WO2020206119A1 - Procédé de production d'amides de pyridone et de promédicaments associés utiles en tant que modulateurs de canaux sodiques - Google Patents

Procédé de production d'amides de pyridone et de promédicaments associés utiles en tant que modulateurs de canaux sodiques Download PDF

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WO2020206119A1
WO2020206119A1 PCT/US2020/026384 US2020026384W WO2020206119A1 WO 2020206119 A1 WO2020206119 A1 WO 2020206119A1 US 2020026384 W US2020026384 W US 2020026384W WO 2020206119 A1 WO2020206119 A1 WO 2020206119A1
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compound
formula
acid
group
another embodiment
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PCT/US2020/026384
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Michael P. Ryan
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Vertex Pharmaceuticals Incorporated
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings

Definitions

  • 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.
  • Navs Voltage-gated sodium channels
  • 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).
  • 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);
  • 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.
  • 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
  • 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)).
  • 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.
  • 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;
  • tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats.
  • 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 Ca 2+ current in the action potentials of nociceptive sensory neurons.
  • TTX tetrodotoxin
  • 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,
  • 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.
  • the invention features a method for preparing a compound of formula I,
  • R 2 and R 3 are independently hydrogen, halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen;
  • R 5 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 C3 ⁇ 4 units of said C1-C6 alkyl may be replaced with -0-;
  • R 7 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-;
  • X is -PO(OH) 2 , -PO(OH)O M + , -P0(0 ) 2* 2M + , or -P0(0 ) 2* D 2+ ;
  • M + is a
  • R 2 , R 3 , R 5 , and R 7 are not simultaneously hydrogen.
  • 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.
  • the method comprises reacting a compound of formula II,
  • 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.
  • the method comprises reacting a compound of formula III,
  • Z is halo (e.g., Cl, Br, I);
  • the present application provides a method for preparing a compound of formula III,
  • R 2 , R 3 , R 5 , R 7 , and Z are as defined herein.
  • the method comprises reacting a halogenating agent (e.g., a chlorinating agent such as thionyl chloride) with a compound of formula IV,
  • a halogenating agent e.g., a chlorinating agent such as thionyl chloride
  • the present application provides a method for preparing a compound of formula IV,
  • R 2 , R 3 , R 5 , and R 7 are as defined herein.
  • the method comprises reacting formalin with a compound of formula V,
  • the reaction is conducted in an aprotic solvent.
  • 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.
  • the reaction is conducted in an ether such as tetrahydrofuran (THF).
  • the reaction is conducted in a non-polar solvent such as benzene, toluene
  • the present application provides a method for preparing a compound of formula V.
  • the method comprises comprising coupling a compound of formula VI,
  • the present application provides a method for preparing a compound of formula VI,
  • the method of preparing the compound of formula VI comprises dealkylating a compound of formula VIII.
  • the method comprises reacting a compound of formula VIII with an acid.
  • 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.
  • the present application provides a method for preparing a compound of formula VIII,
  • the compound of formula VIII may be prepared by coupling a compound of formula IX,
  • R is methoxy or chloro
  • the present application provides a method for preparing a compound of formula V comprising converting the compound of formula XI,
  • the converting comprises dealkylating the compound of formula XI.
  • the dealkylating reaction comprises reacting the compound of formula XI with an acid.
  • the present application provides a method for preparing a compound of formula XI,
  • R is methoxy or chloro; or a salt thereof.
  • the method comprises coupling a compound of formula VII,
  • the present application is directed to methods of preparing compounds, and salts and prodrugs thereof, useful as inhibitors of sodium channels.
  • the compounds and salts of the present application may be represented by formula I,
  • R 2 and R 3 are independently hydrogen, halogen, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen;
  • R 5 is hydrogen, halogen, OH, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with -0-;
  • R 7 is hydrogen, halogen, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with -0-;
  • X is -P0(0H) 2 , -PO(OH)O M + , -P0(0 ) 2* 2M + , or -P0(0 ) 2* D 2+ ;
  • M + is a pharmaceutically acceptable monovalent cation; and
  • D 2+ is a pharmaceutically acceptable divalent cation;
  • R 2 , R 3 , R 5 , and R 7 are not simultaneously hydrogen.
  • 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.
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R 2 is H. In another embodiment, R 2 is halogen. In another embodiment, R 2 is Cl. In another embodiment, R 2 is F. In another embodiment, R 2 is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen.
  • R 2 is CF 3 . In another embodiment, R 2 is H, Cl or CF 3 .
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R 3 is H. In another embodiment, R 3 is halogen. In another embodiment, R 3 is Cl. In another embodiment, R 3 is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen. In another embodiment, R 3 is CF3. In another embodiment, R 3 is CF2CF3.
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R 5 is H.
  • R 5 is halogen.
  • R 5 is Cl.
  • R 5 is F.
  • R 5 is C 1 -C 6 alkyl.
  • R 5 is CH 3 .
  • R 5 is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CFF unit of said C 1 -C 6 alkyl is replaced with -0-.
  • R 5 is OCH 3 .
  • R 5 is OH.
  • R 5 is OCF 3 .
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R 7 is H.
  • R 7 is halogen.
  • R 7 is F.
  • R 7 is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein two non- adjacent C3 ⁇ 4 units of said C1-C6 alkyl are replaced with -0-.
  • R 7 is OCH3.
  • R 7 is OCF3.
  • 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* D 2+ ; M + is Li + , Na + , K + or N(R 9 ) 4 + ; wherein each R 9 is independently H or a C1-C4 alkyl group and D 2+ is Mg 2+ , Ca 2+ or Ba 2+ .
  • 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 + .
  • X is -PO(OH)0 M + and M + is Na + .
  • X is -PO(OH)0 M + and M + is K + .
  • X is -PO(OH)0 M + and M + is N(R 9 ) 4 + ; wherein each R 9 is independently H or a C1-C4 alkyl group.
  • X is -PO(OH)0 M + and M + is N(R 9 )4 + ; wherein each R 9 is a CH3 group.
  • 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
  • X is -P0(0 ) 2* 2M + and M + is K + .
  • X is -P0(0 ) 2* 2M + and M + is N(R 9 ) 4 + ; wherein each R 9 is independently H or a C1-C4 alkyl group.
  • X is -P0(0 ) 2* 2M + and M + is N(R 9 ) 4 + ; wherein each R 9 is a CH3 group.
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein X is -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ , Ca 2+ or Ba 2+ .
  • X is -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ . In another embodiment, X is -P0(0 )2*D 2+ and D 2+ is Ca 2+ . In another embodiment, X is
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein X is -PO(OH)2 .
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R 2 is Cl, R 3 is Cl, R 5 is OCH 3 , R 7 is F and X is -PO(OH) 2 .
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R 2 is Cl, R 3 is Cl, R 5 is OCH 3 , R 7 is F and X is -P0(0 ) 2* 2M + , M + is Li + , Na + , K + or N(R 9 )4 + wherein each R 9 is independently H or a C 1 -C 4 alkyl group.
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R 2 is Cl, R 3 is Cl, R 5 is OCH3, R 7 is F and X is-PO(OH)0 M + , M + is Li + , Na + , K + or N(R 9 )4 + wherein each R 9 is independently H or a C 1 -C 4 alkyl group.
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R 3 is CF 2 CF 3 , R 5 is OCH 3 , R 7 is F and X is -PO(OH) 2 .
