diluted with 2-methyltetrahydrofuran before quenching the reaction with water. The organic phase is isolated and washed with dilute aqueous sodium hydroxide solution and a brine solution. The solvent is distilled and diluted with cyclohexane so that the product can be crystallized from cyclohexane and isolated by filtration. The white to off-white crystalline product is dried with heat and under vacuum.

[00249] General Procedure (when an acid chloride or a chlorinating agent is used as the coupling agent):

[00250] To a vessel containing the compound of formula IX, 2-methyltetrahydrofuran and a small amount of dimethylformamide is added oxalyl chloride with heat. The mixture is stirred until the reaction to the acid chloride is complete. The reaction mixture is distilled to remove volatiles. To the solution of the acid chloride in 2-methyltetrahydrofuran is charged a solution of the compound of formula X and Hunig’s base in 2-methyltetrahydrofuran. The mixture is stirred until the reaction is complete. The reaction is quenched with water and an acid/base work up is performed to afford a solution of the compound of formula VIII in 2-methyltetrahydrofuran. The solvent is distilled and the reaction mixture is diluted with cyclohexane so that the product can be crystallized from cyclohexane and isolated by filtration. The white to off-white crystalline product is dried with heat and under vacuum.

[00251] Alternatively, to a vessel containing the compound of formula IX, toluene and a small amount of dimethylformamide is added oxalyl chloride with heat. The mixture is stirred until the reaction to the acid chloride is complete and a distillation is performed to remove volatiles. The solution of acid chloride in toluene is charged to a mixture of the compound of formula X and Hunig’s base in 2-methyltetrahydrofuran. The combined mixture is stirred until the reaction is complete. The reaction is quenched with water and an acid/base work up is performed to afford a solution of the compound of formula VIII in 2-methyltetrahydrofuran. The solvent is distilled and diluted with cyclohexane so that the product can be crystallized from cyclohexane and isolated by filtration. The white to off-white crystalline product is dried with heat and under vacuum.

[00252] General Procedure:

[00253] DPPC1 is added to a stirring mixture of the compound of formula IX, the compound of formula X, dimethylformamide, and triethylamine with cooling. The mixture is warmed and stirred until complete. The mixture is heated and water is charged to induce crystallization. Alternatively, the solution can be seeded with the compound of formula VIII after water addition. The slurry is diluted with water and cooled. The product is isolated by filtration, washed with a mixture of dimethylformamide and water, washed with pure water, and then dried with heat under vacuum.

[00254] Although the general procedures described above for preparing the compound of formula VIII from the compounds of formulae IX and X is sufficient to enable the skilled artisan to prepare the compound of formula VIII following a variety of procedures within the contours of the general procedures described above, the present application herewith provides a non limiting, exemplary procedure for preparing the compound of formula VIII from the compounds of formulae IX and X.

Specific Examples:

[00255] Specific Example:

[00256] To a vessel containing 2-fluoro-4-(trifluoromethyl)benzoic acid (1) (25.0 g, 116.5 mmol, 1.00 equivs), toluene (200 mL), and a small amount of dimethylformamide (0.17 g, 2.33 mmol, 0.2 mL, 0.02 equivs) was added oxalyl chloride (17.75 g, 139.8 mmol, 1.20 equivs) as a solution in toluene (50 mL). The mixture was heated at 40 - 50 °C and stirred until the reaction to the acid chloride was complete and a distillation was performed to remove volatiles. The concentrated solution of acid chloride (2) in toluene was charged to a mixture of 2- methoxypyridin-4-amine (3) (15.19 g, 122.4 mmol, 1.05 equivs) and Hunig’s base (33.13 g, 44.7 mL, 256.4 mmol, 2.20 equivs) in 2-methyltetrahydrofuran (200 mL). The combined mixture was stirred until the reaction was complete. The reaction was quenched with 1 N aqueous hydrochloric acid solution (40 mL) and the phases were split. The organic solution with the product was washed with 2N aqueous sodium hydroxide solution and again the phases were split. The resulting organic solution of the product 2-fluoro-N-(2-methoxypyridin-4-yl)-4- (trifluoromethyl)benzamide (4) in 2-methyltetrahydrofuran was distilled and diluted with cyclohexane so that the product could be crystallized from cyclohexane and isolated by filtration. The white to off-white crystalline product was dried with heat (45 - 55 °C) and under vacuum to afford 28.3 g (77.3% yield).

[00257] DPPC1 (37.0 mL, 0.179 moles, 1.05 equivs) was added to a stirring mixture of 2- nitro-4-(trifluoromethyl)benzoic acid (1) (40.0 g, 0.170 moles, 1.00 equivs), 2-methoxypyridin- 4-amine (3) (22.18 g, 0.179 moles, 1.05 equivs), dimethylformamide (240 mL), and

triethylamine (71.1 mL, 0.510 moles, 1.291 equivs) with cooling to maintain an internal temperature of 0 - 15 °C. The mixture was warmed to 20 - 30 °C and stirred until complete (typically 1 h). The mixture was heated to 45 - 55 °C and water (300 mL) was charged to induce crystallization while maintaining internal temperature. Alternatively, the solution can be seeded with N-(2-methoxypyridin-4-yl)-2-nitro-4-(trifluoromethyl)benzamide (0.30 g, 0.001 moles, 0.01 equivs, 0.75 wt%) after water addition. The slurry was diluted with water (100 mL) at 40 - 45 °C and then cooled to 18 - 25 °C. The crystalline product was isolated by filtration, washed with a mixture of dimethylformamide and water (1:2, 160 mL), washed with pure water (2 x 160 mL), and then dried with heat (45 - 50 °C) under vacuum to afford 52.25 g (90% yield) of N-(2- methoxypyridin-4-yl)-2-nitro-4-(trifluoromethyl)benzamide (4) .

[00258] Added 2-nitro-4-(trifluoromethyl)benzoic acid (5.0 g, 21.27 mmol, 1.0 eq) to a round bottom (RB) flask. Added 2-chloropyridin-4-amine (2a) (2.77 g, 22.3 mmol, 1.05 eq) to the RB flask. Added DMF (15 mL, 3 vol) to the RB flask. Added triethylamine (6.46 g, 9.0 mL, 63.8 mmol, 3.0 eq) to the RB flask. Stirred the mixture at ambient for 5 min. The reaction mixture was a clear yellow solution. Added 50% solution of T3P in DMF (20.3 g, 31.9 mmol, 1.50 eq) to the RB flask. The reaction mixture remained a clear yellow solution. Heated the reaction mixture to 42 °C and stirred for 1 h. Ion Pair Chromatography (IPC) showed mostly desired product so stirred the reaction mixture at 42 °C for a further 1 h. IPC showed some starting material remaining. Further addition of 50% solution of T3P in DMF (2.0 g, 3.19 mmol, 0.15 eq) to the RB flask was done and the reaction mixture stirred at 42 °C overnight leading to the desired product with a small amount of starting material. Water (32.5 mL, 6.5 vol) was added to the round bottom flask dropwise. Initial crystallization occurred, followed by substantial solid formation to give a thick suspension. The suspension was stirred at 42 °C for 15 min then further water (17.5 mL, 3.5 vol) was added. The mixture was cooled to room temperature before filtering the solid. The solid was washed with water (2 x 20 mL). The product on filter paper was left under vacuum for 15 min then dried in a vacuum oven at 50 °C overnight, yielding 5.57 g of N-(2-chloropyridin-4-yl)-2-nitro-4-(trifluoromethyl)benzamide (3a) at 77% yield. Step B

[00259] In step B, a compound of formula VIII, or a salt thereof, is reacted with a compound of formula VII, or a salt thereof, to afford a compound of formula XI, or a salt thereof. The reaction of the compound of formula VII, or a salt thereof, with the compound of formula VIII, or a salt thereof, may be conducted in the presence of a base. In some embodiments, the conjugate acid of the base has a pKa that is higher than the pKa of the compound of formula VIII. In other embodiments, the base is potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium ie/t-butoxide, sodium ie/t-butoxide, 2-ferf-butyl- 1,1 ,3,3-tetramethylguanidine, l,i,3,3-tetramethylgiiamdine (TMG), 7 -me thy 1-1, 5,7- triazabicyclo[4.4.0]dec-5-ene (MTBD) or l,8-diazabicyclo[5.4.0]undec-7-ene. In still other embodiments, the base is potassium carbonate.

[00260] The reaction of the compound of formula VII, or a salt thereof, with the compound of formula VIII, or a salt thereof, may be conducted in any suitable solvent. In some embodiments, the solvent is N-methyl-2-pyrrolidinone, dimethyl acetamide, diethyleneglycol dimethylether, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, isopropyl acetate, methyl isobutyl ketone, 2-methyltetrahydrofuran, tetrahydrofuran, dichloromethane, chloroform, or tetrachloroethylene. In other embodiments, the solvent is 2-methyltetrahydrofuran or tetrahydrofuran. In still other embodiments, the solvent is 2-methyltetrahydrofuran. In yet other embodiments, the solvent is a ketone solvent, such as methyl isobutyl ketone, methyl ethyl ketone, or acetone. In still yet other embodiments, the solvent is an ethereal solvent, such as tetrahydrofuran, 2-methyltetrahydrofuran, or methyl tert- butyl ether. In other embodiments, the solvent is an ester solvent, such as ethyl acetate or isopropyl acetate. In still other embodiments, the solvent is a halogenated solvent, such as tetrachloroethylene, dichloroethane, chloroform, carbon tetrachloride, or dichloromethane. In yet other embodiments, the solvent is a polar aprotic solvent, such as acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or N-methyl- 2-pyrrolidinone. In still yet other embodiments, the solvent is an aromatic solvent, such as toluene, benzene, or xylene. In other embodiments, the solvent is N-methyl-2-pyrrolidinone.

[00261] In some embodiments, the base is potassium carbonate, and the solvent is N-methyl- 2-pyrrolidinone. In other embodiments, the base is 2-/eri-butyl- l,l,3,3-tetramethylguanidme, and the solvent is acetonitrile. In still other embodiments, the base is 2- er/-buty!-l, 1,3,3- tetramethylguanidine, and the solvent is methyl isobutyl ketone. In yet other embodiments, the base is potassium carbonate, and the solvent is N,N-dimethy!formamide. In still yet other embodiments, the base is potassium carbonate, and the solvent is dimethyl sulfoxide.

[00262] The reaction of the compound of formula VII, or a salt thereof, with the compound of formula VIII, or a salt thereof, may be conducted at any suitable temperature. In some embodiments, the compound of formula VII is reacted with the compound of formula VIII at between about 50 °C and about 110 °C. In other embodiments, the compound of formula VII is reacted with the compound of formula VIII at between about 70 °C and about 100 °C. In a further embodiment, the compound of formula VII is reacted with the compound of formula VIII at between about 80 °C and about 90 °C.

[00263] The reaction of the compound of formula VII, or a salt thereof, with the compound of formula VIII, or a salt thereof, may be conducted at any suitable pressure. For example, the reaction may be conducted at elevated pressure when the temperature exceeds the boiling point of the solvent in which the reaction is conducted. In some embodiments, the pressure is no more than about 100 bars. In other embodiments, the pressure is between about 1 bar and about 100 bars. In still other embodiments, the temperature is between about 10 bars and about 20 bars.

[00264] General Procedure:

[00265] A mixture of the compounds of formulae VII and VIII, in a suitable solvent (such as dimethylformamide), and a suitable base (such as potassium carbonate) is stirred and heated until the reaction is complete. Water is charged and the mixture is cooled. The product is isolated by filtration, washed with a mixture of dimethylformamide and water, washed with pure water, and then dried with heat under vacuum. [00266] Alternatively, a mixture of the compounds of formulae VII and VIII, in a suitable solvent (such as dimethylformamide), and a suitable base (such as potassium carbonate) is stirred and heated until the reaction is complete. The mixture is then cooled and filtered to remove inorganics. The filtered solution is heated and diluted with water. The resulting slurry is cooled and the product isolated by filtration. The white to off-white crystalline product is dried with heat and under vacuum.

[00267] Further, a mixture of the compounds of formulae VII and VIII, dimethylformamide, and potassium carbonate is stirred and heated until the reaction is complete. Water is charged and the mixture is cooled. The product is isolated by filtration, washed with a mixture of dimethylformamide and water, washed with pure water, and then dried with heat under vacuum.

[00268] Although the general procedures described above for preparing the compound of formula XI from the compounds of formulae VII and VIII is sufficient to enable the skilled artisan to prepare the compound of formula XI following a variety of procedures within the contours of the general procedures described above, the present application herewith provides a non-limiting, exemplary procedure for preparing the compound of formula XI from the compounds of formulae VII and VIII.

