Carboxamides as modulators of sodium channels

This application is a National Stage application of International Application No., PCT/US2020/012994 filed on Jan. 9, 2020, which claims the benefit of priority of U.S. Provisional Application Ser. No. 62/790,897, filed on Jan. 10, 2019 and U.S. Provisional Application Ser. No. 62/791,011, filed on Jan. 10, 2019, each of which are incorporated by reference herein in their entirety.

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 injury indications include post amputation pain, post-surgical nerve injury pain, and nerve entrapment injuries like neuropathic back pain.

Voltage-gated sodium channels (Na V s) are involved in pain signaling. Na V s are biological mediators of electrical signaling as they mediate the rapid upstroke of the action potential of many excitable cell types (e.g. neurons, skeletal myocytes, 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 Na V s in pain sensation (Rush, A. M. and T. R. Cummins, Painful Research: Identification of a Small - Molecule Inhibitor that Selectively Targets Na V 1.8 Sodium Channels . Mol. Interv., 2007. 7(4): p. 192-5); England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin. Investig. Drugs 17 (12), p. 1849-64 (2008); Krafte, D. S. and Bannon, A. W., Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8 (1), p. 50-56 (2008)). Na V s mediate the rapid upstroke of the action potential of many excitable cell types (e.g. neurons, skeletal myocytes, cardiac myocytes), and thus are involved in the initiation of signaling in those cells (Hille, Bertil, Ion Channels of Excitable Membranes , Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). Because of the role Na V s play in the initiation and propagation of neuronal signals, antagonists that reduce Na V currents can prevent or reduce neural signaling and Na V channels have been considered likely targets to reduce pain in conditions where hyper-excitability is observed (Chahine, M., Chatelier, A., Babich, O., and Krupp, J. J., Voltage-gated sodium channels in neurological disorders. CNS Neurol. Disord. Drug Targets 7 (2), p. 144-58 (2008)). Several clinically useful analgesics have been identified as inhibitors of Na V channels. The local anesthetic drugs such as lidocaine block pain by inhibiting Na V channels, and other compounds, such as carbamazepine, lamotrigine, and tricyclic antidepressants that have proven effective at reducing pain have also been suggested to act by sodium channel inhibition (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. Eur. J. Pain 6 Suppl. A, p. 3-9 (2002); Wang, G. K., Mitchell, J., and Wang, S. Y., Block of persistent late Na + currents by antidepressant sertraline and paroxetine. J. Membr. Biol. 222 (2), p. 79-90 (2008)).

The Na V s form a subfamily of the voltage-gated ion channel super-family and comprises 9 isoforms, designated Na V 1.1-Na V 1.9. The tissue localizations of the nine isoforms vary. Na V 1.4 is the primary sodium channel of skeletal muscle, and Na V 1.5 is primary sodium channel of cardiac myocytes. Na V s 1.7, 1.8 and 1.9 are primarily localized to the peripheral nervous system, while Na V s 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)).

Upon their discovery, Na V 1.8 channels were identified as likely targets for analgesia (Akopian, A. N., L. Sivilotti, and J. N. Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562): p. 257-62). Since then, Na V 1.8 has been shown to be a carrier of the sodium current that maintains action potential firing in small dorsal root ganglia (DRG) neurons (Blair, N. T. and B. P. Bean, Roles oftetrodotoxin (TTX)-sensitive Na + current, TTX-resistant Na + current, and Ca 2+ current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002. 22(23): p. 10277-90). Na V 1.8 is involved in spontaneous firing in damaged neurons, like those that drive neuropathic pain (Roza, C., et al., The tetrodotoxin-resistant Na + channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J Physiol., 2003. 550 (Pt 3): p. 921-6; Jarvis, M. F., et al., A-803467, a potent and selective Na V 1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc. Natl. Acad. Sci. USA, 2007. 104(20): p. 8520-5; Joshi, S. K., et al., Involvement of the TTX-resistant sodium channel Na V 1.8 in inflammatory and neuropathic, but not post-operative, pain states. Pain, 2006. 123(1-2): pp. 75-82; Lai, J., et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, Na V 1.8 . Pain, 2002. 95(1-2): p. 143-52; Dong, X. W., et al., Small interfering RNA-mediated selective knockdown of Na V 1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. Neuroscience, 2007. 146(2): p. 812-21; Huang, H. L., et al., Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves. Mol. Pain, 2008. 4: p. 33; Black, J. A., et al., Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann. Neurol., 2008. 64(6): p. 644-53; Coward, K., et al., Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states. Pain, 2000. 85(1-2): p. 41-50; Yiangou, Y., et al., SNS/PN3 and SNS2/NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. FEBS Lett., 2000. 467(2-3): p. 249-52; Ruangsri, S., et al., Relationship of axonal voltage-gated sodium channel 1.8 (Na V 1.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats. J Biol. Chem. 286(46): p. 39836-47). The small DRG neurons where Na V 1.8 is expressed include the nociceptors involved in pain signaling. Na V 1.8 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. J Neurosci., 2002. 22(23): p. 10277-90). Na V 1.8 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 Na V 1.7 and Na V 1.8 sodium channels: a computer simulation study. J Neurophysiol. 106(6): p. 3173-84; Renganathan, M., T. R. Cummins, and S. G. Waxman, Contribution of Na(v)1.8 sodium channels to action potential electrogenesis in DRG neurons. J. Neurophysiol., 2001. 86(2): p. 629-40; Roza, C., et al., The tetrodotoxin-resistant Na + channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550 (Pt 3): p. 921-6). In depolarized or damaged DRG neurons, Na V 1.8 appears to be a 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, Na V 1.8 mRNA expression levels have been shown to increase in the DRG (Sun, W., et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats. Brain, 135 (Pt 2): p. 359-75; Strickland, I. T., et al., Changes in the expression of Na V 1.7, Na V 1.8 and Na V 1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. Eur. J. Pain, 2008. 12(5): p. 564-72; Qiu, F., et al., Increased expression of tetrodotoxin-resistant sodium channels Na V 1.8 and Na V 1.9 within dorsal root ganglia in a rat model of bone cancer pain. Neurosci. Lett., 512(2): p. 61-6).

The primary drawback to some known Na V inhibitors is their poor therapeutic window, and this is likely a consequence of their lack of isoform selectivity. Since Na V 1.8 is primarily restricted to the neurons that sense pain, selective Na V 1.8 blockers are unlikely to induce the adverse events common to non-selective Na V blockers. Accordingly, there remains a need to develop additional Na V channel modulators, preferably those that are highly potent and selective for Na V 1.8.

In one aspect, the invention relates to a compound described herein, or a pharmaceutically acceptable salt thereof.

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

In still another aspect, the invention relates to a method of inhibiting a voltage gated sodium channel in a subject by administering the compound, pharmaceutically acceptable salt, or pharmaceutical composition to the subject.

In yet another aspect, the invention relates to a method of treating or lessening the severity in a subject of a variety of diseases, disorders, or conditions, including, but not limited to, chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, and cardiac arrhythmia, by administering the compound, pharmaceutically acceptable salt, or pharmaceutical composition to the subject.

In one aspect, the invention relates to a compound of formula (I) or (II)

or a pharmaceutically acceptable salt thereof, wherein R, R 3a , R 4a , R 1b , R 3b , R 4b , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 are defined as described herein.

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

As used herein, the term “compounds of the invention” refers to the compounds of formulas (I) and (II), and all of the embodiments thereof, as described herein, and to the compounds identified in Tables A, B, C, and D.

As described herein, the compounds of the invention comprise multiple variable groups (e.g., R, R 3a , R 5 , etc.). As one of ordinary skill in the art will recognize, combinations of groups envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds. The term “stable,” in this context, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40° C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

As used herein, the term “substituted,” refers to a group in which one or more hydrogen radicals has been replaced with a specified substituent. Unless otherwise indicated, a substituted group can have a substituent at any 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. As one of ordinary skill in the art will recognize, substituted groups envisioned by this invention are those that result in the formation of stable or chemically feasible compounds.

As used herein, the term “halo” means F, Cl, Br or I.

As used herein, the term “alkyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having the specified number of carbon atoms, which is attached to the rest of the molecule by a single bond. For example, a “C 1 -C 6 alkyl” group is an alkyl group having between one and six carbon atoms.

As used herein, the term “haloalkyl” refers to an alkyl group having the specified number of carbon atoms, wherein one or more of the hydrogen atoms of the alkyl group are replaced by halo groups. For example, a “C 1 -C 6 haloalkyl” group is an alkyl group having between one and six carbon atoms, wherein one or more of the hydrogen atoms of the alkyl group are replaced by halo groups.

As used herein, the term “alkoxy” refers to a radical of the formula —OR a where R a is an alkyl group having the specified number of carbon atoms. For example, a “C 1 -C 6 alkoxy” group is a radical of the formula —OR a where R a is an alkyl group having the between one and six carbon atoms.

As used herein, the term “haloalkoxy” refers to an alkoxy group having the specified number of carbon atoms, wherein one or more of the hydrogen atoms of the of the alkyl group are replaced by halo groups.

As used herein, the term “alkylsulfanyl” refers to a radical of the formula —SR a where R a is an alkyl group having the specified number of carbon atoms. For example, a “C 1 -C 6 alkylsulfanyl” group is a radical of the formula —SR a where R a is an alkyl group having the between one and six carbon atoms.

As used herein, the term “cycloalkyl” refers to a stable, non-aromatic, mono- or bicyclic (fused, bridged, or spiro) saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, having the specified number of carbon ring atoms, and which is attached to the rest of the molecule by a single bond.

As used herein, the term “cycloalkenyl” refers to a stable, non-aromatic, mono- or bicyclic (fused, bridged, or spiro) unsaturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, having the specified number of carbon ring atoms and one or more carbon-carbon double bonds in the ring, and which is attached to the rest of the molecule by a single bond.

As used herein, the term “heteroaryl” refers to a stable, aromatic, mono- or bicyclic ring radical having the specified number of ring atoms and comprising one or more heteroatoms individually selected from nitrogen, oxygen and sulfur.

As used herein, the term “heterocyclyl” refers to a stable, non-aromatic, mono- or bicyclic (fused, bridged, or spiro) saturated or unsaturated radical, having the specified number of ring atoms, including one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which is attached to the rest of the molecule by a single bond.

As used herein, the term “heterocycloalkyl” refers to a stable, non-aromatic, mono- or bicyclic (fused, bridged, or spiro) saturated radical, having the specified number of ring atoms, including one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which is attached to the rest of the molecule by a single bond.

As used herein, the term “heterocycloalkenyl” refers to a stable, non-aromatic, mono- or bicyclic (fused, bridged, or spiro) unsaturated hydrocarbon radical, having the specified number of ring atoms, including one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and one or more carbon-carbon or carbon-heteroatom double bonds in the ring, and which is attached to the rest of the molecule by a single bond.

As used herein, “*6” and “*7” in the following structure designate the carbon atom in formula (I) or (II) to which R 6 and R 7 , respectively, are attached.

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

As used herein, in any chemical structure or formula, a bold or hashed straight bond attached to a stereocenter of a compound, such as in

denotes the relative stereochemistry of the stereocenter, relative to other stereocenter(s) to which bold or hashed straight bonds are attached.

As used herein, the term “compound,” when referring to the compounds of the invention, refers to a collection of molecules having identical chemical structures, except that there may be isotopic variation among the constituent atoms of the molecules. The term “compound” includes such a collection of molecules without regard to the purity of a given sample containing the collection of molecules. Thus, the term “compound” includes such a collection of molecules in pure form, in a mixture (e.g., solution, suspension, or colloid) with one or more other substances, or in the form of a hydrate, solvate, or co-crystal.

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

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

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

As used herein, “ 1 H” 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 at least the natural abundance concentration of protium.

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

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

In some embodiments, the compounds of the invention, and pharmaceutically acceptable salts thereof, include one or more atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the most abundant isotope of the specified element (“isotope-labeled” compounds and salts). Examples of stable isotopes which are commercially available and suitable for the invention include without limitation isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, for example 2 H, 13 C, 15 N, 18 O, 17 O, and 31 P, respectively.

The isotope-labeled compounds and salts can be used in a number of beneficial ways, including as medicaments. In some embodiments, the isotope-labeled compounds and salts are deuterium (2H)-labeled. Deuterium ( 2 H)-labeled compounds and salts are therapeutically useful with potential therapeutic advantages over the non- 2 H-labeled compounds. In general, deuterium ( 2 H)-labeled compounds and salts can have higher metabolic stability as compared to those that are not isotope-labeled 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-labeled 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-labeled reactant by a readily available isotope-labeled reactant.

The deuterium ( 2 H)-labeled compounds and salts can manipulate the rate of oxidative metabolism of the compound by way of the primary kinetic isotope effect. The primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies of the covalent bonds involved in the reaction. Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially. For explanation: if deuterium is bonded to a carbon atom at a non-exchangeable position, rate differences of k H /k D =2-7 are typical. For a further discussion, see S. L. Harbeson and R. D. Tung, Deuterium In Drug Discovery and Development , Ann. Rep. Med. Chem. 2011, 46, 403-417, incorporated in its entirety herein by reference.

The concentration of an isotope (e.g., deuterium) incorporated at a given position of an isotope-labeled compound of the invention, or a pharmaceutically acceptable salt thereof, may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor,” as used herein, means the ratio between the abundance of an isotope at a given position in an isotope-labeled compound (or salt) and the natural abundance of the isotope.

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

In one aspect, the invention relates to a compound of formula (I) or (II)

or a pharmaceutically acceptable salt thereof, wherein:

each R is independently H or C 1 -C 6 alkyl; R 3a is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 4a is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 1b is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 3b is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 4b is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 5 , R 6 , R 7 , and R 8 are defined as follows: (i) R 5 , R 6 , and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R 8 is C 1 -C 6 alkyl; (ii) R 5 is W—(CH 2 ) n —R z , C 1 -C 6 alkylsulfanyl, —O—(CH 2 ) p —R w , or —O—(CH 2 ) p —N(C 1 -C 6 alkyl) 2 ; R 6 and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R 8 is H; (iii) R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is W—(CH 2 ) n —R z , —C≡C—R x , or 3-6 membered cycloalkyl or phenyl, wherein said 3-6 membered cycloalkyl or phenyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H; or (iv) R 5 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 6 and R 7 ,

together with the carbon atoms to which they are attached, form a ring of formula R 14 ; and R 8 is H;

R 9 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 10 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 11 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 12 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 13 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; each R 14 is independently H, halo, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl; each W is independently O or a single bond; R x is C 1 -C 6 alkyl or 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; R z is 3-6 membered heterocyclyl, 7-8 membered cycloalkyl, or 4-8 membered cycloalkenyl, wherein said 3-6 membered heterocyclyl, 7-8 membered cycloalkyl, or 4-8 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; n is 0 or 1; and p is 2 or 3.

In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently C 1 -C 6 alkyl.

In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R 3a and R 4a are each H.

In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R 1b , R 3b , and R 4b are each H.

In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R 5 , R 6 , and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R 8 is C 1 -C 6 alkyl. In other embodiments, R 5 is H; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is C 1 -C 6 alkyl. In other embodiments, R 5 is H; R 6 is CF 3 ; R 7 is H; and R 8 is CH 3 .

In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R 5 is W—(CH 2 ) n —R z , C 1 -C 6 alkylsulfanyl, —O—(CH 2 ) p —R w , or —O—(CH 2 ) p —N(C 1 -C 6 alkyl) 2 ; R 6 and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R 8 is H. In other embodiments, R 5 is W—(CH 2 ) n —R z ; R 6 and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R 8 is H. In other embodiments, R 5 is O—R z , and R z is 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R 5 is O—R z , and R z is 3-6 membered heterocyclyl; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R 5 is O—R z , and R z is oxetanyl or tetrahydrofuranyl; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R 5 is C 1 -C 6 alkylsulfanyl; R 6 and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R 8 is H. In other embodiments, R 5 is C 1 -C 6 alkylsulfanyl; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R 5 is —O—(CH 2 ) p —R w ; R 6 and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R 8 is H. In other embodiments, R 5 is —O—(CH 2 ) p —R w ; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R 5 is —O—(CH 2 ) p —R w , and R w is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R 5 is —O—(CH 2 ) p —R w , and R w is 3-6 membered cycloalkyl; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R 5 is —O—(CH 2 ) 2 —R w , and R w is 3-6 membered cycloalkyl; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R 5 is —O—(CH 2 ) p —N(C 1 -C 6 alkyl) 2 ; R 6 and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R 8 is H. In other embodiments, R 5 is —O—(CH 2 ) p —N(CH 3 ) 2 ; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R 5 is —O—(CH 2 ) 2 —N(C 1 -C 6 alkyl) 2 ; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R 5 is

SCH 3 ,

or O(CH 2 ) 2 N(CH 3 ) 2 ; R 6 is CF 3 ; R 7 is H; and R 8 is H. In other embodiments, R 5 is

R 6 is CF 3 ; R 7 is H; and R 8 is H. In other embodiments, R 5 is SCH 3 ; R 6 is CF 3 ; R 7 is H; and R 8 is H. In other embodiments, R 5 is

R 6 is CF 3 ; R 7 is H; and R 8 is H. In other embodiments, R 5 is O(CH 2 ) 2 N(CH 3 ) 2 ; R 6 is CF 3 ; R 7 is H; and R 8 is H.

In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is W—(CH 2 ) n —R z , —C≡C—R x , or 3-6 membered cycloalkyl or phenyl, wherein said 3-6 membered cycloalkyl or phenyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is W—(CH 2 ) n —R z ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is W—R z ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered heterocyclyl, wherein said 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered heterocyclyl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered heterocycloalkyl, wherein said 5-6 membered heterocycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered heterocycloalkyl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is tetrahydropyran-4-yl or tetrahydrofuran-3-yl, wherein said tetrahydropyran-4-yl or tetrahydrofuran-3-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is tetrahydropyran-4-yl or tetrahydrofuran-3-yl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered heterocycloalkenyl, wherein said 5-6 membered heterocycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered heterocycloalkenyl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl, wherein said 3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 7-8 membered cycloalkyl, wherein said 7-8 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 7-8 membered cycloalkyl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 4-8 membered cycloalkenyl, wherein said 4-8 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered cycloalkenyl, wherein said 5-6 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered cycloalkenyl, wherein said 5-6 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered cycloalkenyl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is cyclohexen-1-yl or cyclopenten-1-yl, wherein said cyclohexen-1-yl or cyclopenten-1-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is cyclohexen-1-yl or cyclopenten-1-yl, wherein said cyclohexen-1-yl or cyclopenten-1-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is cyclohexen-1-yl or cyclopenten-1-yl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is O—R z ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is O—R z , and R z is R z is 4-8 membered cycloalkenyl, wherein said 4-8 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is O—R z , and R z is R z is cyclobutenyl, wherein said cyclobutenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H.

In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is W—(CH 2 ) n —R z ; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is W—R z ; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z ; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered heterocyclyl, wherein said 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered heterocyclyl; and R 8 is H. In other embodiments, R 8 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered heterocycloalkyl, wherein said 5-6 membered heterocycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 8 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered heterocycloalkyl; and R 8 is H. In other embodiments, R 8 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is tetrahydropyran-4-yl or tetrahydrofuran-3-yl, wherein said tetrahydropyran-4-yl or tetrahydrofuran-3-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 8 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is tetrahydropyran-4-yl or tetrahydrofuran-3-yl; and R 8 is H. In other embodiments, R 8 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered heterocycloalkenyl, wherein said 5-6 membered heterocycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 8 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered heterocycloalkenyl; and R 8 is H. In other embodiments, R 8 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl, wherein said 3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 8 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl; and R 8 is H. In other embodiments, R 8 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 7-8 membered cycloalkyl, wherein said 7-8 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 8 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 7-8 membered cycloalkyl; and R 8 is H. In other embodiments, R 8 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 4-8 membered cycloalkenyl, wherein said 4-8 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 8 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered cycloalkenyl, wherein said 5-6 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered cycloalkenyl, wherein said 5-6 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered cycloalkenyl; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is cyclohexen-1-yl or cyclopenten-1-yl, wherein said cyclohexen-1-yl or cyclopenten-1-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is cyclohexen-1-yl or cyclopenten-1-yl, wherein said cyclohexen-1-yl or cyclopenten-1-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is cyclohexen-1-yl or cyclopenten-1-yl; and R 8 is H. In other embodiments, R 8 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is O—R z ; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is O—R z , and R z is R z is 4-8 membered cycloalkenyl, wherein said 4-8 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is O—R z , and R z is R z is cyclobutenyl, wherein said cyclobutenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H.

In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is —C≡C—R x ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is —C≡C—R x , and R x is C 1 -C 6 alkyl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is —C≡C—R x , and R x is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is —C≡C—R x , and R x is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is —C≡C—R x , and R x is 3-6 membered cycloalkyl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is —C≡C—R x , and R x is cyclopropyl or cyclobutyl; and R 8 is H.

In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is —C≡C—R x ; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is —C≡C—R x , and R x is C 1 -C 6 alkyl; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is —C≡C—R x , and R x is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is —C≡C—R x , and R x is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is —C≡C—R x , and R x is 3-6 membered cycloalkyl; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is —C≡C—R x , and R x is cyclopropyl or cyclobutyl; and R 8 is H.

In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is 3-6 membered cycloalkyl or phenyl, wherein said 3-6 membered cycloalkyl or phenyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is cyclohexyl, wherein said cyclohexyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is phenyl, wherein said phenyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H.

In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is 3-6 membered cycloalkyl or phenyl, wherein said 3-6 membered cycloalkyl or phenyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R 8 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is cyclohexyl, wherein said cyclohexyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R 8 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is phenyl, wherein said phenyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

or and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H.

In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R 5 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 6 and R 7 , together with the carbon atoms to which they are attached, form a ring of formula

and R 8 is H. In other embodiments, R 5 is H or halo; R 6 and R 7 , together with the carbon atoms to which they are attached, form a ring of formula

and R 8 is H. In other embodiments, R 5 is H or halo; R 6 and R 7 , together with the carbon atoms to which they are attached, form a ring of formula

and R 8 is H. In other embodiments, R 5 is H or F; R 6 and R 7 , together with the carbon atoms to which they are attached, form a ring of formula

and R 8 is H.

In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R 9 is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 9 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 9 is H, halo, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 9 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 9 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 haloalkoxy. In other embodiments, R 9 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy. In other embodiments, R 9 is C 1 -C 6 alkoxy. In other embodiments, R 9 is OCH 3 , OC( 1 H) 3 , or OCD 3 . In other embodiments, R 9 is OCH 3 . In other embodiments, R 9 is OC( 1 H) 3 . In other embodiments, R 9 is OCD 3 .

In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R 10 is H. In other embodiments, R 10 is halo. In other embodiments, R 10 is F.

In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R 11 is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 11 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 11 is H, halo, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 11 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 11 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 haloalkoxy. In other embodiments, R 11 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy. In other embodiments, R 11 is C 1 -C 6 haloalkoxy. In other embodiments, R 11 is OCF 3 .

In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R 12 is H.

In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R 13 is H.

In some embodiments, the invention relates to a compound of formula (I) or (II), i.e., the compound in non-salt form.

In one aspect, the invention relates to a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

each R is independently H or C 1 -C 6 alkyl; R 3a is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 4a is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 5 , R 6 , R 7 , and R 8 are defined as follows: (i) R 5 , R 6 , and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R 8 is C 1 -C 6 alkyl; (ii) R 5 is W—(CH 2 ) n —R z , C 1 -C 6 alkylsulfanyl, —O—(CH 2 ) p —R w , or —O—(CH 2 ) p —N(C 1 -C 6 alkyl) 2 ; R 6 and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R 8 is H; (iii) R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is W—(CH 2 ) n —R z , —C≡C—R x , or 3-6 membered cycloalkyl or phenyl, wherein said 3-6 membered cycloalkyl or phenyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H; or (iv) R 8 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 6 and R 7 , together with the carbon atoms to which they are attached, form a ring of formula

and R 8 is H;

R 9 , R 10 , R 11 , R 12 , and R 13 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; each R 14 is independently H, halo, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl; each W is independently O or a single bond; R x is C 1 -C 6 alkyl or 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; R z is 3-6 membered heterocyclyl, 7-8 membered cycloalkyl, or 4-8 membered cycloalkenyl, wherein said 3-6 membered heterocyclyl, 7-8 membered cycloalkyl, or 4-8 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; n is 0 or 1; and p is 2 or 3.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently C 1 -C 6 alkyl.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3a and R 4a are each H.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1b , R 3b , and R 4b are each H.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 , R 6 , and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R 8 is C 1 -C 6 alkyl. In other embodiments, R 5 is H; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is C 1 -C 6 alkyl. In other embodiments, R 5 is H; R 6 is CF 3 ; R 7 is H; and R 8 is CH 3 .

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 is W—(CH 2 ) n —R z , C 1 -C 6 alkylsulfanyl, —O—(CH 2 ) p —R w , or —O—(CH 2 ) p —N(C 1 -C 6 alkyl) 2 ; R 6 and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R 8 is H. In other embodiments, R 5 is W—(CH 2 ) n —R z ; R 6 and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R 8 is H. In other embodiments, R 5 is O—R z , and R z is 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R 5 is O—R z , and R z is 3-6 membered heterocyclyl; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R 5 is O—R z , and R z is oxetanyl or tetrahydrofuranyl; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R 5 is C 1 -C 6 alkylsulfanyl; R 6 and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R 8 is H. In other embodiments, R 5 is C 1 -C 6 alkylsulfanyl; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R 5 is —O—(CH 2 ) p —R w ; R 6 and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R 8 is H. In other embodiments, R 5 is —O—(CH 2 ) p —R w ; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R 5 is —O—(CH 2 ) p —R w , and R w is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R 5 is —O—(CH 2 ) p —R w , and R w is 3-6 membered cycloalkyl; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R 5 is —O—(CH 2 ) 2 —R w , and R w is 3-6 membered cycloalkyl; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R 5 is −0-(CH 2 ) p —N(C 1 -C 6 alkyl) 2 ; R 6 and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R 8 is H. In other embodiments, R 5 is —O—(CH 2 ) p —N(CH 3 ) 2 ; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R 5 is —O—(CH 2 ) 2 —N(C 1 -C 6 alkyl) 2 ; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R 5 is

SCH 3 ,

or O(CH 2 ) 2 N(CH 3 ) 2 ; R 6 is CF 3 ; R 7 is H; and R 5 is H. In other embodiments, R 5 is

R 6 is CF 3 ; R 7 is H; and R 8 is H. In other embodiments, R 5 is SCH 3 ; R 6 is CF 3 ; R 7 is H; and R 8 is H. In other embodiments, R 5 is

R 6 is CF 3 ; R 7 is H; and R 8 is H. In other embodiments, R 5 is O(CH 2 ) 2 N(CH 3 ) 2 ; R 6 is CF 3 ; R 7 is H; and R 8 is H.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is W—(CH 2 ) n —R z , —C≡C—R x , or 3-6 membered cycloalkyl or phenyl, wherein said 3-6 membered cycloalkyl or phenyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is W—(CH 2 ) n —R z ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is W—R z ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered heterocyclyl, wherein said 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered heterocyclyl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered heterocycloalkyl, wherein said 5-6 membered heterocycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered heterocycloalkyl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is tetrahydropyran-4-yl or tetrahydrofuran-3-yl, wherein said tetrahydropyran-4-yl or tetrahydrofuran-3-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is tetrahydropyran-4-yl or tetrahydrofuran-3-yl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered heterocycloalkenyl, wherein said 5-6 membered heterocycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered heterocycloalkenyl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl, wherein said 3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 7-8 membered cycloalkyl, wherein said 7-8 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 7-8 membered cycloalkyl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 4-8 membered cycloalkenyl, wherein said 4-8 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered cycloalkenyl, wherein said 5-6 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered cycloalkenyl, wherein said 5-6 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered cycloalkenyl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is cyclohexen-1-yl or cyclopenten-1-yl, wherein said cyclohexen-1-yl or cyclopenten-1-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is cyclohexen-1-yl or cyclopenten-1-yl, wherein said cyclohexen-1-yl or cyclopenten-1-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is cyclohexen-1-yl or cyclopenten-1-yl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is O—R z ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is O—R z , and R z is R z is 4-8 membered cycloalkenyl, wherein said 4-8 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is O—R z , and R z is R z is cyclobutenyl, wherein said cyclobutenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H.

In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is W—(CH 2 ) n —R z ; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is W—R z ; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z ; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 8 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered heterocyclyl, wherein said 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered heterocyclyl; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered heterocycloalkyl, wherein said 5-6 membered heterocycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered heterocycloalkyl; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is tetrahydropyran-4-yl or tetrahydrofuran-3-yl, wherein said tetrahydropyran-4-yl or tetrahydrofuran-3-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is tetrahydropyran-4-yl or tetrahydrofuran-3-yl; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered heterocycloalkenyl, wherein said 5-6 membered heterocycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered heterocycloalkenyl; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl, wherein said 3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 7-8 membered cycloalkyl, wherein said 7-8 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 7-8 membered cycloalkyl; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 4-8 membered cycloalkenyl, wherein said 4-8 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered cycloalkenyl, wherein said 5-6 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered cycloalkenyl, wherein said 5-6 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered cycloalkenyl; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is cyclohexen-1-yl or cyclopenten-1-yl, wherein said cyclohexen-1-yl or cyclopenten-1-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is cyclohexen-1-yl or cyclopenten-1-yl, wherein said cyclohexen-1-yl or cyclopenten-1-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R s is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is cyclohexen-1-yl or cyclopenten-1-yl; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is O—R z ; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is O—R z , and R z is R z is 4-8 membered cycloalkenyl, wherein said 4-8 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is O—R z , and R z is R z is cyclobutenyl, wherein said cyclobutenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H.

In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is —C≡C—R x ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is —C≡C—R x , and R, is C 1 -C 6 alkyl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is —C≡C—R x , and R, is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is —C≡C—R x , and R x is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is —C≡C—R x , and R x is 3-6 membered cycloalkyl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is —C≡C—R x , and R x is cyclopropyl or cyclobutyl; and R 8 is H.

In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is —C≡C—R x ; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is —C≡C—R x , and R x is C 1 -C 6 alkyl; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is —C≡C—R x , and R x is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo; and R s is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is —C≡C—R x , and R x is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is —C≡C—R x , and R x is 3-6 membered cycloalkyl; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is —C≡C—R x , and R x is cyclopropyl or cyclobutyl; and R 8 is H.

In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is 3-6 membered cycloalkyl or phenyl, wherein said 3-6 membered cycloalkyl or phenyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is cyclohexyl, wherein said cyclohexyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is phenyl, wherein said phenyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H.

In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is 3-6 membered cycloalkyl or phenyl, wherein said 3-6 membered cycloalkyl or phenyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is cyclohexyl, wherein said cyclohexyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is phenyl, wherein said phenyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 6 and R 7 , together with the carbon atoms to which they are attached, form a ring of formula

and R 8 is H. In other embodiments, R 5 is H or halo; R 6 and R 7 , together with the carbon atoms to which they are attached, form a ring of formula

and R 8 is H. In other embodiments, R 5 is H or halo; R 6 and R 7 , together with the carbon atoms to which they are attached, form a ring of formula

and R 8 is H. In other embodiments, R s is H or F; R 6 and R 7 , together with the carbon atoms to which they are attached, form a ring of formula

and R 8 is H.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 9 is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 9 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 9 is H, halo, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 9 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 9 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 haloalkoxy. In other embodiments, R 9 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy. In other embodiments, R 9 is C 1 -C 6 alkoxy. In other embodiments, R 9 is OCH 3 , OC( 1 H) 3 , or OCD 3 . In other embodiments, R 9 is OCH 3 . In other embodiments, R 9 is OC( 1 H) 3 . In other embodiments, R 9 is OCD 3 .

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 10 is H. In other embodiments, R 10 is halo. In other embodiments, R 10 is F.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 11 is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 11 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 11 is H, halo, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 11 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 11 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 haloalkoxy. In other embodiments, R 11 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy. In other embodiments, R 11 is C 1 -C 6 haloalkoxy. In other embodiments, R 11 is OCF 3 .

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 12 is H.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 13 is H.

In some embodiments, the invention relates to a compound of formula (I), i.e., the compound in non-salt form.

In one aspect, the invention relates to a compound of formula (II)

or a pharmaceutically acceptable salt thereof, wherein:

each R is independently H or C 1 -C 6 alkyl; R 1b is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 3b is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 4b is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 5 , R 6 , R 7 , and R 8 are defined as follows: (i) R 5 , R 6 , and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R 8 is C 1 -C 6 alkyl; (ii) R 5 is W—(CH 2 ) n —R z , C 1 -C 6 alkylsulfanyl, —O—(CH 2 ) p —R w , or —O—(CH 2 ) p —N(C 1 -C 6 alkyl) 2 ; R 6 and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R 8 is H; (iii) R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is W—(CH 2 ) n —R z , —C≡C—R x , or 3-6 membered cycloalkyl or phenyl, wherein said 3-6 membered cycloalkyl or phenyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H; or (iv) R s is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 6 and R 7 , together with the carbon atoms to which they are attached, form a ring of formula

and R 8 is H;

R 9 , R 10 , R 11 , R 12 , and R 13 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; each R 14 is independently H, halo, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl; each W is independently O or a single bond; R x is C 1 -C 6 alkyl or 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; R z is 3-6 membered heterocyclyl, 7-8 membered cycloalkyl, or 4-8 membered cycloalkenyl, wherein said 3-6 membered heterocyclyl, 7-8 membered cycloalkyl, or 4-8 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; n is 0 or 1; and p is 2 or 3.

In some embodiments, the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein each R is H. In other embodiments, each R is independently C 1 -C 6 alkyl.

In some embodiments, the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 3a and R 4a are each H.

In some embodiments, the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 1b , R 3b , and R 4b are each H.

In some embodiments, the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 5 , R 6 , and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R s is C 1 -C 6 alkyl. In other embodiments, R s is H; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R s is C 1 -C 6 alkyl. In other embodiments, R s is H; R 6 is CF 3 ; R 7 is H; and R 8 is CH 3 .

In some embodiments, the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 5 is W—(CH 2 ) n —R z , C 1 -C 6 alkylsulfanyl, —O—(CH 2 ) p —R w , or —O—(CH 2 ) p —N(C 1 -C 6 alkyl) 2 ; R 6 and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R s is H. In other embodiments, R 5 is W—(CH 2 ) n —R z ; R 6 and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R s is H. In other embodiments, R s is O—R z , and R z is 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R s is O—R z , and R z is 3-6 membered heterocyclyl; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R s is O—R z , and R z is oxetanyl or tetrahydrofuranyl; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R 8 is C 1 -C 6 alkylsulfanyl; R 6 and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R s is H. In other embodiments, R s is C 1 -C 6 alkylsulfanyl; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R s is H. In other embodiments, R s is —O—(CH 2 ) p —R w ; R 6 and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R s is H. In other embodiments, R s is —O—(CH 2 ) p —R w ; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R s is —O—(CH 2 ) p —R w , and R w is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R s is H. In other embodiments, R s is —O—(CH 2 ) p —R w , and R w is 3-6 membered cycloalkyl; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R s is —O—(CH 2 ) 2 —R w , and R w is 3-6 membered cycloalkyl; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R s is H. In other embodiments, R s is —O—(CH 2 ) p —N(C 1 -C 6 alkyl) 2 ; R 6 and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R 8 is H. In other embodiments, R s is —O—(CH 2 ) p —N(CH 3 ) 2 ; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R s is —O—(CH 2 ) 2 —N(C 1 -C 6 alkyl) 2 ; R 6 is C 1 -C 6 haloalkyl; R 7 is H; and R 8 is H. In other embodiments, R 5 is

SCH 3 ,

or O(CH 2 ) 2 N(CH 3 ) 2 ; R 6 is CF 3 ; R 7 is H; and R 8 is H. In other embodiments, R 5 is

R 6 is CF 3 ; R 7 is H; and R 8 is H. In other embodiments, R s is SCH 3 ; R 6 is CF 3 ; R 7 is H; and R 8 is H. In other embodiments, R 5 is

is CF 3 ; R 7 is H; and R 8 is H. In other embodiments, R 5 is O(CH 2 ) 2 N(CH 3 ) 2 ; R 6 is CF 3 ; R 7 is H; and R s is H.

In some embodiments, the invention relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is W—(CH 2 ) n —R z , —C≡C—R x , or 3-6 membered cycloalkyl or phenyl, wherein said 3-6 membered cycloalkyl or phenyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is W—(CH 2 ) n —R z ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is W—R z ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered heterocyclyl, wherein said 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered heterocyclyl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered heterocycloalkyl, wherein said 5-6 membered heterocycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered heterocycloalkyl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is tetrahydropyran-4-yl or tetrahydrofuran-3-yl, wherein said tetrahydropyran-4-yl or tetrahydrofuran-3-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is tetrahydropyran-4-yl or tetrahydrofuran-3-yl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered heterocycloalkenyl, wherein said 5-6 membered heterocycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered heterocycloalkenyl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl, wherein said 3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 7-8 membered cycloalkyl, wherein said 7-8 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 7-8 membered cycloalkyl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 4-8 membered cycloalkenyl, wherein said 4-8 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered cycloalkenyl, wherein said 5-6 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered cycloalkenyl, wherein said 5-6 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is 5-6 membered cycloalkenyl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is cyclohexen-1-yl or cyclopenten-1-yl, wherein said cyclohexen-1-yl or cyclopenten-1-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is cyclohexen-1-yl or cyclopenten-1-yl, wherein said cyclohexen-1-yl or cyclopenten-1-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is R z , and R z is cyclohexen-1-yl or cyclopenten-1-yl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is O—R z ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is O—R z , and R z is R z is 4-8 membered cycloalkenyl, wherein said 4-8 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is O—R z , and R z is R z is cyclobutenyl, wherein said cyclobutenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H.

In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is W—(CH 2 ) n —R z ; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is W—R z ; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z ; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered heterocyclyl, wherein said 5-6 membered heterocyclyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 8 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered heterocyclyl; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered heterocycloalkyl, wherein said 5-6 membered heterocycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered heterocycloalkyl; and R s is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is tetrahydropyran-4-yl or tetrahydrofuran-3-yl, wherein said tetrahydropyran-4-yl or tetrahydrofuran-3-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is tetrahydropyran-4-yl or tetrahydrofuran-3-yl; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered heterocycloalkenyl, wherein said 5-6 membered heterocycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R s is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered heterocycloalkenyl; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl, wherein said 3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 7-8 membered cycloalkyl, wherein said 7-8 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 7-8 membered cycloalkyl; and R s is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 4-8 membered cycloalkenyl, wherein said 4-8 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered cycloalkenyl, wherein said 5-6 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered cycloalkenyl, wherein said 5-6 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is 5-6 membered cycloalkenyl; and R 8 is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is cyclohexen-1-yl or cyclopenten-1-yl, wherein said cyclohexen-1-yl or cyclopenten-1-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring; and R s is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is cyclohexen-1-yl or cyclopenten-1-yl, wherein said cyclohexen-1-yl or cyclopenten-1-yl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R s is H. In other embodiments, R 5 is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is R z , and R z is cyclohexen-1-yl or cyclopenten-1-yl; and R 8 is H. In other embodiments, R s is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is O—R z ; and R 8 is H. In other embodiments, R s is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is O—R z , and R z is R z is 4-8 membered cycloalkenyl, wherein said 4-8 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H. In other embodiments, R s is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is O—R z , and R z is R z is cyclobutenyl, wherein said cyclobutenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; and R 8 is H.

In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is —C≡C—R x ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is —C≡C—R x , and R x is C 1 -C 6 alkyl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is —C≡C—R x , and R x is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is —C≡C—R x , and R, is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is —C≡C—R x , and R, is 3-6 membered cycloalkyl; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is —C≡C—R x , and R x is cyclopropyl or cyclobutyl; and R 8 is H.

In other embodiments, R s is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is —C≡C—R x ; and R 8 is H. In other embodiments, R s is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is —C≡C—R x , and R, is C 1 -C 6 alkyl; and R 8 is H. In other embodiments, R s is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is —C≡C—R x , and R x is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo; and R s is H. In other embodiments, R s is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is —C≡C—R x , and R x is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo; and R 8 is H. In other embodiments, R s is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is —C≡C—R x , and R x is 3-6 membered cycloalkyl; and R 8 is H. In other embodiments, R s is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is —C≡C—R x , and R x is cyclopropyl or cyclobutyl; and R 8 is H.

In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is 3-6 membered cycloalkyl or phenyl, wherein said 3-6 membered cycloalkyl or phenyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is cyclohexyl, wherein said cyclohexyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R 5 and R 6 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 7 is phenyl, wherein said phenyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H.

In other embodiments, R s is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is 3-6 membered cycloalkyl or phenyl, wherein said 3-6 membered cycloalkyl or phenyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R s is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R s is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is cyclohexyl, wherein said cyclohexyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R s is H, halo, or C 1 -C 6 alkyl; R 6 is H; R 7 is phenyl, wherein said phenyl is substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkoxy, CN, and —C(O)NH 2 ; and R 8 is H. In other embodiments, R s is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is R 7 is

and R 8 is H. In other embodiments, R s is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H. In other embodiments, R 5 is H, F, or CH 3 ; R 6 is H; R 7 is

and R 8 is H.

In some embodiments, the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 5 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 6 and R 7 , together with the carbon atoms to which they are attached, form a ring of formula

and R 8 is H. In other embodiments, R 5 is H or halo: R 6 and R 7 , together with the carbon atoms to which they are attached, form a ring of formula

and R 8 is H. In other embodiments, R 5 is H or halo; R 6 and R 7 , together with the carbon atoms to which they are attached, form a ring of formula

and R 8 is H. In other embodiments, R 5 is H or F; R 6 and R 7 , together with the carbon atoms to which they are attached, form a ring of formula

and R 8 is H.

In some embodiments, the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 9 is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 9 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 9 is H, halo, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 9 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 9 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 haloalkoxy. In other embodiments, R 9 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy. In other embodiments, R 9 is C 1 -C 6 alkoxy. In other embodiments, R 9 is OCH 3 , OC( 1 H) 3 , or OCD 3 . In other embodiments, R 9 is OCH 3 . In other embodiments, R 9 is OC( 1 H) 3 . In other embodiments, R 9 is OCD 3 .

In some embodiments, the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 10 is H. In other embodiments, R 10 is halo. In other embodiments, R 10 is F.

In some embodiments, the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 11 is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 11 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 11 is H, halo, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 11 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy. In other embodiments, R 11 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 haloalkoxy. In other embodiments, R 11 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy. In other embodiments, R 11 is C 1 -C 6 haloalkoxy. In other embodiments, R 11 is OCF 3 .

In some embodiments, the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 12 is H.

In some embodiments, the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 13 is H.

In some embodiments, the invention relates to a compound of formula (II), i.e., the compound in non-salt form.

In one aspect, the invention relates to a compound selected from Table A or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to a compound selected from Table A, i.e., the compound in non-salt form.

Compound Numbers and Structures.

1

2

3

4

5

6

7

8

9

10

11

12

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158-a

158-b

159

160

161

162

163

164

165

166

167

168-a

168-b

169-a

169-b

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

255

256

253

254

82

250

252

81

258

108

110

111

251

112

13

14

15

16

17

113

257

In another aspect, the invention relates to a compound selected from Table B or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to a compound selected from Table B, i.e., the compound in non-salt form.

Compound Numbers and Structures.

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

109

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

In some embodiments, the invention relates to a compound selected from Table D or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to a compound selected from Table D, i.e., the compound in non-salt form.

Compound Numbers and Structures.