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R 3 is CF 2 CF 3 , R 5 is OCH 3 , R 7 is F and X is -P0(0 ) 2* 2M + , M + is Li + , Na + , K + or N(R 9 ) 4 + wherein each R 9 is independently H or a C 1 -C 4 alkyl group.
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R 3 is CF2CF3, R 5 is OCH3, R 7 is F and X is-PO(OH)O M + , M + is Li + , Na + , K + or N(R 9 ) 4 + wherein each R 9 is independently H or a C 1 -C 4 alkyl group.
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R 3 is CF 3 , R 5 is CH 3 , R 7 is F and X is -PO(OH) 2 .
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R 3 is CF3, R 5 is CH3, R 7 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 + .
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R 3 is CF3, R 5 is CH3, R 7 is F, X is -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ , Ca 2+ or Ba 2+ . In one embodiment, X is
  • -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ .
  • X is -P0(0 ) 2* D 2+ and D 2+ is Ca 2+ .
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R 2 is CF3, R 5 is CH3, R 7 is F and X is -PO(OH) 2 .
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R 2 is CF3, R 5 is CH3, R 7 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 + .
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R 2 is CF3, R 5 is CH3, R 7 is F, X is -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ , Ca 2+ or Ba 2+ .
  • X is
  • -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ .
  • X is -P0(0 ) 2* D 2+ and D 2+ is Ca 2+ .
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R 3 is Cl, R 5 is CH3, R 7 is F and X is -PO(OH) 2 .
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R 3 is Cl, R 5 is CH3, R 7 is F and X is -P0(0 ) 2* 2M + , M + is Li + , Na + , K + or N(R 9 )4 + wherein each R 9 is independently H or a C1-C4 alkyl group.
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R 3 is Cl, R 5 is CFb, R 7 is F and X is-PO(OH)0 M + , M + is Li + , Na + , K + or N(R 9 )4 + wherein each R 9 is independently H or a C1-C4 alkyl group.
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R 2 is CF 3 , R 5 is CH 3 , R 7 is F and X is -PO(OH) 2 .
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R 2 is CF 3 , R 7 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 + .
  • the invention features a method for preparing a compound of formula I and the attendant definitions, wherein R 2 is CF 3 , R 7 is F, X is -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ , Ca 2+ or Ba 2+ . In one embodiment, X is -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ . In another embodiment, X is -P0(0 ) 2* D 2+ and D 2+ is Ca 2+ .
  • the invention provides a process for preparing a compound of formula I-A,
  • R 2 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen;
  • R 5 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-;
  • R 7 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-;
  • X is -PO(OH) 2 , -PO(OH)O M + , -P0(0 ) 2* 2M + , or -P0(0 ) 2* D 2+ ;
  • M + is a
  • the invention features a compound of formula I-A and the attendant definitions, wherein R 2 is halogen. In another embodiment, R 2 is Cl. In another embodiment, R 2 is F. In another embodiment, R 2 is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen. In another embodiment, R 2 is CF 3 . In another embodiment, R 2 is Cl or CF 3 .
  • the invention features a compound of formula I-A and the attendant definitions, wherein R 5 is halogen.
  • R 5 is Cl.
  • R 5 is F.
  • R 5 is C 1 -C 6 alkyl.
  • R 5 is CH 3 .
  • R 5 is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one C3 ⁇ 4 unit of said C 1 -C 6 alkyl is replaced with -0-.
  • R 5 is OCH 3 .
  • R 5 is OH.
  • R 5 is OCF 3 .
  • R 5 is F, Cl, CH 3 , OCH 3 , OH or OCF3.
  • the invention features a compound of formula I-A and the attendant definitions, wherein R 7 is halogen.
  • R 7 is F.
  • R 7 is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with -0-.
  • R 7 is OCH 3 .
  • R 7 is OCF 3 .
  • R 7 is F, OCH 3 or OCF 3 .
  • 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*D 2+ ; wherein M + is Li + , Na + or K + and wherein D 2+ is Mg 2+ or Ca 2+ .
  • the invention features a compound of formula I-A and the attendant definitions, wherein R 2 is CF 3 , R 5 is Cl, OCH 3 or CH 3 and R 7 is F. In one embodiment, R 2 is CF 3 , R 5 is Cl and R 7 is F. In another embodiment, R 2 is CF 3 , R 5 is OCH 3 and R 7 is F. In another embodiment, R 2 is CF 3 , R 5 is CH 3 and R 7 is F.
  • the invention features a compound of formula I-A and the attendant definitions, wherein R 2 is CF 3 , R 5 is Cl, OCH 3 or CH 3 , R 7 is F and X is -PO(OH) 2 .
  • R 2 is CF 3 , R 5 is Cl, R 7 is F and X is -PO(OH) 2 .
  • R 2 is CF 3 , R 5 is OCH 3 , R 7 is F and X is -PO(OH) 2 .
  • R 2 is CF3, R 5 is CH3, R 7 is F and X is -PO(OH)2.
  • 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*D 2+ ; M + is Li + , Na + , K + or N(R 9 )4 + ; wherein each R 9 is independently H or a C 1 -C 4 alkyl group and D 2+ is Mg 2+ , Ca 2+ or Ba 2+ .
  • the invention features a compound of formula I-A and the attendant definitions, wherein X is -PO(OH)0 M + and M + is Li + .
  • X is -PO(OH)0 M + and M + is Na + .
  • X is -P0(0H)0 M + and M + is K + .
  • X is -P0(0H)0 M + and M + is N(R 9 )4 + ; wherein each R 9 is independently H or a C 1 -C 4 alkyl group.
  • X is -PO(OH)0 M + and M + is N(R 9 )4 + ; wherein each R 9 is a CH3 group.
  • the invention features a compound of formula I-A and the attendant definitions, wherein X is -P0(0 ) 2* 2M + and M + is Li + .
  • X is -P0(0 ) 2* 2M + and M + is Na + .
  • X is -P0(0 ) 2* 2M + and M + is K + .
  • X is -P0(0 ) 2* 2M + and M + is N(R 9 )4 + ; wherein each R 9 is independently H or a C 1 -C 4 alkyl group.
  • X is -P0(0 ) 2* 2M + and M + is N(R 9 )4 + ; wherein each R 9 is a CH 3 group.
  • the invention features a compound of formula I-A and the attendant definitions, wherein X is -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ , Ca 2+ or Ba 2+ .
  • X is -P0(0 )2*D 2+ and D 2+ is Mg 2+ .
  • X is -PO(0 )2»D 2+ and D 2+ is Ca 2+ .
  • X is -P0(0 ) 2* D 2+ and D 2+ is Ba 2+ .
  • the invention features a compound of formula I-A and the attendant definitions, wherein X is -PO(OH)2.
  • the invention features a compound of formula I-A and the attendant definitions, wherein R 2 is CF3, R 5 is CH3, R 7 is F and X is -PO(OH)2.
  • the invention features a compound of formula I-A and the attendant definitions, wherein R 2 is CF 3 , R 5 is CH 3 , R 7 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 + .
  • the invention features a compound of formula I-A and the attendant definitions, wherein R 2 is CF 3 , R 5 is CFb, R 7 is F, X is -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ , Ca 2+ or Ba 2+ . In one embodiment, X is -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ . In another embodiment, X is -P0(0 ) 2* D 2+ and D 2+ is Ca 2+ .
