OA21241A

OA21241A - Substituted tetrahydrofurans as modulators of sodium channels.

Info

Publication number: OA21241A
Application number: OA1202200220
Authority: OA
Inventors: Yvonne Schmidt; Dennis James Hurley; Steven John Durrant; Nadia AHMAD; Elisabeth Mary BECK; Lidio CARVALHO MEIRELES; Ewa Iwona CHUDYK; Gorka ETXEBARRIA JARDI; Bhairavi GALAN; Sara S. Hadida Ruah; Ronald Marcellus KNEGTEL; Timothy Donald Neubert; Joanne Louise Pinder; Joseph Pontillo; Robert PULLIN; David Matthew Shaw; Sarah Skerratt; Dean Stamos; Stephen Andrew Thomson; Anisa Nizarali Virani
Original assignee: Vertex Pharmaceuticals Incorporated
Priority date: 2019-12-06
Filing date: 2020-12-04
Publication date: 2024-03-18

Abstract

Compounds, and pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels are provided. Also provided are pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts and methods of using the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions in the treatment of various disorders, including pain.

Description

SUBSTITUTED TETRAHYDROFURANS AS MODULATORS OF SODIUM CHANNELS

CROSS-REFERENCE TO RELATED APPLICATIONS

This application daims the benefït of U.S. Provisional Application No. 62/944,869, filed December 6, 2019, which is incorporated by reference in its entirety.

BACKGROUND

Pain is a protective mechanism that allows healthy animais 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 benefït from inhibition of pain. Neuropathie 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 neuropathie pain conditions in the general population. Pain, 2008.137(3): p. 681-8). Neuropathie pain can be divided into two categories, pain caused by generalized metabolic damage to the nerve and pain caused by a discrète nerve injury. The metabolic neuropathies include post-herpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Discrète nerve injury indications include post-amputation pain, post-surgical nerve injury pain, and nerve entrapment injuries like neuropathie back pain.

Voltage-gated sodium channels (Navs) are involved in pain signaling. Navs are biological mediators of electrical signaling as they médiate the rapid upstroke of the action potential of many excitable cell types (e.g. neurons, skeletal myocytes, cardiac myocytes). The evidence for the rôle 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 ail point to the central rôle of Navs in pain sensation (Rush, A.M. and T.R. Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Navl.8 Sodium Channels. Mol. Interv., 2007. 7(4): p. 192-5); England, S., Voltage-gated sodium channels: the search for subtype-selective analgésies. Expert Opin. Investig. Drugs 17 (12), p*. 1849-64 (2008); Krafte, D. S. and Bannon, A. W., Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8 (1), p. 50-56 (2008)). Navs médiate 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 rôle Navs play in the initiation and propagation of neuronal signais, antagonists that reduce Nav currents can prevent or reduce neural signaling and Nav channels hâve been considered likely targets to reduce pain in conditions where hyperexcitability is observed (Chahine, M., Chatelier, A., Babich, O., and Krupp, J. J., Voltage-gated sodium channels in neurological disorders. CNS Neurol. Disord. Drug Targets 7 (2), p. 144-58 (2008)). Several clinically useful analgésies hâve been identified as inhibitors of Nav channels. The local anesthetic drugs such as lidocaine block pain by inhibiting Nav channels, and other compounds, such as carbamazepine, lamotrigine, and tricyclic antidepressants that hâve proven effective at reducing pain hâve 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 Navs form a subfamily of the voltage-gated ion channel super-family and comprises 9 isoforms, designated Navl.l -Navl.9. The tissue localizations of the nine isoforms vary. Navl.4is the primary sodium channel of skeletal muscle, and Nav 1.5 is primary sodium channel of cardiac myocytes. Navs 1.7, 1.8 and 1.9 are primarily localized to the peripheral nervous System, while Navs 1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the central and peripheral nervous Systems. The functional behaviors of the nine isoforms are similar but distinct in the spécifies 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, Navl.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, Navl.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, Rôles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na⁺ current, and Ca²⁺ current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002. 22(23): p. 10277-90). Navl.8 is involved in spontaneous firing in damaged neurons, like those that drive neuropathie pain (Roza, C., et al., The tetrodotoxin-resistant

Na⁺ channel Navl .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 sélective Navl.8 sodium channel blocker, atténuâtes neuropathie 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 TTXresistant sodium channel Navl.8 in inflammatory and neuropathie, but not post-operative, pain States. Pain, 2006.123(1-2): pp. 75-82; Lai, J., et al., Inhibition of neuropathie pain by decreased expression of the tetrodotoxin-resistant sodium channel, Navl.8. Pain, 2002. 95(1-2): p. 143-52; Dong, X.W., et al., Small interfering RNA-mediated sélective knockdown of Navl.8 tetrodotoxinresistant sodium channel reverses mechanical allodynia in neuropathie 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 présent 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. FEBSLett., 2000. 467(2-3): p. 249-52; Ruangsri, S., et al., Relationship of axonal voltage-gated sodium channel 1.8 (Navl.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats. J. Biol. Chem. 286(46): p. 39836-47). The small DRG neurons whereNavl.8 is expressed include the nociceptors involved in pain signaling. Navl.8 médiates large amplitude action potentials in small neurons of the dorsal root ganglia (Blair, N.T. and B.P. Bean, Rôles of tetrodotoxin (TTX)-sensitive Na⁺current, TTX-resistant Na⁺ current, and Ca²⁺ current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002. 22(23): p. 10277-90). Navl.8 is necessary for rapid répétitive action potentials in nociceptors, and for spontaneous activity of damaged neurons. (Choi, J.S. and S.G. Waxman, Physiological interactions between Navl.7 and Navl.8 sodium channels: a computer simulation study. J. Neurophysiol. 106(6): p. 3173-84; Renganathan, M., T.R. Cummins, and S.G. Waxman, Contribution ofNa(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 Navl.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, Navl.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, Navl.8 mRNA expression levels hâve 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 ofNavl.7, Navl.8 andNavl.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 Navl.8 and Navl.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 Nav inhibitors is their poor therapeutic window, and this is likely a conséquence of their lack of isoform selectivity. SinceNavl.8 is primarily restricted to the neurons that sense pain, sélective Navl.8 blockers are unlikely to induce the adverse events common to non-selective Nav blockers. Accordingly, there remains a need to develop additional Nav channel modulators, preferably those that are highly potent and sélective for Navl .8.

SUMMARY

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

In another aspect, the invention relates to a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable sait 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 sait, 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, neuropathie pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomy pain, hemiorrhaphy pain or abdominoplasty pain), viscéral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, and cardiac arrhythmia, by administering the compound, pharmaceutically acceptable sait, or pharmaceutical composition to the subject.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 depicts an XRPD pattern characteristic of Compound 7, Form A.

Figure 2 depicts TGA thermogram characteristic of Compound 7, Form A.

Figure 3 depicts DSC thermogram characteristic of Compound 7, Form A.

Figure 4 depicts an XRPD pattern characteristic of Compound 7, Form B.

Figure 5 depicts a solid state ^l3C NMR spectrum characteristic of Compound 7, Form B.

Figure 6 depicts a solid State ^,9F NMR spectrum characteristic of Compound 7, Form B.

Figure 7 depicts a TGA thermogram characteristic of Compound 7, Form B.

Figure 8 depicts a DSC thermogram characteristic of Compound 7, Form B.

Figure 9 depicts an IR spectrum characteristic of Compound 7, Form B.

Figure 10 depicts a thermal ellipsoid plot characteristic of Compound 7, Form B.

Figure 11 depicts a thermal ellipsoid plot characteristic of Compound 9, Form A.

Figure 12 depicts an XRPD pattern characteristic of Compound 11, Form A.

Figure 13 depicts an XRPD pattern characteristic of Compound 11, Form B.

Figure 14 depicts a thermal ellipsoid plot characteristic of Compound 11, Form A.

Figure 15 depicts an XRPD pattern characteristic of Compound 19, Form A.

Figure 16 depicts a solid State ¹³C NMR spectrum characteristic of Compound 19, Form A.

Figure 17 depicts a solid state ¹⁹FNMR spectrum characteristic of Compound 19, Form A.

Figure 18 depicts a thermal ellipsoid plot characteristic of Compound 19, Form A.

Figure 19 depicts an XRPD pattern characteristic of Compound 22, Form A.

Figure 20 depicts a solid state ^,3C NMR spectrum characteristic of Compound 22, Form A.

Figure 21 depicts a solid state ¹⁹F NMR spectrum characteristic of Compound 22, Form A.

Figure 22 depicts an XRPD pattern characteristic of Compound 23, Form A.

Figure 23 depicts a solid state ¹³C NMR spectrum characteristic of Compound 23, Form A.

Figure 24 depicts a solid state ¹⁹F NMR spectrum characteristic of Compound 23, Form A.

Figure 25 depicts a thermal ellipsoid plot characteristic of Compound 23, Form A.

Figure 26 depicts an XRPD pattern characteristic of Compound 25, Form A.

DETAILED DESCRIPTION

In one aspect, the invention relates to a compound of formula (I) _R4b1, _R4b2 or a pharmaceutically acceptable sait thereof, wherein:

X^2a is N, N⁺-O-, or C-R^2a;

X^4a is N, N⁺-O-, or C-R^4a;

X^5a isN, N⁺-O-, or C-R^5a;

X^6a is N, N⁺-O-, or C-R^6a;

each R is independently H or Ci-Cô alkyl;

R^2a, R^4a, R^5a, and R^6a are each independently H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl;

R^4bl and R^4b2 are each independently H, Ci-Cô alkyl, Cj-Cô cycloalkyl, or Ci-Cô haloalkyl;

R^5bl and R^5b2 are each independently H, Ci-Cô alkyl, C3-C6 cycloalkyl, or Ci-Cô haloalkyl;

X^3c is N or C-R^3c;

X^4c is N or C-R^4c;

X^5c isNor C-R^5c;

X^6c is N or C-R^6c;

R^2c is H, OH, halo, Ci-Cô alkyl, C2-C6 alkenyl, Ci-Cô haloalkyl, Ci-Cô alkoxy, Ci-Cô haloalkoxy, or -L*-L²-(C3-Cô cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo;

L* is a bond or O;

L² is a bond or Ci-Cô alkylene;

R^3c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl;

R^4c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl;

R^5c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl; and

R^6c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl;

provided that no more than two of X^2a, X^4a, X^5a, and X^6a are N or N⁺-O; and provided that no more than one of X^3c, X^4c, X^5c, and X^6c are N.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein X^2a is C-R^2a; X^5a is C-R^5a; X^6a is C-R^6a; R^4bl and R^4b2 are each independently H, Ci-Ce alkyl, or Ci-Ce haloalkyl; R^5bl and R^5b2 are each independently H, Ci-C₆ alkyl, or Ci-C₆ haloalkyl; X^3c is C-R^3c; X^4c is C-R^4c; X^5c is C-R^5c; X^6c is C-R^6c; and R^2c is H, OH, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.

For purposes of this invention, the Chemical éléments are identified in accordance with the Periodic Table of the Eléments, CAS version, Handbook of Chemistry and Physics, 75^m 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^Λ 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), (I-A), (I-A-l), (I-B), (I-B-l), (I-C), and (I-C-l), and ail of the embodiments thereof, as described herein, and to the compounds identified in Table A, Table B, and Table C.

As described herein, the compounds of the invention comprise multiple variable groups (e.g., R, X^4a, R^5b, etc.). As one of ordinary skill in the art will recognize, combinations of groups envisioned by this invention are those combinations that resuit 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, détection, 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 température of 40 DC or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

The Chemical structures depicted herein are intended to be understood as they would be understood by one of ordinary skill in the art. For example, with respect to formulas (I), (I-A), (IB), and (I-C), one of ordinary skill in the art would understand that X^5a and X^6a are connected by a double bond and that X^4c and X^5c are connected by a single bond, even though the bonds between these groups may be obscured by the atom labels in the Chemical structures. Moreover, one of ordinary skill would understand that a substituent depicted as “CF3” or “F₃C” in a Chemical structure refers to a trifluoromethyl substituent, regardless of which depiction appears in the Chemical structure.

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 molécule by a single bond. For example, a “Ci-Cô 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 “Ci-Cô 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 “alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds, and having the specified number of carbon atoms, which is attached to the rest of the molécule by a single bond. For example, a “C2-C6 alkenyl” group is an alkenyl group having between two 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 molécule by a single bond. For example, a “C3-C8 cycloalkyl” group is a cycloalkyl group having between three and eight carbon atoms.

As used herein, the term alkylene refers to a divalent, 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 molécule by two single bonds. For example, a “Ci-Cô alkylene” group is an alkylene group having between one and six carbon atoms.

As used herein, the terni optionally substituted” refers to a group that is either unsubstituted or substituted with the subsequently identified substituents. For example, a group that is “optionally substituted with 1-2 halo” is either unsubstituted, substituted with 1 halo group, or substituted with 2 halo groups.

Unless otherwise specified, the compounds of the invention, whether identified by Chemical name or Chemical structure, include ail 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, conformational isomers, and tautomers as well as mixtures of stereoisomers, double bond isomers, conformational 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 (^ or '''''', respectively) attached to a stereocenter of a compound, such as in dénotés the relative stereochemistry of the stereocenter, relative to other stereocenter(s) to which bold or hashed straight bonds are attached.

As used herein, in any Chemical structure or formula, a bold or hashed wedge bond (^ or ··'''', respectively) attached to a stereocenter of a compound, such as in dénotés the absolute stereochemistry of the stereocenter, as well as the relative stereochemistry of the stereocenter, relative to other stereocenter(s) to which bold or hashed wedge bonds are attached.

As used herein, the prefix “rac-,” when used in connection with a chiral compound, refers to a racemic mixture of the compound. In a compound bearing the “rac-” prefix, the (R)- and (S)designators in the Chemical name reflect the relative stereochemistry of the compound.

As used herein, the prefix ^urel-,” when used in connection with a chiral compound, refers to a single enantiomer of unknown absolute configuration. In a compound bearing the “rel-” prefix, the (R)- and (S)- designators in the Chemical name reflect the relative stereochemistry of the compound, but do not necessarily reflect the absolute stereochemistry of the compound.

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

In the spécification and daims, 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 élément. 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 présent at approximately the naturel 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 spécification and daims, “H” refers to hydrogen and includes any stable isotope of hydrogen, namely Ή 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 présent at approximately the naturel abundance concentration of hydrogen.

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

As used herein, “D,” “d,” and “²H” 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 (“isotopelabeled” compounds and salts). Examples of stable isotopes which are commercially available and suitable for the invention include without limitation isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, for example ²H, ¹³C, ^I5N, ¹⁸0,¹⁷O, and ³¹P, respectively.

The isotope-labeled compounds and salts can be used in a number of bénéficiai ways, including as médicaments. In some embodiments, the isotope-labeled compounds and salts are deuterium (²H)-labeled. Deuterium (²H)-labeled compounds and salts are therapeutically useful with potential therapeutic advantages over the non-²H-labelled compounds. In general, deuterium (²H)-labeled compounds and salts can hâve 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 présent invention. The isotopelabeled 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 (²H)-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 tum 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 réduction in the rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point région along the coordinate of a multiproduct reaction, the product distribution ratios can be altered substantially. For example, if deuterium is bonded to a carbon atom at a non-exchangeable position, rate différences of kn/kD= 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 sait 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 sait) and the naturel abundance of the isotope.

Where an atom in a compound of the invention, or a pharmaceutically acceptable sait thereof, is designated as deuterium, such compound (or sait) 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 some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein each R is H. In other embodiments, each R is independently H or CH3. In other embodiments, N (R) 2 is NHCH3.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein X^2a is N. In other embodiments, X^2a is C-R^2a. In some embodiments, R^2a is H, D, halo, or Ci-Cô alkyl. In other embodiments, R^2a is H, D, F, or CH3. In some embodiments, X^2a is N, C-H, C-D, C-(Ci-Cô alkyl), or C-halo. In other embodiments, X^2a is N, C-H, C-D, C-CH3, or C-F.

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

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein X^4a is N. In other embodiments, X^4a is N⁺-O’. In other embodiments, X^4a is C-R^4a. In some embodiments, R^4a is halo. In other embodiments, R^4a is H or halo. In other embodiments, R^4a is H or F. In other embodiments, X^4a is C-F. In some embodiments, X^4a is N, N⁺-O‘, C-H, or C-halo. In other embodiments, X^4a is N, N⁺-O’, C-H, or C-F.

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

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein X^5a is N. In other embodiments, X^5a is C-R^5a. In some embodiments, R^5a is H, D, halo, or Ci-Cô alkyl. In other embodiments, R^5a is H, D, F, or CH3. In some embodiments, X^5a is N, C-H, C-D, C-(Ci-Cô alkyl), or C-halo. In other embodiments, X^5a is N, C-H, C-D, C-CH3, or C-F.

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

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein X^6a is N. In other embodiments, X^6a is C-R^6a. In some embodiments, R^6a is H, D, halo, or Ci-Cô alkyl. In other embodiments, R^6a is H, D, F, or CH3. In some embodiments, X^6a is N, C-H, C-D, C-(Ci-Cô alkyl), or C-halo. In other embodiments, X^6a is N, C-H, C-D, C-CH3, or C-F.

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

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein R^4bl and R^4b2 are each independently H or Ci-Cô alkyl. In other embodiments, R^4bl and R^4b2 are each independently H, Ci-Cô alkyl, or C3-C6 cycloalkyl. In other embodiments, R^4bl and R^4b2 are each independently H or CH3. In other embodiments, R^4bl and R^4b2 are each independently H, CH3, CH2CH3, or cyclopropyl. In other embodiments, R^4bl is Ci-Cô alkyl, and R^4b2 is H. In other embodiments, R^4bl is H, and R^4b2 is Ci-Cô alkyl. In other embodiments, R^4bl is CH3, and R^4b2 is H. In other embodiments, R^4bl is H, and R^4b2is CH₃.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein R^5bl and R^5b2 are each independently Ci-Cô alkyl or Ci-Cô haloalkyl. In other embodiments, R^5bl and R^5b2 are each independently H, Ci-Cô alkyl, or Ci-Cô haloalkyl. In other embodiments, R^5bl and R^5b2 are each independently H, CH3, or CF3. In other embodiments, R^5bl and R^5b2 are each independently H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CHF2, CF2CH3, CH2CF3, or CF3. In other embodiments, R^5bl is Ci-Cô alkyl, and R^5b2 is Cj-Cô haloalkyl. In other embodiments, R^5bl is Ci-Cô haloalkyl, and R^5b2 is Ci-Cô alkyl. In other embodiments, R^5bl is CH3, and R^5b2 is CF3. In other embodiments, R^5bI is CF3, and R^5b2 is CH3.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy. In other embodiments, R^2c is OH, halo, Ci-Cô alkyl, C2-C6 alkenyl, Ci-Cô haloalkyl, Ci-Cô alkoxy, CiCô haloalkoxy, or-L‘-L²-(C3-Cô cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R^2c is H. In other embodiments, R^2c is Ci-Cô alkoxy. In other embodiments, R^2c is Ci-Cô haloalkoxy. In other embodiments, R^2c is -LÏ-Lï-tCs-Ce cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R^2c is OH, OCH3, OCD3, OCH2CH3, or OCHF2. In other embodiments, R^2c is H, F, CH3, CH=CH2, OH,

OCH3, OCD3, OCH2CH3, OCH(CH₃)2, OCHF2, , or . In other embodiments, R^2c is OH. In other embodiments, R^2c is OCH3. In other embodiments, R^2c is OCD3.

In other embodiments, R^2c is OCH2CH3. In other embodiments, R^2c is OCHF2.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein X^3c is N. In other embodiments, X^3c is C-R^3c. In other embodiments, R^3c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl. In other embodiments, R^3c is H, CH3, CH2CH3, CHF2, CF3, F, or Cl. In some embodiments, X^3c is N, C-H, C-CH3, C-CH2CH3, CCHF₂, C-CF3, C-F, or C-Cl.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein X^3c is C-R^3c; and R^3c is H, halo, or Ci-Cô alkyl. In other embodiments, R^3c is halo. In other embodiments, R^3c is Ci-Cô alkyl. In other embodiments,

R^3c is H, F, Cl, or CH3. In other embodiments, R^3c is H. In other embodiments, R^3c is F. In other embodiments, R^3c is Cl. In other embodiments, R^3c is CH₃.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein X^4c is N. In other embodiments, X^4c is C-R^4c. In other embodiments, R^4c is H, halo, or Ci-Cô haloalkyl. In other embodiments, R^4c is H, CHF2, CF3, or F. In some embodiments, X^4c is N, C-H, C-CHF2, C-CF3, or C-F.

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

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

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

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

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein R^6c is H.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein X^2a is N, C-H, C-D, C-(Ci-Cô alkyl), or C-halo; X^4a is N, N⁺-O-, C-H, or C-halo; X^5a is N, C-H, C-D, C-(Ci-C6 alkyl), or C-halo; X^6a is N, C-H, CD, C-(Ci-Cô alkyl), or C-halo; each R is H or CH3; R^4bl and R^4b2 are each independently H, Ci-Cô alkyl, or C3-C6 cycloalkyl; R^5bl and R^5b2 are each independently H, Ci-Ce alkyl, or Ci-Cô haloalkyl; R^2c is OH, halo, Ci-Cô alkyl, C2-C6 alkenyl, Ci-Cô haloalkyl, Ci-Cô alkoxy, Ci-Cô haloalkoxy, orL'-L²-(C3-C6 cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo; X^3c is CR^3c; R^3c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl; X^4c is C-R^4c; R^4c is H, halo, or Ci-Cô haloalkyl; X^5c is C-R^5c; R^5c is H or halo; X^6c is C-R^6c; and R^6c is H or halo.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^4bl and R^4b2 are each independently H or Ci-Cô alkyl; R^5bland R^5b2 are each independently Ci-Cô alkyl or Ci-Cô haloalkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein X^2a is N, C-H, C-D, C-CH3, or C-F; X^4a is N, N⁺O-, C-H, or C-F; X^5a is N, C-H, C-D, C-CH3, or C-F; X^6a is N, C-H, C-D, C-CH3, or C-F; each R is H or CH3; R^4bI and R^4b2 are each independently H, CH3, CH2CH3, or cyclopropyl; R^5bl and R^5b2 are each independently H, CH3, CH₂CH₃, CH(CH₃)2, C(CH₃)3, CHF₂, CF₂CH₃, CH₂CF₃, or CF₃; R^2c is

H, F, CH3, CH=CH₂, OH, OCH3, OCD3, OCH₂CH₃, OCH(CH₃)₂, ochf₂, ^λ V3, _or

F fX-F νΟχ/Α X ; X^3c is N, C-H, C-CH3, C-CH₂CH₃, C-CHF₂, C-CF3, C-F, or C-Cl; X^4c is N, C-H,

C-CHF₂, C-CF₃, or C-F; X^5c is N, C-H, C-D, or C-Cl; and X^6c is N, C-H, or C-F.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^4bl and R^4b2 are each independently H or CH3; R^5bI and R^5b2are each independently H, CH3, or CF3; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-C₆ alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6cis H.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^4bl is Ci-C6 alkyl; R^4b2 is H; R^5bl is Ci-C6 alkyl; R^5b2 is CiCô haloalkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is

C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^4bl is H; R^4b2 is Ci-C₆ alkyl; R^5bl is Ci-Cô alkyl; R^5b2 is CiCô haloalkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^4bl is Ci-C6 alkyl; R^4b2 is H; R^5bl is Ci-C6 haloalkyl; R^5b2 is Ci-Cô alkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^5bl is Ci-C6 haloalkyl; R^5b2 is Ci-C6 alkyl; R^4bl is H; R^4b2 is Ci-Cô alkyl; R^2c is Ci-Cô alkoxy or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^5bl is CH3; R^5b2 is CF3; R^4bl is CH3; R^4b2 is H; R^2c is Ci-C6 alkoxy or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^5bl is CH3; R^5b2 is CF3; R^4bI is H; R^4b2 is CH3; R^2c is Ci-C6 alkoxy or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^5bl is CF3; R^5b2 is CH3; R^4bl is CH3; R^4b2 is H; R^2c is Ci-C6 alkoxy or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^5bl is CF3; R^5b2 is CH3; R^4bl is H, and R^4b2 is CH₃; R^2c is CiCô alkoxy or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

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

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

l-A or a pharmaceutically acceptable sait thereof, wherein:

X^2a isN, N⁺-O-, or C-R^2a;

X^4a isN, N⁺-O-, or C-R^4a;

X^5a is N, N⁺-O-, or C-R^5a;

X^6a is N, N⁺-O-, or C-R^6a;

each R is independently H or Ci-Cô alkyl;

R^4bl and R^4b2 are each independently H, Ci-Cô alkyl, C₃-Cô cycloalkyl, or Ci-Cô haloalkyl;

R^5bl and R^5b2 are each independently H, Ci-Cô alkyl, C₃-Cô cycloalkyl, or Ci-Cô haloalkyl;

X^3c isNor C-R^3c;

X^4c is N or C-R^4c;

X^5c is N or C-R^5c;

X^6c is N or C-R^6c;

R^2c is H, OH, halo, Ci-Cô alkyl, C2-Cô alkenyl, Ci-Cô haloalkyl, Ci-Cô alkoxy, Ci-Cô haloalkoxy, or—L¹-L²-(C3-Cô cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo;

L¹ is a bond or O;

L² is a bond or Ci-Cô alkylene;

R^3c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl;

R^4c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl;

R^5c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl; and

R^6c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl;

provided that no more than two of X^2a, X^4a, X^5a, and X^6a are N or N⁺-0‘; and provided that no more than one of X^3c, X^4c, X^5c, and X^6c are N.