[00269] Specific Example

[00270] A mixture of N-(2-methoxypyridin-4-yl)-2-nitro-4-(trifluoromethyl)benzamide (4) (949.8 g, 2.783 moles, 1.00 equivs), 4-fluoro-2-methylphenol (5) (375.63 g, 2.978 moles, 1.07 equivs), dimethylformamide (6269 mL), and potassium carbonate (1154.04 g, 8.350 moles, 3.00 equivs) was stirred and heated to 95 - 105 °C until the reaction was complete (typically 8 h). Water (7598 mL) was charged and the mixture was cooled to 20 - 30 °C. The crystalline white to off-white product (8) was isolated by filtration, washed with a mixture of dimethylformamide and water (1:2 ratio, 2849 mL), washed with pure water (3 x 2849 mL), and then dried with heat (45 - 50 °C) under vacuum to afford 1053 g (85% yield) of 2-(4-fluoro-2-methylphenoxy)-N-(2- methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide (8).

[00271]

[00272] Added N-(2-chloropyridin-4-yl)-2-nitro-4-(trifluoromethyl)benzamide (3a) (2.0 g, 5.78 mmol, 1.0 eq) to a vial. Added 4-fluoro-2-methylphenol (5) (0.803 g, 6.36 mmol, 1.10 eq) to the vial. Added potassium carbonate (2.42 g, 17.36 mmol, 3.0 eq) to the vial. Added DMF (14 mL, 7 vol) to the vial then heated the reaction mixture to 100 °C for 4 h. The reaction mixture turned dark brown. IPC showed 79.9% conversion to desired product. Stirred the reaction mixture at 100 °C overnight which led to complete conversion to desired product. The mixture was cooled to 75 °C, water (20 mL, 10 vol) was added dropwise while maintaining the temperature between 70-75 °C. The mixture was then cooled slowly to 40 °C over 30 min.

Solid precipitation was observed around 48 °C. Once the suspension reached 40 °C, the mixture was heated back to 60 °C and stirred for 2 h before cooling the suspension down to 30 °C. The mixture was stirred for 15 min before filtering it under vacuum. The solid was washed with water (3 x 4 vol), the wet cake dried under vacuum for 10 min and placed it in vacuum oven at 50 °C overnight. N-(2-Chloropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4- (trifluoromethyl)benzamide (6a) was obtained as a light brown solid (1.94 g, 79%). Step C:

[00273] In step C, the 2-methoxy pyridine of formula XI, or a salt thereof, is converted to its corresponding lactam of formula V, or a salt thereof. Where R is a leaving group, Step C may include a step in which R is first replaced by OPG (as defined above) before converting OPG to OH such that the tautomer of the pyridone of formula V is obtained. Where R is a leaving group, Step C may include a step in which R is replaced by OH such that the tautomer of the pyridone of formula V is obtained. Where R is OPG, the compound is deprotected to obtain the pyridone of formula V.

[00274] Where R is OPG (where the compound of formula XI is a protected alcohol), the conditions for deprotecting the compound of formula XI, or a salt thereof, to afford the compound of formula V, or a salt thereof, are generally well known in the art. See, e.g., P.G.M. Wuts et al., Greene’s Protective Groups in Organic Synthesis (4th ed. 2006). For example, where R is OMe, the deprotection (or dealkylation) of the compound of formula XI, or a salt thereof, may be conducted under any conditions known in the art to be suitable for removing a methyl protecting group from an alcohol, i.e., for converting a methoxy group into a hydroxyl group. In some embodiments, the deprotection of the compound of formula XI, or a salt thereof, is accomplished by reacting the compound of formula XI, or a salt thereof, with trimethylsilyl iodide, trimethylsilyl chloride, sodium iodide, or an acid. In other embodiments, the

deprotection of the compound of formula XI, or a salt thereof, is accomplished by reacting the compound of formula XI, or a salt thereof, with an acid, the acid is hydrobromic acid, hydrogen bromide in acetic acid, or hydrochloric acid. In still other embodiments, the acid is hydrogen bromide in acetic acid (e.g., 33% HBr in acetic acid). In still other embodiments, the acid is pTsOH, which may be used in combination with LiCl or LiBr. In yet other embodiments, between about 2.0 and 3.0 equivalents of hydrogen bromide are used relative to the compound of formula V, or a salt thereof. In still yet other embodiments, the acid is hydrochloric acid.

[00275] The deprotection of the compound of formula XI, or a salt thereof, may be conducted in variety of solvents. In some embodiments, the solvent is acetic acid.

[00276] The deprotection of the compound of formula XI, or a salt thereof, may be conducted at any suitable temperature. In some embodiments, the temperature is between about 0 °C and about 200 °C. In other embodiments, the temperature is between about 40 °C and about 120 °C. In still other embodiments, the temperature is between about 60 °C and about 100 °C. In yet other embodiments, the temperature is between about 70 °C and about 90 °C.

[00277] General Procedure

[00278] A mixture of the compound of formula XI, hydrobromic acid, and acetic acid is stirred and heated until the reaction is complete. The mixture is cooled and water is added to induce crystallization. The mixture is further cooled and diluted with water. The product is isolated by filtration, washed with water, and dried with heat under vacuum.

[00279] Although the general procedures described above for preparing the compound of formula V from the compound of formula XI is sufficient to enable the skilled artisan to prepare the compound of formula V following a variety of procedures within the contours of the general procedures described above, the present application herewith provides a non-limiting, exemplary procedure for preparing the compound of formula V from the compound of formula XI.

[00280] Specific Example:

[00281 ] A mixture of 2-(4-fluoro-2-methylphenoxy)-N-(2-methoxypyridin-4-yl)-4- (trifluoromethyl)benzamide (8) (924.4 g, 2.199 moles, 1.00 equivs), glacial acetic acid (4622 mL), and 33 wt% hydrogen bromide in acetic acid (444.82 g, 5.496 moles, 2.50 equivs) was stirred and heated to 80 - 90 °C until the reaction was complete (approximately 16 h). The mixture was cooled to 50 - 60 °C and water (5546 mL) was added to induce crystallization. The mixture was further cooled to 20 - 25 °C and diluted with more water (1849 mL). The crystalline white to off-white product was isolated by filtration, washed with water (2 x 3696 mL), and dried with heat (45 - 50 °C) under vacuum to afford 804.2 g (90% yield) of 2-(4- fluoro-2-methylphenoxy)-N-(2-oxo- 1 ,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (9).

[00282] Mixed N-(2-chloropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4- (trifluoromethyl)benzamide (8a) (500 mg, 1.45 mol, 1.0 eq), ammonium acetate (2.22 g, 28.8 mmol, 20 eq), and formic acid (10 mL) in a vial. Heated the reaction mixture to 95 °C and stirred for 4 h. IPC showed mostly starting material and a very small amount of a product, so the mixture was stirred at 95 °C overnight. IPC showed starting material as the major component with 23% conversion to a product.

[00283] The reaction was repeated using a high temperature / high pressure flow reactor in which formic acid was used as the system solvent. The solvent (formic acid) was run through the reactor at 1 mL/min and the pressure was raised (-180 bar). The temperature was raised to 250 °C and the system run until the temperature and pressure stabilized. After running approximately 5 mL of solution at 1 mL/min through the flow reactor at 250 °C with -4 min residence time, three fractions of -3 mL each were collected from 6 min onwards. HPLC showed 88% conversion to 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4- (trifluoromethyl)benzamide (9) with 12% starting material remaining. [00284] Process for making 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-l,2-dihydropyridin-4- y 1) -4 -(trifluoromethy l)benzamide (9)

[00285] Step 1: Preparation of compound (4)

[00286] To a solution of compound (1) (5 g, 21.26 mmol, 1.00 equiv.), compound (3) (2.77 g, 22.32 mmol, 1.05 equiv.) and triethylamine (8.96 mL, 63.79 mmol, 3.0 equiv.) in DMF (30 mL, 6.0 vol) at 0-5 °C, was added diphenyl phosphoryl chloride (4.84 mL, 23.39 mmol, 1.1 equiv.) dropwise to the reaction while maintaining internal temperature below 15°C. The reaction mixture was allowed to warm to 22 °C (± 5 °C) and left to stir for 1 h.

[00287] The reaction mixture was then heated to an internal temperature of 50 °C (± 5 °C) and water (37.5 mL, 7.50 vol) added slowly while maintaining the internal temperature between 45- 55°C. The resulting suspension was cooled to an internal temperature of 40-45 °C and stirred for 30 minutes before slowly adding more water (12.5 mL, 2.5 vol). The suspension was left cool to 18-25 °C and stirred overnight (17 h) then filtered under vacuum to afford compound (4). The product was left under vacuum for 10 minutes and the intermediate was used immediately in the next step without further processing.

[00288] Step 2: Conversion of compound (4) to compound (8)

[00289] Intermediate compound (4) from Step 1 (1.0 equiv.), compound (5) (2.72 g, 21.62 mmol, 1.07 equiv.), and potassium carbonate (8.38 g, 60.63 mmol, 3.0 equiv.) were dissolved in DMF (45.52 mL, 6.6 vol). The reaction mixture was then heated to 100 °C (± 5 °C) and stirred for 4 h.

[00290] The reaction mixture was cooled to an internal temperature of 80 °C (± 5 °C) then water (27.59 mL, 4.0 vol) added dropwise. The mixture was cooled to 60-65°C, seeds added, then stirred at 60-65°C for 30 minutes. Water (10.35 mL, 1.5 vol) was added slowly to the suspension, then allowed to cool to an internal temperature of 18-25 °C and stirred overnight (17h). The product was filtered under vacuum then washed with water (27.59 mL, 4.0 vol) and left under vacuum for 10 minutes to afford compound (8). The intermediate (compound (8)) was used immediately in the next step without further processing.

[00291] Step 3: Conversion of compound (8) to compound (9)

[00292] To a solution of intermediate compound (8) from Step 2 (1.0 equiv.) in glacial acetic acid (40.36 mL, 5.0 vol) was added hydrogen bromide (33 wt% in acetic acid, 8.69 mL, 2.5 equiv.) and the reaction mixture heated to 85 °C (± 5 °C) for 8 hours.

[00293] The reaction mixture was cooled to an internal temperature of 75 °C (± 5 °C) before slowly adding water (8.07 mL, 1.0 vol) while maintaining the temperature between 75 °C (± 5 °C). The solution was then cooled to 65 °C (± 5 °C) and water (12.11 mL, 1.5 vol) was slowly added maintaining the temperature at 65 °C (± 5 °C). The mixture was stirred for lh then water (12.11 mL, 1.5 vol) was added maintaining the temperature at 65°C (± 5 °C). The suspension was cooled to 45 °C (± 5 °C) and further water (32.28 mL, 4.0 vol) was slowly added

maintaining the temperature at 45 °C (± 5 °C). The suspension was left to cool to an internal temperature of 18-25 °C and stirred for 2h. The suspension was filtered under vacuum, washed with water (2 x 4.0 vol, 32.28 mL), then dried under vacuum at 50 °C for 17 hours to afford compound (9) (2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-lH-pyridin-4-yl)-4- (trifluoromethyl)benzamide)) (5.95 g, 68.9%).

[00294] ¾ NMR (400 MHz, Chloroform-d) d 9.74 (s, 1H), 8.45 - 8.38 (m, 1H), 7.46 (dd, J = 8.6, 1.6 Hz, 1H), 7.39 - 7.33 (m, 1H), 7.10 (dd, J = 8.7, 2.6 Hz, 1H), 7.07 - 6.96 (m, 2H), 6.86 (d, J = 1.6 Hz, 1H), 6.83 - 6.76 (m, 2H), 2.24 (s, 3H) ppm.

[00295] Where R is a leaving group (e.g., a halogen group), Step D includes a step in which R is first replaced by OPG (as defined above) before converting OPG to OH to obtain the tautomer of the pyridone of formula VI.

[00296] Where R is OPG (such that the compound of formula VIII is a protected alcohol), conditions for deprotecting the compound of formula VIII, or a salt thereof, to afford the compound of formula VI, or a salt thereof, are generally well known in the art. See, e.g., P.G.M. Wuts et ah, Greene’s Protective Groups in Organic Synthesis (4th ed. 2006). For example, the deprotection (or dealkylation) of the compound of formula VIII, or a salt thereof, may be conducted under any conditions known in the art to be suitable for removing a methyl protecting group from an alcohol, i.e., for converting a methoxy group into a hydroxyl group. In some embodiments, the deprotection of the compound of formula VIII, or a salt thereof, is

accomplished by reacting the compound of formula VIII, or a salt thereof, with trimethylsilyl iodide, trimethylsilyl chloride, sodium iodide, or an acid. In other embodiments, where the deprotection of the compound of formula VIII, or a salt thereof, is accomplished by reacting the compound of formula VIII, or a salt thereof, with an acid, the acid is hydrobromic acid, hydrogen bromide in acetic acid, or hydrochloric acid. In still other embodiments, the acid is hydrogen bromide in acetic acid (e.g., 33% HBr in acetic acid). In yet other embodiments, between about 2.0 and about 3.0 equivalents of hydrogen bromide are used relative to the compound of formula IV, or a salt thereof. In still yet other embodiments, the acid is hydrochloric acid.

[00297] The deprotection of the compound of formula VIII, or a salt thereof, may be conducted in variety of solvents. In some embodiments, the solvent is acetic acid.