  • the invention provides a process for preparing a compound of formula I-B,
  • R 3 is halogen, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen;
  • R 5 is halogen, OH, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with -0-;
  • R 7 is halogen, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with -0-;
  • X is -PO(OH) 2 , -PO(OH)O M + , -P0(0 ) 2* 2M + , or -P0(0 ) 2* D 2+ ;
  • M + is a
  • the invention features a compound of formula I-B and the attendant definitions, wherein R 3 is halogen. In another embodiment, R 3 is Cl. In another embodiment, R 3 is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen.
  • R 3 is CF 3 . In another embodiment, R 3 is CF 2 CF 3 .
  • the invention features a compound of formula I-B and the attendant definitions, wherein R 5 is halogen.
  • R 5 is Cl.
  • R 5 is F.
  • R 5 is C 1 -C 6 alkyl.
  • R 5 is CH 3 .
  • R 5 is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with -0-.
  • R 5 is OCH 3 .
  • R 5 is OH.
  • R 5 is OCF 3 .
  • the invention features a compound of formula I-B and the attendant definitions, wherein R 7 is halogen.
  • R 7 is F.
  • R 7 is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein two non-adjacent CH2 units of said C1-C6 alkyl are replaced with -0-.
  • R 7 is OCH3.
  • R 7 is OCF3.
  • 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* D 2+ ; wherein M + is Li + , Na + or K + and wherein D 2+ is Mg 2+ or Ca 2+ .
  • the invention features a compound of formula I-B and the attendant definitions, wherein R 3 is CF3, R 5 is F or CH3 and R 7 is F. In one embodiment, R 3 is Cl, R 5 is CH3 and R 7 is F. In another embodiment, R 3 is CF2CF3, R 5 is OCH3 and R 7 is F.
  • the invention features a compound of formula I-B and the attendant definitions, wherein R 3 is CF3, R 5 is F or CH3, R 7 is F and X is -PO(OH)2.
  • R 3 is Cl, R 5 is CFb, R 7 is F and X is -PO(OH)2. In another embodiment, R 3 is CF2CF3, R 5 is OCH3, R 7 is F and X is -PO(OH)2.
  • 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* D 2+ ; M + is Li + , Na + , K + or N(R 9 )4 + ; wherein each R 9 is independently H or a C1-C4 alkyl group and D 2+ is Mg 2+ , Ca 2+ or Ba 2+ .
  • the invention features a compound of formula I-B and the attendant definitions, wherein X is -P0(0H)0 M + and M + is Li + .
  • X is -PO(OH)0 M + and M + is Na + .
  • X is -P0(0H)0 M + and M + is K + .
  • X is -PO(OH)0 M + and M + is N(R 9 )4 + ; wherein each R 9 is independently H or a C1-C4 alkyl group.
  • X is -PO(OH)0 M + and M + is N(R 9 )4 + ; wherein each R 9 is a CH3 group.
  • the invention features a compound of formula I-B and the attendant definitions, wherein X is -P0(0 ) 2* 2M + and M + is Li + .
  • X is -P0(0 ) 2* 2M + and M + is Na + .
  • X is -P0(0 ) 2* 2M + and M + is K + .
  • X is -P0(0 ) 2* 2M + and M + is N(R 9 )4 + ; wherein each R 9 is independently H or a C 1 -C 4 alkyl group.
  • X is -P0(0 ) 2* 2M + and M + is N(R 9 )4 + ; wherein each R 9 is a CH 3 group.
  • the invention features a compound of formula I-B and the attendant definitions, wherein X is -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ , Ca 2+ or Ba 2+ .
  • X is -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ .
  • X is -P0(0 ) 2* D 2+ and D 2+ is Ca 2+ .
  • X is -P0(0 ) 2* D 2+ and D 2+ is Ba 2+ .
  • the invention features a compound of formula I-B and the attendant definitions, wherein X is -PO(OH)2.
  • the invention features a compound of formula I-B and the attendant definitions, wherein R 3 is CF 2 CF 3 , R 5 is OCH 3 , R 7 is F and X is -PO(OH) 2 .
  • the invention features a compound of formula I-B and the attendant definitions, wherein R 3 is CF 2 CF 3 , R 5 is OCH 3 , R 7 is F and X is
  • M + is Li + , Na + , K + or N(R 9 )4 + wherein each R 9 is independently H or a Ci- C 4 alkyl group.
  • the invention features a compound of formula I-B and the attendant definitions, wherein R 3 is CF2CF3, R 5 is OCH3, R 7 is F and X is
  • M + is Li + , Na + , K + or N(R 9 )4 + wherein each R 9 is independently H or a Ci- C 4 alkyl group.
  • the invention features a compound of formula I-B and the attendant definitions, wherein R 3 is CF 3 , R 5 is CH 3 , R 7 is F and X is -PO(OH) 2 .
  • the invention features a compound of formula I-B and the attendant definitions, wherein R 3 is CF 3 , R 5 is CH 3 , R 7 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 + .
  • the invention features a compound of formula I-B and the attendant definitions, wherein R 3 is CF 3 , R 5 is CH 3 , R 7 is F, X is -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ , Ca 2+ or Ba 2+ . In one embodiment, X is -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ . In another embodiment, X is -P0(0 ) 2* D 2+ and D 2+ is Ca 2+ .
  • the invention features a compound of formula I-B and the attendant definitions, wherein R 3 is Cl, R 5 is CFb, R 7 is F and X is -PO(OH)2.
  • the invention features a compound of formula I-B and the attendant definitions, wherein R 3 is Cl, R 5 is CH 3 , R 7 is F and X is -P0(0 ) 2* 2M + , M + is Li + , Na + , K + or N(R 9 )4 + wherein each R 9 is independently H or a C 1 -C 4 alkyl group.
  • the invention features a compound of formula I-B and the attendant definitions, wherein R 3 is Cl, R 5 is CH 3 , R 7 is F and X is -PO(OH)0 M + , M + is Li + , Na + , K + or N(R 9 )4 + wherein each R 9 is independently H or a C 1 -C 4 alkyl group.
  • the invention provides a process for preparing a compound of formula I-C,
  • R 2 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen;
  • R 7 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-;
  • X is -PO(OH) 2 , -PO(OH)O M + , -P0(0 ) 2* 2M + , or -P0(0 ) 2* D 2+ ;
  • M + is a
  • the invention features a compound of formula I-C and the attendant definitions, wherein R 2 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R 2 is CF3.
  • the invention features a compound of formula I-C and the attendant definitions, wherein R 7 is halogen.
  • R 7 is F.
  • R 7 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C1-C6 alkyl may be replaced with -0-.
  • R 7 is OCF 3 .
  • 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» D 2+ ; wherein M + is Li + , Na + or K + and wherein D 2+ is Mg 2+ or Ca 2+ .
  • the invention features a compound of formula I-C and the attendant definitions, wherein R 2 is CF 3 and R 7 is F or OCF 3 .
  • the invention features a compound of formula I-C and the attendant definitions, wherein R 2 is CF 3 , R 7 is F or OCF 3 and X is -PO(OH) 2 .
  • 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» D 2+ ; M + is Li + , Na + , K + or N(R 9 )4 + ; wherein each R 9 is independently H or a C 1 -C 4 alkyl group and D 2+ is Mg 2+ , Ca 2+ or Ba 2+ .
  • the invention features a compound of formula I-C and the attendant definitions, wherein X is -PO(OH)0 M + and M + is Li + .
  • X is -PO(OH)0 M + and M + is Na + .
  • X is -P0(0H)0 M + and M + is K + .
  • X is -P0(0H)0 M + and M + is N(R 9 )4 + ; wherein each R 9 is independently H or a C 1 -C 4 alkyl group.