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein X^2a is C-R^2a; X^5a is C-R^5a; X^6a is C-R^6a; R^4bl and R^4b2 are each independently H, Ci-Cô alkyl, or Ci-Cô haloalkyl; R^5bI and R^5b2 are each independently H, Ci-Cô alkyl, or Ci-C₆ haloalkyl; X^3c is C-R^3c; X^4c is C-R^4c; X^5c is C-R^5c; X^6c is C-R^6c; and R^2c is H, OH, halo, Ci-Cô alkyl, Ci-Cô haloalkyl, Ci-Cô alkoxy, or Ci-Cô haloalkoxy.

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

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein X^2a is N. In other embodiments, X^2a is C-R^2a. In some embodiments, R^2a is H, D, halo, or Ci-Cô alkyl. In other embodiments, R^2a is H, D, F, or CH3. In some embodiments, X^2a is N, C-H, C-D, C-(Ci-Cô alkyl), or C-halo. In other embodiments, X^2a is N, C-H, C-D, C-CH3, or C-F.

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

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein X^4a is N. In other embodiments, X^4a is N⁺-O*. In other embodiments, X^4a is C-R^4a. In some embodiments, R^4a is halo. In other embodiments, R^4a is H or halo. In other embodiments, R^4a is H or F. In other embodiments, X^4a is C-F. In some embodiments, X^4a is N, N⁺-O', C-H, or C-halo. In other embodiments, X^4a is N, N⁺-O‘, C-H, or C-F.

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

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein X^5a is N. In other embodiments, X^5a is C-R^5a. In some embodiments, R^5a is H, D, halo, or Ci-Cô alkyl. In other embodiments, R^5a is H, D, F, or CH3. In some embodiments, X^5a is N, C-H, C-D, C-(Ci-Cô alkyl), or C-halo. In other embodiments, X^5a is N, C-H, C-D, C-CH3, or C-F.

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

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein X^6a is N. In other embodiments, X^6a is C-R^6a. In some embodiments, R^6a is H, D, halo, or Ci-Cô alkyl. In other embodiments, R^6a is H, D, F, or CH3. In some embodiments, X^6a is N, C-H, C-D, C-(Ci-Cô alkyl), or C-halo. In other embodiments, X^6a is N, C-H, C-D, C-CH3, or C-F.

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

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein R^4bl and R^4b2 are each independently H or Ci-Cô alkyl. In other embodiments, R^4bl and R^4b2 are each independently H, Ci-Cô alkyl, or C3-C6 cycloalkyl. In other embodiments, R^4bl and R^4b2 are each independently H or CH3. In other embodiments, R^4bl and R^4b2 are each independently H, CH3, CH2CH3, or cyclopropyl. In other embodiments, R^4bl is Ci-Cô alkyl, and R^4b2 is H. In other embodiments, R^4bl is H, and R^4b2 is Ci-Cô alkyl. In other embodiments, R^4bl is CH3, and R^4b2 is H. In other embodiments, R^4bl is H, and R^4b2is CH₃.

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein R^5bl and R^5b2 are each independently Ci-Cô alkyl or Ci-Cô haloalkyl. In other embodiments, R^5bl and R^5b2 are each independently H, Ci-Cô alkyl, or Ci-Cô haloalkyl. In other embodiments, R^5bl and R^5b2 are each independently H, CH3, or CF3. In other embodiments, R^5bl and R^5b2 are each independently H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CHF2, CF2CH3, CH2CF3, or CF3. In other embodiments, R^5bl is Ci-Cô alkyl, and R^5b2 is Ci-Cô haloalkyl. In other embodiments, R^5bl is Ci-Cô haloalkyl, and R^5b2 is Ci-Cô alkyl. In other embodiments, R^5bl is CH3, and R^5b2 is CF3. In other embodiments, R^5bI is CF3, and R^5b2 is CH3.

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy. In other embodiments, R^2c is OH, halo, Ci-Cô alkyl, C2-C6 alkenyl, Ci-Cô haloalkyl, Ci-Cô alkoxy, CiCô haloalkoxy, or-L'-L²-(C3-C6 cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R^2c is H. In other embodiments, R^2c is Ci-Cô alkoxy. In other embodiments, R^2c is Ci-Cô haloalkoxy. In other embodiments, R^2c is -L*-L²-(C3-Cô cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R^2c is OH, OCH3, OCD3, OCH2CH3, or OCHF2. In other embodiments, R^2c is H, F, CH3, CH=CH2, OH,

In other embodiments, R^2c is OCH2CH3. In other embodiments, R^2c is OCHF2.

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein X^3c is N. In other embodiments, X^3c is C-R^3c. In other embodiments, R^3c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl. In other embodiments, R^3c is H, CH3, CH2CH3, CHF2, CF3, F, or Cl. In some embodiments, X^3c is N, C-H, C-CH3, C-CH2CH3, CCHF2, C-CF3, C-F, or C-Cl.

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein X^3c is C-R^3c; and R^3c is H, halo, or Ci-Cô alkyl. In other embodiments, R^3c is halo. In other embodiments, R^3c is Ci-Cô alkyl. In other embodiments, R^3c is H, F, Cl, or CH3. In other embodiments, R^3c is H. In other embodiments, R^3c is F. In other embodiments, R^3c is Cl. In other embodiments, R^3c is CH3.

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein X^4c is N. In other embodiments, X^4c is C-R^4c. In • other embodiments, R^4c is H, halo, or Ci-Cô haloalkyl. In other embodiments, R^4c is H, CHF2, CF3, or F. In some embodiments, X^4c is N, C-H, C-CHF₂, C-CF3, or C-F.

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

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

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein X^5c is C-R^5c; and R^5c is H.

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

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

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein X^2a is N, C-H, C-D, C-(Ci-Cô alkyl), or C-halo; X^4a is N, N⁺-O-, C-H, or C-halo; X^5a is N, C-H, C-D, C-(Ci-C₆ alkyl), or C-halo; X^6a is N, C-H, CD, C-(Ci-Cô alkyl), or C-halo; each R is H or CH3; R^4bl and R^4b2 are each independently H, Ci-Cô alkyl, or C3-C6 cycloalkyl; R^5bl and R^5b2 are each independently H, Ci-Cô alkyl, or Ci-Cô haloalkyl; R^2c is OH, halo, Ci-Cô alkyl, C2-C6 alkenyl, Ci-Cô haloalkyl, Ci-Cô alkoxy, Ci-Cô haloalkoxy, orL'-L²-(C3-C6 cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo; X^3c is CR^3c; R^3c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl; X^4c is C-R^4c; R^4c is H, halo, or Ci-Cô haloalkyl; X^5c is C-R^5c; R^5c is H or halo; X^6c is C-R^6c; and R^6c is H or halo.

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^4bl and R^4b2 are each independently H or Ci-Cô alkyl; R^5bland R^5b2 are each independently Ci-Cô alkyl or Ci-Cô haloalkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein X^2a is N, C-H, C-D, C-CH3, or C-F; X^4a is N, N⁺O-, C-H, or C-F; X^5a is N, C-H, C-D, C-CH3, or C-F; X^6a is N, C-H, C-D, C-CH3, or C-F; each R is H or CH3; R^4bl and R^4b2 are each independently H, CH3, CH2CH3, or cyclopropyl; R^5bl and R^5b2 are each independently H, CH3, CH2CH3, CH(CH3)₂, C(CH₃)3, CHF2, CF2CH3, CH2CF3, or CF₃; R^2c is

Η, F, CH₃, CH=CH₂, OH, OCH₃, OCD₃, OCH₂CH₃, OCH(CH₃)₂, OCHF₂, or

F /A-f x ; X^3c is N, C-H, C-CH₃, C-CH₂CH₃, C-CHF₂, C-CF₃, C-F, or C-Cl; X^4c is N, C-H,

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^4bl and R^4b2 are each independently H or CH3; R^5bl and R^5b2are each independently H, CH3, or CF₃; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-C₆ alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6cis H.

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^4bl is Ci-C6 alkyl; R^4b2 is H; R^Sbl is Ci-C6 alkyl; R^5b2 is CiCô haloalkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^Sc is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^4bl is H; R^4b2 is Ci-C6 alkyl; R^5bl is Ci-C6 alkyl; R^5b2 is CiCô haloalkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^4bl is Ci-Cô alkyl; R^4b2 is H; R^5bl is Ci-Cô haloalkyl; R^5b2 is Ci-Cô alkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^5bl is Ci-C6 haloalkyl; R^5b2 is Ci-C6 alkyl; R^4bl is H; R^4b2 is

Ci-Cô alkyl; R^2c is Ci-Cô alkoxy or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^5bl is CH3; R^5b2 is CF3; R^4bI is CH3; R^4b2 is H; R^2c is Ci-C6 alkoxy or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^5bl is CH3; R^5b2 is CF3; R^4bl is H; R^4b2 is CH3; R^2c is Ci-C6 alkoxy or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^5bl is CF3; R^5b2 is CH3; R^4bl is CH3; R^4b2 is H; R^2c is Ci-C6 alkoxy or Ci-Cô haloalkoxy, X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^5bl is CF3; R^5b2 is CH3; R^4bl is H, and R^4b2 is CH₃; R^2c is CiCô alkoxy or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

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

In some embodiments, the invention relates to a compound of formula (I-A-l)

r^4c

Ι-Α-1 or a pharmaceutically acceptable sait thereof, wherein:

X^4a is N, N⁺-O-, orC-R^4a;

each R is independently H or Ci-Cô alkyl;

R^4a is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl;

R^4bl and R^4b2 are each independently H, Ci-Cô alkyl, or Ci-Cô haloalkyl;

R^5bl and R^5b2 are each independently H, Ci-Cô alkyl, or Ci-Cô haloalkyl;

R^2c is H, OH, halo, Ci-Cô alkyl, Ci-Cô haloalkyl, Ci-Cô alkoxy, or Ci-Cô haloalkoxy;

R^3c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl; and

R^4c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl.

In some embodiments, the invention relates to a compound of formula (I-A-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N. In other embodiments, X^4a is N⁺-O'. In other embodiments, X^4a is C-R^4a. In other embodiments, X^4a is C-F.

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

In some embodiments, the invention relates to a compound of formula (I-A-l), or a pharmaceutically acceptable sait thereof, wherein R^4a is halo.

In some embodiments, the invention relates to a compound of formula (I-A-l), or a pharmaceutically acceptable sait thereof, wherein R^4bl and R^4b2 are each independently H or Ci-Cô alkyl. In other embodiments, R^4bl and R^4b2 are each independently H or CH3. In other embodiments, R^4bl is Ci-Cô alkyl, and R^4b2 is H. In other embodiments, R^4bl is H, and R^4b2 is Ci-Cô alkyl. In other embodiments, R^4bl is CH3, and R^4b2 is H. In other embodiments, R^4bl is H, and R^4b2is CH₃.

In some embodiments, the invention relates to a compound of formula (I-A-l), or a pharmaceutically acceptable sait thereof, wherein R^5bl and R^5b2 are each independently Ci-Cô alkyl or Ci-Cô haloalkyl. In other embodiments, R^5bl and R^5b2 are each independently H, CH3, or CF3. In other embodiments, R^5bl is Ci-C6 alkyl, and R^5b2 is Ci-C6 haloalkyl. In other embodiments, R^5bl is Ci-Cô haloalkyl, and R^5b2 is Ci-Cô alkyl. In other embodiments, R^5bl is CH3, and R^5b2 is CF3. In other embodiments, R^5bl is CF3, and R^5b2 is CH₃.

In some embodiments, the invention relates to a compound of formula (I-A-l), or a pharmaceutically acceptable sait thereof, wherein R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy. In other embodiments, R^2c is Ci-Cô alkoxy. In other embodiments, R^2c is Ci-Cô haloalkoxy. In other embodiments, R^2c is OH, OCH3, OCD3, OCH2CH3, or OCHF2. In other embodiments, R^2c is OH. In other embodiments, R^2c is OCH3. In other embodiments, R^2c is OCD₃. In other embodiments, R^2c is OCH2CH3. In other embodiments, R^2c is OCHF2.

In some embodiments, the invention relates to a compound of formula (I-A-l), or a pharmaceutically acceptable sait thereof, wherein R^3c is H, halo, or Ci-Cô alkyl. In other embodiments, R^3c is halo. In other embodiments, R^3c is Ci-Cô alkyl. In other embodiments, R^3c is H, F, Cl, or CH₃. In other embodiments, R^3c is H. In other embodiments, R^3c is F. In other embodiments, R^3c is Cl. In other embodiments, R^3c is CH3.

In some embodiments, the invention relates to a compound of formula (I-A-l), or a pharmaceutically acceptable sait thereof, wherein R^4c is halo. In other embodiments, R^4c is F.

In some embodiments, the invention relates to a compound of formula (I-A-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl and R^4b2 are each independently H or Ci-Cô alkyl; R^5bl and R^5b2 are each independently Ci-Cô alkyl or Ci-Cô haloalkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-A-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl and R^4b2 are each independently H or CH3; R^5bl and R^5b2 are each independently H, CH3, or CF3; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-A-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is Ci-Cô alkyl; R^4b2 is

H; R^5bl is Ci-Cô alkyl; R^5b2 is Ci-Cô haloalkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-A-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is H; R^4b2 is Ci-Cô alkyl; R^5bl is Ci-Cô alkyl; R^5b2 is Ci-Cô haloalkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; R^3cis H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-A-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is Ci-Cô alkyl; R^4b2 is H; R^5bI is Ci-Cô haloalkyl; R^5b2 is Ci-Cô alkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-A-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is H; R^4b2 is Ci-Cô alkyl; R^5bl is Ci-Cô haloalkyl; R^5b2 is Ci-Cô alkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; R^3cis H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-A-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is CH3; R^4b2 is H; R^5blis CH3; R^5b2 is CF₃; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy, R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-A-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is H; R^4b2 is CH3; R^5blis CH3; R^5b2 is CF₃; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy, R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-A-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is CH3; R^4b2 is H; R^5blis CF3; R^5b2 is CH₃; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-A-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is H, and R^4b2 is CH3; R^5bI is CF3; R^5b2 is CH₃; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy, R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

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

In some embodiments, the invention relates to a compound of formula (I-B)

χ³Λ , x^5c x^4c l-B 9 or a pharmaceutically acceptable sait thereof, wherein:

X^2a isN, N⁺-O-, or C-R^2a;

X^4a is N, N⁺-O-, orC-R^4a;

X^5a is N, N⁺-O-, or C-R^5a;

X^6a isN, N⁺-O-, orC-R^6a;

each R is independently H or Ci-Cô alkyl;

R^4bl and R^4b2 are each independently H, Ci-Cô alkyl, C3-C6 cycloalkyl, or Ci-Cô haloalkyl;

X^3c isNor C-R^3c;

X^4c isNor C-R^4c;

X^5c isNorC-R^5c;

X^6c is N or C-R^6c;

R^2c is H, OH, halo, Ci-Cô alkyl, C2-C6 alkenyl, Ci-Cô haloalkyl, Ci-Cô alkoxy, Ci-Cô haloalkoxy, or-L'-lAfCs-Cô cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo;

L¹ is a bond or O;

L² is a bond or Ci-Cô alkylene;

R^3c is H, halo, Ci-Ce alkyl, or Ci-Cô haloalkyl;

R^4c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl;

R^5c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl; and

R^6c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl;

provided that no more than two of X^2a, X^4a, X^5a, and X^6a are N or N⁺-O'; and provided that no more than one of X^3c, X^4c, X^5c, and X^6c are N.

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X^2a is C-R^2a; X^5a is C-R^5a; X^6a is C-R^6a; R^4bl and R^4b2 are each independently H, Ci-C6 alkyl, or Ci-C6 haloalkyl; R^5bl and R^5b2 are each independently H, Ci-Cô alkyl, or Ci-C6 haloalkyl; X^3c is C-R^3c; X^4c is C-R^4c; X^5c is C-R^5c; X^6c is C-R^6c; and R^2c is H, OH, halo, Ci-Cô alkyl, Ci-Cô haloalkyl, Ci-Cô alkoxy, or Ci-Cô haloalkoxy.

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

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X^2a is N. In other embodiments, X^2a is C-R^2a. In some embodiments, R^2a is H, D, halo, or Ci-Cô alkyl. In other embodiments, R^2a is H, D, F, or CH3. In some embodiments, X^2a is N, C-H, C-D, C-(Ci-Cô alkyl), or C-halo. In other embodiments, X^2a is N, C-H, C-D, C-CH3, or C-F.

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X^2a is C-R^2a; and R^2a is H.

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X^4a is N. In other embodiments, X^4a is N⁺-O'. In other embodiments, X^4a is C-R^4a. In some embodiments, R^4a is halo. In other embodiments, R^4a is H or halo. In other embodiments, R^4a is H or F. In other embodiments, X^4a is C-F. In some embodiments, X^4a is N, N⁺-O, C-H, or C-halo. In other embodiments, X^4a is N, N⁺-O’, C-H, or C-F.

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

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X^5a is N. In other embodiments, X^5a is C-R^5a. In some embodiments, R^5a is H, D, halo, or Ci-Cô alkyl. In other embodiments, R^5a is H, D, F, or CH3. In some embodiments, X^5a is N, C-H, C-D, C-(Ci-Cô alkyl), or C-halo. In other embodiments, X^5a is N, C-H, C-D, C-CH3, or C-F.

In sonie embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X$^a is C-R^^a; and R^5a is H.

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X^6a is N. In other embodiments, X^6a is C-R . In some embodiments, R^ba is H, D, halo, or Ci-Cô alkyl. In other embodiments, R is H, D, F, or CH3. In some embodiments, X^6a is N, C-H, C-D, C-(Ci-C₆ alkyl), or C-halo. In other embodiments, X^6a is N, C-H, C-D, C-CH3, or C-F.

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

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein R^4bl and R^4b2 are each independently H or Ci-C6 alkyl. In other embodiments, R^4bl and R^4b2 are each independently H, Ci-C6 alkyl, or C3-C6 cycloalkyl. In other embodiments, R^4bl and R^4b2 are each independently H or CH3. In other embodiments, R^4bl and R^4b2 are each independently H, CH3, CH2CH3, or cyclopropyl. In other embodiments, R^4bl is Ci-Cô alkyl, and R^4b2 is H. In other embodiments, R^4bl is H, and R^4b2 is Ci-Cô alkyl. In other embodiments, R^4bl is CH3, and R^4b2 is H. In other embodiments, R^4bl is H, and R^4b2is CH3.

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein R^5bl and R^5b2 are each independently Ci-Cô alkyl or Ci-Cô haloalkyl. In other embodiments, R^5bI and R^5b2 are each independently H, Ci-Cô alkyl, or Ci-Cô haloalkyl. In other embodiments, R^5bl and R^5b2 are each independently H, CH3, or CF3. In other embodiments, R^5bl and R^5b2 are each independently H, CH3, CH2CH3, CH(CH3)2, C(CH3)j, CHF₂, CF2CH3, CH2CF3, or CF3. In other embodiments, R^5bl is Ci-Cô alkyl, and R^5b2 is Ci-Cô haloalkyl. In other embodiments, R^5bl is Ci-Cô haloalkyl, and R^5b2 is Ci-Cô alkyl. In other embodiments, R^5bI is CH3, and R^5b2 is CF3. In other embodiments, R^5bl is CF3, and R^5b2 is CH3.

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy. In other embodiments, R^2c is OH, halo, Ci-Cô alkyl, C2-C6 alkenyl, Ci-Cô haloalkyl, Ci-Cô alkoxy, CiCô haloalkoxy, or-L'-L²-(C3-Cô cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R^2c is H. In other embodiments, R^2c is Ci-Cô alkoxy. In other embodiments, R^2c is Ci-Cô haloalkoxy. In other embodiments, R^2c is -L'-L²-(C3-C6 cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R^2c is OH, OCH3, OCD3, OCH2CH3, or OCHF2. In other embodiments, R^2c is H, F, CH3, CH=CH2, OH,

OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCHF2,

or

F . In other embodiments, R^2c is OH. In other embodiments, R^2c is OCH3. In other embodiments, R^2c is OCD3.

In other embodiments, R^2c is OCH2CH3. In other embodiments, R^2c is OCHF2.

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X^3c is N. In other embodiments, X^3c is C-R^3c. In other embodiments, R^3c is H, halo, Ci-C₆ alkyl, or Ci-C₆ haloalkyl. In other embodiments, R^3c is H,

CH3, CH2CH3, CHF2, CF3, F, or Cl. In some embodiments, X^3c is N, C-H, C-CH3, C-CH2CH3, CCHF₂, C-CF3, C-F, or C-Cl.

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X^3c is C-R^3c; and R^3c is H, halo, or Ci-Cô alkyl. In other embodiments, R^3c is halo. In other embodiments, R^3c is Ci-Cô alkyl. In other embodiments, R^3c is H, F, Cl, or CH3. In other embodiments, R^3c is H. In other embodiments, R^3c is F. In other embodiments, R^3c is Cl. In other embodiments, R^3c is CH3.

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X^4c is N. In other embodiments, X^4c is C-R^4c. In other embodiments, R^4c is H, halo, or Ci-Cô haloalkyl. In other embodiments, R^4c is H, CHF2, CF3, or F. In some embodiments, X^4c is N, C-H, C-CHF2, C-CF3, or C-F.

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

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

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

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X^6c is N. In other embodiments, X^6c is C-R^6c. In other embodiments, R^6c is H or halo. In other embodiments, R^6c is H or F. In some embodiments, X^6c isN, C-H, or C-F.

In some embodiments, the invention relates to a compound of formula (IB), or a pharmaceutically acceptable sait thereof, wherein R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X^2a is N, C-H, C-D, C-(Ci-Cô alkyl), or C-halo; X^4a is N, N⁺-Q-, C-H, or C-halo; X^5a is N, C-H, C-D, C-(Ci-C6 alkyl), or C-halo; X^6a is N, C-H, CD, C-(Ci-Cô alkyl), or C-halo; each R is H or CH3; R^4bl and R^4b2 are each independently H, Ci-Cô alkyl, or C3-Cô cycloalkyl; R^5bl and R^5b2 are each independently H, Ci-Cô alkyl, or Ci-Cô haloalkyl; R^2c is OH, halo, Ci-C6 alkyl, C₂-C₆ alkenyl, Ci-C₆ haloalkyl, Ci-C₆ alkoxy, Ci-C₆ haloalkoxy, orL'-L²-(C3-C6 cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo; X^3c is Cr3c; R3c j_s halo, Ci-Cô alkyl, or Ci-Cô haloalkyl; X^4c is C-R^4c; R^4c is H, halo, or Ci-Cô haloalkyl; X^5c is C-R^5c; R^5c is H or halo; X^6c is C-R^6c; and R^6c is H or halo.