1040

1041

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound has the relative stereochemistry of the first eluting diastereomer when a mixture of the diastereomers is separated by HPLC Method B, as described in Example 68. Such compound is considered to be a “compound of the invention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound has the relative stereochemistry of the second eluting diastereomer when a mixture of the diastereomers is separated by HPLC Method B, as described in Example 68. Such compound is considered to be a “compound of the invention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound has the relative stereochemistry of the first eluting diastereomer when a mixture of the diastereomers is separated by HPLC Method B, as described in Example 24. Such compound is considered to be a “compound of the invention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound has the relative stereochemistry of the second eluting diastereomer when a mixture of the diastereomers is separated by HPLC Method B, as described in Example 24. Such compound is considered to be a “compound of the invention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound has the relative stereochemistry of the first eluting diastereomer when a mixture of the diastereomers is separated by HPLC Method B, as described in Example 24. Such compound is considered to be a “compound of the invention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound has the relative stereochemistry of the second eluting diastereomer when a mixture of the diastereomers is separated by HPLC Method B, as described in Example 24. Such compound is considered to be a “compound of the invention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound has formula

wherein the compound has the relative stereochemistry of the first eluting diastereomer when a mixture of the diastereomers is separated by HPLC Method B, as described in Example 204.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound has formula

wherein the compound has the relative stereochemistry of the second eluting diastereomer when a mixture of the diastereomers is separated by HPLC Method B, as described in Example 204.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound has formula

wherein the compound has the relative stereochemistry of the first eluting diastereomer when a mixture of the diastereomers is separated by HPLC Method B, as described in Example 209.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound has formula

wherein the compound has the relative stereochemistry of the second eluting diastereomer when a mixture of the diastereomers is separated by HPLC Method B, as described in Example 209.

Salts, Compositions, Uses, Formulation, Administration and Additional Agents

Pharmaceutically acceptable salts and compositions

As discussed herein, the invention provides compounds, and pharmaceutically acceptable salts thereof, that are inhibitors of voltage-gated sodium channels, and thus the present compounds, and pharmaceutically acceptable salts thereof, are useful for the treatment of diseases, disorders, and conditions including, but not limited to chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomy pain, herniorrhaphy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia. Accordingly, in another aspect of the invention, pharmaceutical compositions are provided, wherein these compositions comprise a compound as described herein, or a pharmaceutically acceptable salt thereof, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

As used herein, 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” of a compound of this invention includes any non-toxic salt 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 salt may be in pure form, in a mixture (e.g., solution, suspension, or colloid) with one or more other substances, or in the form of a hydrate, solvate, or co-crystal. As used herein, the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of a voltage-gated sodium channel.

Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compound of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

As described herein, the pharmaceutically acceptable compositions of the invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

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

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

Uses of Compounds and Pharmaceutically Acceptable Salts and Compositions

In another aspect, the invention features a method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject a compound of the invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In another aspect, the voltage-gated sodium channel is Na V 1.8.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomy pain, herniorrhaphy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of gut pain, wherein gut pain comprises inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis pain wherein said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of neuropathic pain comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some aspects, the neuropathic pain comprises post-herpetic neuralgia, small fiber neuropathy or idiopathic small-fiber neuropathy. As used herein, the phrase “idiopathic small-fiber neuropathy” shall be understood to include any small fiber neuropathy.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of neuropathic pain, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia; post spinal cord injury pain, small fiber neuropathy, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia wherein said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of musculoskeletal pain comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some aspects, the musculoskeletal pain comprises osteoarthritis pain.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain wherein said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain or vulvodynia wherein said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain wherein said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain wherein said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

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

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of acute pain comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some aspects, the acute pain comprises acute post-operative pain.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of postsurgical pain (e.g., herniorrhaphy pain, bunionectomy pain or abdominoplasty pain) comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

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

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

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

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of visceral pain comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some aspects, the visceral pain comprises visceral pain from abdominoplasty.

In yet another aspect, the invention features a method wherein the subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with an effective amount of the compound, pharmaceutically acceptable salt or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

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

In another aspect, the invention features a method of treating or lessening the severity in a subject of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head pain, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain (e.g., herniorrhaphy pain, bunionectomy pain or abdominoplasty pain), cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastro-intestinal motility, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

In another aspect, the invention features a method of treating or lessening the severity in a subject of femur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headaches; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy induced neuropathic pain; radiotherapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom pain; intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury pain; exercise pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, burn pain, trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogenital disease; urinary incontinence, pathological cough; hyperactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS), type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal extreme pain, pruritus, tinnitus, or angina-induced pain, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

Compounds, Pharmaceutically Acceptable Salts, and Compositions for Use

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use as a medicament.

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

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., herniorrhaphy pain, bunionectomy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of gut pain, wherein gut pain comprises inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis pain.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of neuropathic pain. In some aspects, the neuropathic pain comprises post-herpetic neuralgia, small fiber neuropathy or idiopathic small-fiber neuropathy. As used herein, the phrase “idiopathic small-fiber neuropathy” shall be understood to include any small fiber neuropathy.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of neuropathic pain, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia; post spinal cord injury pain, small fiber neuropathy, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of musculoskeletal pain. In some aspects, the musculoskeletal pain comprises osteoarthritis pain.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain or vulvodynia.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of pathological cough.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of acute pain. In some aspects, the acute pain comprises acute post-operative pain.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of postsurgical pain (e.g., herniorrhaphy pain, bunionectomy pain or abdominoplasty pain).

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of bunionectomy pain.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of heriorrhaphy pain.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of abdominoplasty pain.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of visceral pain. In some aspects, the visceral pain comprises visceral pain from abdominoplasty.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method wherein the subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with an effective amount of the compound, pharmaceutically acceptable salt or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

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

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head pain, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain (e.g., herniorrhaphy pain, bunionectomy pain or abdominoplasty pain), cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastro-intestinal motility.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of femur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headaches; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy induced neuropathic pain; radiotherapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom pain; intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury pain; exercise pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, burn pain, trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogenital disease; urinary incontinence, pathological cough; hyperactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS), type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal extreme pain, pruritus, tinnitus, or angina-induced pain.

Manufacture of Medicaments

In another aspect, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament.

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

In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., herniorrhaphy pain, bunionectomy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia.

In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia.

In yet another aspect, the invention provides the use of the compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity in a subject of gut pain, wherein gut pain comprises inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis pain.

In yet another aspect, the invention provides a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of neuropathic pain. In some aspects, the neuropathic pain comprises post-herpetic neuralgia, small fiber neuropathy or idiopathic small-fiber neuropathy.

In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in a treating or lessening the severity in a subject of neuropathic pain, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia; post spinal cord injury pain, small fiber neuropathy, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic neuropathy.

In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of musculoskeletal pain. In some aspects the musculoskeletal pain comprises osteoarthritis pain.

In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain.

In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain or vulvodynia.

In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain.

In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.

In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of pathological cough.

In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of acute pain. In some aspects, the acute pain comprises acute post-operative pain.

In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of postsurgical pain (e.g., herniorrhaphy pain, bunionectomy pain or abdominoplasty pain).

In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of herniorrhaphy pain.

In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of bunionectomy pain.

In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of abdominoplasty pain.

In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of visceral pain. In some aspects, the visceral pain comprises visceral pain from abdominoplasty.

In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in combination with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

In another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head pain, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain (e.g., herniorrhaphy pain, bunionectomy pain or abdominoplasty pain), cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastro-intestinal motility.

In another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity of femur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headaches; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy induced neuropathic pain; radiotherapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom pain; intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury pain; exercise pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory, burn pain, trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogenital disease; urinary incontinence; pathological cough; hyperactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS) type I; complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal extreme pain, pruritus, tinnitus, or angina-induced pain.

Administration of Pharmaceutically acceptable salts and compositions.

In certain embodiments of the invention an “effective amount” of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is that amount effective for treating or lessening the severity of one or more of the conditions recited above.

The compounds, salts, and compositions, according to the method of the invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the pain or non-pain diseases recited herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition, the particular agent, its mode of administration, and the like. The compounds, salts, and compositions of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compounds, salts, and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound or salt employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound or salt employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound or salt employed, and like factors well known in the medical arts. The term “subject” or “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the condition being treated. In certain embodiments, the compound, salts, and compositions of the invention may be administered orally or parenterally at dosage levels of about 0.001 mg/kg to about 100 mg/kg, or about 0.01 mg/kg to about 50 mg/kg, of subject body weight per day, one or more times a day, effective to obtain the desired therapeutic effect.

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

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of the compounds of the invention, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

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

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound or salt is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragées, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The active compound or salt can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragées, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound or salt may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound or salt of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are useful as inhibitors of voltage-gated sodium channels. In one embodiment, the compounds are inhibitors of Na V 1.8 and thus, without wishing to be bound by any particular theory, the compounds, salts, and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of Na V 1.8 is implicated in the disease, condition, or disorder. When activation or hyperactivity of Na V 1.8 is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as a “Na V 1.8-mediated disease, condition or disorder.” Accordingly, in another aspect, the invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of Na V 1.8 is implicated in the disease state.

The activity of a compound utilized in this invention as an inhibitor of Na V 1.8 may be assayed according to methods described generally in International Publication No. WO 2014/120808 A9 and U.S. Publication No. 2014/0213616 A1, both of which are incorporated by reference in their entirety, methods described herein, and other methods known and available to one of ordinary skill in the art.

Additional Therapeutic Agents

It will also be appreciated that the compounds, salts, and pharmaceutically acceptable compositions of the invention can be employed in combination therapies, that is, the compounds, salts, and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” For example, exemplary additional therapeutic agents include, but are not limited to: non-opioid analgesics (indoles such as Etodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such as Nabumetone; oxicams such as Piroxicam; para-aminophenol derivatives, such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylates such as Aspirin, Choline magnesium trisalicylate, Diflunisal; fenamates such as meclofenamic acid, Mefenamic acid; and pyrazoles such as Phenylbutazone); or opioid (narcotic) agonists (such as Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesic approaches may be utilized in conjunction with administration of one or more compounds of the invention. For example, anesthesiologic (intraspinal infusion, neural blockade), neurosurgical (neurolysis of CNS pathways), neurostimulatory (transcutaneous electrical nerve stimulation, dorsal column stimulation), physiatric (physical therapy, orthotic devices, diathermy), or psychologic (cognitive methods-hypnosis, biofeedback, or behavioral methods) approaches may also be utilized. Additional appropriate therapeutic agents or approaches are described generally in The Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and the Food and Drug Administration website, www.fda.gov, the entire contents of which are hereby incorporated by reference.

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

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

(2) a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen (including without limitation intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketorolac (including without limitation ketorolac tromethamine (e.g., Toradol®)), meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

(3) a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal or thiopental;

(4) a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;

(5) a histamine (H 1 ) antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;

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

(7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine;

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

(9) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1, 2,3,4-tetrahydroisoquinolin-2-yl)-5-(2-pyridyl) quinazoline;

(10) a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline;

(11) an anticonvulsant, e.g. carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®) or valproate;

(12) a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g. (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione (TAK-637), 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S);

(13) a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

(14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

(15) a coal-tar analgesic, in particular paracetamol;

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

(17) a vanilloid receptor agonist (e.g. resinferatoxin or civamide) or antagonist (e.g. capsazepine, GRC-15300);

(18) a beta-adrenergic such as propranolol;

(19) a local anesthetic such as mexiletine;

(20) a corticosteroid such as dexamethasone;

(21) a 5-HT receptor agonist or antagonist, particularly a 5-HT 1B/1D agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

(22) a 5-HT 2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);

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

(24) Tramadol®, Tramadol ER (Ultram ER®), Tapentadol ER (Nucynta®);

(25) a PDE5 inhibitor, such as 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]-pyrido[3,4-b]indole-1,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;

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

(27) a cannabinoid such as KHK-6188;

(28) metabotropic glutamate subtype 1 receptor (mGluR1) antagonist;

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

(30) a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion, nomifensine and viloxazine (Vivalan®), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine;

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

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

(33) an acetylcholinesterase inhibitor such as donepezil;

(34) a prostaglandin E2 subtype 4 (EP4) antagonist such as N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;

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

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

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

(38) a Na V 1.7 blocker, such as XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893 BIIB-074, BIIB-095, ASP-1807, DSP-3905, OLP-1002, RQ-00432979, FX-301, DWP-17061, IMB-110, IMB-111, IMB-112 and such as those disclosed in WO2011/140425 (US2011/306607); WO2012/106499 (US2012196869); WO2012/112743 (US2012245136); WO2012/125613 (US2012264749), WO2012/116440 (US2014187533), WO2011026240 (US2012220605), U.S. Pat. Nos. 8,883,840, 8,466,188, or WO2013/109521 (US2015005304), the entire contents of each application hereby incorporated by reference.

(38a) a Na V 1.7 blocker such as (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl)-(4-isopropoxy-3-methyl-phenyl)methanone, 2,2,2-trifluoro-1-[1′-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]-(4-isobutoxy-3-methoxy-phenyl)methanone, 1-(4-benzhydrylpiperazin-1-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy]propan-2-ol, (4-butoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]-(5-isopropoxy-6-methyl-2-pyridyl)methanone, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone, 5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carbonyl]phenyl]pyridine-2-carbonitrile, (4-isopropoxy-3-methyl-phenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone, 2,2,2-trifluoro-1-[1′-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone, 2,2,2-trifluoro-1-[1′-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-3,3-dimethyl-spiro[2,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone, 2,2,2-trifluoro-1-[1′-(5-isopentyloxypyridine-2-carbonyl)-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone, (4-isopropoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone, 2,2,2-trifluoro-1-[1′-(5-isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone, 1-[(3S)-2,3-dimethyl-1′-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]-2,2,2-trifluoro-ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]-[3-methoxy-4-[(1R)-1-methylpropoxy]phenyl]methanone, 2,2,2-trifluoro-1-[1′-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone, 1-[1′-[4-methoxy-3-(trifluoromethyl)benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]-2,2-dimethyl-propan-1-one, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone, [2-methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]-[4-(3,3,3-trifluoropropoxymethyl)phenyl]methanone, 4-bromo-N-(4-bromophenyl)-3-[(1-methyl-2-oxo-4-piperidyl)sulfamoyl]benzamide or (3-chloro-4-isopropoxy-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone.

(39) a Na V 1.8 blocker, such as PF-04531083, PF-06372865 and such as those disclosed in WO2008/135826 (US2009048306), WO2006/011050 (US2008312235), WO2013/061205 (US2014296313), US20130303535, WO2013131018, U.S. Pat. No. 8,466,188, WO2013114250 (US2013274243), WO2014/120808 (US2014213616), WO2014/120815 (US2014228371) WO2014/120820 (US2014221435), WO2015/010065 (US20160152561), WO2015/089361 (US20150166589) and WO2019014352 (US20190016671), the entire contents of each application hereby incorporated by reference.

(39a) a Na V 1.8 blocker such as 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide, 5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-((5-fluoro-2-hydroxybenzyl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide, 2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide, [4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate, 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinic acid, 2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide, 3-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoline-3-carboxamide, N-(3-sulfamoylphenyl)-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide, 3-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinic acid, 3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)quinoxaline-2-carboxamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4-yl)quinoxaline-2-carboxamide, 3-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, N-(4-carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)benzoic acid, N-(4-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 5-(2-(2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)benzoic acid, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 4-(2-(2-chloro-4-fluorophenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4-chloro-2-methylphenoxy)benzamido)benzoic acid, 5-(4-(tert-butyl)-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4-dimethoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(2-chloro-4-fluorophenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4-difluorophenoxy)benzamido)picolinic acid, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3-sulfamoylphenyl)benzamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzamide, 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, 4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2,3,4-trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, N-(2-carbamoyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide, 4-[[6-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(4-carbamoyl-3-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-pentafluoroethyl)benzamide, 4-[[4-(difluoromethoxy)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[4-cyclopropyl-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide, 5-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzamide, or 4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide.

(40) a combined Na V 1.7 and Na V 1.8 blocker, such as DSP-2230, Lohocla201 or BL-1021;

(41) a 5-HT3 antagonist, such as ondansetron;

(42) a TPRV 1 receptor agonist, such as capsaicin (NeurogesX®, Qutenza®); and the pharmaceutically acceptable salts and solvates thereof,

(43) a nicotinic receptor antagonist, such as varenicline;

(44) an N-type calcium channel antagonist, such as Z-160;

(45) a nerve growth factor antagonist, such as tanezumab;

(46) an endopeptidase stimulant, such as senrebotase;

(47) an angiotensin II antagonist, such as EMA-401;

(48) acetaminophen (including without limitation intravenous acetaminophen (e.g., Ofirmev®));

(49) bupivacaine (including without limitation bupivacaine liposome injectable suspension (e.g., Exparel®) bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll) and transdermal bupivacaine (Eladur®)); and

(50) bupivacaine and meloxicam combination (e.g., HTX-011).

In one embodiment, the additional appropriate therapeutic agents are selected from V-116517, Pregabalin, controlled release Pregabalin, Ezogabine (Potiga®). Ketamine/amitriptyline topical cream (Amiket®), AVP-923, Perampanel (E-2007), Ralfinamide, transdermal bupivacaine (Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561 or ARC-4558.

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

In another embodiment, the additional therapeutic agent is selected from a GlyT2/5HT2 inhibitor, such as Operanserin (VVZ149), a TRPV modulator such as CA008, CMX-020, NE06860, FTABS, CNTX4975, MCP101, MDR16523, or MDR652, a EGRI inhibitor such as Brivoglide (AYX1), an NGF inhibitor such as Tanezumab, Fasinumab, ASP6294, MEDI7352, a Mu opioid agonist such as Cebranopadol, NKTR181 (oxycodegol), a CB-1 agonist such as NEO1940 (AZN1940), an imidazoline 12 agonist such as CR4056 or a p75NTR-Fc modulator such as LEVI-04.

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

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

The amount of additional therapeutic agent present in the compositions of this invention may be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. The amount of additional therapeutic agent in the presently disclosed compositions may range from about 10% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

The compounds and salts of this invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the invention, in another aspect, includes a composition for coating an implantable device comprising a compound or salt of the invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In still another aspect, the invention includes an implantable device coated with a composition comprising a compound or salt of the invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to inhibiting Na V 1.8 activity in a biological sample or a subject, which method comprises administering to the subject, or contacting said biological sample with a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. The term “biological sample,” as used herein, includes, without limitation, cell cultures or extracts thereof, biopsied material obtained from a mammal or extracts thereof, and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of Na V 1.8 activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, the study of sodium channels in biological and pathological phenomena; and the comparative evaluation of new sodium channel inhibitors.

Synthesis of the Compounds of the Invention

The compounds of the invention can be prepared from known materials by the methods described in the Examples, and other methods known to one skilled in the art.

The compounds of the invention also can be prepared from known materials by the following methods, similar methods, and other methods known to one skilled in the art. As one skilled in the art would appreciate, the functional groups of the intermediate compounds in the methods described below may need to be protected by suitable protecting groups. Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art. The use of protecting groups is described in detail in T. G. M. Wuts et al., Greene's Protective Groups in Organic Synthesis (4th ed. 2006).

In general, the compounds of formulas (I) and (II) can be synthesized according to the general methods outlined in Scheme 1 and the specific procedures discussed in the Examples. Scheme 1 depicts the synthesis of the compounds of formula (I). The compounds of formula (II) can be synthesized by analogous methods. The starting materials for the synthesis described in Scheme 1 and the Examples are commercially available or can be prepared according to methods known to one skilled in the art.

Radiolabeled Analogs of the Compounds of the Invention

In another aspect, the invention relates to radiolabeled analogs of the compounds of the invention. As used herein, the term “radiolabeled analogs of the compounds of the invention” refers to compounds that are identical to the compounds of the invention, including the compounds of formulas (I) and (II), and all of the embodiments thereof, as described herein, and the compounds identified in Tables A-D, as described herein, except that one or more atoms has been replaced with a radioisotope of the atom present in the compounds of the invention.

As used herein, the term “radioisotope” refers to an isotope of an element that is known to undergo spontaneous radioactive decay. Examples of radioisotopes include 3 H, 4 C, 32 P 35 S, 18 F, 36 Cl, and the like, as well as 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).

The radiolabeled analogs can be used in a number of beneficial ways, including in various types of assays, such as substrate tissue distribution assays. For example, tritium (3H)- and/or carbon-14 ( 14 C)-labeled compounds may be useful for various types of assays, such as substrate tissue distribution assays, due to relatively simple preparation and excellent detectability.

In another aspect, the invention relates to pharmaceutically acceptable salts of the radiolabeled analogs, in accordance with any of the embodiments described herein in connection with the compounds of the invention.

In another aspect, the invention relates to pharmaceutical compositions comprising the radiolabeled analogs, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle, in accordance with any of the embodiments described herein in connection with the compounds of the invention.

In another aspect, the invention relates to methods of inhibiting voltage-gated sodium channels and methods of treating or lessening the severity of various diseases and disorders, including pain, in a subject comprising administering an effective amount of the radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, in accordance with any of the embodiments described herein in connection with the compounds of the invention.

In another aspect, the invention relates to radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use, in accordance with any of the embodiments described herein in connection with the compounds of the invention.

In another aspect, the invention relates to the use of the radiolabeled analogs, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments, in accordance with any of the embodiments described herein in connection with the compounds of the invention.

In another aspect, the radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, can be employed in combination therapies, in accordance with any of the embodiments described herein in connection with the compounds of the invention.

General methods. 1 H NMR (400 MHz) spectra were obtained as solutions in an appropriate deuterated solvent such as dimethyl sulfoxide-d 6 (DMSO-d6).

Compound purity, retention time, and electrospray mass spectrometry (ESI-MS) data were determined by LC/MS analysis using one of the following methods or in another method described in the individual examples.

LC/MS Method A. LC/MS analysis was conducted using a Waters Acquity Ultra Performance LC system by reverse phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 m particle) made by Waters (pn: 186002349), and a dual gradient run from 1-99% mobile phase B over 1.0-1.2 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B═CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

LC/MS Method B. LC/MS analysis was conducted using a Waters Acquity Ultra Performance LC system by reverse phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 m particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 2.9-3.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B═CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

LC/MS Method C. LC/MS analysis was conducted using a Waters Acquity Ultra Performance LC system by reverse phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 m particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 4.5-5.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B═CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

LC/MS Method D. LC/MS analysis was conducted using an Acquity UPLC BEH C s column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002877) with a (2.1×5 mm, 1.7 m particle) guard column (pn: 186003978), and a dual gradient run from 2-98% mobile phase B over 1.15 minutes. Mobile phase A=H 2 O (10 mM ammonium formate with 0.05% ammonium hydroxide). Mobile phase B=acetonitrile. Flow rate=1.0 mL/min, injection volume=2 μL, and column temperature=45° C.

LC/MS Method E. LC/MS analysis was conducted using an Acquity UPLC BEH C 8 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002877) with a (2.1×5 mm, 1.7 m particle) guard column (pn: 186003978), and a dual gradient run from 2-98% mobile phase B over 4.45 minutes. Mobile phase A=H 2 O (10 mM ammonium formate with 0.05% ammonium hydroxide). Mobile phase B=acetonitrile. Flow rate=0.6 mL/min, injection volume=2 μL, and column temperature=45° C.

LC/MS Method F. LC/MS analysis was conducted using an Acquity UPLC BEH C 8 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002877) with a (2.1×5 mm, 1.7 m particle) guard column (pn: 186003978), and a dual gradient run from 2-98% mobile phase B over 1.5 minutes. Mobile phase A=H 2 O (10 mM ammonium formate with 0.05% ammonium hydroxide). Mobile phase B=acetonitrile. Flow rate=0.6 mL/min, injection volume=2 μL, and column temperature=45° C.

LC/MS Method G. LC/MS analysis was conducted using a Shimadzu 10-A LC system by reverse phase HPLC using an Onyx Monolithic C 18 column (50×4.6 mm) made by Phenomenex (pn:CHO-7644), and a dual gradient run from 5-100% mobile phase B over 4.2 minutes. Mobile phase A ═H 2 O (0.1% CF 3 CO 2 H). Mobile phase B═CH 3 CN (0.1% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume 10 μL and with the column at ambient temperature.

LC/MS Method H. LC/MS analysis was conducted using a Shimadzu 10-A LC system by reverse phase HPLC using an Onyx Monolithic C 18 column (50×4.6 mm) made by Phenomenex (pn:CHO-7644), and a dual gradient run from 5-100% mobile phase B over 12 minutes. Mobile phase A ═H 2 O (0.1% CF 3 CO 2 H). Mobile phase B═CH 3 CN (0.1% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume 10 μL and with the column at ambient temperature.

LC/MS Method I. LC/MS analysis was conducted using an Acquity UPLC HSS T3 C s column (50×2.1 mm, 1.8 μm particle) made by Waters (pn: 186003538), and a dual gradient run from 1-99% mobile phase B over 2.90 minutes. Mobile phase A=H 2 O (10 mM ammonium formate). Mobile phase B=acetonitrile. Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

LC/MS Method J. LC/MS analysis was conducted using Cortex 2.7 M C 18 (3.0 mm×50 mm) column made by Waters, at a temperature of 55° C. with a flow rate of 1.2 mL/minutes and a dual gradient run from 5-100% mobile phase B over 4 minutes. Mobile phase A=water with 0.1% trifluoroacetic (TFA) acid. Mobile phase B=acetonitrile with 0.1% TFA acid.

LC/MS Method K. LC/MS analysis was conducted using a Phenomenex Luna C 18 column (3×50 mm, 3 m particle) over 2 minutes. Mobile phase conditions: 5-95% acetonitrile (0.1% formic acid) with water (0.1% formic acid) over 1 minute, then hold for 1 minute at 95% acetonitrile (0.1% formic acid). Flow rate=2 mL/min and column temperature 45° C.

LC/MS Method L: LC/MS analysis was conducted using a Phenomenex Kinetex Polar C 18 column (3×50 mm, 2.6 m particle) over 3 minutes. Mobile phase conditions: 5-95% acetonitrile (0.1% formic acid) in water (0.1% formic acid). Flow rate=1.2 mL/min.

LC/MS Method M: LC/MS analysis was conducted using a Phenomenex Kinetex Polar C 18 column (3×50 mm, 2.6 m particle, Phenomenex) over 6 minutes. Mobile phase conditions: 5-95% acetonitrile (0.1% formic acid) in water (0.1% formic acid). Flow rate=1.2 mL/min.

LC/MS Method N: LC/MS analysis was conducted using a Millipore Sigma Chromolith SpeedROD C 18 column (50×4.6 mm, 2 m particle) over 12 minutes. Mobile phase conditions: 5-100% acetonitrile (0.1% trifluoroacetic acid) in water (0.1% trifluoroacetic acid).

LC/MS Method O: LC/MS analysis was conducted using a Phenomenex Luna C 18 column (3×5 mm, 3 m particle) over 2.5 minutes. Mobile phase conditions: 5-100% acetonitrile (0.1% formic acid) in water (0.1% formic acid) over 1.3 minutes, then hold for 1.2 minutes at 95% acetonitrile (0.1% formic acid). Flow rate=1.5 mL/min and column temperature 45° C.

LC/MS Method P: LC/MS analysis was conducted using an Agilent ZORBAX Extend C 18 column (4.6×50 mm 1.8 m particle) over 5 minutes. Mobile phase conditions: 10-90% acetonitrile in water (10 mM ammonium acetate). Flow rate=1.2 mL/min.

LCMS Method Q: LC/MS analysis was conducted using a Waters Cortecs C 18 column (3×50 mm, 2.7 m particle) over 6 minutes. Mobile phase conditions: 5-100% acetonitrile (0.1% trifluoroacetic acid) in water (0.1% trifluoroacetic acid) over 4 minutes, then hold at 100% acetonitrile (0.1% trifluoroacetic acid) for 0.5 minutes, then equilibration to 5% acetonitrile (0.1% trifluoroacetic acid) over 1.5 minutes. Flow rate=1.2 mL/min and column temperature 55° C.

LC/MS Method R: LC/MS analysis was conducted using a YMC Triart C 18 column (2.1×33 mm. 3 m particle) over 3 minutes. Mobile phase conditions: 2-98% acetonitrile in water (5 mM ammonium acetate). Flow rate=1.0 mL/min.

LC/MS Method S: LC/MS analysis was conducted using a Millipore Sigma Chromolith SpeedROD C 18 column (4.6×50 mm) over 6 minutes. Mobile phase conditions: 5-95% acetonitrile (0.1% trifluoroacetic acid) in water (0.11% trifluoroacetic acid).

LC/MS Method T: LC/MS analysis was conducted using a Waters XBridge C 18 (4.6×50 mm, m particle) over 5 minutes. Mobile phase conditions 10-90% acetonitrile in water (10 mM ammonium acetate). Flow rate=1.2 mL/min.

LC/MS Method U: LC/MS analysis was conducted using a Waters Acquity BEH C 18 column (2.1×50 mm, 1.7 m particle) over 4.5 minutes. Mobile phase conditions 3-98% acetonitrile in water (0.1% formic acid). Flow rate=1.3 mL/min and column temperature 35° C.

LC/MS Method V. LC/MS analysis was conducted using a Merckmillipore Chromolith SpeedROD C 18 column (50×4.6 mm) and a dual gradient run from 5-100% mobile phase B over 6 minutes. Mobile phase A=H 2 O (0.1% TFA). Mobile phase B═CH 3 CN (0.1% TFA).

LC/MS Method W. LC/MS analysis was conducted using a Waters Cortex C 18 column (50 mm×3.0 mm, 2.7 m particle). Mobile phase A=H 2 O (0.1% TFA). Mobile phase B═CH 3 CN (0.1% TFA), dual gradient from 5% to 100% mobile phase B over 4 minutes, 100% B for 0.5 minutes, with equilibration to 5% B over 1.5 min. Flow rate=1.2 mL/min and column temperature=55° C.

Unless otherwise noted, where purification by reverse phase HPLC is indicated in the Examples below, samples were purified using a reverse phase HPLC-MS method using the general conditions as follows:

a. When using 5 mM HCl aqueous phase modifier: Phenomenex Luna C 18 (2) column (30×75 mm, 5 μm particle size) using an acetonitrile gradient runtime ranging from 9.5 minutes up to 15 minutes. Initial gradient acetonitrile concentration ranged from 1 to 40%, and final acetonitrile gradient concentration ranged from 30 to 99%. Flow rate=50 mL/min, injection volume=950 μL, and column temperature=25° C. b. When using 0.1% ammonium hydroxide aqueous phase modifier: Waters X-bridge OBD C 18 column (19×150 mm, 5 μm particle size) using an acetonitrile gradient run over 9 minutes. The acetonitrile gradient concentration was either 38-53% acetonitrile or 47-95% acetonitrile. Flow rate=19 mL/min. c. When using 0.05% trifluoroacetic aqueous phase modifier: Waters Sunfire C 18 column (19×150 mm, 5 m particle size) with a gradient from 1-100% acetonitrile over 11 minutes. Flow rate=19 mL/min.

Unless otherwise noted, or where the context dictates otherwise, the following abbreviations shall be understood to have the following meanings:

Preparation 1

Methyl 4-Amino-5-Methyl-Pyridine-2-Carboxylate

2-Chloro-5-methyl-pyridin-4-amine (0.5 g, 4 mmol) was diluted in methanol (6.6 mL) in an autoclave. Pd(dppf)Cl 2 -dichloromethane (70 mg, 0.086 mmol) and TEA (1.0 mL, 7.2 mmol) were added and the autoclave was purged with nitrogen, then with carbon monoxide. The mixture was heated to 130° C. and the carbon monoxide pressure was adjusted to 120 psi. The mixture was stirred for 18 hours at 130° C., and then cooled to 25° C. The mixture was purged with nitrogen and concentrated in vacuo. After purification by silica gel chromatography (0-10% methanol/ethyl acetate), the resulting material was triturated with MTBE (10 mL) for 1 hour. The solid was isolated by filtration, washed with MTBE (5 mL) and dried under vacuum at 50° C. for 3 hours to provide methyl 4-amino-5-methyl-pyridine-2-carboxylate (380 mg, 64%) as a beige solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.20 (s, 1H), 7.39 (s, 1H), 4.31 (br s, 2H), 3.95 (s, 3H), 2.16 (s, 3H) ppm. ESI-MS m z calc. 166.07, found 167.4 (M+1) + ; LC/MS retention time (Method K): 0.2 minutes.

Preparation 2

3-Chloro-4-Fluoro-2-Methyl-Phenol

A 500-mL round-bottom flask was charged with 3-chloro-4-fluorophenol (25.0 g, 165.5 mmol), N,N-diethylcarbamoyl chloride (45.1 g, 43.0 mL, 326 mmol) and pyridine (125 mL). The resulting mixture was heated at 100° C. and stirred at this temperature for 21 hours. The mixture was cooled to room temperature and was poured into water (250 mL). The resulting solution was extracted with MTBE (2×125 mL). The combined organic layers were washed with 10% aqueous HCl (3×250 mL), 10% aqueous NaOH (2×250 mL), brine (125 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give (3-chloro-4-fluoro-phenyl) N,N-diethylcarbamate (41.2 g, 100%) as a yellow oil. ESI-MS m z calc. 245.06, found 246.1 (M+1) + ; LC/MS retention time (Method L): 2.06 minutes. 1 H NMR (300 MHz, CDCl 3 ) δ 7.22 (dd, J=6.2, 2.6 Hz, 1H), 7.17-7.07 (m, 1H), 7.06-6.97 (m, 1H), 3.48-3.33 (m, 4H), 1.32-1.15 (m, 6H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −120.33-−120.55 (m, 1F) ppm.

A 25-mL round-bottom flask under nitrogen was charged with (3-chloro-4-fluoro-phenyl) N,N-diethylcarbamate (500 mg, 1.97 mmol), THF (3 mL) and N,N,N,N-tetramethylethylenediamine (271 mg, 0.35 mL, 2.33 mmol). The mixture was cooled to −78° C. and sec-butyllithium (1.7 mL of 1.4 M solution in cyclohexane, 2.4 mmol) was then added slowly over ˜ 15 minutes. The resulting mixture was stirred at −78° C. for 2 hours and then treated with methyl iodide (480 mg, 0.21 mL, 3.4 mmol). The resulting mixture was stirred for 2 hours while being allowed to warm to 0° C. Water (5 mL) was then added and the resulting solution extracted with MTBE (3×5 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to provide (3-chloro-4-fluoro-2-methyl-phenyl) N,N-diethylcarbamate (612 mg, 104% yield, purity 87%) as a yellow oil. ESI-MS m z calc. 259.08, found 260.1 (M+1) + ; LC/MS retention time (Method L): 2.11 minutes. 1 H NMR (300 MHz, CDCl 3 ) δ 7.05-6.93 (m, 2H), 3.47 (q, J=7.3 Hz, 2H), 3.39 (q, J=7.1 Hz, 2H), 2.27 (s, 3H), 1.28 (t, J=7.2 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −116.99-17.13 (m, 1F) ppm.

To a solution of (3-chloro-4-fluoro-2-methyl-phenyl) N,N-diethylcarbamate (508 mg, 1.96 mmol) in THF (3 mL) at room temperature was added LiAlH 4 (150 mg, 3.95 mmol) in one portion. The mixture was stirred at 50° C. for 6 hours and then at room temperature (˜15° C.) overnight. A saturated aqueous NH 4 Cl solution (15 mL) was added dropwise to the mixture and the resulting suspension was stirred at room temperature for 20 minutes. The mixture was filtered over Celite and the solid washed with MTBE (35 mL) and water (5 mL). The layers were separated and the aqueous layer was extracted with MTBE (2×35 mL). The combined organic layers were extracted with aqueous 2 M NaOH solution (4×20 mL). The combined aqueous layers were acidified (pH<4) with aqueous concentrated HCl (˜15 mL) and the resulting solution was extracted with MTBE (3×50 mL). The combined organic layers were washed with brine (25 mL), dried over Na 2 SO 4 filtered and concentrated in vacuo to provide 3-chloro-4-fluoro-2-methyl-phenol (258 mg, 81%) as a light brown solid. ESI-MS m z calc. 160.01, found 159.1 (M−1) − ; LC/MS retention time (Method L): 1.82 minutes. 1 H NMR (300 MHz, CDCl 3 ) δ 6.88 (t, J=8.7 Hz, 1H), 6.65 (dd, J=8.8, 4.4 Hz, 1H), 4.70 (br. s., 1H), 2.32 (s, 3H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −123.29 (d, J=12.2 Hz, 1F) ppm.

Preparation 3

2-Chloro-3,4-Difluoro-Phenol

To a mixture of 3,4-difluorophenol (10.0 g, 76.9 mmol) and K 2 CO 3 (13.9 g, 101 mmol) in acetone (100 mL) was added chloro(methoxy)methane (9.0 g, 8.5 mL, 112 mmol). The resulting mixture was stirred for 2 days at room temperature. Additional chloro(methoxy)methane (5.3 g, 5.0 mL, 66 mmol) and diisopropylethylamine (9.6 g, 13 mL, 75 mmol) were added and the mixture was stirred at 25° C. overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% ethyl acetate/heptane) to provide 1,2-difluoro-4-(methoxymethoxy)benzene (7.54 g, 56%) as a clear liquid. 1 H NMR (300 MHz, CDCl 3 ) δ 7.06 (dt, J=10.0, 9.1 Hz, 1H), 6.89 (ddd, J=12.0, 6.8, 2.9 Hz, 1H), 6.74 (dtd, J=9.0, 3.3, 1.8 Hz, 1H), 5.11 (s, 2H), 3.47 (s, 3H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −135.51 (dt, J=21.4, 10.7 Hz, 1F), −146.74-−147.11 (m, 1F) ppm.

2,2,6,6-Tetramethylpiperidine (5.27 g, 6.3 mL, 37 mmol) and 1,2-difluoro-4-(methoxymethoxy)benzene (6.5 g, 37 mmol) were added consecutively to a solution of n-butyllithium (15 mL of 2.5 M in hexanes, 38 mmol) in THF (65 mL) at −78° C. After stirring for 2 hours at −78° C., 1,1,2-trichloro-1,2,2-trifluoroethane (7.1 g, 4.5 mL, 38 mmol) was added and the mixture was stirred at 0° C. for 1 hour. Water (100 mL) was added and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% ethyl acetate/heptane) to provide 3-chloro-1,2-difluoro-4-(methoxymethoxy)benzene (9.43 g, 85%) as yellow oil. 1 H NMR (300 MHz, CDCl 3 ) δ 7.02 (td, J=9.4, 8.2 Hz, 1H), 6.96-6.88 (m, 1H), 5.21 (s, 2H), 3.52 (s, 3H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −135.20 (dd, J=21.4, 9.2 Hz, 1F), −143.05-−143.37 (m, 1F) ppm.

Aqueous HCl (50 mL of 6 M, 300 mmol) was added to a solution of 3-chloro-1,2-difluoro-4-(methoxymethoxy)benzene (9.43 g, 31.7 mmol) in THF (55 mL) and the mixture was stirred at 25° C. overnight. The mixture was diluted with water (100 mL) and extracted with diethyl ether (3×100 mL). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-30% dichloromethane/pentane) to afford 2-chloro-3,4-difluoro-phenol (4.65 g, 66%) as yellow oil. ESI-MS m z calc. 163.984, found 163.0 (M−1) − ; LC/MS retention time (Method M): 2.34 minutes. 1 H NMR (300 MHz, CDCl 3 ) δ 7.02 (td, J=9.5, 8.5 Hz, 1H), 6.76 (ddd, J=9.3, 4.2, 2.3 Hz, 1H), 5.50 (s, 1H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −136.22 (dd, J=21.4, 9.2 Hz, 1F), −144.97-−145.28 (m, 1F) ppm.

Preparation 4

2-Cyclopropyl-3,6-Difluoro-Phenol

To a solution of 2-bromo-1,4-difluoro-3-methoxy-benzene (1.0 g, 4.5 mmol) in dichloromethane (5.0 mL) was added BBr 3 (4.5 g, 1.7 mL, 18 mmol) dropwise at 0° C. The mixture was stirred for 2 hours at room temperature. Water was then added dropwise at 0° C. and the layers separated. The organic layer was dried over anhydrous MgSO 4 , filtered and concentrated in vacuo to provide 2-bromo-3,6-difluoro-phenol (1.04 g, 100%) as colorless oil. LC/MS retention time=3.94 minutes (Method N).

Nitrogen was bubbled though a solution of 2-bromo-3,6-difluoro-phenol (14.27 g, 68.28 mmol), cyclopropyl boronic acid (11.73 g, 136.6 mmol), K 3 PO 4 (58.0 g, 273 mmol), tricyclohexylphosphonium tetrafluoroborate (2.51 g, 6.84 mmol) and Pd(OAc) 2 (3.07 g, 13.7 mmol) in a mixture of toluene (265 mL) and water (65 mL) for 10 minutes in a pressure flask. The flask was sealed and heated at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate (700 mL), washed with water and brine, dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo and purified using silica gel chromatography (0-40% ethyl acetate/hexane). The isolated product was dissolved in ethyl acetate (300 mL) and extracted with 1 M aqueous NaOH (4×50 mL). The combined aqueous layers were adjusted to pH˜2 with 6 M aqueous HCl and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with water and brine, dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo to obtain 2-cyclopropyl-3,6-difluoro-phenol (9.1 g, 74%) as yellow oil. ESI-MS m z calc. 170.05, found 171.2 (M+1) + ; LC/MS retention time (Method N): 4.86 minutes. 1 H NMR (500 MHz, CDCl 3 ) δ 6.93-6.84 (m, 1H), 6.56-6.48 (m, 1H), 5.51 (d, J=4.0 Hz, 1H), 1.84-1.75 (m, 1H), 1.05-0.97 (m, 2H), 0.97-0.89 (m, 2H) ppm.

Preparation 5

4-(Difluoromethyl)-2-Methoxy-Phenol

(Diethylamino)sulfur trifluoride (39 g, 32 mL, 242 mmol) was slowly added to a cold (10° C.) solution of 4-hydroxy-3-methoxy-benzaldehyde (18.0 g, 118 mmol) in dichloromethane (300 mL). The mixture was warmed to room temperature and stirred overnight. The mixture was treated with 5% aqueous NaHCO 3 (500 mL), stirred for 30 minutes, then extracted with dichloromethane (3×200 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-30% ethyl acetate/heptane) to afford 4-(difluoromethyl)-2-methoxy-phenol (10.88 g, 47%) as an orange oil that crystallized on standing. ESI-MS m z calc. 174.0492, found 173.0 (M−1) − ; LC/MS retention time (Method M): 2.03 minutes. 1 H NMR (300 MHz, CDCl 3 ) δ 7.05-6.92 (m, 3H), 6.57 (t, J=61.1 Hz, 1H), 5.79 (s, 1H), 3.94 (s, 3H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −107.50-−107.92 (m, 2F) ppm.

Preparation 6

2,3-Dichloro-4-Fluoro-Phenol

A 500-mL round-bottom flask was charged with 3-chloro-4-fluorophenol (25.0 g, 165.5 mmol), N,N-diethylcarbamoyl chloride (45 g, 43 mL, 326 mmol) and pyridine (125 mL). The mixture was stirred at 100° C. for 21 hours. The mixture was cooled to room temperature, poured into water (250 mL) and extracted with MTBE (2×125 mL). The combined organic layers were washed with 10% aqueous HCl (3×250 mL), 10% aqueous NaOH (2×250 mL) and brine (125 mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo to provide (3-chloro-4-fluoro-phenyl) N,N-diethylcarbamate (41.2 g, 100%) as a yellow oil (99% purity). ESI-MS m z calc. 245.06, found 246.1 (M+1) + ; LC/MS retention time (Method L): 2.06 minutes. 1 H NMR (300 MHz, CDCl 3 ) δ 7.22 (dd, J=6.2, 2.6 Hz, 1H), 7.17-7.07 (m, 1H), 7.06-6.97 (m, 1H), 3.48-3.33 (m, 4H), 1.32-1.15 (m, 6H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −120.33-−120.55 (m, 1F) ppm.