  • X is -PO(OH)0 M + and M + is N(R 9 )4 + ; wherein each R 9 is a CH3 group.
  • the invention features a compound of formula I-C and the attendant definitions, wherein X is -P0(0 ) 2* 2M + and M + is Li + .
  • X is -P0(0 ) 2* 2M + and M + is Na + .
  • X is -P0(0 ) 2* 2M + and M + is K + .
  • X is -P0(0 ) 2* 2M + and M + is N(R 9 )4 + ; wherein each R 9 is independently H or a C 1 -C 4 alkyl group.
  • X is -P0(0 ) 2* 2M + and M + is N(R 9 )4 + ; wherein each R 9 is a CH 3 group.
  • the invention features a compound of formula I-C and the attendant definitions, wherein X is -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ , Ca 2+ or Ba 2+ . In one embodiment, X is -P0(0 )2*D 2+ and D 2+ is Mg 2+ . In another embodiment, X is
  • -P0(0 ) 2* D 2+ and D 2+ is Ca 2+ .
  • X is -P0(0 ) 2* D 2+ and D 2+ is Ba 2+ .
  • the invention features a compound of formula I-C and the attendant definitions, wherein X is -PO(OH)2.
  • the invention features a compound of formula I-C and the attendant definitions, wherein R 2 is CF 3 , R 5 is CH 3 , R 7 is F and X is -PO(OH) 2 .
  • the invention features a compound of formula I-C and the attendant definitions, wherein R 2 is CF 3 , R 7 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 + .
  • the invention features a compound of formula I-C and the attendant definitions, wherein R 2 is CF 3 , R 7 is F, X is -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ , Ca 2+ or Ba 2+ . In one embodiment, X is -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ . In another embodiment, X is -P0(0 )2*D 2+ and D 2+ is Ca 2+ .
  • the invention provides a process for preparing a compound of formula I-D,
  • R 3 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen;
  • R 7 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-;
  • X is -PO(OH) 2 , -PO(OH)O M + , -P0(0 ) 2* 2M + , or -P0(0 ) 2* D 2+ ;
  • M + is a
  • the invention features a compound of formula I-D and the attendant definitions, wherein R 3 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R 3 is CF3. In another embodiment, R 3 is
  • the invention features a compound of formula I-D and the attendant definitions, wherein R 7 is halogen.
  • R 7 is F.
  • R 7 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-.
  • R 7 is OCF3.
  • 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* D 2+ ; wherein M + is Li + , Na + or K + and wherein D 2+ is Mg 2+ or Ca 2+ .
  • the invention features a compound of formula I-D and the attendant definitions, wherein R 3 is CF3 and R 7 is CF3. In another embodiment, R 3 is CF2CF3 and R 7 is F. [00106] In another embodiment, the invention features a compound of formula I-D and the attendant definitions, wherein R 3 is CF3, R 7 is CF3 and X is -PO(OH)2. In another embodiment, R 3 is CF2CF3, R 7 is F and X is -PO(OH)2.
  • 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* D 2+ ; M + is Li + , Na + , K + or N(R 9 )4 + ; wherein each R 9 is independently H or a C 1 -C 4 alkyl group and D 2+ is Mg 2+ , Ca 2+ or Ba 2+ .
  • the invention features a compound of formula I-D and the attendant definitions, wherein X is -PO(OH)0 M + and M + is Li + .
  • X is -PO(OH)0 M + and M + is Na + .
  • X is -P0(0H)0 M + and M + is K + .
  • X is -P0(0H)0 M + and M + is N(R 9 )4 + ; wherein each R 9 is independently H or a C 1 -C 4 alkyl group.
  • X is -PO(OH)0 M + and M + is N(R 9 )4 + ; wherein each R 9 is a CFb group.
  • the invention features a compound of formula I-D and the attendant definitions, wherein X is -P0(0 ) 2* 2M + and M + is Li + .
  • X is -P0(0 ) 2* 2M + and M + is Na + .
  • X is -P0(0 ) 2* 2M + and M + is K + .
  • X is -P0(0 ) 2* 2M + and M + is N(R 9 )4 + ; wherein each R 9 is independently H or a C 1 -C 4 alkyl group.
  • X is -P0(0 ) 2* 2M + and M + is N(R 9 )4 + ; wherein each R 9 is a CH 3 group.
  • the invention features a compound of formula I-D and the attendant definitions, wherein X is -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ , Ca 2+ or Ba 2+ . In one embodiment, X is -P0(0 )2*D 2+ and D 2+ is Mg 2+ . In another embodiment, X is
  • -P0(0 ) 2* D 2+ and D 2+ is Ca 2+ .
  • X is -P0(0 ) 2* D 2+ and D 2+ is Ba 2+ .
  • the invention features a compound of formula I-D and the attendant definitions, wherein X is -PO(OH)2.
  • the invention provides a process for preparing a compound of formula I-E,
  • R 2 and R 3 are independently halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is
  • R 7 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-;
  • X is -PO(OH) 2 , -PO(OH)O M + , -PO(0) 2* 2M + , or -P0(0 ) 2* D 2+ ;
  • M + is a
  • the invention features a compound of formula I-E and the attendant definitions, wherein R 2 is halogen. In another embodiment, R 2 is Cl.
  • the invention features a compound of formula I-E and the attendant definitions, wherein R 3 is halogen. In another embodiment, R 3 is Cl.
  • the invention features a compound of formula I-E and the attendant definitions, wherein R 7 is halogen. In one embodiment, R 7 is F.
  • 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» D 2+ ; wherein M + is Li + , Na + or K + and wherein D 2+ is Mg 2+ or Ca 2+ .
  • the invention features a compound of formula I-E and the attendant definitions, wherein R 2 and R 3 are Cl and R 7 is F.
  • the invention features a compound of formula I-E and the attendant definitions, wherein R 2 and R 3 are Cl, R 7 is F and X is -PO(OH) 2 .
  • 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» D 2+ ; M + is Li + , Na + , K + or N(R 9 )4 + ; wherein each R 9 is independently H or a C1-C4 alkyl group and D 2+ is Mg 2+ , Ca 2+ or Ba 2+ .
  • the invention features a compound of formula I-E and the attendant definitions, wherein X is -PO(OH)0 M + and M + is Li + .
  • X is -PO(OH)0 M + and M + is Na + .
  • X is -P0(0H)0 M + and M + is K + .
  • X is -P0(0H)0 M + and M + is N(R 9 )4 + ; wherein each R 9 is independently H or a C1-C4 alkyl group.
  • X is -PO(OH)0 M + and M + is N(R 9 )4 + ; wherein each R 9 is a CH3 group.
  • the invention features a compound of formula I-E and the attendant definitions, wherein X is -P0(0 ) 2* 2M + and M + is Li + .
  • X is -P0(0 ) 2* 2M + and M + is Na + .
  • X is -P0(0 ) 2* 2M + and M + is K + .
  • X is -P0(0 ) 2* 2M + and M + is N(R 9 )4 + ; wherein each R 9 is independently H or a C1-C4 alkyl group.
  • X is -P0(0 ) 2* 2M + and M + is N(R 9 )4 + ; wherein each R 9 is a CH3 group.
  • the invention features a compound of formula I-E and the attendant definitions, wherein X is -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ , Ca 2+ or Ba 2+ . In one embodiment, X is -P0(0 )2*D 2+ and D 2+ is Mg 2+ . In another embodiment, X is
  • -P0(0 ) 2* D 2+ and D 2+ is Ca 2+ .