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^4bl and R^4b2 are each independently H or Ci-Cô alkyl; R^5bland R^5b2 are each independently Ci-Cô alkyl or Ci-Cô haloalkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-C₆ alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X^2a is N, C-H, C-D, C-CH3, or C-F; X^4a is N, N⁺O-, C-H, or C-F; X^5a is N, C-H, C-D, C-CH3, or C-F; X^6a is N, C-H, C-D, C-CH3, or C-F; each R is H or CH3; R^4bI and R^4b2 are each independently H, CH3, CH2CH₃, or cyclopropyl; R^5bl and R^5b2 are each independently H, CH3, CH2CH3, CH(CH3)₂, C(CH3)3, CHF2, CF2CH3, CH2CF3, or CF3; R^2c is

H, F, CH3, CH=CH₂, OH, OCH₃, OCD3, OCH2CH3, OCH(CH₃)2, OCHF2, or

F rV-F \ ; X^3c is N, C-H, C-CH3, C-CH₂CH₃, C-CHF₂, C-CF₃, C-F, or C-Cl; X^4c is N, C-H,

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R , R is H, X is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^4bl and R^4b2 are each independently H or Clh; R^5bl and R^5b2are each independently H, CH3, or CF3; R^2c is OH, Ci-C6 alkoxy, or Ci-C₆ haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-C₆ alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H, X is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^4bl is Ci-C6 alkyl; R^4b2 is H; R^5bl is Ci-C6 alkyl; R^5b2 is CiCô haloalkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H, X^3a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^4bl is H; R^4b2 is Ci-Cô alkyl; R^5bl is Ci-Cô alkyl; R^5b2 is CiCô haloalkyl; R^2c is OH, Ci-C₆ alkoxy, or Ci-C₆ haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^4bl is Ci-Cô alkyl; R^4b2 is H; R^5bl is Ci-Cô haloalkyl; R^5b2 is Ci-Cô alkyl; R^2c is OH, Ci-C6 alkoxy, or Ci-C6 haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-C6 alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^5bl is Ci-C₆ haloalkyl; R^5b2 is Ci-Cô alkyl; R^4bl is H; R^4b2 is Ci-Cô alkyl; R^2c is Ci-Cô alkoxy or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X²³ is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^5bl is CH3; R^5b2 is CF3; R^4bl is CH3; R^4b2 is H; R^2c is Ci-C6 alkoxy or Ci-C₆ haloalkoxy, X^3c is C-R^3c; R^3c is H, halo, or Ci-C₆ alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H, X^2a is C-R , R is H, X is C-R^Sa; R^5a is H; X^6a is C-R^6a; R^6a is H; R^5bl is CH3; R^5b2 is CF3; R^4bl is H; R^4b2 is CH3; R^2c is Ci-C6 alkoxy or Ci-C₆ haloalkoxy, X^3c is C-R^3c; R^3c is H, halo, or Ci-C₆ alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R ,R is H, X is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^5bl is CF3; R^5b2 is CH3; R^4bl is CH3; R^4b2 is H; R^2c is Ci-C6 alkoxy or Ci-C₆ haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-C₆ alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^Sc; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a, R is H, X is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^5bl is CF3; R^5b2 is CH3; R^4bl is H, and R^4b2 is CH3; R^2c is CiCô alkoxy or Ci-C6 haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-C₆ alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

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

In some embodiments, the invention relates to a compound of formula (I-B-l)

R^5b;

R^5b2n or a pharmaceutically acceptable sait thereof, wherein:

X^4a isN, N⁺-O-, or C-R^4a;

each R is independently H or Ci-Cô alkyl;

R^4a is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl;

R^4bl and R^4b2 are each independently H, Ci-Cô alkyl, or Ci-Cô haloalkyl;

R^5bl and R^5b2 are each independently H, Ci-Cô alkyl, or Ci-Cô haloalkyl;

R^3c is H, halo, Ci-C₆ alkyl, or Ci-Cô haloalkyl; and

R^4c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl.

In some embodiments, the invention relates to a compound of formula (I-B-l ), or a pharmaceutically acceptable sait thereof, wherein X^4a is N. In other embodiments, X is N -O . In other embodiments, X^4a is C-R^4a. In some embodiments, R^4a is halo. In other embodiments, X^4a is C-F.

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

In some embodiments, the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable sait thereof, wherein R^4a is halo. .

In some embodiments, the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable sait thereof, wherein R^4bl and R^4b2 are each independently H or Ci-C6 alkyl. In other embodiments, R^4bl and R^4b2 are each independently H or CH3. In other embodiments, R^4bl is Ci-Cô alkyl, and R^4b2 is H. In other embodiments, R^4bl is H, and R^4b2 is Ci-Cô alkyl. In other embodiments, R^4bl is CH3, and R^4b2 is H. In other embodiments, R^4bI is H, and R^4b2is CH3.

In some embodiments, the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable sait thereof, wherein R^5bl and R^5b2 are each independently Ci-Cô alkyl or Ci-Cô haloalkyl. In other embodiments, R^5bl and R^5b2 are each independently H, CH3, or CF3. In other embodiments, R^5bl is Ci-Cô alkyl, and R^5b2 is Ci-Cô haloalkyl. In other embodiments, R^5bl is Ci-Cô haloalkyl, and R^5b2 is Ci-Cô alkyl. In other embodiments, R^5bl is CH3, and R^5b2 is CF3. In other embodiments, R^5bl is CF3, and R^5b2 is CH3.

In some embodiments, the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable sait thereof, wherein R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy. In other embodiments, R^2c is Ci-C6 alkoxy. In other embodiments, R^2c is Ci-Cô haloalkoxy. In other embodiments, R^2c is OH, OCH3, OCD3, OCH2CH3, or OCHF2. In other embodiments, R^2c is OH. In other embodiments, R^2c is OCH3. In other embodiments, R^2c is OCD3. In other embodiments, R^2c is OCH2CH3. In other embodiments, R^2c is OCHF2.

In some embodiments, the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable sait thereof, wherein R^3c is H, halo, or Ci-Cô alkyl. In other embodiments, R^3c is halo. In other embodiments, R^3c is Ci-Cô alkyl. In other embodiments, R^3c is H, F, Cl, or CH₃. In other embodiments, R^3c is H. In other embodiments, R^3c is F. In other embodiments, R^3c is Cl. In other embodiments, R^3c is CH3.

In some embodiments, the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable sait thereof, wherein R^4c is halo. In other embodiments, R is F.

In some embodiments, the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl and R^4b2 are each independently H or Ci-C6 alkyl; R^5bl and R^5b2 are each independently Ci-C6 alkyl or Ci-C₆haloalkyl; R^2c is OH, Ci-C₆ alkoxy, or Ci-Cô haloalkoxy; R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl and R are each independently H or CH3; R^5bl and R^5b2 are each independently H, CH3, or CF3; R^2c is OH, Ci-C6 alkoxy, or Ci-Cô haloalkoxy; R^3c is H, halo, or Ci-C6 alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is Ci-Cô alkyl, R is H; R^5bl is Ci-Cô alkyl; R^5b2 is Ci-C6 haloalkyl; R^2c is OH, Ci-C6 alkoxy, or Ci-C₆ haloalkoxy; R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is H; R^4b2 is Ci-Cô alkyl; R^5b‘ is Ci-C6 alkyl; R^5b2 is Ci-C6 haloalkyl; R^2c is OH, Ci-C₆ alkoxy, or Ci-C₆ haloalkoxy; R^3cis H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is Ci-Cô alkyl; R^4b2 is H; R^5bl is Ci-C6 haloalkyl; R^5b2 is Ci-C6 alkyl; R^2c is OH, Ci-C₆ alkoxy, or Ci-C₆ haloalkoxy; R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is H; R^4b2 is Ci-Cô alkyl; R^5bl is Ci-C6 haloalkyl; R^5b2 is Ci-C6 alkyl; R^2c is OH, Ci-C₆ alkoxy, or Ci-C₆ haloalkoxy, R^3cis H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is CH3; R^4b2 is H; R^5blis CH₃; R^5b2 is CF3; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is H; R^4b2 is CH3; R^5bIis CH3; R^5b2 is CF3; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy, R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is CH3; R^4b2 is H; R^5blis CF3; R^5b2 is CH3; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is H, and R^4b2 is CH3; R^5bI is CF3; R^5b2 is CH3; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

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

In some embodiments, the invention relates to a compound of formula (I-C) c Λ _y6a _Y4a

3.0 χ5ο x^4c l-C or a pharmaceutically acceptable sait thereof, wherein:

X^2a is N, N⁺-O-, or C-R^2a;

X^4a isN, N⁺-O-, or C-R^4a;

X^5a is N, N⁺-O-, or C-R^5a;

X^6a isN, N⁺-O-, or C-R^6a;

each R is independently H or Ci-Cô alkyl;

X^3c is N or C-R^3c;

X^4c is N or C-R^4c;

X^5c isNor C-R^5c;

X^6c is N or C-R^6c;

R^2c is H, OH, halo, Ci-Cô alkyl, Cz-Cô alkenyl, Ci-Cô haloalkyl, Ci-Cô alkoxy, Ci-Cô haloalkoxy, or -L'-L²-(C3-Cô cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo;

L¹ is a bond or O;

L² is a bond or Ci-Cô alkylene;

R^3c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl;

R^4c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl;

R^5c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl; and

R^6c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl;

provided that no more than two of X^2a, X^4a, X^5a, and X^6a are N or N⁺-O‘; and provided that no more than one of X^3c, X^4c, X^5c, and X^6c are N.

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein X^2a is C-R^2a; X^5a is C-R^5a; X^6a is C-R^6a; R^4bl and R^4b2 are each independently H, Ci-Cô alkyl, or Ci-Cô haloalkyl; R^5bl and R^5b2 are each independently H, Ci-Cô alkyl, or Ci-C₆ haloalkyl; X^3c is C-R^3c; X^4c is C-R^4c; X^5c is C-R^5c; X^6c is C-R^6c; and R^2c is H, OH, halo, Ci-Cô alkyl, Ci-Cô haloalkyl, Ci-Cô alkoxy, or Ci-Cô haloalkoxy.

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

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein X^2a is N. In other embodiments, X^2a is C-R^2a. In some embodiments, R^2a is H, D, halo, or Ci-Cô alkyl. In other embodiments, R^2a is H, D, F, or CH3. In some embodiments, X^2a is N, C-H, C-D, C-(Ci-Cô alkyl), or C-halo. In other embodiments, X^2a is N, C-H, C-D, C-CH3, or C-F.

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

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein X^4a is N. In other embodiments, X^4a is N⁺-O'. In other embodiments, X^4a is C-R^4a. In some embodiments, R^4a is halo. In other embodiments, R^4a is H or halo. In other embodiments, R^4a is H or F. In other embodiments, X^4a is C-F. In some embodiments, X^4a is N, N⁺-0‘, C-H, or C-halo. In other embodiments, X^4a is N, N⁺-O’, C-H, or C-F.

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

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein X^5a is N. In other embodiments, X^5a is C-R^5a. In some embodiments, R^5a is H, D, halo, or Ci-Cô alkyl. In other embodiments, R^5a is H, D, F, or CH3. In some embodiments, X^5a is N, C-H, C-D, C-(Ci-Cô alkyl), or C-halo. In other embodiments, X^5a is N, C-H, C-D, C-CH3, or C-F.

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

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein X^6a is N. In other embodiments, X^6a is C-R^6a. In some embodiments, R^6a is H, D, halo, or Ci-Cô alkyl. In other embodiments, R^6a is H, D, F, or CH3. In some embodiments, X^6a is N, C-H, C-D, C-(Ci-Cô alkyl), or C-halo. In other embodiments, X^6a is N, C-H, C-D, C-CH3, or C-F.

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

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein R^4bl and R^4b2 are each independently H or Ci-Cô alkyl. In other embodiments, R^4bl and R^4b2 are each independently H, Ci-Cô alkyl, or C3-Cô cycloalkyl. In other embodiments, R^4bl and R^4b2 are each independently H or CH3. In other embodiments, R^4bl and R^4b2 are each independently H, CH3, CH2CH3, or cyclopropyl. In other embodiments, R^4bl is Ci-Cô alkyl, and R^4b2 is H. In other embodiments, R^4bl is H, and R^4b2 is Ci-Cô alkyl. In other embodiments, R^4bl is CH3, and R^4b2 is H. In other embodiments, R^4bl is H, and R^4b2is CH₃.

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein R^5bl and R^5b2 are each independently Ci-Cô alkyl or Ci-Cô haloalkyl. In other embodiments, R^5bl and R^5b2 are each independently H, Ci-Cô alkyl, or Ci-Cô haloalkyl. In other embodiments, R^5bl and R^5b2 are each independently H, CH3, or CF3. In other embodiments, R^5bl and R^5b2 are each independently H, CH3, CH2CH₃, CH(CH₃)2, C(CH₃)₃, CHF2, CF2CH5, CH2CF3, or CF₃. In other embodiments, R^5bl is Ci-Cô alkyl, and R^5b2 is Ci-Cô haloalkyl. In other embodiments, R^5bl is Ci-Cô haloalkyl, and R^5b2 is Ci-Cô alkyl. In other embodiments, R^5bl is CH3, and R^5b2 is CF3. In other embodiments, R^5bl is CF3, and R^5b2 is CH3.

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy. In other embodiments, R^2c is OH, halo, Ci-Cô alkyl, C2-C6 alkenyl, Ci-Cô haloalkyl, Ci-Cô alkoxy, CiCô haloalkoxy, or-L’-L²-(C3-Cô cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R^2c is H. In other embodiments, R^2c is Ci-Cô alkoxy. In other embodiments, R^2c is Ci-Cô haloalkoxy. In other embodiments, R^2c is -L'-L²-(C3-Cô cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo. In other embodiments, R^2c is OH,

OCH3, OCD₃, OCH2CH3, or OCHF2. In other embodiments, R^2c is H, F, CH3, CH=CH2, OH,

OCH3, OCD3, OCH2CH3, OCH(CH₃)₂, OCHF2,

embodiments, R^2c is OH. In other embodiments, R^2c is OCH3. In other embodiments, R^2c is OCD3.

In other embodiments, R^2c is OCH2CH3. In other embodiments, R^2c is OCHF2.

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein X^3c is N. In other embodiments, X^3c is C-R^3c. In other embodiments, R^3c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl. In other embodiments, R^3c is H, CH3, CH2CH3, CHF2, CF3, F, or Cl. In some embodiments, X^3c is N, C-H, C-CH3, C-CH2CH3, CCHF₂, C-CF3, C-F, or C-Cl.

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein X^3c is C-R^3c; and R^3c is H, halo, or Ci-Cô alkyl. In other embodiments, R^3c is halo. In other embodiments, R^3c is Ci-Cô alkyl. In other embodiments, R^3c is H, F, Cl, or CH3. In other embodiments, R^3c is H. In other embodiments, R^3c is F. In other embodiments, R^3c is Cl. In other embodiments, R^3c is CH3.

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein X^4c is N. In other embodiments, X^4c is C-R^4c. In other embodiments, R^4c is H, halo, or Ci-Cô haloalkyl. In other embodiments, R^4c is H, CHF2, CF3, or F. In some embodiments, X^4c is N, C-H, C-CHF2, C-CF3, or C-F.

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

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

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

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

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

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein X^2a is N, C-H, C-D, C-(Ci-Cô alkyl), or C-halo; X^4a is N, N⁺-O-, C-H, or C-halo; X^5a is N, C-H, C-D, C-(Ci-C₆ alkyl), or C-halo; X^6a is N, C-H, CD, C-(Ci-Cô alkyl), or C-halo; each R is H or CH3; R^4bl and R^4b2 are each independently H, Ci-Cô alkyl, or C3-C6 cycloalkyl; R^5bl and R^5b2 are each independently H, Ci-Cô alkyl, or Ci-Cô haloalkyl; R^2c is OH, halo, Ci-Cô alkyl, C2-C6 alkenyl, Ci-Cô haloalkyl, Ci-Cô alkoxy, Ci-Cô haloalkoxy, or — L'-L²-(C3-Cô cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo; X^3c is CR^3c; R^3c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl; X^4c is C-R^4c; R^4c is H, halo, or Ci-Cô haloalkyl; X^5c is C-R^5c; R^5c is H or halo; X^6c is C-R^6c; and R^6c is H or halo.

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^4bl and R^4b2 are each independently H or Ci-Cô alkyl; R^5bland R^5b2 are each independently Ci-Cô alkyl or Ci-Cô haloalkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-C₆ alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein X^2a is N, C-H, C-D, C-CH3, or C-F; X^4a is N, N⁺O-, C-H, or C-F; X^5a is N, C-H, C-D, C-CH3, or C-F; X^6a is N, C-H, C-D, C-CH3, or C-F; each R is H or CH3; R^4bl and R^4b2 are each independently H, CH3, CH2CH3, or cyclopropyl; R^5bl and R^5b2 are each independently H, CH3, CH2CH3, CH(CH₃)₂, C(CH₃)3, CHF₂, CF2CH3, CH2CF3, or CF₃; R^2c is

H, F, CH₃, CH=CH₂, OH, OCH₃, OCD3, OCH2CH3, OCH(CH₃)₂, OCHF2, ^X A , _or

F \ ; X^3c is N, C-H, C-CH₃, C-CH₂CH₃, C-CHF₂, C-CF₃, C-F, or C-Cl; X^4c is N, C-H,

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^4bl and R^4b2 are each independently H or CH3; R^5bl and R^5b2are each independently H, CH3, or CF₃; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-C₆ alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6cisH.

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^4bl is Ci-C6 alkyl; R^4b2 is H; R^5bl is Ci-C6 alkyl; R^5b2 is CiCô haloalkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^4bl is H; R^4b2 is Ci-C6 alkyl; R^5bl is Ci-C6 alkyl; R^5b2 is CiCô haloalkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^4bl is Ci-C6 alkyl; R^4b2 is H; R^5bl is Ci-C6 haloalkyl; R^5b2 is Ci-Cô alkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^5bl is Ci-C6 haloalkyl; R^5b2 is Ci-C6 alkyl; R^4bl is H; R^4b2 is Ci-Cô alkyl; R^2c is Ci-Cô alkoxy or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^5bl is CH3; R^5b2 is CF3; R^4bl is CH3; R^4b2 is H; R^2c is Ci-C6 alkoxy or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^5bl is CH3; R^5b2 is CF3; R^4bI is H; R^4b2 is CH3; R^2c is Ci-C6 alkoxy or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^5bI is CF3; R^5b2 is CH3; R^4bl is CH3; R^4b2 is H; R^2c is Ci-C6 alkoxy or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; X^2a is C-R^2a; R^2a is H; X^5a is C-R^5a; R^5a is H; X^6a is C-R^6a; R^6a is H; R^5bl is CF3; R^5b2 is CH3; R^4bI is H, and R^4b2 is CH₃; R^2c is CiCô alkoxy or Ci-Cô haloalkoxy; X^3c is C-R^3c; R^3c is H, halo, or Ci-Cô alkyl; X^4c is C-R^4c; R^4c is halo; X^5c is C-R^5c; R^5c is H; X^6c is C-R^6c; and R^6c is H.

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

In some embodiments, the invention relates to a compound of formula (I-C-l)

r^4c l-C-1 or a pharmaceutically acceptable sait thereof, wherein:

X^4a isN, N⁺-O-, or C-R^4a;

each R is independently H or Ci-Cô alkyl;

R^4a is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl;

R^4bl and R^4b2 are each independently H, Ci-Cô alkyl, or Ci-Cô haloalkyl;

R^5bl and R^5b2 are each independently H, Ci-Cô alkyl, or Ci-Cô haloalkyl;

R^3c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl; and

R^4c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl.

In some embodiments, the invention relates to a compound of formula (I-C-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N. In other embodiments, X^4a is N⁺-O. In other embodiments, X^4a is C-R^4a. In some embodiments, R^4a is halo. In other embodiments, X^4a is C-F.

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

In some embodiments, the invention relates to a compound of formula (I-C-l), or a pharmaceutically acceptable sait thereof, wherein R^4a is halo.

In some embodiments, the invention relates to a compound of formula (I-C-l), or a pharmaceutically acceptable sait thereof, wherein R^4bl and R^4b2 are each independently H or Ci-Cô alkyl. In other embodiments, R^4bl and R^4b2 are each independently H or CH3. In other embodiments, R^4bl is Ci-Cô alkyl, and R^4b2 is H. In other embodiments, R^4bl is H, and R^4b2 is Ci-Cô alkyl. In other embodiments, R^4bl is CH3, and R^4b2 is H. In other embodiments, R^4bl is H, and R^4b2is CH3.

In some embodiments, the invention relates to a compound of formula (I-C-l), or a pharmaceutically acceptable sait thereof, wherein R^5bl and R^5b2 are each independently Ci-Cô alkyl or Ci-Cô haloalkyl. In other embodiments, R^5bl and R^5b2 are each independently H, CH3, or CF3. In other embodiments, R^5bl is Ci-Cô alkyl, and R^5b2 is Ci-Cô haloalkyl. In other embodiments, R^5bl is Ci-Cô haloalkyl, and R^5b2 is Ci-Cô alkyl. In other embodiments, R^5bl is CH3, and R^5b2 is CF3. In other embodiments, R^5bl is CF3, and R^5b2 is CH3.

In some embodiments, the invention relates to a compound of formula (I-C-l), or a pharmaceutically acceptable sait thereof, wherein R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy. In other embodiments, R^2c is Ci-Cô alkoxy. In other embodiments, R^2c is Ci-Cô haloalkoxy. In other embodiments, R^2c is OH, OCH₃, OCD₃, OCH2CH3, or OCHF2. In other embodiments, R^2c is OH. In other embodiments, R^2c is OCH3. In other embodiments, R^2c is OCD3. In other embodiments, R^2c is OCH2CH3. In other embodiments, R^2c is OCHF2.

In some embodiments, the invention relates to a compound of formula (I-C-l), or a pharmaceutically acceptable sait thereof, wherein R^3c is H, halo, or Ci-Cô alkyl. In other embodiments, R^3c is halo. In other embodiments, R^3c is Ci-Cô alkyl. In other embodiments, R^3c is H, F, Cl, or CH3. In other embodiments, R^3c is H. In other embodiments, R^3c is F. In other embodiments, R^3c is Cl. In other embodiments, R^3c is CH3.

In some embodiments, the invention relates to a compound of formula (I-C-l), or a pharmaceutically acceptable sait thereof, wherein R^4c is halo. In other embodiments, R^4c is F.

In some embodiments, the invention relates to a compound of formula (I-C-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl and R^4b2 are each independently H or Ci-Cô alkyl; R^5bI and R^5b2 are each independently Ci-Cô alkyl or Ci-Cô haloalkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-C-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl and R^4b2 are each independently H or CH3; R^5bl and R^5b2 are each independently H, CH3, or CF3; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-C-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is Ci-Cô alkyl; R^4b2 is H; R^5bl is Ci-Cô alkyl; R^5b2 is Ci-Cô haloalkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-C-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is H; R^4b2 is Ci-Cô alkyl; R^5bl is Ci-Cô alkyl; R^5b2 is Ci-Cô haloalkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; R^3cis H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-C-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is Ci-Cô alkyl; R^4b2 is H; R^5bl is Ci-Cô haloalkyl; R^5b2 is Ci-Cô alkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-C-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is H; R^4b2 is Ci-Cô alkyl; R^5bl is Ci-Cô haloalkyl; R^5b2 is Ci-Cô alkyl; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; R^3cis H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-C-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is CH3; R^4b2 is H; R^5blis CH3; R^5b2 is CF₃; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-C-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is H; R^4b2 is CH3; R^5blis CH3; R^5b2 is CF₃; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-C-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bl is CH3; R^4b2 is H; R^5bIis CF3; R^5b2 is CH₃; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

In some embodiments, the invention relates to a compound of formula (I-C-l), or a pharmaceutically acceptable sait thereof, wherein X^4a is N; each R is H; R^4bI is H, and R^4b2 is CH3; R^5bl is CF3; R^5b2 is CH₃; R^2c is OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy; R^3c is H, halo, or Ci-Cô alkyl; and R^4c is halo.

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

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

Table A. Compound Structures and Names.