[00298] The deprotection of the compound of formula VIII, or a salt thereof, may be conducted at any suitable temperature. In some embodiments, the temperature is between about 0 °C and about 200 °C. In other embodiments, the temperature is between about 40 °C and about 120 °C. In still other embodiments, the temperature is between about 60 °C and about 100 °C. In yet other embodiments, the temperature is between about 70 °C and about 90 °C.

[00299] General Procedure

[00300] To a vessel containing an agitated and heated mixture of the compound of formula VIII and acetic acid is added a solution of hydrobromic acid in acetic acid. The mixture is stirred and heated until the reaction is complete. The mixture is cooled and toluene is added. The mixture is further cooled and the product isolated by filtration. The white to off-white crystalline product is dried with heat and under vacuum.

[00301 ] Although the general procedures described above for preparing the compound of formula VI from the compound of formula VIII is sufficient to enable the skilled artisan to prepare the compound of formula VI following a variety of procedures within the contours of the general procedures described above, the present application herewith provides a non-limiting, exemplary procedure for preparing the compound of formula VI from the compound of formula VIII. [00302] Specific Example:

[00303] To a vessel containing an agitated and heated (50 - 60 °C) mixture of 2-fluoro-N-(2- methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide (10) (1.0 kg, 3.199 moles) and acetic acid (6.7 L) was added a solution of hydrogen bromide in acetic acid (764 g in 1.5 L). The mixture was stirred and heated at 80 - 90 °C until the reaction was complete (approximately 18 h). The mixture was cooled to 45 - 55 °C and toluene (3.0 L) was added. The mixture was further cooled to 18 - 25 °C and the product isolated by filtration and washed with toluene (3 L). The white to off-white crystalline hydrobromide salt of the product was dried with heat (35 - 45 °C) and under vacuum to afford 1160 g (96% yield) of 2-fluoro-N-(2-oxo-l,2-dihydropyridin-4-yl)- 4-(trifluoromethyl)benzamide hydrobromide (ll.HBr).

[00304] N-(2-chloropyridin-4-yl)-2-fluoro-4-(trifluoromethyl)benzamide (10a) can also be converted to the corresponding pyridone (11) using acetic acid and ammonium acetate as described above for the preparation of N-(2-chloropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)- 4-(trifluoromethyl)benzamide (8a). Step E

[00305] In step E, a compound of formula VI, or a salt thereof, is reacted with a compound of formula VII, or a salt thereof, to afford a compound of formula V, or a salt thereof. The reaction of the compound of formula VI, or a salt thereof, with the compound of formula VII, or a salt thereof, may be conducted in the presence of a base. In some embodiments, the conjugate acid of the base has a pKa that is higher than the pKa of the compound of formula VIII. In other embodiments, the base is potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium phosphate, potassium ie/ -butoxide, sodium ieri-butoxide, 2-feri-butyl- 1,1 ,3,3-tetramethylguanidine, or l,8-diazabicyclo[5.4.0]undec-7-ene. In still other embodiments, the base is potassium carbonate.

[00306] The reaction of the compound of formula VI, or a salt thereof, with the compound of formula VII, or a salt thereof, may be conducted in any suitable solvent. In some embodiments, the solvent is N-methyl-2-pyrrolidinone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, isopropyl acetate, methyl isobutyl ketone, 2-methyltetrahydrofuran, tetrahydrofuran, dichloromethane, chloroform, or tetrachloroethylene. In other embodiments, the solvent is 2- methyltetrahydrofuran or tetrahydrofuran. In still other embodiments, the solvent is 2- methyltetrahydrofuran. In yet other embodiments, the solvent is a ketone solvent, such as methyl isobutyl ketone, methyl ethyl ketone, or acetone. In still yet other embodiments, the solvent is an ethereal solvent, such as tetrahydrofuran, 2-methyltetrahydrofuran, or methyl tert- butyl ether. In other embodiments, the solvent is an ester solvent, such as ethyl acetate or isopropyl acetate. In still other embodiments, the solvent is a halogenated solvent, such as tetrachloroethylene, dichloroethane, chloroform, carbon tetrachloride, or dichloromethane. In yet other

embodiments, the solvent is a polar aprotic solvent, such as acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or N-methyl-2-pyrrolidinone. In still yet other embodiments, the solvent is an aromatic solvent, such as toluene, benzene, or xylene. In other embodiments, the solvent is N-methyl-2-pyrrolidinone.

[00307] In some embodiments, the base is potassium carbonate, and the solvent is N-methyl- 2-pyrrolidinone. In other embodiments, the base is 2-/eri-butyl- 1,1,3, 3-tetramethylguanidine, and the solvent is acetonitrile. In still other embodiments, the base is 2- er/-buty!-l, 1,3,3- tetramethylguanidine, and the solvent is methyl isobutyl ketone. In yet other embodiments, the base is potassium carbonate, and the solvent is N,N-dimethy!formamide. In still yet other embodiments, the base is potassium carbonate, and the solvent is dimethyl sulfoxide.

[00308] The reaction of the compound of formula VI, or a salt thereof, with the compound of formula VII, or a salt thereof, may be conducted at any suitable temperature. In some

embodiments, the compound of formula VI is reacted with the compound of formula VII at between 50 °C and about 110 °C. In other embodiments, the compound of formula VI is reacted with the compound of formula VII at between about 70 °C and about 100 °C. In a further embodiment, the compound of formula VI is reacted with the compound of formula VII at between about 80 °C and about 90 °C.

[00309] General Procedure:

[00310] A mixture of the compound of formula VI, or a salt thereof, and the compound of formula VII, or a salt thereof, a suitable base, and a suitable solvent is heated and stirred under nitrogen until the reaction is complete. Water is added to the reaction mixture and the phases are separated. The organic phase is then diluted with water and the mixture is cooled to allow isolation of the product by filtration. The white to off-white crystalline product is dried with heat and under vacuum.

[00311 ] Alternatively, a mixture of the compound of formula VI, or a salt thereof, and the compound of formula VII, or a salt thereof, a suitable base, and a suitable solvent is heated and stirred under nitrogen until the reaction is complete. The mixture is then cooled and filtered to remove inorganics. The filtered solution is heated and diluted with water. The resulting slurry is cooled and the product isolated by filtration. The white to off-white crystalline product is dried with heat and under vacuum. [00312] Although the general procedures described above for preparing the compound of formula V from the compounds of formulae VI and VII is sufficient to enable the skilled artisan to prepare the compound of formula V following a variety of procedures within the contours of the general procedures described above, the present application herewith provides a non-limiting, exemplary procedure for preparing the compound of formula V from the compounds of formulae VI and VII.

[00313] Specific Example:

[00314] A mixture of 4-fluoro-2-methylphenol (5) (364 g, 2.89 moles, 1.10 equivs), 2-fluoro- N-(2-oxo-l,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (11) hydrobromide (1000 g, 2.62 moles, 1.00 equivs), -325 mesh potassium carbonate (1088 g, 7.87 moles, 3.00 equivs), and dimethylformamide (5000 mL) was heated at 75 - 90 °C and stirred under nitrogen until the reaction was complete (approximately 5 h). The mixture was then cooled to 15 - 25 °C and filtered to remove inorganics. The reactor and solids on the filter were washed with

dimethylformamide (1000 mL). The filtered solution was combined with the wash and was heated to 80 - 90 °C and diluted with water (6000 mL). The resulting slurry was cooled to 15 - 30 °C and the product isolated by filtration. The white to off-white crystalline product was dried with heat (60 - 65 °C) and under vacuum to afford 906 g (85.0% yield) of 2-(4-fluoro-2- methylphenoxy)-N-(2-oxo- 1 ,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (9).

[00315] Compound (9) was also prepared in accordance with the following procedure.

[00316] K2CO3 (1.1 kg, 3 equivs) and compound (5) (364 g, 1.1 equivs) were charged into a clean and inert reactor. DMF (2.5 L) was added to the reactor. The jacket temperature of reactor was set to 20 - 30 °C and the mixture was stirred. In a separate vessel, a solution of compound (11) (1.00 kg, 1.00 equivs) in DMF (2.5 L) was prepared. The DMF solution of compound (11) was added to the reactor at a rate that suitably controls gas evolution and maintains an internal temperature not more than (NMT) 35 °C. The content of the tank was heated to 80 - 85 °C. Reaction was considered complete with < 1% compound (11) remaining.

[00317] The mixture was cooled to 25 °C, filtered off the inorganic salts from the reaction mixture, the mother liquor was transferred to a crystallizer. The reactor and the solids on the filter were washed with DMF (1.00 L) and added the filtrate to the crystallizer. The content of the crystallizer was heated to 80 - 85 °C before adding water (2.9 L) to the reactor, maintaining temperature from 80 - 85 °C. The reactor mixture was cooled to 72.5 - 77.5 °C and stirred for 1 h before charging additional water (1.2 L) over 5 h at 72.5 - 77.5 °C. The mixture was cooled over 8 h to 20 - 25 °C, filtered, and washed the cake with water (2 L). The wet cake was dried at 60 - 65 °C in nitrogen-purged vacuum oven to afford compound (9).

Step F

[00318] In Step F, a compound of formula V is converted to a compound of formula IV by reaction of the compound of formula V with formaldehyde.

[00319] General Procedure:

[00320] A mixture of the compound of formula V, tetrahydrofuran, and formaldehyde is stirred and heated until the reaction is complete. The mixture is cooled and water is added. The resulting slurry is filtered and the solids are washed with water. The product, a crystalline white to off-white solid is dried with heat under vacuum.

[00321 ] Although the general procedures described above for preparing the compound of formula IV from the compound of formula V is sufficient to enable the skilled artisan to prepare the compound of formula IV following a variety of procedures within the contours of the general procedures described above, the present application herewith provides a non-limiting, exemplary procedure for preparing the compound of formula IV from the compound of formula V.

[00322] Specific Example

[00323] A mixture of 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4-

(trifluoromethyl)benzamide (9) (50 g, 123.05 mmol, 1.00 equivs) and tetrahydrofuran (250 mL) was stirred and heated at 55 - 65 °C to obtain a solution. To the mixture was added 37 wt% aqueous formalin solution (29.96 g, 369.15 mmol, 3.00 equivs, 27.48 mL - reagent contains 10-

15% methanol as a stabilizer). The mixture was stirred and heated at 55 - 65 °C until the reaction was complete (approximately 1 h). The resulting slurry was cooled to 15 - 30 °C and diluted with water (100 mL). The slurry was filtered to obtain the product as a white to off-white crystalline solid that was dried with heat (35 - 45 °C) and under vacuum to afford 41.5 g (77.3% yield) of 2-(4-fluoro-2-methylphenoxy)-N-(l-(hydroxymethyl)-2-oxo-l,2-dihydropyridin-4-yl)-

4-(trifluoromethyl)benzamide (13). It was found that seeding (1 wt%) with crystalline

Compound (13) after reaction completion increases the yield of Compound (13).

[00324] Compound (13) was also prepared in accordance with the following procedure.

[00325] Compound (9) (15 g, 36.91 mmol, 1.00 equiv.) and THF (75 mL) were charged to a

100 mL bottom drain jacketed flask reactor with a mechanical stirrer, a condenser, a

thermocouple, and N2 bubbler. The mixture was heated to 55 - 65 °C to obtain a solution.

Formalin (8.99 g, 8.25 mL, 110.74 mmol, 3.00 equiv.) was charged at a rate of 0.5 equivs per hour. The reaction mixture was stirred at 55 - 65 °C for 1 h until reaction is complete (reaction is considered complete with < 5 mol% compound (9) remaining). The resulting slurry was stirred for 1 h before cooling it to 0 - 25 °C over 6 h. Water (75.0 mL) was charged over 6 h and the resulting slurry was stirred at 0 - 25 °C for 2 h, filtered, and washed the solids on the filter with water (2x30 mL) to afford compound (13). It was found that seeding (1 wt%) with crystalline Compound (13) after reaction completion increases the yield of Compound (13).

[00326] The following example provides a large scale synthesis of compound (13) from compound (9)

[00327] Compound (9) (1.850 kg) and THF (9.25 L) were charged to a 20 L bottom drain jacketed reactor with a mechanical stirrer, a condenser, a thermocouple, and N2 bubbler. The mixture was heated to 55 - 65 °C to obtain a solution. A 37 wt% aqueous formalin solution (68.35 g) was charged over 1 h. The reaction mixture was seeded with 1 wt% crystalline Compound (13) and a second addition of 37 wt% aqueous formalin solution (205.06 g) was charged at a rate of 68.35 g per hour. The reaction mixture was stirred at 55 - 65 °C for 1 h until reaction is complete (reaction is considered complete with < 5 mol% compound (9) remaining). Water (9.25 L) was charged over 5 h and the mixture was then cooled to 15 - 25 °C over 2 h.

The mixture was stirred at 0 - 25 °C for at least 2 h before isolating the product by filtration.