A flask under nitrogen was charged with (3-chloro-4-fluoro-phenyl) N,N-diethylcarbamate (10 g, 41 mmol), THF (60 mL) and N,N,N,N-tetramethylethylenediamine (5.4 g, 7.0 mL, 47 mmol). The mixture was cooled to −78° C. and sec-butyllithium (34 mL of 1.4 M in cyclohexane, 48 mmol) was then added slowly (over −15 min). The mixture was stirred at −78° C. for 2 hours and then treated with 1,1,2-trichloro-1,2,2-trifluoro-ethane (8.4 g, 5.3 mL, 45 mmol). The resulting mixture was allowed to warm to 0° C. over 1 hour. Water (50 mL) was then added and the resulting solution extracted with diethyl ether (3×150 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% ethyl acetate/heptane) to provide (2,3-dichloro-4-fluoro-phenyl) N,N-diethylcarbamate (8.92 g, 78%) as yellow oil. ESI-MS m z calc. 279.02, found 280.1 (M+1) + ; LC/MS retention time (Method L): 2.13 minutes. 1 H NMR (300 MHz, CDCl 3 ) δ 7.23-6.92 (m, 2H), 3.55-3.30 (m, 4H), 1.37-1.13 (m, 6H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −113.45 (d, J=6.1 Hz, 1F) ppm.

LiAlH 4 (45 mg, 1.3 mmol) was added to a solution of (2,3-dichloro-4-fluoro-phenyl) N,N-diethylcarbamate (300 mg, 1.07 mmol) in THF (5 mL) and the mixture was stirred at room temperature overnight. Additional LiAlH 4 (40 mg, 1.2 mmol) was added and the mixture was heated at 50° C. for 7 hours, and then at reflux for 2 hours. The mixture was cooled to room temperature, then treated slowly with a saturated aqueous NH 4 Cl solution (50 mL) and stirred at room temperature for 20 minutes. The mixture was filtered over Celite and the solid washed with MTBE (50 mL) and water (10 mL). The filtrate layers were separated and the aqueous layer was extracted with MTBE (2×50 mL). The combined organic layers were then extracted with 2 M aqueous NaOH (4×25 mL). The combined aqueous extracts were acidified (pH<4) with 6 M aqueous HCl and the resulting solution was extracted with diethyl ether (3×50 mL). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo. Silica gel chromatography (0-30% dichloromethane/pentane) provided 2,3-dichloro-4-fluoro-phenol (164 mg, 55%) as a yellow oil that solidified to an off-white solid upon standing. 1 H NMR (300 MHz, CDCl 3 ) δ 7.02-6.91 (m, 1H), 6.90-6.81 (m, 1H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −120.56 (t, J=7.6 Hz, 1F) ppm.

Preparation 7

4-(Difluoromethoxy)-3-Fluoro-2-Methoxy-Phenol

A mixture of 4-bromo-2-fluoro-3-methoxy-phenol (11.5 g, 52.0 mmol), K 2 CO 3 (28.8 g, 208 mmol) and sodium 2-chloro-2,2-difluoro-acetate (23.8 g, 156 mmol) in DMF (200 mL) and water (50 mL) was degassed with nitrogen for 5 minutes and was heated at 100° C. for 18 hours. The mixture was cooled to room temperature, then extracted with diethyl ether (4×200 mL). The combined organic layers were washed with water (2×100 mL) and 1 M aqueous NaOH (2×100 mL). The organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to provide 1-bromo-4-(difluoromethoxy)-3-fluoro-2-methoxy-benzene (9.62 g, 64%) as a yellow oil. 1 H NMR (300 MHz, CDCl 3 ): δ 7.33-7.26 (m, 1H), 6.92-6.84 (m, 1H), 6.53 (t, J=72.6 Hz, 1H), 3.99 (d, J=1.4 Hz, 3H) ppm. 19 F NMR (282 MHz, CDCl 3 ): δ −81.8 (dd J=72.4 Hz, 4.3 Hz, 2F), −143.1 (s, 1F) ppm.

A mixture of 1-bromo-4-(difluoromethoxy)-3-fluoro-2-methoxy-benzene (9.1 g, 33.6 mmol), Me 4 tButylXphos (493 mg, 1.03 mmol) and KOH (5.75 g, 102.5 mmol) in dioxane (28 mL) and water (28 mL) was degassed with nitrogen bubbling for 10 minutes. Pd 2 dba 3 (474 mg, 0.518 mmol) was added and the reaction vessel purged with nitrogen (3×). The mixture was stirred at 90° C. for 3 hours, and then cooled to room temperature and diluted with water (100 mL). The aqueous mixture was washed with ether (4×200 mL). The aqueous phase was then acidified with 3 M aqueous HCl until pH 1-2 and extracted with ether (3×150 mL). The combined organic extracts were washed with saturated aqueous NaHCO 3 (3×50 mL) and brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to provide 4-(difluoromethoxy)-3-fluoro-2-methoxy-phenol (5.90 g, 75%) as a light orange oil. ESI-MS m z calc. 208.03, found 207.0 (M−1) − ; LC/MS retention time (Method M): 2.33 minutes. 1 H NMR (300 MHz, CDCl 3 ) δ 6.90-6.79 (m, 1H), 6.73-6.18 (m, 2H), 5.73-5.65 (m, 1H), 4.03 (d, J=2.1 Hz, 3H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −81.05-−82.50 (m, 1F), −145.68-−146.31 (m, 1F) ppm.

Preparation 8

2-Ethyl-3-Fluoro-4-(Trifluoromethoxy)Phenol

To a solution of 3-fluoro-4-(trifluoromethoxy)phenol (5.0 g, 25.5 mmol) and DIPEA (9.6 g, 13 mL, 75 mmol) in dichloromethane (130 mL) at 0° C. was added chloromethyl methyl ether (3.7 g, 3.9 mL, 42 mmol). The resulting mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue purified by silica gel chromatography (0-40% dichloromethane/hexanes) to provide 2-fluoro-4-(methoxymethoxy)-1-(trifluoromethoxy)benzene (5.11 g, 83%) as a colorless oil. 1 H NMR (300 MHz, CDCl 3 ) δ 7.20 (td, J=8.9, 1.0 Hz, 1H), 6.91 (dd, J=11.6, 2.8 Hz, 1H), 6.81 (ddd, J=9.0, 2.9, 1.6 Hz, 1H), 5.15 (s, 2H), 3.48 (s, 3H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −59.34 (br. s., 3F), −125.89-−126.37 (m, 1F) ppm.

To a solution of 2-fluoro-4-(methoxymethoxy)-1-(trifluoromethoxy)benzene (5.0 g, 20.8 mmol) in THF (100 mL) at −78° C. was added n-butyllithium (10 mL of 2.5 M in hexanes, 25 mmol) dropwise over 20 minutes. After 30 minutes at this temperature, iodoethane (8.7 g, 4.5 mL, 56 mmol) was added dropwise over 10 minutes and the mixture was stirred at this temperature for 30 minutes. The mixture was allowed to warm to 0° C. and stirred for 2 hours, and then stirred at ˜ 5° C. for 1.5 hours. The mixture was treated with saturated aqueous NaHCO 3 (75 mL) and water (50 mL) and concentrated in vacuo to remove the organic solvents. The remaining aqueous mixture was partitioned between water (100 mL) and dichloromethane (300 mL) and the layers separated. The aqueous layer was extracted with additional dichloromethane. The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. Reverse phase chromatography (5-95% acetonitrile/0.1% aqueous formic acid) product fractions were combined and concentrated in vacuo to remove the acetonitrile. Water (200 mL) was added to the remaining aqueous mixture which was extracted with dichloromethane (3×). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to provide 2-ethyl-3-fluoro-1-(methoxymethoxy)-4-(trifluoromethoxy)benzene (4.08 g, 73%) as a pale yellow oil. 1 H NMR (300 MHz, CDCl 3 ) δ 7.11-6.99 (m, 1H), 6.84 (d, J=9.1 Hz, 1H), 5.20 (s, 2H), 3.48 (s, 3H), 2.78-2.64 (m, 2H), 1.16 (t, J=7.5 Hz, 3H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −59.20 (s, 3F), −132.77 (s, 1F) ppm.

To a solution of 2-ethyl-3-fluoro-1-(methoxymethoxy)-4-(trifluoromethoxy)benzene (4.08 g, 15.2 mmol) in dioxane (60 mL) at room temperature was added aqueous concentrated HCl (1.3 mL of 12 M, 15.6 mmol). The mixture was stirred at 40° C. for 5 hours, and then overnight at 35° C. The mixture was concentrated in vacuo and partitioned between water (300 mL) and dichloromethane (150 mL). The layers were separated and the aqueous layer was extracted with additional dichloromethane (100 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. Reverse phase purification (5-95% acetonitrile/0.1% aqueous formic acid) provided product fractions which were combined and concentrated in vacuo to remove the acetonitrile. Water (200 mL) was added to the remaining aqueous mixture, which was extracted with dichloromethane (3×). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to provide 2-ethyl-3-fluoro-4-(trifluoromethoxy)phenol (2.62 g, 76%) as a yellow oil. 1 H NMR (300 MHz, CDCl 3 ) δ 7.05-6.94 (m, 1H), 6.53 (dd, J=9.0, 1.9 Hz, 1H), 4.89 (d, J=1.2 Hz, 1H), 2.69 (qd, J=7.6, 1.9 Hz, 2H), 1.19 (t, J=7.5 Hz, 3H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −59.32 (s, 3F), −132.31-−132.53 (m, 1F) ppm.

Preparation 9

2-Cyclopropyl-3-Fluoro-4-(Trifluoromethoxy)Phenol

To a solution of 2-fluoro-4-(methoxymethoxy)-1-(trifluoromethoxy)benzene (5.0 g, 20.8 mmol, Preparation 8, Step 1) in THF (65 mL) at −78° C. under a nitrogen atmosphere was added dropwise n-butyllithium (10 mL of 2.5 M in hexanes, 25 mmol). The resulting mixture was stirred at this temperature for 1 hour, then bromine (5.0 g, 1.6 mL, 31 mmol) was slowly added over 10 minutes. The mixture was stirred at this temperature for 1 hour. The dry ice bath was removed and the mixture was treated with saturated aqueous NaHCO 3 (150 mL). The mixture was partitioned between dichloromethane (150 mL) and water (100 mL). The layers were separated and the aqueous layer was extracted with additional dichloromethane (150 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. Silica gel chromatography (0-20% ethyl acetate/heptane) provided 2-bromo-3-fluoro-1-(methoxymethoxy)-4-(trifluoromethoxy)benzene (6.51 g, 98%) as a colorless oil. 1 H NMR (300 MHz, CDCl 3 ) δ 7.22 (ddd, J=9.2, 8.2, 1.0 Hz, 1H), 6.96 (dd, J=9.4, 2.1 Hz, 1H), 5.26 (s, 2H), 3.52 (s, 3H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −59.15-−59.39 (m, 3F), −117.43 (d, J=6.1 Hz, 1F) ppm.

A solution of 2-bromo-3-fluoro-1-(methoxymethoxy)-4-(trifluoromethoxy)benzene (11.38 g, 33.53 mmol) in toluene (165 mL) was degassed by nitrogen bubbling for 1 hour, then cyclopropylboronic acid (6.0 g, 70 mmol), K 3 PO 4 (18.3 g, 102 mmol), tricyclohexylphosphine tetrafluoroborate (2.5 g, 6.8 mmol), palladium (II) acetate (770 mg, 3.43 mmol) and nitrogen-degassed water (16.5 mL) were added. The mixture was stirred at 100° C. for 10 hours. The mixture was cooled to room temperature and filtered through a pad of Celite, rinsing with additional ethyl acetate (100 mL). The filtrate was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. Silica gel chromatography (0-15% ethyl acetate/heptane), followed by reverse phase chromatography (5-95% acetonitrile/0.1% aqueous formic acid) provided 2-cyclopropyl-3-fluoro-1-(methoxymethoxy)-4-(trifluoromethoxy)benzene (6.62 g, 70%) as a colorless oil. 1 H NMR (300 MHz, CDCl 3 ) δ 7.07-6.98 (m, 1H), 6.82 (dd, J=9.2, 1.9 Hz, 1H), 5.19 (s, 2H), 3.50 (s, 3H), 1.94-1.83 (m, 1H), 1.03-0.90 (m, 4H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −59.03-−59.39 (m, 3F), −131.68-−131.95 (m, 1F) ppm.

To a mixture of 2-cyclopropyl-3-fluoro-1-(methoxymethoxy)-4-(trifluoromethoxy)benzene (6.41 g, 22.9 mmol) in THF (80 mL) at room temperature was added concentrated aqueous HCl (3.3 mL of 12 M, 39.600 mmol) dropwise. The mixture was stirred at 40° C. for 5 hours, and then at room temperature overnight. Approximately half of the THF was removed under reduced pressure, and then the mixture was partitioned between water (200 mL) and dichloromethane (150 mL). The layers were separated and the aqueous layer was extracted with additional dichloromethane (2×100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. Silica gel chromatography (0-30% ethyl acetate/heptane) followed by reverse phase chromatography (5-95% acetonitrile/0.1% aqueous formic acid) provided a product residue which was partitioned between water and dichloromethane. The aqueous layer was extracted with additional dichloromethane (3×), and the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to provide 2-cyclopropyl-3-fluoro-4-(trifluoromethoxy)phenol (3.76 g, 68%) as a pale yellow oil. ESI-MS m z calc. 236.05, found 235.0 (M−1) − ; LC/MS retention time (Method M): 3.02 minutes. 1 H NMR (300 MHz, CDCl 3 ) δ 7.07 (t, J=8.7 Hz, 1H), 6.64 (dd, J=9.1, 2.1 Hz, 1H), 5.75 (s, 1H), 1.66-1.56 (m, 1H), 1.14-1.06 (m, 2H), 0.78-0.70 (m, 2H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −59.36 (d, J=6.1 Hz, 3F), −129.15-−129.33 (m, 1F) ppm.

Preparation 10

2-Ethoxy-4-(Trifluoromethoxy)Phenol

To a mixture of 2-bromo-5-(trifluoromethoxy)phenol (5.2 g, 20 mmol) and iodoethane (1.64 mL, 20.5 mmol) in DMF (20 mL) was added K 2 CO 3 (3.38 g, 24.5 mmol). The mixture was stirred at room temperature overnight. Additional iodoethane (500 μL, 6.25 mmol) was added and the mixture stirred for 90 minutes, then allowed to stand overnight. The mixture was diluted with water (50 mL) and extracted with MTBE (3×50 mL). The combined organic extracts were washed with water (3×50 mL) and brine (50 mL), dried (phase separation cartridge) and concentrated in vacuo to afford 1-bromo-2-ethoxy-4-(trifluoromethoxy)benzene (5.587 g, 97%) as a pale yellow oil. 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.70 (d, J=8.7 Hz, 1H), 7.15-7.10 (m, 1H), 6.91 (ddq, J=8.7, 2.5, 1.2 Hz, 1H), 4.16 (q, J=7.0 Hz, 2H), 1.36 (t, J=7.0 Hz, 3H) ppm.

A three-necked flask with a thermometer and nitrogen inlet was charged under a nitrogen atmosphere with THF (150 mL) and was cooled to −78° C. n-Butyllithium (27 mL of 2.5 M in hexanes, 67.5 mmol) was added over 5 minutes while maintaining the internal temperature below −60° C. 1-Bromo-2-ethoxy-4-(trifluoromethoxy)benzene (16.9 g, 59.3 mmol) was added dropwise over 5 minutes while maintaining temperature below −65° C. The solution was stirred for 15 minutes, then treated with trimethyl borate (9 mL, 80 mmol) over 10 minutes, keeping the temperature below −65° C. After complete addition, the mixture was stirred at −78° C. for an additional hour. The mixture was treated dropwise with 2 M aqueous HCl (32 mL, 64 mmol) until pH=1 and the mixture was allowed to warm to room temperature. The aqueous phase was separated and extracted with MTBE (2×150 mL). The combined organic phases were washed with brine, dried over MgSO 4 and concentrated in vacuo to afford [2-ethoxy-4-(trifluoromethoxy)phenyl]boronic acid (14.1 g, 95%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.79 (s, 2H), 7.61 (d, J=8.0 Hz, 1H), 6.96-6.88 (m, 2H), 4.10 (q, J=7.0 Hz, 2H), 1.36 (t, J=6.9 Hz, 3H) ppm. 19 F NMR (376 MHz, DMSO) δ −56.48 ppm.

[2-Ethoxy-4-(trifluoromethoxy)phenyl]boronic acid (14.1 g, 54.5 mmol) was dissolved in THF (150 mL) and water (150 mL). Sodium perborate monohydrate (16.7 g, 167 mmol) was added in one portion, resulting in an exotherm to 37° C. after the addition. The mixture was stirred at room temperature for 20 minutes. The resulting white suspension was filtered, and the solid washed with water and MTBE. The filtrate phases were separated and the aqueous phase was extracted again with MTBE (100 mL). The combined organic phases were dried (phase separation cartridge) and concentrated in vacuo to afford 2-ethoxy-4-(trifluoromethoxy)phenol (12.4 g, 100%) as a yellow-orange oil. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.25 (s, 1H), 6.90 (d, J=2.7 Hz, 1H), 6.83 (d, J=8.7 Hz, 1H), 6.78-6.70 (m, 1H), 4.04 (q, J=7.0 Hz, 2H), 1.33 (t, J=7.0 Hz, 3H) ppm. 19 F NMR (376 MHz, DMSO) δ −57.17 ppm.

Preparation 11

3,4-Difluoro-2-Methyl-Phenol

To a stirring suspension of 1,2-difluoro-3-methyl-benzene (10 g, 78 mmol) and iron powder (1.9 g, 7.5 mmol) in CHCl 3 (50 mL) under nitrogen was added Br 2 (12.1 g, 75.7 mmol) in a single portion. The mixture was stirred at room temperature for 19 hours, and then concentrated in vacuo to a volume of −25 mL. The residue was purified using silica gel column chromatography (100% hexanes) to provide 1-bromo-3,4-difluoro-2-methyl-benzene (15 g, 93%) as a clear oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.27 (ddd, J=8.9, 4.6, 2.2 Hz, 1H), 7.03-6.76 (m, 1H), 2.35 (s, 3H) ppm.

A mixture of 1-bromo-3,4-difluoro-2-methyl-benzene (22 g, 106 mmol), Me 4 tButylXphos (1.51 g, 3.14 mmol) and KOH (18.2 g, 324 mmol) in dioxane (63 mL) and water (63 mL) was degassed with nitrogen bubbling for 10 minutes. Pd 2 dba 3 (1.5 g, 1.6 mmol) was added and the mixture purged with nitrogen (3×). The mixture was stirred at 90° C. for 5 hours, and then diluted with water (100 mL) and washed with ether (3×80 mL). The aqueous layer was acidified with 3 M aqueous HCl to pH 1-2, and then extracted with ether (3×100 mL). The organic extracts were combined and washed with saturated aqueous NaHCO 3 (3×50 mL) and brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to provide 3,4-difluoro-2-methyl-phenol (16.9 g, 85%) as a light orange oil. ESI-MS m z calc. 144.04, found 143.3 (M−1) − ; LC/MS retention time (Method M): 2.37 minutes. 1 H NMR (300 MHz, CDCl 3 ) δ 6.85 (q, J=9.1 Hz, 1H), 6.52-6.40 (m, 1H), 5.10-4.94 (m, 1H), 2.23-2.13 (m, 3H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −139.60 (dd, J=21.4, 6.1 Hz, 1F), −148.15 (dd, J=21.4, 6.1 Hz, 1F) ppm.

4-[[2-[(6-Chloro-2-Methoxy-3-Pyridyl)Oxy]-5-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (1)

A solution of 2-bromo-5-(trifluoromethyl)benzoic acid (1 g, 3.7173 mmol) and 4-aminopyridine-2-carboxamide (515 mg, 3.7553 mmol) in pyridine (20.000 mL) was cooled to −10° C. followed by drop-wise addition of POCl 3 (855.40 mg, 520 μL, 5.5788 mmol) with stirring. Stirring was continued for 90 minutes at −10° C. The reaction was then quenched with water (20 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (30 mL×3) and brine, dried over anhydrous MgSO 4 and filtered. The filtrate was concentrated under vacuo, and the residue dried under vacuum to afford 2-bromo-N-(2-cyano-4-pyridyl)-5-(trifluoromethyl)benzamide (1.34 g, 88%) as an orange solid. ESI-MS m/z calc. 368.9725, found 369.9 (M+1) + ; Retention time: 5.27 minutes. LCMS Method: Merckmillipore Chromolith SpeedROD C 18 column (50×4.6 mm) and a dual gradient run from 5-100% mobile phase B over 12 minutes. Mobile phase A=water (0.1% CF3CO2H). Mobile phase B=acetonitrile (0.1% CF3CO2H); LCMS Method Detail: null.

To a solution of mixture of 2-bromo-N-(2-cyano-4-pyridyl)-5-(trifluoromethyl)benzamide (13.01 g, 31.635 mmol) and K 2 CO 3 (6.56 g, 47.465 mmol) in DMSO (390.30 mL) was added H 2 O 2 (107.61 mL of 30% w/v, 949.05 mmol) dropwise at 10° C. with stirring. The reaction mixture was allowed to warm to ambient temperature and stirred for a further 30 minutes. The reaction mixture was then cooled to 4° C., diluted with ethyl acetate (600 mL) and quenched with 10% aqueous Na 2 S 2 O 3 (500 mL). The organic layer was washed with 10% aq. Na 2 S 2 O 3 (250 mL), water (250 mL×3), brine (250 mL), dried over anhydrous MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to afford 4-[[2-bromo-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (9.28 g, 72%) as an orange solid. ESI-MS m/z calc. 386.983, found 388.2 (M+1) + ; Retention time: 1.83 minutes. 1H NMR (500 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 8.38 (d, J=2.1 Hz, 1H), 8.11 (dd, J=8.4, 2.6 Hz, 2H), 8.02 (d, J=8.4 Hz, 1H), 7.88-7.81 (m, 2H), 7.67 (s, 1H) ppm. LCMS Method: Water Cortex 2.7u C 18 (3.0 mm×50 mm), Temp: 55c; Flow: 1.2 mL/minutes; MP: 100% water with 0.1% trifluoroacetic (TFA) acid then 100% acetonitrile with 0.1% TFA acid, grad:5% to 100% B over 4 min, with stay at 100% B for 0.5 min, equilibration to 5% B over 1.5 min; LCMS Method Detail: null.

Step 3: 4-[[2-[(6-Chloro-2-Methoxy-3-Pyridyl)Oxy]-5-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (1)

A solution of 4-[[2-bromo-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (40 mg, 0.1031 mmol) in DMSO (0.25 mL) was added to 6-chloro-2-methoxy-pyridin-3-ol (32.90 mg, 0.2062 mmol) followed by CsF (62.65 mg, 15.22 μL, 0.4124 mmol). The reaction mixture was capped and allowed to stir at 110° C. for 40 minutes. The product was purified by HPLC to provide 4-[[2-[(6-chloro-2-methoxy-3-pyridyl)oxy]-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (20.5 mg, 42%) was obtained. ESI-MS m/z calc. 466.06558, found 467.05 (M+1) + ; Retention time (Method B): 1.77 minutes. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.08 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.33 (d, J=2.1 Hz, 11), 8.12 (d, J=2.8 Hz, 1), 8.06 (d, J 2.3 Hz, 1), 7.88 (dd, J 5.5, 2.2 Hz, 1H), 7.82 (dd, J 8.8, 2.4 Hz, 1H), 7.72 (d, J=8.1 Hz, 1), 7.66 (s, 11), 7.19 (d, J=8.2 Hz, 1H), 7.05 (d, J=8.8 Hz, 1), 3.83 (s, 3H).

The compounds set forth in Table 1 were prepared by methods analogous to the preparation of compound 1 in Example 1.

4-[[6-(2,3-Difluoro-4-Isopropoxy-Phenoxy)-2-Fluoro-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (18)

To an ice-cooled solution of 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (250 mg, 0.8711 mmol) in DCM (10 mL) was added DMF (5 μL, 0.06457 mmol) oxalyl chloride (230 μL, 2.637 mmol) and the mixture was stirred and warmed to RT over 3.5 h. The reaction mixture was concentrated in vacuo, dissolved in DCM (10 mL) and added drop-wise to a solution of methyl 4-aminopyridine-2-carboxylate (160 mg, 1.052 mmol) and TEA (610 μL, 4.377 mmol) in DCM (10 mL) at 0° C. The resulting mixture was stirred and warmed to ambient temperature over 18 h. The reaction mixture was quenched with water and the layers separated. The aqueous layer was extracted with DCM (×2) and the combined organics extracts were dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was purified by column chromatography (0 to 75% EtOAc/Petroleum Ether) to give methyl 4-[[6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate (98.1 mg, 27%) as a pale yellow solid. ESI-MS m/z calc. 419.97327, found 423.0 (M+1) + ; 421.0 (M−1) − ; Retention time (Method E): 0.78 minutes. 1 H NMR (500 MHz, Chloroform-d) δ 8.76 (d, J=5.4 Hz, 1H), 8.21 (d, J=1.9 Hz, 1H), 8.07 (dd, J=5.5, 2.1 Hz, 1H), 7.87 (s, 1H), 7.66-7.61 (m, 2H), 4.04 (s, 3H); 19F NMR (471 MHz, Chloroform-d) 6-61.47 (d, J=12.9 Hz), −112.56 (q, J=12.9 Hz) ppm.

To a solution of methyl 4-[[6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate (13.46 g, 31.961 mmol) in MeCN (160 mL) was added NH 4 Cl (600 mg, 11.217 mmol) and NH 4 OH (153.00 g, 170 mL of 28% w/v, 4.3657 mol) with stirring at ambient temperature. The reaction mixture was stirred at ambient temperature overnight then diluted with ethyl acetate (400 mL) and washed with water (150 mL×2), brine, dried over anhydrous MgSO 4 and filtered. Filtrate was evaporated, residue was subjected to flash purification (330 g SG column; dry loading; gradient 0->90% EtOAc/hexane/2%(7N NH 3 /MeOH) in 60 minutes) to afford 4-[[6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (8.266 g, 60%) as off-white solid. ESI-MS m/z calc. 404.9736, found 406.0 (M+1) + ; Retention time: 1.87 minutes. 1H NMR (500 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.60 (d, J=5.4 Hz, 1H), 8.35 (d, J=2.1 Hz, 1H), 8.14 (s, 1H), 7.98-7.85 (m, 2H), 7.81 (dd, J=5.4, 2.2 Hz, 1H), 7.70 (s, 1H) ppm. LCMS Method: Water Cortex 2.7u C 18 (3.0 mm×50 mm), Temp: 55c; Flow: 1.2 mL/minutes; MP: 100% water with 0.1% trifluoroacetic (TFA) acid then 100% acetonitrile with 0.10% TFA acid, grad:5% to 100% B over 4 min, with stay at 100% B for 0.5 min, equilibration to 5% B over 1.5 min; LCMS Method Detail: null.

Step 3: 4-[[6-(2,3-Difluoro-4-Isopropoxy-Phenoxy)-2-Fluoro-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (18)

A mixture of 4-[[6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (50 mg, 0.1231 mmol), 2,3-difluoro-4-isopropoxy-phenol (23.16 mg, 0.1231 mmol), Cs 2 CO 3 (80.22 mg, 0.2462 mmol), CuI (14.07 mg, 0.07386 mmol), and DMF (1.000 mL), was stirred at 100° C. for 1 hour. The reaction was diluted with DMSO (500 uL), filtered, and purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to give 4-[[6-(2,3-difluoro-4-isopropoxy-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (23.8 mg, 37%) as a white solid. ESI-MS m/z calc. 513.1123, found 513.9 (M+1) + ; Retention time (Method B): 1.77 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 8.33 (d, J=2.1 Hz, 1H), 8.14 (s, 1H), 7.86 (dd, J=10.5, 6.9 Hz, 2H), 7.69 (s, 1H), 7.31-7.06 (m, 2H), 6.95 (d, J=8.9 Hz, 1H), 4.67 (hept, J=6.1 Hz, 1H), 1.30 (d, J=6.0 Hz, 6H) ppm.

The compounds set forth in Table 2 were prepared by methods analogous to the preparation of compound 18 and Example 2.

4-[[6-(4-Fluoro-2-Methoxy-Phenoxy)-2-Methoxy-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (52)

4-[[6-Bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (1.50 g, 3.693 mmol) was dissolved in MeOH (15 mL). Sodium methoxide (8.0 mL of 25% w/v, 37.02 mmol) was added and the reaction mixture allowed to stir at 85° C. for 5 h. The cooled reaction mixture was taken up in ethyl acetate (75 mL) and washed with aqueous HCl (0.5 M, 1×75 mL) and brine (1×75 mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude product was chromatographed on silica gel eluting with a ethyl acetate-hexane gradient to yield 4-[[6-bromo-2-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (620 mg, 40%) was obtained as a white foamy solid. ESI-MS m z calc. 416.9936, found 420.0 (M+3)+; Retention time (Method C): 1.31 minutes.

Step 2: 4-[[6-(4-Fluoro-2-Methoxy-Phenoxy)-2-Methoxy-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (52)

A vial was loaded with 4-[[6-bromo-2-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (20 mg, 0.04783 mmol) and 4-fluoro-2-methoxy-phenol (33.98 mg, 27.25 μL, 0.2391 mmol). A solution of CsF (14.53 mg, 3.531 μL, 0.09566 mmol) in DMSO (0.25 mL) was added. Cs 2 CO 3 (31.17 mg, 0.09566 mmol) was added under nitrogen gas. The vial was capped, and the reaction mixture was stirred at 100° C. for 20 minutes. The product was purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to provide 4-[[6-(4-fluoro-2-methoxy-phenoxy)-2-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (3.4 mg, 14%). ESI-MS m/z calc. 479.11044, found 480.0 (M+1) + ; Retention time (Method B): 1.71 minutes. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.38 (s, 1H), 8.56 (s, 1H), 8.41 (s, 1H), 8.16 (s, 1H), 7.89 (s, 1H), 7.72 (s, 1H), 7.67 (d, J=8.9 Hz, 1H), 7.25 (dd, J=8.9, 5.8 Hz, 1H), 7.16 (dd, J=10.7, 2.9 Hz, 1H), 6.86 (td, J=8.5, 2.9 Hz, 1H), 6.48 (d, J=8.8 Hz, 1H), 3.90 (s, 3H), 3.77 (s, 3H) ppm.

The compounds set forth in Table 3 were prepared by methods analogous to the preparation of compound 52 in Example 3.

4-[[2-(2,3-Difluoro-4-Isopropoxy-Phenoxy)-6-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (72)

To a solution of 2-fluoro-6-(trifluoromethyl)benzoic acid (7.00 g, 33.64 mmol) in DCM (70 mL) and DMF (100 μL, 1.291 mmol) at 0° C. was added oxalyl chloride (23.5 mL, 269.4 mmol) drop-wise. The reaction mixture was allowed to stir at RT for 1 hour. The reaction mixture was concentrated under reduced pressure and taken up in NMP (7 mL). This acid chloride solution was then added to a prepared solution of 4-aminopyridine-2-carboxamide (4.61 g, 33.62 mmol) and DIEA (35. mL, 200.9 mmol) in NMP (70 mL) and DMF (7 mL) at 0° C. The final reaction mixture was allowed to slowly warm to RT and stirred overnight. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (1×100 mL) and brine (1×100 mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude product was chromatographed on a 120 gram silica gel column eluting with a 0-100% EtOAc/hexane gradient over 60 minutes. 4-[[2-fluoro-6-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (881 mg, 8%) was obtained as an orange oil. ESI-MS m/z calc. 327.06308, found 328.2 (M+1) + ; Retention time (Method B): 1.12 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H), 8.57 (d, J=5.4 Hz, 1H), 8.32 (d, J=2.1 Hz, 1H), 8.12 (d, J=2.9 Hz, 1H), 7.87-7.74 (m, 4H), 7.72-7.62 (m, 1H) ppm.

Step 2: 4-[[2-(2,3-Difluoro-4-Isopropoxy-Phenoxy)-6-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (72)

A solution of 4-[[2-fluoro-6-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (40 mg, 0.1222 mmol) in DMSO (0.5 mL) was added to 2,3-difluoro-4-isopropoxy-phenol (68.98 mg, 0.3666 mmol). Finely ground K 2 CO 3 (50.67 mg, 0.3666 mmol) was then added. The reaction mixture was allowed to stir at 120° C. for 2 h. The mixture was purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to afford 4-[[2-(2,3-difluoro-4-isopropoxy-phenoxy)-6-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (9.3 mg, 15%). ESI-MS m/z calc. 495.12173, found 496.31 (M+1) + ; Retention time (Method B): 1.63 minutes. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.40 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.33 (d, J=2.1 Hz, 1H), 8.13 (d, J=2.8 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.72-7.59 (m, 3H), 7.28 (d, J=8.0 Hz, 1H), 7.10 (t, J=5.2 Hz, 2H), 4.65 (p, J=6.1 Hz, 1H), 1.30 (d, J=6.0 Hz, 6H) ppm.

The compounds set forth in Table 4 were prepared by methods analogous to the preparation of compound 72 in Example 4.

4-[[2-Ethoxy-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (83)

A flask equipped with a reflux condenser was charged with 4-aminopyridine-2-carboxamide (1.12 g, 8.17 mmol), benzenesulfonylsulfanylbenzene (1.85 g, 7.39 mmol), 2-isocyano-2-methyl-propane (3.0 mL, 27 mmol), copper (I) iodide (60 mg, 0.32 mmol) and molecular sieves (2.2 g) in 2-methyltetrahydrofuran (10 mL), and the mixture was heated at 75° C. for 24 hours. The reaction mixture was filtered through Celite and the cake was rinsed with ethyl acetate. The filtrate was concentrated and dried under vacuum. The residue was purified by silica gel chromatography (0-60% ethyl acetate/hexanes) to obtain 4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide (1.25 g, 51%). ESI-MS m/z calc. 328.14, found 329.2 (M+1) + ; retention time (Method B): 1.07 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (dd, J=5.3, 0.6 Hz, 1H), 7.94 (d, J=3.0 Hz, 1H), 7.49 (s, 1H), 7.28 (dd, J=2.2, 0.6 Hz, 1H), 7.25-7.17 (m, 5H), 6.74 (dd, J=5.3, 2.2 Hz, 1H), 6.66 (s, 1H), 1.35 (s, 9H) ppm.

A pressure flask was charged with 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (5 g, 17.42 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (4.35 g, 20.90 mmol), cesium carbonate (11.35 g, 34.84 mmol) and toluene (50 mL). The mixture was degassed with nitrogen. After ca. 2 minutes, copper (I) iodide (663 mg, 3.48 mmol) was added and the reaction was stirred at 100° C. for lhr. The reaction was diluted with 300 mL ethyl acetate and 200 mL of water and the phases were separated. The aqueous layer was acidified to pH-3 and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/hexane gradient, followed by 9:1 dichloromethane:methanol) to afford 2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoic acid (5.4503 g, 76%) as a pale green solid. ESI-MS m/z calc. 414.03, found 415.0 (M+1) + ; retention time (Method B): 1.94 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 7.53 (t, J=8.4 Hz, 1H), 7.27-7.11 (m, 2H), 6.99 (ddd, J=8.8, 2.7, 1.3 Hz, 1H), 6.49 (d, J=8.8 Hz, 1H), 3.80 (s, 3H) ppm.

Step 3: 4-[[2-Fluoro-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide

A microwave vial charged with 4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide (75 mg, 0.29 mmol), tris[(Z)-1-methyl-3-oxo-but-1-enoxy]iron (approximately 2 mg, 0.0057 mmol) and 2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoic acid (94 mg, 0.29 mmol) in isopropanol (2 mL) was heated at 83° C. for 16 hours. The reaction mixture was cooled to room temperature and the solvent evaporated. The crude material was taken up in dichloromethane and washed with 1N HCl. The organic layer was dried over MgSO 4 , filtered and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/hexane gradient) to afford 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (80 mg, 64%). ESI-MS m/z calc. 533.08215, found 534.1 (M+1) + ; retention time (Method B): 1.77 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.32 (d, J=2.2 Hz, 1H), 8.12 (d, J=2.7 Hz, 1H), 7.86-7.77 (m, 2H), 7.72-7.64 (m, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.27 (d, J=2.8 Hz, 1H), 7.08-7.01 (m, 1H), 6.68 (d, J=8.9 Hz, 1H), 3.79 (s, 3H) ppm.

Step 4: 4-[[2-Ethoxy-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (83)

To ethanol (12.95 mg, 16.41 μL, 0.2812 mmol) was added a solution of 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (30 mg, 0.05625 mmol) in DMSO (0.5 mL). Finely ground K 2 CO 3 (31.10 mg, 0.2250 mmol) was then added. The reaction mixture was capped and allowed to stir at 140° C. for 30 minutes. The reaction mixture was purified by HPLC to afford 4-[[2-ethoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (10.7 mg, 33%). ESI-MS m/z calc. 559.1178, found 560.3 (M+1) + ; Retention time (Method B): 1.88 minutes. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.32 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.37 (d, J=2.1 Hz, 1H), 8.12 (s, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 7.75-7.61 (m, 2H), 7.32 (d, J=8.8 Hz, 1H), 7.24 (d, J=2.7 Hz, 1H), 7.09-6.98 (m, 1H), 6.53 (d, J=8.9 Hz, 1H), 4.13 (q, J=7.0 Hz, 2H), 3.79 (s, 3H), 1.24 (t, J=7.0 Hz, 3H).

The compounds set forth in Table 5 were prepared by methods analogous to the preparation of compound 83 in Example 5.

4-[[2-Fluoro-4-(p-Tolyl)-6-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]Benzoyl]Amino]Pyridine-2-Carboxamide (88)

Step 1: 4-[[2-Fluoro-4-(p-Tolyl)-6-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]Benzoyl]Amino]Pyridine-2-Carboxamide (88)

A solution of 4-(2-trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy)-4-bromo-6-fluorobenzamido)picolinamide, p-tolylboronic acid (approximately 15 mg, 0.110 mmol), K 2 CO 3 (approximately 15 mg, 0.110 mmol), Pd(dppf) 2 Cl 2 (8 mg, 0.0098 mmol) in dioxane (500 μL) and water (50 μL) was flushed with N 2 and heated at 100° C. for 16 h. The reaction mixture was purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to give 4-[[2-fluoro-4-(p-tolyl)-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (22.6 mg, 74%). ESI-MS m/z calc. 558.1606, found 559.4 (M+1) + ; Retention time (Method B): 1.95 minutes. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.32 (s, 1H), 8.54 (d, J=5.4 Hz, 1H), 8.32 (s, 1H), 8.13 (s, 1H), 7.84 (d, J=4.2 Hz, 1H), 7.68 (s, 1H), 7.50 (d, J=7.8 Hz, 2H), 7.45 (d, J=10.4 Hz, 1H), 7.31-7.24 (m, 3H), 7.17 (d, J=2.6 Hz, 1H), 7.02-6.92 (m, 1H), 6.82 (s, 1H), 2.33 (s, 3H) ppm.

The compounds set forth in Table 6 were prepared by methods analogous to the preparation of compound 88 in Example 6.

4-[[4-Cyclopentyl-2-Fluoro-6-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]Benzoyl]Amino]Pyridine-2-Carboxamide (96)

A mixture of Cs 2 CO 3 (7.89 g, 24.22 mmol), 2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (3.54 g, 16.77 mmol) and methyl 4-bromo-2,6-difluoro-benzoate (4.00 g, 15.93 mmol) in DMF (70 mL) was stirred at ambient temperature for 20 h. The reaction was diluted with ethyl acetate and washed with water (×3) and brine. The organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. Silica gel chromatography (0-10% ethyl acetate/hexane) provided methyl 4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoate (6.091 g, 86%). ESI-MS m/z calc. 440.99142, found 443.1 (M+1) + ; Retention time (Method A): 0.82 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 7.47 (dd, J=9.0, 1.7 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.24 (d, J=2.8 Hz, 1H), 7.00 (ddd, J=8.8, 2.7, 1.3 Hz, 1H), 6.73 (t, J=1.5 Hz, 1H), 3.83 (s, 3H) ppm.

Methyl 4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoate (6.09 g, 13.77 mmol) was dissolved in MeOH (60 mL) and treated with NaOH (40 mL of 1 M, 40.00 mmol). The reaction was heated to 40° C. and stirred for 2 h resulting in partial hydrolysis. Additional NaOH (23 mL of 6 M, 138.0 mmol) was added and the reaction stirred at 45° C. for 1 hour. The reaction mixture was acidified with HCl (210 mL of 1 M, 210.0 mmol) and extracted into ethyl acetate (×3). The combined organic layers were dried over anhydrous MgSO 4 , filtered and concentrated reduced pressure to provide 4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoic acid (5.81 g, 99%) as a glassy oil. ESI-MS m/z calc. 426.97577, found 429.0 (M+1) + ; Retention time (Method A): 0.72 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 13.78 (s, 1H), 7.42 (dd, J=8.9, 1.6 Hz, 1H), 7.25-7.20 (m, 2H), 7.00 (ddd, J=8.8, 2.7, 1.3 Hz, 1H), 6.67 (t, J=1.4 Hz, 1H) ppm.

Step 3: 4-[[4-Bromo-2-Fluoro-6-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]Benzoyl]Amino]Pyridine-2-Carboxamide

To a solution of 4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoic acid (4.0 g, 9.343 mmol), DMF (210 μL, 2.712 mmol) and DCM (48 mL) at 0° C. under N 2 (g) was added oxalyl dichloride (7 mL, 80.24 mmol). The reaction was stirred at 0° C. for 10 minutes and then at RT for additional 1 h. The mixture was concentrated under reduced pressure and redissolved in NMP (5 mL). This solution was added drop-wise to a suspension of 4-aminopyridine-2-carboxamide (1.28 g, 9.334 mmol), DMF (1.5 mL, 19.37 mmol), and DIEA (10 mL, 57.41 mmol) in NMP (10 mL) under N 2 atmosphere at 0° C. The resulting reaction mixture was slowly warmed to RT and stirred overnight. The mixture was partitioned between water and ethyl acetate. The phases were separated and the aqueous layer was extracted with ethyl acetate (1×). The combined organic layers were washed with brine (2×), water (2×) then brine (1×). The organic layer was dried over Na 2 SO 4 , filtered and concentrated to give a light brown foam. The crude was purified by silica chromatography eluting with a gradient of ethyl acetate-hexanes to give 4-[[4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (1.26 g, 25%). ESI-MS m/z calc. 546.0241, found 549.0 (M+1) + ; Retention time (Method B): 1.94 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.54 (d, J=5.4 Hz, 1H), 8.29 (d, J=2.1 Hz, 1H), 8.16-7.99 (m, 1H), 7.82 (dd, J=5.6, 2.2 Hz, 1H), 7.65 (d, J=2.8 Hz, 1H), 7.52 (dd, J=8.6, 1.5 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.10-6.91 (m, 1H), 6.75 (s, 1H) ppm.

Step 4: 4-[[4-(Cyclopenten-1-Yl)-2-Fluoro-6-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]Benzoyl]Amino]Pyridine-2-Carboxamide

A solution of 4-[[4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (25 mg, 0.04568 mmol), cyclopenten-1-ylboronic acid (13 mg, 0.1161 mmol), K 2 CO 3 (13 mg, 0.09406 mmol), ferrous; cyclopenta-1,4-dien-1-yl(diphenyl)phosphane; DCM; dichloropalladium (8 mg, 0.009796 mmol) in dioxane (500 μL) and water (50 μL) was heated at 100° C. for 16 h. The reaction mixture was filtered and purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to obtain 4-[[4-(cyclopenten-1-yl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (18.2 mg, 74%). ESI-MS m/z calc. 534.1606, found 534.96 (M+1) + ; Retention time (Method B): 2.01 minutes.