4-((2R,3R,4R,5S)-3-(4-fluoro-2-methoxyphenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5S)-3-(4-fluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran2-carboxamido)picolinamide

4-((2R,3S,4R,5S)-3-(4-fluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran2-carboxamido)picolinamide

4-((2R,3R,4S,5S)-3-(4-fluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran2-carboxamido)picolinamide

4-((2R,3R,4R,5R)-3-(4-fluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran2-carboxamido)picolinamide

4-((2S,3S,4R,5S)-3-(4-fluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4S,5S)-3-(4-fluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran2-carboxamido)picolinamide

4-((2S,3R.4R,5R)-3-(4-fliioro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran2-carboxamido)picolinamide

4-((2R₁3S,4S,5S)-3-(4-fluoro-2-methoxyphenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R,5R)-3-(4-fluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran2-carboxamido)picolinamide

4-((2R,3R,4S,5R)-3-(4-fluoro-2-methoxyphenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4S,5S)-3-(4-fluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran2-carboxamido)picolinamide

4-((2S,3S,4R,5R)-3-(4-fluoro-2-methoxyphenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4S,5R)-3-(4-fluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran2-carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(4-fluoro-2-methoxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4S,5R)-3-(4-fluoro-2-methoxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5methyI-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,5S)-3-(3,4-difluoro-2-methoxyphenyl)5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,5S)-3-(3₁4-difluoro-2-methoxyphenyl)-5methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,5S)-3-(3,4-difliioro-2-methoxyphenyl)-5methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,5R)-3-(3,4-difIuoro-2-methoxyphenyl)-5methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4R,5S)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5S)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R.3S,4R,5S)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4S,5S)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4R>5R)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4R,5S)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

0 AA VxÂnaAt ^NH2 ^F3° ^H o 0 \==^ ^F””^f ^f 4-((2S,3R,4S,5S)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide	O AA \/⁰\ Α.ΑΑζ^νη2 4-((2S,3R,4R,5R)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide
0 fa N ^F3^C J-V ^H O A ^f 4-((2R,3S,4S,5S)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide	O fa'N vAnAA™^{2 F}3^C' \—l. ^H Q fa A A 4-((2R,3S,4R,5R)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide
o fau νΑ-ΑΛ FaC' W H J A ^F 4-((2R,3R,4S,5R)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide	O fatt A,. 0·^^ A ^f 4-((2S,3S,4S,5S)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4R,5R)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4S,5R)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4S_l5R)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R.3R,4R,5S)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifl uoromethyl)tetrahyd rof u ran-2carboxamido)picolinamide

4-((2S,3R,4R,5S)-3-(3,4-difluoro2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R.4S,5S)-3-(3,4-difluoro2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R.3R.4R,5R)-3-(3,4-difluoro2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4R,5S)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4S,5S)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5R)-3-(3₁4-difluoro2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinannide

4-((2R,3S,4S,5S)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4S,5S)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxyphenyl)4_t5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4S,5R)-3-(3,4-difluoro2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

2-carbamoyl-4-((2R.3R,4R,5S)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2S,3R,4R,5S)-3-(3.4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifl uoromethyl)tetrahyd rof u ran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2R,3S,4R,5S)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2R,3R,4S,5S)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifIuoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2R,3R,4R,5F?)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2S,3S,4R.5S)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyI-4-((2S,3/^:?,4S,5S)-3-(3_l4difluoro-2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2S,3R,4R,5R)-3-(3,4-difluoro2-methoxyphenyl)-4,5-dimethyl-5(trifiuoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2R_t3S,4S,5S)-3-(3,4-difluoro2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2R,3S,4R.5R)-3-(3,4difluoro-2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2R,3R,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyI-4-((2S,3S,4S,5S)-3-(3,4-difluoro2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2S,3S,4R,5R)-3-(3,4-difluoro2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2S,3R,4S₁5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2R,3S,4S,5R)-3-(3,4difluoro-2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2S,3S,4S,5R)-3-(3,4-difIuoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

4-((2R,3R,4R.5S)-3-(3,4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R.5S)-3-(3,4-difIuoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R,5S)-3-(3,4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pico!inamide

4-((2R,3R₁4S,5S)-3-(3,4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4R₁5R)-3-(3,4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4R,5S)-3-(3,4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S₁3R,4S,5S)-3-(3,4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5R)-3-(3,4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S₁5S)-3-(3,4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R₁3S₁4R,5R)-3-(3,4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4S,5R)-3-(3,4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4S,5S)-3-(3,4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S_I3S₁4R,5R)-3-(3₁4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4S_I5R)-3-(3,4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S₁4S,5R)-3-(3,4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4R.5S)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5S)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R₁3S,4R,5S)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4S,5S)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4R,5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4R_l5S)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4S,5S)-3-(2-(difluoromethoxy)-3₁4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pico!inamide

4-((2S,3R,4R₁5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5S)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R,5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4S,5R)-3-(2-(difluoromethoxy)-3_I4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4S,5S)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4R₁5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4S,5R)-3-(2-(difluoromethoxy)-3₁4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R₁3S,4S,5R)-3-(2-(difluoromethoxy)-3₁4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S_l3S,4S,5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

2-carbamoyl-4-((2R,3R,4R,5S)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran2-carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2S,3R,4R,5S)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2R,3S,4R,5S)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4.5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2R,3R,4S,5S)-3-(2(difluoromethoxy)-3,4-difIuorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2R,3R₁4R,5R)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2S,3S,4R,5S)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2S,3R,4S,5S)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyI-5(trifiuoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2S,3R,4R,5R)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyI-4-((2R,3S,4S,5S)-3-(2(difluoiOmethoxyj-S^-difluorophenylH.Sdimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2R,3S,4R,5R)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyI-4-((2 R, 3R,4S,5R)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2 S.3S.4S, 5S)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran2-carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2 S, 3S,4R,5R)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran2-carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2 S,3R,4S, 5R)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2R,3S,4S,5R)-3-(2(difluoromethoxyJ-S^-difluorophenylH.Sdimethyl-5-(trifluoromethyl)tetrahydrofuran2-carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2S,3S,4S,5R)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

4-((2R,3R,4R,5S)-3-(2-(difluoromethoxy)-3₁4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-/V-methylpicolinamide

4-((2S,3R,4R,5S)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-/\/-methylpicolinamide

4-((2R,3S,4R,5S)-3-(2-(difluoromethoxy)-3_I4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-A/-methylpicolinamide

4-((2R_I3R,4S,5S)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-M-methylpicolinamide

4-((2R,3R,4R,5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-/V-methylpicolinamide

4-((2S,3S,4R,5S)-3-(2-(difluoromethoxy)3,4-difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-A/-methylpicolinamide

O A N _u r- y ⁿ π ³° J—( ^H O ° \=Y ^F”^F F F 4-((2S,3R,4S,5S)-3-(2-(difluoromethoxy)S^-difluorophenyO-A.S-dimethyl-S(trifluoromethyl)tetrahydrofuran-2carboxamido)-/V-methylpicolinamide	O I^N _uχ n A AJAk ^FsC /y _χ ^Η ° ⁰ \=A F F 4-((2S,3R,4R,5R)-3-(2-(difluoromethoxy)3,4-difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-A/-methylpicolinamide
, n î Πΐ H ^F3^{C H} Q ^o-_Ç^ ^F F F 4-((2R,3S,4S,5S)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifIuoromethyl)tetrahydrofuran-2carboxamido)-/V-methylpicolinamide	. A î Γΐϊ H P a\ Άν ^F3C / \ ^H 0 An 4-((2R,3S,4R,5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyI)tetrahydrofuran-2carboxamido)-/V-methylpicolinamide
< A U O H p λΑΜ''' F₃G V/ H Π 4-((2R,3R,4S₁5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-/V-methylpicolinamide	^F~S F 4-((2S,3S,4S,5S)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-A/-methylpicolinamide

4-((2S,3S,4R,5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-/V-methylpicolinamide

4-((2S,3R,4S,5R)-3-(2-(difluoromethoxy)3,4-difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-A/-methylpicolinamide

4-((2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-/\/-methylpicolinamide

4-((2S,3S,4S_I5R)-3-(2-(difluoromethoxy)-3,4difluorophenyO-ÀS-dimethyl-S(trifluoromethyl)tetrahydrofuran-2carboxamido)-/V-methylpicolinamide

4-((2R,3R,5S)-3-(3-chloro-4-fluoro-2methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,5S)-3-(3-chloro-4-fluoro-2methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,5S)-3-(3-chloro-4-fluoro-2methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,5R)-3-(3-chloro-4-fluoro-2methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,5S)-3-(3-chloro-4-fluoro-2methoxyphenyl)-5-methyl-5(trifIuoromethyl)tetrahydrofuran-2carboxamidojpicolinamide

4-((2S,3R,5R)-3-(3-chloro-4-fluoro-2methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,5R)-3-(3-chloro-4-fluoro-2methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,5R)-3-(3-chloro-4-fluoro-2methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

(2R,3R,4R,5S)-A/-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide (2S,3R,4R,5S)-/V-(3-carbamoyl-4-fluorophenyl)3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamide

(2R,3S,4R,5S)-/\/-(3-carbamoyl-4-fluorophenyl)3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamide (2R,3R,4S,5S)-/V-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide

(2R,3R,4R,5R)-/V-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide (2S,3S,4R,5S)-/V-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide

(2S,3R,4S,5S)-/V-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide (2S,3R,4R,5R)-A/-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide

(2R,3S,4S,5S)-/\/-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide (2R,3S,4R,5R)-/V-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3₁4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide

(2R,3R,4S,5R)-/V-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide (2S,3S,4S,5S)-/V-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifl uoromethyl)tetrahyd rofu ran-2carboxamide

(2S,3S,4R,5R)-/V-(3-carbamoyl-4fIuorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide (2S,3R,4S,5R)-/V-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide

(2R,3S,4S,5R)-/\/-(3-carbamoyl-4fluorophenyl)-3-(2-(difliioromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide (2S,3S₁4S,5R)-/V-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyI)tetrahydrofuran-2carboxamide

4-((2R,3R,4R,5S)-3-(2-ethoxy-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5S)-3-(2-ethoxy-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R,5S)-3-(2-ethoxy-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4S,5S)-3-(2-ethoxy-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4R.5R)-3-(2-ethoxy-3.4-difluorophenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S.3S,4R.5S)-3-(2-ethoxy-3.4-difIuorophenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4S,5S)-3-(2-ethoxy-3,4-difluorophenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamidojpicolinamide

4-((2S,3R,4R,5R)-3-(2-ethoxy-3,4-difluorophenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S₁5S)-3-(2-ethoxy-3,4-difluorophenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R₁3S,4R₁5R)-3-(2-ethoxy-3,4-difluorophenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4S,5R)-3-(2-ethoxy-3,4-difIuorophenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4S,5S)-3-(2-ethoxy-3,4-difluorophenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4R₁5R)-3-(2-ethoxy-3,4-difIuorophenyl)4₁5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4S,5R)-3-(2-ethoxy-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(2-ethoxy-3,4-difluorophenyl)4,5-dimethyl-5-(trifIuoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4S,5R)-3-(2-ethoxy-3,4-difluorophenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4R,5S)-3-(2-(difluoromethoxy)-4-fluoro-3methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5S)-3-(2-(difluoromethoxy)-4fluoro-3-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R,5S)-3-(2-(difluoromethoxy)-4fluoro-3-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R, 3R,4 S, 5S)-3-(2-(difl uoromethoxy)-4-fl uoro-3methylphenyl)-4,5-dimethyl-5(trifIuoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4R,5R)-3-(2-(difluoromethoxy)-4-fluoro3-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4R,5S)-3-(2-(difluoromethoxy)-4fluoro-3-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4S,5S)-3-(2-(difluoromethoxy)-4-fluoro3-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5R)-3-(2-(difluoromethoxy)-4fluoro-3-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S₁5S)-3-(2-(difluoromethoxy)-4fluoro-3-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R,5R)-3-(2-(difluoromethoxy)-4fluoro-3-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R₁4S,5R)-3-(2-(difluoromethoxy)-4fluoro-3-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4S,5S)-3-(2-(difluoromethoxy)-4fluoro-3-methylphenyl)-4,5-dimethyl-5(trifIuoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4R,5R)-3-(2-(difluoromethoxy)-4fluoro-3-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4S,5R)-3-(2-(difluoromethoxy)-4-fluoro3-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S_t5R)-3-(2-(difluoromethoxy)-4fluoro-3-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4S,5R)-3-(2-(difluoromethoxy)-4fluoro-3-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4R,5S)-3-(3₁4-difluoro-2-methoxyphenyl)4-methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5S)-3-(3,4-difluoro-2methoxypheny!)-4-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R.3S,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)4-methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)4-methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxyphenyl)4-methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S₁3S,4R,5S)-3-(3₁4-difluoro-2methoxyphenyl)-4-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S.3R,4S.5S)-3-(3,4-difluoro-2-methoxyphenyl)4-methyl-5-(trifIuoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5R)-3-(3,4-difluoro-2methoxyphenyl)-4-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5S)-3-(3_l4-difluoro-2methoxyphenyl)-4-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R,5R)-3-(3₁4-difluoro-2methoxyphenyl)-4-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4S,5R)-3-(3,4-dif1uoro-2methoxyphenyl)-4-methyI-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)4-methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxyphenyl)4-methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)4-methyl-5-(trifIuoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S.4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)4-methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R₁3R,4R,5S)-3-(3,4-difluoro-2-hydroxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5S)-3-(3,4-difluoro-2-hydroxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S.4R,5S)-3-(3,4-difluoro-2-hydroxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4S,5S)-3-(3.4-difluoro-2-hydroxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4R,5R)-3-(3,4-difluoro-2-hydroxyphenyl)4₁5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S.3S,4R.5S)-3-(3,4-difluoro-2hydroxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4S.5S)-3-(3,4-difluoro-2-hydroxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5R)-3-(3,4-difluoro-2-hydroxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S_I5S)-3-(3,4-difluoro-2-hydroxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R,5R)-3-(3,4-difluoro-2-hydroxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S₁4S,5S)-3-(3.4-difluoro-2-hydroxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4R,5R)-3-(3,4-difIuoro-2-hydroxyphenyl)4,5-dimethyl-5-(trifluoromethyI)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R₎4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4S,5R)-3-(3₁4-difluoro-2-hydroxyphenyl)4₁5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

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

Table B. Compound Structures andNames.

(2S,3R,5S)-/V-(3-carbarnoy!-4-fluorophenyl)-3-(3,4difluoro-2-methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide (2R,3S,5R)-A/-(3-carbamoyl-4-fluorophenyl)-3-(3,4difluoro-2-methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide

2-carbamoy 1-4-((2 R, 3 S, 5R)-3-(3,4-difluoro-2methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2S,3R,5S)-3-(3,4-difluoro-2methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2 S, 3R,4R, 5 S)-3-(2-ethoxy-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2 R, 3 S,4 S, 5R)-3-(2-ethoxy-3,4difluoropheny!)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

(2S,3R,4R,5S)-/\/-(3-carbamoylphenyl)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamide (2R,3S,4S,5R)-A/-(3-carbamoylphenyl)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamide

4-((2S,3R,5S)-3-(3-chloro-4-fluoro-2methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-/V-methylpicolinamide

4-((2R,3S,5S)-3-(3-chloro-4-fluoro-2methoxyphenyl)-5-methyl-5(trifiuoromethyl)tetrahydrofuran-2-carboxamido)N-methylpicolinamide

4-((2R,3S,5R)-3-(3-chloro-4-fluoro-2methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-/V-methylpicolinamide

4-((2S,3R,5R)-3-(3-chloro-4-fluoro-2methoxyphenyI)-5-methyl-5(trifIuoromethyl)tetrahydrofuran-2carboxamido)-/V-methylpicolinamide

4-((2S,3R,5S)-3-(3,4-difluoro-2methoxyphenyl)-5-ethyl-5(trifIuoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,5R)-3-(3,4-difluoro-2methoxyphenyl)-5-ethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,5S)-5-(tert-butyl)-3-(3,4-difluoro2-methoxyphenyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,5R)-5-(tert-butyl)-3-(3,4-difIuoro2-methoxyphenyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,5S)-3-(4-fluoro-2-methoxyphenyl)5-methyl-5-(trifluoromethyl)tetrahydrofuran2-carboxamido)picolinamide

4-((2R,3S,5R)-3-(4-fluoro-2-methoxyphenyl)5-methyl-5-(trifluoromethyl)tetrahydrofuran2-carboxamido)picolinamide

4-((2R,3R,5S)-3-(4-fIuoro-2-methoxyphenyl)5-methyl-5-(trifluoromethyl)tetrahydrofuran2-carboxamido)picoIinamide

4-((2S,3S,5R)-3-(4-fluoro-2-methoxyphenyl)5-methyl-5-(trifluoromethyl)tetrahydrofuran2-carboxamido)picolinamide

4-((2S,3R,5S)-3-(4-fluoro-2-methoxy-3methylphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,5R)-3-(4-fIuoro-2-methoxy-3methylphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,5S)-3-(2-(difluoromethoxy)-4fluorophenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,5R)-3-(2-(difIuoromethoxy)-4fluorophenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,5S)-3-(3-ethyl-4-fluoro-2methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,5R)-3-(3-ethyl-4-fluoro-2methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,5S)-3-(2,4-difluoro-3methylphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,5R)-3-(2,4-difluoro-3methylphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,5S)-3-(2-fluoro-6methoxyphenyl)-5-methyI-5(trifluoromethy!)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,5R)-3-(2-fIuoro-6methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,5S)-3-(3,4-difluoro-2methoxyphenyl)-5-methyl-5-(2,2,2trifluoroethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,5R)-3-(3,4-difluoro-2methoxyphenyl)-5-methyl-5-(2,2,2trifluoroethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,5R)-3-(3,4-difluoro-2methoxyphenyl)-5-methyl-5-(2,2,2trifluoroethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,5S)-3-(3,4-difluoro-2methoxyphenyl)-5-methyl-5-(2,2,2trifluoroethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,5S)-3-(3,4-difluoro-2-methoxyphenyl)5-(1,1 -difluoroethyl)-5-methyltetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,5S)-3-(3,4-difluoro-2-methoxyphenyl)5-(1,1-difluoroethyl)-5-methyltetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,5R)-3-(3,4-difluoro-2methoxyphenyl)-5-(1,1 -difluoroethyl)-5methyltetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,5R)-3-(3,4-difluoro-2-methoxyphenyl)5-(1,1-difluoroethyl)-5-methyltetrahydrofuran-2carboxamidojpicolinamide

2-carbamoyl-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2(methoxy-d3)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide (2S,3R,4R,5S)-/V-(3-carbamoylphenyl)-3(3,4-difIuoro-2-isopropoxyphenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamide

(2R,3S,4S,5R)-/V-(3-carbamoylphenyl)-3(3,4-difluoro-2-isopropoxyphenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamide

4-((2S,3R,4R,5S)-3-(3,4-difluorophenyl)4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(3,4-difluorophenyl)4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5S)-3-(3,4-difluoro-2methoxyphenyI)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4-ethyl-5-methyl-5(trifIuoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5S)-4-cyclopropyl-3-(3,4difluoro-2-methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-4-cyclopropyl-3-(3,4difluoro-2-methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R,5S)-3-(3,4-difluoro-2methoxyphenyli-5-(difluoromethyl)-4,5dimethyltetrahydrofuran-2carboxamido)picolinamide

4-((2S_l3R,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-5-(difluoromethyl)-4,5dimethyltetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5S)-3-(3,4-difluoro-2methoxyphenylj-5-(difluoromethyl)-4,5dimethyltetrahydrofuran-2carb'oxamido)picolinamide

4-((2R,3S_t4S₁5R)-3-(3,4-difluoro-2methoxyphenyl)-5-(difluoromethyl)-4,5dimethyltetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5S)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamido)/V-methylpicolinamide

Ο \ ΖΚ J/ I W A νΑ,,Α J) Η ?—'. Η fî ^Χ Η\ ο Α > 4-((2R,3S,4S,5R)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-/V-methylpicolinamide	° r^V^F XY ^F3^c\_/ νΆΑκ _NH2 y--\ H if J=\ o A > (2S,3R,4R,5S)-W-(3-carbamoyl-4-fluorophenyl)3-(2-(difluoromethoxy)-4-fluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamide
p AA Y Γ ^f3^c \_/ νΆΑκ _Nh₂ y^- '·, π Jj 7⁼⁼\ ⁰ ρΆ_# A > (2R,3S,4S,5R)-A/-(3-carbamoyl-4-fluorophenyl)3-(2-(difluoromethoxy)-4-fluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamide	. ⁰ ° p \_7 F ^F 4-((2S₁3S,4R)-3-(3,4-difluoro-2-methoxyphenyl)- 4,5,5-trimethyItetrahydrofuran-2carboxamido)picolinamide
Aoa Γ ^N^ν^ΝΗ ₂ /° >==/ F ^F 4-((2R,3R,4S)-3-(3,4-difluoro-2methoxyphenyl)-4,5,5trimethyltetrahydrofuran-2carboxamido)picolinamide	Α/·^λνΑα \-A H ^VNH₂ oA / ^z F ^F 4-((2S,3R,4S)-3-(3,4-difluoro-2-methoxyphenyl)- 4,5,5-trimethyltetrahydrofuran-2carboxamido)picolinamide

O Y/O.J/ [ N ζ H^^yNH₂ /° 5==/ F ^F 4-((2R,3S,4R)-3-(3,4-difluoro-2methoxyphenyl)-4,5.5-trimethyltetrahydrofuran2-carboxamido)picolinamide	O -yM. A «^N A—? H--ÇnH₂ 0 O-\ / / M F ^F 4-((2S,3R,4R)-3-(3,4-difluoro-2methoxyphenyl)-4,5,5trimethyltetrahydrofuran-2carboxamido)picolinamide
⁰j N 'o-T) ⁰ / )=\ F ^F 4-((2R,3S,4S)-3-(3,4-difluoro-2methoxyphenyl)-4,5,5trimethyltetrahydrofuran-2carboxamido)picolinamide	Xjl / H ^'y-^NH2 rT ° /° M F ^F 4-((2S,3R,4R,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5dimethyltetrahydrofuran-2carboxamido)picolinamide
θ O 11 / N A II \_J H^)T^NH2'' ⁰/°M F ^F4-((2R,3S,4S,5S)-3-(3,4-difluoro-2methoxyphenyl)-4,5dimethyltetrahydrofuran-2carboxamido)picolinamide	F₃C^°yA jTjF V_/ h^^\-^NH2 7=\ o /°M F ^F 4-((2S,3R,5S)-3-(3₁4-difluoro-2- methoxyphenyl)-5- (trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,5S)-3-(4-fluoro-2methoxy-3-methylphenyl)-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,5R)-3-(3,4-difluoro-2methoxyphenyl)-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,5R)-3-(4-fIuoro-2-methoxy3-methylphenyl)-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5S)-3-(3,4-difluoro-2methoxyphenyl)-5-isopropyl-4methyltetrahydrofuran-2carboxamido)picolinamide

6-((2R,3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

6-((2R,3S,4S,5R)-3-(3₁4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyrazine-2-carboxamide

5-((2R,3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)nicotinamide

4-((2R₁3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-5-methylpicolinamide

4-((2R,3S,4S₁5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-5-fluoropicolinamide

2-((2R,3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)isonicotinamide

4-((2R₁3S₁4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-3-fluoropicolinamide (2R,3S,4S,5R)-/\/-(3-carbamoyl-4-fluorophenyl)3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl5-(trifluoromethyl)tetrahydrofuran-2carboxamide

4-((2R₁3S,4S,5R)-3-(3,4-difluQro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-6-methylpicolinamide

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-6-fluoropicolinamide

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2methoxyphenylH.S-dimethyl-S(trifluoromethyl)tetrahydrofuran-2carboxamido)-3-methylpicolinamide

4-((2S,3R,4R,5S)-3-(3,4-difluoro-2methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R,5S)-3-(3,4-difluoro-2methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4S,5R)-3-(3,4-difluoro-2methylphenyl)~4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5S)-3-(4-(difluoromethyl)-3fluoro-2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(4-(difluoromethyl)-3fluoro-2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(3-(difluoromethyl)-4fluoro-2-methoxyphenyl)-4,5-dimethyl-5(trifIuoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5S)-3-(3-(difluoromethyl)-4fluoro-2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(2-methoxy-3(trifluoromethyl)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5S)-3-(2-methoxy-3(trifluoromethyl)phenyl)-4,5-dimethyI-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5S)-3-(2-methoxy-6(trifluoromethyl)pyridin-3-yl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(2-methoxy-6(trifluoromethyl)pyridin-3-yl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(4-methoxy-6(trifluoromethyl)pyridin-3-yl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5S)-3-(4-methoxy-6(trifluoromethyl)pyridin-3-yl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(2-ethyl-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

100

ο \_ζο. Λ / ^Ν F₃c< )·· .... /-\ ^Η \^ΝΗ2 /\ 0 Ο-<\ // / Ν-\ / ^FF 4-((2S,3R,4R,5S)-3-(6-(difluoromethyl)-2methoxypyridin-3-yl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide	O \.O J/ l N f₃c-Y / nAI ' AA o o-A / / N-\ / ^FF 4-((2R,3S,4S,5R)-3-(6-(difluoromethyl)-2methoxypyridin-3-yl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide
Me „ P FgΟ,.νθνΑ f N y_/ h ^Me' AA O o—C / r z\_J r=\ F F 4-((2R,3S,4S,5R)-3-(2-((3,3- difluorocyclobutyl)methoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide	F₃C..V⁰'sU. f VJ, P) ^Me' AA ° O\ / 4-((2R,3S,4S,5R)-3-(2-cyclobutoxy-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide
f₃4M X //^N( h^Xnh₂ / F F 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl-5-d)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide	θ O- Jj 1 F₃C _NH₂ »*** H ' /^A ° F F 2-carbamoyl-4-((2R,3S,4S,5R)-3-(3,4difluoro-2-hydroxyphenyl)-4,5-dimethyl-5(trifIuoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

101

6-((2R,3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyrimidine-4-carboxamide

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2vinylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-5-methylpicolinamide

4-((2S,3R₁4R,5S)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-5-methylpicoIinamide

F

4-((2R,3S,4S,5R)-3-(5-chloro-3,4-difluoro2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(4-fluoro-2hydroxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

102

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide-5-c/

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide-3-d ²H

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide-6-d

4-((2S,3R,4R,5S)-3-(3methoxypyridin-2-yl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(3methoxypyridin-2-y!)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

103

4-((2S,3R,4R,5S)-3-(3-methoxy-2methylpyridin-4-yl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

O

4-((2R,3S,4S,5R)-3-(3-methoxy-2methylpyridin-4-yl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

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

Table C. Compound Names.