The reactor and the solids on the filter were washed with water (7.4 L). The product was dried with heat at 40 - 55 °C and under vacuum to afford 1.85 kg (93.3% yield) of Compound (13) as a crystalline solid.

[00328] Continuous preparation of compound (13)

[00329] The method of preparing compound (13) as described above in detail can be carried out as a batch process or as a continuous process. The skilled artisan could adapt these processes to make compound (13) in continuous process in which the starting point is obtaining or preparing compound (1), compound (3), compound (4), compound (5), compound (8), compound (9), or compound (11). In one aspect, the reaction steps for converting compound (1), compound (3), compound (4), compound (5), compound (8), compound (9), or compound (11) to compound (13) as described above are performed in reaction vessels customary for such reactions, the reactions being carried out in a continuous, semi-continuous or batchwise manner.

[00330] In another aspect, the continuous process for producing compound (13) comprises: 1) preparing compound (4) in a first stage; 2) converting compound (4) to compound (8) in a second stage; 3) converting compound (8) to compound (9) in a third stage; and 4) converting compound (9) to compound (13) in a fourth stage. In another aspect, the continuous process for producing compound (13) comprises: 1) preparing compound (9) from compound (5) and compound (11) in a first stage; and 2) converting compound (9) to compound (13) in a second stage.

[00331] In another aspect, the continuous process for producing compound (13) comprises: 1) converting compound (4) to compound (8) in a first stage; 2) converting compound (8) to compound (9) in a second stage; and 3) converting compound (9) to compound (13) in a third stage. In another aspect, the continuous process for producing compound (13) comprises: 1) converting compound (8) to compound (9) in a first stage; and 2) converting compound (9) to compound (13) in a second stage.

Step G

[00332] The compound of formula IV may be converted to the compound of formula III by reacting the compound of formula IV with a halogenating agent. In one embodiment, the halogenating agent is a chlorinating agent. In such an embodiment, the compound of formula III is a compound of formula Ilia:

Ilia. [00333] Any chlorinating agent suitable for chlorinating the compound of formula IV may be used. The reaction between the compound of formula IV and the chlorinating agent may be conducted in the presence of non-nucleophilic base such as triethylamine, diisopropyl ethylamine, N-methylmorpholine, l,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, butylamine, or l,5-diazabicyclo(4.3.0)non-5-ene, or a mixture thereof. In some embodiments, the reaction between the compound of formula IV and the chlorinating agent is conducted at a temperature of no more than about 60 °C.

[00334] General Procedure:

[00335] A mixture of the compound of formula IV, toluene, and thionyl chloride is stirred and heated until the reaction is complete. The mixture is distilled to remove volatiles. The resulting concentrated mixture of the product in toluene is diluted with ethyl acetate to be used in the next step.

[00336] Alternatively, a mixture of the compound of formula IV, ethyl acetate, and methane sulfonyl chloride is stirred and cooled. To the mixture is added Hunig’s base and the mixture is stirred until the reaction is complete and the mixture can be used directly in the next step.

[00337] In a further general procedure, a mixture of the compound of formula IV, 2- methyltetrahydrofuran, and methanesulfonyl chloride is stirred and cooled. To the mixture is added Hunig’s base and the mixture is stirred until the reaction is complete and the mixture can be used in the next step.

[00338] In a yet a further procedure, a mixture of the compound of formula IV, 2- methyltetrahydrofuran, and phosphoms(V) oxychloride is stirred and cooled. The mixture is stirred until the reaction is complete.

[00339] Although the general procedures described above for preparing the compound of formula III from the compound of formula IV is sufficient to enable the skilled artisan to prepare the compound of formula III following a variety of procedures within the contours of the general procedures described above, the present application herewith provides a non-limiting, exemplary procedure for preparing the compound of formula III from the compound of formula IV. [00340] Specific Example

[00341] A mixture of 2-(4-fluoro-2-methylphenoxy)-N-(l-(hydroxymethyl)-2-oxo-l,2- dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (13) (20 g, 45.83 mmol, 1.00 equivs) and toluene (200 mL) was stirred and heated at 35 - 45 °C. To the mixture was added thionyl chloride (7.63 g, 64.17 mmol, 1.40 equivs, 4.68 mL) and the mixture was stirred and heated at 35 - 45 °C until the reaction was complete (approximately 1 h). The resulting solution was concentrated by distillation and twice chased with toluene (100 mL). The final concentrated mixture of the product in toluene was diluted with ethyl acetate (200 mL). A solvent swap was performed to obtain the product as a solution in ethyl acetate (200 mL). The mixture was washed with water (104 mL), again with water (40 mL), and finally a mixture of saturated aqueous sodium bicarbonate (5 mL) with 7 wt% brine (35 mL). The organic phase was concentrated 50% by distillation and then diluted as required with ethyl acetate to obtain a total volume of 240 mL. The mixture was heated to 75 °C, then the mixture was slowly cooled 30 °C over 3 h. The resulting slurry was diluted with n-heptane (360 mL) to obtain a 1:1.5 % ratio of ethyl acetate to n-heptane. The mixture was cooled to 20 °C and the solids isolated by filtration to give N-( 1 -(chloromethyl)-2-oxo- 1 ,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4- (trifluoromethyl)benzamide (14) as a white to off-white crystalline solid (75% yield), which was dried with heat at 40 °C and under vacuum.

[00342] The following example provides a large scale synthesis of compound (14) from compound (13). [00343] A mixture of 2-(4-fluoro-2-methylphenoxy)-N-(l-(hydroxymethyl)-2-oxo-l,2- dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (13) (1.85 kg) and ethyl acetate (1.85 L) was stirred and cooled at 0 - 5 °C in a 20 L bottom drain jacketed reactor with a mechanical stirrer, a condenser, a thermocouple, and N2 bubbler. Methane sulfonyl chloride (631 g) was added to the stirring mixture over at least 5 minutes. Diisopropylethylamine (822 g) was then added over about 15 minutes while keeping the stirring reaction mixture at 0 - 5 °C. The mixture was stirred for at least 4 h and until the reaction was determined complete by HPLC (i.e., Compound (9) was observed at less than 5% by HPLC). Water (5.55 L) was then charged and the reaction mixture was warmed to 15 - 25 °C. The layers were separated, and the organic phase was twice washed with an aqueous sodium chloride solution (14wt%, 2 x 2.46 L). To the stirring organic phase was added n-heptane (24.1 L) over 5 h. The resulting slurry was filtered and dried with heat at 40 - 55 °C and under vacuum to obtain 1.66 kg (85.8% yield) of N-(l-(chloromethyl)-2- oxo- 1 ,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (14) as a white to off-white crystalline solid.

[00344] Alternative preparation of compound (16)

[00345] A mixture of 2-(4-fluoro-2-methylphenoxy)-N-(l-(hydroxymethyl)-2-oxo-l,2- dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (13) (20 g, 45.83 mmol, 1.00 equivs) and ethyl acetate (200 mL) was stirred and cooled at 5 - 15 °C. To the mixture was added methane sulfonyl chloride (6.30 g, 4.3 mL, 55.0 mmol, 1.20 equivs) followed by the addition of N,N- diisopropylethylamine (8.89 g, 12.0 mL, 68.75 mmol, 1.50 equivs). The mixture was stirred at 5 - 15 °C until the chlorination was complete (typically 4 h). The stirring mixture was then combined with sodium iodide (1.37 g, 9.17 mmol, 0.20 equivs) and potassium di-tert-butyl phosphate (17.07 g, 68.75 mmol, 1.50 equivs) and heated at 65 - 75 °C until the reaction was complete (typically 5 h). The mixture was cooled to 35 - 45 °C and washed with an aqueous citric acid solution made up via dilution of 20.9 %w/w aqueous citric acid solution (20 mL) with water (50 mL). The organic phase was then washed with water (60 mL) and concentrated via vacuum distillation at 35 - 45 °C to a total volume of approximately 100 mL. To the resulting organic phase was added a 1 M aqueous solution of sodium acetate (15.6 g, 115 mL, 114.6 mmol, 2.50 equivs) and methanol (42 mL), while stirring. The mixture was heated at 60 - 65 °C until the mono-deprotection was complete (typically 5 h).

[00346] The resulting mixture was then was cooled to 15 - 25 °C and the phases were separated. The organic phase was diluted with ethyl acetate (103 mL) and washed with water (155 mL). The aqueous phase was washed with ethyl acetate (103 mL) and diluted with methanol (312 mL). Acidification with an aqueous solution of 2 M sulfuric acid (40.6 mL) provided a slurry that was filtered to obtain the product as a white to off-white crystalline solid, which was dried with heat at 35 - 40 °C and under vacuum to afford 19.7 g (75% yield) of tert- butyl ((4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-l(2H)- yl)methyl) hydrogen phosphate (16).

Step H

[00347] The compound of formula III may be converted to the compound of formula II by reacting the compound of formula III, or a salt thereof, with K(tBu)₂P0₄ in the presence of a base. Suitable bases include potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium ieri-butoxide, sodium ieri-butoxide, 2-fcri-butyl-l, 1,3,3- tetramethylguanidine, and l,8-diazabicyclo[5.4.0]undec-7-ene. The reaction between the compound of formula III, or a salt thereof, and K(tBu)₂P0₄ may be conducted at a temperature of no more than about 60 °C using a solvent comprising one or more of NMP, DMF, DMSO, acetonitrile, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, 2-methyltetrahydrofuran, dichloromethane, chloroform, and tetrachloroethylene, including any mixture thereof.

[00348] General Procedure:

[00349] A mixture of the compound of formula III, toluene and ethyl acetate (such as that prepared in Step G above) is stirred over potassium carbonate. To the slurry is charged sodium iodide and potassium di-tert-butyl phosphate. The mixture is heated and stirred until the reaction is complete. The product solution is cooled and washed with an aqueous citric acid solution.

The organic is then washed with water. The product can be isolated from the ethyl acetate solution as described below or taken on to the next step as a mixture.

[00350] Alternatively, the mixture of the compound of formula III and ethyl acetate (such as that prepared in Step G above) is stirred and to the mixture is added sodium iodide along with potassium di-tert-butyl phosphate. The mixture is heated and stirred until the reaction is complete. The mixture is cooled and washed with an aqueous citric acid solution. The organic is then washed with water. The product can be isolated from the ethyl acetate solution as described below or taken on to the next step as a mixture.

[00351 ] The product may be isolated by concentrating and cooling the ethyl acetate solution. The mixture is diluted with n-heptane and cooled further. The slurry is filtered to obtain the product as a white to off-white crystalline solid, which is dried with heat and under vacuum.

[00352] Although the general procedures described above for preparing the compound of formula II from the compound of formula III is sufficient to enable the skilled artisan to prepare the compound of formula II following a variety of procedures within the contours of the general procedures described above, the present application herewith provides a non-limiting, exemplary procedure for preparing the compound of formula II from the compound of formula III.

[00353] Specific Examples

14 [00354] A mixture of N-(l-(chloromethyl)-2-oxo-l,2-dihydropyridin-4-yl)-2-(4-fluoro-2- methylphenoxy)-4-(trifluoromethyl)benzamide (14) in toluene and ethyl acetate from the previous step was stirred over potassium carbonate (3.17 g, 22.92 mmol, 0.5 equivs) for 30 m at 35 - 45 °C. To the slurry was charged sodium iodide (687 mg, 4.58 mmol, 0.1 equivs) and potassium di-ie/ -butyl phosphate (13.66 g, 55 mmol, 1.2 equivs). The mixture was heated at 60 - 80 °C and stirred until the reaction was complete (approximately 1 h) to afford di-ieri-butyl ((4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-l(2H)- yl)methyl) phosphate (15). The product solution was cooled to 35 - 45 °C and washed with an aqueous citric acid solution made up via dilution of 20.9 %w/w citric acid solution (20 mL) with water (50 mL). The organic phase was then washed with water (60 mL). The product was isolated from the ethyl acetate solution as described below or taken on to the next step as a mixture.

[00355] The ethyl acetate solution was distilled to approximately 100 mL and cooled to 25 - 35 °C. The mixture was diluted with n-heptane (100 mL) and cooled to 5 - 15 °C. The slurry was filtered to obtain the product as a white to off-white crystalline solid, which was dried with heat (20 - 30 °C) and under vacuum to obtain 24 g (83% yield) of di-ieri-butyl ((4-(2-(4-fluoro- 2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-l(2H)-yl)methyl) phosphate (15).

[00356] Di-ieri-butyl ((4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2- oxopyridin-l(2H)-yl)methyl) phosphate may also prepared in accordance with the following procedure.