Step 5: 4-[[4-Cyclopentyl-2-Fluoro-6-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]Benzoyl]Amino]Pyridine-2-Carboxamide (96)

A solution of 4-[[4-(cyclopenten-1-yl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (9 mg, 0.01680 mmol) in ethyl acetate (250 μL) and MeOH (250 μL) was flushed with N2 (g). Palladium on Carbon (0.1788 mg, 0.001680 mmol) was added and the resulting mixture was purged with H 2 (balloon). The reaction was stirred at RT under a hydrogen atmosphere for 16 h. The mixture was filtered and purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) giving 4-[[14-cyclopentyl-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (6.6 mg, 73%). ESI-MS m/z cac. 536.1762, found 537.2 (M+1) + ; Retention time (Method B): 1.94 minutes. 1 HNMR (400 MHz, DMSO-d 6 ) δ 11.25 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.32 (d, J=2.1 Hz, 1H), 8.13 (s, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.69 (s, 1H), 7.22 (d, J=8.7 Hz, 1H), 7.18 (d, J=2.7 Hz, 1H), 7.03 (d, J=10.2 Hz, 1H), 6.99 (d, J=8.9 Hz, 1H), 6.46 (s, 1H), 2.95 (p, J=9.0 Hz, 1H), 1.98-1.91 (m, 2H), 1.75-1.67 (min, 2H), 1.649-1.56 (i, 2H), 1.462-1.41 ((, 2H) ppm.

The compounds set forth in Table 7 were prepared by methods analogous to the preparation of compound 96.

4-[[5-Fluoro-2-[12-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]-4-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (99)

To a solution of 2,5-difluoro-4-(trifluoromethyl)benzoic acid (5 g, 22.11 mmol) in ethanol (50 mL) was added H 2 SO 4 (1.5 mL, 28.14 mmol) dropwise over 5 minutes. The solution was heated at reflux for 48 h, then the reaction mixture was cooled to RT and concentrated under reduced pressure to provide ethyl 2,5-difluoro-4-(trifluoromethyl)benzoate (4.57 g, 81%) as a clear colorless liquid. ESI-MS m/z calc. 254.03662, Retention time (Method A): 0.71 minutes (product does not ionize). 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (dd, J=10.1, 5.6 Hz, 2H), 4.37 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H) ppm.

Step 2: 5-Fluoro-2-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]-4-(Trifluoromethyl)Benzoic Acid

A mixture of 2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (7.69 g, 36.42 mmol), ethyl 2,5-difluoro-4-(trifluoromethyl)benzoate (8.41 g, 33.09 mmol) and Cs 2 CO 3 (16.17 g, 49.63 mmol) in acetonitrile (102.6 mL) was heated under reflux under N 2 overnight. The reaction mixture was diluted with water and acidified to ˜pH 2 with 6 N HCl. The mixture was extracted with DCM (3×50 mL) and the combined organic layers dined over MgSO 4 , filtered and concentrated. The residue was dissolved in MeOH (50 mL) and treated with solid NaOH (2.647 g, 66.18 mmol) dissolved in 50 mL water. The mixture was stirred for 20 minutes then acidified with an aqueous solution of HCl (9 mL of 12 M, 108.0 mmol). The aqueous mixture was extracted with ethyl acetate, and the organic layer dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-3% MeOH/DCM with 0.2% AcOH) and product fractions were concentrated and the solid triturated 2× with hexanes to provide 5-fluoro-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoic acid as a white solid. ESI-MS m/z calc. 417.05264, found 418.1 (M+1) + ; Retention time (Method A): 0.74 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 13.69 (br s, 1H), 7.88 (d, J=10.4 Hz, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.14 (d, J=5.7 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H) ppm.

Step 3: 5-Fluoro-2-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]-4-(Trifluoromethyl)Benzoyl Chloride

To a solution of 5-fluoro-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoic acid (1.8 g, 4.314 mmol) and DMF (10 μL, 0.1291 mmol) in DCM (15 mL) at 0° C. was added oxalyl chloride (565 μL, 6.477 mmol) drop-wise under N 2 atmosphere. The ice bath was removed after 10 minutes and the reaction was stirred at RT for 1.5 h. The solvent was evaporated under reduced pressure to afford 5-fluoro-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl chloride. The intermediate was used in the next step without further purification.

Step 4: 4-[[5-Fluoro-2-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]-4-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (99)

To 5-fluoro-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl chloride (60 mg, 0.1377 mmol) in NMP (0.3 mL) was added to a mixture of 4-aminopyridine-2-carboxamide (28.32 mg, 0.2065 mmol) and DIEA (71.19 mg, 95.94 μL, 0.5508 mmol) in NMP (0.3 mL). The reaction was stirred at RT for 2 h. The crudes were filtered and purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to give 4-[[5-fluoro-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (30.00 mg, 41%). ESI-MS m/z calc. 536.101, found 537.31 (M+1) + ; Retention time (Method B): 1.83 minutes.

5-[[5-Fluoro-2-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]-4-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (100)

To a solution of 5-fluoro-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl chloride (60 mg, 0.1377 mmol) in NMP (0.3 mL) was added a mixture of 5-aminopyridine-2-carboxamide (28.32 mg, 0.2065 mmol) and DIEA (71.19 mg, 95.94 μL, 0.5508 mmol) in NMP (0.3 mL). The reactions were stirred at RT for 2 h. The crude was filtered and purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to give 5-[[5-fluoro-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (27.80 mg, 37%). ESI-MS m/z calc. 536.101, found 536.96 (M+1) + ; Retention time (Method B): 1.98 minutes. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.07 (s, 1H), 8.84 (d, J=2.4 Hz, 1H), 8.22 (dd, J=8.6, 2.5 Hz, 1H), 8.07-8.00 (m, 2H), 7.95 (d, J=10.1 Hz, 1H), 7.58 (s, 1H), 7.21 (dd, J=7.4, 5.3 Hz, 2H), 7.16 (d, J=2.7 Hz, 1H), 6.97 (dd, J=9.0, 2.3 Hz, 1H) ppm.

5-[[2-Fluoro-6-(4-Fluoro-2-Methyl-Phenoxy)-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (101)

A solution of 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (24 g, 83.62 mmol), 4-fluoro-2-methyl-phenol (11.33 g, 89.83 mmol), Cs 2 CO 3 (27.43 g, 84.19 mmol) in toluene (200 mL) was bubbled with N 2 for 10 minutes then CuI (3.1 g, 16.28 mmol) was added. The flask was flushed with N 2 , capped, and heated at 100° C. with vigorous stirring for 3 h. The mixture was allowed to cool then diluted with ethyl acetate and water (350 mL). The two layers were separated, the aqueous was layer acidified with HCl (375 mL of 1 M, 375.0 mmol) and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×2), dried over Na 2 SO 4 , filtered through a plug of celite and concentrated undere reduced pressure. The crude product was titurated with hexane and filtered to obtain 2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoic acid (16 g, 58%) as a cream colored solid. ESI-MS m/z calc. 332.04718, found 333.1 (M+1) + ; Retention time (Method C): 2.39 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 14.11 (s, 1H), 7.76 (t, J=8.6 Hz, 1H), 7.28 (dd, J=9.4, 3.0 Hz, 1H), 7.22-7.11 (m, 2H), 6.58 (d, J=8.9 Hz, 1H), 2.13 (s, 3H) ppm.

To 2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoic acid (600 mg, 1.806 mmol) and DMF (15 μL, 0.1937 mmol) in DCM (6 mL) at 0° C. was added oxalyl chloride (237 μL, 2.717 mmol) dropwise under N 2 atmosphere. The ice bath was removed after 10 minutes and the reaction was stirred at RT for 1 h. The solvent was evaporated under reduced pressure to afford 2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoyl chloride. The intermediate was used in the next step without further purification.

Step 3: 5-[[2-Fluoro-6-(4-Fluoro-2-Methyl-Phenoxy)-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (101)

To 5-aminopyridine-2-carboxamide (28.15 mg, 0.2053 mmol) in NMP (400 μL), and DIEA (66.34 mg, 89.41 μL, 0.5133 mmol) at 0° C. was added a solution of 2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoyl chloride (60 mg, 0.1711 mmol) in NMP (200 μL) slowly. The reaction was stirred at RT for 16 h. The crude product was filtered and purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) yield 5-[[2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (39.5 mg, 51%). ESI-MS m/z calc. 451.09552, found 452.0 (M+1) + ; Retention time (Method B): 1.81 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.86 (d, J=2.4 Hz, 1H), 8.31 (dd, J=8.7, 2.4 Hz, 1H), 8.07 (d, J=8.6 Hz, 1H), 8.03 (s, 1H), 7.83 (t, J=8.7 Hz, 1H), 7.58 (s, 1H), 7.24 (ddd, J=17.5, 9.1, 4.0 Hz, 2H), 7.15 (td, J=8.5, 3.0 Hz, 1H), 6.65 (d, J=8.9 Hz, 1H), 2.14 (s, 3H) ppm.

4-[[2-Fluoro-6-(4-Fluoro-2-Methyl-Phenoxy)-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (102)

To 4-aminopyridine-2-carboxamide (28.15 mg, 0.2053 mmol) in NMP (400 μL) and DIEA (66.34 mg, 89.41 μL, 0.5133 mmol) at 0° C. was added a solution of 2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoyl chloride (60 mg, 0.1711 mmol) in NMP (200 μL) slowly. The reaction was stirred at RT for 16 h. The crude product was filtered and purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to yield 4-[[2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (28.9 mg, 37%). ESI-MS m/z calc. 451.09552, found 452.0 (M+1) + ; Retention time (Method B): 1.8 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 8.57 (d, J=5.4 Hz, 1H), 8.33 (d, J=2.1 Hz, 1H), 8.11 (d, J=2.8 Hz, 1H), 7.94-7.80 (m, 2H), 7.67 (s, 1H), 7.36-7.07 (m, 3H), 6.64 (d, J=8.9 Hz, 1H), 2.13 (d, J=5.0 Hz, 3H) ppm.

4-[[2-Fluoro-6-(4-Fluoro-2-Methoxy-Phenoxy)-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (103)

A solution of 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (20 g, 69.68 mmol), 4-fluoro-2-methoxy-phenol (10 g, 70.36 mmol), Cs 2 CO 3 (25 g, 76.73 mmol) in toluene (250 mL) was bubbled with N 2 for 15 minutes then CuI (2.8 g, 14.70 mmol) added. The flask was flushed with N 2 , and stirred at RT for 16 h, then heated to 100° C. with stirring for 5 h. The mixture was allowed to cool, then diluted with ethyl acetate and water. The water layer was acidified with HCl (142 mL of 1 M, 142.0 mmol) and the product extracted into ethyl acetate. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The resulting gummy residue was dissolved in ethyl acetate and filtered through a pad of celite and the filtrate was concentrated. The brown residue was dissolved in DCM/ethyl acetate and purified by silica chromatography in a 330 g silica column with a shallow (0-10%) gradient system of DCM/MeOH (0.5% AcOH). The resultant material was dissolved in a minimum amount of DCM and hexanes and allowed to stand overnight. The resultant precipitate was filtered, washed with hexane and dried under vacuum to give 2-fluoro-6-(4-fluoro-2-methoxy-phenoxy)-3-(trifluoromethyl)benzoic acid (9.8 g, 31%) as a light brown solid. ESI-MS m/z calc. 348.0421, found 349.1 (M+1) + ; Retention time (Method A): 0.58 minutes.

To a solution of 2-fluoro-6-(4-fluoro-2-methoxy-phenoxy)-3-(trifluoromethyl)benzoic acid (700 mg, 1.568 mmol) and DMF (34 μL, 0.4391 mmol) in DCM (6.5 mL) at 0° C. was added oxalyl chloride (1.1 mL, 12.61 mmol) dropwise under N 2 atmosphere. The ice bath was removed after 10 minutes and the reaction was stirred at RT for 50 minutes. The mixture was concentrated to dryness under reduced pressure to afford the crude 2-fluoro-6-(4-fluoro-2-methoxy-phenoxy)-3-(trifluoromethyl)benzoyl chloride. The intermediate was immediately used in the next step without purification.

Step 3: 4-[[2-Fluoro-6-(4-Fluoro-2-Methoxy-Phenoxy)-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (103)

To a solution of 4-aminopyridine-2-carboxamide (13.46 mg, 0.09818 mmol), DMF (5.981 mg, 6.336 μL, 0.08182 mmol) and NMP (200 μL) was added DIEA (31.73 mg, 42.76 μL, 0.2455 mmol) under N 2 atmosphere and the resulting clear solution was cooled to 0° C. A solution of 2-fluoro-6-(4-fluoro-2-methoxy-phenoxy)-3-(trifluoromethyl)benzoyl chloride (30 mg, 0.08182 mmol) in NMP (200 μL) was added and the reaction was stirred at RT for 16 h. The mixture was filtered and purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) giving the desired product 4-[[2-fluoro-6-(4-fluoro-2-methoxy-phenoxy)-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (18.4 mg, 48%). ESI-MS m/z calc. 467.09045, found 468.0 (M+1) + ; Retention time (Method B): 1.73 minutes. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.47 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 8.34 (d, J=2.1 Hz, 1H), 8.14 (s, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 7.80 (t, J=8.7 Hz, 1H), 7.76-7.65 (m, 1H), 7.34-7.08 (m, 2H), 6.88 (td, J=8.5, 2.8 Hz, 1H), 6.59 (dd, J=30.6, 8.9 Hz, 1H), 3.76 (d, J=2.2 Hz, 3H) ppm.

The compounds set forth in Table 8 were prepared by methods analogous to the preparation of compound 103 in example 12.

4-[[2-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]-5-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (105)

To a stirring solution of 2-fluoro-5-(trifluoromethyl)benzaldehyde (5.02 g, 26.13 mmol) in DMF (50 mL) in an ice bath was added Cs 2 CO 3 (10.68 g, 32.78 mmol) and 2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (6.50 g, 30.78 mmol). The reaction mixture was warmed to RT then stirred for 16 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, 50% saturated aqueous NaHCO 3 and brine, then dried over MgSO 4 , filtered and concentrated in vacuo. Silica gel chromatography (220 g silica, 0-30% ethyl acetate/hexane) provided 2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzaldehyde (8.84 g, 88%). ESI-MS m/z calc. 383.06717, found 384.0 (M+1) + ; Retention time (Method A): 0.81 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.06 (s, 1H), 7.92 (dd, J=8.9, 2.4 Hz, 1H), 7.44 (d, J=8.7 Hz, 1H), 7.29 (d, J=2.5 Hz, 1H), 7.07 (d, J=8.7 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H) ppm.

A mixture of 2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzaldehyde (8.84 g, 23.07 mmol) and NaH 2 PO 4 (2.92 g, 24.34 mmol) in tert-butyl alcohol (80 mL)/water (40 mL)/acetonitrile (40 mL) was cooled in an ice bath then 2-methy-2-butene (11 mL, 103.8 mmol) was added. Sodium chlorite (3.12 g, 27.60 mmol) was then added portion wise over 10 minutes. The mixture was allowed to warm to RT then stirred for 16 h. The reaction mixture was acidified to pH 1-2 using aqueous HCl (8 mL of 12 M, 96.00 mmol), and partitioned with ethyl acetate. The organic layer was separated, dried over MgSO 4 and concentrated in vacuo to afford 2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoic acid (7.55 g, 82%) as a white solid. ESI-MS m/z calc. 399.06207, found 400.1 (M+1) + ; Retention time (Method A): 0.72 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H), 8.07 (d, J=2.4 Hz, 1H), 7.81 (dd, J=8.9, 2.4 Hz, 1H), 7.28-7.20 (m, 2H), 7.01 (dd, J=8.9, 1.7 Hz, 1H), 6.83 (d, J=8.7 Hz, 1H) ppm.

To 2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoic acid (1.5 g, 3.757 mmol) and DMF (10 μL, 0.1291 mmol) in DCM (12 mL) at 0° C. was added oxalyl chloride (492 μL, 5.640 mmol) dropwise under N 2 atmosphere. The ice bath was removed after 10 minutes and the reaction was stirred at RT for 1.5 h. The solvent was evaporated under reduced pressure to afford 2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoyl chloride. The intermediate was used in the next step without further purification.

Step 4: 4-[[2-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]-5-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide(105)

2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoyl chloride (50 mg, 0.1197 mmol) in NMP (0.3 mL) was added to a mixture of 4-aminopyridine-2-carboxamide (16.42 mg, 0.1197 mmol) and DIEA (15.47 mg, 20.85 μL, 0.1197 mmol) in NMP (0.3 mL), and the reaction was stirred at RT for 2 h. The crude was filtered and purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to give 4-[[2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (34.70 mg, 56%). ESI-MS m/z calc. 518.1104, found 519.32 (M+1) + ; Retention time (Method B): 1.84 minutes.

The compounds set forth in Table 9 were prepared by methods analogous to the preparation of compound 105 in Example 13.

4-[[2-(3-Chloro-4-Fluoro-Phenoxy)-4-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (107)

To a solution of 2-bromo-4-(trifluoromethyl)benzoic acid (1 g, 3.7173 mmol) and 4-aminopyridine-2-carboxamide (510 mg, 3.7189 mmol) in pyridine (30 mL) was added POCl 3 (575.75 mg, 0.350 mL, 3.7549 mmol) at −25° C. and stirred for 30 minutes at this temperature. The reaction was quenched by addition of water (20 mL) then extracted with ethyl acetate (100×2). The organics were washed with water (3×30 mL), brine, dried over MgSO 4 , filtered then concentrated in vacuo to provide a 4-[[2-bromo-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide. ESI-MS m/z calc. 386.983, found 388.6 (M+1) + ; Retention time (Method H): 4.18 minutes. Used directly in the next step without further purification.

Step 2: 4-[[2-(3-Chloro-4-Fluoro-Phenoxy)-4-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (107)

To a mixture of 4-[[2-bromo-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (25 mg, 0.06441 mmol), 3-chloro-4-fluoro-phenol (9.439 mg, 0.06441 mmol), Cs 2 CO 3 (41.97 mg, 0.1288 mmol), CuI (7.361 mg, 0.03865 mmol), CsF (48.91 mg, 11.89 μL, 0.3220 mmol), and DMF (500.0 μL), was stirred at 150° C. for 1 h. The reaction was diluted with DMSO (500 uL), filtered, and purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to give 4-[[2-(3-chloro-4-fluoro-phenoxy)-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (11.9 mg, 39%) as a white solid. ESI-MS m/z calc. 453.05032, found 453.9 (M+1) + ; Retention time (Method B): 1.68 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.10 (d, J=2.7 Hz, 1H), 8.02-7.88 (m, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.74-7.68 (m, 1H), 7.66 (d, J=2.7 Hz, 1H), 7.52-7.40 (m, 2H), 7.36 (d, J=1.6 Hz, 1H), 7.17 (ddd, J=9.1, 3.9, 3.0 Hz, 1H) ppm.

The compounds set forth in Table 10 were prepared by methods analogous to the preparation of compound 107 in Example 13

4-[[2,2-Difluoro-5-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]-1,3-Benzodioxole-4-Carbonyl]Amino]Pyridine-2-Carboxamide (114)

To a solution of 2, 2, 6, 6-tetramethylpiperidine (12.03 g, 14.5 mL, 85.20 mmol) in THF (170 mL) was added n-butyl lithium in hexanes (33.5 mL of 2.5 M, 83.75 mmol) at 0° C. and the mixture was stirred at this temperature for 30 minutes, then cooled to −78° C. and stirred for 30 minutes. To a −78° C. solution of 5-bromo-2,2-difluoro-1,3-benzodioxole (20 g, 84.389 mmol) in THF (30 mL) was added the previously prepared LiTMP via cannula at −78° C. over 25 minutes. The reaction was stirred at this temperature for 25 minutes, then the reaction mixture was transferred, using the same cannula, into a wide mouthed flask containing crushed CO 2 (200.00 g, 4.54 mol) and stirred gently. Then, the reaction was slowly warmed to room temperature over 12 h. The reaction was diluted with NaOH (1M, 950 mL), washed with Et 2 O (3×650 mL), and the aqueous phase was acidified at 0° C. with HCl (6 M, until pH=1, gas evolved) and extracted with Et 2 O (3×750 mL), dried over MgSO 4 , then filtered and concentrated under reduced pressure to provide pure 5-bromo-2,2-difluoro-1,3-benzodioxole-4-carboxylic acid (19.27 g, 81%). 1 H NMR (500 MHz, DMSO-d6) δ 7.58 (d, J=9 Hz, 1H), 7.51 (d, J=9 Hz, 1H) ppm. ESI-MS m/z calc. 279.9183, found 281.1 (M+1) + ; Retention time: 1.87 minutes. LCMS Method: Water Cortex 2.7u C 18 (3.0 mm×50 mm), Temp: 55c; Flow: 1.2 mL/min; MP: 100% water with 0.1% trifluoroacetic (TFA) acid then 100% acetonitrile with 0.10% TFA acid, grad:5% to 100% B over 4 min, with stay at 100% B for 0.5 min, equilibration to 5% B over 1.5 min.

Step 2: 2,2-Difluoro-5-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]-1,3-Benzodioxole-4-Carboxylic Acid

A solution of 5-bromo-2,2-difluoro-1,3-benzodioxole-4-carboxylic acid (2 g, 7.117 mmol), 2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (1.52 g, 7.199 mmol), Cs 2 CO 3 (2.38 g, 7.305 mmol) in toluene (15 mL) was bubbled with N 2 for 10 minutes, then CuI (286 mg, 1.502 mmol) added. The flask was flushed with N 2 , capped, and heated at 100° C. with vigorous stirring for 7 h. The mixture was allowed to cool then diluted with ethyl acetate and 50 mL water. The two layers were separated. The organic layer contained some product. The water layer was acidified with HCl (30 mL of 1 M, 30.00 mmol) and the product was extracted into ethyl acetate (×3). The combined organic layer was washed with brine (×2), dried over Na 2 SO 4 , filtered through a plug of celite and concentrated. The crude product was purified on silica gel (gradient of 0-50% ethyl acetate in hexane). The product was titurated with hexane to yield 2,2-difluoro-5-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-4-carboxylic acid (1.1206 g, 38%) as a light brown solid. ESI-MS m/z calc. 411.0457, found 412.2 (M+1) + ; Retention time (Method C): 2.48 minutes (5 minutes run).

Step 3: 2,2-Difluoro-5-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]-1,3-Benzodioxole-4-Carbonyl Chloride

To a slurry of 2,2-difluoro-5-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-4-carboxylic acid (300 mg, 0.7295 mmol) and DMF (15 μL, 0.1937 mmol) in DCM (2.5 mL) at 0° C. was added oxalyl chloride (192 μL, 2.201 mmol) dropwise under N 2 atmosphere. The ice bath was removed after 10 minutes and the reaction was stirred at RT for 1.5 h. The solvent was evaporated under reduced pressure to afford 2,2-difluoro-5-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-4-carbonyl chloride. The intermediate was used in the next step without further purification. ESI-MS m/z calc. 478.12427, found 479.2 (M+1) + ; Retention time (Method A): 0.77 minutes.

Step 4: 4-[[2,2-Difluoro-5-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]-1,3-Benzodioxole-4-Carbonyl]Amino]Pyridine-2-Carboxamide (114)

To 4-aminopyridine-2-carboxamide (22.97 mg, 0.1675 mmol) in NMP (500 μL), and DIEA (54.13 mg, 72.95 μL, 0.4188 mmol) at 0° C. was added a solution of 2,2-difluoro-5-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-4-carbonyl chloride (60 mg, 0.1396 mmol) in NMP (200 μL) slowly. The mixture was stirred at RT for 16 h. The crude product was filtered and purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to yield 4-[[2,2-difluoro-5-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-4-carbonyl]amino]pyridine-2-carboxamide (24.0 mg, 32%). ESI-MS m/z calc. 530.094, found 530.96 (M+1) + ; Retention time (Method B): 1.85 minutes. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.32 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.27 (d, J=2.1 Hz, 1H), 8.12 (d, J=2.9 Hz, 1H), 7.82 (dd, J=5.6, 2.1 Hz, 1H), 7.68 (s, 1H), 7.50 (d, J=8.9 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.15 (d, J=2.7 Hz, 1H), 6.96 (d, J=9.1 Hz, 1H), 6.67 (d, J=8.9 Hz, 1H) ppm.

The compounds set forth in Table 11 were prepared by methods analogous to the preparation of compound 114.

5-[[2-Methyl-6-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (116)

To a stirred solution of 2-bromo-4-fluoro-1-(trifluoromethyl)benzene (17.004 g, 10 mL, 67.877 mmol) in anhydrous THF (600 mL) was added LDA (37 mL of 2.0 M, 74.000 mmol) drop-wise over 15 minutes at −78° C. The reaction mixture was stirred at this temperature for 2 h. The resulting yellow solution was then transferred via cannula onto crushed CO 2 and the resulting emulsion was stirred gently for 17 h. The solvent was evaporated in vacuo and the slurry was taken up in NaOH solution (500 mL, 1M) and extracted once with diethyl ether (500 mL). The aqueous layer was acidified to pH=1 and then extracted with diethyl ether (3×500 mL). The combined organic layer was washed with brine (200 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give 2-bromo-6-fluoro-3-(trifluoromethyl)benzoic acid (16.3 g, 79%) as an off-white solid. ESI-MS m/z calc. 285.9253, found 287.1 (M+1) + ; Retention time: 1.84 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 8.01 (dd, J=8.9, 5.6 Hz, 1H), 7.63 (t, J=8.6 Hz, 1H) ppm.

LCMS Method: Water Cortex 2.7u C 18 (3.0 mm×50 mm), Temp: 55c; Flow: 1.2 mL/minutes; MP: 100% water with 0.1% trifluoroacetic (TFA) acid then 100% acetonitrile with 0.1% TFA acid, grad:5% to 100% B over 4 min, with stay at 100% B for 0.5 min, equilibration to 5% B over 1.5 min.

A stirring mixture of 2-bromo-6-fluoro-3-(trifluoromethyl)benzoic acid (8.0 g, 27.87 mmol), tert-butoxycarbonyl tert-butyl carbonate (9.1 g, 41.70 mmol), DMAP (680 mg, 5.566 mmol), and t-BuOH (8 mL) was heated at 90° C. for 1 hour. The reaction mixture cooled to RT and directly purified by silica gel column chromatography using a gradient of 1-10% EtOAc in Hexanes to give tert-butyl 2-bromo-6-fluoro-3-(trifluoromethyl)benzoate (8.1 g, 85%) as a white solid. ESI-MS m/z calc. 341.98785, found 344.8 (M+1) + ; Retention time (Method B): 2.02 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (dd, J=9.0, 5.7 Hz, 1H), 7.64 (t, J=8.6 Hz, 1H), 1.58 (s, 9H) ppm.

Step 3: Tert-Butyl 2-Bromo-6-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]-3-(Trifluoromethyl)Benzoate

A mixture of tert-butyl 2-bromo-6-fluoro-3-(trifluoromethyl)benzoate (500 mg, 1.3115 mmol), 2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (360.02 mg, 1.7050 mmol), and K 2 CO 3 (362.51 mg, 2.6230 mmol) in DMSO (2 mL) was heated at 100° C. for 1 h. The reaction mixture was allowed to cool to RT, poured onto 50 mL of water and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to give crude tert-butyl 2-bromo-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate (800 mg, 103%) as a purple oil. ESI-MS m/z calc. 533.03516, found 534.3 (M+1) + ; Retention time: 4.39 minutes; LCMS Method: Merckmillipore Chromolith SpeedROD C 18 column (50×4.6 mm) and a dual gradient run from 5-100% mobile phase B over 6 minutes. Mobile phase A=water (0.1% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.1% CF 3 CO 2 H); LCMS Method Detail: null.

Step 4: Tert-Butyl 2-Methyl-6-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]-3-(Trifluoromethyl)Benzoate

A mixture of tert-butyl 2-bromo-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate (1.6 g, 2.6953 mmol), methylboronic acid (1.06 g, 17.354 mmol), K 2 CO 3 (1.2 g, 8.5090 mmol) and Pd(dppf) 2 Cl 2 (200 mg, 0.2679 mmol) in dioxane (10 mL) and water (1 mL) was flushed with nitrogen, capped and heated at 120° C. for 30 minutes in microwave. The reaction mixture was allowed to cool to RT and diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine, filtered, and concentrated in vacuo to give tert-butyl 2-methyl-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate (1.3 g, 98%) as a pale yellow solid which was used in next step without purification. ESI-MS m/z calc. 469.1403, found 470.5 (M+1) + ; Retention time: 4.42 minutes. LCMS Method: Merckmillipore Chromolith SpeedROD C 18 column (50×4.6 mm) and a dual gradient run from 5-100% mobile phase B over 6 minutes. Mobile phase A=water (0.1% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.1% CF 3 CO 2 H).

Step 5: 2-Methyl-6-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]-3-(Trifluoromethyl)Benzoic Acid

A solution of tert-butyl 2-methyl-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate (2.6 g, 4.4313 mmol) in THF (10 mL)/Water (5 mL) was added TFA (51.800 g, 35 mL, 454.29 mmol) and stirred at rt for 1 h. The reaction mixture was extracted with ether (3×100 mL). The combined organic layer was washed with 10% NaHCO 3 solution (50 mL), water (50 mL), brine (50 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The resulting pale yellow oil was triturated with DCM (5 mL)/Hexanes (50 mL) and the resulting solid was filtered and dried in vacuo to give 2-methyl-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoic acid (1.8 g, 93%) as a white solid. 1 H NMR (500 MHz, DMSO-d6) 7.64 (d, J=8.9 Hz, 1H), 7.26 (d, J=2.8 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.01 (ddd, J=8.8, 2.8, 1.3 Hz, 1H), 6.59 (d, J=8.8 Hz, 1H), 2.40 (d, J=1.8 Hz, 3H) ppm.

Step 6: 5-[[2-Methyl-6-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (116)

A solution of 2-methyl-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoic acid (150 mg, 0.3629 mmol) and DMF (25 μL, 0.3229 mmol) were dissolved in DCM (3 mL). Oxalyl chloride (250 μL, 2.866 mmol) was slowly added dropwise to the reaction mixture at RT. After 1 h the reaction mixture was concentrated under vacuo to give 2-methyl-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl chloride as an oil. This was dissolved in NMP (0.4 mL). This solution was slowly added to a prepared solution of 5-aminopyridine-2-carboxamide (19.91 mg, 0.1452 mmol) and DIEA (56.29 mg, 75.86 μL, 0.4355 mmol) in NMP (0.4 mL) at RT. The reaction mixture was allowed to stir overnight. The product was isolated by reverse-phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to afford 5-[[2-methyl-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (28.2 mg, 73%). ESI-MS m/z calc. 532.1261, found 533.2 (M+1) + ; Retention time (Method B): 1.85 minutes. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.18 (s, 1H), 8.90 (d, J=2.4 Hz, 1H), 8.34 (dd, J=8.6, 2.5 Hz, 1H), 8.08-8.01 (m, 2H), 7.72 (d, J=8.9 Hz, 1H), 7.57 (s, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.24 (d, J=2.7 Hz, 1H), 7.07-6.95 (m, 1H), 6.64 (d, J=8.9 Hz, 1H), 2.46-2.41 (m, 3H) ppm.

The compounds set forth in Table 12 were prepared by methods analogous to the preparation of compound 116 in Example 16.

5-[[6-(3,4-Difluoro-2-Methoxy-Phenoxy)-2-Fluoro-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (118)

A solution of 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (1 g, 3.484 mmol), 3,4-difluoro-2-methoxy-phenol (557 mg, 3.479 mmol), Cs 2 CO 3 (2.3 g, 7.059 mmol) in toluene (20 mL) was bubbled with N 2 for 10 minutes then CuI (132 mg, 0.6931 mmol) was added. The flask was flushed with N 2 , capped, and heated at 100° C. with vigorous stirring for 1 h. The mixture was allowed to cool then diluted with ethyl acetate and water. The water layer was acidified with HCl (5.2 mL of 1 M, 5.200 mmol) and the product extracted into ethyl acetate. The organic layer was evaporated to dryness under reduced pressure and the residue was purified by silica gel column chromatography using a gradient eluent of 1-10% MeOH in DCM to give to provide 6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (1.2 g, 92%) as a white solid. ESI-MS m/z calc. 366.03268, found 367.0 (M+1) + ; Retention time (Method B): 1.66 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (t, J=8.6 Hz, 1H), 7.39-7.21 (m, 1H), 7.14 (ddd, J=9.3, 5.1, 2.2 Hz, 1H), 6.75 (d, J=8.9 Hz, 1H), 3.85 (s, 3H) ppm.

Step 2: 5-[[6-(3,4-Difluoro-2-Methoxy-Phenoxy)-2-Fluoro-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (118)

A mixture of 6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (102.1 mg, 0.2731 mmol), oxalyl dichloride (23.11 mg, 15.88 μL, 0.1821 mmol), DMF (0.3328 mg, 0.3525 μL, 0.004553 mmol), and DCM (1.001 mL) was stirred under nitrogen at RT for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure. To the residue was added DCM (500.5 μL), N-ethyl-N-isopropyl-propan-2-amine (35.30 mg, 47.57 μL, 0.2731 mmol), and 5-aminopyridine-2-carboxamide (18.73 mg, 0.1366 mmol). The reaction mixture was stirred at ambient temperature for 1 h. The reaction was diluted with DMSO (500 uL), filtered, and purified by HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to give 5-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (54.8 mg, 41%) as a white solid. ESI-MS m/z calc. 485.08102, found 486.0 (M+1) + ; Retention time (Method B): 1.62 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.86 (d, J=2.4 Hz, 1H), 8.32 (dd, J=8.6, 2.5 Hz, 1H), 8.07 (d, J=8.5 Hz, 1H), 8.03 (d, J=2.7 Hz, 1H), 7.83 (t, J=8.6 Hz, 1H), 7.58 (d, J=2.8 Hz, 1H), 7.39-7.23 (m, 1H), 7.17 (ddd, J=9.3, 5.2, 2.1 Hz, 1H), 6.81 (d, J=8.9 Hz, 1H), 3.85 (d, J=1.2 Hz, 3H) ppm.

4-[[4-Bromo-2-Fluoro-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]Benzoyl]Amino]Pyridine-2-Carboxamide (119)

To methyl 4-bromo-2,6-difluoro-benzoate (6.1 g, 24.30 mmol) was added 2-methoxy-4-(trifluoromethoxy)phenol (5.2 g, 24.98 mmol), Cs 2 CO 3 (6.3 g, 19.34 mmol) and DMF (74 mL). The vial was sealed, the reaction mixture stirred at 80° C. for 1 hour, and the crude mixture cooled to RT. Ethyl acetate (˜150 mL) was added and the reaction mixture was washed with brine (3×75 ml). The organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo. Column chromatography (silica, 100:0-80:20 hexanes:EtOAc) afforded methyl 4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate (9.23 g, 87%) as a clear oil. ESI-MS m/z calc. 437.9726, found 463.1; Retention time (Method B): 2.09 minutes.

To a slurry of methyl 4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate (6 g, 13.66 mmol) in MeOH (60 mL) and water (60 mL) was added NaOH (5.5 g, 137.5 mmol). The reaction mixture was stirred at RT for 5 h. The solvent was evaporated and the residue was taken up in water, cooled in an ice bath and quenched with 6N HCl (pH˜ 2) slowly. The resultant solid product was filtered and washed with water. The residue was dissolved in DCM/ethyl acetate and dried over MgSO 4 , filtered and concentrated. The filtrate was extracted by ethyl acetate and dried over MgSO 4 and combined with the residue to obtain 4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid (5.6 g, 96%) as clear oil. ESI-MS m/z calc. 423.95694, found 427.0 (M+1) + ; Retention time (Method B):1.82 minutes. The oil was dried under high vacuum to for 24 h and taken on without further purification.

Step 3: 4-[[4-Bromo-2-Fluoro-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]Benzoyl]Amino]Pyridine-2-Carboxamide (119)

To a solution of 4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid (2 g, 4.704 mmol), DMF (100 μL, 1.291 mmol) and DCM (24.0 mL) at 0° C. under N 2 (g) was added oxalyl dichloride (3.3 mL, 37.83 mmol). The reaction was stirred at 0° C. for 10 minutes and then at RT for 1 h. The mixture was concentrated under reduced pressure and redissolved in NMP (5 mL). This solution was added drop-wise to a suspension of 4-aminopyridine-2-carboxamide (700 mg, 5.104 mmol), DMF (720 μL, 9.299 mmol), DIEA (5 mL, 28.71 mmol) in NMP (10 mL) under N 2 atmosphere at 0° C. The resulting reaction mixture was slowly warmed to RT and stirred at RT for 18 h. The reaction mixture turned from light brown suspension into a dark brown solution with time. The mixture was partitioned between water and ethyl acetate. The phases were separated and the aqueous layer was extracted with ethyl acetate (1×). The combined organic layer was washed with brine (2×), water (2×) then brine (1×). The organic layer was dried over Na 2 SO 4 , filtered and concentrated to give light brown foam. The crude was purified by ISCO silica chromatography (80 g silica gel column) eluting with a gradient system of hexane/EtOAc starting from 100% hexane to 70% EtOAc over 30 minutes to afford 4-[[4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (710 mg, 28%) as a white solid. ESI-MS m/z calc. 543.0053, found 546.1 (M+1) + ; Retention time (Method B): 1.72 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.29 (d, J=2.1 Hz, 1H), 8.10 (d, J=2.8 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.65 (d, J=2.8 Hz, 1H), 7.52 (dd, J=8.6, 1.6 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.05-6.97 (m, 1H), 6.75 (d, J=1.6 Hz, 1H), 3.78 (s, 3H) ppm.

4-[[6-(3,4-Difluoro-2-Methoxy-Phenoxy)-2-Methyl-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (120)

To a solution of 2-bromo-6-fluoro-3-(trifluoromethyl)benzoic acid (3.5 g, 12.19 mmol) and methylboronic acid (2.189 g, 36.57 mmol) in THF (35 mL) was added Cs 2 CO 3 (12 g, 36.83 mmol) followed by Pd(dppf) 2 Cl 2 (498 mg, 0.6098 mmol) under nitrogen gas. The reaction mixture was allowed to stir at 65° C. overnight and then heated under reflux in a 75° C. oil bath for 3 h. The reaction mixture was diluted with EtOAc (75 mL) and washed with aqueous HCl (0.5 M, 1×75 mL) and brine (1×75 mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The resultant oil was purified by silica gel column chromatography using a MeOH/DCM eluent. 6-fluoro-2-methyl-3-(trifluoromethyl)benzoic acid (2.27 g, 84%) was obtained as a ˜1.3:1 mixture of 6-fluoro-2-methyl-3-(trifluoromethyl)benzoic acid and 6-fluoro-3-(trifluoromethyl)benzoic acid as a crystalline solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.95 (s, 1H), 7.85 (dd, J=8.9, 5.5 Hz, 1H), 7.38 (t, J=8.8 Hz, 1H), 2.42 (d, J=1.9 Hz, 3H) ppm.

6-fluoro-2-methyl-3-(trifluoromethyl)benzoic acid (900 mg, 4.052 mmol) was dissolved in dichloromethane (13 mL). DMF (125 μL, 1.614 mmol) was added followed by the slow drop wise addition of oxalyl chloride (2.5 mL, 28.66 mmol). The reaction mixture was allowed to stir at RT for 30 minutes. The reaction mixture was concentrated under reduced pressure. Additional dichloromethane (˜5 mL) was added, and the solution was again concentrated to dryness. The remaining residue was taken up in NMP (2.7 mL) and was added to a prepared solution of 4-aminopyridine-2-carboxamide (833 mg, 6.074 mmol) and DIEA (4.2 mL, 24.11 mmol) in NMP (2.7 mL). This reaction mixture was allowed to stir at RT overnight. The reaction mixture was diluted with EtOAc (75 mL) and washed with water (2×75 mL), aqueous HCl (2×75 mL, 0.5 M) and brine (2×75 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was chromatographed on silica gel eluting with an EtOAc/hexane gradient to provide 4-[[6-fluoro-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (800 mg, 58%) as a white solid. ESI-MS m/z calc. 341.07874, found 342.1 (M+1) + ; Retention time (Method B): 1.25 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.60-8.55 (m, 1H), 8.36 (d, J=2.1 Hz, 1H), 8.12 (d, J=2.8 Hz, 1H), 7.92 (dd, J=8.9, 5.5 Hz, 1H), 7.84 (dd, J=5.4, 2.2 Hz, 1H), 7.67 (d, J=2.9 Hz, 1H), 7.47 (t, J=8.7 Hz, 1H), 2.44 (d, J=1.8 Hz, 3H) ppm.

Step 3: 4-[[6-(3,4-Difluoro-2-Methoxy-Phenoxy)-2-Methyl-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (120)

To a solution of 4-[[6-fluoro-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (25 mg, 0.07326 mmol) in DMSO (0.5 mL) was added to 3,4-difluoro-2-methoxy-phenol (approximately 35.19 mg, 0.2198 mmol). Finely ground K 2 CO 3 (30.38 mg, 0.2198 mmol) was then added. The reaction mixture was capped and allowed to stir at 120° C. for 30 minutes then at 140° C. for 1.5 h. The product was isolated by mass-triggered reverse-phase HPLC. Samples were and purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to afford 4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (7.1 mg, 20%). ESI-MS m/z calc. 481.1061, found 482.2 (M+1) + ; Retention time (Method B): 1.65 minutes. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.33 (s, 1H), 8.55 (d, J=5.4 Hz, 1H), 8.39 (d, J=2.1 Hz, 1H), 8.12 (s, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 7.67 (s, 1H), 7.28 (q, J=9.3 Hz, 1H), 7.14-7.06 (m, 1H), 6.77 (d, J=8.9 Hz, 1H), 3.83 (s, 3H), 2.44 (s, 3H) ppm.

The compounds set forth in Table 13 were prepared by methods analogous to the preparation of compound 120 in Example 19.

4-[[2-Fluoro-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-3-(Trifluoromethyl)Benzoyl]Amino]-1-Oxido-Pyridin-1-Ium-2-Carboxamide (150)

To a stirred slurry of 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (200 mg, 0.3736 mmol) in anhydrous DCM (1.8 mL) under N 2 at 0° C. was added 3-chlorobenzenecarboperoxoic acid (253 mg, 1.129 mmol). The reaction was allowed to warm up to RT and stirred for 13 h. The solvent was evaporated under reduced pressure. The crude material was purified by silica gel chromatography EtOAc/hexanes as eluant to yield 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide (190 mg, 93%) as a white solid. ESI-MS m/z calc. 549.0771, found 549.9 (M+1) + ; Retention time (Method C): 2.36 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 10.59 (d, J=4.6 Hz, 1H), 8.55 (d, J=3.2 Hz, 1H), 8.38 (d, J=7.2 Hz, 1H), 8.28 (d, J=4.5 Hz, 1H), 7.87 (dd, J=7.2, 3.2 Hz, 1H), 7.82 (t, J=8.6 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.27 (d, J=2.7 Hz, 1H), 7.09-7.01 (m, 1H), 6.69 (d, J=8.9 Hz, 1H), 3.79 (s, 3H) ppm.

4-[[6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-2-Methyl-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (151)

A stirring mixture of tert-butyl 2-bromo-6-fluoro-3-(trifluoromethyl)benzoate (3.0 g, 8.744 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (2.1 g, 10.09 mmol), K 2 CO 3 (2.4 g, 17.37 mmol), and DMSO (12 mL) was heated at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and was then directly purified by silica gel column chromatography using a gradient of 1-100% EtOAc in hexanes to give tert-butyl 2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate (4.1 g, 87%) as a clear oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J=8.9 Hz, 1H), 7.36-7.17 (m, 2H), 7.12-6.94 (m, 1H), 6.83 (d, J=8.9 Hz, 1H), 3.81 (s, 3H), 1.53 (s, 9H) ppm.