(27?,37?,47?,57î)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (27?,37?,47?,55)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifIuoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (27î,37?,45,57î)-4-[[3-[2-(difiuoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (2R, 35,47?, 57?)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (25,37?,47?,57?)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (27?,37?,45,55)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (27?,35,47?,55)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide

104 (25,37?,47?,55)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (27?,35,45,57î)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (25,37?, 45,57?)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (25,35,47?, 57?)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (27?,35,45,55)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (25,37?,45,55)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (25,35,47?,55)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (25,35,45,57?)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (25,35,45,55)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (27î,37?,47?,57?)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (27?,37?,47î,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (27?,37î,45,57?)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2-carboxamide

105 (2R,3S,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (25,3R,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (2R,3R,45,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (2R,35',4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5dimethyl-5-(trifluoiOmethyl)tetrahydrofuran-2-carboxamide (25,3R,4R,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2-carboxamide (2R,35,45,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (25,3R,45',5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (25,35,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (2Æ,3S,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (25’,3J?,45’,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (2S,35',4R,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (2S,3S,4S,5Æ)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

106 (25,35,45,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (2R,3R,4R,5^)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,47?,55)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (2R,3/?,4S,5R)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydroftiran-2-carbonyl]amino]pyridine-2-carboxamide (27?,35,47?,57?)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,47?,57?)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,45,55)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (2Æ,3S,4R,5S)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (2S',3R,4R,5S)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (2/?,35,4S,57î)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,45,5Æ)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,41?,51?)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

107 (2R, 35,45,55)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyI-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,45,55)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,47?,55)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5(trifIuoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,57?)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,55)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27î,37?,47?,57?)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,47?,55)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,45,57?)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27î,35,47î,57?)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,47î,57î)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37î,45,55)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,35,47?,55)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

108 (25,37?,47?,55)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (2R, 35,45,5Æ)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?, 45,57?)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,47?, 57?)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,35,45,55)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,45,55)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,47?, 55)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,57?)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,55)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37î,57î)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide (27?,37?,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide (27?,35,57?)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide

109 (25,37?,57î)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide (27î,35,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofüran-2-carboxamide (25,37?,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide (25,35,57?)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide (25,35,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide (27?,37?,47?,57?)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (27?,3/?,47?,55)-N-(3-carbamoyIphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (2/?,37?,45,57?)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyI]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (27?,35,47?,57?)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (25,37?,47?,57?)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyI]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (27î,31î,45,55)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (21?,35,42?,55)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

110 (25,3/î,4R,55)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (2R,35',4S,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (25',37?,40',57?)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (2S,3S,4/?,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (2/?,35,4S,55)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (2S,37?,4S,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (25,35,47?,55)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2-carboxamide (2S,3S,4S,5Æ)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (2S,35,4S,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (27?,37î,57î)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide (27?,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide (21î,35',57î)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide

111 (25,37?,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide (2R, 35,55) -4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide (25,37?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide (25,35,57î)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide (25,35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide (27?,37î,47î,57?)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide (27?,37?,47?,55)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide (27î,37?,45,57?)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide (27?,35,47?,57?)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide (25,37î,47î,57?)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide (27?,37?,45,55)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide (27Î,35,47?,55)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide

112 (25,37?,4/?,55)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide (27?,35,45,57î)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide (25,37?,45,57?)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l -oxido-pyridin- l-ium-2-carboxamide (25,35,47?,57?)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide (27î,35,45,55)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide (25,37?, 45,55)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide (25,35,47?,55)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide (25,35,45,57?)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydroftiran-2-carbonyl]amino]-l-oxido-pyridin-l-iuni-2-carboxamide (25,35,45,55)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide

4-[[(27?,37?,47?,57?)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide

4-[[(27?,37?,47?,55)-3-(3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide

4-[[(27?,37?,45,57?)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide

113

4-[[(27?,35,47?,57?)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide

4-[[(25,37?,47î,57?)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide

4-[[(27?,37?,45,55)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide

4-[[(27?,35,47?,55)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide

4-[[(25,37?,4/?,55)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide

4-[[(27?,35,45,5R)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide

4-[[(25,37?,45,57?)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide

4-[[(25,35,47?,57?)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide

4-[[(27?,35,45,55)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyI]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide

4-[[(25,37?,45,55)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyI-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide

4-[[(25,35,47?,55)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyndin-l-ium-2-carboxamide

4-[[(25,35,45,57?)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyI-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide

114

4-[[(25,35,45,55)-3-(3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide

4-[[(27?,37?,47?,57?)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide

4-[[(27î,37?,47?, 55)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide

4-[[(27?,37?,45,57?)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide

4-[[(27?,35,47?, 57?)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide

4-(((25,37?,47?,57?)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide

4-[[(27?, 37?,45,55)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide

4-[[(27?,35,47?,55)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide

4-[[(25,37?,47?,55)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide

4-[[(27î,35,45,57?)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide

4-[[(25,37?,45,57?)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide

4-[[(25,35,47?, 57î)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide

115

4-[[(27î,35,45,55)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide

4-[[(25,37?,45, 55)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide

4-[[(25,35,47?, 55)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide

4-[[(25,35,45,57?)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide

4-[[(25,35,45,55)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide (27?,37?,47?,57?)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (27?,37?,47?,55)-4-[[3-(3-chloro-4-fluoiO-2-methoxy-phenyI)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (2Æ,3Æ,45,57?)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (27?,35,47?,57?)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (25,37?,47?,57?)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (27?,37î,45,55)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyI-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (27?,35,47?, 55)-4-[[3-(3-chloro-4-fIuoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide

116 (25,37?,47?,55)-4-[[3-(3-chIoro-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (2R, 35,45,57?)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (25,37?,45,57?)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (25,35,47?,57?)-4-[[3-(3-chloro-4-fluoro-2-inethoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (27?,35,45,55)-4-[[3-(3-chIoro-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (25,37?,45,55)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (25,35,47?,55)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (25,35,45,57?)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (25,35,45,55)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (27?,37?,47?,57?)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,47î,55)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (27î,37î,45,57?)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

117 (27Î,35,47?,57î)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,47?,57î)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (2R, 3 7?,45,55)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,35,47?,55)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?, 47?, 55)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27Î,35,45,57?)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyI-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,45,57?)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,47?, 57î)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27î,35,45,55)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,45,55)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,47?,55)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,57?)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

118 (2S,35,4S, 55)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27î,37?,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyI)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (27?,3R,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofiiran2-carbonyl]amino]pyridine-2-carboxamide (27?,35,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (25,3Æ,5Æ)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (27?,35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (25,37î,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (25,35,5Æ)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (25,35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofiiran2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,57?)-4-[[5-ter/-butyl-3-(3,4-difluoro-2-methoxy-phenyI)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27î,37?,55)-4-[[5-/er/-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (2R,35,5R)-4-[[5-ter/-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2carbonyl] amino]pyridine-2-carboxamide

119 (25,37?,57?)-4-[[5-ZerZ-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (2R, 35,55)-4-[[5-/er/-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,37?,55)-4-[[5-Zer/-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,35,5_K)-4-[[5-ZerZ-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,35,55)-4-[[5-ZerZ-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27î,37î,57î)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (27î,32î,55)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?,35,57?)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,37î,57î)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (2R,35,55) -4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,37?,55)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]ammo]pyridine-2-carboxamide (25,35,5R)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide

120 (25,35,55)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27î,37î,57î)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27î,37î,55)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (22?,35,52î)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,5À)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27î,35,55)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,3Æ,55)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,5Æ)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,55)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,5A)-4-[[3-[2-(difluoiOmethoxy)-4-fluoro-phenyl]-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27î,37?,55)-4-[[3-[2-(difluoroinethoxy)-4-fluoro-phenyl]-5-methyl-5(trifluoromethyI)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,35,5/?)-4-[[3-[2-(difluoromethoxy)-4-fluoiO-phenyl]-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

121 (2S,3Æ,57?)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyI]-5-rnethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (2R,35',5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (2S,37î,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (2S,3S,57?)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,55)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27î,37î,57î)-4-[[3-(2,4-difluoro-3-methyI-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27î,37î,5S)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (22?,35,5R)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (25,37î,57î)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (27?,3S',55)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (25,37î,5S)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (25,35,5R)-4-[[3-(2,4-difluoro-3-niethyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide

122 (25,35,55)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,57?)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (2Æ,37?,5S)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,35,57?)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,52?)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (2R, 35,55) -4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,55)-4-[[3-(3-ethyl-4-fluoiO-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,57?)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,55)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,31?,57?)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofiiran2-carbonyl]amino]pyridme-2-carboxamide (27?,37?,55)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27î,35,5R)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide

123 (25,37?,57î)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyI]amino]pyridine-2-carboxamide (27?,35,55)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]pyridine-2-carboxamide (25,37?,55)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,35,57î)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]pyridine-2-carboxamide (25,35,5S)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?,37î,57î)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27î,37?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27î,35,57î)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyI-5-(2,2,2trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyI)-5-methyl-5-(2,2,2trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

124 (25,35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,57?)-4-[[5-(l,l-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27î,37?,55)-4-[[5-(l,l-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,35,57?)-4-[[5-(l,l-difluoroethyI)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,51?)-4-[[5-(l,l-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (2R, 35,55)-4-((5-(1, l-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?, 55)-4-((5-( 1,1-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,57?)-4-[(5-( 1,1 -difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,55)-4-[[5-( 1,1 -difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyltetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,42?,57?)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyI)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,47?,55)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (2R,37?,45,57î)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

125 (2Æ,3S,4R,5Æ)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,47?,57?)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (21?,3??,45,55)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydiOfuran-2-carbonyl]amino]pyridine-2-carboxamide (2R,3S, 4R, 55)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,31?,41?,55)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (2R, 35,45,5J?)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyI)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,3R,45,5R)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,4J?,57?)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (2R,35,45,55)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyI)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,3R,45,55)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,41?,55)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,57?)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

126 (25,35,45,55)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofüran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,47î,57?)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?,37?,47?,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?,37?,45,57?)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (2R, 35,47?, 57?)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,37?,47î,57î)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?,37?,45,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?,35,47?,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,37?,47î,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?,35,45,57?)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,37?,45,57?)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]pyridine-2-carboxamide (25,35,47?,57?)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide

127 (27?, 35,45,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,37?,45,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,35,47?, 55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridme-2-carboxamide (25,35,45,57?)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofÎiran-2carbonyl]amino]pyridine-2-carboxamide (25,35,45,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?,37?,47?,57î)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,47?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyI-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37î,45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,35,47?,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,47?,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydroftiran-2-carbonyl]amino]pyridine-2-carboxamide (27?,35,47?, 55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

128 (25,37?,47?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (2R, 35,45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,47?,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,35,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,47?, 55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,47î,57?)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,47?,55)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,45,57?)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofùran-2-carbonyl]amino]pyridine-2-carboxamide

129 (27?,35,47?,57?)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,47?,57?)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (27?,3Æ,45,55)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyI)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (2R, 35,47?, 55)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,47?,55)-4-[[4-cyclopiOpyl-3-(3,4-difluoro-2-methoxy-phenyI)-5-methyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (27?,35,45,57?)-4-[[4-cyclopropyI-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,45,57?)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,47?,57î)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,35,45,55)-4-[[4-cyclopropyl-3 -(3,4-difluoro-2-methoxy-phenyl)-5 -methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,45,55)-4- [[4-cyclopropyl-3 -(3,4-difluoro-2-methoxy-phenyl)-5 -methyl-5 (trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,47?,55)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,57î)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyI)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

130 (25,35,45,55)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27î,37?,47?,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,47?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,45,57î)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,35,47?,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?, 47?, 57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyI)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,35,47?, 55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,47?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27Î,35,45,57î)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,47?,57î)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

131 (2R, 35,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,47?, 55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (27î,37î,57î)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27î,37?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27î,35,57î)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,37î,57î)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?,35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,37?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,35,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide

132 (25,35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?,37?,47?,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofiiran-2carbonyl]amino]pyridine-2-carboxamide (27?,37?,47?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyI)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27î,37?,45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?,35,47î,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,37?,47?,57î)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?,37?,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (2R, 35,47?, 55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,37?,47?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?, 35,45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,37?,45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,35,47?,57î)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofiiran-2carbonyl]amino]pyridine-2-carboxamide

133 (27?, 35,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,37?,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofüran-2carbonyl]amino]pyridine-2-carboxamide (25,35,47?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,35,45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,35,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (21î,37?,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?,37?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?,35,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]pyridine-2-carboxamide (25,37?,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyI]amino]pyridine-2-carboxamide (27?,35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoiOmethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,37?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,35,57î)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]pyridine-2-carboxamide

134 (25,35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?,37?,57?)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (27î,37?,55)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?,35,57?)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,37?,57?)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?,35,55)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,37?,55)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,35,57î)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,35,55)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?,37?,42?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?, 3R, 4R, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27î,37?,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide

135 (27?, 35,47?, 57?)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2carbonyl] amino]pyridine-2-carboxamide (25,37?,47?,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27î,37î,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyI-4-methyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,37?,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofiiran-2carbonyl]amino]pyridine-2-carboxamide (27Î,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,37?,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-niethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,35,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofiiran-2carbonyl]amino]pyridine-2-carboxamide (25,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofiiran-2carbonyl]amino]pyridine-2-carboxamide (25,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide

136 (25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide

6-[[(27î,37?,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

6-[[(27?, 3R, 4R, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-[[(27?,37?,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

6-[[(27?, 35,47?, 57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-[[(25,37?,47?,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-[[(27?,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-[[(27?,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-[[(25,37?, 47Î, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

6-[[(27?,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-[[(25,37?,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-[[(25,35,47?,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

137

6-[[(27?, 35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-[[(25,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-[[(25,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-[[(25,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-[[(27?,37?,47?,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide

6-[[(27î,37î,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide

6-[[(27?,37?,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide

6-[[(27?,35,47?,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide

6-[[(25,37?,47?,57?)-3-(3,4-difluoiO-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide

6-[[(27?,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyrazine-2-carboxamide

6-[[(27?,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide

138

6-[[(25,37î, 4R, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide

6-[[(27?,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide

6-[[(25,37?,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide

6-[[(25,35,47?, 57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide

6-[[(27?,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide

6-[[(25,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide

6-[[(25,35,4R, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide

6-[[(25,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyrazine-2-carboxamide

6-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide

5-[[(27?,37?,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide

5-[[(27?,37?, 47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide

5-[[(27î,37î,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-3-carboxamide

139

5-[[(27?, 35,47?, 57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide

5-[[(25,37î,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide

5-[[(27?,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide

5-[[(27?,35,47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-3-carboxamide

5-[[(25,37î,47î,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide

5-[[(27?,35,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide

5-[[(25,37î,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-3-carboxamide

5-[[(25,35,47?,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide

5-[[(27?,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethÿl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide

5-[[(25,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide

5-[[(25,35,47?«,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide

5-[[(25,35,45,57?)-3-(3,4-difluoiO-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide

140

5-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide

4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide

4-[[(25, 35, 45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide

4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide

141

4-[[(27?,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide

4-[[(25,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofÎiran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide

4-[[(25,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide

4-[[(25,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide

2-[[(27?,37?,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide

2-[[(27?, 37?, 47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide

2-[[(27?,37î,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide

2-[[(27?,35,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide

2-[[(25,37?,47?,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide

2-[[(27?,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-4-carboxamide

2-[[(27?,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide

142

2-(((25,37?, 47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide

2-[[(27?,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide

2-(((25,37?,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide

2-(((25,35,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-4-carboxamide

2-([(27?,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide

2-(((25,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-4-carboxamide

2-(((25,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide

2-(((25,35,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide

2-(((25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyI)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide

6-[[(27î,37?,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyrimidine-4-carboxamide

6-[[(27?,37?,47Î,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide

6-[[(27î,37î,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyrimidine-4-carboxamide

143

6-[[(27?, 35,47?, 57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide

6-[[(25,37î,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide

6-[[(27?,37î,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide

6-[[(27î,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide

6-[[(25,37?,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide

6-[[(27?,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide

6-[[(25,37?,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyrimidine-4-carboxamide

6-[[(25,35,47?,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide

6-[[(27?,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide

6-[[(25,37î,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide

6-(((25,35,47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide

6-[[(25,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyrimidine-4-carboxamide

144

6-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyrimidine-4-carboxamide

4-[[(27?,37?,47?, 57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide

4-[[(27?,37?,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide

4-[[(27?,37î,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide

4-[[(27?,35,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide

4-[[(25,37î,47î,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide

4-[[(27?,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide

4-[[(27î,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyI)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide

4-[[(25,37?,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide

4-[[(27?,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide

4-[[(25,37?,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide

4-[[(25,35,47?, 57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide

145

4-[[(27î, 35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide

4-[[(25,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide

4-[[(25,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide

4-[[(25,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide

4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyI)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide (27?,37?,47î,57?)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (27î,37?,47?,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (27?,37?,45,57?)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2-carboxamide (27?,35,47?,57?)-N-(3-carbamoyl-4-fluoro-phenyI)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (25,37?,47?,53?)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (27î,37?,45,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2-carboxamide (27î,35,47?,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

146 (25,37?,47?,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofùran-2-carboxamide (27?,35,45,57î)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (25,37?,45,57?)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2-carboxamide (25,35,47?,57?)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2-carboxamide (27î,35,45,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (25,37î,45,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (25,35,47î,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (25,35,45,57î)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (2S,35,45,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

5-deuterio-4-[[(27?,37?,42?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

5-deuterio-4-[[(27?, 3R, 47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

5-deuterio-4-[[(27î,37?,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

147

5-deuterio-4-[[(27?, 35,47?, 57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

5-deuterio-4-[[(25,37?,47?,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

5-deuterio-4-[[(27?, 3 R,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

5-deuterio-4-[[(27?,35,47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

5-deuterio-4-[[(25,37?, 47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

5-deuterio-4-[[(27?,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

5-deuterio-4-[[(25,37?,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

5-deuterio-4-[[(25,35,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

5-deuterio-4-[[(27?,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

5-deuterio-4-[[(25,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

5-deuterio-4-[[(25,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofbran-2-carbonyl]amino]pyridine-2-carboxamide

5-deuterio-4-[[(25,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

148

5-deuterio-4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,37?,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide

4-[[(27?,37?, 47?, 55)-3-(3,4-difluoro-2-methoxy-phenyI)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide

4-[[(27?,37?,45,57?)-3-(3,4-diiluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide

4-[[(27?,35,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide

4-[[(25,37?,47?,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofùran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide

4-[[(27?,37î,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide

4-[[(27?,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide

4-[[(25,37?,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide

4-[[(27?,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide

4-[[(25,37?,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide

4-[[(25,35,47?,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide

149

4-[[(27?,35,45,55)-3-(3,4-difluoiO-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide

4-[[(25,3R,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide

4-[[(25,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyi-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide

4-[[(25,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyI)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide

4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide

4-[[(27?,37î,47?,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide

4-[[(27?,37?,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide

4-[[(27?,37?,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide

4-[[(27?,35,47?, 57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide

4-[[(25,37?,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide

4-[[(27î, 37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide

4-[[(27?,35,47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide

150

4-[[(25,3R, 4R, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide

4-[[(27?,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide

4-[[(25,37?,45,57?)-3-(3,4-difluoiO-2-methoxy-phenyI)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide

4-[[(25,35,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide

4-[[(27î,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofùran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide

4-[[(25,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide

4-[[(25,35,47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide

4-[[(25,35,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide

4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide

4-[[(27?,37?,47?,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide

4-[[(27?,37?,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide

4-[[(27?,37?,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide

151

4-[[(27?, 35,47?, 57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyI-pyridine-2-carboxamide

4-[[(25,37î,47?,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide

4-[[(27?, 37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide

4-[[(27?,35,47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide

4-[[(25,37?,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyI-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide

4-[[(27?,35,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide

4-[[(25,37?,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide

4-[[(25,35,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide

4-[[(27?,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide

4-[[(25,37î,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide

4-[[(25,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide

4-[[(25,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide

152

4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide

4-[[(27î,37?,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyI]amino]-3-methyl-pyridine-2-carboxamide

4-[[(27?,37?,47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide

4-[[(27?,37?,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide

4-[[(27?,35,47?, 57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide

4-[[(25,37?,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide

4-[[(27?,37î,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide

4-[[(27?,35,47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide

4-[[(25,37î,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide

4-[[(27?,35,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide

4-[[(25,37?,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide

4-[[(25,35,47?, 57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide

153

4-[[(27?,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide

4-[[(25,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide

4-[[(25,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide

4-[[(25,35,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide

4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide

3-deuterio-4-[[(27?,37î,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

3-deuterio-4-[[(27î,37?,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

3-deuterio-4-[[(27?,37?,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

3-deuterio-4-[[(27?,35,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxàmide

3-deuterio-4-[[(25,37?,47?,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide · '·

3-deuterio-4-[[(27?,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

3-deuterio-4-[[(27î,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

154

3-deuterio-4-[[(25, 37?, 47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

3-deuterio-4-[[(27î,35,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

3-deuterio-4-[[(25,37î,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

3-deuterio-4-[[(25,35,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

3-deuterio-4-[[(27î,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

3-deuterio-4-[[(25,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

3-deuterio-4-[[(25,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

3-deuterio-4-[[(25,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

3-deuterio-4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-deuterio-4-[[(27î,37?,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyI)tetrahydrofuran-2-carbonyI]amino]pyridine-2-carboxamide

6-deuterio-4-[[(27?, 37?, 47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-deuterio-4-[[(27?,37?,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

155

6-deuterio-4-[[(27?,35,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-deuterio-4-[[(25,37?,47î,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-deuterio-4-[[(27?,37î,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-deuterio-4-[[(27?,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-deuterio-4-[[(25,37?,47Î,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-deuterio-4-[[(27?,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]arnino]pyridine-2-carboxamide

6-deuterio-4-[[(25,37î,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-deuterio-4-[[(25,35,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-deuterio-4-[[(27?,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-deuterio-4-[[(25,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