[00357] To a 50 liter jacketed glass reactor fitted with an N2 inlet and a mechanical stirrer, and with a jacket temperature set at 41 °C, was added N-(l-(chloromethyl)-2-oxo-l,2- dihydropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (14) (1199.5 g, 2.64 moles, 1.0 eq) under nitrogen. Ethyl acetate (12 liters) was added with stirring to produce a suspension. To the mixture was added potassium di-/_{<? /'/}-butyl phosphate (792.7 g @ 95% purity, 3.03 moles, 1.15 eq), then TBAI (9.7 g, 0.026 moles, 0.01 eq), and the jacket temperature was ramped to 71 °C over 20 minutes. The resulting gelatinous suspension was stirred for 4.5 hours at which point HPLC analysis indicated that the reaction was complete. The jacket temperature was ramped to 30 °C over 15 minutes, and then water (6 liters) was added with stirring. The aqueous layer was drained off, 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 down to 3.0-3.5 volumes at 40 °C using a rotovap. Heptane (1.8 liters) was added as an antisolvent, and then the bath heater of the rotovap was turned off, and the mixture was allowed to cool to room temperature and was stirred at 40 rpm overnight. The solids were collected by filtration, rinsed with heptanes (1.2 liters), and then dried in vacuo at 45 °C to give 1417.7g (88%) of di-/_{<? /'/}-butyl ((4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-l(2H)- yl)methyl) phosphate (15) as a crystalline, light amber solid. Step

[00358] In Step J, the compound of formula II is deprotected to afford the compound of formula I in which X is -PO(OH)₂, -PO(OH)O M⁺, -P0(0 )_2*2M⁺, or

-P0(0 )_2*D²⁺; M⁺ is a pharmaceutically acceptable monovalent cation; and D²⁺ is a

pharmaceutically acceptable divalent cation. The deprotection step comprises reacting the compound of formula II with a suitable acid in a suitable solvent. Suitable solvents include iso propyl alcohol, dimethyl sulfoxide, acetone, tetrahydrofuran, methanol, methyl ethyl ketone, 2- methyltetrahydrofuran, methyl iso-butyl ketone, ethyl acetate, iso-propyl acetate, water, and mixtures thereof. Suitable acids may include sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, p-toluene sulfonic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, and trifluoroborate etherate. The deprotection step may comprises keeping the compound of formula II at between about 10 °C and about 70 °C for 30 minutes to one week. Further, the compound of formula I, or a salt thereof, may be obtained without chromatographic purification. The compound of formula I may also be converted to a pharmaceutically acceptable salt of the compound of formula I such that the compound of formula I is obtained as a salt of the compound of formula I, wherein said salt of the compound of formula I is a pharmaceutically acceptable salt of the compound of formula I wherein the pharmaceutically acceptable salt of the compound of formula I may be obtained without chromatographic purification. The compound of formula I may be recrystallized from a solvent system comprising DMSO to afford a DMSO- solvate of the compound of formula I in which X is -PO(OH)₂. The reaction mixture is heated until the reaction is complete. The product is isolated by filtration and dried with heat and under vacuum. The compound of formula I may be isolated as a solid mixed with an acid and a solvent. [00359] The compound of formula II may be converted in accordance with the general procedure described above. In particular, a compound of formula I may be prepared in accordance with the following non-limiting, exemplary procedure.

[00360] Specific Example

[00361] To a 72 liter jacketed glass reactor fitted with an N2 inlet and a mechanical stirrer, and with a jacket temperature set at 40 °C, was added di-ie/ -butyl ((4-(2-(4-fluoro-2- methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin- l(2H)-yl)methyl) phosphate (15) (2820.9 g, 4.49 moles, 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, resulting in a clear solution. The clear solution was polish filtered and transferred to a 50 liter jacketed glass reactor system with stirring at 100 rpm. Water (5.6 liters) was added, and the jacket temperature was ramped to 71 °C over 20 minutes. After 4.5 hours of stirring and heating, HPLC analysis indicated that the reaction was complete. The jacket temperature was ramped down to 19 °C over 3 hours, and the product began crystallizing out of solution. The solid was collected by filtration, rinsed with acetone (5 liters) and dried in vacuo at 50 °C to give 1917.7 g (83%) of (4- (2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-l(2H)-yl)methyl dihydrogen phosphate (17) as a crystalline white solid. Partial De la Ila:

[00362] The compound of formula II may be partially protected to afford the compound of formula Ila. Basic conditions are usually suitable for partial deprotection. Suitable bases include ammonium acetate, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, sodium formate, ammonium formate, sodium citrate tribasic, and ammonium citrate. The reaction may be conducted in methanol, ethyl acetate, iso-propyl alcohol, acetone,

tetrahydrofuran, methyl ethyl ketone, methyl iso-butyl ketone, 2-methyltetrahydrofuran, or mixtures thereof. Methanol, acetic acid, acetonitrile, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, and iso-propyl alcohol may be used as co-solvents.

[00363] In general, a mixture of the compound of formula II, a base, and a suitable solvent system is heated and stirred for a period long enough to partially deprotect the compound of formula II. The mixture is cooled and the aqueous phase separated and retained. The aqueous phase is washed with a suitable solvent (such as the solvent used in the reaction). The aqueous phase may be diluted with a co-solvent and acidified such that the compound of formula Ila is isolated by filtration and dried with heat and under vacuum.

[00364] Alternatively, the compound of formula II from a process stream is mixed with a base and a suitable solvent while heating and stirring. The mixture is cooled and the aqueous phase separated and retained. The aqueous phase is washed with a suitable solvent (such as the solvent used in the reaction). The aqueous phase is diluted with a co-solvent and acidified to afford a slurry. The product (the compound of formula Ila) is isolated by filtration and dried with heat and under vacuum.

[00365] Although the general procedures described above for preparing the compound of formula Ila from the compound of formula II is sufficient to enable the skilled artisan to prepare the compound of formula Ila by following a variety of procedures within the contours of the general procedures described above, the present application herewith provides a non-limiting, exemplary procedure for preparing the compound of formula Ila from the compound of formula

II.

[00366] Specific Example:

[00367] Di-ieri-butyl ((4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2- oxopyridin-l(2H)-yl)methyl) phosphate (15) from the process stream was adjusted to 4.6 vol of ethyl acetate by distillation and mixed with a 1 M sodium acetate solution (2.5 equivs) and methanol (1.7 vol). The mixture was heated at 60 -70 °C and stirred until the reaction was complete (approximately 5 h). The mixture was cooled to 15 - 30 °C and the aqueous phase was separated and retained. The organic phase was diluted with ethyl acetate (4 vol) and washed with water (6 vol). The combined aqueous phases were washed with ethyl acetate (4 vol) and then diluted with methanol (448 mL). The mixture was acidified with 2 M sulfuric acid (51.8 mL) to a pH of below 2 while maintaining an internal temperature below 35 °C. tert- Butyl ((4- (2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-l(2H)-yl)methyl) hydrogen phosphate (16) was isolated by filtration, washed with water (3x6 vol) and dried with heat (35 - 45 °C) and under vacuum (90% yield). [00368] Deprotecting compound (16) to give compound (17) with phosphoric acid in isopropyl acetate

[00369] tert- Butyl ((4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2- oxopyridin-l(2H)-yl)methyl) hydrogen phosphate (compound (16), 9 g) was combined with isopropyl acetate (81 mL) and phosphoric acid (9 mL) and stirred at 25 °C until the reaction was judged complete by HPLC. The mixture was filtered to obtain (4-(2-(4-fluoro-2- methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-l(2H)-yl)methyl dihydrogen phosphate as a white, crystalline solid of compound (17). The vessel and filter cake were twice washed with water (36 mL) and isopropyl acetate (36 mL). The solids were dried under vacuum at 40-65 °C with a nitrogen bleed to obtain 7.3 g of dried product (89.9% yield).

[00370] Deprotecting compound Ila (16) to give compound I (17) with acetic acid in isopropyl acetate

[00371 ] tert- Butyl ((4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2- oxopyridin-l(2H)-yl)methyl) hydrogen phosphate (16) (9 g) was combined with isopropyl acetate (45 mL), acetic acid (36 mL), and water (9 mL) and the stirring mixture was heated at 55 °C until the reaction was judged complete by HPLC. The mixture was cooled to 25 °C and filtered to obtain (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2- oxopyridin-l(2H)-yl)methyl dihydrogen phosphate as a white, crystalline solid of compound (17). The vessel and filter cake were twice washed with a 1:1 ratio of isopropyl acetate and water (36 mL). The solids were dried under vacuum at 40-65 °C with a nitrogen bleed to obtain 7.3 g of dried product (89.9 % yield). [00372] The following example provides a large scale synthesis of compound (17) from compound (15).

[00373] A mixture of di-ie/t-butyl ((4-(2-(4-fluoro-2-methylphenoxy)-4- (trifluoromethyl)benzamido)-2-oxopyridin-l(2H)-yl)methyl) phosphate (15) (74.8 kg) and isopropyl alcohol (427.4 kg) and acetic acid (370.4 kg) was stirred in a reactor and heated at 40 - 45 °C. Water (140.3 kg) was charged over 1 h and the mixture was then heated at 60 - 65 °C for at least 1.5 h and until the reaction was observed to be complete by HPLC (i.e., when no more than 1% of Compound (16), by HPLC, remains or when Compound (9) is observed to be greater than 1% by HPLC). The mixture was cooled to 5 - 15 °C over 6 h, during which time the product crystallized from solution. The slurry was aged for 10.5 h at 5 - 15 °C, after which time the solid was collected by filtration, rinsed with acetone (117.5 kg) and dried in vacuo at ambient temperature (15 - 25 °C) to give 51.2 kg (83%) of (4-(2-(4-fluoro-2-methylphenoxy)-4- (trifluoromethyl)benzamido)-2-oxopyridin-l(2H)-yl)methyl dihydrogen phosphate (17) as a crystalline white solid.

[00374] Compound (17) may also be prepared in accordance with the following procedure.

[00375] Compound (16) (1.0 kg) is charged to inerted reactor at 20 -25 °C. Isopropanol (5.7 kg) is charged to the reactor and the mixture is stirred to disperse the solids. Glacial acetic acid (4.94 Kg) is charged to the reactor before the heting the mixture to to an internal temperature of 40 +/- 3 °C. Water (1.87 kg) is added to the raction mixture. The internal temperature of the reactor is raised to 75+/- 2 °C over 2 hours with a linear ramp of about 17.5 °C/hour while stirring the mixture. The reaction mixture is maintained at 75+/- 2 °C until the raction is complete. The reaction is considered complete in ths experiment when no more than 0.5% of compound (16) remains or when compound (9), if present, is observed to be greater than 1.5%. The mixture is cooled to 20 °C at a rate of 5 - 10 °C/hour. The reaction mixture is stirred for no less than (NLT) 2 hours once the target temperature of 20+/- 3 °C is obtained. The slurry is filtered and the resulting cake is washed with 2.0 liters of acetone and dried with nitrogen stream or by nitrogen-purged oven at 23 +/-5 °C to afford compound (17). Purification of the Compound of formula I

[00376] The compound of formula I may be recrystallized using suitable solvent systems. For example, a mixture of the compound of formula I, ethyl acetate, and dimethyl sulfoxide is heated and stirred. The mixture is seeded with previously isolated crystals of the compound of formula I DMSO solvate to induce crystallization. The slurry is diluted with ethyl acetate and then cooled. The product is isolated by filtration and dried with heat and under vacuum. This crystallization is performed to ensure removal of impurities in the synthesis (such as the compound of formula III). A specific impurity that this recrystallization is aimed to remove is a compound of formula III such as N-(l-(chloromethyl)-2-oxo-l,2-dihydropyridin-4-yl)-2-(4- fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide.

[00377] For example, (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2- oxopyridin-l(2H)-yl)methyl dihydrogen phosphate may be purified in accordance with the following procedure.

[00378] Crude (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2- oxopyridin-l(2H)-yl)methyl dihydrogen phosphate (17) (40 g) was dissolved in a 1:1 mixture of ethyl acetate and dimethyl sulfoxide (90.1 mL) with stirring at 40 - 50 °C. The stirring solution was seeded with (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2- oxopyridin-l(2H)-yl)methyl dihydrogen phosphate DMSO (17· DMSO) solvate (0.40 g, 1 wt%). The resulting slurry was aged for an hour before being diluted with ethyl acetate (272.4 mL) over at least five hours. The slurry was cooled to 15 - 25 °C over eight hours and the white to off- white crystalline solid product was isolated by filtration. After drying at 30 - 40 °C under vacuum, 46.9 g (90% yield) of (4-(2-(4-fluoro-2-methylphenoxy)-4- (trifluoromethyl)benzamido)-2-oxopyridin-l(2H)-yl)methyl dihydrogen phosphate-DMSO

(17· DMSO) solvate was obtained.

[00379] (4-(2-(4-Fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin- l(2H)-yl)methyl dihydrogen phosphate-DMSO (17· DMSO) solvate may further be

recrystallized to prepare solid Form B of the compound. For example, a mixture of (4-(2-(4- fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-l(2H)-yl)methyl dihydrogen phosphate-DMSO solvate, water, and tetrahydrofuran is heated and stirred. The mixture is polish filtered and diluted with ethyl acetate to obtain a slurry. The slurry is cooled and the product is isolated by filtration before drying with heat and under vacuum. The following procedure provides a specific method for obtaining solid Form B of (4-(2-(4-fluoro-2- methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-l(2H)-yl)methyl dihydrogen phosphate (17). Form B of compound (17) is described in U.S. Patent N. 9,163,042, col 20, line 47 through col. 25, line 53, col. 26, lines 39-51, and Figures 2-4, which are incorporated herein by reference for the teaching thereof.