A microwave vial was loaded with tert-butyl 2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate (1.0 g, 1.882 mmol), methylboronic acid (563 mg, 9.405 mmol), ferrous; cyclopenta-1,4-dien-1-yl(diphenyl)phosphane; dichloromethane; dichloropalladium (154 mg, 0.1886 mmol), and K 2 CO 3 (780 mg, 5.644 mmol). The reaction vial was capped, purged with nitrogen, and 1,4-dioxane (6.0 mL) and water (600 μL) were added via syringe. The reaction was heated at 120° C. (oil bath) for 30 minutes. The reaction mixture was cooled to room temperature and was then directly purified by silica gel column chromatography using a gradient of 1-100% EtOAc in hexanes to give tert-butyl 6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoate (780 mg, 89%) as a clear oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J=8.9 Hz, 1H), 7.25 (d, J=2.7 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H), 7.08-6.92 (m, 1H), 6.68 (d, J=8.8 Hz, 1H), 3.81 (s, 3H), 2.38 (d, J=2.1 Hz, 3H), 1.50 (s, 9H) ppm.

A solution of tert-butyl 6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoate (4.0 g, 8.577 mmol), TFA (100 mL, 1.298 mol), water (6 mL, 333.1 mmol), and THF (16 mL), was stirred at room temperature for 1 hour. The solution was evaporated to dryness under reduced pressure and the residue was purified by silica gel column chromatography using a gradient eluent of 1-10% MeOH in dichloromethane to give 6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoic acid (3.4 g, 92%) as a light brown semisolid. 1 H NMR (400 MHz, DMSO-d6) δ 13.51 (s, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.25 (d, J=2.7 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.12-6.90 (m, 1H), 6.59 (d, J=8.8 Hz, 1H), 3.80 (s, 3H), 2.40 (s, 3H) ppm. ESI-MS m/z calc. 410.0589, found 411.0 (M+1) + ; Retention time (Method B): 1.87 minutes.

6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoic acid (1.11 g, 2.706 mmol) was dissolved in dichloromethane (18 mL). DMF (25 μL, 0.3229 mmol) was added. Oxalyl chloride (1.65 mL, 18.91 mmol) was slowly added dropwise while stirring the reaction mixture in a 0° C. ice bath. The ice bath was then removed, and the reaction mixture was allowed to stir at room temperature for 1 hour. Volatiles were then removed under reduced pressure. Additional dichloromethane was added (˜20 mL), and the solution was again concentrated to dryness. 6-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl chloride was obtained as a colorless oil which was used directly in the next step.

Step 5: 4-[[6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-2-Methyl-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (151)

A solution of 6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl chloride (500 mg, 1.166 mmol) in NMP (4 mL) was added to a prepared solution of 4-aminopyridine-2-carboxamide (320 mg, 2.333 mmol) and DIEA (1.22 mL, 7.004 mmol) in NMP (4 mL). The reaction mixture was allowed to stir at room temperature overnight. It was then diluted with EtOAc (75 mL) and washed with water (2×75 mL) and brine (3×75 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was chromatographed on silica gel column eluting with a 0-70% EtOAc/hexane gradient to provide 4-[[6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (202 mg, 32%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.25 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.37 (d, J=2.1 Hz, 1H), 8.09 (d, J=2.9 Hz, 1H), 7.86 (dd, J=5.5, 2.1 Hz, 1H), 7.71 (d, J=8.9 Hz, 1H), 7.64 (d, J=2.8 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.23 (d, J=2.6 Hz, 1H), 7.06-7.00 (m, 1H), 6.64 (d, J=8.8 Hz, 1H), 3.78 (s, 3H), 2.43 (s, 3H) ppm. ESI-MS m/z calc. 529.10724, found 530.3 (M+1) + ; Retention time (Method B): 1.79 minutes.

The compounds set forth in Table 14 were prepared by methods analogous to the preparation of compound 151 in Example 21.

4-[[4-(3-Furyl)-2-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]Benzoyl]Amino]Pyridine-2-Carboxamide (154)

To a solution of 4-bromo-2-fluoro-benzaldehyde (3.70 g, 18.23 mmol) in DMF (35 mL) was added Cs 2 CO 3 (7.50 g, 23.02 mmol) and 2-methoxy-4-(trifluoromethoxy)phenol (4.17 g, 20.04 mmol). The reaction mixture was stirred at RT for 16 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, aqueous NaHCO 3 (50%) and brine, then dried over MgSO 4 , filtered and concentrated in vacuo. Purification by silica gel column chromatography using a EtOAc/hexanes eluent provided 4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzaldehyde (6.77 g, 95%). ESI-MS m/z calc. 389.97147, found 392.9 (M+1) + ; Retention time (Method A): 0.8 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.48-7.43 (m, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.28 (d, J=2.7 Hz, 1H), 7.05 (ddd, J=8.8, 2.8, 1.3 Hz, 1H), 6.88 (d, J=1.7 Hz, 1H), 3.80 (s, 3H) ppm.

A mixture of 4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzaldehyde (6.74 g, 17.23 mmol) and NaH 2 PO 4 (3.10 g, 25.84 mmol) in tert-butyl alcohol (60 mL)/water (35 mL)/acetonitrile (35 mL) at 0° C. was treated with 2-methylbut-2-ene (8.0 mL, 75.51 mmol) followed by the portion-wise addition of sodium chlorite (2.92 g, 25.83 mmol) over 10 minutes. The mixture was allowed to warm to RT and stirred for 16 h. Additional NaH 2 PO 4 (3.10 g, 25.84 mmol) and sodium chlorite (2.92 g, 25.83 mmol) were added and the reaction mixture stirred for 30 minutes. The reaction mixture was acidified to pH 1-2 with aqueous HCl (175 mL of 1 M, 175.0 mmol) and partitioned with ethyl acetate. Excess sodium sulfite solid was added to the aqueous layer to remove the faint yellow color. The two layers were separated and the aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organics were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to an off-white solid. The solid was stirred/triturated with hexane (100 mL) for 1 h then filtered to provide 4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid (6.70 g, 96%) as a white solid. ESI-MS m/z calc. 405.96637, found 407.9 (M+1) + ; Retention time (Method A): 0.72 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.39 (dd, J=8.3, 1.8 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.09 (d, J=8.8 Hz, 1H), 6.99-6.94 (m, 1H), 6.88 (d, J=1.8 Hz, 1H), 3.80 (s, 3H) ppm.

4-Bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid (2.011 g, 4.939 mmol) in anhydrous DCM (16 mL) under nitrogen was treated with DMF (20 μL, 0.2583 mmol), cooled in an ice bath and the suspension treated dropwise with oxalyl chloride (700 μL, 8.024 mmol). The solution was stirred for 15 minutes and then at 35° C. for 15 minutes (until no further gas evolution was observed). The acid chloride solution was concentrated under vacuo and the resulting solid was dissolved in DCM (5 mL) then added drop-wise to a cold solution of 4-aminopyridine-2-carboxamide (0.812 g, 5.921 mmol) and DIEA (2.2 mL, 12.63 mmol) in NMP (20 mL). The clear orange-colored reaction mixture was then stirred at RT for 2 h. The reaction was concentrated in vacuo, diluted with ethyl acetate and washed with water (2×), aqueous NaHCO 3 (50%) and brine. The organic phase was dried over Na2SO4, filtered and concentrated. The resulting light orange solid was triturated with cold DCM (25 mL) and filtered. The solid was rinsed with minimal cold DCM to remove color and air dried to provide 4-[[4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (1.210 g, 47%). ESI-MS m/z calc. 525.0147, found 527.0 (M+1) + ; Retention time (Method A): 0.71 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.08 (d, J=2.9 Hz, 1H), 7.85 (dd, J=5.5, 2.1 Hz, 1H), 7.64 (d, J=8.1 Hz, 2H), 7.45 (dd, J=8.2, 1.7 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.19 (d, J=2.6 Hz, 1H), 7.05-6.97 (m, 1H), 6.93 (d, J=1.7 Hz, 1H), 3.77 (s, 3H) ppm.

Step 4: 4-[[4-(3-Furyl)-2-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]Benzoyl]Amino]Pyridine-2-Carboxamide (154)

A solution of 4-[[4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (30 mg, 0.05701 mmol), 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (17 mg, 0.08671 mmol), Pd(dppf) 2 Cl 2 (5 mg, 0.006123 mmol), K 2 CO 3 (15 mg, 0.1085 mmol) in dioxane (500 μL)/water (50 μL) was flushed with N 2 and heated at 100° C. for 16 h. The reaction mixture was purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to give 4-[[4-(3-furyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (1.0 mg, 3%), ESI-MS m/z calc. 513.11475, found 514.2 (M+1) + ; Retention time (Method B): 1.75 minutes.

The compounds set forth in Table 15 were prepared by methods analogous to the preparation of compound 154 and Example 22.

4-[[2-(4-Fluoro-2-Methoxy-Phenoxy)-4-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (159)

To a solution of 2-bromo-4-(trifluoromethyl)benzoic acid (5.0 g, 18.59 mmol) in DMF (135 μL, 1.744 mmol), and DCM (50 mL) at 0° C. was added oxalyl chloride (7.6 mL, 87.12 mmol) dropwise over 3 minutes. The mixture was stirred at RT for 2 h then concentrated in vacuo. The intermediate was taken up in DCM (5 mL) and added drop-wise to a solution of 4-aminopyridine-2-carboxamide (2.4 g, 17.50 mmol), DIEA (3.0 mL, 17.22 mmol), and DCM (25 mL) at 0° C. The reaction mixture was stirred at RT for 2 h. The reaction mixture concentrated under vacuo and purified by silica gel column chromatography using a MeOH/DCM eluent. The resultant material was triturated with diethyl ether (100 mL) and filtered to give 4-[[2-bromo-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (1.2 g, 17%) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 8.38 (d, J=2.3 Hz, 1H), 8.19 (d, J=1.7 Hz, 1H), 8.17-8.09 (m, 1H), 7.98-7.82 (m, 3H), 7.69 (d, J=2.8 Hz, 1H) ppm.

Step 2: 4-[[2-(4-Fluoro-2-Methoxy-Phenoxy)-4-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (159)

A mixture of 4-[[2-bromo-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (25 mg, 0.06441 mmol), 4-fluoro-2-methoxy-phenol (9.154 mg, 7.341 μL, 0.06441 mmol), Cs 2 CO 3 (20.99 mg, 0.06441 mmol), CuI (3.679 mg, 0.01932 mmol), CsF (48.91 mg, 11.89 μL, 0.3220 mmol), and DMF (500.0 μL), was heated at 150° C. for 1 h. The crude was then purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to give 4-[[2-(4-fluoro-2-methoxy-phenoxy)-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (8.0 mg, 25%) as a white solid. ESI-MS m/z calc. 449.09988, found 450.3 (M+1) + ; Retention time (Method B): 1.63 minutes. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.08 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.35 (d, J=2.1 Hz, 1H), 8.12 (d, J=2.8 Hz, 1H), 7.88 (t, J=6.1 Hz, 2H), 7.67 (d, J=2.9 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.32 (dd, J=8.9, 5.8 Hz, 1H), 7.16 (ddd, J=10.6, 7.6, 2.9 Hz, 1H), 6.91-6.83 (m, 2H), 3.74 (s, 3H) ppm.

The compounds set forth in Table 16 were prepared by methods analogous to the preparation of compound 159 and Example 23.

4-[[2-Fluoro-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-4-[4-(Trifluoromethyl)Cyclohexyl]Benzoyl]Amino]Pyridine-2-Carboxamide (Two Diastereoisomers) (168)

Step 1: 4-[[2-Fluoro-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-4-[4-(Trifluoromethyl)Cyclohexen-1-Yl]Benzoyl]Amino]Pyridine-2-Carboxamide

A solution of 4-[[4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (25 mg, 0.046 mmol), 4,4,5,5-tetramethyl-2-[4-(trifluoromethyl)cyclohexen-1-yl]-1,3,2-dioxaborolane (25 mg, 0.092 mmol), K 2 CO 3 (13 mg, 0.092 mmol), Pd(dppf) 2 Cl 2 (7.5 mg, 0.0092 mmol), in dioxane (0.5 mL) and water (50 μL) was heated at 100° C. for 16 h. The reaction mixture was purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to give 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexen-1-yl]benzoyl]amino]pyridine-2-carboxamide (21.3 mg, 76%). ESI-MS m/z calc. 613.1448, found 614.3 (M+1) + ; Retention time (Method B): 2.01 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.29 (d, J=2.2 Hz, 1H), 8.09 (d, J=2.9 Hz, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.64 (d, J=2.9 Hz, 1H), 7.24-7.14 (m, 3H), 6.97 (dd, J=9.2, 2.3 Hz, 1H), 6.61 (s, 1H), 6.17 (s, 1H), 3.77 (s, 3H), 2.40 (d, J=7.3 Hz, 3H), 2.28-2.09 (m, 2H), 2.03 (d, J=12.4 Hz, 1H), 1.55 (td, J=12.4, 6.0 Hz, 1H) ppm.

Step 2: 4-[[2-Fluoro-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-4-[4-(Trifluoromethyl)Cyclohexyl]Benzoyl]Amino]Pyridine-2-Carboxamide (Two Diastereoisomers) (168)

A solution of 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexen-1-yl]benzoyl]amino]pyridine-2-carboxamide (15 mg, 0.02445 mmol) in EtOAc (250 μL)/MeOH (250 μL) was treated with Pd/C (1 mg, 0.009397 mmol). The mixture was degassed with a flow of N 2 (g) for 2 minutes, then purged with H 2 (balloon). The reaction was stirred at RT for 16 h. The mixture was purified by reverse phase HPLC Method B, resulting in two diastereoisomers. It is appreciated that both diastereomers of 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexyl]benzoyl]amino]pyridine-2-carboxamide (168) were isolated and that those diastereomers have the structure of compounds 168-a and 168-b (above). However, the relative stereochemistry of diastereomers 1 and 2 was not determined.

Diastereomer 1: 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexyl]benzoyl]amino]pyridine-2-carboxamide (4.1 mg, 71%). ESI-MS m/z calc. 615.1604, found 616.2 (M+1) + ; Retention time (Method B): 1.97 minutes. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.27 (s, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.32 (d, J=2.1 Hz, 1H), 8.12 (s, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.67 (s, 1H), 7.24 (d, J=8.8 Hz, 1H), 7.19 (d, J=2.7 Hz, 1H), 7.05-6.95 (m, 2H), 6.43 (s, 1H), 3.76 (s, 3H), 2.82-2.72 (m, 1H), 2.46 (m, 1H, obscured by DMSO), 1.75-1.55 (m, 8H) ppm.

Diastereomer 2: 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexyl]benzoyl]amino]pyridine-2-carboxamide (1.7 mg, 29%), ESI-MS m/z calc. 615.1604, found 616.3 (M+1) + ; Retention time (Method B): 2.03 minutes respectively.

The compounds set forth in Table 17 were prepared by methods analogous to the preparation of compound 168. It is appreciated that both diastereomers of 4-[[4-(4-tert-butylcyclohexyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (169) were isolated and that those diastereomers have the structure of compounds 169-a and 169-b (see Table A, above). However, the relative stereochemistry of the first and second eluting diastereomers was not determined.

5-[[2-Fluoro-4-(4-Fluorophenyl)-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]Benzoyl]Amino]Pyridine-2-Carboxamide(170)

A solution of 4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid (1.22 g, 2.870 mmol), (4-fluorophenyl)boronic acid (830 mg, 5.932 mmol), Pd(PPh 3 ) 4 (550 mg, 0.4760 mmol) and Na 2 CO 3 (500 mg, 4.717 mmol) were combined in DMF (30 mL) and H 2 O (10 mL), then heated at 100° C. for 3 h. The reaction was poured carefully into 1N HCl (caution: gas evolution) then washed with DCM. The organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo. Purification by silica gel column chromatography using a EtOAc/hexanes eluent gave 2-fluoro-4-(4-fluorophenyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid (970 mg, 77%). ESI-MS m/z calc. 440.06833, found 441.0 (M+1) + ; Retention time (Method B): 1.99.

To a solution of 2-fluoro-4-(4-fluorophenyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid (500 mg, 1.136 mmol) and DMF (25 μL, 0.3229 mmol) in DCM (6 mL) at 0° C. was added oxalyl chloride (800 μL, 9.171 mmol) dropwise under a N 2 atmosphere. The ice bath was removed after 10 minutes and the reaction was stirred at RT for 50 minutes. The mixture was concentrated in vacuo to afford the crude 2-fluoro-4-(4-fluorophenyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl chloride (520 mg, 100%) which was taken on without further purification.

Step 3: 5-[[2-Fluoro-4-(4-Fluorophenyl)-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]Benzoyl]Amino]Pyridine-2-Carboxamide (170)

To a solution of 5-aminopyridine-2-carboxamide (9.715 mg, 0.07084 mmol), DMF (3.983 mg, 4.219 μL, 0.05449 mmol) and NMP (400 μL) was added DIEA (21.13 mg, 28.48 μL, 0.1635 mmol) under a N 2 atmosphere and the resulting clear solution was cooled to 0° C. A solution of 2-fluoro-4-(4-fluorophenyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl chloride (25 mg, 0.05449 mmol) in NMP (200 μL) was then added and the reaction was stirred at RT for 16 h. The mixture was purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to give 5-[[2-fluoro-4-(4-fluorophenyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (21.1 mg, 69%). ESI-MS m/z calc. 559.11664, found 559.91 (M+1) + ; Retention time (Method B): 1.97 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 8.86 (d, J=2.4 Hz, 1H), 8.26 (dd, J=8.7, 2.4 Hz, 1H), 8.05 (s, 1H), 8.03 (s, 1H), 7.67 (dd, J=8.6, 5.4 Hz, 2H), 7.56 (s, 1H), 7.52-7.44 (m, 1H), 7.35-7.23 (m, 3H), 7.17 (d, J=2.7 Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 6.87 (s, 1H), 3.77 (s, 3H) ppm.

4-[[4-(4-Chlorophenyl)-2-Fluoro-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]Benzoyl]Amino]Pyridine-2-Carboxamide (171)

Step 1: 4-[[4-(4-Chlorophenyl)-2-Fluoro-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]Benzoyl]Amino]Pyridine-2-Carboxamide (171)

A solution of 4-[[4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (25 mg, 0.04593 mmol), (4-chlorophenyl)boronic acid (approximately 14.36 mg, 0.09186 mmol), K 2 CO 3 (12.70 mg, 0.09186 mmol), Pd(dppf) 2 Cl 2 (7.502 mg, 0.009186 mmol) in dioxane (500 μL) and water (50 μL) was flushed with N 2 and heated at 100° C. for 16 h. The reaction mixture was purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) giving 4-[[4-(4-chlorophenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (14.6 mg, 55%). ESI-MS m/z calc. 575.0871, found 576.1 (M+1) + ; Retention time (Method B): 1.97 minutes. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.33 (s, 1H), 8.54 (d, J=5.4 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H), 8.12 (d, J=2.7 Hz, 1H), 7.86-7.81 (m, 1H), 7.65 (d, J=8.9 Hz, 3H), 7.57-7.48 (m, 3H), 7.28 (d, J=8.8 Hz, 1H), 7.18 (d, J=2.6 Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 6.88 (s, 1H), 3.78 (s, 3H) ppm.

The compounds set forth in Table 18 were prepared by methods analogous to the preparation of compound 171 and Example 26.

N-(2-Carbamoyl-4-Pyridyl)-3-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]-5-(Trifluoromethyl)Pyridine-2-Carboxamide (173)

Concentrated sulfuric acid (8 mL, 150.1 mmol) was added to a solution of 3-fluoro-5-(trifluoromethyl)pyridine-2-carboxylic acid (10 g, 47.82 mmol) in methanol (200 mL) and the resulting reaction was stirred at 65° C. for 19.5 h. The residue was taken up in ethyl acetate and water and the layers were separated. The organic layer was washed with saturated aqueous NaHCO 3 (×1) and brine (×1). The aqueous layer was extracted with EtOAc (×1) and the organic layer was washed with saturated aqueous NaHCO 3 (×1) and brine (×1). The combined organic layer was dried over Na 2 SO 4 filtered and concentrated in vacuo to yield methyl 3-fluoro-5-(trifluoromethyl)pyridine-2-carboxylate (8.2311 g, 77%) as a cream colored solid. ESI-MS m/z calc. 223.02563, found 224.0 (M+1) + ; Retention time (Method C): 1.46 minutes.

Step 3: Methyl 3-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]-5-(Trifluoromethyl)Pyridine-2-Carboxylate

A solution of methyl 3-fluoro-5-(trifluoromethyl)pyridine-2-carboxylate (2 g, 8.964 mmol), 2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (2.06 g, 9.756 mmol), and Cs 2 CO 3 (2.966 g, 9.103 mmol) in DMF (15 mL) was heated at 100° C. for 16 h. The reaction was diluted with EtOAc and washed with water (×3) and brine (×1). The organic layer was dried over Na 2 SO 4 , filtered and the concentrated in vacuo to yield methyl 3-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate (3.44 g, 93%) as an orange viscous liquid. ESI-MS m/z calc. 414.07297, found 415.1 (M+1) + ; Retention time (Method C): 2.71 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.77-8.70 (m, 1H), 7.61-7.53 (m, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.22 (d, J=2.8 Hz, 1H), 7.01-6.93 (m, 1H), 3.88 (s, 3H) ppm.

Step 4: 3-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]-5-(Trifluoromethyl)Pyridine-2-Carboxylic Acid

A solution of methyl 3-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate (3.14 g, 7.580 mmol) in methanol (30 mL) was treated with aqueous NaOH (30 mL of 1 M, 30.00 mmol). The reaction was stirred at 60° C. for 2 h. The reaction was acidified to pH˜1 with concentrated HCl. The reaction was diluted with water and extracted with EtOAc (×1). The organic layer was washed with brine (×1), dried over Na 2 SO 4 , filtered and concentrated under vacuo to yield 3-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylic acid (2.9 g, 96%) as a cream colored solid. ESI-MS m/z calc. 400.0573, found 401.1 (M+1) + ; Retention time (Method C): 2.39 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 13.89 (s, 1H), 8.83-8.66 (m, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.29-7.23 (m, 2H), 7.09-6.93 (m, 1H) ppm.

Step 5: 3-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]-5-(Trifluoromethyl)Pyridine-2-Carbonyl Chloride

To 3-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylic acid (540 mg, 1.349 mmol) and DMF (15 μL, 0.1937 mmol) in DCM (4 mL) at 0° C. was added oxalyl chloride (180 μL, 2.063 mmol) dropwise under a N 2 atmosphere. The ice bath was removed after 10 minutes and the reaction was stirred at RT for 30 minutes then at 50° C. for 2 h. The reaction mixture was concentrated in vacuo to afford 3-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carbonyl chloride. The intermediate was used in the next step without further purification.

Step 6: N-(2-Carbamoyl-4-Pyridyl)-3-[2-(Trideuteriomethoxy)-4-(Trifluoromethoxy)Phenoxy]-5-(Trifluoromethyl)Pyridine-2-Carboxamide (173)

To 4-aminopyridine-2-carboxamide (23.59 mg, 0.1720 mmol) in NMP (500 μL) and DIEA (55.56 mg, 74.88 μL, 0.4299 mmol) at 0° C. was added a solution of 3-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carbonyl chloride (60 mg, 0.1433 mmol) in NMP (200 μL) slowly. The mixture was stirred at RT for 16 h. The crude product was filtered and purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to yield N-(2-carbamoyl-4-pyridyl)-3-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxamide (26.5 mg, 35%). ESI-MS m/z calc. 519.10565, found 519.9 (M+1) + ; Retention time (Method B): 1.77 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.85 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.40 (d, J=2.2 Hz, 1H), 8.10 (s, 1H), 7.92-7.86 (m, 1H), 7.70-7.61 (m, 2H), 7.31 (d, J=8.8 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.03-6.99 (m, 1H) ppm.

The compounds set forth in Table 19 were prepared by methods analogous to the preparation of compound 173 and Example 27.

4-[[2-(4-Fluoro-2-Methoxy-Phenyl)-4-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (175)

A solution of 2-bromo-4-(trifluoromethyl)benzoic acid (2 g, 7.435 mmol) and H 2 SO 4 (1.094 g, 594.6 μL, 11.15 mmol) in MeOH (50 mL) was heated at 65° C. overnight. The reaction mixture was cooled to RT and concentrated in vacuo. The residue was taken up in ethyl acetate (20 mL) and water (20 mL) and the layers separated. The aqueous layer was extracted further with ethyl acetate (2×20 mL) and the combined organic layers washed with saturated aqueous NaHCO 3 (1×20 mL), dried over MgSO 4 and concentrated in vacuo to afford the product as a colorless oil. 1 H NMR (500 MHz, Chloroform-d) δ 7.97-7.86 (m, 2H), 7.64 (ddt, J=8.0, 1.3, 0.7 Hz, 1H), 3.99 (s, 3H) ppm.

A mixture of methyl 2-bromo-4-(trifluoromethyl)benzoate (500 mg, 1.767 mmol), (4-fluoro-2-methoxy-phenyl)boronic acid (450 mg, 2.648 mmol), K 2 CO 3 (488 mg, 3.531 mmol), Pd(PPh 3 ) 4 (41 mg, 0.03548 mmol), DMF (4.5 mL) and water (500 μL) was heated at 80° C. for 2 h. The solution was concentrated in vacuo and the residue was purified by silica gel column chromatography using a EtOAc/hexanes eluent to give methyl 2-(4-fluoro-2-methoxy-phenyl)-4-(trifluoromethyl)benzoate (510 mg, 88%) as a clear oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J=8.1 Hz, 1H), 7.90-7.78 (m, 1H), 7.64 (d, J=1.9 Hz, 1H), 7.35 (dd, J=8.4, 6.8 Hz, 1H), 6.98 (dd, J=11.3, 2.5 Hz, 1H), 6.88 (td, J=8.5, 2.5 Hz, 1H), 3.68 (s, 3H), 3.66 (s, 3H) ppm.

A mixture of methyl 2-(4-fluoro-2-methoxy-phenyl)-4-(trifluoromethyl)benzoate (500 mg, 1.523 mmol), NaOH (1.2 g, 30.00 mmol) in H 2 O (2.5 mL), and THF (2.5 mL) was heated at 100° C. for 2 h. The reaction mixture was acidified to pH=2 (1.0 N aqueous HCl) and partitioned between water (50 mL) and EtOAc (100 mL). The reaction was concentrated in vacuo and the residue purified by silica gel column chromatography using a EtOAc/hexanes eluent to give 2-(4-fluoro-2-methoxy-phenyl)-4-(trifluoromethyl)benzoic acid (230 mg, 48%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.86-7.76 (m, 1H), 7.59 (d, J=1.9 Hz, 1H), 7.30 (dd, J=8.4, 6.8 Hz, 1H), 6.97 (dd, J=11.4, 2.5 Hz, 1H), 6.85 (td, J=8.5, 2.5 Hz, 1H), 3.69 (s, 3H) ppm.

Step 4: 4-[[2-(4-Fluoro-2-Methoxy-Phenyl)-4-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (175)

To a solution of 2-(4-fluoro-2-methoxy-phenyl)-4-(trifluoromethyl)benzoic acid (100 mg, 0.3182 mmol), DMF (3 μL, 0.03874 mmol), and DCM (1 mL), at 0° C. (ice-bath), was added oxalyl chloride (55 μL, 0.6305 mmol) dropwise over 3 minutes. The mixture was stirred at RT for 2 h then concentrated in vacuo. The intermediate was dissolved in DCM (5 mL) and added drop-wise to a solution of 4-aminopyridine-2-carboxamide (44 mg, 0.3208 mmol), DIEA (140 μL, 0.8038 mmol) in DCM (500 μL) at a 0° C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated under vacuo and the residue purified by silica gel column chromatography using a EtOAc/hexanes eluent. The resultant material was triturated with diethyl ether (100 mL) and filtered to give 4-[[2-(4-fluoro-2-methoxy-phenyl)-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (13.1 mg, 9%) as a white solid. ESI-MS m/z calc. 433.10495, found 434.0 (M+1) + ; Retention time (Method B): 1.31 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.50 (d, J=5.6 Hz, 1H), 8.30 (d, J=2.2 Hz, 1H), 8.16 (s, 1H), 7.90 (d, J=1.4 Hz, 2H), 7.79 (dd, J=5.7, 2.2 Hz, 1H), 7.70 (d, J=7.3 Hz, 2H), 7.40 (dd, J=8.4, 6.7 Hz, 1H), 6.94-6.82 (m, 2H), 3.54 (s, 3H) ppm.

5-[[6-(2-Chloro-4-Fluoro-Phenoxy)-2-Fluoro-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide(176)

A solution of 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (5 g, 17.42 mmol), 2-chloro-4-fluoro-phenol (3.0 g, 20.47 mmol), Cs 2 CO 3 (11.4 g, 34.99 mmol) in toluene (100 mL) was degassed with N 2 for 10 minutes, then CuI (664 mg, 3.486 mmol) was added. The reaction was flushed with N 2 then heated at 100° C. with vigorous stirring for 1 h. The mixture was allowed to cool then diluted with ethyl acetate and water. The water layer was acidified with HCl (26 mL of 1 M, 26.00 mmol) and the product extracted with ethyl acetate. The organic layer was concentrated under vacuo and the residue was purified by silica gel column chromatography using a MeOH/DCM eluent to provide 6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (5.1 g, 80%) as a white solid. ESI-MS m/z calc. 351.99255, found 353.0 (M+1) + ; Retention time (Method B): 1.66 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 14.19 (s, 1H), 7.89-7.58 (m, 2H), 7.59-7.22 (m, 2H), 6.69 (d, J=8.9 Hz, 1H) ppm.

Step 2: 5-[[6-(2-Chloro-4-Fluoro-Phenoxy)-2-Fluoro-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (176)

A mixture of 6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (50 mg, 0.1390 mmol), oxalyl chloride (17.64 mg, 12.12 μL, 0.1390 mmol), and DMF (0.2541 mg, 0.2692 μL, 0.003476 mmol) in DCM (285.9 μL) was stirred under nitrogen at RT for 1 h. The reaction mixture was concentrated in vacuo. To the residue was added DCM (143.0 μL), 5-aminopyridine-2-carboxamide (28.59 mg, 0.2085 mmol), and DIEA (26.95 mg, 36.32 μL, 0.2085 mmol). The reaction mixture was stirred at RT for 1 h. The crude mixture was purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to give amide 5-[[6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (8.7 mg, 9%) as a white solid. ESI-MS m/z calc. 471.04092, found 471.9 (M+1) + ; Retention time (Method B): 1.77 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.87 (d, J=2.4 Hz, 1H), 8.31 (dd, J=8.6, 2.4 Hz, 1H), 8.07 (d, J=8.6 Hz, 1H), 8.04 (d, J=2.7 Hz, 1H), 7.86 (t, J=8.6 Hz, 1H), 7.70 (dd, J=8.3, 3.0 Hz, 1H), 7.64-7.54 (m, 1H), 7.50 (dd, J=9.1, 5.2 Hz, 1H), 7.38 (td, J=9.2, 8.7, 3.0 Hz, 1H), 6.76 (d, J=8.9 Hz, 1H) ppm.

4-[[2-Fluoro-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-3-Phenyl-Benzoyl]Amino]Pyridine-2-Carboxamide (177)

A solution of 6-bromo-3-chloro-2-fluoro-benzoic acid (2 g, 7.891 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (1.66 g, 7.976 mmol), Cs 2 CO 3 (2.69 g, 8.256 mmol) in toluene (15 mL) was bubbled with N 2 for 10 minutes, then CuI (359.6 mg, 1.888 mmol) was added. The reaction was heated at 100° C. with vigorous stirring for 3 h. The mixture was allowed to cool, then diluted with ethyl acetate and water (50 mL) and then acidified with 1 M HCl. The two layers were separated and the aqueous layer was extracted with EtOAc (×3). The combined organic layer was washed with water (×2), brine (×1), dried over Na 2 SO 4 , filtered through a plug of celite and concentrated in vacuo. Purification by silica gel column chromatography using a EtOAc/hexanes eluent followed by purification by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to yield 3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid (510.6 mg, 17%). ESI-MS m/z calc. 380.00748, found 381.1 (M+1) + ; Retention time (Method B): 2.53 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 13.92 (s, 1H), 7.56 (t, J=8.8 Hz, 1H), 7.29-7.14 (m, 2H), 6.99 (dd, J=8.8, 2.5 Hz, 1H), 6.56 (d, J=9.0 Hz, 1H), 3.79 (s, 3H) ppm.

Step 2: 4-[[3-Chloro-2-Fluoro-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]Benzoyl]Amino]Pyridine-2-Carboxamide

To 3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid (83.8 mg, 0.2201 mmol) and DMF (15 μL, 0.1937 mmol) in DCM (1 mL) at 0° C. was added oxalyl chloride (53 μL, 0.6076 mmol) dropwise under a N 2 atmosphere. The ice bath was removed after 10 minutes and the reaction was stirred at RT for 2.5 h. The reaction was concentrated in vacuo to afford 3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl chloride. The intermediate was taken onto the next step without further purification.

To 4-aminopyridine-2-carboxamide (36.2 mg, 0.2640 mmol) in NMP (0.5 mL) and DIEA (115 μL, 0.6602 mmol) at 0° C. was added a solution of 3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl chloride in NMP (0.2 mL) slowly. The mixture was stirred at RT for 1 h. The crude product was purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to yield 4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (25.8 mg, 23%). ESI-MS m/z calc. 499.05582, found 500.0 (M+1) + ; Retention time (Method A): 0.55 minutes.

Step 3: 4-[[2-Fluoro-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-3-Phenyl-Benzoyl]Amino]Pyridine-2-Carboxamide (177)

A solution of 4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (26 mg, 0.05202 mmol), phenylboronic acid (19.5 mg, 0.1599 mmol), Pd(dppf) 2 Cl 2 (4.1 mg, 0.005021 mmol) and K 2 CO 3 (79 μL of 2 M, 0.1580 mmol) in dioxane (500 μL) was heated in the microwave at 120° C. for 20 minutes. Further Pd(dppf) 2 Cl 2 (11 mg) and K 2 CO 3 (79 μL of 2 M, 0.1580 mmol) were added to the reaction which was heated at 130° C. for 40 minutes in the microwave. Further Pd(dppf) 2 Cl 2 (11 mg), K 2 CO 3 (79 μL of 2 M, 0.1580 mmol), and phenylboronic acid (19.5 mg, 0.1599 mmol) were added to the reaction mixture which was then heated in the microwave at 130° C. for 40 minutes. The crude product was purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to yield 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-phenyl-benzoyl]amino]pyridine-2-carboxamide (2.8 mg, 10%). ESI-MS m/z calc. 541.1261, found 542.2 (M+1) + ; Retention time (Method C): 2.61 minutes (5 minutes run). 1 H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.54 (d, J=5.3 Hz, 1H), 8.35 (s, 1H), 8.12 (s, 1H), 7.92-7.80 (m, 1H), 7.67 (s, 1H), 7.61-7.48 (m, 5H), 7.48-7.38 (m, 1H), 7.32 (d, J=8.9 Hz, 1H), 7.23 (s, 1H), 7.03 (d, J=8.3 Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 3.80 (s, 3H) ppm.

4-[[2-Ethyl-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-4-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (178)

To a solution containing freshly distilled diisopropylamine (4 mL, 28.54 mmol) was added n-butyl lithium in hexanes (11 mL of 2.5 M, 27.5 mmol) over 10 minutes at 0° C. The mixture was then stirred at this temperature for 30 minutes, then cooled to −78° C., and stirred at this temperature for 30 minutes. This solution was then transferred via cannula into a solution of 1-bromo-3-fluoro-5-(trifluoromethyl)benzene (5 g, 20.576 mmol) in THF (20 mL) at −78° C. The resulting pale amber solution was transferred via cannula to crushed CO 2 and the resulting golden solution was stirred gently for 18 h. The reaction was diluted with NaOH (0.1M, 200 mL), and washed with Et 2 O (3×200 mL), the aqueous phase was acidified with HCl (3M, until pH=1), and was extracted with Et 2 O (3×200 mL), dried over MgSO 4 , filtered and concentrated under reduced pressure to provide 2-bromo-6-fluoro-4-(trifluoromethyl)benzoic acid (5.34 g, 90%). ESI-MS m/z calc. 285.92526, found 287.0 (M+1) + ; Retention time: 4.4 minutes; LCMS Method: Merckmillipore Chromolith SpeedROD C 18 column (50×4.6 mm) and a dual gradient run from 5-100% mobile phase B over 12 minutes. Mobile phase A=water (0.1% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.1% CF 3 CO 2 H); LCMS Method Detail: null.

To a solution of 2-bromo-6-fluoro-4-(trifluoromethyl)benzoic acid (50 mg, 0.174 mmol) and 4-aminopyridine-2-carboxamide (24 mg, 0.175 mmol) in pyridine (1.5 mL) was added POCl3 (0.016 mL, 0.172 mmol) at −20° C. to −15° C. and stirred 30 min at this temperature. The reaction was quenched by addition of water (1 mL), then extracted with EtOAc (2×10 mL). The combined organic phases were washed with water (3×2 mL), brine, dried over MgSO 4 , and concentrated under reduced pressure to give 4-[[2-bromo-6-fluoro-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (70 mg, 99%). ESI-MS m/z calc. 404.9736, found 406.0 (M+1) + ; Retention time: 3.78 minutes and used directly in the next step without further purification.

Step 3: 4-[[2-Bromo-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-4-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide

A solution of 4-[[2-bromo-6-fluoro-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (1.00 g, 2.46 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (564 mg, 2.71 mmol) and Cs 2 CO 3 (1.60 g, 4.91 mmol) in NMP (15 mL) was heated at 95° C. for 2 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated and washed with water and brine. The organic layer was dried over MgSO 4 , then purified by silica gel column chromatography using a ethyl acetate-dichloromethane gradient to give 4-[[2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (690 mg, 47%). ESI-MS m/z calc. 593.0021, found 595.0 (M+1) + ; Retention time (Method B): 1.68 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.05 (dd, J=13.5, 2.5 Hz, 2H), 7.93-7.81 (m, 2H), 7.63 (d, J=2.8 Hz, 1H), 7.48 (dd, J=5.6, 2.2 Hz, 1H), 6.86 (d, J=2.5 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 6.73 (d, J=8.6 Hz, 1H), 3.50 (s, 3H) ppm.

Step 4: 4-[[2-Ethyl-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-4-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (178)

Diethylzinc (80 μL of 2 M, 0.1600 mmol) was added under nitrogen to a solution of 4-[[2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (48 mg, 0.08077 mmol) and Pd(dppf)Cl 2 (3.1 mg, 0.004237 mmol) in dioxane (0.6 mL) in a capped vial and the resulting pale yellow solution heated at 100° C. for 1 h. Additional diethylzinc (80 μL of 2 M, 0.1600 mmol) was added and the solution heated at 100° C. for a further 1 h. The reaction was quenched with MeOH (500 uL) and partitioned between ethyl acetate and 1 M aqueous HCl. The organic layer was dried over Na 2 SO 4 , filtered and concentrated. HPLC purification (10-100% CH 3 CN/5 mM HCl) gave partially purified product. The product fractions were concentrated to a cloudy white suspension with some solid precipitate. The cloudy solution was decanted from the white solid. The solid was dried under vacuum, then suspended in hexane and dissolved with the slow addition of DCM. The DCM was slowly removed under rotary vacuum until a white solid began to precipitate. The precipitate was allowed to settle and the mother liquor decanted. The isolated solid was dried under high vacuum to give 4-[[2-ethyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (7.1 mg, 15%). ESI-MS m/z calc. 543.12286, found 544.6 (M+1) + ; Retention time (Method B): 1.77 minutes. 1 H NMR (400 MHz, Methanol-d4) δ 8.42 (d, J=5.5 Hz, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.63 (dd, J=5.5, 2.1 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 6.69-6.55 (m, 3H), 3.47 (s, 3H), 2.75 (q, J=7.6 Hz, 2H), 1.24 (t, J=7.6 Hz, 3H) ppm.

5-[[6-(3,4-Difluoro-2-Methoxy-Phenoxy)-2-Methyl-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (179)

To a stirred solution of 2-bromo-4-fluoro-1-(trifluoromethyl)benzene (2.5 mL, 17 mmol) in anhydrous THF (150 mL) was added LDA (10 mL of 2.0 M, 20 mmol) at −78° C. The reaction mixture was stirred at this temperature for 2 h. The resulting yellow solution was then transferred via cannula onto crushed CO 2 and the resulting emulsion was stirred gently for 17 h. The slurry was taken up 0.2 M NaOH solution (150 mL) and extracted with diethyl ether (200 mL). The aqueous layer was acidified to pH=1 and then extracted with diethyl ether (3×250 mL). The combined organic layer was washed with brine (200 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give 2-bromo-6-fluoro-3-(trifluoromethyl)benzoic acid (4.62 g, 90%) as an off-white solid. ESI-MS m/z calc. 285.9253, found 287.3 (M+1) + ; Retention time (Method G): 2.53 minutes.

A solution of 2-bromo-6-fluoro-3-(trifluoromethyl)benzoic acid (8.0 g, 27.87 mmol), tert-butoxycarbonyl tert-butyl carbonate (9.1 g, 41.70 mmol), DMAP (680 mg, 5.566 mmol) and t-BuOH (8 mL) was heated at 90° C. for 1 h. The reaction mixture cooled to RT and directly purified by silica gel column chromatography using a EtOAc/hexanes eluent to give tert-butyl 2-bromo-6-fluoro-3-(trifluoromethyl)benzoate (8.1 g, 85%) as a white solid. ESI-MS m/z calc. 341.98785, found 344.8 (M+1) + ; Retention time (Method B): 2.02 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (dd, J=9.0, 5.7 Hz, 1H), 7.64 (t, J=8.6 Hz, 1H), 1.58 (s, 9H) ppm.

A solution of tert-butyl 2-bromo-6-fluoro-3-(trifluoromethyl)benzoate (1.0 g, 2.915 mmol), 3,4-difluoro-2-methoxy-phenol (700 mg, 4.372 mmol), K 2 CO 3 (806 mg, 5.832 mmol), in DMF (3 mL) was purged with nitrogen and heated at 100° C. for 1 h. The reaction mixture was cooled to RT and then directly purified by silica gel column chromatography using a EtOAc/hexanes eluent. to give tert-butyl 2-bromo-6-(3,4-difluoro-2-methoxy-phenoxy)-3-(trifluoromethyl)benzoate (1.3 g, 92%) as a clear oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J=8.9 Hz, 1H), 7.29 (q, J=9.3 Hz, 1H), 7.20-7.05 (m, 1H), 6.92 (d, J=8.9 Hz, 1H), 3.86 (s, 3H), 1.55 (s, 9H) ppm.

A solution of tert-butyl 2-bromo-6-(3,4-difluoro-2-methoxy-phenoxy)-3-(trifluoromethyl)benzoate (1.3 g, 2.690 mmol), methylboronic acid (829 mg, 13.85 mmol), Pd(dppf) 2 Cl 2 (226 mg, 0.2767 mmol), and K 2 CO 3 (1.1 g, 7.959 mmol) in dioxane (6.0 mL) and water (600 μL) was heated at 120° C. for 30 minutes. The reaction mixture was cooled to RT and then directly purified by silica gel column chromatography using a EtOAc/hexanes eluent to give tert-butyl 6-(3,4-difluoro-2-methoxy-phenoxy)-2-methyl-3-(trifluoromethyl)benzoate (1.0 g, 89%) as a clear oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J=8.9 Hz, 1H), 7.25 (q, J=9.3 Hz, 1H), 7.01 (ddd, J=9.3, 5.1, 2.2 Hz, 1H), 6.74 (d, J=8.8 Hz, 1H), 3.86 (s, 3H), 2.40 (s, 3H), 1.53 (s, 9H) ppm.