  • X is -P0(0 ) 2* D 2+ and D 2+ is Ba 2+ .
  • the invention features a compound of formula I-E and the attendant definitions, wherein X is -PO(OH)2.
  • the invention provides a process for preparing a compound of formula I-F,
  • R 2 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen
  • R 5 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-;
  • X is -PO(OH) 2 , -PO(OH)O M + , -P0(0 ) 2* 2M + , or -P0(0 ) 2* D 2+ ;
  • M + is a
  • the invention features a compound of formula I-F and the attendant definitions, wherein R 2 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R 2 is CF3.
  • the invention features a compound of formula I-F and the attendant definitions, wherein R 5 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with -0-.
  • R 5 is CH 3 .
  • R 5 is OCF3.
  • 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» D 2+ ; wherein M + is Li + , Na + or K + and wherein D 2+ is Mg 2+ or Ca 2+ .
  • the invention features a compound of formula I-F and the attendant definitions, wherein R 2 is CF3, R 7 is CH3 or OCF3 and X is -PO(OH) 2 .
  • 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» D 2+ ; M + is Li + , Na + , K + or N(R 9 )4 + ; wherein each R 9 is independently H or a C1-C4 alkyl group and D 2+ is Mg 2+ , Ca 2+ or Ba 2+ .
  • the invention features a compound of formula I-F and the attendant definitions, wherein X is -P0(0H)0 M + and M + is Li + .
  • X is -PO(OH)0 M + and M + is Na + .
  • X is -PO(OH)0 M + and M + is K + .
  • X is -PO(OH)0 M + and M + is N(R 9 )4 + ; wherein each R 9 is independently H or a C1-C4 alkyl group.
  • X is -PO(OH)0 M + and M + is N(R 9 )4 + ; wherein each R 9 is a CH3 group.
  • the invention features a compound of formula I-F and the attendant definitions, wherein X is -R0(0 ) 2 ⁇ 2M + and M + is Li + .
  • X is -R0(0 ) 2 ⁇ 2M + and M + is Na + .
  • X is -R0(0 ) 2 ⁇ 2M + and M + is K + .
  • X is -R0(0 ) 2 ⁇ 2M + and M + is N(R 9 )4 + ; wherein each R 9 is independently H or a C 1 -C 4 alkyl group.
  • X is -P0(0 ) 2* 2M + and M + is N(R 9 ) 4 + ; wherein each R 9 is a CH 3 group.
  • the invention features a compound of formula I-F and the attendant definitions, wherein X is -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ , Ca 2+ or Ba 2+ . In one embodiment, X is -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ . In another embodiment, X is
  • -P0(0 ) 2* D 2+ and D 2+ is Ca 2+ .
  • X is -P0(0 ) 2* D 2+ and D 2+ is Ba 2+ .
  • the invention features a compound of formula I-F and the attendant definitions, wherein X is -PO(OH)2.
  • the invention provides a process for preparing a compound of formula I-G,
  • R 2 and R 3 are independently halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is
  • R 5 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-;
  • R 7 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-;
  • X is -PO(OH) 2 , -PO(OH)O M + , -P0(0 ) 2* 2M + , or -P0(0 ) 2* D 2+ ;
  • M + is a
  • the invention features a compound of formula I-G and the attendant definitions, wherein R 2 is halogen. In another embodiment, R 2 is Cl. [00136] In another embodiment, the invention features a compound of formula I-G and the attendant definitions, wherein R 3 is halogen. In another embodiment, R 3 is Cl.
  • the invention features a compound of formula I-G and the attendant definitions, wherein R 5 is halogen.
  • R 5 is Cl.
  • R 5 is F.
  • R 5 is C1-C6 alkyl.
  • R 5 is CH3.
  • R 5 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-.
  • R 5 is OCH3.
  • R 5 is OH.
  • R 5 is OCF3.
  • the invention features a compound of formula I-G and the attendant definitions, wherein R 7 is halogen. In one embodiment, R 7 is F.
  • 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* D 2+ ; wherein M + is Li + , Na + or K + and wherein D 2+ is Mg 2+ or Ca 2+ .
  • the invention features a compound of formula I-G and the attendant definitions, wherein R 2 and R 3 are Cl, R 5 is OCH3 and R 7 is F.
  • the invention features a compound of formula I-G and the attendant definitions, wherein R 2 and R 3 are Cl, R 7 is F, R 5 is OCH3 and X is
  • 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* D 2+ ; M + is Li + , Na + , K + or N(R 9 )4 + ; wherein each R 9 is independently H or a C1-C4 alkyl group and D 2+ is Mg 2+ , Ca 2+ or Ba 2+ .
  • 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 + .
  • X is -P0(0H)0 M + and M + is N(R 9 )4 + ; wherein each R 9 is independently H or a C1-C4 alkyl group.
  • X is -PO(OH)0 M + and M + is N(R 9 )4 + ; wherein each R 9 is a CH3 group.
  • the invention features a compound of formula I-G and the attendant definitions, wherein X is -P0(0 ) 2* 2M + and M + is Li + .
  • X is -P0(0 ) 2* 2M + and M + is Na + .
  • X is -P0(0 ) 2* 2M + and M + is K + .
  • X is -P0(0 ) 2* 2M + and M + is N(R 9 )4 + ; wherein each R 9 is independently H or a C 1 -C 4 alkyl group.
  • X is -P0(0 ) 2* 2M + and M + is N(R 9 ) 4 + ; wherein each R 9 is a CH 3 group.
  • the invention features a compound of formula I-G and the attendant definitions, wherein X is -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ , Ca 2+ or Ba 2+ . In one embodiment, X is -P0(0 ) 2* D 2+ and D 2+ is Mg 2+ . In another embodiment, X is
  • -P0(0 ) 2* D 2+ and D 2+ is Ca 2+ .
  • X is -P0(0 ) 2* D 2+ and D 2+ is Ba 2+ .
  • the invention features a compound of formula I-G and the attendant definitions, wherein X is -PO(OH)2.
  • the invention features a compound of formula I-G and the attendant definitions, wherein R 2 is Cl, R 3 is Cl, R 5 is OCH3, R 7 is F and X is
  • the invention features a compound of formula I-G and the attendant definitions, wherein R 2 is Cl, R 3 is Cl, R 5 is OCH 3 , R 7 is F, X is
  • M + is Li + , Na + , K + or N(R 9 )4 + wherein each R 9 is independently H or a C 1 -C 4 alkyl group.
  • the invention features a compound of formula I-G and the attendant definitions, wherein R 2 is Cl, R 3 is Cl, R 5 is OCH 3 , R 7 is F, X is -PO(OH)0 M + and M + is Li + , Na + , K + or N(R 9 )4 + wherein each R 9 is independently H or a C 1 -C 4 alkyl group.
  • the compounds prepared in accordance with the methods of the present application may be selected from the following group (or a salt thereof):
  • R 2 , R 3 , R 5 , and R 7 are as defined in any of embodiments above; comprising deprotecting a compound of formula II,
  • 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.
  • the deprotection step comprises reacting the compound of formula II with an acid.
  • 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.
  • the acid is acetic acid or propionic acid.
  • 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.
  • the compound of formula I 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 solvent system comprises DMSO and ethyl acetate.
  • 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.
  • the deprotecting step comprises reacting the compound of formula II with a base to afford a compound of formula Ila,
  • any combination of suitable base and reaction conditions may be used to convert the compound of formula II to the compound of formula Ila.
  • 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.