[00380] (4-(2-(4-Fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin- l(2H)-yl)methyl dihydrogen phosphate-DMSO (17-DMSO) solvate may also be prepared in accordance with the following procedure.

[00381] Compound (17) (50.5 kg, 1.00 equivs) was charged to a reactor. A 1:1 mixture of DMSO and ethyl acetate was prepared by pre-mixing DMSO (63.1 kg) and ethyl acetate (52.0 kg). The combined solvent mixture was charged to the reactor and the mixture was heated at 45 °C until a solution was obtained. The mixture was seeded with compound 17 DMSO Solvate (1.00 wt%, 505.2 g) and aged for no less than 60 minutes. Upon obtaining visual confirmation that the seeds had held, the slurry was diluted with ethyl acetate (310.2) via a slow addition of the solvent over no less than 5 h at a rate of about 1,36 L/h. After completing the addition, the slurry was slowly cooled to 20 °C over NLT 8 h at a rate of about 0.05 °C/min. The mixture was held at 20 °C for no less than 2 h and filtered. The reactor and the solids on the filter were washed with ethyl acetate (2 vol, 2000 mL). Compound (17)- DMSO Solvate (17· DMSO) was dried at 40 °C under vacuum with a nitrogen bleed to obtain 56.6 kg (86.0% yield) of product.

[00382] (4-(2-(4-Fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin- l(2H)-yl)methyl dihydrogen phosphate DMSO (17 DMSO) solvate (40.0 g) was dissolved in a separately prepared 10.5% by volume water in tetrahydrofuran solvent mixture (313 mL) and heated at 40 - 50 °C. The stirring solution was polish filtered at 40 - 50 °C and the filtered solution was diluted with ethyl acetate (625 mL) over two hours while maintaining a temperature of 40 - 50 °C. The resulting slurry was cooled to 15 - 25 °C over eight hours and the white to off-white crystalline solid product was isolated by filtration. After drying at 30 - 40 °C under vacuum, 27.6 g (90% yield) of solid Form B of (4-(2-(4-fluoro-2-methylphenoxy)-4- (trifluoromethyl)benzamido)-2-oxopyridin-l(2H)-yl)methyl dihydrogen phosphate (17) was obtained.

[00383] Compound (17)- DMSO Solvate (17 DMSO) may be converted to Form B (4-(2-(4- fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-l(2H)-yl)methyl dihydrogen phosphate in accordance with the following procedure.

[00384] Compound (17)- DMSO Solvate (52.9 kg, 1.00 equivs) was charged to a reactor. A pre-mixed solvent mixture of THF (329.8 kg) and water (43.5 kg) was added. The mixture was stirred and heated at 45 °C until a solution is obtained (heating the mixture to 50 °C if necessary). The solution was aged for NLT 15 m. The solution was polish filtered at 45 °C. While maintaining an internal temperature of 45 °C, the stirring filtered solution was diluted with ethyl acetate (746.7 kg) via a slow addition of the solvent through the filter over NLT 2 h. The resulting slurry was stirred and aged for NLT 1 h. The slurry was slowly cooled to 20 °C over NLT 8 h at a rate of about 0.1 °C/min. The mixture was held at 20 °C for NLT 15 h and filtered. The reactor and the solids on the filter were washed with ethyl acetate (95.7 kg). Form B of compound (17) was dried at 35 °C under vacuum with a nitrogen bleed to obtain 36.3 kg (89.2% yield) of product.

[00385] Continuous process for making Compound (17)

[00386] The method of preparing compound (17) as described above in detail can be carried out as a batch process or as a continuous process. The skilled artisan could adapt these processes to make compound (17) in continuous process in which the starting point is preparation of compound (13), compound (14), compound (15) or compound (16). In one aspect, the reaction steps for converting compound (13), compound (14), compound (15) or compound (16) to compound (17) as described above are performed in reaction vessels customary for such reactions, the reactions being carried out in a continuous, semi-continuous or batchwise manner.

[00387] In another aspect, the continuous process for producing compound (17) comprises: 1) preparing compound (13) in a first stage; 2) converting compound (13) to compound (14) in a second stage; 3) converting compound (14) to compound (15) in a third stage; 4) converting compound (15) to compound (16) in a fourth stage; and 5) converting compound (16) to compound (17) in a fifth stage. In another aspect, the continuous process for producing compound (17) comprises: 1) preparing compound (14) in a first stage; 2) converting compound

(14) to compound (15) in a second stage; 3) converting compound (15) to compound (16) in a third stage; and 4) converting compound (16) to compound (17) in a fourth stage. In another aspect, the continuous process for producing compound (17) comprises: 1) preparing compound

(15) in a first stage; 2) converting compound (15) to compound (16) in a second stage; and 3) converting compound (16) to compound (17) in a third stage. In another aspect, the continuous process for producing compound (17) comprises: 1) preparing compound (16) in a first stage; and 2) converting compound (16) to compound (17) in a second stage.

DEFINITIONS and METHODS

[00388] HPLC analysis was conducted using a Poroshell EG.C18 column (4.6 x 150 mm, 2.7 mhi particle) made by Agilent (PN: 693975-902(T)), and a dual gradient run from 5-100% mobile phase B over 35 minutes. Mobile phase A: ¾0 (0.1 % TFA). Mobile phase B: CH3CN (0.1 % TFA). Flow rate: 1.000 mL/min. Injection volume= 10 pF. Column temperature= 30.0°C.

[00389] ¹ H NMR (400 MHz) spectra were obtained as solutions in an appropriate deuterated solvent such as Chloroform-d.

[00390] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed. Additionally, general principles of organic chemistry are described in“Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and“March’s Advanced Organic Chemistry,” 5^th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[00391 ] As described herein, compounds of the invention can optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. As described herein, the variables R², R³, R⁵, and R⁷ in formulas I-XI encompass specific groups, such as, for example, alkyl and cycloalkyl. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds. The term“stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not

substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

[00392] The phrase“optionally substituted” may be used interchangeably with the phrase “substituted or unsubstituted.” In general, the term“substituted,” whether preceded by the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. A ring substituent, such as a heterocycloalkyl, can be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one common atom.

As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds. [00393] The phrase“up to,” as used herein, refers to zero, any integer number, or fraction thereof, that is equal to or less than the number following the phrase. For example,“up to 4” means any one of 0, 1, 2, 3, and 4.

[00394] The term“aliphatic,”“aliphatic group” or“alkyl” as used herein, means a straight- chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1 - 20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1 - 10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1 - 8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1 - 6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1 - 4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups.

[00395] The terms“cycloaliphatic” or“cycloalkyl” mean a monocyclic hydrocarbon ring, or a polycyclic hydrocarbon ring system that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic and has a single point of attachment to the rest of the molecule. The term“polycyclic ring system,” as used herein, includes bicyclic and tricyclic 4- to 12- membered structures that form at least two rings, wherein the two rings have at least one atom in common (e.g., 2 atoms in common) including fused, bridged, or spirocyclic ring systems.

[00396] The term“halogen” or“halo” as used herein, means F, Cl, Br or I.

[00397] Unless otherwise specified, the term“heterocycle,”“heterocyclyl,”

“heterocycloaliphatic,”“heterocycloalkyl,” or“heterocyclic” as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring atoms in one or more ring members is an independently selected heteroatom. Heterocyclic ring can be saturated or can contain one or more unsaturated bonds. In some embodiments, the“heterocycle,”

“heterocyclyl,”“heterocycloaliphatic,”“heterocycloalkyl,” or“heterocyclic” group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the ring system contains 3 to 7 ring members. [00398] The term“heteroatom” means oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4- d i h y dro -2H- p y rro 1 y 1 ) , NH (as in pyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl)).

[00399] The term“unsaturated,” as used herein, means that a moiety has one or more units of unsaturation but is not aromatic.

[00400] The term“alkoxy,” or“thioalkyl,” as used herein, refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

[00401] The term“aryl” used alone or as part of a larger moiety as in“aralkyl,”“aralkoxy,” or “aryloxyalkyl,” refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring carbon atoms, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring carbon atoms. The term“aryl” may be used

interchangeably with the term“aryl ring.”

[00402] The term“heteroaryl,” used alone or as part of a larger moiety as in“heteroaralkyl” or“heteroarylalkoxy,” refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term“heteroaromatic.”

[00403] Unless otherwise stated, structures depicted herein are also meant to include all stereoisomers (e.g., enantiomers, diastereomers) and geometric (or conformational) isomers of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Thus, included within the scope of the invention are tautomers of compounds and salts of formulas I- XI. The structures also include zwitterionic forms of the compounds or salts of formulas I- XI where appropriate.

[00404] Unless otherwise specified, any atom not specifically designated as a particular isotope in any compound of the invention is meant to represent any stable isotope of the specified element. In the Examples, where an atom is not specifically designated as a particular isotope in any compound of the invention, no effort was made to enrich that atom in a particular isotope, and therefore a person of ordinary skill in the art would understand that such atom likely was present at approximately the natural abundance isotopic composition of the specified element.

[00405] As used herein, the term“stable,” when referring to an isotope, means that the isotope is not known to undergo spontaneous radioactive decay. Stable isotopes include, but are not limited to, the isotopes for which no decay mode is identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[00406] As used herein,“H” refers to hydrogen and includes any stable isotope of hydrogen, namely ¹ H and D. In the Examples, where an atom is designated as“H,” no effort was made to enrich that atom in a particular isotope of hydrogen, and therefore a person of ordinary skill in the art would understand that such hydrogen atom likely was present at approximately the natural abundance isotopic composition of hydrogen.

[00407] As used herein,“Ή” refers to protium. Where an atom in a compound of the invention, or a pharmaceutically acceptable salt thereof, is designated as protium, protium is present at the specified position at least the natural abundance concentration of protium.

[00408] As used herein,“D,”“d,” and“²H” refer to deuterium.

[00409] In some embodiments, the compounds of the invention, and pharmaceutically acceptable salts thereof, include each constituent atom at approximately the natural abundance isotopic composition of the specified element.

[00410] In some embodiments, the compounds of the invention, and pharmaceutically acceptable salts thereof, include one or more atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the most abundant isotope of the specified element (“isotope-labelled” compounds and salts). Examples of stable isotopes which are commercially available and suitable for the invention include without limitation isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, for example ²H, ¹³C, ¹⁵N, ¹⁸0, ¹⁷0, and ³¹P, respectively.

[00411 ] The isotope-labelled compounds and salts can be used in a number of beneficial ways, including as medicaments. In some embodiments, the isotope-labelled compounds and salts are deuterium (²H)-labelled. Deuterium (²H)-labelled compounds and salts are

therapeutically useful with potential therapeutic advantages over the non-²H-labelled

compounds. In general, deuterium (²H)-labelled compounds and salts can have higher metabolic stability as compared to those that are not isotope-labelled owing to the kinetic isotope effect described below. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which under most circumstances would represent a preferred embodiment of the present invention. The isotope-labelled compounds and salts can usually be prepared by carrying out the procedures disclosed in the synthesis schemes, the examples and the related description, replacing a non-isotope-labelled reactant by a readily available isotope-labelled reactant.

[00412] The deuterium (²H)-labelled compounds and salts can manipulate the rate of oxidative metabolism of the compound by way of the primary kinetic isotope effect. The primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies of the covalent bonds involved in the reaction. Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate- limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle -point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially. For explanation: if deuterium is bonded to a carbon atom at a non-exchangeable position, rate differences of k_H/ko = 2-7 are typical. For a further discussion, see S. L. Harbeson and R. D. Tung, Deuterium In Drug Discovery and Development , Ann. Rep. Med. Chem. 2011, 46, 403-417, incorporated in its entirety herein by reference. [00413] The concentration of an isotope (e.g., deuterium) incorporated at a given position of an isotope-labelled compound of the invention, or a pharmaceutically acceptable salt thereof, may be defined by the isotopic enrichment factor. The term“isotopic enrichment factor,” as used herein, means the ratio between the abundance of an isotope at a given position in an isotope-labeled compound (or salt) and the natural abundance of the isotope.

[00414] Where an atom in a compound of the invention, or a pharmaceutically acceptable salt thereof, is designated as deuterium, such compound (or salt) has an isotopic enrichment factor for such atom of at least 3000 (45% deuterium incorporation). In some embodiments, the isotopic enrichment factor is at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[00415] The term“salt,” when referring to a salt of the compounds disclosed herein, includes pharmaceutically acceptable salts, as that term is defined herein, as well those salts that are unsuitable for pharmaceutical use (e.g., because they would cause undue toxicity, irritation, allergic response, or the like).

[00416] The term“pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. As used herein, the term“inhibitorily active metabolite or residue thereof’ means that a metabolite or residue thereof is also an inhibitor of a voltage-gated sodium channel.