A solution of tert-butyl 6-(3,4-difluoro-2-methoxy-phenoxy)-2-methyl-3-(trifluoromethyl)benzoate (1.0 g, 2.390 mmol), TFA (27 mL, 350.5 mmol), water (1.7 mL, 94.36 mmol) and THF (5 mL) was stirred at RT for 1 h. The reaction was concentrated under vacuo and purified by silica gel column chromatography using a EtOAc/hexanes eluent to give 6-(3,4-difluoro-2-methoxy-phenoxy)-2-methyl-3-(trifluoromethyl)benzoic acid (390 mg, 45%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.75 (s, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.25 (q, J=9.3 Hz, 1H), 7.03 (ddd, J=9.5, 5.1, 2.2 Hz, 1H), 6.72 (d, J=8.9 Hz, 1H), 3.85 (s, 3H), 2.47-2.29 (m, 3H) ppm.

Step 6: 5-[[6-(3,4-Difluoro-2-Methoxy-Phenoxy)-2-Methyl-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (179)

To a solution of 6-(3,4-difluoro-2-methoxy-phenoxy)-2-methyl-3-(trifluoromethyl)benzoic acid (50 mg, 0.1380 mmol) in DCM (750 μL) was added DMF (3 μL, 0.03874 mmol) followed by the slow dropwise addition of oxalyl chloride (72 μL, 0.8254 mmol). The reaction mixture was allowed to stir at RT for 30 minutes then concentrated in vacuo. Additional DCM (1 mL) was added, and the solution again concentrated in vacuo. The remaining residue was taken up in NMP (300 μL) and added to a solution of 5-aminopyridine-2-carboxamide (32 mg, 0.2333 mmol) and DIEA (120 μL, 0.6889 mmol) in NMP (300 μL). The reaction mixture was allowed to stir at 75° C. overnight then purified by reverse phase HPLC (gradient of 10-99% acetonitrile in water containing HCl as a modifier) to give 5-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (18 mg, 24%) as a white solid. ESI-MS m/z calc. 481.1061, found 482.5 (M+1) + ; Retention time (Method I): 1.65 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.89 (d, J=2.4 Hz, 1H), 8.35 (dd, J=8.6, 2.4 Hz, 1H), 8.14-7.93 (m, 2H), 7.73 (d, J=8.9 Hz, 1H), 7.56 (s, 1H), 7.27 (q, J=9.3 Hz, 1H), 7.09 (ddd, J=9.4, 5.1, 2.1 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 3.84 (s, 3H), 2.45 (s, 3H) ppm.

The compounds set forth in Table 20 were prepared by methods analogous to the preparation of compound 179.

4-[[3-Cyclopropyl-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-2-Methyl-Benzoyl]Amino]Pyridine-2-Carboxamide (181)

To 3-bromo-6-fluoro-2-methyl-benzaldehyde (2400 mg, 11.06 mmol) and 2-methoxy-4-(trifluoromethoxy)phenol (2.19 g, 10.52 mmol) in N,N-dimethylformamide (50 mL) was added Cs 2 CO 3 (3.42 g, 10.50 mmol) under a N 2 atm. and the mixture was heated at 100° C. for 1.25 hours. After cooling to RT the mixture was diluted with ethyl acetate and wash with water, brine, dried over Na 2 SO 4 , and concentrated under reduced pressure. The residue was purified by column chromatography using a gradient of ethyl acetate in hexanes (0-15%) to yield 3-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzaldehyde (709 mg, 16%) as an off white solid. 1 H NMR (400 MHz, Chloroform-d) δ 10.68 (s, 1H), 7.58 (d, J=8.9 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.85 (d, J=9.5 Hz, 2H), 6.46 (d, J=8.9 Hz, 1H), 3.79 (s, 3H), 2.71 (s, 3H) ppm. ESI-MS m/z calc. 405.99, found 407.14 (M+1) + ; Retention time (Method A): 0.89 minutes.

To a flask charged with 3-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzaldehyde (80 mg, 0.197 mmol) and palladium tri-tert-butylphosphane (18 mg, 0.0352 mmol), under an atmosphere of N 2 at 0° C. was added THF (1 mL) followed by bromo(cyclopropyl)zinc (600 μL of 0.5 M, 0.30 mmol) in THF and the reaction mixture was gradually warmed to room temperature over 1 h. The mixture as stirred at RT for 30 minutes. The reaction mixture was quenched with 1N HCl, the aq. layer was extracted with DCM (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography using a gradient of ethyl acetate in hexanes (0-15%) to yield 3-cyclopropyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzaldehyde (69 mg, 95%) as a white solid. 1 H NMR (400 MHz, Chloroform-d) δ 10.72 (s, 1H), 7.16 (d, J=8.6 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 6.85 (d, J=2.7 Hz, 1H), 6.80 (d, J=8.9 Hz, 1H), 6.51 (d, J=8.6 Hz, 1H), 3.82 (s, 3H), 2.72 (s, 3H), 1.86 (td, J=8.1, 4.1 Hz, 1H), 1.05-0.87 (m, 2H), 0.56 (h, J=4.3 Hz, 2H) ppm. ESI-MS m/z calc. 366.108, found 367.26 (M+1) + ; Retention time (Method A): 0.85 minutes.

To a solution of 3-cyclopropyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzaldehyde (69 mg, 0.188 mmol) in tert-butyl alcohol (1 mL), acetonitrile (0.6 mL), and water (0.6 mL) was added sodium dihydrogen phosphate (26 mg, 0.217 mmol) and 2-methyl-2-butene (100 μL, 0.945 mmol) (cooled container in ice prior to syringing out). To this mixture was added sodium chlorite (22 mg, 0.243 mmol) and the reaction was stirred at RT for 1.75 h. The mixture was diluted with 1 N HCl (15 mL) and extracted with ethyl acetate (3×). The combined organics were dried over Na 2 SO 4 and concentrated under reduced pressure to give 3-cyclopropyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid (71 mg, 94%). 1 H NMR (400 MHz, Chloroform-d) δ 7.06 (d, J=8.3 Hz, 1H), 7.01 (d, J=8.6 Hz, 1H), 6.82 (d, J=9.0 Hz, 2H), 6.50 (d, J=8.6 Hz, 1H), 3.81 (s, 3H), 2.53 (s, 3H), 1.83 (td, J=9.1, 8.2, 4.6 Hz, 1H), 1.01-0.86 (m, 2H), 0.58 (t, J=5.2 Hz, 2H) ppm. ESI-MS m/z calc. 382.1028, found 383.25 (M+1) + ; Retention time (Method A): 0.74 minutes.

Step 4: 4-[[3-Cyclopropyl-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-2-Methyl-Benzoyl]Amino]Pyridine-2-Carboxamide (181)

To a solution of 3-cyclopropyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid (70 mg, 0.1831 mmol) in DCM (2 mL) cooled in an ice bath was added DMF (2 μL, 0.0258 mmol) followed by the dropwise addition of oxalyl chloride (32 μL, 0.367 mmol). The mixture was stirred at on ice for 10 minutes and then at RT for 2 h. The reaction was concentrated under reduced pressure and flushed with N 2 to afford the acid chloride, which was taken directly into the next step.

A solution of methyl 4-aminopyridine-2-carboxylate (35 mg, 0.230 mmol) and DIEA (82 μL, 0.471 mmol) in DCM (2 mL) was cooled on ice and the crude acid chloride in DCM (2 mL) was added dropwise. The ice bath was removed and the reaction mixture was stirred at RT overnight. The reaction was quenched into water and extract with DCM (3×). The combined organics were dried over Na 2 SO 4 , and concentrated under reduced pressure. The major product was isolated by silica gel column chromatography using a gradient of ethyl acetate in hexanes and was used directly in the next step. The isolated material was treated with NH 3 (10 mL of 7 M, 70.00 mmol) in methanol for 28 hours. The solvent was removed under reduced pressure to give 4-[[3-cyclopropyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide (39 mg, 40%) as an off white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.37 (d, J=2.1 Hz, 1H), 8.07 (d, J=3.1 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.62 (d, J=3.0 Hz, 1H), 7.18-7.07 (m, 2H), 7.04 (d, J=8.7 Hz, 1H), 6.98-6.87 (m, 1H), 6.48 (d, J=8.6 Hz, 1H), 3.74 (s, 3H), 2.37 (s, 3H), 1.90 (h, J=6.0 Hz, 1H), 1.00-0.85 (m, 2H), 0.57 (h, J=4.0 Hz, 2H) ppm. ESI-MS m/z calc. 501.15115, found 502.42 (M+1) + ; Retention time (Method B): 1.87 minutes.

The compounds set forth in Table 21 were prepared by methods analogous to the preparation of compound 181.

4-[[2-Ethyl-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (183)

K 2 CO 3 (6.3 g, 45.58 mmol) was added to a completely soluble solution of tert-butyl 2-bromo-6-fluoro-3-(trifluoromethyl)benzoate (7.7 g, 22.44 mmol) and 2-methoxy-4-(trifluoromethoxy)phenol (4.8 g, 23.06 mmol) in DMSO (27.0 mL). The mixture was heated at 100° C. for 1.25 hours and then cooled to RT. To the mixture was added heptane (58 mL) and water (38 mL). The layers were separated and the organic layer was washed with water, dried over MgSO4, concentrated under reduced pressure to give tert-butyl 2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate (12.19 g, 102%). 1 H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J=8.9 Hz, 1H), 7.32-7.22 (m, 2H), 7.07-6.98 (m, 1H), 6.83 (d, J=8.9 Hz, 1H), 3.81 (s, 3H), 1.53 (s, 9H) ppm.

tert-Butyl 2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate (1.00 g, 1.88 mmol) and vinylboronic acid (203 mg, 2.82 mmol) were combined and dissolved in DMSO (10 mL). Aqueous potassium carbonate (2.8 mL of 2 M, 5.600 mmol) was added followed by ferrous; cyclopenta-1,4-dien-1-yl(diphenyl)phosphane; dichloromethane; dichloropalladium (77 mg, 0.0943 mmol). The reaction mixture was stirred at 75° C. for 1 hour. The reaction mixture was diluted with EtOAc (75 mL) and washed with water (1×75 mL) and brine (1×75 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column eluting with a EtOAc/hexane gradient to give tert-butyl 6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)-2-vinyl-benzoate (644 mg, 72%) as a clear colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J=8.8 Hz, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 7.00 (d, J=9.7 Hz, 1H), 6.91-6.83 (m, 1H), 6.76 (d, J=8.8 Hz, 1H), 5.64 (d, J=11.6 Hz, 1H), 5.56 (d, J=17.6 Hz, 1H), 1.53 (s, 3H), 1.45 (s, 9H) ppm. ESI-MS m/z calc. 478.1215, found 423.1 (M−55)+; Retention time (Method B): 2.37 minutes

tert-Butyl 6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)-2-vinyl-benzoate (644 mg, 1.346 mmol) was dissolved in ethanol (15 mL) and the reaction was flushed with N 2 . Palladium (32 mg, 0.3007 mmol) (10 wt % on carbon, wet, degussa) was added. The reaction mixture was allowed to stir under an atmosphere of hydrogen gas overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column eluting with a 0-10% EtOAc/hexane gradient to give tert-butyl 2-ethyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate (522 mg, 81%) as a clear colorless oil. ESI-MS m/z calc. 480.13715, found 407.1 (M−73)+; Retention time (Method B): 2.46 minutes.

tert-Butyl 2-ethyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate (544 mg, 1.132 mmol) was dissolved into a prepared solution of TFA (1 mL, 12.98 mmol) in DCM (2 mL). The reaction mixture was allowed to stir at room temperature for 30 minutes. The reaction mixture was diluted with EtOAc (75 mL) and washed with water (1×75 mL) and brine (1×75 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC eluting with a 35-99% acetonitrile/water (0.5 mM HC 1) gradient to give 2-ethyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoic acid (297 mg, 62%) as a white sticky foam. 1 H NMR (400 MHz, DMSO-d6) δ 13.67 (s, 1H), 7.64 (d, J=8.9 Hz, 1H), 7.25 (d, J=2.7 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.05-6.97 (m, 1H), 6.60 (d, J=8.9 Hz, 1H), 3.80 (s, 3H), 2.78 (q, J=7.5 Hz, 2H), 1.22 (t, J=7.5 Hz, 3H) ppm.

Step 5: 4-[[2-Ethyl-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (183)

2-Ethyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoic acid (43 mg, 0.101 mmol) was dissolved in dichloromethane (0.5 mL). DMF (approximately 0.37 mg, 0.39 μL, 0.0051 mmol) was added followed by the slow dropwise addition of oxalyl chloride (approximately 35 μL, 0.405 mmol). The reaction mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. Additional dichloromethane (˜5 mL) was added, and the solution was again concentrated to dryness. The remaining residue was taken up in NMP (0.5 mL) and added to a mixture of 4-aminopyridine-2-carboxamide (approximately 21 mg, 0.152 mmol) and DIEA (approximately 106 μL, 0.608 mmol). The reaction mixture was allowed to stir at 70° C. overnight. The product was isolated by reverse-phase HPLC eluting with a 30-99% acetonitrile/water (5 mM HCl) gradient to give 4-[[2-ethyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (16.3 mg, 28%). 1 H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.39 (d, J=2.2 Hz, 1H), 8.16-8.07 (m, 1H), 7.86 (dd, J=5.6, 2.1 Hz, 1H), 7.72 (d, J=8.9 Hz, 1H), 7.66 (s, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.24 (d, J=2.6 Hz, 1H), 7.04 (d, J=9.1 Hz, 1H), 6.65 (d, J=8.9 Hz, 1H), 3.78 (s, 3H), 2.81 (q, J=7.5 Hz, 2H), 1.23 (t, J=7.4 Hz, 3H) ppm. ESI-MS m/z calc. 543.12286, found 544.2 (M+1) + ; Retention time (Method B): 1.88 minutes.

The compounds set forth in Table 22 were prepared by methods analogous to the preparation of compound 183.

4-[[3-Isobutyl-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-2-Methyl-Benzoyl]Amino]Pyridine-2-Carboxamide (185)

To a flask charged with 3-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzaldehyde (250 mg, 0.617 mmol) and palladium tri-tert-butylphosphane (56 mg, 0.11 mmol), under an atmosphere of N 2 at 0° C. was added THF (3 mL) followed by bromo(tert-butyl)zinc (1.9 mL of 0.5 M, 0.950 mmol) in THF and the reaction mixture was gradually warmed to room temperature over 1 h. The reaction mixture was quenched with 1N HCl, the aq. layer was extracted with DCM (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography using a gradient of ethyl acetate in hexanes to yield 3-isobutyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzaldehyde (65 mg, 22%). 1 H NMR (400 MHz, Chloroform-d) δ 10.73 (d, J=5.6 Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 6.89-6.84 (m, 1H), 6.84-6.78 (m, 1H), 6.53 (d, J=8.3 Hz, 1H), 3.82 (s, 3H), 2.55 (s, 3H), 2.50 (d, J=7.8 Hz, 2H), 1.81 (hept, J=6.7 Hz, 1H), 0.91 (d, J=6.6 Hz, 6H) ppm. ESI-MS m/z calc. 382.1392, found 383.29 (M+1) + ; Retention time (Method A): 0.94 minutes.

To a solution of 3-tert-butyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzaldehyde (60 mg, 0.126 mmol) in tert-butyl alcohol (1 mL), acetonitrile (0.5 mL), and water (0.5 mL) was added sodium dihydrogen phosphate (22 mg, 0.183 mmol) and 2-methyl-2-butene (83 μL, 0.785 mmol). To this mixture was added sodium chlorite (19 mg, 0.210 mmol) and the reaction was stirred at RT for 1.75 h. The mixture was diluted with 1 N HCl (15 mL) and extracted with ethyl acetate (3×). The combined organics were dried over Na 2 SO 4 and concentrated under reduced pressure to give 3-isobutyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid (63 mg, 101%). ESI-MS m/z calc. 398.1341, found 399.29 (M+1) + ; Retention time (Method A): 0.84 minutes.

Step 3: 4-[[3-Isobutyl-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-2-Methyl-Benzoyl]Amino]Pyridine-2-Carboxamide (185)

To a solution of 3-isobutyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid (60 mg, 0.121 mmol) in DCM (2 mL) cooled in an ice bath was added DMF (2 μL, 0.02583 mmol) followed by the dropwise addition of oxalyl chloride (26 μL, 0.298 mmol). The mixture was stirred on ice for 10 mins then at RT for 1.5 h. The reaction was concentrated under reduced pressure and flushed with N 2 to afford the acid chloride, which was taken directly into the next step.

A solution of methyl 4-aminopyridine-2-carboxylate (46 mg, 0.302 mmol) and DIEA (67 μL, 0.385 mmol) in DCM (2 mL) was cooled on ice and the crude acid chloride in DCM (2 mL) was added dropwise. The ice bath was removed and the reaction mixture was stirred at RT overnight. The reaction was quenched into water and extract with DCM (3×). The combined organics were dried over Na 2 SO 4 , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of ethyl acetate in hexanes and was used directly in the next step. The isolated material was treated with NH 3 (7 mL of 7 M, 49.00 mmol) in methanol for 28 hours. The solvent was removed under reduced pressure and the residue as purified by medium pressure C 18 reverse phase chromatography (acetonitrile, water (5 mMHCl) gradient) to give 4-[[3-isobutyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide (6 mg, 10%). 1 H NMR (400 MHz, Chloroform-d) δ 9.55 (s, 1H), 9.08 (s, 1H), 8.71 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.11 (s, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.88 (d, J=8.5 Hz, 2H), 6.52 (d, J=8.5 Hz, 1H), 5.81 (s, 1H), 3.88 (s, 3H), 2.49 (d, J=7.1 Hz, 2H), 2.40 (s, 3H), 1.83 (p, J=6.5 Hz, 1H), 0.92 (d, J=6.5 Hz, 6H) ppm. ESI-MS m/z calc. 517.18243, found 518.45 (M+1) + ; Retention time (Method B): 2.06 minutes.

4-[[2-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-6-Methyl-4-(Trifluoromethyl)Benzoyl]Amino]-5-Methyl-Pyridine-2-Carboxamide (186)

To a solution of 2-bromo-6-fluoro-4-(trifluoromethyl)benzoic acid (15 g, 49.65 mmol) in tert-butanol (285 mL) was added DMAP (607 mg, 4.919 mmol) followed by tert-butoxycarbonyl tert-butyl carbonate (21.7 g, 96.45 mmol) at room temperature. The reaction mixture was stirred at 40° C. overnight. The mixture was cooled to RT and concentrated under reduced pressure. The residue was triturated with 50 mL of hexanes and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl 2-bromo-6-fluoro-4-(trifluoromethyl)benzoate (14.94 g, 88%) as a pale yellow oil, which was used in next step without purification. 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.95 (d, J=9.0 Hz, 1H), 1.57 (s, 9H) ppm.

A mixture of tert-butyl 2-bromo-6-fluoro-4-(trifluoromethyl)benzoate (2.97 g, 8.66 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (2.4 g, 11.53 mmol) and potassium carbonate (2.4 g, 17.37 mmol) in DMSO (12 mL) was heated at 100° C. for 1 h. The reaction mixture was allowed to cool to RT, was poured onto 50 mL of water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography eluting with gradient of EtOAc and hexanes to give tert-butyl 2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoate (4.10 g, 89%). 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.25 (d, J=2.8 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 7.06 (s, 1H), 7.04-6.93 (m, 1H), 3.81 (s, 3H), 1.48 (s, 9H) ppm.

A mixture of tert-butyl 2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoate (1 g, 1.882 mmol), methylboronic acid (740 mg, 12.11 mmol), potassium carbonate (838 mg, 5.942 mmol) and ferrous; cyclopenta-1,4-dien-1-yl(diphenyl)phosphane dichloromethane dichloropalladium (154 mg, 0.1886 mmol) in dioxane (6 mL)/water (600 μL) was flushed with nitrogen, capped and heated at 120° C. for 30 minutes in an oil bath. The reaction mixture was allowed to cool to room temperature and was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, filtered, and concentrated reduced pressure. The residue was purified by silica column chromatography eluting with a EtOAc/hexanes gradient to giving tert-butyl 2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethyl)benzoate (693 mg, 79%). 1 H NMR (400 MHz, DMSO-d6) δ 7.46 (s, 1H), 7.22 (d, J=2.6 Hz, 1H), 7.04-6.89 (m, 3H), 3.81 (s, 3H), 2.38 (s, 3H), 1.43 (s, 9H) ppm.

tert-Butyl 2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethyl)benzoate (693 mg, 1.49 mmol) was dissolved in a solution of TFA (2 mL, 25.96 mmol) in DCM (6 mL). The mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure to give 2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethyl)benzoic acid (610 mg, 79%), which was used directly in the next step. ESI-MS m/z calc. 410.0589, found 411.3 (M+1) + ; Retention time (Method B): 1.87 minutes.

To a solution of 2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethyl)benzoic acid (500 mg, 1.219 mmol), DMF (26 μL, 0.3358 mmol) and DCM (8 mL) at 0° C. under N 2 (g) was added oxalyl chloride (855 μL, 9.801 mmol). The reaction was stirred at 0° C. for 10 min and then at RT for 1 h. The reaction was concentrated under reduced pressure and the residue was used directly in the next step.

Step 6: Methyl 4-[[2-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-6-Methyl-4-(Trifluoromethyl)Benzoyl]Amino]-5-Methyl-Pyridine-2-Carboxylate

In a vial was combined methyl 4-amino-5-methylpicolinate, DIEA (61 μL) and NMP (400 μL). The mixture was cooled in ice bath and a solution of 2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethyl)benzoyl chloride (50 mg) in NMP (200 μL) was added drop wise. The resulting mixture was stirred at RT for 16 h. The reaction was purified directly by reverse phase HPLC (C-18 Column and gradient system of 1-99% ACN/H2O with 5 mM HCl modifier) giving methyl 4-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate (11 mg, 17%). ESI-MS m/z calc. 558.12256, found 559.3 (M+1) + ; Retention time (Method B): 1.6 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.57 (d, J=7.2 Hz, 2H), 7.50 (d, J=1.6 Hz, 1H), 7.29-7.19 (m, 2H), 7.02 (ddd, J=8.9, 2.8, 1.3 Hz, 1H), 6.78 (s, 1H), 3.89 (s, 3H), 3.79 (s, 3H), 2.47 (s, 3H), 2.31 (s, 3H) ppm.

Step 7: 4-[[2-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-6-Methyl-4-(Trifluoromethyl)Benzoyl]Amino]-5-Methyl-Pyridine-2-Carboxamide (186)

A vial containing methyl 4-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate (10 mg, 0.0179 mmol) was treated with ammonia in methanol (500 μL of 7 M, 3.50 mmol). The solution was stirred at RT for 18 h. Solvent was evaporated and the residue was purified by reverse phase LC-MS on C-18 column with gradient of 1-99% ACN/H 2 O (5 mM HCl) to give 4-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide (6.0 mg, 62%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.46 (d, J=5.7 Hz, 2H), 8.07 (s, 1H), 7.61 (s, 1H), 7.50 (s, 1H), 7.30-7.20 (m, 2H), 7.06-6.99 (m, 1H), 6.77 (s, 1H), 3.80 (s, 3H), 2.48 (s, 3H), 2.29 (s, 3H) ppm. ESI-MS m/z calc. 543.12286, found 544.2 (M+1) + ; Retention time (Method B): 1.35 minutes.

The compounds set forth in Table 23 were prepared by methods analogous to the preparation of compound 186.

4-[[2-(3,4-Difluoro-2-Methoxy-Phenoxy)-6-Methyl-4-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (189)

A mixture of tert-butyl 2-bromo-6-fluoro-4-(trifluoromethyl)benzoate (5 g, 14.57 mmol), 3,4-difluoro-2-methoxy-phenol (3.03 g, 18.92 mmol) and potassium carbonate (4.03 g, 29.16 mmol) in DMSO (20 mL) was heated at 100° C. for 1 h. The reaction mixture was cooled to RT, poured onto 50 mL of water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in under reduced pressure. The residue was purified by silica chromatography on eluting with gradient of EtOAc/hexanes to give tert-butyl 2-bromo-6-(3,4-difluoro-2-methoxy-phenoxy)-4-(trifluoromethyl)benzoate (5.74 g, 82%) as an oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.24 (q, J=9.3 Hz, 1H), 7.16 (s, 1H), 7.02 (ddd, J=9.4, 5.1, 2.3 Hz, 1H), 3.87 (s, 3H), 1.51 (s, 9H) ppm.

A mixture of tert-butyl 2-bromo-6-(3,4-difluoro-2-methoxy-phenoxy)-4-(trifluoromethyl)benzoate (1 g, 2.069 mmol), methylboronic acid (815 mg, 13.34 mmol), potassium carbonate (921 mg, 6.53 mmol) and ferrous; cyclopenta-1,4-dien-1-yl(diphenyl)phosphane; dichloromethane; dichloropalladium (170 mg, 0.208 mmol) in dioxane (6 mL) and water (600 μL) was flushed with nitrogen, capped and heated at 120° C. for 30 minutes in oil bath. The reaction mixture was allowed to cool to room temperature and diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, filtered, and concentrated under reduced pressure. The residue was then purified by silica column chromatography eluting with a EtOAc/hexanes gradient to give tert-butyl 2-(3,4-difluoro-2-methoxy-phenoxy)-6-methyl-4-(trifluoromethyl)benzoate (388 mg, 45%) as clear colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.48 (s, 1H), 7.21 (q, J=9.3 Hz, 1H), 6.96 (s, 1H), 6.93-6.84 (m, 1H), 3.87 (s, 3H), 2.40 (d, J=3.7 Hz, 3H), 1.48 (s, 9H) ppm.

tert-butyl 2-(3,4-difluoro-2-methoxy-phenoxy)-6-methyl-4-(trifluoromethyl)benzoate (388 mg, 0.93 mmol) was dissolved in a solution of TFA (2 mL, 25.96 mmol) in DCM (6 mL). The mixture was stirred at RT for 16 h. The mixture was concentrated under reduced pressure to give a thick oil. The oil was titurated with hexanes to give 2-(3,4-difluoro-2-methoxy-phenoxy)-6-methyl-4-(trifluoromethyl)benzoic acid (204 mg, 27%) as a white solid. ESI-MS m/z calc. 362.05774, found 363.1 (M+1) + ; Retention time (Method B): 1.78 minutes.

Step 4: 4-[[2-(3,4-Difluoro-2-Methoxy-Phenoxy)-6-Methyl-4-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (189)

A solution of 2-(3,4-difluoro-2-methoxy-phenoxy)-6-methyl-4-(trifluoromethyl)benzoic acid (25 mg, 0.06901 mmol) in DCM (75.00 μL) was treated with DMF (approximately 5 μL, 0.069 mmol), and the mixture was cooled in an ice bath. To this solution was added oxalyl chloride (approximately 18 μL, 0.207 mmol) dropwise. The resulting mixture was stirred in an ice bath for 10 min, and then allowed to stir at RT for 1 h. The mixture was concentrated to dryness under vacuum to give a light yellow solid which was used directly in the next step.

The acid chloride intermediate was dissolved in NMP (300 μL) and added dropwise to a cooled solution of 4-aminopyridine-2-carboxamide (approximately 19 mg, 0.138 mmol) and DIEA (approximately 36 μL, 0.207 mmol) in NMP (250 μL). The reaction mixture was stirred at RT for 16 h. The mixture was filtered and purified by reverse phase HPLC on C-18 column eluting with gradient 1-99% ACN/H 2 O (5 mM HCl) to give 4-[[2-(3,4-difluoro-2-methoxy-phenoxy)-6-methyl-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (17 mg, 50%) as a white solid. ESI-MS m/z calc. 481.1061, found 482.2 (M+1) + ; Retention time (Method B): 1.66 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 8.54 (d, J=5.4 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H), 8.12-8.07 (m, 1H), 7.86-7.80 (m, 1H), 7.65 (s, 1H), 7.53 (s, 1H), 7.24 (q, J=9.3 Hz, 1H), 7.03 (s, 1H), 6.93 (s, 1H), 3.82 (s, 3H), 2.43 (s, 3H) ppm.

5-[[6-(2-Chloro-4-Fluoro-Phenoxy)-2-Methyl-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (190)

A stirring mixture of tert-butyl 2-bromo-6-fluoro-3-(trifluoromethyl)benzoate (1.0 g, 2.91 mmol), 2-chloro-4-fluoro-phenol (493 mg, 3.364 mmol), K 2 CO 3 (800 mg, 5.788 mmol), and DMSO (4 mL) was heated at 100° C. for 1 hour. The reaction mixture was cooled to RT and was then directly purified by silica gel column chromatography using a gradient of EtOAc in hexanes to give tert-butyl 2-bromo-6-(2-chloro-4-fluoro-phenoxy)-3-(trifluoromethyl)benzoate (1.3 g, 95%) as a clear oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J=8.9 Hz, 1H), 7.72 (dd, J=8.4, 2.9 Hz, 1H), 7.52-7.23 (m, 2H), 6.92 (d, J=8.9 Hz, 1H), 1.53 (s, 9H) ppm.

To a stirring solution of tert-butyl 2-bromo-6-(2-chloro-4-fluoro-phenoxy)-3-(trifluoromethyl)benzoate (800 mg, 1.703 mmol), Pd(dppf)C 12 (16 mg, 0.02187 mmol), and 1,4-dioxane (8 mL), under nitrogen, was added dimethylzinc (450 μL, 3.393 mmol). The reaction mixture was heated at 100° C. for 2 hours. The cooled reaction was directly purified by silica gel column chromatography using a gradient of 1-100% EtOAc in hexanes to give tert-butyl 6-(2-chloro-4-fluoro-phenoxy)-2-methyl-3-(trifluoromethyl)benzoate (450 mg, 65%) as a clear oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.76-7.64 (m, 2H), 7.35-7.22 (m, 2H), 6.77 (d, J=8.8 Hz, 1H), 2.40 (s, 3H), 1.50 (s, 9H) ppm.

A solution of tert-butyl 6-(2-chloro-4-fluoro-phenoxy)-2-methyl-3-(trifluoromethyl)benzoate (400 mg, 0.9882 mmol), TFA (11.4 mL, 148.0 mmol), water (700 μL, 38.86 mmol), and THF (400 μL), was stirred at room temperature for 1 hour. The solution was evaporated to dryness under reduced pressure and the residue was diluted with DMSO (500 uL), filtered, and purified by reverse phase preparative chromatography using a C 18 column and a gradient eluent of 1 to 99% acetonitrile in water (5 mM HCl) to give 6-(2-chloro-4-fluoro-phenoxy)-2-methyl-3-(trifluoromethyl)benzoic acid (180 mg, 34%) as a clear oil. ESI-MS m/z calc. 348.01764, found 351.0 (M+1) + ; Retention time (Method B): 1.87 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 14.12-13.25 (m, 1H), 7.68 (dd, J=8.8, 5.7 Hz, 2H), 7.45-7.17 (m, 2H), 6.66 (d, J=8.8 Hz, 1H), 2.41 (s, 3H) ppm.

Step 4: 5-[[6-(2-Chloro-4-Fluoro-Phenoxy)-2-Methyl-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (190)

6-(2-Chloro-4-fluoro-phenoxy)-2-methyl-3-(trifluoromethyl)benzoic acid (25 mg, 0.0717 mmol) was dissolved in dichloromethane (375 μL). DMF (2 μL, 0.0258 mmol) was added followed by the slow dropwise addition of oxalyl chloride (40 μL, 0.4585 mmol). The reaction mixture was allowed to stir at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. Additional dichloromethane (˜1 mL) was added, and the solution was again concentrated to dryness. The remaining residue was taken up in NMP (150 μL) and added to a prepared solution of 5-aminopyridine-2-carboxamide (17 mg, 0.124 mmol) and DIEA (62 μL, 0.356 mmol) in NMP (150 μL). This reaction mixture was allowed to stir at 75° C. overnight. The reaction was diluted with DMSO (500 uL), filtered, and purified by reverse phase preparative chromatography using a C 18 column and a gradient eluent of 1 to 99% acetonitrile in water (5 mM HCl) to give 5-[[6-(2-chloro-4-fluoro-phenoxy)-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (16 mg, 47%) as a white solid. ESI-MS m/z calc. 467.06598, found 468.0 (M+1) + ; Retention time (Method B): 1.65 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 8.88 (d, J=2.4 Hz, 1H), 8.33 (dd, J=8.6, 2.4 Hz, 1H), 8.06 (d, J=8.6 Hz, 1H), 8.04-7.97 (m, 1H), 7.75 (d, J=8.9 Hz, 1H), 7.67 (dd, J=8.4, 2.9 Hz, 1H), 7.61-7.49 (m, 1H), 7.41 (dd, J=9.1, 5.3 Hz, 1H), 7.35 (td, J=8.5, 2.8 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 2.46 (s, 3H) ppm.

4-[[2-Chloro-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (191)

2-Chloro-6-fluoro-3-(trifluoromethyl)benzoic acid (900 mg, 3.710 mmol) was dissolved in dichloromethane (13 mL). DMF (125 μL, 1.614 mmol) was added followed by the slow dropwise addition of oxalyl chloride (2.5 mL, 28.66 mmol). The reaction mixture was allowed to stir at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. Additional dichloromethane (˜5 mL) was added, and the solution was again concentrated to dryness. The remaining residue was taken up in NMP (2.7 mL) and added to a prepared solution of 4-aminopyridine-2-carboxamide (833 mg, 6.074 mmol) and DIEA (4.2 mL, 24.11 mmol) in NMP (2.7 mL). This reaction mixture was allowed to stir at 25° C. overnight. The reaction mixture was diluted with EtOAc (75 mL) and washed with water (2×75 mL), aqueous HCl (2×75 mL, 0.5 M) and brine (2×75 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column eluting with a EtOAc/hexane gradient to provide 4-[[2-chloro-6-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (430 mg, 32%) as a white solid. ESI-MS m/z calc. 361.0241, found 362.1 (M+1) + ; Retention time (Method B): 1.25 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 8.59 (d, J=5.4 Hz, 1H), 8.34 (d, J=2.2 Hz, 1H), 8.22-8.05 (m, 2H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.77-7.59 (m, 2H) ppm.

Step 2: 4-[[2-Chloro-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (191)

A mixture of 4-[[2-chloro-6-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (30 mg, 0.0829 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (56 mg, 0.269 mmol), K 2 CO 3 (36 mg, 0.261 mmol), and DMSO (150 μL) was stirred at 120° C. for 30 minutes. The reaction was diluted with DMSO (500 uL), filtered, and purified by reverse phase preparative chromatography using a C 18 column and a gradient eluent of 1 to 99% acetonitrile in water (5 mM hydrochloric acid) to give 4-[[2-chloro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (29 mg, 61%) as a white solid. ESI-MS m/z calc. 549.0526, found 550.0 (M+1) + ; Retention time (Method B): 1.78 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 8.38 (d, J=2.1 Hz, 1H), 8.29-8.07 (m, 1H), 8.03-7.81 (m, 2H), 7.81-7.60 (m, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.27 (d, J=2.7 Hz, 1H), 7.05 (ddq, J=8.8, 2.5, 1.2 Hz, 1H), 6.81 (d, J=8.9 Hz, 1H), 3.80 (s, 3H) ppm.

The compounds set forth in Table 24 were prepared by methods analogous to the preparation of compound 191.

4-[[2-Bromo-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (194)

To a solution of 2-bromo-6-fluoro-3-(trifluoromethyl)benzoic acid (25 g, 87.106 mmol) in anhydrous pyridine (800 mL) (dried over CaH 2 for 18 h) was added methyl 4-aminopyridine-2-carboxylate (13.87 g, 91.159 mmol). The mixture was cooled to −14° C. and POCl 3 (8.4 mL, 90.119 mmol) was added dropwise. The reaction was stirred at −14° C. to −10° C. for 30 minutes then warmed to RT and stirred for 3 h. The reaction was quenched with water (800 mL), extracted with EtOAc (2×1.2 L), and the combined organic layers were washed with water (3×500 mL), brine, dried over MgSO 4 , filtered and concentrated under reduced pressure to provide methyl 4-[[2-bromo-6-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate (26.47 g, 72%) as an amber oil. ESI-MS m/z calc. 419.9733, found 421.0 (M+1) + ; Retention time (Method H): 4.31 minutes. This material was used directly in the next step without further purification.

To a solution of methyl 4-[[2-bromo-6-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate (26.47 g, 62.85 mmol) in CH 3 CN (312 mL) was added NH 4 Cl (1.18 g, 22.06 mmol) and NH 4 OH (334 mL of 28% w/v, 2.669 mol) and the reaction was stirred at RT for 5 h. Reaction mixture was diluted with EtOAc (1 L) and washed with water (350 mL×2), brine, dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using an EtOAc (containing 2% of 7N NH 3 /MeOH)/hexanes gradient) to provide 8.69 g of product as a sticky off-white foam. An additional 5 g of product containing fractions contaminated with an impurity were re-purified by silica gel chromatography using an EtOAc (containing 2% of 7N NH 3 /MeOH)—hexanes gradient and the purified samples were combined to give 4-[[2-bromo-6-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (12.699 g, 49%). ESI-MS m/z calc. 404.9736, found 406.8 (M+1) + ; Retention time (Method H): 4.18 minutes.

Step 3: 4-[[2-Bromo-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (194)

4-[[2-bromo-6-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (250 mg, 0.616 mmol) and 2-methoxy-4-(trifluoromethoxy)phenol (141 mg, 0.677 mmol) were combined and dissolved in DMSO (0.5 mL). Solid potassium carbonate (255 mg, 1.845 mmol) was added. The reaction mixture was allowed to stir overnight at 75° C. The reaction mixture was filtered purified by silica gel chromatography using a EtOAc/hexane gradient to give 4-[[2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (325 mg, 82%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.36 (d, J=2.1 Hz, 1H), 8.10 (d, J=2.9 Hz, 1H), 7.88-7.82 (m, 2H), 7.66 (d, J=2.9 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.26 (d, J=2.7 Hz, 1H), 7.04 (ddq, J=8.8, 2.4, 1.2 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 3.80 (s, 3H) ppm. ESI-MS m/z calc. 593.0021, found 596.1 (M+3)+; Retention time (Method B): 1.52 minutes.

The compounds set forth in Table 25 were prepared by methods analogous to the preparation of compound 194.

4-[[3-Cyclopropyl-6-[3-Fluoro-2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-2-Methyl-Benzoyl]Amino]Pyridine-2-Carboxamide (196)

A solution of 3-bromo-2-methyl-benzoic acid (5000 mg, 23.25 mmol), Pd(OAc) 2 (262 mg, 1.166 mmol), I 2 (7.67 g, 30.22 mmol), and PhI(OAc) 2 (9.74 g, 30.22 mmol) in DMF (130 mL) was heated at 100° C. for 16 hours. The mixture was cooled to RT and the DMF was removed under reduced pressure. To the residue was added DCM and sat. Na 2 S 2 O 3 and the mixture as stirred for 15 minutes. To the mixture was added 1N HCl until the pH was <3 and the layers were separated. The aqueous layer was extracted with DCM (3×) and the combined organics were washed with a mixture of sat. Na 2 SO 3 and 1 N HCl. The organic phase was dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by medium pressure reverse phase chromatography (C 18 , CH 3 CN/water (5 mM HCl)) to give 3-bromo-6-iodo-2-methyl-benzoic acid (5.43 g, 69%) as a white solid. 1 H NMR (400 MHz, Chloroform-d) δ 7.60-7.47 (m, 1H), 7.33 (dd, J=8.5, 1.8 Hz, 1H), 2.49 (s, 3H) ppm.

To a solution of 6-bromo-2-fluoro-3-(trifluoromethoxy)phenol (10 g, 36.36 mmol) in DMF (20 mL) was added K 2 CO 3 (6.5 g, 47.03 mmol) and iodomethane (4.1 mL, 65.86 mmol) and the mixture heated to 50° C. for 2 h. The reaction mixture was allowed to cool down, filtered, concentrated under reduced pressure and the residue was partitioned between diethyl ether (30 ml) and water (30 ml). The aqueous layer was further extracted with diethyl ether (10 mL). Combined organic fractions were washed with brine, dried over magnesium sulfate and concentrated under reduce pressure to an oil. The product was purified by silica gel chromatography eluting with 100% petroleum ether to give 1-bromo-3-fluoro-2-methoxy-4-(trifluoromethoxy)benzene (8.1 g, 77%) as an oil. 1 H NMR (400 MHz, Chloroform-d) δ 7.34 (dd, J=9.0, 2.4 Hz, 1H), 6.95 (ddq, J=8.5, 7.2, 1.2 Hz, 1H), 4.01 (d, J=1.7 Hz, 3H) ppm.

To a solution of 1-bromo-3-fluoro-2-methoxy-4-(trifluoromethoxy)benzene (7 g, 24.22 mmol) in dioxane (84 mL) was added (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one palladium (554 mg, 0.6050 mmol), di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (709 mg, 1.670 mmol) and KOH (2.8 g, 49.91 mmol) followed by water (56 mL) and the mixture heated to 90° C. for 5 hours. The reaction mixture was allowed to cool to RT, filtered and partitioned between diethyl ether (30 ml) and water (100 ml). The aqueous fraction was separated and was acidified to ˜ pH 1 with 2M HCl and extracted twice with diethyl ether (2×50 ml). The combined organics where dried (MgSO 4 ) and concentrated under reduced pressure to afford 3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (3.6 g, 66%). 1 H NMR (400 MHz, Chloroform-d) δ 6.91 (ddq, J=9.1, 7.8, 1.2 Hz, 1H), 6.70 (dd, J=9.1, 2.2 Hz, 1H), 5.92 (s, 1H), 4.04 (d, J=2.0 Hz, 3H) ppm.

To a pressure flask was added 3-bromo-6-iodo-2-methyl-benzoic acid (1000 mg, 2.933 mmol), 3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (530 mg, 2.344 mmol), cesium carbonate (1.2 g, 3.683 mmol), toluene (5.3 mL) and a stir bar. The reaction mixture was bubbled with nitrogen for 10 minutes, then copper (I) iodide (446 mg, 2.342 mmol) was added. The flask was flushed with nitrogen, capped, and heated at 100° C. with vigorous stirring for 16 hours. The mixture was allowed to cool, then diluted with ethyl acetate and water. The water layer was acidified with 1 M HCl and the product extracted into ethyl acetate. The biphasic mixture was filtered and the layers separated. The organic layer was washed with brine, dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of MeOH in dichloromethane to give 3-bromo-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid (453 mg, 44%) as a light yellow oil. ESI-MS m/z calc. 437.9726, found 439.0 (M+1) + ; Retention time (Method B): 1.55 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 13.66 (s, 1H), 7.63 (d, J=8.9 Hz, 1H), 7.30 (ddq, J=9.5, 8.4, 1.2 Hz, 1H), 6.87 (dd, J=9.3, 2.2 Hz, 1H), 6.78 (dd, J=8.8, 0.7 Hz, 1H), 3.89 (s, 3H), 2.36 (s, 3H) ppm.

A mixture of 3-bromo-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid (900 mg, 2.049 mmol), di-tert-butyl dicarbonate (670 mg, 3.070 mmol), DMAP (50 mg, 0.4093 mmol), and tert-BuOH (900 μL), was heated at 90° C. for 2 hours. The reaction mixture was directly purified by silica gel column chromatography using a gradient of EtOAc in hexanes to give tert-butyl 3-bromo-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate (340 mg, 34%) as a clear oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J=8.8 Hz, 1H), 7.35-7.20 (m, 1H), 6.85 (dd, J=8.8, 0.7 Hz, 1H), 6.78 (dd, J=9.4, 2.2 Hz, 1H), 3.90 (d, J=0.8 Hz, 3H), 2.34 (s, 3H), 1.41 (s, 9H) ppm.