6-deuterio-4-[[(25,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

6-deuterio-4-[[(25,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

156

6-deuterio-4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,47?,57?)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,47?,55)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37î,45,57?)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (2R,35,47?, 57?)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,47?,57î)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37î,45,55)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27Î,35,47?,55)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,47?,55)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydroftiran-2-carbonyl]amino]pyridine-2-carboxamide (27?,35,45,57?)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,45,57î)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,47?,57î)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

157 (25,35,45,55)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,55)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,55)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,55)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,55)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,55)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide (25,35,45,55)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide (25,35,45,55)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide (25,35,45,55)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide (25,35,45,55)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide

158 (27?,37?,45,55)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dirnethyl-5(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide (2R, 3S,4R, 5S)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide (25,37?,47?,55)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide (2R, 35,45,57î)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide (25,37?,45,57î)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl) tetrahydrofiiran-2-carbonyl] amino]pyridine-2-carboxamide (25,35,47?,57?)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide (27?,35,45,55)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide (25,37?,45,55)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide (25,35,47î,55)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl) tetrahydrofiiran-2-carbonyl] amino]pyridine-2-carboxamide

159 (25,35,45,57?)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide (25,35,45,55)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl) tetrahydrofiiran-2-carbonyl] amino]pyridine-2-carboxamide (27?,37?,47?,57?)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,47?,55)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,45,57î)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27Î,35,47?,57î)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,47?,57?)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27î,37?,45,55)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (27?,35,47?, 55)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,47î,55)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27Î,35,45,57?)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,45,57?)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoiOmethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

160 (25,35,47?,57?)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyI-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,35,45,55)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,45,55)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,47?,55)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,57?)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyI-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,55)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,47?,57î)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,47?,55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37î,45,57?)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (27?,35,47?,57?)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,47?,57?)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27î,37?,45,55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

161 (2R, 3S,4R, 55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,47?,55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (2R, 35,45,57?)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,45,57?)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,47?, 57?)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (2R,35,45,55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,45,55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,47?,55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,57?)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37î,47î,57î)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyI]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,47?,55)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

162 (27?,37?,45,57?)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (27Î,35,47?,57î)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,47?,57?)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,45,55)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,35,47?,55)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37î,47?,55)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,35,45,57?)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,45,57?)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,47?,57?)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27Î,35,45,55)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,45,55)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,47?,55)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

163 (25,35,45,57?)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,55)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,47?,57?)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,47?,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,45,57?)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (2/?,35,4Æ,57?)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (25,37?,47?,57?)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,45,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran2-carbonyl]amino]pyridine-2-carboxamide (27?,35,47?,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (25,37?,47?,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (22?,35,45,57?)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (25,37?,45,57?)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide

164 (25,3S,4R, 57?)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (27?,35,45,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,37?,45,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,35,47?,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,35,45,57î)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (25,35,45,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (27?,37î,47î,57î)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37î,47?,55)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,45,57î)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]aniino]pyridine-2-carboxamide (27?,35,47?,57?)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,47î,57?)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (27?,37?,45,55)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

165 (27?,35,47?,55)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,47?,55)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (2R, 35,45,57?)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5(trifluoromethyI)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,45,57î)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,47?, 57?)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (27?,35,45,55)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,37?,45,55)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,47?, 55)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,57?)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,55)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,37?,47?,57?)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,37î,47î,55)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

166

4-[[(27?,37?,45,57?)-3-[2-[(3,3-difluorocycIobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,35,47?,57?)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,37?,47?,57?)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27î,37?,45,55)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl5-(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,35,47?,55)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,37?,47?,55)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl5-(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,35,45,57?)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(2S,37?,4S,57?)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(2S,3S,4Æ,5Æ)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?, 35,45,5S)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl5-(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,31?,45,55)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,35,47?,55)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl5-(trifluoromethyl)tetrahydrofiiran-2-carbonyl]ammo]pyridine-2-carboxamide

167

4-[[(25,35,45,57î)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl5-(trifiuoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,35,45,55)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27î,37?,47î,57î)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,37?,47?,55)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27î,37?,45,57?)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?, 35,47?, 57?)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,37î,47?,57?)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofijran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,37?,45,55)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27î,35,47?,55)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,37?,47?,55)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,35,45,57?)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,37?,45,57?)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

168

4-[[(25,3S,4R, 57?)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?, 35,45,55)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,37?,45,55)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,35,47?,55)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,35,45,57?)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,35,45,55)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,37?,47?,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,37?,47?,55)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,37?,45,57?)-3-(5-deuterio-3,4-difIuoro-2-methoxy-phenyI)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,35,47?, 57?)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,37î,47î,57?)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,37?,45,55)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

169

4-[[(27?, 35,47?, 55)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,37î,47î,55)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27î,35,45,57î)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,37?,45,57?)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,35,47?,57î)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,35,45,55)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,37î,45,55)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,35,47î,55)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,35,45,57?)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,35,45,55)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(triiluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27î,37î,47î,57î)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,37?, 47?, 55)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

170

4-[[(27î,37?, 45,57?)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,35,47?,57?)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,37?,47?,57?)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,37?,45,55)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,35,47?,55)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,37î,47?,55)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide 4-[[(27î,35,45,57?)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,37?,45,57?)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,35,47?,57î)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide 4-[[(27?,35,45,55)-3-(3,4-difluoro-2-vinyI-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide 4-[[(25,37î,45,55)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide 4-[[(25,35,47?,55)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

171

4-[[(25,35,45,55)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,35,45,55)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25,35,45,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyI-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide (25,35,45,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide (25,35,45,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide (25,35,45,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide (25,35,45,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide (25,35,45,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofùran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide (25,35,45,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide (25,35,45,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide (25,35,45,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide (25,35,45,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide

172 (25,35,47?,57?)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide (27?,35,45,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide (25,37?,45,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide (25,35,47?,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide (25,35,45,57?)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide (25,35,45,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide 4-[[(27?,37?,47?,57î)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27î,37?,47?,55)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,37?,45,57î)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,35,47?,57?)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,37?,47î,57?)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,37?,45,55)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

173

4-[[(27?, 35,47?, 55)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,37?,47î,55)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,35,45,57î)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,37?,45,57î)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyI)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,35,47?, 57?)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,35,45,55)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,37?,45,55)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,35,47?,55)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,35,45,57?)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,35,45,55)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,37?,47î,57?)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27î,37î,47?,5S)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

174

4-[[(27?,37î,45,57î)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27î,35,47?,57î)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-(((25,37?,47?,57?)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,37î,45,55)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydroftiran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,35,47?,55)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-(((25,37?,47î,55)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27?,35,45,57?)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-(((25,37?,45,57?)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,35,47?, 57?)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(27î,35,45,55)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-(((25,37Î,45,55)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-(((25,35,47?,55)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-diinethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

175

4-[[(25,35,45,5A)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

4-[[(25,35,45,55)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

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

F or a pharmaceutically acceptable sait thereof, wherein the compound has the absolute stereochemistry of the First eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 1, Step 6. 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

F or a pharmaceutically acceptable sait thereof, wherein the compound has the absolute stereochemistry of the second eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 1, Step 6. 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

176

or a pharmaceutically acceptable sait thereof, wherein the compound has the absolute stereochemistry of the first eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 1 (Chiralpak AS-H column). Such compound is considered to be a 5 “compound of the invention,” as that terni is used herein.

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

F or a pharmaceutically acceptable sait thereof, wherein the compound has the absolute stereochemistry of the second eluting isomer when a racemic mixture of enantiomers is separated by

SFC as described in Example 1 (Chiralpak AS-H column). 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 sait thereof, wherein the compound has the absolute stereochemistry of the first eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 2, Step 10. 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

177

or a pharmaceutically acceptable sait thereof, wherein the compound has the absolute stereochemistry of the second eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 2, Step 10. 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 sait thereof, wherein the compound has the absolute stereochemistry of the first eluting isomer when a racemic mixture of enantiomers is separated by

SFC as described in Example 3, Step 13. 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 sait thereof, wherein the compound has the absolute stereochemistry of the second eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 3, Step 13. Such compound is considered to be a “compound of the invention,” as that term is used herein.

178

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

or a pharmaceutically acceptable sait thereof. 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 sait thereof, wherein the compound has the absolute stereochemistry of the first eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 3. 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

179

or a pharmaceutically acceptable sait thereof, wherein the compound has the absolute stereochemistry of the second eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 3. Such compound is considered to be a “compound of the invention,” 5 as that term is used herein.

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

180

D₃CO—Y ^f >

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

181

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

or a pharmaceutically acceptable sait thereof, wherein the compound has the absolute stereochemistry of the second eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 1 (Chiralpak AS-H column). 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 sait thereof, wherein the compound has the absolute stereochemistry of the first eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 4, Step 4. 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

182 or a pharmaceutically acceptable sait thereof, wherein the compound has the absolute stereochemistry of the second eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 4, Step 4. 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

F or a pharmaceutically acceptable sait thereof, wherein the compound has the absolute stereochemistry of the first eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 4, Step 4 (Chiralpak AS-H column). 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

SFC as described in Example 4, Step 4 (Chiralpak AS-H column). 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

183

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

or a pharmaceutically acceptable sait thereof, wherein the compound has the absolute stereochemistry of the First eluting isomer when a mixture of racemic diastereomers (epimeric at the 5-position) is separated by SFC as described in Example 6, Step 7. 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

184

or a pharmaceutically acceptable sait thereof, wherein the compound has the absolute stereochemistry of the second eluting isomer when a mixture of racemic diastereomers (epimeric at the 5-position) is separated by SFC as described in Example 6, Step 7. 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 sait thereof, wherein the compound has the absolute stereochemistry of the third eluting isomer when a mixture of racemic diastereomers (epimeric at the 5-position) is separated by SFC as described in Example 6, Step 7. 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

185

or a pharmaceutically acceptable sait thereof, wherein the compound has the absolute stereochemistry of the fourth eluting isomer when a mixture of racemic diastereomers (epimeric at the 5-position) is separated by SFC as described in Example 6, Step 7. 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 sait thereof, wherein the compound has the absolute stereochemistry of the First eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 7, Step 11. 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

186

or a pharmaceutically acceptable sait thereof, wherein the compound has the absolute stereochemistry of the second eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 7, Step 11. 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

Solid Forms of Compounds of the Invention

In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable sait thereof, in solid form. In some embodiments, the compound of the invention, or pharmaceutically acceptable sait thereof, is in crystalline solid form.

Solid Forms of Compound 7

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

187 wherein the compound has the absolute stereochemistry of the second eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 3, Step 13, wherein the compound is in crystalline solid form.

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

In some embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 thêta ± 0.2) of 9.9, 13.9, 15.7, and 19.0. In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, or at least three diffractions at angles (degrees 2 thêta ± 0.2) of 9.9, 13.9, 15.7, and 19.0. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 thêta ± 0.2) of 7.3, 9.9, 13.9, 15.7, 19.0, 20.1, 20.3, and 25.4. In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, at least fïve, at least six, or at least seven diffractions at angles (degrees 2 thêta ± 0.2) of 7.3, 9.9, 13.9, 15.7, 19.0, 20.1, 20.3, and 25.4. In other embodiments, Form A is characterized by an XRPD pattern substantially similar to Figure 1.

In some embodiments, Form A is characterized by a DSC thermogram having a melting onset of 186 °C with a peak at 187 °C.

In some embodiments, Form A is obtainable by crystallization from methanol at 60 °C.

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

In some embodiments, Form B is characterized by an XRPD pattern having diffractions at angles (degrees 2 theta± 0.2) of 12.8, 14.1, 15.2, 18.5, and 20.3. In other embodiments, Form B is characterized by an XRPD pattern having at least one, at least two, at least three, or at least four diffractions at angles (degrees 2 thêta ± 0.2) of 12.8, 14.1, 15.2, 18.5, and 20.3. In other embodiments, Form B is characterized by an XRPD pattern having diffractions at angles (degrees 2 thêta ± 0.2) of 12.0, 12.8, 14.1, 15.2, 16.9, 18.4, 18.5, 18.7, 19.3, and 20.3. In other embodiments, Form B is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine diffractions at angles (degrees 2 thêta ± 0.2) of 12.0, 12.8, 14.1, 15.2, 16.9, 18.4, 18.5, 18.7, 19.3, and 20.3. In other embodiments, Form B is characterized by an XRPD pattern having diffractions at angles (degrees 2 thêta ±0.2) of7.6, 9.2, 12.0, 12.8, 14.1, 15.1, 15.2, 16.2, 16.9, 17.6, 18.4, 18.5, 18.7, 19.3,20.3, 21.7, 22.0, 22.2, 22.9, 23.6, 24.0, 24.2, 25.2, 26.9, 27.0, 27.4, 28.6, and 28.9. In other embodiments,

188

Form B is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, at least fïve, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, or at least twenty-seven diffractions at angles (degrees 2 thêta ± 0.2) of7.6, 9.2, 12.0, 12.8, 14.1, 15.1, 15.2, 16.2, 16.9, 17.6, 18.4, 18.5, 18.7, 19.3, 20.3, 21.7, 22.0, 22.2, 22.9, 23.6, 24.0, 24.2, 25.2, 26.9, 27.0, 27.4, 28.6, and 28.9. In other embodiments, Form B is characterized by an XRPD pattern substantially similar to Figure 4.

In some embodiments, Form B is characterized by a solid State ¹³C NMR spectrum having peaks at Chemical shifts of 172.5, 172.1, 168.5, 168.3, 168.0, 151.5, 148.3, 147.8, 127.7, 122.7, 116.6, 115.1, 110.6, 86.5, 80.2, 63.2, 44.3, 23.0, and 13.1 ppm. In some embodiments, Form B is characterized by a solid State ¹³C NMR spectrum substantially similar to Figure 5.

In some embodiments, Form B is characterized by a solid State ^l9F NMR spectrum having peaks at Chemical shifts of-137.1 and -152.8 ppm. In some embodiments, Form B is characterized by a solid State ^,9F NMR spectrum substantially similar to Figure 6.

In some embodiments, Form B is characterized by a DSC thermogram having a melting onset of 182 °C with a peak at 183 °C.

In some embodiments, Form B is characterized by an IR spectrum having peaks at 3501, 3356, 1684, 1565, 1505, and 1122 cm'¹. In some embodiments, Form B is characterized by an IR spectrum substantially similar to Figure 9.

In some embodiments, Form B is characterized by an orthorhombic crystal System, as determined by single-crystal X-ray analysis. In other embodiments, Form B is characterized by a P212i2i space group, as determined by single-crystal X-ray analysis. In other embodiments, Form B is characterized by a unit cell, as determined by single-crystal X-ray analysis, of the following dimensions: a=7.3929(2) Â; b=14.5827(4) Â; c=18.9312(6) Â; α=90°; β=90°; and γ=90°.

In some embodiments, Form B is obtainable by dissolving the compound in ethyl acetate and then crystallizing the compound by adding n-heptane as an antisolvent. In other embodiments, Form B is obtainable by the procedure described in Example 3. '

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

189

wherein the compound is in crystalline solid form.

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

In some embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 thêta ± 0.2) of 9.9, 13.9, 15.7, and 19.0. In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, or at least three diffractions at angles (degrees 2 thêta ± 0.2) of 9.9, 13.9, 15.7, and 19.0. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 thêta ± 0.2) of 7.3, 9.9, 13.9, 15.7, 19.0, 20.1, 20.3, and 25.4. In other embodiments, Form A is characterized by an XRPD pattem having at least one, at least two, at least three, at least four, at least five, at least six, or at least seven diffractions at angles (degrees 2 thêta ± 0.2) of 7.3, 9.9, 13.9, 15.7, 19.0, 20.1, 20.3, and 25.4. In other embodiments, Form A is characterized by an XRPD pattem substantially similar to Figure 1.

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

In some embodiments, Form B is characterized by an XRPD pattem having diffractions at angles (degrees 2 thêta ± 0.2) of 12.8, 14.1, 15.2, 18.5, and 20.3. In other embodiments, Form B is characterized by an XRPD pattem having at least one, at least two, at least three, or at least four diffractions at angles (degrees 2 thêta ± 0.2) of 12.8, 14.1, 15.2, 18.5, and 20.3. In other embodiments, Form B is characterized by an XRPD pattem having diffractions at angles (degrees 2 thêta ± 0.2) of 12.0, 12.8, 14.1, 15.2, 16.9, 18.4, 18.5, 18.7, 19.3, and 20.3. In other embodiments, Form B is characterized by an XRPD pattem having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine diffractions at angles (degrees 2 thêta ± 0.2) of 12.0, 12.8, 14.1, 15.2, 16.9, 18.4, 18.5, 18.7, 19.3, and 20.3. In other

190 embodiments, Form B is characterized by an XRPD pattern having diffractions at angles (degrees 2 thêta ± 0.2) of 7.6, 9.2, 12.0, 12.8, 14.1, 15.1, 15.2, 16.2, 16.9, 17.6, 18.4, 18.5, 18.7, 19.3, 20.3, 21.7, 22.0, 22.2, 22.9, 23.6, 24.0, 24.2, 25.2, 26.9, 27.0, 27.4, 28.6, and 28.9. In other embodiments, Form B is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, at least fïve, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fïfteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-fïve, at least twenty-six, or at least twenty-seven diffractions at angles (degrees 2 thêta ± 0.2) of 7.6, 9.2, 12.0, 12.8, 14.1, 15.1, 15.2, 16.2, 16.9, 17.6, 18.4, 18.5, 18.7, 19.3, 20.3, 21.7, 22.0, 22.2, 22.9, 23.6, 24.0, 24.2, 25.2, 26.9, 27.0, 27.4, 28.6, and 28.9. In other embodiments, Form B is characterized by an XRPD pattern substantially similar to Figure 4.

In some embodiments, Form B is characterized by a solid State ¹³C NMR spectrum having peaks at Chemical shifts of 172.5, 172.1, 168.5, 168.3, 168.0, 151.5, 148.3, 147.8, 127.7, 122.7, 116.6, 115.1, 110.6, 86.5, 80.2, 63.2, 44.3, 23.0, and 13.1 ppm. In other embodiments, Form B is characterized by a solid State ¹³C NMR spectrum substantially similar to Figure 5.

In some embodiments, Form B is characterized by a solid State ¹⁹F NMR spectrum having peaks at Chemical shifts of -137.1 and -152.8 ppm. In other embodiments, Form B is characterized by a solid State ^,9F NMR spectrum substantially similar to Figure 6.

In some embodiments, Form B is characterized by an IR spectrum having peaks at 3501, 3356, 1684, 1565, 1505, and 1122 cm'¹. In other embodiments, Form B is characterized by an IR spectrum substantially similar to Figure 9.

191

In some embodiments, Form B is obtainable by dissolving the compound in ethyl acetate and then crystallizing the compound by adding n-heptane as an antisolvent. In other embodiments, Form B is obtainable by the procedure described in Example 3.

Solid Forms of Compound 9

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

wherein the compound is in crystalline solid form.

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

In some embodiments, Form A is characterized by an orthorhombic crystal System, as determined by single-crystal X-ray analysis. In other embodiments, Form A is characterized by an 1222 space group, as determined by single-crystal X-ray analysis. In other embodiments, Form A is characterized by a unit cell, as determined by single-crystal X-ray analysis, of the following dimensions: a=12.0172(5) Â; b=15.6682(6) Â; c=24.1406(l 1) Â; α=90°; β=90°; and γ=90°.

In some embodiments, Form A is obtainable by dissolving the compound in a 10/90 dichloromethane/dichloroethane solution, followed by vapor diffusion of pentane. In some embodiments, Form A is obtainable by the procedure described in Example 3.

Solid Forms of Compound 11

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

192 wherein the compound is in crystalline solid form.

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

In some embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 thêta ± 0.2) of 10.1, 13.7, 14.1, 16.3, and 20.0. In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, or at least four diffractions at angles (degrees 2 thêta ± 0.2) of 10.1, 13.7, 14.1, 16.3, and 20.0. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 thêta ± 0.2) of 7.3, 10.1, 13.7, 14.1, 16.0, 16.3, 20.0, 20.4, 23.7, and 24.8. In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine diffractions at angles (degrees 2 thêta ± 0.2) of 7.3, 10.1, 13.7, 14.1, 16.0, 16.3, 20.0, 20.4, 23.7, and 24.8. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 thêta ±0.2) of 7.1, 7.3, 10.1, 13.7, 14.1, 16.0, 16.3, 17.6, 18.5, 18.9,20.0, 20.4,21.5, 23.7,24.8, 25.7, and 26.1. In other embodiments, Form A is characterized by an XRPD pattem having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, or at least sixteen diffractions at angles (degrees 2 thêta ± 0.2) of 7.1, 7.3, 10.1, 13.7, 14.1, 16.0, 16.3, 17.6, 18.5, 18.9, 20.0, 20.4, 21.5, 23.7, 24.8, 25.7, and 26.1. In other embodiments, Form A is characterized by an XRPD pattem substantially similar to Figure 12.

In some embodiments, Form A is obtainable by suspending the compound in water. In other embodiments, Form A is obtainable by the procedure described in Example 4.

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

In some embodiments, Form B is characterized by an XRPD pattem having diffractions at angles (degrees 2 thêta ± 0.2) of 6.8, 13.2, 16.1, 20.6, and 21.3. In other embodiments, Form B is characterized by an XRPD pattem having at least one, at least two, at least three, or at least four diffractions at angles (degrees 2 thêta ± 0.2) of 6.8, 13.2, 16.1, 20.6, and 21.3. In other embodiments, Form B is characterized by an XRPD pattem having diffractions at angles (degrees 2 thêta ± 0.2) of 6.8, 11.5, 13.2, 13.6, 14.4, 16.1, 16.3, 18.8, 20.6, and 21.3. In other embodiments, Form B is characterized by an XRPD pattem having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine diffractions at angles

193 (degrees 2 thêta ± 0.2) of 6.8, 11.5, 13.2, 13.6, 14.4, 16.1, 16.3, 18.8, 20.6, and 21.3. In other embodiments, Form B is characterized by an XRPD pattern having diffractions at angles (degrees 2 thêta ±0.2) of6.8, 11.5, 13.2, 13.6, 14.4, 15.6, 16.1, 16.3, 17.6, 18.0, 18.8, 19.4, 20.6,21.3,22.3, 23.3, 24.2, and 27.4. In other embodiments, Form B is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fîfteen, at least sixteen, or at least seventeen diffractions at angles (degrees 2 thêta ± 0.2) of 6.8, 11.5, 13.2, 13.6, 14.4, 15.6, 16.1, 16.3, 17.6, 18.0, 18.8, 19.4, 20.6, 21.3, 22.3, 23.3, 24.2, and 27.4. In other embodiments, Form B is characterized by an XRPD pattern substantially similar to Figure

13.

In some embodiments, Form A is characterized by a monoclinic crystal System, as determined by single-crystal X-ray analysis. In other embodiments, Form A is characterized by a P2i space group, as determined by single-crystal X-ray analysis. In other embodiments, Form A is characterized by a unit cell, as determined by single-crystal X-ray analysis, of the following dimensions: a=12.0863(2) Â; b=7.48310(10) Â; c=23.9904(4) Â; α=90°; β=90.0130(10)°; and γ=90°.

In some embodiments, Form B is obtainable by recrystallization from acetonitrile. In other embodiments, Form B is obtainable by the procedure described in Example 4.

Solid Form of Compound 19

In some embodiments, the invention relates to a compound of formula wherein the compound is in crystalline solid form.

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

In some embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 thêta ± 0.2) of 13.7, 15.2, and 18.2. In other embodiments, Form A is

194 characterized by an XRPD pattern having at least one or at least two diffractions at angles (degrees 2 thêta ± 0.2) of 13.7, 15.2, and 18.2. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 thêta ± 0.2) of 13.7, 15.2, 18.2, 18.3, 20.8, and 23.8. In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, or at least five diffractions at angles (degrees 2 thêta ± 0.2) of 13.7, 15.2, 18.2, 18.3, 20.8, and 23.8. In other embodiments, Form A is characterized by an XRPD pattem having diffractions at angles (degrees 2 thêta ± 0.2) of 13.7, 14.3, 15.2, 18.2, 18.3, 20.8, 22.5, 23.8, and 25.8. In other embodiments, Form A is characterized by an XRPD pattem having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight diffractions at angles (degrees 2 thêta ± 0.2) of 13.7, 14.3, 15.2, 18.2, 18.3, 20.8, 22.5, 23.8, and 25.8. In other embodiments, Form A is characterized by an XRPD pattem having diffractions at angles (degrees 2 thêta ± 0.2) of 6.8, 13.7, 14.3, 15.2, 16.1, 18.2, 18.3, 19.1, 20.6, 20.8, 22.5, 23.8, 24.0, 25.8, 26.3, and 26.6. In other embodiments, Form A is characterized by an XRPD pattem having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, or at least fifteen diffractions at angles (degrees 2 thêta ± 0.2) of 6.8, 13.7, 14.3, 15.2, 16.1, 18.2, 18.3, 19.1, 20.6, 20.8, 22.5, 23.8, 24.0, 25.8, 26.3, and 26.6. In other embodiments, Form A is characterized by an XRPD pattem substantially similar to Figure 15.