[00417] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(Ci-4 alkyl)4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.

Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[00418] The term“reacting,” when referring to a chemical reaction, means to add or mix two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product. [00419] The term“conducted in a solvent,” when referring to a reaction, means that the substrate(s) and reagent(s) are dissolved or suspended in the specified solvent or in a mixture of solvents comprising the specified solvent.

[00420] The term“chromatographic purification” refers to any method of purification based on differential retention by a stationary phase. Methods of chromatographic purification include flash chromatography, medium pressure liquid chromatography, preparative thin layer chromatography, and high performance liquid chromatography.

[00421 ] The term“converting,” as used herein to refer to a step of converting a first compound or salt to a second compound or salt, refers to a process of transforming the first compound or salt to the second compound or salt in one or more chemical steps.

[00422] The term“base” refers to a chemical species whose conjugate acid has a pKa (in water) of greater than 7. The term includes“inorganic bases,” such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate (mono-, di-, or tri-basic), sodium hydride, and potassium hydride. The term also includes“anionic organic bases,” such as methyl lithium, butyl lithium, lithium diisopropyl amide, and sodium acetate. The term also includes“neutral organic bases,” such as trimethylamine, dimethylethylamine, diethylmethylamine, triethylamine, di-n-propylmethylamine, dimethylcyclohexylamine, diisopropylethylamine, tri-n-propylamine, diisopropylisobutylamine, dimethyl-n-nonylamine, tri-n-butylamine, di-n-hexylmethylamine, dimethyl-n-dodecylamine, tri-n-pentylamine, l,4-diazabicyclo[2.2.2] octane (DABCO), dimethylaminopyridine (DMAP), l,5-diazabicyclo[4.3.0] non-5-ene (DBN), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6- lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,4-collidine, 2,4,5-collidine, 2,5,6-collidine, 2,4,6-collidine, 3,4,5-collidine, and 3,5,6-collidine.

[00423] The term“alcohol protecting group” refers to a chemical moiety suitable to protect an alcohol group against undesirable side reactions during synthetic procedures. Common alcohol protecting groups include methyl, ethyl, isopropyl, benzyl, 2-tetrahydropyranyl, acetyl, trifluoroacetyl, trialkylsilyl, aryldialkylsilyl, alkyldiarylsilyl, or triarylsilyl. Other alcohol protecting groups also are well known in the art. See, e.g., P.G.M. Wuts et al., Greene’s Protective Groups in Organic Synthesis (4th ed. 2006).

[00424] The term“deprotecting” refers to a step of reacting a compound or salt containing a protecting group, such as an alcohol protecting group, under conditions suitable to remove the protecting group and reveal the protected moiety. For example, where a compound or salt contains an alcohol protecting group, the term“deprotecting” refers to reacting the compound or salt under conditions suitable to remove the alcohol protecting group and reveal the alcohol (or a tautomer of the alcohol). Conditions for removing various protecting groups are well known in the art. See, e.g., P.G.M. Wuts et al., Greene’s Protective Groups in Organic Synthesis (4th ed. 2006).

[00425] The term“hydrogenation catalyst” refers to any homogeneous or heterogeneous catalyst that catalyzes the hydrogenolysis of benzylic carbon-oxygen single bonds. Suitable hydrogenation catalysts are well-known in the art and include palladium on activated carbon, platinum oxide, and Raney Nickel.

[00426] The term“acid” refers to a chemical species having a pKa (in water) of less than 7. The term includes inorganic (mineral) acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, and the like. The term also includes organic acids such as acetic acid, propionic acid, zz-butyric acid, z-butyric acid, zz- valeric acid, z- valeric acid, zz-hexanoic acid, succinic acid, glutaric acid, adipic acid, aspartic acid, formic acid, citric acid, o-chlorobenzoic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, nicotinic acid, lactic acid, oxalic acid, picric acid, picolinic acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, phthalic acid, isophthalic acid, terephthalic acid, maleic acid, malonic acid, and the like.

[00427] The term“coupling,” when referring to a reaction between a carboxylic acid or acid halide and an amine, refers to a net transformation linking the carboxylic acid or acid halide and the amine to form an amide. The term includes a direct reaction between the carboxylic acid and the amine, as well as a reaction between an activated derivative of the carboxylic acid (such as the derivative formed by the reaction between the carboxylic acid and a coupling reagent) and the amine. [00428] The term“coupling reagent” refers to a reagent suitable to react with a carboxylic acid to activate the carboxylic acid for coupling with an amine to form an amide bond. Coupling reagents are well known in the art. Coupling reagents include, but are not limited to, thionyl chloride, oxalyl chloride, l,l'-carbonylbis-(4,5-dicyanoimidazole) (CBDCI), 1,1'- carbonyldiimidazole (CDI), propylphosphonic anhydride, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI), N, N’-dicyclohexylcarbodiimide (DCC), 1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), and 1-hydroxybenzo triazole (HOBt).

[00429] The term“monovalent cation” refers to any cation with a charge of +1, such as alkali metal cations, NHC, and tetraalkylammonium.

[00430] The term“alkali metal cation” refers to a cation derived from a Group I metal atom, including without limitation lithium (Li⁺), sodium (Na⁺), potassium (K⁺), rubidium (Rb⁺), and cesium (Cs⁺).

[00431] The term“substituted benzyl” refers to a benzyl group that is substituted with 1-3 substituents selected from the group consisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, halogen, and cyano.

[00432] The term“ketone solvent” refers to a compound having the formula

C_nH_2n+;C(0)C_mH_2m+;, wherein n and m are each independently an integer between 1 and 6. The C_ftHz_ft+i and Cmthm+i and groups may be linear or branched and each may be substituted with up to 3 halogens. Ketone solvents include without limitation acetone, methyl ethyl ketone, 3- pentanone, and methyl ie/ -butyl ketone.

[00433] The term“ethereal solvent” refers to an organic solvent having at least one ether moiety. Ethereal solvents include without limitation tetraliydofuran, dimethoxye thane, dioxane, and dialkyl ethers such as diethyl ether and methyl isobutyl ether.

[00434] The term“ester solvent” refers to a compound having the formula

C_nH2_n+;0C(0)C_mH2_m+;, wherein n and m are each independently an integer between 1 and 6.

The C_«H 2n+i and Cmthm+i and groups may be linear or branched and each may be substituted with up to 3 halogens. Ester solvents include without limitation ethyl acetate, isopropyl acetate, butyl acetate, and ethylpropionate. [00435] The term“halogenated solvent” refers to a C_\-Ce alkane or C2-C6 alkene substituted with up to six halogens. Halogenated solvents include without limitation dichloromethane, dichloroethane. chloroform, tetrachloroethylene, and carbon tetrachloride.

[00436] The term“polar aprotic solvent” refers to an organic solvent having a dielectric constant of at least 20 and having no exchangeable protons. Polar aprotic solvents include without limitation N,N-dimethylformamide, acetonitrile, dimethylsulfoxide, N- methy 1 pyrroli done , and hex amethy 1 p ho sphorami de .

[00437] The term“aromatic solvent” refers to a C6-10 aromatic hydrocarbon. The aromatic hydrocarbon may be substituted with up to six halogens. Aromatic solvents include without limitation benzene, trifluoromethylbenzene, xylene, and toluene.

[00438] The term“about” means that the stated number can vary from that value by ±10%. Where the term defines a temperature, the stated temperature can vary by ±10%. For example, about 80 °C means between 72 °C and 88 °C. Where the term defines pressure, the term“about” means the pressure can vary by ±10%. Thus, about 100 bars means between 90 and 110 bars. Where the term defines quantity (such as equivalents or weight), the term means the quantity can vary by ±10%. For example, about 1 equivalent means between 0.9 and 1.1 equivalents. Where the term defines time, the term means the stated time can vary by ±10%. For example, about 1 hour means between 0.9 and 1.1 hours.

[00439] The term“leaving group” is a chemical group that is readily displaced by a desired incoming chemical moiety. Thus, the choice of the specific suitable leaving group is predicated upon its ability to be readily displaced by the incoming chemical moiety of formula A. Suitable leaving groups are well known in the art, e.g., see, "Advanced Organic Chemistry," Jerry March, 5.sup.th Ed., pp. 351-357, John Wiley and Sons, N.Y. Such leaving groups include, but are not limited to, halogen, alkoxy, sulphonyloxy, optionally substituted alkylsulphonyl, optionally substituted alkenylsulfonyl, optionally substituted arylsulfonyl, nitro, and diazonium moieties. Examples of suitable leaving groups include chloro, iodo, bromo, fluoro, methanesulfonyl (mesyl), tosyl, triflate, nitro-phenylsulfonyl (nosyl), and bromo-phenylsulfonyl (brosyl). In some embodiments, the leaving group is nitro, fluoro, or diazonium. [00440] Abbreviations

[00441 ] Except where the context expressly or impliedly indicates otherwise, the following abbreviations used in the Examples and throughout the application have the following meanings:

Abbreviation Meaning

T3P Propylphosphonic anhydride

2-Me-THF 2-Methyltetrahydrofuran

TEA Triethylamine

°C Degrees Celsius

HBr Hydrogen bromide

AcOH Acetic acid

h, hr, hrs Hours

K2CO3 Potassium carbonate

NMP V-Mcthyl-2-pyrrolidonc

EtOAc Ethyl acetate

DMF N,N-D\ m ethyl fo r m a m i dc

DAB CO 1,4-diazabicyclo [2.2.2] octane

K(tBu)₂P0₄ Potassium di-ie/ -butylphosphate

H2O Water

IPA Isopropyl alcohol

N₂ Nitrogen

rpm Revolutions per minute

L Liters

vol Volumes

g Grams

mol Moles

kg Kilograms

%w/w Weight- weight percentage

min Minutes

HPLC High performance liquid chromatography

NaOH Sodium hydroxide

Na₂S0₄ Sodium sulfate

mbar millibars

MeBr Methyl bromide

eq Equivalents

ml or mL Milliliters

TBAI Tetrabutylammonium iodide

NCS N-chlorosuccinimide

Claims

What is claimed is:

1. A method for preparing a compound of formula I,

I,

or a salt thereof, wherein, independently for each occurrence:

R² and R³ are independently hydrogen, halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen;

R⁵ is hydrogen, halogen, OH, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH₂ units of said C1-C6 alkyl may be replaced with -0-;

R⁷ is hydrogen, halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH₂ units of said C1-C6 alkyl may be replaced with -0-; and

provided that R², R³, R⁵, and R⁷ are not simultaneously hydrogen; comprising deprotecting a compound of formula II,

fford a compound of formula I wherein X is -PO(OH)2.

2. The method of claim 1, wherein said deprotecting comprises reacting the compound of formula II with an acid.

3. The method of claim 2, wherein said acid is selected from the group consisting of sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, p-toluene sulfonic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, and trifluoroborate etherate.

4. The method of claim 2, wherein said acid is acetic acid or phosphoric acid.

5. The method of claim 1, wherein said deprotecting comprises keeping the compound of formula II at between about 10 °C and about 70 °C for 30 minutes to about 72 hours.

6. The method of claim 2, wherein the compound of formula I, or a salt thereof, is

obtained without chromatographic purification.

7. The method of claim 2, wherein said method affords the compound of formula I, further comprising converting the compound of formula I to a pharmaceutically acceptable salt of the compound of formula I.

8. The method of claim 7, wherein said method affords a salt of the compound of formula I, wherein said salt of the compound of formula I is a pharmaceutically acceptable salt of the compound of formula I.

9. The method of claim 7, wherein said method affords a salt of the compound of

formula I, further comprising converting the salt of the compound of formula I to a pharmaceutically acceptable salt of the compound of formula I.

10. The method of any one of claims 7-9, wherein the pharmaceutically acceptable salt of the compound of formula I is obtained without chromatographic purification.

11. The method of any of claims 2-4, further comprising recrystallizing the compound of formula I, wherein X is -PO(OH)2, from a solvent system comprising DMSO to afford a DMSO-solvate of the compound of formula I in which X is -PO(OH)2.

12. The method of claim 11, wherein the solvent system comprises DMSO and ethyl acetate.

13. The method of claim 11, wherein the DMSO-solvate of the compound of formula I is recrystallized from a solvent mixture comprising water, THF and ethyl acetate.

14. The method of any of claims 1-13, wherein said deprotecting comprises reacting the compound of formula II with a base to afford a compound of formula Ila,

15. The method of claim 14, wherein said deprotecting further comprises reacting the compound of formula Ila with an acid.

16. The method of claim 15, wherein said acid is selected from the group consisting of sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, p-toluene sulfonic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, and trifluoroborate etherate.

17. The method of claim 16, wherein said acid is acetic acid or phosphoric acid.

18. The method of claim 15, wherein said deprotecting further comprises keeping the compound of formula Ila at between about 10 °C and about 70 °C for 30 minutes to about 72 hours.

19. The method of any of claims 1-18, further comprising reacting a compound of

formula Ilia,

Ilia, or a salt thereof with K(tBu)₂P0₄ to afford the compound of formula II.