Step 6: Tert-Butyl 3-Cyclopropyl-6-[3-Fluoro-2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-2-Methyl-Benzoate

To a vial charged with tert-butyl 3-bromo-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate (140 mg, 0.2827 mmol), palladium tritert-butylphosphane (approximately 7 mg, 0.0141 mmol), and THF (1 mL) under an atmosphere of N 2 at 0° C. was added bromo(cyclopropyl)zinc (approximately 735 μL of 0.5 M, 0.367 mmol) in THF slowly and the reaction mixture was gradually warmed to room temperature over 1 h and stirred at RT for 15 minutes. The reaction mixture was quenched with 1N HCl, and the aq. layer was extracted with DCM (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography using a gradient of ethyl acetate in hexanes to yield tert-butyl 3-cyclopropyl-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate (104 mg, 81%). 1 H NMR (400 MHz, Chloroform-d) δ 7.00 (d, J=8.5 Hz, 1H), 6.89 (ddq, J=9.1, 7.9, 1.2 Hz, 1H), 6.62 (d, J=8.5 Hz, 1H), 6.59 (dd, J=9.3, 2.3 Hz, 1H), 3.98 (d, J=0.8 Hz, 3H), 2.43 (s, 3H), 1.84 (tt, J=8.5, 5.4 Hz, 1H), 1.47 (s, 9H), 1.02-0.87 (m, 2H), 0.67-0.53 (m, 2H) ppm.

To a solution of tert-butyl 3-cyclopropyl-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate (105 mg, 0.230 mmol) in THF (0.75 mL) and water (165 μL, 9.203 mmol) cooled on ice was added TFA (2.65 mL, 34.50 mmol) over approximately 4 minutes dropwise. The ice bath was removed and the solution was stirred at RT for 1 h. The stir bar was removed and the mixture was concentrated under reduced pressure to give 3-cyclopropyl-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid (89 mg, 92%). ESI-MS m/z calc. 400.09338, found 401.23 (M+1) + ; Retention time (Method A): 0.81 minutes.

Step 8: 4-[[3-Cyclopropyl-6-[3-Fluoro-2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-2-Methyl-Benzoyl]Amino]Pyridine-2-Carboxamide (196)

To a solution of 3-cyclopropyl-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid (88 mg, 0.209 mmol) in DCM (2.5 mL) cooled in an ice bath was added DMF (approximately 2 μL, 0.0295 mmol) followed by the dropwise addition of oxalyl chloride (approximately 36 μL, 0.418 mmol). The mixture was stirred at on ice for 10 minutes then at RT for 2 h. The reaction was concentrated under reduced pressure and flushed with N 2 to afford the acid chloride, which was taken directly into the next step.

A solution of methyl 4-aminopyridine-2-carboxylate (approximately 79 mg, 0.522 mmol) and DIEA (93 μL, 0.537 mmol) in DCM (2.5 mL) was cooled on ice and the crude acid chloride in DCM (2.5 mL) was added dropwise. The ice bath was removed and the reaction mixture was stirred at RT overnight, and then at 50° C. for 2 hours. The reaction was cooled to RT and quenched into water and extract with DCM (3×). The combined organics were dried over Na 2 SO 4 , filter and concentrated under reduced pressure. The major product was isolated by silica gel column chromatography using a gradient of ethyl acetate in hexanes and was used directly in the next step. The isolated material was treated with NH 3 (10 mL of 7 M, 70.00 mmol) in methanol for 8 hours. The solvent was removed under reduced pressure to give 4-[[3-cyclopropyl-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide (39 mg, 36%). 1 H NMR (400 MHz, Chloroform-d) δ 8.99 (s, 1H), 8.50 (d, J=5.6 Hz, 1H), 8.38 (s, 1H), 8.14-7.89 (m, 2H), 7.06 (d, J=8.6 Hz, 1H), 6.99 (td, J=8.4, 7.8, 1.3 Hz, 1H), 6.85 (dd, J=9.2, 2.2 Hz, 1H), 6.58 (d, J=8.5 Hz, 1H), 5.35 (s, 1H), 3.75 (d, J=1.5 Hz, 3H), 2.52 (s, 3H), 1.87 (ddd, J=13.9, 8.5, 5.5 Hz, 1H), 1.03-0.91 (m, 2H), 0.60 (td, J=6.0, 4.4 Hz, 2H) ppm. ESI-MS m/z calc. 519.1417, found 520.43 (M+1) + ; Retention time Method B): 1.79 minutes.

The compounds set forth in Table 26 were prepared by methods analogous to the preparation of compound 196.

4-[[6-[2-Chloro-4-(Trifluoromethoxy)Phenoxy]-3-Cyclopropyl-2-Methyl-Benzoyl]Amino]Pyridine-2-Carboxamide (199)

To a pressure flask was added 3-bromo-6-iodo-2-methyl-benzoic acid (1.170 g, 3.43 mmol), 2-chloro-4-(trifluoromethoxy)phenol (730 mg, 3.434 mmol), cesium carbonate (1.8 g, 5.53 mmol), toluene (22 mL) and a stir bar. The reaction mixture was bubbled with nitrogen for 10 minutes, then copper (I) iodide (660 mg, 3.465 mmol) was added. The flask was flushed with nitrogen, capped, and heated at 100° C. with vigorous stirring for 16 hours. The mixture was allowed to cool, then diluted with ethyl acetate and water. The water layer was acidified with 1 M HCl and the product extracted into ethyl acetate. The aqueous layer was extracted with additional ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over MgSO 4 , filtered and concentrated under reduced pressure. HPLC purification (30-99% CH 3 CN/water (5 mM HCl)) provided 3-bromo-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid (800 mg, 55%) as a white solid. ESI-MS m/z calc. 423.9325, found 426.9 (M+1) + ; Retention time (Method A): 0.75 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 13.65 (s, 1H), 7.76 (dd, J=2.9, 0.8 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.39 (ddd, J=9.0, 2.8, 1.1 Hz, 1H), 7.10 (d, J=9.0 Hz, 1H), 6.77 (d, J=8.7 Hz, 1H), 2.36 (s, 3H) ppm.

A mixture of 3-bromo-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid (795 mg, 1.868 mmol), tert-butoxycarbonyl tert-butyl carbonate (610 mg, 2.795 mmol), DMAP (46 mg, 0.377 mmol), and t-BuOH (800 μL) was heated at 90° C. for 1 hour (gas evolution during first several minutes). The reaction mixture was cooled and additional tert-butoxycarbonyl tert-butyl carbonate (610 mg, 2.795 mmol) added. The reaction was stirred at 90° C. for 5 minutes with gas evolution. After gas evolution had ceased (5 min) the reaction mixture cooled to RT and directly purified by silica gel column chromatography with an ethyl acetate/hexanes gradient to provide tert-butyl 3-bromo-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate (845 mg, 94%) as a clear, colorless oil. ESI-MS m z calc. 479.9951, found 426.8 (M-tBu+1)+; Retention time (Method A): 0.84 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (dd, J=3.0, 0.8 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.39-7.31 (m, 1H), 6.94 (dd, J=9.0, 1.4 Hz, 2H), 2.35 (s, 3H), 1.35 (s, 9H) ppm.

To a vial charged with tert-butyl 3-bromo-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate (140 mg, 0.291 mmol), palladium tritert-butylphosphane (approximately 7 mg, 0.0145 mmol), and THF (1 mL) under an atmosphere of N 2 at 0° C. was added bromo(cyclopropyl)zinc (639 μL of 0.5 M, 0.320 mmol) in THF slowly and the reaction mixture was gradually warmed to room temperature over 1 h and stirred at RT for 15 minutes. The reaction mixture was quenched with 1N HCl, the aqueous layer was extracted with DCM (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of ethyl acetate in hexanes to yield tert-butyl 6-[2-chloro-4-(trifluoromethoxy)phenoxy]-3-cyclopropyl-2-methyl-benzoate (98 mg, 76%). 1H NMR (400 MHz, Chloroform-d) δ 7.33 (dq, J=2.9, 0.9 Hz, 1H), 7.06-6.97 (m, 2H), 6.80 (d, J=9.0 Hz, 1H), 6.67 (d, J=8.5 Hz, 1H), 2.44 (s, 3H), 1.85 (tt, J=8.5, 5.4 Hz, 1H), 1.44 (s, 9H), 1.00-0.87 (m, 2H), 0.67-0.58 (m, 2H) ppm.

To a solution of tert-butyl 6-[2-chloro-4-(trifluoromethoxy)phenoxy]-3-cyclopropyl-2-methyl-benzoate (95 mg, 0.2145 mmol) in THF (750 μL) and water (150 μL) cooled on ice was added TFA (2.5 mL, 32.45 mmol) over approximately 4 minutes dropwise. The ice bath was removed and the solution was stirred at RT for 1.25 h. The reaction was concentrated under reduced pressure to give 6-[2-chloro-4-(trifluoromethoxy)phenoxy]-3-cyclopropyl-2-methyl-benzoic acid (83 mg, 100%). ESI-MS m/z calc. 386.05328, found 387.23 (M+1) + ; Retention time (Method B): 0.83 minutes.

Step 5: 4-[[6-[2-Chloro-4-(Trifluoromethoxy)Phenoxy]-3-Cyclopropyl-2-Methyl-Benzoyl]Amino]Pyridine-2-Carboxamide (199)

To a solution of 6-[2-chloro-4-(trifluoromethoxy)phenoxy]-3-cyclopropyl-2-methyl-benzoic acid (82 mg, 0.212 mmol) in DCM (2.5 mL) cooled in an ice bath was added DMF (2 μL, 0.03 mmol) followed by the dropwise addition of oxalyl chloride (37 μL, 0.425 mmol). The mixture was stirred at on ice for 10 mins then at RT for 1.25 h. The reaction was concentrated under reduced pressure and flushed with N 2 to afford the acid chloride, which was taken directly into the next step.

A solution of methyl 4-aminopyridine-2-carboxylate (80 mg, 0.53 mmol) and DIEA (94 μL, 0.545 mmol) in DCM (2.5 mL) was cool on ice and the crude acid chloride in DCM (2.5 mL) was added drop wise. The ice bath was removed and the reaction mixture was stirred at RT overnight, then at 50° C. for 2 hours. The reaction was quenched into water and extract with DCM (3×). The combined organics were dried over Na 2 SO 4 , filter and concentrated under reduced pressure. The major product was isolated by silica gel chromatography using a gradient of ethyl acetate in hexanes which was used directly in the next step. The isolated material was treated with NH 3 (11.6 mL of 7 M, 81 mmol) in methanol for 28 hours. The solvent was removed under reduced pressure to give 4-[[6-[2-chloro-4-(trifluoromethoxy)phenoxy]-3-cyclopropyl-2-methyl-benzoyl]amino]pyridine-2-carboxamide (53 mg, 49%). 1H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 1H), 8.50 (d, J=5.6 Hz, 1H), 8.35 (s, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.29 (d, J=2.3 Hz, 1H), 7.16-6.91 (m, 3H), 6.57 (d, J=8.5 Hz, 1H), 5.25 (s, 1H), 2.51 (s, 3H), 1.87 (td, J=8.4, 4.2 Hz, 1H), 1.04-0.93 (m, 2H), 0.70-0.53 (m, 2H) ppm. ESI-MS m/z calc. 505.10162, found 506.38 (M+1) + ; Retention time (Method B): 1.81 minutes.

4-[[4-(Difluoromethyl)-2-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-6-Methyl-Benzoyl]Amino]Pyridine-2-Carboxamide (200)

To 4-bromo-3-fluoro-5-methyl-benzaldehyde (5 g, 23.04 mmol) in dichloromethane (30 mL) was added diethylaminosulfur trifluoride (36 mL, 272.5 mmol) dropwise and the mixture was stirred under nitrogen for 5 hours. The reaction was quenched whilst ice-cooled by drop wise addition of aqueous NaOH (2 M) until basic. The organic layer was separated, dried (MgSO4) and concentrated to give an orange oil. Purification by silica gel chromatography with a ethyl acetate in heptane gradient gave 2-bromo-5-(difluoromethyl)-1-fluoro-3-methyl-benzene (5.02 g, 91%). 1H NMR (500 MHz, DMSO-d6) δ 7.50-7.39 (m, 2H), 7.02 (t, J=55.5 Hz, 1H), 2.46 (s, 3H) ppm.

2-bromo-5-(difluoromethyl)-1-fluoro-3-methyl-benzene (4.5 g, 18.83 mmol) in DMF (45 mL) was treated with Pd(PPh 3 ) 4 (1.12 g, 0.969 mmol) and Zn(CN) 2 (2.641 g, 22.49 mmol) then degassed by a nitrogen purge and heated at 120° C. under nitrogen for 5 hours. The cooled mixture was diluted with EtOAc and washed with sat. aq. NaHCO 3 (2×), brine (2×) and water. The organic layer was dried over MgSO 4 and concentrated under reduced pressure. The residue as purified by silica gel chromatography with an ethyl acetate in heptane gradient to give 4-(difluoromethyl)-2-fluoro-6-methyl-benzonitrile (2.908 g, 83%). 1H NMR (500 MHz, DMSO-d6) δ 7.59 (d, J=9.5 Hz, 1H), 7.57 (s, 1H), 7.10 (t, J=55.1 Hz, 1H), 2.57 (s, 3H) ppm.

2-Methoxy-4-(trifluoromethoxy)phenol (670.7 mg, 3.222 mmol), 4-(difluoromethyl)-2-fluoro-6-methyl-benzonitrile (571 mg, 3.085 mmol) and Cs 2 CO 3 (1.12 g, 3.437 mmol) were combined in DMF (3.5 mL), degassed by multiple N 2 flush and vacuum cycles and then heated at 80° C. for 2.5 hours. Additional Cs 2 CO 3 (203 mg, 0.624 mmol) and 2-methoxy-4-(trifluoromethoxy)phenol (130 mg, 0.624 mmol) were added and heating was continued for 2 hours. The mixture was allowed to cool. The mixture was diluted with EtOAc and washed with 2M NaOH (2×) and brine (2×). The organic layer dried over MgSO 4 and concentrated under reduced pressure to give 4-(difluoromethyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzonitrile (1.316 g, 114%). This was used without further purification. 1H NMR (500 MHz, DMSO-d6) δ 7.41 (d, J=8.8 Hz, 1H), 7.36 (s, 1H), 7.30 (d, J=2.7 Hz, 1H), 7.07 (ddq, J=8.7, 2.4, 1.1 Hz, 1H), 6.99 (t, J=55.2 Hz, 1H), 6.68 (s, 1H), 3.79 (s, 3H), 2.58 (s, 3H) ppm.

4-(Difluoromethyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzonitrile (1.316 g, 3.526 mmol) in EtOH (13 mL) and NaOH (17 mL of 2 M, 34.00 mmol) was stirred at 90° C. for 1.5 hours. Additional NaOH (2 g, 50.00 mmol) was added and heating was continued for 6 hours. The mixture was allowed to cool and then diluted with EtOAc and washed with brine. The organic layer was dried (MgSO4) and concentrated under reduced pressure to give 4-(difluoromethyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzamide (1.34 g, 97%). 1H NMR (500 MHz, DMSO-d6) δ 7.83 (t, J=2.2 Hz, 1H), 7.65-7.55 (m, 1H), 7.21 (d, J=2.8 Hz, 1H), 7.18 (s, 1H), 7.14 (d, J=8.8 Hz, 1H), 7.01-6.96 (m, 1H), 6.86 (d, J=55.7 Hz, 1H), 6.63 (s, 1H), 3.82 (s, 3H), 2.36 (s, 3H) ppm.

Step 5: Methyl 4-[[4-(Difluoromethyl)-2-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-6-Methyl-Benzoyl]Amino]Pyridine-2-Carboxylate

A solution of methyl 4-bromopyridine-2-carboxylate (87.2 mg, 0.404 mmol), Xantphos (36.4 mg, 0.0629 mmol), cesium carbonate (246 mg, 0.755 mmol), Pd(OAc) 2 (11.2 mg, 0.0499 mmol) and 4-(difluoromethyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzamide (130 mg, 0.332 mmol) in dioxane (3 mL) was degassed with multiple nitrogen flush-vacuum cycles and then heated at 100° C. under nitrogen for 2.75 hours. The mixture was diluted with EtOAc and washed with sat. aq. NaHCO 3 . The organic layer was dried over MgSO 4 and concentrated under reduced pressure to give methyl 4-[[4-(difluoromethyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoyl]amino]pyridine-2-carboxylate (174.9 mg, 100%). ESI-MS m/z calc. 526.11633, found 527.6 (M+1) + ; Retention time (Method D): 0.91 minutes.

Step 6: 4-[[4-(Difluoromethyl)-2-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-6-Methyl-Benzoyl]Amino]Pyridine-2-Carboxamide (200)

Methyl 4-[[4-(difluoromethyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoyl]amino]pyridine-2-carboxylate (175 mg, 0.3324 mmol) was dissolved in ammonia (in methanol) (3 mL of 7 M, 21.00 mmol) and stirred at RT overnight. Purification by C 18 reverse phase HPLC gave 4-[[4-(difluoromethyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoyl]amino]pyridine-2-carboxamide (68.2 mg, 40%). 1H NMR (500 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.53 (d, J=5.4 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H), 8.07 (d, J=2.9 Hz, 1H), 7.85 (dd, J=5.5, 2.2 Hz, 1H), 7.63 (d, J=2.9 Hz, 1H), 7.28 (s, 1H), 7.25 (d, J=8.8 Hz, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.01 (ddd, J=8.8, 2.7, 1.3 Hz, 1H), 6.93 (d, J=55.6 Hz, 1H), 6.71 (s, 1H), 3.78 (s, 3H), 2.39 (s, 3H) ppm. ESI-MS m/z calc. 511.11667, found 512.5 (M+1) + ; Retention time (Method E): 3.08 minutes.

N-(2-Carbamoyl-4-Pyridyl)-5,6-Dicyclopropyl-3-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]Pyridine-2-Carboxamide (201)

A mixture of methyl 5-bromo-6-chloro-3-fluoro-pyridine-2-carboxylate (1 g, 3.725 mmol), cyclopropyl boronic acid (2 g, 23.28 mmol), K 3 PO 4 (2.8 g, 13.19 mmol), Pd(OAc) 2 (170 mg, 0.757 mmol) and tricyclohexylphosphane (105 mg, 0.374 mmol) in toluene (20 mL) and water (5 mL) was heated at 100° C. for 24 hours. Additional cyclopropylboronic acid (640 mg, 7.451 mmol) was added and the reaction mixture heated for a further 24 h. The reaction mixture was cooled to RT and diluted with water (20 mL) and EtOAc (20 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2×25 mL) and the combined organic layers were washed with saturated aqueous sodium carbonate solution, dried (MgSO 4 ) and concentrated under reduced pressure to give methyl 5,6-dicyclopropyl-3-fluoro-pyridine-2-carboxylate (910 mg, 68%) as a pale brown oil. This was used without purification. ESI-MS m/z calc. 235.10086, found 236.6 (M+1) + ; Retention time (Method D): 0.87 minutes.

To methyl 5,6-dicyclopropyl-3-fluoro-pyridine-2-carboxylate (300 mg, 0.8289 mmol) in DMF (5 mL) was added 2-methoxy-4-(trifluoromethoxy)phenol (173 mg, 0.831 mmol) and cesium carbonate (810 mg, 2.486 mmol) and the resulting mixture was heated at 90° C. for 48 h. The reaction mixture was cooled to RT and diluted with water (10 mL) and ethyl acetate (10 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2×5 mL). The aqueous layer was acidified to pH3 by addition of 1N HCl and then extracted with EtOAc (3×10 mL). The combined organic extracts were dried over MgSO 4 and concentrated under reduced pressure to give crude (approximately 60% pure) of 5,6-dicyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carboxylic acid (190 mg, 52%) as a dark oil which was taken on into the next step without purification. ESI-MS m/z calc. 409.1137, found 410.6 (M+1) + ; Retention time (Method D): 0.64 minutes.

Step 3: N-(2-Carbamoyl-4-Pyridyl)-5,6-Dicyclopropyl-3-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]Pyridine-2-Carboxamide (201)

DMF (5 μL, 0.0646 mmol) and oxalyl chloride (0.15 mL, 1.72 mmol) was added to an ice cooled solution of crude 5,6-dicyclopropyl-3-fluoro-pyridine-2-carboxylic acid (187 mg, approximately 60% pure) in DCM (4 mL) and the resulting mixture stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure and the residue dissolved in DCM (4 mL) and methyl 4-aminopyridine-2-carboxylate (250 mg, 1.643 mmol) and Et 3 N (100 μL, 0.718 mmol) was added and the resulting mixture stirred at RT overnight. The reaction mixture was concentrated under reduced pressure and then ammonia in MeOH (3 mL of 7 M, 21.00 mmol) was added and the resulting mixture stirred at RT overnight. The reaction mixture was concentrated under reduced pressure and purified by C 18 HPLC to yield N-(2-carbamoyl-4-pyridyl)-5,6-dicyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carboxamide (4.96 mg, 7%) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.50 (d, J=5.3 Hz, 1H), 8.34 (d, J=2.1 Hz, 1H), 8.07 (d, J=2.8 Hz, 1H), 7.90 (dd, J=5.5, 2.2 Hz, 1H), 7.61 (d, J=2.9 Hz, 1H), 7.14 (d, J=2.5 Hz, 1H), 6.95-6.84 (m, 3H), 3.79 (s, 3H), 2.55 (td, J=8.1, 4.1 Hz, 1H), 2.24 (tt, J=8.5, 5.4 Hz, 1H), 1.15 (dq, J=4.9, 3.4 Hz, 2H), 1.02 (ddt, J=8.5, 6.5, 4.1 Hz, 4H), 0.67-0.60 (m, 2H) ppm. ESI-MS m/z calc. 528.16205, found 529.6 (M+1) + ; 527.8 (M−1) − ; Retention time (Method E): 3.51 minutes.

4-[[2,2-Difluoro-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-4-Methyl-1,3-Benzodioxole-5-Carbonyl]Amino]Pyridine-2-Carboxamide (202)

To 2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylic acid (2 g, 9.253 mmol), was added palladium(II) acetate (340 mg, 1.514 mmol), tetrabutylammonium iodide (3.6 g, 9.746 mmol), (acetyloxy)(phenyl)-lambda3-iodanyl acetate (6.28 g, 19.50 mmol), iodine (4.94 g, 19.46 mmol) and DCE (20 mL) and the reaction was stirred at 60° C. for 14 h. Additional palladium(II) acetate (340 mg, 1.514 mmol), tetrabutylammonium iodide (3.6 g, 9.746 mmol), (acetyloxy)(phenyl)-lambda3-iodanyl acetate (6.28 g, 19.50 mmol) and iodine (4.94 g, 19.46 mmol) were added and to the reaction and stirred at 60° C. for 93 h. The reaction was acidified with 1 M HCl and a saturated aqueous solution of sodium bisulfite was added. The reaction was extracted with DCM (×3). The combined organic layers were washed with brine and dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure. The crude product was dissolved in DMSO, filtered and purified using a reverse phase HPLC C 18 column (CH 3 CN/water (5 mM HCi) gradient) to yield 2,2-difluoro-6-iodo-4-methyl-1,3-benzodioxole-5-carboxylic acid (1.59 g, 50%) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.80 (s, 1H), 7.82 (s, 1H), 2.26 (s, 3H) ppm. ESI-MS m/z calc. 341.92004, found 343.0 (M+1) + ; Retention time (Method C): 2.02 minutes.

Step 2: 2,2-Difluoro-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-4-Methyl-1,3-Benzodioxole-5-Carboxylic Acid

A flask containing 2,2-difluoro-6-iodo-4-methyl-1,3-benzodioxole-5-carboxylic acid (1.47 g, 4.298 mmol), toluene (30 mL) and a stirrer bar was flushed with N 2 for 10 min. 2-Methoxy-4-(trifluoromethoxy)phenol (901.4 mg, 4.331 mmol) and cesium carbonate (2.89 g, 8.87 mmol) were added to the reaction and flushed with N 2 for 10 min. Copper (I) iodide (177 mg, 0.933 mmol) was added to the reaction and flushed with N 2 for 10 min. The reaction was stirred at 60° C. with vigorous stirring under N 2 for 14 h. Additional 2-methoxy-4-(trifluoromethoxy)phenol (901 mg, 4.331 mmol), cesium carbonate (2.89 g, 8.870 mmol), iodocopper (177 mg, 0.933 mmol) and toluene (24 mL) were added to the reaction, which was flushed with N 2 for 10 min and the reaction was stirred at 60° C. for 1 h. The mixture was allowed to cool, and then diluted with ethyl acetate and water and acidified with 1 M HCl. The two layers were separated. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were filtered and the filtrate was washed with water and brine, dried over sodium sulfate, filtered through a plug of celite and concentrated under reduced pressure. The crude product was dissolved in DMSO, filtered and purified using a reverse phase HPLC C 18 column (CH 3 CN/water (5 mM HCl) gradient) to yield 2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methyl-1,3-benzodioxole-5-carboxylic acid (370.0 mg, 20%) as a brown solid. ESI-MS m/z calc. 422.04248, found 423.4 (M+1) + ; Retention time (Method C): 2.75 minutes.

Step 3: 2,2-Difluoro-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-4-Methyl-1,3-Benzodioxole-5-Carbonyl Chloride

To 2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methyl-1,3-benzodioxole-5-carboxylic acid (370 mg, 0.8762 mmol) and DMF (15 μL, 0.194 mmol) in DCM (3.5 mL) at 0° C. was added oxalyl chloride (216 μL, 2.476 mmol) dropwise under a N 2 atmosphere. The ice bath was removed after 10 min and the reaction was stirred at room temperature for 1.5 h. The mixture was concentrated under reduced pressure to afford 2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methyl-1,3-benzodioxole-5-carbonyl chloride, which was used directly in the next step.

Step 4: 4-[[2,2-Difluoro-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-4-Methyl-1,3-Benzodioxole-5-Carbonyl]Amino]Pyridine-2-Carboxamide (202)

To 4-aminopyridine-2-carboxamide (approximately 39 mg, 0.281 mmol) in NMP (500 μL), and DIEA (approximately 122 μL, 0.704 mmol) at 0° C. was added a solution of 2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methyl-1,3-benzodioxole-5-carbonyl chloride (62 mg, 0.1407 mmol) in NMP (500 μL) slowly. The reaction was stirred at RT for 19 hours follow by 75° C. for 7 hours. The crude product was filtered and purified using a reverse phase HPLC C 18 column (CH 3 CN/water (5 mM HCl) gradient) to yield 4-[[2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methyl-1,3-benzodioxole-5-carbonyl]amino]pyridine-2-carboxamide (23.0 mg, 30%). 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.31 (d, J=2.1 Hz, 1H), 8.09 (d, J=2.8 Hz, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.64 (d, J=2.8 Hz, 1H), 7.16-7.10 (m, 2H), 7.01-6.86 (m, 2H), 3.74 (s, 3H), 2.29 (s, 3H) ppm. ESI-MS m/z calc. 541.0908, found 542.1 (M+1) + ; Retention time (Method C): 2.67 minutes.

The compounds set forth in Table 27 were prepared by methods analogous to the preparation of compound 202.

4-[[3-(3,3-Difluorocyclobutoxy)-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-2-Methyl-Benzoyl]Amino]Pyridine-2-Carboxamide (204)

A solution of 3,3-difluorocyclobutanol (2 g, 18.50 mmol) and pyridine (4.9 mL, 60.58 mmol) in DCM (20 mL) was cooled to −78° C. and triflic anhydride (4.1 mL, 24.37 mmol) was added dropwise. After the addition, the cooling bath was replaced with and ice bath and the reaction mixture stirred for an additional 20 minutes. The reaction mixture was poured in to 0.1N HCl and extracted with DCM (3×). The combined organics were washed with 0.1N HCl (2×), water, brine, dried over Na 2 SO 4 , filtered through a short plug of silica and evaporated to dryness to give (3,3-difluorocyclobutyl) trifluoromethanesulfonate that was used directly in the next step.

A solution of methyl 3-hydroxy-2-methyl-benzoate (2 g, 12.04 mmol) in DMF (20 mL) was cooled to 0° C., NaH (950 mg of 60% w/w, 23.75 mmol) was added in portions and the reaction mixture stirred at this temperature for 10 minutes. A solution of (3,3-difluorocyclobutyl) trifluoromethanesulfonate in DMF (5 mL) was added dropwise over 5 minutes, the cooling bath was removed and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was poured in to water, the pH was adjusted with 1N HCl to ˜2 and the mixture was extracted with EtOAc (3×). The organics phases were combined washed with 0.1N HCl (2×), brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a EtOAc in hexane gradient to give 3-(3,3-difluorocyclobutoxy)-2-methyl-benzoic acid (1.11 g, 38%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.22 (dd, J=8.0 Hz, 1H), 7.01 (dd, J=8.2, 1.2 Hz, 1H), 4.86-4.71 (m, 1H), 3.29-3.14 (m, 2H), 2.80-2.61 (m, 2H), 2.34 (s, 3H) ppm.

To a solution of 3-(3,3-difluorocyclobutoxy)-2-methyl-benzoic acid (220 mg, 0.908 mmol), iodine (461 mg, 1.817 mmol), and (acetyloxy)(phenyl)-lambda3-iodanyl acetate (585 mg, 1.816 mmol) in DMF (2.5 mL) was degased by bubbling nitrogen through the solution for 5 min. To the reaction mixture was added palladium (II) acetate (33 mg, 0.1470 mmol) and the reaction mixture was stirred at 100° C. for 45 min. The reaction mixture was poured into 0.1 N HCl and extracted with EtOAc (3×). The organics phases were combined, washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a MeOH in DCM gradient to give 3-(3,3-difluorocyclobutoxy)-6-iodo-2-methyl-benzoic acid (160 mg, 48%) as a cream solid. ESI-MS m/z calc. 367.9721, found 369.0 (M+1) + ; Retention time (Method A): 0.55 minutes.

A suspension of 3-(3,3-difluorocyclobutoxy)-6-iodo-2-methyl-benzoic acid (160 mg, 0.435 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (145 mg, 0.697 mmol) and Cs 2 CO 3 (296 mg, 0.909 mmol) was degassed by bubbling nitrogen through the solution for 3 min, copper (I) iodide (19 mg, 0.0998 mmol) was added and the reaction mixture stirred at 100° C. for 1 hour. The reaction mixture was poured into water, the pH was adjusted to 2 with 1N HCl and the mixture was extracted with EtOAc (3×). The organic phases were combined, washed with 0.1N HCl, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a EtOAc in hexanes gradient to give 3-(3,3-difluorocyclobutoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid (58 mg, 30%) as an off-white solid. ESI-MS m/z calc. 448.09454, found 449.1 (M+1) + ; Retention time (Method A): 0.68 minutes.

Step 4: 4-[[3-(3,3-Difluorocyclobutoxy)-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-2-Methyl-Benzoyl]Amino]Pyridine-2-Carboxamide (204)

To a solution of 3-(3,3-difluorocyclobutoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid (58 mg, 0.129 mmol) in DCM (1 mL) and DMF (12 μL, 0.155 mmol) was added oxalyl chloride (25 μL, 0.287 mmol) and the reaction mixture was stirred at RT for 15 min. The reaction mixture was then concentrated under reduced pressure, toluene was added and the mixture was concentrated again under reduced pressure. The residue was taken up in DCM and added dropwise to a solution of 4-aminopyridine-2-carboxamide (29 mg, 0.212 mmol) and DIEA (68 μL, 0.390 mmol) in NMP (580.0 μL) and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was evaporated to half its original volume, diluted with MeOH, filtered and purification by HPLC (CH 3 CN/Water (5 mM HCl) gradient) to give 4-[[3-(3,3-difluorocyclobutoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide (Hydrochloride salt) (8.2 mg, 10%) as a white solid. ESI-MS m/z calc. 567.1429, found 568.1 (M+1) + ; Retention time (Method B): 1.76 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.33 (d, J=2.1 Hz, 1H), 8.08 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.63 (s, 1H), 7.10 (d, J=2.7 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 6.95-6.88 (m, 2H), 6.62 (d, J=8.9 Hz, 1H), 4.76 (m, J=11.7, 7.3 Hz, 1H), 3.73 (s, 3H), 3.28-3.18 (m, 2H), 2.78-2.60 (m, 2H), 2.17 (s, 3H) ppm.

N-(6-Carbamoyl-3-Pyridyl)-5,6-Dicyclopropyl-3-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]Pyridine-2-Carboxamide (205)

DMF (5 μL, 0.0646 mmol) was added to an ice cooled solution of 5,6-dicyclopropyl-3-fluoro-pyridine-2-carboxylic acid (70 mg, 0.316 mmol) (side product from example 44, step 1) and oxalyl chloride (100 μL, 1.146 mmol) in DCM (2 mL) and the resulting mixture stirred at RT for 2 h. The solvent was removed under reduced pressure and the residue dissolved in DCM (2 mL) and methyl 5-aminopyridine-2-carboxylate (50 mg, 0.329 mmol) and Et 3 N (100 μL, 0.718 mmol) were added and the resulting mixture stirred at RT overnight. The reaction mixture was concentrated under reduced pressure and ammonia in methanol (2.5 mL of 7 M, 17.50 mmol) was added and the resulting mixture stirred at RT over the weekend. The reaction mixture was concentrated under reduced pressure to leave a dark brown oil which was dissolved in DCM (10 mL) and water (10 mL) and the layers separated. The organic layer was washed with additional water (1×10 mL), dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a EtOAc in petroleum ether gradient to give N-(6-carbamoyl-3-pyridyl)-5,6-dicyclopropyl-3-fluoro-pyridine-2-carboxamide (56 mg, 42%) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.99 (d, J=2.4 Hz, 1H), 8.33 (dd, J=8.5, 2.5 Hz, 1H), 8.09-8.02 (m, 2H), 7.54 (s, 1H), 7.43 (d, J=11.7 Hz, 1H), 2.60-2.52 (m, 1H), 2.31 (ddd, J=13.5, 8.4, 5.1 Hz, 1H), 1.23-1.15 (m, 2H), 1.14-1.06 (m, 2H), 1.02 (dq, J=8.2, 3.5 Hz, 2H), 0.88-0.81 (m, 2H) ppm. ESI-MS m/z calc. 340.13354, found 314.6 (M+1) + ; 339.8 (M−1) − ; Retention time (Method D): 0.79 minutes.

Step 3: N-(6-Carbamoyl-3-Pyridyl)-5,6-Dicyclopropyl-3-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]Pyridine-2-Carboxamide (205)

A mixture of 2-methoxy-4-(trifluoromethoxy)phenol (15 mg, 0.0721 mmol), N-(6-carbamoyl-3-pyridyl)-5,6-dicyclopropyl-3-fluoro-pyridine-2-carboxamide (22 mg, 0.0646 mmol) and Cs 2 CO 3 (63 mg, 0.193 mmol) in DMF (2 mL) was heated at 100° C. overnight. The reaction mixture was cooled to RT and purified by HPLC to give N-(6-carbamoyl-3-pyridyl)-5,6-dicyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carboxamide (trifluoroacetic acid (2)) (4.8 mg, 10%) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.90 (d, J=2.5 Hz, 1H), 8.26 (dd, J=8.5, 2.4 Hz, 1H), 8.02 (d, J=8.6 Hz, 2H), 7.52 (s, 1H), 7.14 (d, J=2.5 Hz, 1H), 6.95-6.86 (m, 3H), 3.78 (s, 3H), 2.56 (td, J=8.1, 4.0 Hz, 1H), 2.24 (tt, J=8.4, 5.3 Hz, 1H), 1.15 (dd, J=5.0, 2.5 Hz, 2H), 1.08-0.96 (m, 4H), 0.67-0.58 (m, 2H) ppm. ESI-MS m/z calc. 528.16205, found 529.6 (M+1) + ; 527.7 (M−1) − ; Retention time (Method E): 3.49 minutes.

5-[[6-[2-Cyclopropyl-4-(Trifluoromethoxy)Phenoxy]-2-Fluoro-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (206)

6-Bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.0 g, 6.968 mmol) was dissolved in dichloromethane (28 mL). DMF (215 μL, 2.777 mmol) was added followed by the slow dropwise addition of oxalyl chloride (2.7 mL, 30.95 mmol). The reaction mixture was allowed to stir at RT for 30 minutes. The reaction mixture was concentrated under reduced pressure. Additional dichloromethane (˜5 mL) was added, and the solution was again concentrated to dryness. The remaining residue was taken up in NMP (6 mL) and added to a prepared solution of 5-aminopyridine-2-carboxamide (1.4 g, 10.21 mmol) and DIEA (7.3 mL, 41.91 mmol) in NMP (6 mL). This reaction mixture was allowed to stir at 25° C. for 4 hours. The reaction mixture was purified by silica gel column chromatography using a gradient of EtOAc in hexanes to give 5-[[6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (1.5 g, 53%) as a white solid. ESI-MS m/z calc. 404.9736, found 406.1 (M+1) + ; Retention time (Method B): 1.01 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.86 (d, J=2.4 Hz, 1H), 8.31 (dd, J=8.5, 2.5 Hz, 1H), 8.20-7.99 (m, 2H), 8.00-7.79 (m, 2H), 7.71-7.41 (m, 1H) ppm.

Step 2: 5-[[6-[2-Cyclopropyl-4-(Trifluoromethoxy)Phenoxy]-2-Fluoro-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (206)

5-[[6-Bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (50 mg, 0.123 mmol), 2-cyclopropyl-4-(trifluoromethoxy)phenol (approximately 32 mg, 0.148 mmol), Cs 2 CO 3 (approximately 60 mg, 0.185 mmol), and copper (I) iodide (approximately 9 mg, 0.0492 mmol) in toluene (0.5 mL) were purged with nitrogen. The mixture was stirred at 100° C. for 60 minutes. The reaction mixture was allowed to cool to RT, filtered, and purified by reverse phase chromatography using a C 18 column and a gradient of acetonitrile in water (5 mM hydrochloric acid) to give 5-[[6-[2-cyclopropyl-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (4.7 mg, 7%). ESI-MS m/z calc. 543.1029, found 544.0 (M+1) + ; Retention time (Method B): 1.92 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 8.85 (s, 1H), 8.30 (d, J=10.8 Hz, 1H), 8.10-7.96 (m, 2H), 7.87 (s, 1H), 7.57 (s, 1H), 7.29 (s, 2H), 7.01 (s, 1H), 6.74 (d, J=8.9 Hz, 1H), 1.98 (s, 1H), 0.87 (d, J=10.1 Hz, 2H), 0.71 (d, J=5.3 Hz, 2H) ppm.

The compounds set forth in Table 28 were prepared by methods analogous to the preparation of compound 206.

5-[[6-[3-Fluoro-2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-2-Methyl-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (224)

6-Fluoro-2-methyl-3-(trifluoromethyl)benzoic acid (2.95 g, 13.28 mmol) in anhydrous DCM (30 mL) under nitrogen was treated with DMF (50 μL, 0.646 mmol), cooled in an ice bath and treated dropwise with oxalyl chloride (2.2 mL, 25.22 mmol). The reaction was stirred for 10 minutes in the ice bath then the bath was removed. The clear solution was stirred at RT for 1 hour. The mixture was concentrated to dryness under reduced pressure. The orange residue was dissolved in DCM (7.5 mL) and the solution was added dropwise to a cold mixture of 5-aminopyridine-2-carboxamide (2.2 g, 16.04 mmol) and DIEA (7 mL, 40.19 mmol) in NMP (30 mL). The mixture was stirred at RT for 16 h. The mixture was concentrated under reduced pressure and the residue was diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (1×75 mL). The combined organic layers were washed with brine (2×), dried over Na 2 SO 4 , filtered and concentrated to give white solid. The crude material was purified by silica chromatography eluting with a gradient of methanol in DCM to give 5-[[6-fluoro-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (3.14 g, 69%) as off-white solid. ESI-MS m/z calc. 341.07874, found 342.2 (M+1) + ; Retention time (Method B): 0.87 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.87 (d, J=2.4 Hz, 1H), 8.33 (dd, J=8.6, 2.5 Hz, 1H), 8.15-8.00 (m, 2H), 7.92 (dd, J=9.0, 5.5 Hz, 1H), 7.58 (s, 1H), 7.46 (t, J=8.7 Hz, 1H), 2.45 (d, J=1.8 Hz, 3H) ppm.

Step 2: 5-[[6-[3-Fluoro-2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-2-Methyl-3-(Trifluoromethyl)Benzoyl]Amino]Pyridine-2-Carboxamide (224)

5-[[6-Fluoro-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (75 mg, 0.220 mmol) and 3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (150 mg, 0.663 mmol) were dissolved in DMSO (200 L). To this clear solution was added finely ground potassium carbonate (92 mg, 0.666 mmol). The reaction mixture was stirred at 125° C. for 5 h. The mixture was cooled to RT, filtered and purified by reverse phase HPLC (C18, 1M99% CH 3 CN/H 2 O with 5 mM HCl) to give 5-[[6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (11.3 mg, 9%) as an off-white solid. ESI-MS m/z calc. 547.09784, found 548.2 (M+1) + ; Retention time (Method B): 1.82 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 8.87 (d, J=2.4 Hz, 1H), 8.32 (dd, J=8.6, 2.5 Hz, 1H), 8.05 (d, 9=8.5 Hz, 1H), 8.01 (s, 1H), 7.76 (d, (=8.9 Hz, 1H), 7.55 (sc, 1H), 7.42-7.33 (m, 1H), 7.13 (dd, ==9.4, 2.2 Hz, 1H), 6.90 (d, 7=8.8 Hz, 1H), 3.84 (d, J=0.9 Hz, 3H), 2.46 (d, J=1.9 Hz, 3H) ppm.

The compounds set forth in Table 29 were prepared by methods analogous to the preparation of compound 224.

4-[[4-Tert-Butyl-2-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-6-Methyl-Benzoyl]Amino]Pyridine-2-Carboxamide (237)

A pressure vessel was charged with methyl 4-bromo-2-fluoro-6-methyl-benzoate (5 g, 20.24 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (4.4 g, 21.14 mmol), Cs 2 CO 3 (6.6 g, 20.26 mmol) and DMF (61 mL). The vessel was sealed, the reaction mixture stirred at 100° C. for 16 hours, and the mixture was cooled to RT. The mixture was diluted with EtOAc, washed with brine (3×100 ml), and the organic layer dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with a EtOAc in hexanes gradient to give methyl 4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoate (2.9 g, 33%) as a clear oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J=1.8 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 6.97 (ddd, J=8.9, 2.7, 1.4 Hz, 1H), 6.68 (d, J=1.8 Hz, 1H), 3.80 (s, 6H), 2.27 (s, 3H) ppm.

To a solution of methyl 4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoate (300 mg, 0.689 mmol), 1,3-dicyclohexylimidazol-1-ium tetrafluoroborate (44 mg, 0.137 mmol) and dichloronickel 1,2-dimethoxyethane (30 mg, 0.137 mmol) in THF (20 mL) cooled to −15° C. was added tert-butyl(chloro)magnesium (861 μL of 1 M, 0.861 mmol) in portions over 5 minutes. The mixture was allowed to stir at −15 C for 30 minutes. Additional tert-butyl(chloro)magnesium (861 μL of 1 M, 0.8610 mmol) was added over 5 mins at −10° C. The reaction mixture was quenched with aqueous NH 4 Cl and partitioned between ethyl acetate (30 ml) and water (30 ml). The aqueous layer was further extracted with EtOAc (50 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The product was purified by silica gel chromatography with a EtOAc in petroleum ether gradient to give methyl 4-tert-butyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoate (170 mg, 48%) as an oil. 1H NMR (500 MHz, Chloroform-d) δ 7.00 (dd, J=1.7, 0.8 Hz, 1H), 6.90-6.83 (m, 2H), 6.79-6.74 (m, 1H), 6.72 (d, J=1.9 Hz, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 2.42-2.37 (m, 3H), 1.25 (s, 9H) ppm. ESI-MS m/z calc. 412.14975, found 413.5 (M+1) + ; Retention time (Method E): 3.21 minutes.