In some embodiments, Form A is characterized by a solid State ¹³C NMR spectrum having peaks at Chemical shifts of 171.4, 141.6, 118.0, 112.2, 23.0, and 11.6 ppm. In other embodiments, Form A is characterized by a solid State ^l3C NMR spectrum having peaks at Chemical shifts of 171.4, 164.2, 151.8, 149.5, 148.4, 146.6, 144.0, 141.6, 138.7, 126.2, 123.8, 118.0, 112.2, 86.4, 78.8, 63.3, 47.6, 43.8, 23.0, and 11.6 ppm. In other embodiments, Form A is characterized by a solid State ¹³C NMR spectrum substantially similar to Figure 16.

In some embodiments, Form A is characterized by a solid State ^l9F NMR spectrum having peaks at Chemical shifts of -74.6, -141.5, and -154.6 ppm. In other embodiments, Form A is characterized by a solid State ¹⁹F NMR spectrum substantially similar to Figure 17.

In some embodiments, Form A is characterized by a monoclinic crystal system, as determined by single-crystal X-ray analysis. In other embodiments, Form A is characterized by a P2i space group, as determined by single-crystal X-ray analysis. In other embodiments, Form A is

195 characterized by a unit cell, as determined by single-crystal X-ray analysis, of the following dimensions: a=l 1.2266(3) Â; b=7.3948(2) Â; c=13.1432(4) Â; α=90°; β=100.3980(1)°; and γ=90°.

In some embodiments, Form A is obtainable by précipitation from methanol via addition of heptane antisolvent. In other embodiments, Form A is obtainable from a suspension of the compound in éthanol, acetonitrile, and water by lyophilization. In other embodiments, Form A is obtainable by dissolving the compound in methanol and allowing slow diffusion of heptane antisolvent. In other embodiments, Form A is obtainable by the procedure described in Example 5.

Solid Form of Compound 22

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

wherein the compound has the absolute stereochemistry of the third eluting isomer when a mixture of racemic diastereomers (epimeric at the 5-position) is separated by SFC as described in Example 6, Step 7, wherein the compound is in crystalline solid form.

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

In some embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 thêta ± 0.2) of 9.2, 10.4, and 15.7. In other embodiments, Form A is characterized by an XRPD pattern having at least one or at least two diffractions at angles (degrees 2 thêta ± 0.2) of 9.2, 10.4, and 15.7. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 thêta ± 0.2) of 7.7, 9.2, 10.4, 12.9, 15.7, and 18.4. In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, or at least five diffractions at angles (degrees 2 thêta ± 0.2) of 7.7, 9.2, 10.4, 12.9, 15.7, and 18.4. In other embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 thêta ± 0.2) of 7.7, 9.2, 10.4, 12.9, 15.7, 18.4, 19.8, 21.7, and 24.0. In other embodiments, Form A is characterized by an XRPD pattern having at least one, at least two,

196 at least three, at least four, at least five, at least six, at least seven, or at least eight diffractions at angles (degrees 2 thêta ± 0.2) of 7.7, 9.2, 10.4, 12.9, 15.7, 18.4, 19.8, 21.7, and 24.0. In other embodiments, Form A is characterized by an XRPD pattem having diffractions at angles (degrees 2 thêta ± 0.2) of 7.7, 9.2, 10.4, 12.9, 13.8, 14.7, 15.7, 16.1, 18.4, 19.8, 21.7, 22.3, and 24.0. In other embodiments, Form A is characterized by an XRPD pattem having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, or at least twelve diffractions at angles (degrees 2 thêta ± 0.2) of 7.7, 9.2, 10.4, 12.9, 13.8, 14.7, 15.7, 16.1, 18.4, 19.8, 21.7, 22.3, and 24.0. In other embodiments, Form Ais characterized by an XRPD pattem substantially similar to Figure 19.

In some embodiments, Form A is characterized by a solid State ^I3C NMR spectrum having peaks at Chemical shifts of 167.7, 126.0, 115.9, 43.5, and 20.3 ppm. In other embodiments, Form A is characterized by a solid State ¹³C NMR spectrum having peaks at Chemical shifts of 172.6, 167.7, 158.7, 156.8, 151.8, 148.7, 128.6, 126.0, 115.9, 113.1, 112.3, 88.0, 85.5, 62.0, 60.5, 55.6, 43.5, 37.7, 29.6, 21.1, and 20.3 ppm. In other embodiments, Form A is characterized by a solid State ^l3C NMR spectrum substantially similar to Figure 20.

In some embodiments, Form A is characterized by a solid State ^,9F NMR spectrum having peaks at Chemical shifts of-82.2, -83.1, -111.7, and -114.4 ppm. In other embodiments, Form A is characterized by a solid State ¹⁹F NMR spectrum substantially similar to Figure 21.

In some embodiments, Form A is obtainable by slow évaporation of a 1:1 2methyltetrahydrofuran/heptane solution. In other embodiments, Form A is obtainable by the procedure described in Example 6.

Solid Form of Compound 23

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

197 wherein the compound is in crystalline solid form.

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

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

In some embodiments, Form A is characterized by a solid state ^l3C NMR spectrum having peaks at Chemical shifts of 171.1, 149.3, 123.3, 41.6, and 20.0 ppm. In other embodiments, Form A is characterized by a solid State ¹³C NMR spectrum having peaks at Chemical shifts of 171.1, 166.7, 156.8, 155.5, 151.9, 149.3, 147.3, 131.5, 123.3, 119.0, 114.2, 112.8, 86.0, 85.0, 61.7, 61.0,44.4, 41.6, and 20.0 ppm. In other embodiments, Form A is characterized by a solid State ¹³C NMR spectrum substantially similar to Figure 23.

198

In some embodiments, Form A is characterized by a solid State ¹⁹F NMR spectrum having peaks at Chemical shifts of-78.2, -113.5, and -115.1 ppm. In other embodiments, Form A is characterized by a solid State ^I9F NMR spectrum substantially similar to Figure 24.

In some embodiments, Form A is characterized by a monoclinic ciystal System, as determined by single-crystal X-ray analysis. In other embodiments, Form A is characterized by a P2i space group, as determined by single-crystal X-ray analysis. In other embodiments, Form A is characterized by a unit cell, as determined by single-crystal X-ray analysis, of the following dimensions: a=7.8661(3) Â; b=7.9167(3) Â; c=16.8777(7) Â; α=90°; β=98.487(2)°; and γ=90°.

In some embodiments, Form A is obtainable by slow évaporation of a 1:1 2methyltetrahydrofuran/heptane solution. In other embodiments, Form A is obtainable by dissolving the compound in methanol and allowing slow diffusion of heptane vapor. In other embodiments, Form A is obtainable by the procedure described in Example 6.

Solid Form of Compound 25

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

wherein the compound has the absolute stereochemistry of the second eluting isomer when a racemic mixture of enantiomers is separated by SFC as described in Example 7, Step 11, wherein the compound is in crystalline solid form.

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

In some embodiments, Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 thêta ± 0.2) of 6.8, 7.9, and 13.8. In other embodiments, Form A is characterized by an XRPD pattern having at least one or at least two diffractions at angles (degrees 2 thêta ± 0.2) of 6.8, 7.9, and 13.8. In other embodiments, Form A is characterized by an XRPD pattem having diffractions at angles (degrees 2 thêta ± 0.2) of 6.8, 7.9, 11.0, 13.7, 13.8, and 27.4. In other embodiments, Form A is characterized by an XRPD pattem having at least one, at least two, at least

199 three, at least four, or at least five diffractions at angles (degrees 2 thêta ± 0.2) of 6.8, 7.9, 11.0, 13.7, 13.8, and 27.4. In other embodiments, Form A is characterized by an XRPD pattem having diffractions at angles (degrees 2 thêta ±0.2) of6.8, 7.9, 11.0, 13.7, 13.8, 15.9, 16.3, 23.2, and 27.4. In other embodiments, Form A is characterized by an XRPD pattem having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight diffractions at angles (degrees 2 thêta ± 0.2) of 6.8, 7.9, 11.0, 13.7, 13.8, 15.9, 16.3, 23.2, and 27.4. In other embodiments, Form A is characterized by an XRPD pattem having diffractions at angles (degrees 2 thêta ±0.2) of3.2, 6.8, 7.9, 11.0, 11.8, 13.7, 13.8, 15.1, 15.9, 16.3, 17.5, 18.6, 19.0, 19.5,21.6,21.9, 23.2, 27.0, 27.4, 29.4, and 30.3. In other embodiments, Form A is characterized by an XRPD pattem having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, or at least twenty diffractions at angles (degrees 2 thêta ± 0.2) of 3.2, 6.8, 7.9, 11.0, 11.8, 13.7, 13.8, 15.1, 15.9, 16.3, 17.5, 18.6, 19.0, 19.5, 21.6, 21.9, 23.2, 27.0, 27.4, 29.4, and 30.3. In other embodiments, Form A is characterized by an XRPD pattem substantially similar to Figure 26.

In some embodiments, Form A is obtainable by slow évaporation of a 1:1 2methyltetrahydrofuran/heptane solution. In other embodiments, Form A is obtainable by the procedure described in Example 7.

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 présent 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, neuropathie pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomy pain, hemiorrhaphy pain or abdominoplasty pain), viscéral 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

200 these compositions comprise a compound as described herein, or a pharmaceutically acceptable sait 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 sait” 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 animais without undue toxicity, irritation, allergie response and the like, and are commensurate with a reasonable benefit/risk ratio. A “pharmaceutically acceptable sait” of a compound of this invention includes any non-toxic sait that, upon administration to a récipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active métabolite or residue thereof. The sait 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, solvaté, or cocrystal. As used herein, the term “inhibitorily active métabolite or residue thereof’ means that a métabolite 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, glycérophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2hydroxy-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, stéarate,

201 succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali métal, alkaline earth métal, ammonium and N⁺(Cm alkyl)4 salts. Représentative alkali or alkaline earth métal salts include sodium, lithium, potassium, calcium, magnésium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quatemary 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 ail solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonie 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 varions carriers used in formulating pharmaceutically acceptable compositions and known techniques for the préparation 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 stéarate, lecithin, sérum proteins, such as human sérum 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, colloïdal silica, magnésium 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 dérivatives 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;

202 buffering agents such as magnésium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonie saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnésium stéarate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be présent 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 sait 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 sait 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 sait thereof or a pharmaceutical composition thereof. In another aspect, the voltage-gated sodium channel is Navl.8.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathie pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomy pain, hemiorrhaphy pain or abdominoplasty pain), viscéral 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 sait 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, neuropathie pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, bunionectomy pain, hemiorrhaphy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia comprising

203 administering an effective amount of a compound of the invention, a pharmaceutically acceptable sait 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 sait 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 neuropathie pain comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable sait thereof or a pharmaceutical composition thereof. In some aspects, the neuropathie 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 some aspects, the neuropathie pain comprises diabetic neuropathy.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of neuropathie pain, wherein neuropathie pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, buming 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 régional 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 autonomie cephalalgia wherein said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable sait 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 sait thereof or a pharmaceutical composition thereof. In some aspects, the musculoskeletal pain comprises osteoarthritis pain.

204

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, bum pain or dental pain wherein said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable sait 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 sait 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 sait 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 sait 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 sait 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 sait 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., bunionectomy pain, hemiorrhaphy pain or abdominoplasty pain) comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable sait thereof or a pharmaceutical composition thereof.

205

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 sait 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 hemiorrhaphy pain comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable sait 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 sait 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 viscéral pain comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable sait thereof or a pharmaceutical composition thereof. In some aspects, the viscéral pain comprises viscéral pain from abdominoplasty.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of a neurodegenerative disease comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable sait thereof or a pharmaceutical composition thereof. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt Hopkins Syndrome (PTHS).

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 subséquent to treatment with an effective amount of the compound, pharmaceutically acceptable sait 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 sait thereof or a pharmaceutical composition thereof. In another aspect, the voltage-gated sodium channel is Navl.8.

In another aspect, the invention features a method of treating or lessening the severity in a subject of acute pain, chronic pain, neuropathie pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy

206 conditions, neurodegenerative disorders, psychiatrie disorders, anxiety, dépréssion, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, viscéral 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., bunionectomy pain, hemiorrhaphy pain or abdominoplasty pain), cancer pain, stroke, cérébral ischemia, traumatic brain injury, amyotrophie latéral 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 sait thereof or a pharmaceutical composition thereof.

In another aspect, the invention features a method of treating or lessening the severity in a subject of fémur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathie low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic viscéral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headaches; chronic and acute neuropathie 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 neuropathie pain; radiotherapy-induced neuropathie pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex régional 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 viscéral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hemias; chest pain, cardiac pain; pelvic pain, rénal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, bum pain, trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anémia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis (MS) pain; pain in dépréssion; 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 urogénital disease; urinary incontinence, pathological cough; hyperactive bladder; painful bladder syndrome;

207 interstitial cystitis (IC); prostatitis; complex régional pain syndrome (CRPS), type I, complex régional 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 sait 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 sait or pharmaceutical composition thereof, for use as a médicament.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable sait or pharmaceutical composition thereof, for use in a method of inhibiting a voltagegated sodium channel in a subject. In another aspect, the voltage-gated sodium channel is Navl.8.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable sait or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathie pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomy pain, hemiorrhaphy pain or abdominoplasty pain), viscéral 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 sait or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathie pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, bunionectomy pain, hemiorrhaphy 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 sait 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 sait or pharmaceutical composition thereof, for use in a method of treating or lessening

208 the severity in a subject of neuropathie pain. In some aspects, the neuropathie pain comprises postherpetic neuralgia, small liber 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 some aspects, the neuropathie pain comprises diabetic neuropathy.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable sait or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of neuropathie pain, wherein neuropathie pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, buming 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 régional 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 autonomie cephalalgia.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable sait ôr 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 sait 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, bum pain or dental pain.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable sait 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.

209 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 sait 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 sait 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 sait 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 postoperative pain.

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

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

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

210

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable sait or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of a neurodegenerative disease. In some aspects, the neurodegenerative y disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt Hopkins Syndrome (PTHS).

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable sait 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 subséquent to treatment with an effective amount of the compound, pharmaceutically acceptable sait 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 sait or pharmaceutical composition thereof, for use in a method of inhibiting a voltagegated sodium channel in a biological sample comprising contacting the biological sample with an effective amount of a compound of the invention, a pharmaceutically acceptable sait thereof or a pharmaceutical composition thereof. In another aspect, the voltage-gated sodium channel is Navl.8.

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable sait or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of acute pain, chronic pain, neuropathie pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatrie disorders, anxiety, dépréssion, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, viscéral 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., bunionectomy pain, hemiorrhaphy pain or abdominoplasty pain), cancer pain, stroke, cérébral ischemia, traumatic brain injury, amyotrophie latéral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastro-intestinal motility.

211 the severity in a subject of fémur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathie low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic viscéral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headaches; chronic and acute neuropathie 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 neuropathie pain; radiotherapy-induced neuropathie pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex régional 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 viscéral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hemias; chest pain, cardiac pain; pelvic pain, rénal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, bum pain, trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anémia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis (MS) pain; pain in dépréssion; 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 urogénital disease; urinary incontinence, pathological cough; hyperactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex régional pain syndrome (CRPS), type I, complex régional pain syndrome (CRPS) type II; widespread pain, paroxysmal extreme pain, pruritus, tinnitus, or angina-induced pain.

Manufacture of Médicaments

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

In another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable sait thereof, or a pharmaceutical composition thereof for the

212 manufacture of a médicament for use in inhibiting a voltage-gated sodium channel. In another aspect, the voltage-gated sodium channel is Navl .8.

In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable sait thereof, or a pharmaceutical composition thereof for the manufacture of a médicament for use in treating or lessening the severity in a subject of chronic pain, gut pain, neuropathie pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomy pain, hemiorrhaphy pain or abdominoplasty pain), viscéral 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 sait thereof, or a pharmaceutical composition thereof for the manufacture of a médicament for use in treating or lessening the severity in a subject of chronic pain, gut pain, neuropathie pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, bunionectomy pain, hemiorrhaphy 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 sait, or pharmaceutical composition described herein for the manufacture of a médicament 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 sait thereof, or a pharmaceutical composition thereof for the manufacture of a médicament for use in treating or lessening the severity in a subject of neuropathie pain. In some aspects, the neuropathie pain comprises post-herpetic neuralgia, small fiber neuropathy or idiopathic small-fiber neuropathy. In some aspects, the neuropathie pain comprises diabetic neuropathy.

In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable sait thereof, or a pharmaceutical composition thereof for the manufacture of a médicament for use in a treating or lessening the severity in a subject of neuropathie pain, wherein neuropathie pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, buming mouth syndrome, post

213 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 régional 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 autonomie neuropathy.

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

In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable sait thereof, or a pharmaceutical composition thereof for the manufacture of a médicament 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 sait thereof, or a pharmaceutical composition thereof for the manufacture of a médicament 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 sait thereof, or a pharmaceutical composition thereof for the manufacture of a médicament 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 sait thereof, or a pharmaceutical composition thereof for the

214 manufacture of a médicament 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 sait thereof, or a pharmaceutical composition thereof for the manufacture of a médicament 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 sait thereof, or a pharmaceutical composition thereof for the manufacture of a médicament for use in treating or lessening the severity in a subject of postsurgical pain (e.g., bunionectomy pain, hemiorrhaphy pain or abdominoplasty pain).

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

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

In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable sait or pharmaceutical composition thereof, for the manufacture of a médicament for use in treating or lessening the severity in a subject of a neurodegenerative disease. In some aspects, the

215 neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt Hopkins Syndrome (PTHS).

In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable sait thereof, or a pharmaceutical composition thereof for the manufacture of a médicament for use in combination with one or more additional therapeutic agents administered concurrently with, prior to, or subséquent 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 sait thereof, or a pharmaceutical composition thereof for the manufacture of a médicament for use in treating or lessening the severity of acute pain, chronic pain, neuropathie pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatrie disorders, anxiety, dépréssion, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, viscéral 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., bunionectomy pain, hemiorrhaphy pain or abdominoplasty pain), cancer pain, stroke, cérébral ischemia, traumatic brain injury, amyotrophie latéral 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 sait thereof, or a pharmaceutical composition thereof for the manufacture of a médicament for use in treating or lessening the severity of fémur cancer pain; nonmalignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathie low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic viscéral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headaches; chronic and acute neuropathie 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

216 distal discharges; radiculopathy; chemotherapy induced neuropathie pain; radiotherapy-induced neuropathie pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex régional 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 viscéral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hemias; chest pain, cardiac pain; pelvic pain, rénal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory, bum pain, trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anémia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis (MS) pain; pain in dépréssion; 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 urogénital disease; urinary incontinence; pathological cough; hyperactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex régional pain syndrome (CRPS) type I; complex régional 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 sait 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, âge, 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 discrète unit of agent appropriate for the subject to be treated. It

217 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 spécifie effective dose level for any particular subject or organism will dépend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the spécifie compound or sait employed; the spécifie composition employed; the âge, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excrétion of the spécifie compound or sait employed; the duration of the treatment; drugs used in combination or coincidental with the spécifie compound or sait 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 animais orally, rectally, parenterally, intracistemally, 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 émulsions, microemulsions, solutions, suspensions, syrups and élixirs. In addition to the active compound or sait, 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 préparations, for example, stérile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and

218 suspending agents. The stérile injectable préparation may also be a stérile injectable solution, suspension or émulsion 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 isotonie sodium chloride solution. In addition, stérile, 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 préparation of injectables.

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

In order to prolong the effect of the compounds of the invention, it is often désirable to slow the absorption of the compounds from subeutaneous 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 dépends upon its rate of dissolution that, in tum, may dépend upon crystal size and crystalline form. Altematively, 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 biodégradable 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 biodégradable 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 sait 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 température but liquid at body température 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 sait is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate

219 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 paraffm, f) absorption accelerators such as quatemary 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 stéarate, magnésium stéarate, 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, dragees, 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 sait can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, 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 sait 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 magnésium stéarate 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

220 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 sait of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under stérile 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 contemplâtes the use of transdermal patches, which hâve 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 ofNavl.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 Navl.8 is implicated in the disease, condition, or disorder. When activation or hyperactivity of Navl.8 is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as a “Navl.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 Navl.8 is implicated in the disease state.

The activity of a compound utilized in this invention as an inhibitor of Navl.8 may be assayed according to methods described generally in International Publication No. WO 2014/120808 A9 and U.S. Publication No. 2014/0213616 Al, both of which are incorporated by référencé in their entirety, methods described herein, and other methods known and available to one of ordinary skill in the art.

Additional Therapeutic Agents

221

It will also be appreciated that the compounds, salts, and pharmaceutically acceptable compositions of the invention can be employed in combination thérapies, that is, the compounds, salts, and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subséquent to, one or more other desired therapeutics or medical procedures. The particular combination of thérapies (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 thérapies 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: nonopioid analgésies (indoles such as Etodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such as Nabumetone; oxicams such as Piroxicam; para-aminophenol dérivatives, such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylates such as Aspirin, Choline magnésium trisalicylate, Diflunisal; fenamates such as meelofenamie acid, Mefenamic acid; and pyrazoles such as Phenylbutazone); or opioid (narcotic) agonists (such as Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprénorphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgésie approaches may be utilized in conjonction 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 psychologie (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

222

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 analgésie, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaïne, codeine, dihydrocodéine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprénorphine, 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®)), meelofenamie acid, mefenamic acid, meloxicam, IV meloxicam (e.g., Anjeso®), nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

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

(4) a benzodiazépine having a sédative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazépam, oxazepam, temazepam or triazolam;

(5) a histamine (Hi) antagonist having a sédative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;

(6) a sédative 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-Nmethylmorphinan) or its métabolite 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

223 (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-l- piperidinyl]-l-hydroxyethyl-3,4-dihydro-2(lH)quinolinone;

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

(10) atricyclic 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,l 1 -tetrahydro-9-methyl-5-(4methylphenyl)-7H-[l,4]diazocino[2,l-g][l,7]-naphthyridine-6-13-dione (TAK-637), 5- [[(2R,3S)-2[(lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-l,2dihydro-3H-l,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 sélective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

(15) a coal-tar analgésie, in particular paracétamol;

(16) a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, rispéridone, 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;

224 (21) a 5-HT receptor agonist or antagonist, particularly a 5-HTib/id agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

(22) a 5-HT₂a receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-l-[2-(4fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);

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

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

(25) a PDE5 inhibitor, such as 5-[2-ethoxy-5-(4-methyl-l-piperazinyl-sulphonyl)phenyl]-lmethyl-3-n-propyl-l,6-dihydro-7H-pyrazoIo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',r:6,l]-pyrido[3,4b]indole-l,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-l-yl-l-sulphonyl)-phenyl]5-methyl-7-propyl-3H-imidazo[5,l-f][l,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3pyridinyl)-3-ethyl-2-(l-ethyl-3-azetidinyl)-2,6-dihydro-777- pyrazolo[4,3-i/]pyrimidin-7-one, 5-(5acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(l-isopropyl-3-azetidinyl)-2,6-dihydro-77/-pyrazolo[4,3rf]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-l-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2methoxyethyl]-2,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one, 4-[(3-chloro-4methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-l-yl]-N-(pyrimidin-2ylmethyl)pyrimidine-5-carboxamide, 3-(l- methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo[4,3d]pyrimidin-5-yl)-N-[2-(l-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, (l[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3amino-5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)proline, [(lR,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(l-aminomethylcyclohexylmethyl)-4H-[ 1,2,4]oxadiazol-5-one, C-[ 1 -( 1 H-tetrazol-5-ylmethyl)-cycloheptyl]methylamine, (3S,4S)-(l-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino

225

5-methyl-octanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and (3R,4R,5R)-3-amino4,5-dimethyl-octanoic acid;

(27) a cannabinoid such as KHK-6188;

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

(29) a serotonin reuptake inhibitor such as sertraline, sertraline métabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl métabolite), fluvoxamine, paroxetine, citalopram, citalopram métabolite 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 métabolite hydroxybupropion, nomifensine and viloxazine (Vivalan®), especially a sélective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine;

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

(32) an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(liminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(l-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(l-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(liminoethyl)amino]-5-heptenoic acid, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)-butyl]thio]-Schloro-S-pyridinecarbonitrile; 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5- thiazolyl)butyl]thio]-4chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5- (trifluoromethyl)phenyl]thio]-5thiazolebutanol, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl) butyl]thio]-6-(trifluoromethyl)-3pyridinecarbonitrile, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(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 7V-[( {2-[4-(2-ethyl-4,6- dimethyllH-imidazo[4,5-c]pyridin-l-yl)phenyl]ethyl}amino)-carbonyl]-4- methylbenzenesulfonamide or 4[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3- yl]carbonyl}amino)ethyl]benzoic acid;

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

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

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

(38) aNavl.7 blocker, such as XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893, BIIB-074 (Vixotrigine), BIIB-095, ASP-1807, DSP-3905, OLP-1002, RQ00432979, 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), US8883840, US8466188, or W02013/109521 (US2015005304), the entire contents of each application hereby incorporated by reference.