  • a weaker base is used to partially deprotect the compound of formula II, higher temperature and/or longer reaction time may be used.
  • 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.
  • the acid may be acetic acid or propionic acid.
  • 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.
  • the present application also provides for a method of preparing the compound of formula II comprising reacting a compound of formula III,
  • the compound of formula III is a compound of formula Ilia:
  • 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.
  • the reaction between the compound of formula III, or a salt thereof, and KitBujiPCU may be conducted in the presence of a base.
  • 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.
  • the reaction between the compound of formula III, or a salt thereof, and K(tBu) 2 P0 4 may be conducted at a temperature of no more than about 90 °C.
  • reaction between the compound of formula III, or a salt thereof, and K(tBu) 2 P0 4 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) 2 P0 4 may be conducted at a temperature of no more than about 70 °C.
  • the reaction between the compound of formula III, or a salt thereof, and K(tBu) 2 P0 4 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.
  • the reaction between the compound of formula III, or a salt thereof, and K(tBu) 2 P0 4 may be conducted in the presence of Nal.
  • the present application provides for a method of preparing a compound of formula
  • the halogenating agent is a chlorinating agent.
  • the compound of formula III is a compound of formula Ilia:
  • 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.
  • any chlorinating agent suitable for chlorinating the compound of formula IV may be used.
  • the chlorinating agent is thionyl chloride, methanesulfonyl chloride, phosphorus oxychloride or phosphorus pentachloride.
  • the chlorinating agent is methanesulfonyl chloride.
  • the chlorinating agent is thionyl chloride.
  • 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.
  • the reaction between the compound of formula IV and the chlorinating agent is conducted at a
  • 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.
  • 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.
  • 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.
  • the source of formaldehyde is a formalin solution.
  • the formalin solution comprises methanol and/or water.
  • 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.
  • the compound of formula V is reacted with formaldehyde at between about room temperature and about 80°C.
  • any suitable leaving group may be used.
  • the leaving group is N 2 + , NO, NOi, S0 2 R ⁇ NMe 3 + , CF 3 , CHO, COR, COOH, S0 3 , Br, Cl, I, COO , or F wherein R’ is an alkyl group with 1-4 carbon atoms.
  • the leaving group is CF 3 , S0 3 , Br, Cl, I, COO , or F.
  • the leaving group may be CF 3 , Cl, or F.
  • the leaving group is CF 3 or F.
  • the leaving group is F.
  • 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.
  • R is Cl or methoxy
  • 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.
  • any dealkylating agent may be suitable to dealkylate the compound of formula VIII to afford the compound of formula VI.
  • 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.
  • 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.
  • the acid is hydrochloric acid, hydrobromic acid, acetic acid, propionic acid, or mixtures thereof.
  • the acid is hydrobromic acid, acetic acid, propionic acid, or mixtures thereof.
  • R is a halo, such as chloro
  • the present application provides for a method of preparing a compound of formula VIII, comprising reacting a compound of formula IX,
  • the reaction between the compounds of formulae IX and X is conducted in the presence of a coupling reagent.
  • a 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.
  • the coupling reagent is diethyl chlorophosphate, diphenyl chlorophosphate, propylphosphonic anhydride (T3P), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), N-(3-dimethylaminopropyl)-N’ -ethylcarbodiimide
  • the coupling reagent is diphenyl phosphoryl chloride (DPPC1) or propylphosphonic anhydride (T3P).
  • R is Cl or methoxy; to the compound of formula V.
  • R is an alkoxy group (such as methoxy)
  • the conversion reaction is a dealkylation reaction.
  • R is alkoxy, reacting the compound of formula XI with a dealkylating agent affords the compound of formula V.
  • 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.
  • any dealkylating agent may be suitable to dealkylate the compound of formula XI, or a salt thereof, to afford the compound of formula V.
  • 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.
  • 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.
  • 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.
  • R is Cl or methoxy
  • 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.
  • the leaving group is N 2 + , NO, NO 2 , SO 2 R’, NMe 3 + , CF 3 , CHO, COR’, COOH, SOT, Br, Cl, I, COO , or F wherein R’ is an alkyl group with 1-4 carbon atoms.
  • the leaving group is CF3, SO3 , Br, Cl, I, COO , or F.
  • the leaving group is CF3, SO3 , Br, Cl, I, COO , or F.
  • the leaving group is N2 + , NO, NO2, CF3, Cl, or F.
  • the leaving group is N2 + , NO, or NO2.
  • the leaving group is NO2.
  • 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.
  • the present application provides for a method of preparing a compound of formula
  • the reaction between the compounds of formulae IX and X is conducted in the presence of a coupling reagent.
  • a 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.
  • 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).
  • the coupling reagent is diphenyl phosphonic anhydride (T
  • 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.
  • the halogenating agent is a chlorinating agent.
  • the compound of formula III is a compound of formula Ilia:
  • 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.
  • any source of formaldehyde may be used. Suitable sources of formaldehyde include
  • the source of formaldehyde is a formalin solution.
  • the formalin solution comprises methanol and/or water.
  • 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.
  • the compound of formula V is reacted with formaldehyde at between about room temperature and about 80 °C.
  • any chlorinating agent suitable for chlorinating the compound of formula IV may be used.
  • 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.
  • the non-nucleophilic base is triethylamine or diisopropyl ethylamine.
  • the non-nucleophilic base is diisopropyl ethylamine.
  • the reaction between the compound of formula IV and the chlorinating agent is conducted at a temperature of no more than about 60 °C.
  • the reaction between the compounds of formulae IX and X is conducted in the presence of a coupling reagent.
  • a 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.
  • 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).
  • the coupling reagent is diphenyl phosphonic anhydride (T
  • Any dealkylating agent may be suitable to dealkylate the compound of formula VIII to afford the compound of formula VI.
  • the dealkylating agent is an acid.
  • 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.
  • 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.
  • 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.
  • any suitable leaving group may be used.
  • the leaving group is
  • the leaving group is CF 3 , S0 3 , Br, Cl, I, COO , or F. In other embodiments, the leaving group may be CF 3 , Cl, or F. In some embodiments, the leaving group is CF 3 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.
  • 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.
  • the reaction between the compounds of formulae IX and X is conducted in the presence of a coupling reagent.
  • a 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.
  • 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).
  • the coupling reagent is diphenyl phosphonic anhydride (T
  • 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.
  • 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 some embodiments, the leaving group is CF3, SO3 , Br, Cl, I, COO , or F. In some
  • 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.
  • 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.
  • 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.
  • the dealkylating agent is an acid.
  • 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.
  • 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.
  • the method of preparing the compound of formula I can be carried out as a batch process or as a continuous process.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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
  • 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.
  • 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.
  • 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
  • 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).
  • orthopedic procedure pain e.g., total knee replacement, total hip replacement and laminectomy
  • hernia pain e.g., hemorrhoid pain
  • dental pain e.g., third molar extractions
  • 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.
  • 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.
  • the pain comprises gut pain, including inflammatory bowel disease pain, Crohn’s disease pain or interstitial cystitis pain.
  • the pain comprises neuropathic pain
  • 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.
  • the pain comprises musculoskeletal pain, such as
  • osteoarthritis pain back pain, cold pain, bum pain or dental pain.
  • the pain comprises inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain or vulvodynia.
  • the pain comprises inflammatory pain, such as rheumatoid arthritis pain.
  • the pain comprises idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.
  • the method comprises treating pathological cough.
  • the method comprises treating trigeminal neuralgia or herpetic neuralgia.