Methyl 4-tert-butyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoate (225 mg, 0.546 mmol) was dissolved in ethanol (10 mL) and then aqueous LiOH (1000 μL of 2 M, 2.000 mmol) was added and the mixture heated to 60 C for 1 h. An additional 2 mL aqueous LiOH (2M) was added and heating was continued for 5 h. The reaction was quenched with 2M HCl and the mixture was concentrated under reduced pressure to give 4-tert-butyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoic acid (200 mg, 92%). 1H NMR (400 MHz, Chloroform-d) δ 7.28 (s, 1H), 7.12-6.99 (m, 2H), 6.87 (s, 1H), 6.84-6.77 (m, 1H), 6.68 (dd, J=1.8, 0.6 Hz, 1H), 3.85 (s, 3H), 2.55 (d, J=1.2 Hz, 1H), 2.55 (s, 2H), 1.23 (s, 9H) ppm. ESI-MS m/z calc. 398.1341, found 397.2 (M−1) − ; Retention time (Method D): 0.67 minutes.

4-tert-Butyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoic acid (200 mg, 0.502 mmol) was dissolved in DCM (10 mL) at 0° C., DMF (4 μL, 0.0517 mmol) was added, followed by the dropwise addition of oxalyl chloride (440 μL, 5.044 mmol). After 1 h, the mixture was concentrated under reduced pressure, and the residue was taken up in DCM (10 mL) and added dropwise to a stirring solution of NH 3 in dioxane (10 mL of 0.5 M, 5.000 mmol). The mixture was stirred overnight and concentrated under reduced pressure. The residue was purified by silica gel chromatography with a EtOAc in heptanes gradient to give 4-tert-butyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzamide (35 mg, 18%). 1 H NMR (400 MHz, Chloroform-d) δ 6.99-6.83 (m, 2H), 6.78-6.64 (m, 2H), 6.53 (dd, J=1.8, 0.6 Hz, 1H), 6.28 (s, 1H), 5.97 (s, 1H), 3.73 (s, 3H), 2.39 (s, 3H), 1.67 (dt, J=13.6, 6.8 Hz, OH), 1.13 (s, 9H) ppm. ESI-MS m/z calc. 397.1501, found 398.1 (M+1) + ; Retention time (Method D): 0.97 minutes.

Step 5: 4-[[4-Tert-Butyl-2-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-6-Methyl-Benzoyl]Amino]Pyridine-2-Carboxamide (237)

4-tert-Butyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzamide (40 mg, 0.101 mmol), methyl 4-bromopyridine-2-carboxylate (26 mg, 0.120 mmol), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (12 mg, 0.0207 mmol) and cesium carbonate (75 mg, 0.230 mmol) were suspended in dioxane (2 mL), then degassed with N 2 (flush and evacuation cycles). Then palladium(II) acetate (5 mg, 0.0223 mmol) was added and additional degassing was done. The mixture was heated to 100° C. The mixture was concentrated under reduced pressure and the residue dissolved in 5 mL 7M ammonia in MeOH and stirred overnight at 45° C. The material was purified by reverse phase HPLC to give 4-[[4-tert-butyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoyl]amino]pyridine-2-carboxamide (0.5 mg, 1%). 1H NMR (400 MHz, Chloroform-d) δ 8.93 (s, 1H), 8.50 (d, J=5.6 Hz, 1H), 8.38 (s, 1H), 8.03 (s, 1H), 7.87 (s, 1H), 7.13-7.02 (m, 2H), 6.93-6.80 (m, 3H), 6.69 (d, J=1.7 Hz, 1H), 3.90 (d, J=2.7 Hz, 3H), 2.55 (s, 3H), 1.25 (s, 9H) ppm. ESI-MS m/z calc. 517.18243, found 518.1 (M+1) + ; Retention time (Method E): 1.02 minutes.

5-Tert-Butyl-N-(2-Carbamoyl-4-Pyridyl)-3-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]Pyridine-2-Carboxamide (238)

To a solution of 5-bromo-3-fluoro-pyridine-2-carbonitrile (500 mg, 2.488 mmol), 1,3-diisopropylimidazol-1-ium chloride (approximately 188 mg, 0.995 mmol) and dichloronickel 1,2-dimethoxyethane (approximately 219 mg, 0.995 mmol) in THF (10 mL) cooled to −15° C. was added tert-butylchloromagnesium (approximately 3.1 mL of 1 M, 3.1 mmol) in portions over 2-3 minutes. The mixture was allowed to stir at −15° C. for 30 minutes and then allowed to warm to RT. The mixture was cooled to −20° C. and additional tert-butylchloromagnesium (approximately 3.1 mL of 1 M, 3.1 mmol) was added. The reaction mixture was quenched with aqueous NH 4 Cl and partitioned between ethyl acetate (30 ml) and water (30 ml). The aqueous layer was extracted with EtOAc (50 mL) and the combined organic layers were washed with brine (1×20 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with a EtOAc in petroleum ether gradient to give 5-tert-butyl-3-fluoro-pyridine-2-carbonitrile (90 mg, 19%) as an oil. 1H NMR (500 MHz, Chloroform-d) δ 8.61 (t, J=1.7 Hz, 1H), 7.56 (dd, J=10.1, 1.9 Hz, 1H), 1.41 (s, 9H) ppm. ESI-MS m/z calc. 178.09062, found 179.3 (M+1) + ; Retention time (Method E): 2.26 minutes.

2-Methoxy-4-(trifluoromethoxy)phenol (53.2 mg, 0.256 mmol), 5-tert-butyl-3-fluoro-pyridine-2-carbonitrile (40 mg, 0.213 mmol) and Cs 2 CO 3 (approximately 104 mg, 0.320 mmol) were combined in DMF (456 μL) and sealed and heated at 70° C. for 1 hour. The reaction mixture was allowed to cool to RT and partitioned between ethyl acetate (30 ml) and water (30 ml). The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (1×20 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a EtOAc in petroleum ether gradient to give 5-tert-butyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carbonitrile (61 mg, 66%). ESI-MS m/z calc. 366.11914, found 367.5 (M+1) + ; Retention time (Method E): 2.91 minutes.

To 5-tert-butyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carbonitrile (75 mg, 0.205 mmol) was added HCl (341 μL of 12 M, 4.09 mmol) and the mixture stirred overnight at RT. To the mixture was added some ice and then 5N NaOH until the pH was 8-9. The reaction mixture was partitioned between ethyl acetate (5 ml) and water (5 ml). The aqueous layer was extracted with EtOAc (5 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure and used as such in the next step. 5-tert-Butyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carboxamide (81 mg, 79%). ESI-MS m/z calc. 384.1297, found 385.5 (M+1) + ; Retention time (Method E): 2.26 minutes.

Step 4: Methyl 4-[[5-Tert-Butyl-3-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]Pyridine-2-Carbonyl]Amino]Pyridine-2-Carboxylate

5-tert-Butyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carboxamide (80 mg, 0.208 mmol), Xantphos (18 mg, 0.0311 mmol), cesium carbonate (149 mg, 0.457 mmol), Pd(OAc) 2 (7 mg, 0.0312 mmol) and methyl 4-bromopyridine-2-carboxylate (58 mg, 0.269 mmol) were combined in dioxane (3 mL) and heated at 100° C. for 3 hours. The reaction mixture was allowed to cool to RT and was partitioned between ethyl acetate (30 ml) and water (30 ml). The aqueous layer was extracted with EtOAc (50 mL) and the combined organic layers were washed with brine (1×20 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a EtOAc in petroleum ether gradient to give methyl 4-[[5-tert-butyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carbonyl]amino]pyridine-2-carboxylate (65 mg, 60%). ESI-MS m/z calc. 519.16174, found 520.5 (M+1) + ; Retention time (Method D): 1.01 minutes

Step 5: 5-Tert-Butyl-N-(2-Carbamoyl-4-Pyridyl)-3-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]Pyridine-2-Carboxamide (238)

Methyl 4-[[5-tert-butyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carbonyl]amino]pyridine-2-carboxylate (70 mg, 0.1348 mmol) was added to ammonia (2.6 mL, 18.32 mmol) (7N in methanol) and the mixture was stirred overnight at RT. The mixture was concentrated under reduced pressure to give 5-tert-butyl-N-(2-carbamoyl-4-pyridyl)-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carboxamide (35 mg, 41%). 1H NMR (500 MHz, DMSO-d6) δ 8.55 (d, J=1.9 Hz, 1H), 8.51 (d, J=5.4 Hz, 1H), 8.44 (d, J=2.1 Hz, 1H), 8.06 (d, J=2.8 Hz, 1H), 7.90 (dd, J=5.6, 2.1 Hz, 1H), 7.61 (d, J=2.8 Hz, 1H), 7.30 (d, J=1.9 Hz, 1H), 7.24-7.16 (m, 2H), 7.13-7.05 (m, 2H), 6.99-6.87 (m, 1H), 3.79 (s, 3H), 1.29 (s, 7H) ppm. ESI-MS m/z calc. 504.16205, found 505.6 (M+1) + ; Retention time (Method E): 3.34 minutes.

4-[[6-[2-Chloro-4-(Trifluoromethoxy)Phenoxy]-2,2-Difluoro-4-Methyl-1,3-Benzodioxole-5-Carbonyl]Amino]Pyridine-2-Carboxamide (239)

To 2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylic acid (2.5 g, 11.57 mmol) was added palladium(II) acetate (610 mg, 2.717 mmol), tetramethylammonium bromide (2.9 g, 18.83 mmol), (acetyloxy)(phenyl)-lambda3-iodanyl acetate (7.9 g, 24.53 mmol), iodine (6.5 g, 25.61 mmol) and DCE (25 mL) and the reaction was stirred at 60° C. for 16 h. Additional palladium(II) acetate (610 mg, 2.717 mmol), tetramethylammonium bromide (2.9 g, 18.83 mmol), (acetyloxy)(phenyl)-lambda3-iodanyl acetate (7.9 g, 24.53 mmol), and iodine (6.5 g, 25.61 mmol) were added to the reaction and it was and heated at 60° C. for 68 h. The reaction was allowed to cool to RT and was acidified with 1 M HCl. A solution of sodium bisulfite (˜ 40%) was added to the mixture and it was extracted with DCM (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure. The crude product was dissolved in DMSO, filtered and purified by reverse phase HPLC (C 18 column, gradient of CH 3 CN and water (5 mM HCl)) to yield 6-bromo-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylic acid (1.3118 g, 38%) as a white solid. ESI-MS m/z calc. 293.93393, found 295.0 (M+1) + ; Retention time (Method A): 0.56 minutes.

Step 2: 6-[2-Chloro-4-(Trifluoromethoxy)Phenoxy]-2,2-Difluoro-4-Methyl-1,3-Benzodioxole-5-Carboxylic Acid

A flask containing 6-bromo-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylic acid (1.3 g, 4.406 mmol), toluene (30 mL) and a stirrer bar was flushed with N 2 for 10 min. 2-Chloro-4-(trifluoromethoxy)phenol (1.01 g, 4.752 mmol) and cesium carbonate (3.04 g, 9.33 mmol) were added to the mixture and it was flushed with N 2 for 10 min. Copper iodide (186 mg, 0.977 mmol) was added and the mixture was flushed with N 2 for 10 min. The reaction was stirred at 80° C. with vigorous stirring under N 2 for 14 h. The mixture was allowed to cool to RT, and then diluted with ethyl acetate and water, and acidified with 1 M HCl. The layers were separated and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were filtered and the filtrate was washed with water and brine, dried over sodium sulfate, filtered through a plug of celite and concentrated under reduced pressure. The crude product was dissolved in DMSO, filtered and purified by reverse phase HPLC (C 18 column, gradient of CH 3 CN and water (5 mM HCl)) to yield 6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylic acid (482.5 mg, 26%) as an off-white solid. ESI-MS m/z calc. 425.99295, found 427.1 (M+1) + ; Retention time (Method A): 0.77 minutes.

Step 3: 6-[2-Chloro-4-(Trifluoromethoxy)Phenoxy]-2,2-Difluoro-4-Methyl-1,3-Benzodioxole-5-Carbonyl Chloride

To 6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylic acid (203 mg, 0.476 mmol) and DMF (15 μL, 0.194 mmol) in DCM (2 mL) at 0° C. was added oxalyl chloride (120 μL, 1.376 mmol) dropwise under a N 2 atmosphere. The ice bath was removed after 10 min and the reaction was stirred at RT for 1.5 h. The solvent was evaporated under reduced pressure to afford 6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carbonyl chloride, which was used directly in the next step.

Step 4: 4-[[6-[2-Chloro-4-(Trifluoromethoxy)Phenoxy]-2,2-Difluoro-4-Methyl-1,3-Benzodioxole-5-Carbonyl]Amino]Pyridine-2-Carboxamide (239)

To 4-aminopyridine-2-carboxamide (approximately 41.9 mg, 0.306 mmol) in NMP (500 μL), and DIEA (133 μL, 0.764 mmol) at 0° C. was added a solution of the above acid chloride (68 mg, 0.153 mmol) in NMP (500 μL) slowly. The reaction was stirred at RT for 2.5 h and at 75° C. for 1 h. The crude product was filtered and purified by reverse phase HPLC (C 18 column, gradient of CH 3 CN and water (5 mM HCl)) to yield 4-[[6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carbonyl]amino]pyridine-2-carboxamide (17.1 mg, 21%). ESI-MS m/z calc. 545.0413, found 546.1 (M+1) + ; Retention time (Method C): 2.72 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.27 (d, J=2.1 Hz, 1H), 8.09 (d, J=2.8 Hz, 1H), 7.75 (dd, J=5.5, 2.2 Hz, 1H), 7.69-7.60 (m, 2H), 7.40-7.34 (m, 1H), 7.30 (s, 1H), 7.19 (d, J=9.1 Hz, 1H), 2.31 (s, 3H) ppm.

The compounds set forth in Table 30 were prepared by methods analogous to the preparation of compound 239.

4-[[2-[2-Chloro-4-(Trifluoromethoxy)Phenoxy]-6-Methyl-4-(Trifluoromethoxy)Benzoyl]Amino]Pyridine-2-Carboxamide (241)

2-Methyl-4-(trifluoromethoxy)benzoic acid (7.0 g, 31.80 mmol), (diacetoxyiodo)benzene (12.3 g, 38.19 mmol), I 2 (9.7 g, 38.22 mmol) and Pd(OAc) 2 (380 mg, 1.693 mmol) were combined in DMF (100 mL) under N 2 . The mixture was de-gassed (×3 vacuum-N 2 flush cycles). N 2 was replaced with Ar and the mixture was stirred overnight at 105° C. The mixture was cooled to RT and partitioned between EtOAc and saturated sodium thiosulfate solution. The aqueous phase was extracted with EtOAc (2×) and the combined organics were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with an EtOAc-heptane gradient to give 2-iodo-6-methyl-4-(trifluoromethoxy)benzoic acid (3.57 g, 30%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.75 (s, 1H), 7.71 (dt, J=2.5, 0.9 Hz, 1H), 7.37 (ddt, J=3.1, 2.2, 1.1 Hz, 1H), 2.51 (p, J=1.8 Hz, 3H) ppm. ESI-MS m/z calc. 345.93137, found 345.0 (M−1) − ; Retention time (Method E): 0.84 minutes.

2-Iodo-6-methyl-4-(trifluoromethoxy)benzoic acid (1.0 g, 2.688 mmol) and 2-chloro-4-(trifluoromethoxy)phenol (686 mg, 3.227 mmol) were dissolved in toluene (20 mL) and Cs 2 CO 3 (2.3 g, 7.06 mmol) was added. The mixture was de-gassed (×2 vacuum-N 2 flush cycles) and tetrakis(acetonitrile)copper(I) hexafluorophosphate (246 mg, 0.660 mmol) was added. The mixture was de-gassed and heated at reflux overnight. The mixture was cooled to RT and partitioned between EtOAc and 2M HCl. The aqueous phase was extracted with EtOAc and the combined organics were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with an EtOAc-heptane gradient to give 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoic acid (433 mg, 37%). 1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 7.77 (dd, J=2.9, 0.8 Hz, 1H), 7.41 (ddq, J=9.0, 3.0, 1.0 Hz, 1H), 7.20 (dt, J=2.3, 1.1 Hz, 1H), 7.13 (d, J=9.0 Hz, 1H), 6.84 (d, J=2.1 Hz, 1H), 2.39 (s, 3H) ppm. ESI-MS m/z calc. 430.00427, found 431.0 (M+1) + ; 429.0 (M−1) − ; Retention time (Method D): 0.68 minutes.

2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoic acid (200 mg, 0.4644 mmol) was dissolved in DCM (3 mL) under N 2 and the solution cooled in an ice bath. Oxalyl chloride (120 μL, 1.376 mmol) was added dropwise with stirring, followed by the addition of DMF (3 μL, 0.0387 mmol). After stirring for 35 minutes, the mixture was concentrated and the residue re-dissolved in DCM (3 mL) under N 2 . Ammonia in dioxane (10 mL of 0.5 M, 5.000 mmol) was added with cooling in an ice bath, and after 5 minutes the ice bath was removed and the resulting cloudy solution stirred for 30 minutes. The mixture was concentrated under reduced pressure and the residue partitioned was between EtOAc and water. The aqueous phase was extracted with EtOAc and the combined organics were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzamide (153 mg, 73%) which was taken directly on to the next reaction without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.75 (dt, J=2.8, 0.8 Hz, 1H), 7.65 (s, 1H), 7.42 (ddt, J=9.0, 2.9, 1.1 Hz, 1H), 7.24-7.07 (m, 2H), 6.81-6.68 (m, 1H), 2.41-2.34 (m, 3H) ppm. ESI-MS m/z calc. 429.02026, found 430.0 (M+1) + ; 428.0 (M−1) − ; Retention time (Method D): 0.97 minutes.

Step 4: 4-[[2-[2-Chloro-4-(Trifluoromethoxy)Phenoxy]-6-Methyl-4-(Trifluoromethoxy)Benzoyl]Amino]Pyridine-2-Carboxamide (241)

2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzamide (153 mg, 0.338 mmol), methyl 4-bromopyridine-2-carboxylate (90 mg, 0.417 mmol), Xantphos (40 mg, 0.0691 mmol) and Cs 2 CO 3 (245 mg, 0.752 mmol) were combined in dioxane (4 mL) under N 2 . The mixture was de-gassed (×2 vacuum-N 2 flush cycles) and Pd(OAc) 2 (14 mg, 0.0624 mmol) was added. The mixture was de-gassed (×2 cycles) then heated at 100° C. for 3 hours. The mixture was cooled to RT and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and the combined organics washed with brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was stirred with ammonia in MeOH (5 mL of 7 M) under N 2 over the weekend. The mixture was concentrated and the residue taken up in DMSO, filtered and purified by HPLC. The resulting white solid was only ˜90% pure and was taken up in MeOH and passed through SPE bicarbonate cartridges. The filtrate was concentrated and the residue further purified by silica gel chromatography eluting with an EtOAc-heptane gradient. This material was also ˜90% pure. A final purification by HPLC was carried out to give 4-[[2-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide (34.13 mg, 18%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.31 (d, J=2.1 Hz, 1H), 8.07 (s, 1H), 7.79 (dd, J=5.5, 2.2 Hz, 1H), 7.71 (d, J=2.9 Hz, 1H), 7.63 (s, 1H), 7.49-7.40 (m, 1H), 7.30 (d, J=9.0 Hz, 1H), 7.26 (s, 1H), 6.85 (s, 1H), 2.40 (s, 3H) ppm. ESI-MS m/z calc. 549.0526, found 550.0 (M+1) + ; 548.0 (M−1) − ; Retention time (Method E): 3.46 minutes.

4-[[2-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-6-Methyl-4-(Trifluoromethoxy)Benzoyl]Amino]Pyridine-2-Carboxamide (242)

2-Iodo-6-methyl-4-(trifluoromethoxy)benzoic acid (1.0 g, 2.312 mmol) and 2-methoxy-4-(trifluoromethoxy)phenol (600 mg, 2.883 mmol) were dissolved in toluene (20 mL) and Cs 2 CO 3 (1.9 g, 5.831 mmol) was added. The mixture was de-gassed (×2 vacuum-N 2 flush cycles) and tetrakis(acetonitrile)copper(I) hexafluorophosphate (212 mg, 0.5688 mmol) was added. The mixture was de-gassed and heated at reflux overnight. The mixture was cooled to RT and partitioned between EtOAc and 2M HCl. The aqueous phase was extracted with EtOAc and the combined organics were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using an EtOAc-heptane gradient to give 2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoic acid (651 mg, 66%). 1H NMR (400 MHz, DMSO-d6) δ 13.44 (s, 1H), 7.22 (d, J=2.8 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 7.05 (dt, J=2.2, 1.0 Hz, 1H), 6.99 (ddq, J=8.8, 2.4, 1.2 Hz, 1H), 6.43 (dt, J=2.2, 0.9 Hz, 1H), 3.80 (s, 3H), 2.36 (s, 3H) ppm. ESI-MS m/z calc. 426.0538, found 427.0 (M+1) + ; 425.0 (M−1) − ; Retention time (Method D): 0.67 minutes.

2-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoic acid (200 mg, 0.4692 mmol) was dissolved in DCM (3 mL) under N 2 , the solution was cooled in an ice bath, and oxalyl chloride (120 μL, 1.376 mmol) was added dropwise with stirring followed by the addition of DMF (3 μL, 0.03874 mmol). After stirring for 35 minutes the mixture was concentrated and the residue dissolved in DCM (3 mL) under N 2 . Ammonia in dioxane (10 mL of 0.5 M, 5.000 mmol) was added with cooling in an ice bath. After 5 minutes the ice bath was removed and the resulting cloudy solution stirred for 30 minutes. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and the combined organics were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give 2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzamide (184 mg, 83%) which was taken directly on to the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.61 (s, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.16 (d, J=8.8 Hz, 1H), 7.04-6.97 (m, 2H), 6.39-6.35 (m, 1H), 3.81 (s, 3H), 2.34 (d, J=0.7 Hz, 3H) ppm. ESI-MS m/z calc. 425.0698, found 426.0 (M+1) + ; 424.0 (M−1) − ; Retention time (Method D): 0.94 minutes.

Step 3: 4-[[2-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-6-Methyl-4-(Trifluoromethoxy)Benzoyl]Amino]Pyridine-2-Carboxamide (242)

2-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzamide (184 mg, 0.389 mmol), methyl 4-bromopyridine-2-carboxylate (102 mg, 0.472 mmol), Xantphos (45 mg, 0.0777 mmol) and Cs 2 CO 3 (280 mg, 0.859 mmol) were combined in dioxane (5 mL) under N 2 . The mixture was de-gassed (×2 vacuum-N 2 flush cycles) and Pd(OAc) 2 (15 mg, 0.0661 mmol) added. The mixture was de-gassed (×2 cycles) then heated at 100° C. for 90 minutes. The mixture was cooled to RT and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and the combined organics were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was stirred with ammonia in MeOH (5 mL of 7 M) under N 2 over the weekend. The mixture was concentrated and the residue taken up in DMSO, filtered and purified by HPLC. The resulting white solid was only ˜90% pure by UV. Further purification by silica gel chromatography using an EtOAc-heptane elution gave 4-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide (63.50 mg, 29%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.35 (d, J=2.1 Hz, 1H), 8.07 (d, J=2.8 Hz, 1H), 7.84 (dd, J=5.6, 2.2 Hz, 1H), 7.63 (d, J=2.8 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.19 (d, J=2.7 Hz, 1H), 7.12 (s, 1H), 7.04-6.97 (m, 1H), 6.48 (s, 1H), 3.77 (s, 3H), 2.38 (s, 3H) ppm. ESI-MS m/z calc. 545.1022, found 546.0 (M+1) + ; 544.0 (M−1) − ; Retention time (Method E): 3.38 minutes.

5-[[2-[2-Chloro-4-(Trifluoromethoxy)Phenoxy]-6-Methyl-4-(Trifluoromethoxy)Benzoyl]Amino]Pyridine-2-Carboxamide (243)

A solution of 5-bromopyridine-2-carboxylic acid (10 g, 49.5 mmol) in methanol (165 mL) was treated with sulfuric acid (4.9 g, 2.6 mL, 49.5 mmol) and refluxed overnight. The solution was concentrated and the resulting product partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was separated and the aqueous layer extracted with additional ethyl acetate (2×). The combined organic layers were dried and concentrated to provide methyl 5-bromopyridine-2-carboxylate (10 g).

Step 2: 5-[[2-[2-Chloro-4-(Trifluoromethoxy)Phenoxy]-6-Methyl-4-(Trifluoromethoxy)Benzoyl]Amino]Pyridine-2-Carboxamide (243)

2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzamide (179 mg, 0.354 mmol), methyl 5-bromopyridine-2-carboxylate (92 mg, 0.43 mmol), Xantphos (41 mg, 0.07 mmol) and Cs 2 CO 3 (255 mg, 0.783 mmol) were combined in dioxane (4 mL) under nitrogen. The mixture was degassed (2×vacuum-nitrogen cycles) and Pd(OAc) 2 (13 mg, 0.058 mmol) added. The mixture was again degassed (2×vacuum-nitrogen cycles) then heated at 100° C. for 2 hours. The reaction mixture was cooled to RT and partitioned between ethyl acetate and water. The aqueous phase was extracted with additional ethyl acetate and the combined organics washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was stirred with ammonia in methanol (5 mL, 7 M) under nitrogen overnight. The reaction mixture was concentrated and purified sequentially by silica gel chromatography (ethyl acetate-heptane gradient) and HPLC (acetonitrile/water gradient with ammonia modifier) to provide 5-[[2-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide (23 mg, 12%). ESI-MS m/z calc. 549.05, found 550.0 (M+1) + ; 548.0 (M−1) − ; Retention time (Method E): 3.41 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.82 (d, J=2.5 Hz, 1H), 8.23 (dd, J=8.7, 2.4 Hz, 1H), 8.02 (d, J=8.6 Hz, 1H), 7.99 (s, 1H), 7.71 (d, J=2.8 Hz, 1H), 7.53 (s, 1H), 7.44 (d, J=9.4 Hz, 1H), 7.28 (d, J=9.0 Hz, 2H), 6.89 (s, 1H), 2.41 (s, 3H) ppm.

4-[[3-(Difluoromethyl)-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-2-Methyl-Benzoyl]Amino]Pyridine-2-Carboxamide (244)

To a pressure flask was added 3-bromo-6-iodo-2-methyl-benzoic acid (1000 mg, 2.933 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (611 mg, 2.94 mmol), Cs 2 CO 3 (1.44 g, 4.42 mmol), toluene (18 mL) and a stir bar. The reaction mixture was bubbled with nitrogen for 10 minutes, then copper (I) iodide (563 mg, 2.96 mmol) added. The flask was flushed with nitrogen, capped, and heated at 100° C. with vigorous stirring for 16 hours. The mixture was allowed to cool, and then diluted with ethyl acetate and water. The water layer was acidified with 1 M HCl and the product extracted into ethyl acetate (3×). The combined organics were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. Medium pressure reverse phase chromatography (C 18 , CH 3 CN/water (5 mM HCl) gradient) provided 3-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid (455 mg, 37%). 1 H NMR (400 MHz, Chloroform-d) δ 7.47 (d, J=8.8 Hz, 1H), 7.15-7.06 (m, 1H), 6.85 (ddd, J=6.9, 2.4, 1.1 Hz, 2H), 6.46 (dd, J=8.9, 0.7 Hz, 1H), 3.81 (s, 3H), 2.52 (s, 3H) ppm.

3-Bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid (450 mg, 1.07 mmol) was dissolved in a mixture of dichloromethane (7 mL) and methanol (1.1 mL, 27.16 mmol) and cooled in an ice bath under nitrogen. Diazomethyl(trimethyl)silane in hexanes (1.4 mL of 2 M, 2.8 mmol) was added dropwise and the reaction was stirred on ice for 15 minutes. A solution of acetic acid in methanol (1:5) was added dropwise to quench excess reagent (removal of yellow color and bubbling). The reaction was concentrated and the crude material was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to provide methyl 3-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate (423 mg, 91%) as a clear oil. ESI-MS m/z calc. 434.00, found 435.1 (M+1) + ; Retention time (Method A): 0.82 minutes. 1 H NMR (400 MHz, Chloroform-d) δ 7.43 (d, J=8.8 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 6.83 (d, J=2.7 Hz, 1H), 6.81-6.76 (m, 1H), 6.44 (d, J=8.8, 0.7 Hz, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 2.38 (s, 3H) ppm.

Methyl 3-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate (260 mg, 0.597 mmol) was dissolved in THF (1 mL) and cooled in an ice bath under nitrogen. Isopropylmagnesium chloride in THF (150 μL of 2 M, 0.3 mmol) was added and the reaction mixture was stirred for 5 minutes. n-Butyllithium (240 μL of 2.5 M, 0.6000 mmol) was then added and the reaction was stirred an additional 10 minutes. DMF (100 μL, 1.29 mmol) was added dropwise and the reaction was stirred for 30 minutes. The mixture was quenched with a saturated citric acid solution and extracted with ethyl acetate. The organics were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. Silica gel chromatography (ethyl acetate/hexanes gradient) provided methyl 3-formyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate (103 mg, 45%) as a clear oil. ESI-MS m/z calc. 384.08, found 385.0 (M+1) + ; Retention time (Method A): 0.7 minutes. 1 H NMR (400 MHz, Chloroform-d) δ 10.18 (s, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.13-7.08 (m, 1H), 6.88-6.82 (m, 2H), 6.56 (d, J=8.7 Hz, 1H), 3.96 (s, 3H), 3.79 (s, 3H), 2.65 (s, 3H) ppm.

Methyl 3-formyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate (100 mg, 0.260 mmol) was dissolved in dichloromethane (1 mL) and bis(2-methoxyethyl)aminosulfur trifluoride (240 μL, 1.30 mmol) was added dropwise and the solution was allowed to stir at RT for 3 hours. The reaction was cooled in an ice bath and a saturated solution of sodium bicarbonate was added dropwise until bubbling had ceased. The reaction mixture was extracted with dichloromethane. The organic phase was washed with brine, dried over Na 2 SO 4 and evaporated. Silica gel chromatography (ethyl acetate/hexanes gradient) provided methyl 3-(difluoromethyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate (83 mg, 79%) as a clear oil. 1 H NMR (400 MHz, Chloroform-d) δ 7.41 (d, J=8.6 Hz, 1H), 7.05 (d, J=8.6 Hz, 1H), 6.85-6.79 (m, 2H), 6.72 (t, J=55.4 Hz, 1H), 6.55 (d, J=8.7 Hz, 1H), 3.93 (s, 3H), 3.80 (s, 3H), 2.39 (d, J=1.3 Hz, 3H) ppm.

Methyl 3-(difluoromethyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate (80 mg, 0.20 mmol) and NaOH (500 mg, 12.5 mmol) were combined in a mixture of DMF (5 mL)/water (5 mL) and heated in a sealed vial at 120° C. for 16 hours. The reaction was acidified with conc. HCl to a pH of ˜1 and extracted with ethyl acetate (3×10 mL). The combined organics were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. HPLC purification (CH 3 CN/water (5 mM HCl) gradient) provided 3-(difluoromethyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid (39.6 mg, 51%). ESI-MS m/z calc. 392.07, found 393.3 (M+1) + ; Retention time (Method A): 0.69 minutes.

Step 6: 4-[[3-(Difluoromethyl)-6-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-2-Methyl-Benzoyl]Amino]Pyridine-2-Carboxamide (244)

3-(Difluoromethyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid (36.6 mg, 0.093 mmol) and oxalyl chloride (50 μL, 0.57 mmol) were combined in dichloromethane (800 μL) and a drop of DMF was added. The reaction was stirred at 50° C. for 30 minutes then evaporated to dryness to provide the corresponding acid chloride. The acid chloride was dissolved in dichloromethane (0.5 mL) and added to a solution of 4-aminopyridine-2-carboxamide (14 mg, 0.10 mmol) and DIEA (50 μL, 0.29 mmol) in NMP (0.5 mL). The reaction mixture was stirred at RT for 24 hours. The mixture was filtered and purified by HPLC (CH 3 CN/water (5 mM HCl) gradient) to provide 4-[[3-(difluoromethyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide (6.4 mg, 13%). ESI-MS m/z calc. 511.12, found 512.0 (M+1) + ; Retention time (Method B): 1.64 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.39 (d, J=2.1 Hz, 1H), 8.12 (s, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 7.67 (s, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.20 (t, J=55 Hz, 1H), 7.20 (s, 1H), 7.03-6.98 (m, 1H), 6.61 (d, J=8.6 Hz, 1H), 3.77 (s, 3H), 2.39 (s, 3H) ppm.

5-[[2-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-6-Methyl-4-(Trifluoromethoxy)Benzoyl]Amino]Pyridine-2-Carboxamide (245)

2-Iodo-6-methyl-4-(trifluoromethoxy)benzoic acid (1.0 g, 2.3 mmol) and 2-methoxy-4-(trifluoromethoxy)phenol (600 mg, 2.88 mmol) were dissolved in toluene (20 mL) and Cs 2 CO 3 (1.9 g, 5.8 mmol) added. The mixture was degassed (2×vacuum-nitrogen cycles) and tetrakis(acetonitrile) copper(I) hexafluorophosphate (212 mg, 0.569 mmol) added. The mixture was again degassed and heated at reflux overnight. The reaction mixture was cooled to RT and partitioned between ethyl acetate and 2 M HCl. The aqueous phase was extracted with additional ethyl acetate and the combined organics dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. Silica gel chromatography (ethyl acetate/heptane gradient) provided 2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoic acid (651 mg, 66%). 1 H NMR (400 MHz, DMSO-d6) δ 13.44 (s, 1H), 7.22 (d, J=2.8 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 7.05 (dt, J=2.2, 1.0 Hz, 1H), 6.99 (ddq, J=8.8, 2.4, 1.2 Hz, 1H), 6.43 (dt, J=2.2, 0.9 Hz, 1H), 3.80 (s, 3H), 2.36 (s, 3H) ppm.

2-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoic acid (200 mg, 0.469 mmol) was dissolved in dichloromethane (3 mL) and the solution cooled in an ice bath under nitrogen atmosphere. Oxalyl chloride (120 μL, 1.38 mmol) was added dropwise with stirring, followed by the addition of DMF (3 μL, 0.04 mmol). After stirring for 35 minutes, the reaction mixture was concentrated. The residue was redissolved in dichloromethane (3 mL), cooled to 0° C. under nitrogen, and treated with ammonia in dioxane (10 mL of 0.5 M, 5 mmol). After 5 minutes the ice bath was removed and the resulting cloudy solution stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organics washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to provide 2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzamide (184 mg, 83%). ESI-MS m/z calc. 425.07, found 426.0 (M+1) + ; 424.0 (M−1) − ; Retention time (Method D): 0.94 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.61 (s, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.16 (d, J=8.8 Hz, 1H), 7.04-6.97 (m, 2H), 6.39-6.35 (m, 1H), 3.81 (s, 3H), 2.34 (d, J=0.7 Hz, 3H) ppm.

Step 3: 5-[[2-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-6-Methyl-4-(Trifluoromethoxy)Benzoyl]Amino]Pyridine-2-Carboxamide (245)

2-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzamide (185 mg, 0.370 mmol), methyl 5-bromopyridine-2-carboxylate (96 mg, 0.44 mmol), Xantphos (43 mg, 0.0743 mmol) and Cs 2 CO 3 (266 mg, 0.816 mmol) were combined in dioxane (4 mL) under nitrogen. The mixture was degassed (2×vacuum-nitrogen cycles) and Pd(OAc) 2 (14 mg, 0.062 mmol) added. The mixture was again degassed (2×cycles) then heated at 100° C. for 60 minutes. The reaction mixture was cooled to RT and partitioned between ethyl acetate and water. The aqueous phase was extracted with additional ethyl acetate and the combined organics washed with brine, dried Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-100% ethyl acetate/heptane) to provide methyl 5-(2-(2-methoxy-4-(trifluoromethoxy)phenoxy)-6-methyl-4-(trifluoromethoxy)benzamido)picolinate. The ester product was stirred with ammonia in methanol (5 mL of 7 M) under nitrogen overnight. The reaction mixture was concentrated and purified by HPLC to provide 5-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide (98.5 mg, 48%). ESI-MS m/z calc. 545.10, found 546.0 (M+1) + ; 544.0 (M−1) − ; Retention time (Method E): 3.35 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.88 (dd, J=2.5, 0.7 Hz, 1H), 8.30 (dd, J=8.6, 2.5 Hz, 1H), 8.08-8.01 (m, 1H), 7.99 (s, 1H), 7.53 (s, 1H), 7.25 (d, J=8.8 Hz, 1H), 7.19 (d, J=2.8 Hz, 1H), 7.13 (dd, J=2.2, 1.2 Hz, 1H), 7.00 (ddd, J=8.9, 2.7, 1.3 Hz, 1H), 6.49 (d, J=2.0 Hz, 1H), 3.77 (s, 3H), 2.39 (s, 3H) ppm.

N-(2-Carbamoyl-4-Pyridyl)-6-Cyclopropyl-3-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-5-(Trifluoromethyl)Pyridine-2-Carboxamide (246)

To 3-fluoro-5-(trifluoromethyl)pyridine-2-carboxylic acid (1.40 g, 6.70 mmol) in DMF (14 mL) was added 2-methoxy-4-(trifluoromethoxy)phenol (1.39 g, 6.69 mmol) and Cs 2 CO 3 (6.54 g, 20.1 mmol). The reaction was stirred at 90° C. for 72 hours. The reaction was filtered through a pad of Celite and the filtrate was partitioned between water and ethyl acetate. The organic layer was washed with water, aqueous NaHCO 3 and brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. Silica gel chromatography (10-100% ethyl acetate/hexanes) provided 3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylic acid (1.80 g, 68%) as a white solid. ESI-MS m/z calc. 397.04, found 398.2 (M+1) + ; retention time (Method A): 0.61 minutes.

To an ice-cooled solution of 3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylic acid (4 g, 10.07 mmol) in dichloromethane (50 mL) was added DMF (50 μL, 0.65 mmol) and carefully oxalyl chloride (2.7 mL, 31 mmol). The reaction mixture was allowed to warm to room temperature over 30 minutes. Methanol (15 mL, 370 mmol) was cautiously added and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water (3×30 mL), dried over MgSO 4 and concentrated under reduced pressure to provide methyl 3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate (3.8 g, 92%). ESI-MS m/z calc. 411.05, found 412.5 (M+1) + ; Retention time (Method D): 0.96 minutes. 1 H NMR (500 MHz, Chloroform-d) δ 8.60 (d, J=1.6 Hz, 1H), 7.23 (dd, J=1.7, 0.7 Hz, 1H), 7.17-7.12 (m, 1H), 6.92-6.85 (m, 2H), 4.00 (s, 3H), 3.77 (s, 3H) ppm.

Step 3: Methyl 3-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-1-Oxido-5-(Trifluoromethyl)Pyridin-1-Ium-2-Carboxylate

To a solution of methyl 3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate (1.9 g, 4.6 mmol) in dichloromethane (30 mL) at 0° C. was added urea hydrogen peroxide (915 mg, 9.73 mmol) followed by the slow addition of trifluoroacetic anhydride (1.3 mL, 9.4 mmol). The resulting mixture was stirred at room temperature for 2 hours, then diluted with dichloromethane (30 mL) and treated with a saturated aqueous solution of NaHCO 3 (50 mL). The mixture was stirred for 40 minutes at room temperature. Additional dichloromethane (100 mL) was added and layers were separated. The organic phase was washed with saturated aqueous NaHCO 3 (50 mL), 10% aqueous Na 2 S 2 O 3 (50 mL) and brine (50 mL), then dried over MgSO 4 , filtered and concentrated under reduced pressure to afford methyl 3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-1-oxido-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate (1.95 g, 99%). ESI-MS m/z calc. 427.05, found 428.5 (M+1) + ; 426.6 (M−1) − ; Retention time (Method D): 0.88 minutes. 1 H NMR (500 MHz, Chloroform-d) δ 8.21 (dd, J=1.3, 0.7 Hz, 1H), 7.19 (dd, J=8.2, 0.8 Hz, 1H), 6.93-6.86 (m, 2H), 6.68 (dd, J=1.4, 0.7 Hz, 1H), 4.03 (s, 3H), 3.81 (s, 3H) ppm.

Step 4: Methyl 6-Chloro-3-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-5-(Trifluoromethyl)Pyridine-2-Carboxylate

Methyl 3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-1-oxido-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate (1.0 g, 2.3 mmol) in phosphoryl trichloride (10 mL, 107 mmol) was stirred at 50° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (80 mL) and saturated aqueous NaHCO 3 (50 mL) and the layers separated. The organic layer was washed with brine (50 mL), dried over MgSO 4 , filtered and evaporated under reduced pressure to provide methyl 6-chloro-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate (874 mg, 84%). ESI-MS m/z calc. 445.02, found 446.4 (M+1) + ; Retention time (Method D): 1.08 minutes. 1 H NMR (500 MHz, Chloroform-d) δ 7.35 (s, 1H), 7.18-7.12 (m, 1H), 6.92-6.82 (m, 2H), 3.99 (s, 3H), 3.79 (s, 3H) ppm.

Step 5: Methyl 6-Cyclopropyl-3-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-5-(Trifluoromethyl)Pyridine-2-Carboxylate

A mixture of methyl 6-chloro-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate (690 mg, 1.55 mmol), cyclopropyl boronic acid (1.20 g, 14.0 mmol), K 3 PO 4 (1.50 g, 7.07 mmol), Pd(OAc) 2 (175 mg, 0.780 mmol) and tricyclohexylphosphane (240 μL, 0.780 mmol) in toluene (14 mL) and water (3.5 mL) was heated at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and filtered through Celite. HPLC purification provided methyl 6-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate (522 mg, 75%). 1 H NMR (500 MHz, Chloroform-d) δ 7.28 (s, 1H), 7.04 (d, J=8.7 Hz, 1H), 6.88 (d, J=2.6 Hz, 1H), 6.85 (ddd, J=8.7, 2.7, 1.1 Hz, 1H), 3.94 (s, 3H), 3.83 (s, 3H), 2.36-2.23 (m, 1H), 1.28-1.20 (m, 2H), 1.11-1.01 (m, 2H) ppm.

Step 6: 6-Cyclopropyl-3-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-5-(Trifluoromethyl)Pyridine-2-Carboxylic Acid

Sodium hydroxide (in water) (12 mL of 2 M, 24.00 mmol) was added to a solution of methyl 6-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate (600 mg, 1.329 mmol) in tetrahydrofuran (30 mL) at 0° C. and the resulting mixture stirred at RT for 2 h. The solvent was removed in vacuo and the residual aqueous mixture was acidified to pH-2 by careful addition of 1N HCl. The resulting mixture was extracted with ethyl acetate (3×30 mL) and the combined organic extracts were dried over MgSO 4 and concentrated under reduced pressure to leave 6-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylic acid (560 mg, 96%). 1 H NMR (500 MHz, Chloroform-d) δ 10.53 (s, 1H), 7.24 (s, 1H), 7.15-6.98 (m, 1H), 6.87-6.64 (m, 2H), 3.71 (s, 3H), 2.27 (tdd, J=7.9, 6.4, 3.2 Hz, 1H), 1.11 (d, J=6.3 Hz, 4H) ppm.

Step 7: Methyl 4-[[6-Cyclopropyl-3-[2-Methoxy-4-(Trifluoromethoxy)Phenoxy]-5-(Trifluoromethyl)Pyridine-2-Carbonyl]Amino]Pyridine-2-Carboxylate

To an ice cold solution of methyl 4-aminopyridine-2-carboxylate (47 mg, 0.1043 mmol) in DCM (2.8 mL) was added oxalyl chloride (20 uL, 0.229 mmol) and DMF (0.5 uL, 0.0065 mmol) and the mixture was stirred at RT for 30 minutes. The mixture was