20. The method of claim 19, wherein said reacting a compound of formula Ilia, or a salt thereof, with KOBujiPCU is conducted in the presence of a base.

21. The method of claim 20, wherein the base is potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium ie/ -butoxide, sodium tert- butoxide, 2-½ri-butyl-l,l,3,3-tetramethylguanidine, or l,8-diazabicyclo[5.4.0]undec- 7-ene.

22. The method of any one of claims 19-21, wherein said reacting a compound of

formula Ilia, or a salt thereof, with KOBujiPCU is conducted at a temperature of no more than about 70 °C.

23. The method of claim 22, wherein said reacting a compound of formula Ilia, or a salt thereof, with KOBujiPCU is conducted in a solvent selected from the group consisting of NMP, DMF, DMSO, acetonitrile, isopropyl acetate, methyl isobutyl ketone, 2- methyltetrahydrofuran, dichloromethane, chloroform, tetrachloroethylene, ethyl acetate, and a mixture thereof.

24. The method of any of claims 19-23, wherein the compound of formula Ilia is reacted with K(tBu)₂P0₄ in the presence of Nal.

25. The method of any of claims 1-24, further comprising reacting a compound of

formula IV,

with a chlorinating agent to afford the compound of formula III.

26. The method of claim 25, wherein said chlorinating agent is selected from the group consisting of thionyl chloride, methane sulfonyl chloride, phosphorus oxychloride and phosphorus pentachloride.

27. The method of claim 26, wherein said reaction between the compound of formula IV and the chlorinating agent is conducted in the presence of non-nucleophilic base.

28. The method of claim 27, wherein said non-nucleophilic base is selected from the group consisting of triethylamine, diisopropyl ethylamine, N-methylmorpholine, 1,8- diazabicyclo[5.4.0]undec-7-ene, pyridine, butylamine, l,5-diazabicyclo(4.3.0)non-5- ene, and a mixture thereof.

29. The method of any of claims 25-28, wherein said reaction between the compound of formula IV and the chlorinating agent is conducted at a temperature of no more than about 60 °C.

30. The method of any of claims 1-25, further comprising reacting a compound of

formula V,

with formaldehyde to afford the compound of formula IV.

31. The method of claim 30, wherein said formaldehyde is paraformaldehyde, formalin solution, trioxane, or monomeric formaldehyde.

32. The method of claim 31, wherein said formaldehyde is a formalin solution.

33. The method of claim 32, wherein the compound of formula V is reacted with

formalin at between about room temperature and about 80 °C.

34. The method of any of claims 1-33, further comprising reacting a compound of formula VI,

with a compound of formula VII,

wherein Y is a leaving group;

to afford the compound of formula V.

35. The method of claim 34, wherein said leaving group is selected from the group consisting of N₂ ⁺, NO, N0₂, S0₂R, NMe ⁺, CF₃, CHO, COR, COOH, S0₃ , Br, Cl, I, COO , and F wherein R is an alkyl group with 1-4 carbon atoms.

36. The method of claim 35, wherein the leaving group is CF₃, S0₃ , Br, Cl, I, COO , or F.

37. The method of claim 36, wherein the leaving group is CF₃, Cl, or F.

38. The method of claim 37, wherein the leaving group is CF₃ or F.

39. The method of claim 38, wherein the leaving group is F.

40. The method of claim 39, wherein the compound of formula VI is reacted with the compound of formula VII at between about 50 °C and about 110 °C.

41. The method of claim 40, wherein the compound of formula VI is reacted with the compound of formula VII at between about 70 °C and about 100 °C.

42. The method of claim 41, wherein the compound of formula VI is reacted with the compound of formula VII at between about 80 °C and about 90 °C.

43. The method of any of claims 1-42, further comprising converting a compound of formula VIII,

wherein R is Cl or methoxy; to the compound of formula VI.

44. The method of claim 43, wherein said converting is reacting with a dealkylating agent with the compound of formula VIII.

45. The method of claim 44, wherein said dealkylating agent is an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, p-toluene sulfonic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, trifluoroborate etherate, and a mixture thereof.

46. The method of claim 45, wherein said acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, acetic acid, phosphoric acid, and a mixture thereof.

47. The method of claim 46, wherein said acid is selected from the group consisting of hydrobromic acid, acetic acid, phosphoric acid, and a mixture thereof.

or an acid chloride thereof; with a compound of formula X,

wherein R is Cl or methoxy; to afford the compound of formula VIII.

49. The method of claim 48, wherein said reaction between the compounds of formulae IX and X is conducted in the presence of a coupling reagent.

50. The method of claim 49, wherein said coupling reagent is selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), N-(3- dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDAC-HC1), diphenyl phosphoryl chloride (DPPC1), propylphosphonic anhydride, thionyl chloride, 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide (EDCI), l-[bis(dimethylamino)methylene]- lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), and 1- hydroxybenzo triazole (HOBt).

51. The method of claim 49 or 50, wherein said coupling reagent is diphenyl phosphoryl chloride (DPPC1).

52. The method of any of claims 1-33, further comprising converting a compound of formula XI,

wherein R is Cl or methoxy; to the compound of formula V.

53. The method of claim 52, wherein said converting is reacting a dealkylating agent with the compound of formula XI.

54. The method of claim 53, wherein said dealkylating agent is an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, p-toluene sulfonic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, trifluoroborate etherate, and a mixture thereof.

55. The method of claim 54, wherein said acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, acetic acid, phosphoric acid, and a mixture thereof.

56. The method of claim 55, wherein said acid is selected from the group consisting of hydrobromic acid, acetic acid, phosphoric acid, and a mixture thereof.

57. The method of any of claims 52-56, further comprising reacting a compound of formula VIII,

wherein R is Cl or methoxy; with a compound of formula VII,

wherein Y is a leaving group;

to afford the compound of formula XI.

58. The method of claim 57, wherein said leaving group is selected from the group

consisting of N₂ ⁺, NO, N0₂, S0₂R, NMe ⁺, CF₃, CHO, COR, COOH, S0₃ , Br, Cl, I, COO , and F wherein R is an alkyl group with 1-4 carbon atoms.

59. The method of claim 58, wherein the leaving group is CF₃, S0₃ , Br, Cl, I, COO , or F.

60. The method of claim 59, wherein the leaving group is N2⁺, NO, NO2, CF3, Cl, or F.

61. The method of claim 60, wherein the leaving group is N2⁺, NO, or NO2.

62. The method of claim 61, wherein the leaving group is NO2.

or an acid chloride thereof; with a compound of formula X,

wherein R is Cl or methoxy; to afford the compound of formula VIII.

64. The method of claim 63, wherein said reaction between the compounds of formulae IX and X is conducted in the presence of a coupling reagent.

65. The method of claim 64, wherein said coupling reagent is selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), N-(3- dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDAC-HC1), diphenyl phosphoryl chloride (DPPC1), propylphosphonic anhydride, thionyl chloride, 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide (EDCI), l-[bis(dimethylamino)methylene]- lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), and 1- hydroxybenzo triazole (HOBt).

66. The method of claim 63 or 64, wherein said coupling reagent is diphenyl phosphoryl chloride (DPPC1).

67. The method of any of claims 1-18, further comprising, reacting a compound of formula V,

with formaldehyde to afford the compound of formula IV ; and

reacting a compound of formula IV,

with a chlorinating agent to afford the compound of formula Ilia:

Ilia.

68. The method of claim 67, wherein said formaldehyde is paraformaldehyde, formalin solution, trioxane, or monomeric formaldehyde.

69. The method of claim 68, wherein said formaldehyde is a formalin solution.

70. The method of claim 69, wherein the compound of formula V is reacted with

formalin at between about room temperature and about 80 °C.

71. The method of claim 67, wherein said chlorinating agent is selected from the group consisting of thionyl chloride, methane sulfonyl chloride, phosphorus oxychloride and phosphorus pentachloride.

72. The method of claim 71, wherein said reaction between the compound of formula IV and the chlorinating agent is conducted in the presence of non-nucleophilic base.

73. The method of claim 72, wherein said non-nucleophilic base is selected from the group consisting of triethylamine, diisopropyl ethylamine, N-methylmorpholine, 1,8- diazabicyclo[5.4.0]undec-7-ene, pyridine, butylamine, l,5-diazabicyclo(4.3.0)non-5- ene, and a mixture thereof.

74. The method of any of claims 71-74, wherein said reaction between the compound of formula IV and the chlorinating agent is conducted at a temperature of no more than about 60 °C.

75. The method of any of claims 67-74, further comprising reacting a compound of formula IX,

or an acid chloride thereof; with a compound of formula X,

wherein R is Cl or methoxy; to afford the compound of formula VIII,

converting the compound of formula VIII to the compound of formula VI,

and reacting a compound of formula VI with a compound of formula VII,

wherein Y is a leaving group;

to afford the compound of formula V.

76. The method of claim 75, wherein said converting is reacting a dealkylating agent with the compound of VIII.

77. The method of claim 76, wherein said dealkylating agent is an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, p-toluene sulfonic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, trifluoroborate etherate, and a mixture thereof.

78. The method of claim 77, wherein said acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, acetic acid, phosphoric acid, and a mixture thereof.

79. The method of claim 78, wherein said acid is selected from the group consisting of hydrobromic acid, acetic acid, phosphoric acid, and a mixture thereof.

80. The method of claim 75, wherein said reaction between the compounds of formulae IX and XI is conducted in the presence of a coupling reagent.

81. The method of claim 75, wherein said coupling reagent is selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), N-(3- dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (ED AC HC1), diphenyl phosphoryl chloride (DPPC1), propylphosphonic anhydride (T3P), thionyl chloride, 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1- [bis(dimethylamino)methylene] - 1 H- 1 ,2,3 -triazolo [4,5-b]pyridinium 3 -oxid hexafluorophosphate (HATU), and 1-hydroxybenzo triazole (HOBt).

82. The method of claim 81, wherein said coupling reagent is diphenyl phosphoryl

chloride (DPPC1) or propylphosphonic anhydride (T3P).

83. The method of claim 75, wherein said leaving group is selected from the group

84. The method of claim 83, wherein the leaving group is CF₃, S0₃ , Br, Cl, I, COO , or F.

85. The method of claim 84, wherein the leaving group is CF₃, Cl, or F.

86. The method of claim 85, wherein the leaving group is CF3 or F.

87. The method of claim 86, wherein the leaving group is F.

88. The method of claim 75, wherein the compound of formula VI is reacted with the compound of formula VII at between about 50 °C and about 110 °C.

89. The method of claim 88, wherein the compound of formula VI is reacted with the compound of formula VII at between about 70 °C and about 100 °C.

90. The method of claim 89, wherein the compound of formula VI is reacted with the compound of formula VII at between about 80 °C and about 90 °C.

91. The method of any of claims 67-74, further comprising reacting a compound of formula IX,

or an acid chloride thereof; with a compound of formula X,

wherein R is Cl or methoxy; to afford the compound of formula VIII,

reacting a compound of formula VIII with a compound of formula VII,

wherein Y is a leaving group;

to afford the compound of formula XI,

converting the compound of formula XI to the compound of formula V.

92. The method of claim 91, wherein said converting is reacting the compound of

formula XI with a dealkylating agent.

93. The method of claim 92, wherein said dealkylating agent is an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, p-toluene sulfonic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, trifluoroborate etherate, and a mixture thereof.

94. The method of claim 93, wherein said acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, acetic acid, phosphoric acid, and a mixture thereof.

95. The method of claim 94, wherein said acid is selected from the group consisting of hydrobromic acid, acetic acid, phosphoric acid, and a mixture thereof.

96. The method of claim 91, wherein said leaving group is selected from the group

97. The method of claim 96, wherein the leaving group is CF₃, S0₃ , Br, Cl, I, COO , or F.

98. The method of claim 96, wherein the leaving group is N₂ ⁺, NO, N0₂, CF₃, Cl, or F.

99. The method of claim 98, wherein the leaving group is N₂ ⁺, NO, N0₂.

100. The method of claim 99, wherein the leaving group is N0₂.

101. The method of claim 91, wherein said reaction between the compounds of formulae IX and X is conducted in the presence of a coupling reagent.

102. The method of claim 101, wherein said coupling reagent is selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), N-(3- dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (ED AC HC1), diphenyl phosphoryl chloride (DPPC1), propylphosphonic anhydride, thionyl chloride, 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide (EDCI), l-[bis(dimethylamino)methylene]- lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), and 1- hydroxybenzo triazole (HOBt).

103. The method of claim 101 or 102, wherein said coupling reagent is diphenyl

phosphoryl chloride (DPPC1).

104. The method of claim 91, wherein the compound of formula VII is reacted with the compound of formula VIII at between about 50 °C and about 110 °C.

105. The method of claim 104, wherein the compound of formula VII is reacted with the compound of formula VIII at between about 70 °C and about 100 °C.

106. The method of claim 105, wherein the compound of formula VII is reacted with the compound of formula VIII at between about 80 °C and about 90 °C.