  • the pain comprises musculoskeletal pain. In some embodiments, the pain comprises musculoskeletal pain.
  • the musculoskeletal pain comprises osteoarthritis pain.
  • the pain comprises neuropathic pain.
  • the neuropathic pain comprises idiopathic small-fiber neuropathy.
  • the phrase“idiopathic small-fiber neuropathy” includes any small fiber neuropathy.
  • the neuropathic pain comprises small-fiber neuropathy.
  • the pain comprises acute pain.
  • the acute pain comprises acute post-operative pain.
  • the pain comprises postsurgical pain.
  • 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.
  • the neurodegenerative disease is multiple sclerosis.
  • the neurodegenerative disease is a genetic form of autism called Pitt Hopkins Syndrome (PTHS).
  • each occurrence of the following variables independently has the following definition: R 2 , R 3 , R 5 , R 7 , 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.
  • R may be Cl or F.
  • 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.
  • 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.
  • R is OPG
  • PG may be methyl, ethyl, isopropyl, benzyl, 2- tetrahydropyranyl, acetyl, trifluoroacetyl, trialkylsilyl, aryldialkylsilyl, alkyldiarylsilyl, or triarylsilyl.
  • PG is methyl.
  • 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.
  • 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.
  • 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.
  • 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.
  • Y is F or NO2.
  • 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.
  • 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.
  • 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).
  • T3P propylphosphonic anhydride
  • EDCI diethyl chlorophosphate
  • diphenyl chlorophosphate diphenyl chlorophosphate
  • thionyl chloride l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • 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).
  • DMAP N,N- dimethylaminopyridine
  • 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.
  • 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.
  • the base is a neutral organic base.
  • 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.
  • the base is triethylamine.
  • the coupling reagent is propylphosphonic anhydride
  • the base is triethylamine
  • 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.
  • the solvent is N-methyl-2-pyrrolidinone, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, isopropyl acetate, methyl isobutyl ketone, 2- methyltetrahydrofuran, tetrahydrofuran, dichloromethane, chloroform, or tetrachloroethylene.
  • the solvent is 2-methyltetrahydrofuran or tetrahydrofuran.
  • the solvent is 2-methyltetrahydrofuran.
  • the solvent is a ketone solvent, such as methyl isobutyl ketone, methyl ethyl ketone, or acetone.
  • the solvent is an ethereal solvent, such as tetrahydrofuran, 2- methyltetrahydrofuran, or methyl tert- butyl ether.
  • the solvent is an ester solvent, such as ethyl acetate or isopropyl acetate.
  • the solvent is a halogenated solvent, such as tetrachloroethylene, dichloroethane, chloroform, carbon
  • the solvent is a polar aprotic solvent, such as acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or N-methyl-2- pyrrolidinone.
  • the solvent is an aromatic solvent, such as toluene, benzene, or xylene.
  • the solvent is 2-methyltetrahydrofuran, tetrahydrofuran, methylene chloride, or ethyl acetate.
  • 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
  • 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.
  • 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.
  • 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
  • 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) .
  • 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.
  • the conjugate acid of the base has a pKa that is higher than the pKa of the compound of formula VIII.
  • 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.
  • the base is potassium carbonate.
  • 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.
  • 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.
  • the solvent is 2-methyltetrahydrofuran or tetrahydrofuran.
  • the solvent is 2-methyltetrahydrofuran.
  • the solvent is a ketone solvent, such as methyl isobutyl ketone, methyl ethyl ketone, or acetone.
  • the solvent is an ethereal solvent, such as tetrahydrofuran, 2-methyltetrahydrofuran, or methyl tert- butyl ether.
  • the solvent is an ester solvent, such as ethyl acetate or isopropyl acetate.
  • the solvent is a halogenated solvent, such as tetrachloroethylene, dichloroethane, chloroform, carbon tetrachloride, or dichloromethane.
  • the solvent is a polar aprotic solvent, such as acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or N-methyl- 2-pyrrolidinone.
  • the solvent is an aromatic solvent, such as toluene, benzene, or xylene.
  • the solvent is N-methyl-2-pyrrolidinone.
  • the base is potassium carbonate, and the solvent is N-methyl- 2-pyrrolidinone.
  • the base is 2-/eri-butyl- l,l,3,3-tetramethylguanidme, and the solvent is acetonitrile.
  • the base is 2- er/-buty!-l, 1,3,3- tetramethylguanidine, and the solvent is methyl isobutyl ketone.
  • the base is potassium carbonate, and the solvent is N,N-dimethy!formamide.
  • the base is potassium carbonate, and the solvent is dimethyl sulfoxide.
  • 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.
  • the compound of formula VII is reacted with the compound of formula VIII at between about 50 °C and about 110 °C.
  • the compound of formula VII is reacted with the compound of formula VIII at between about 70 °C and about 100 °C.
  • the compound of formula VII is reacted with the compound of formula VIII at between about 80 °C and about 90 °C.
  • 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.
  • the reaction may be conducted at elevated pressure when the temperature exceeds the boiling point of the solvent in which the reaction is conducted.
  • the pressure is no more than about 100 bars.
  • the pressure is between about 1 bar and about 100 bars.
  • the temperature is between about 10 bars and about 20 bars.
  • 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.
  • a suitable solvent such as dimethylformamide
  • a suitable base such as potassium carbonate
  • 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).
  • 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.
  • 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.
  • 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.
  • R is OPG, the compound is deprotected to obtain the pyridone of formula V.
  • 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).
  • 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.
  • 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.
  • 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.
  • the deprotection of the compound of formula XI, or a salt thereof is accomplished by reacting the compound of formula XI, or a salt
  • 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.
  • the acid is hydrogen bromide in acetic acid (e.g., 33% HBr in acetic acid).
  • the acid is pTsOH, which may be used in combination with LiCl or LiBr.
  • between about 2.0 and 3.0 equivalents of hydrogen bromide are used relative to the compound of formula V, or a salt thereof.
  • the acid is hydrochloric acid.
  • the deprotection of the compound of formula XI, or a salt thereof, may be conducted in variety of solvents.
  • the solvent is acetic acid.
  • the deprotection of the compound of formula XI, or a salt thereof may be conducted at any suitable temperature.
  • 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.
  • 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.
  • Step 1 Preparation of compound (4)
  • 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.
  • Step 2 Conversion of compound (4) to compound (8)
  • Step 3 Conversion of compound (8) to compound (9)
  • 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
  • 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.
  • OPG as defined above
  • 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).
  • 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.
  • the deprotection of the compound of formula VIII, or a salt thereof is
  • 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.
  • the acid is hydrogen bromide in acetic acid (e.g., 33% HBr in acetic acid).
  • 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.
  • the acid is hydrochloric acid.
  • the deprotection of the compound of formula VIII, or a salt thereof, may be conducted in variety of solvents.
  • the solvent is acetic acid.
  • the deprotection of the compound of formula VIII, or a salt thereof may be conducted at any suitable temperature.
  • 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.
  • 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 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.
  • the conjugate acid of the base has a pKa that is higher than the pKa of the compound of formula VIII.
  • 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.
  • the base is potassium carbonate.
  • 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.
  • 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.
  • the solvent is 2- methyltetrahydrofuran or tetrahydrofuran.
  • the solvent is 2- methyltetrahydrofuran.
  • the solvent is a ketone solvent, such as methyl isobutyl ketone, methyl ethyl ketone, or acetone.
  • the solvent is an ethereal solvent, such as tetrahydrofuran, 2-methyltetrahydrofuran, or methyl tert- butyl ether.
  • the solvent is an ester solvent, such as ethyl acetate or isopropyl acetate.
  • the solvent is a halogenated solvent, such as tetrachloroethylene, dichloroethane, chloroform, carbon tetrachloride, or dichloromethane.
  • a ketone solvent such as methyl isobutyl ketone, methyl ethyl ketone, or acetone.
  • the solvent is an ethereal solvent, such as tetrahydrofuran, 2-methyltetrahydrofuran, or methyl tert- butyl ether.
  • the solvent is
  • the solvent is a polar aprotic solvent, such as acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or N-methyl-2-pyrrolidinone.
  • the solvent is an aromatic solvent, such as toluene, benzene, or xylene.
  • the solvent is N-methyl-2-pyrrolidinone.
  • the base is potassium carbonate, and the solvent is N-methyl- 2-pyrrolidinone.
  • the base is 2-/eri-butyl- 1,1,3, 3-tetramethylguanidine, and the solvent is acetonitrile.
  • the base is 2- er/-buty!-l, 1,3,3- tetramethylguanidine, and the solvent is methyl isobutyl ketone.
  • the base is potassium carbonate, and the solvent is N,N-dimethy!formamide.
  • the base is potassium carbonate, and the solvent is dimethyl sulfoxide.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • thermocouple thermocouple, and N2 bubbler. The mixture was heated to 55 - 65 °C to obtain a solution.
  • 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 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the halogenating agent is a chlorinating agent.
  • the compound of formula III is a compound of formula Ilia:
  • 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.
  • the reaction between the compound of formula IV and the chlorinating agent is conducted at a temperature of no more than about 60 °C.
  • 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.
  • 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 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).
  • 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) 2 P0 4 in the presence of a base.
  • 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) 2 P0 4 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.
  • 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.
  • 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.
  • sodium iodide and potassium di-tert-butyl phosphate 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • M + is a pharmaceutically acceptable monovalent cation
  • D 2+ is a
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • Compound (17) may also be prepared in accordance with the following procedure.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • the continuous process for producing compound (17) comprises: 1) preparing compound (14) 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.
  • the continuous process for producing compound (17) comprises: 1) preparing compound (14) in a first stage; 2) converting compound
  • the continuous process for producing compound (17) comprises: 1) preparing compound
  • 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.
  • 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 3 ⁇ 40 (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.
  • 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.
  • substituents such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
  • the variables R 2 , R 3 , R 5 , and R 7 in formulas I-XI encompass specific groups, such as, for example, alkyl and cycloalkyl.
  • substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.
  • stable 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.
  • a stable compound or chemically feasible compound is one that is not
  • phrases“optionally substituted” may be used interchangeably with the phrase “substituted or unsubstituted.”
  • 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
  • aliphatic 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.
  • 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.
  • 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.
  • 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.
  • polycyclic ring system 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.
  • halogen or“halo” as used herein, means F, Cl, Br or I.
  • 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.
  • 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)).
  • alkoxy refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.
  • 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.
  • aryl may be used
  • 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.”
  • 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.
  • 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.
  • 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).
  • “H” refers to hydrogen and includes any stable isotope of hydrogen, namely 1 H and D.
  • an atom is designated as“H”
  • protium 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.
  • 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.
  • 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).
  • isotope-labelled compounds and salts include without limitation isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, for example 2 H, 13 C, 15 N, 18 0, 17 0, and 31 P, respectively.
  • the isotope-labelled compounds and salts can be used in a number of beneficial ways, including as medicaments.
  • the isotope-labelled compounds and salts are deuterium ( 2 H)-labelled.
  • Deuterium ( 2 H)-labelled compounds and salts are
  • deuterium ( 2 H)-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.
  • the deuterium ( 2 H)-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.
  • 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.
  • isotopic enrichment factor 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.
  • 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).
  • 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).
  • 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.
  • 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.
  • compositions 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • 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.
  • 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,
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • converting refers to a process of transforming the first compound or salt to the second compound or salt in one or more chemical steps.
  • 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
  • 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).
  • 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.
  • a protecting group such as 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).
  • 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.
  • 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.
  • organic acids such as acetic acid, propionic acid, zz-butyric acid, z-butyric acid, zz- valeric acid, z- valeric acid, zz-
  • 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.
  • 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).
  • CBDCI thionyl chloride
  • CDI 1,1'- carbonyldiimidazole
  • CDI 1,1'- carbony
  • the term“monovalent cation” refers to any cation with a charge of +1, such as alkali metal cations, NHC, and tetraalkylammonium.
  • 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 + ).
  • substituted benzyl refers to a benzyl group that is substituted with 1-3 substituents selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogen, and cyano.
  • ketone solvent refers to a compound having the formula
  • Ketone solvents include without limitation acetone, methyl ethyl ketone, 3- pentanone, and methyl ie/ -butyl ketone.
  • 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.
  • ester solvent refers to a compound having the formula
  • n H2 n+ 0C(0)C m H2 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.
  • 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.
  • 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 .
  • 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.
  • the term“about” means that the stated number can vary from that value by ⁇ 10%.
  • the stated temperature can vary by ⁇ 10%.
  • about 80 °C means between 72 °C and 88 °C.
  • the term“about” means the pressure can vary by ⁇ 10%.
  • about 100 bars means between 90 and 110 bars.
  • quantity such as equivalents or weight
  • the term means the quantity can vary by ⁇ 10%.
  • about 1 equivalent means between 0.9 and 1.1 equivalents.
  • time the term means the stated time can vary by ⁇ 10%. For example, about 1 hour means between 0.9 and 1.1 hours.
  • the term“leaving group” is a chemical group that is readily displaced by a desired incoming chemical moiety.
  • 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.
  • suitable leaving groups include chloro, iodo, bromo, fluoro, methanesulfonyl (mesyl), tosyl, triflate, nitro-phenylsulfonyl (nosyl), and bromo-phenylsulfonyl (brosyl).
  • the leaving group is nitro, fluoro, or diazonium.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation de composés de formule I, et des intermédiaires de ceux-ci ainsi que des sels pharmaceutiquement acceptables, R2, R3, R5, R7 et X étant tels que définis dans la description. Les composés de formule I inhibent les canaux sodiques et sont utiles pour traiter des troubles, par exemple la douleur.
PCT/US2020/026384 2019-04-02 2020-04-02 Procédé de production d'amides de pyridone et de promédicaments associés utiles en tant que modulateurs de canaux sodiques WO2020206119A1 (fr)

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US20150166589A1 (en) * 2013-12-13 2015-06-18 Vertex Pharmaceuticals Incorporated Prodrugs of pyridone amides useful as modulators of sodium channels
WO2018213426A1 (fr) * 2017-05-16 2018-11-22 Vertex Pharmaceuticals Incorporated Amides de pyridone deutérés et leurs promédicaments utilisés en tant que modulateurs de canaux sodiques

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US20150166589A1 (en) * 2013-12-13 2015-06-18 Vertex Pharmaceuticals Incorporated Prodrugs of pyridone amides useful as modulators of sodium channels
US9163042B2 (en) 2013-12-13 2015-10-20 Vertex Pharmaceuticals Incorporated Prodrugs of pyridone amides useful as modulators of sodium channels
WO2018213426A1 (fr) * 2017-05-16 2018-11-22 Vertex Pharmaceuticals Incorporated Amides de pyridone deutérés et leurs promédicaments utilisés en tant que modulateurs de canaux sodiques

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