(38a) aNavl.7 blocker such as (2-benzylspiro[3,4-dihydropyrrolo[l,2-a]pyrazine-l,4'piperidine]-r-yl)-(4-isopropoxy-3-methyl-phenyl)methanone, 2,2,2-trifluoro-l-[r-[3-methoxy-4-[2(trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethyI-spiro[3,4-dihydropyrrolo[l,2-a]pyrazine-l,4'piperidine]-6-yl]ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[l,2a]pyrazine-l,4'-piperidine]-r-yl]-(4-isobutoxy-3-methoxy-phenyl)methanone, l-(4benzhydrylpiperazin-l-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy]propan-2-ol, (4-butoxy-3-methoxyphenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[ 1,2-a]pyrazine-1,4'-piperidine]-ryl]methanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[ 1,2-a]pyrazine-1,4'piperidine]-r-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]-Γyl]methanone, 5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[l,2a]pyrazine-1,4'-piperidine]-1 '-carbonyl]phenyl]pyridine-2-carbonitrile, (4-isopropoxy-3-methylphenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pynOlo[ 1,2-a]pyrazine-1,4'-piperidine]-1 'yl]methanone, 2,2,2-trifluoro-l-[r-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2-methylspiro[3,4-dihydropyrrolo[ 1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 2,2,2-trifluoro-1-[ 1 '-(5

227 isopropoxy-6-methyl-pyridine-2-carbonyl)-3,3-dimethyl-spiro[2,4-dihydropyrroIo[l,2-a]pyrazine1,4'-piperidine]-6-yl]ethanone, 2,2,2-trifluoro-1 -[r-(5-isopentyloxypyridine-2-carbonyl)-2-methylspiro[3,4-dihydropyrrolo[l,2-a]pyrazine-l,4'-piperidine]-6-yl]ethanone, (4-isopropoxy-3-methoxyphenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[ 1,2-a]pyrazine-1,4'-piperidine]-1 'yl]methanone, 2,2,2-trifluoro-l-[r-(5-isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4dihydropyrrolo[l,2-a]pyrazine-l,4'-piperidine]-6-yl]ethanone, l-[(3S)-2,3-dimethyl-l'-[4-(3,3,3trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[l,2-a]pyrazine-l,4'-piperidine]-6-yl]2,2,2-trifluoro-ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[l,2a]pyrazine-1,4'-piperidine]-1 ’-yl]-[3 -methoxy-4-[( 1 R)-1 -methylpropoxy]phenyl]methanone, 2,2,2trifluoro-l-[r-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4dihydropyrrolo[ 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-l-one, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6(trifluoromethyl)spiro[3,4-dihydropyrrolo[ 1,2-a]pyrazine-1,4'-piperidine]-1 '-yl]methanone, [2methyl-6-(l-methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[ 1,2-a]pyrazine-1,4'-piperidine]l'-yl]-[4-(3,3,3-trifluoropropoxymethyl)phenyl]methanone, 4-bromo-N-(4-bromophenyl)-3-[(lmethyl-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) aNavl.8 blocker, such as PF-04531083, PF-06372865 and such as those disclosed in WO2008/135826 (US2009048306), WQ2006/011050 (US2008312235), WQ2013/061205 (US2014296313), US20130303535, W02013131018, US8466188, WO2013114250 (US2013274243), W02014/120808 (US2014213616), W02014/120815 (US2014228371) WQ2014/120820 (US2014221435), WQ2015/010065 (US20160152561), WO2015/089361 (US20150166589), WO2019014352 (US20190016671), WO2018/213426, WO2020/146682, WO2020/146612, W02020/014243, W02020/014246, WQ2020/092187, and W02020/092667 (US2020140411), the entire contents of each application hereby incorporated by reference.

(39a) a Navl.8 blocker such as 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-l,2dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4yl)-4-(perfluoroethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-l,2-dihydropyridin-4

228 yl)benzamide, 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4yl)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-l,2-dihydropyndin4-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-l,2-dihydropyridin-4-yl)-5(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin4-yl)benzamide, 4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4yl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4yl)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-1 H-pyridin-4-yl)-4(trifluoromethyl)benzamide, [4-[[2-(4-fluoro-2-methyl-phenoxy)-4(trifluoromethyl)benzoyl]amino]-2-oxo-l-pyridyl]methyl dihydrogen phosphate, 2-(4-fluoro-2(methyl-d₃)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, (4-(2-(4fluoro-2-(methyl-d₃)phenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-l(2H)-yl)methyl dihydrogen phosphate, 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline2-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-2methoxyphenoxy)-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-(3sulfamoylphenyl)quinoline-3-carboxamide, 3-(2,4-difluorophenoxy)-N-(3sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-sulfamoylphenyl)-2-(4(trifluoromethoxy)phenoxy)quinoline-3-carboxamide, N-(3-sulfamoylphenyl)-3-(4229 (trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide, 3-(4-chloro-2-methylphenoxy)-N-(3sulfamoylphenyl)quinoxaline-2-carboxamide, 5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaIine-2carboxamido)picolinic acid, 3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-lHbenzo[d]imidazol-5-yl)quinoxaline-2-carboxamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4yl)quinoxaline-2-carboxamide, 3-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2carboxamide, 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-(4fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 5-(4,5-dichloro-2-(4-fluoro-2methoxyphenoxy)benzamido)picolinic acid, 5-(2-(2,4-dimethoxyphenoxy)-4,6bis(trifluoromethyl)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2methoxyphenoxy)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4,6bis(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-2methoxyphenoxy)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-dichIoro-2-(4(trifluoromethoxy)phenoxy)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4-chloro-2methylphenoxy)benzamido)benzoic acid, 5-(4-(tert-butyl)-2-(4-fluoro-2methoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4(trifluoromethoxy)phenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2methylphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4dimethoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(2-chloro-4fluorophenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-fluoro-2methylphenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-chloro-2methoxyphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4difluorophenoxy)benzamido)picolinic acid, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4230 (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-(3sulfamoylphenyl)benzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3sulfamoylphenyl)benzamide, 2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3sulfamoylphenyl)benzamide, 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6bis(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6bis(trifluoromethyl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3sulfamoylphenyl)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-(4fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-4cyano-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-carbamoyl4-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-[[3chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2carboxamide, 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-6231

[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-6-[2chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4fluoro-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-[3chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(4carbamoyl-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-carbamoyI-4-fluoro-phenyl)-2fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4fluoro-phenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-( 1,1,2,2,2pentafluoroethyl)benzamide, 4-[[4-(difluoromethoxy)-2-fluoro-6-[2-methoxy-4(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluorophenyl)-2-fluoro-6-[2-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[4cyclopropyl-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2carboxamide, 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-(3carbamoyl-4-fluoro-phenyl)-2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzamide, or4-[[2fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide;

(40) a combined Navl.7 and Navl.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 solvatés thereof;

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

(44) anN-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 V116517, 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-(6amino-5-(2,3,5-trichlorophenyl)pyridin-2-yl)acetamide; N-(6-amino-5-(2-chloro-5methoxyphenyl)pyridin-2-yl)-1 -methyl-1 H-pyrazole-5-carboxamide; or 3-((4-(4(trifluoromethoxy)phenyl)-lH-imidazol-2-yl)methyl)oxetan-3-amine.

In another embodiment, the additional therapeutic agent is selected from a GlyT2/5HT2 inhibitor, such as Operanserin (WZ149), a TRPV modulator such as CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101, MDR16523, or MDR652, a EGR1 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 LEVI04.

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

In another embodiment, the additional therapeutic agent is aNavl.7 blocker such as ST-2427 and those disclosed in WO2010129864, WO2015157559, WO2017059385, WO2018183781,

233

WO2018183782, and W02020072835 the entire contents of each application hereby incorporated by référencé.

In another embodiment, the additional therapeutic agent is ASP18071, CC-8464, ANP-230, ANP-231, NOC-100, NTX-1175, ASN008, NW3509, AM-6120, AM-8145, AM-0422, BL-017881, NTM-006, Opiranserin (Unafra™), brivoligide, SR419, NRD.E1, LX9211, LY3016859, ISC-17536, NFX-88, LAT-8881, AP-235, NYX 2925, CNTX-6016, S-600918, S-637880, RQ-00434739, KLS2031, MEDI 7352, orXT-150.

In another embodiment, the additional therapeutic agent is a sodium channel inhibitor (also known as a sodium channel blocker), such as the Navl.7 and Navl.8 blockers identified above.

The amount of additional therapeutic agent présent 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 présent 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 cathéters. Accordingly, the invention, in another aspect, includes a composition for coating an implantable device comprising a compound or sait 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 sait 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 préparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric matériels 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.

234

Another aspect of the invention relates to inhibiting Navl.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 sait 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 Navl.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 évaluation 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, other 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 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).

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, as described herein (including ail embodiments thereof), except that one or more atoms has been replaced with a radioisotope of the atom présent 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 ³H, ¹⁴C, ³²P, ³⁵S, ^I8F, ³⁶CI, and the like, as well as the isotopes for which a decay mode is identified in V.S. Shirley &

235

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 bénéficiai ways, including in varions types of assays, such as substrate tissue distribution assays. For example, tritium (³H)- and/or carbon-14 (¹⁴C)-labeled compounds may be useful for varions types of assays, such as substrate tissue distribution assays, due to relatively simple préparation 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 varions 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 médicaments, 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 thérapies, in accordance with any of the embodiments described herein in connection with the compounds of the invention.

236

EXAMPLES

General methods. Ή NMR (400 MHz) spectra were obtained as solutions in an appropriate deuterated solvent such as dimethyl sulfoxide-dô (DMSO-de).

Analytical supercritical fluid chromatography (SFC) séparation of varions isomeric mixtures was accomplished using a Waters UPC2-SFC instrument comprising a convergence manager, a sample manager, a binary solvent manager, a column manager-30S, a PDA detector, an isocratic solvent manager and a QDa detector. Columns used include those by manufactured by Regis Technologies (e.g., R’R Whelk 0-1, 3.5pm particle size, 5.0 cm x 3.0 mm size) with a mobile phase of Solvent A: liquid CO₂ (58-60 bar/40 °C) Solvent B: methanol HPLC grade with 20mM NH3 at a flow rate of 2ml/min and an injection volume of 2μ1. Gradient: at 0 min (95:5) A:B, at 3.5 min (50:50) A:B, at 3.55 min (40:60) A:B, at 3.95 min (40:60) A:B and at 4.0min (95:5) A:B. Samples for analytical SFC were dissolved in methanol at approximately 0.5mg/ml concentration.

Préparative SFC used the same stationary and mobile phases as those described above for analytical SFC but the samples were purified using a different instrument and gradient method as follows. Préparative SFC séparation of various isomeric mixtures was accomplished using a Waters Prep-100 SFC instrument comprising a Back Pressure Regulator, a 2767 Sample Manager, a 2545 Quartemary Gradient Module, a Column Oven, a 2998 PDA detector, an Isocratic Solvent Manager, a P-200 CO2 pump, SFC Flow Splitter-100, 3 Heat exchangers, a Sériés III LC pump and a QDa detector. Columns used include those manufactured by Regis Technologies (e.g., R’R Whelk 0-1, 5.0pm particle size, 25.0 cm x 21.1 mm size) with a mobile phase of Solvent A: liquid CO2 (5860 bar/40 °C) Solvent B: methanol HPLC grade with 20mM NH3 at a flow rate of lOOml/min and an injection volume of 500μ1 (50mg crude loading), 2:1 ratio of methanol to dichloroethane was used for solubilization and SFC injection of crude compound. For injection 500pl/50mg loading the following method was used: Isocratic: at 0 min to 7.6min (80:20) A:B, Gradient: at 8.1min (75:25) A:B, Isocratic at 8.2 to 10.6min (75:25) (A:B), Gradient: at 10.7min (80:20) A:B and Isocratic: at 11min (80:20) (A:B). For injection 1500pl/150mg loading the following method was used: Isocratic: at 0 min to 7.5min (80:20) A:B, Gradient: at 7.6min (75:25) A:B, Gradient: at 8.1min (60:40) A:B, Isocratic: at 8.7min to 10.6min (60:40) A:B, Gradient: at 10.7min (80:20) A:B and Isocratic: at 12min (80:20) A:B.

237

LC/MS Method: LC/MS analysis was conducted using an Acquity UPLC BEH Cs column (50 x 2.1 mm, 1.7 pm particle) made by Waters (pn: 186002877) with a (2.1 ^x 5 mm, 1.7 pm particle) guard column (pn: 186003978), and a dual gradient run from 2-98% mobile phase B over 4.45 minutes. Mobile phase A = H2O (10 mM ammonium formate with 0.05 % ammonium hydroxide). Mobile phase B = acetonitrile. Flow rate = 0.6 mL/min, injection volume = 2 pL, and column température = 45 °C.

X-ray powder diffraction (XRPD) analysis was performed at room température in transmission mode using a PANalytical Empyrean System equipped with a sealed tube source and a PIXcel 1D Medipix-3 detector (Malvem PANalytical Inc, Westborough, Massachusetts). The XRay generator operated at a voltage of 45 kV and a current of 40 mA with copper radiation (1.54060 Â). The powder sample was placed on a 96 well sample holder with mylar film and Ioaded into the instrument. The sample was scanned over the range of about 3° to about 40°20 with a step size of 0.0131303° and 49s per step.

Solid State NMR analysis was conducted on a Bruker-Biospin 400 MHz wide-bore spectrometer equipped with Bruker-Biospin 4mm HFX probe was used. Samples were packed into 4mm ZrO₂ rotors and spun under Magic Angle Spinning (MAS) condition with spinning speed typically set to 12.5 kHz. The proton relaxation time was measured using Ή MAS Ti saturation recovery relaxation experiment in order to set up proper recycle delay of the ^l3C cross-polarization (CP) MAS experiment. The fluorine relaxation time was measured using ¹⁹F MAS Ti saturation recovery relaxation experiment in order to set up proper recycle delay of the ¹⁹F MAS experiment. The CP contact time of carbon CPMAS experiment was set to 2 ms. A CP proton puise with linear ramp (from 50% to 100%) was employed. The carbon Hartmann-Hahn match was optimized on extemal reference sample (glycine). Both carbon and fluorine spectra were recorded with proton decoupling using TPPM15 decoupling sequence with the field strength of approximately 100 kHz.

Thermogravimetric analysis (TGA) data were collected on a TA Discovery Thermogravimetric Analyzer or équivalent instrumentation. A sample with weight of approximately 1-5 mg was scanned from 25 °C to 350 °C at a heating rate of 10 °C/min. Data were collected by Thermal Advantage Q SeriesTM software and analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE).

238

Differential scanning calorimetry (DSC) data were acquired using a TA Instruments Q2000 or équivalent instrumentation. A sample with a weight between 1 and 10 mg was weighed into an aluminum pan. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. The heating program was set to heat the sample at a heating rate of 10° C/min to a température of 300° C. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE).

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

X-ray diffraction data were acquired on a Bruker diffractometer equipped with Cu

Ka radiation (λ=1.5478 Â) and a CCD detector. The structure was solved and refined using SHELX programs (Sheldrick, G.M., Acta Cryst., (2008) A64, 112-122).

Abbreviations

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

Abbreviation	Meanîng
NMR	Nuclear magnetic résonance
ESI-MS	Electrospray mass spectrometry
LC/MS	Liquid chromatography-mass spectrometry
UPLC	Ultra performance liquid chromatography '
HPLC/MS/MS	High performance liquid chromatography/tandem mass
	spectrometry
IS	Internai standard
HPLC	High performance liquid chromatography
SFC	Supercritical fluid chromatography
MD AP	Mass directed auto purification
ESI	Electrospray ionization
LED	Light-emitting diode

239

g	grams
mg	milligrams
L	Liter(s)
mL	Milliliters
pL	Microliters
nL	nanoliters
mmol	millimoles
hr, h	hours
min	Minutes
ms	millisecond
mm	Millimeters
pm	Micrometers
nm	nanometer
MHz	Mégahertz
Hz	Hertz
N	Normal (concentration)
M	Molar (concentration)
mM	Millimolar (concentration)
μΜ	Micromolar (concentration)
ppm	Parts per million
% w/v	Weight-volume concentration
ArBPin	2-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-
	1,3,2-dioxaborolane
t-BuOH	terZ-butyl alcohol
DAST	Diethylaminosulfur trifluoride
DCM	Dichloromethane
DCE	Dichloroethane
DIEA, DIPEA	N, N-Diisopropyl ethyl amine
DMA	N,N -Dimethylacetamide

240

DMF	Ν,Ν-Dimethylformamide
DMSO	Dimethyl sulfoxide
DRG	Dorsal root ganglia
EtOH	Ethanol
EtOAc	Ethyl acetate
HATU	l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5b]pyridinium 3-oxide hexafluorophosphate
EDCI	l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
T3P	Propylphosphonic anhydride, i.e., 2,4,6-tripropyl-l,3,5,2,4,6trioxatriphosphinane 2,4,6-trioxide
TCFH	Ν,Ν,Ν',Ν'-Tetramethylchloroformamidinium
MeOH	hexafluorophosphate Methanol
MTBE	Methyl te/7-butyl ether
NMP	N-Methylpyrrolidone
THF	Tetrahydrofuran
TEA	triethylamine
RB	Round bottom (flask)
RT	Room température
ca.	Circa (approximately)
E-VIPR	Electrical stimulation voltage ion probe reader
HEK	Human embryonic kidney
KIR2.1	Inward-rectifier potassium ion channel 2.1
DMEM	Dulbecco's Modified Eagle's Medium
FBS	Fêtai bovine sérum
NEAA	Non-essential amino acids
HEPES	2-[4-(2-hydroxyethyl)piperazin-1 -yl]ethanesulfonic acid
DiSBAC₆(3) CC2-DMPE	Bis-(l,3-dihexyl-thiobarbituric acid) trimethine oxonol Chlorocoumarin-2-dimyristoyl phosphatidylethanolamine

241

VABSC-1 Voltage Assay Background Suppression Compound

HS Human sérum

BSA Bovine Sérum Albumin

Example 1 re/-(25,37?,47?,55)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (1) and rel5 (27?, 35,45,57?)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (2)

1) ArBPin, Pd(PPh₃)₃,

4) (COCI)₂, cat. DMF, DCM, 0 °C to RT then methyl 4-aminopyridine-2carboxylate, NEt₃, DCM, 0 °C to RT, 95%

5) 7N NH₃, MeOH, 98%

6) SPC

2) Mg, MeOH, 90 °C, 88%

3) KOf-Bu, t-BuOH then LiOH, EtOH, 100 °C, 71%

1, first eluting Isomer

2, second eluting isomer

Step 1:

A mixture of ethyl rac-(25,37î)-2,3-dimethyl-2-(trifluoromethyl)-410 (trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (3.0 g, 7.77 mmol), 2-[2-(difluoromethoxy)-4fluoro-phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (“ArBPin”, 2.33 g, 8.09 mmol), Pd(PPh₃)4 (380 mg, 0.33 mmol), and sodium carbonate (16 mL of 2 M, 32.00 mmol) in dioxane (60 mL) was heated at 100 °C for 1 hour. The solution was diluted in EtOAc and water, the layers separated and the organic layer washed with brine, dried (MgSCL), filtered and concentrated in vactto. Purification by flash chromatography (220 g SiO₂, 0 to 30% EtOAc in petroleum ether) gave ethyl rac-(25,37î)242

4-[2-(difluoromethoxy)-4-fluoro-phenyl]-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (2.0 g, 65%). Ή NMR (500 MHz, Chloroform-d) δ 7.19 (dd, J = 8.5, 6.4 Hz, 1H), 6.99 - 6.89 (m, 2H), 6.44 (t, J = 73.3 Hz, 1H), 4.14 (qd, J = 7.1, 1.7 Hz, 2H), 3.45 (q, J = 7.4 Hz, 1H), 1.72 - 1.65 (m, 3H), 1.14 (t, J = 7.1 Hz, 3H), 1.12 - 1.08 (m, 3H) ppm. ESI-MS m/z cale. 398.09528, found 399.0 (M+l)⁺.

Step 2:

Magnésium fïlings (3.5 g, 144.0 mmol) were ground in a mortar and added to a solution of ethyl rac-(25’,37?)-4-[2-(difluoromethoxy)-4-fluoro-phenyl]-2,3-dimethyl-2-(trifluoromethyl)-3Hfuran-5-carboxylate (2.0 g, 5.02 mmol) in MeOH (60 mL). The flask was purged with nitrogen and the reaction was stirred at ambient température until the observed exotherm finished (30 mins). The reaction was then heated at 90 °C for 3 hours before being cooled to 0 °C and quenched and acidified by carefiil addition of 2 M HCl. The mixture was concentrated in vacuo and extracted with DCM (3 x 100 mL). The combined organic layers were dried (MgSCU), filtered and concentrated in vacuo to give methyl rac-(37?,47?,5S)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.7 g, 88%) as a mixture of epimers at the position adjacent to the ester (stereochemical assignments tentative). ESI-MS m/z cale. 386.09528, found 387.0 (M+l)⁺.

Step 3:

To a solution of methyl rac-(31?,47?,5S)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5dimethyl-5-(trifluoromethyI)tetrahydrofuran-2-carboxylate (3.2 g, 8.28 mmol) in t-BuOH (80 mL) was added KOt-Bu (4.25 g, 37.87 mmol). The reaction was stirred at ambient température ovemight then quenched by addition of saturated aqueous NH4CI solution and diluted with EtOAc. The aqueous layer was separated and extracted with EtOAc and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in EtOH (20 mL) and LiOH (15 mL of 2 M, 30.00 mmol) and the mixture stirred at 110 °C for 1 hour. The reaction was quenched by addition of saturated aqueous NH4CI solution and diluted with EtOAc. The aqueous layer was separated and extracted with EtOAc and the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography (80 g S1O2, 0 to 100% EtOAc in heptanes) gave rac-(37î,4R,55)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (2.2 g, 71%) as a mixture of epimers

243 at the position adjacent to the ester (stereochemical assignments tentative). ESI-MS m/z cale. 372.07962, found 371.2 (M-l)’.

Step 4:

To a solution of rac-(37?,47?,55)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (650 mg, 1.75 mmol) in DCM (24 mL) stirring at 0 °C was added DMF (50 pL, 0.65 mmol) and oxalyl chloride (400 pL, 4.59 mmol). The reaction was warmed to ambient température over 30 mins then concentrated in vacuo. The residue was further dried on a high-vacuum apparatus for 5 mins to give a white foam, which was dissolved in DCM (24 mL) and added dropwise to a solution of methyl 4-aminopyridine-2-carboxylate (305 mg, 2.01 mmol) and NEtî (800 pL, 5.74 mmol) in DCM (9 mL) with stirring at 0 °C. The reaction was warmed to ambient température over 4 hours, then quenched by addition of MeOH (2 mL) and concentrated in vacuo. Purification by flash chromatography (12 g SiO₂, 0 to 70% EtOAc in heptane, loaded in DCM) gave methyl rac-(37?,47?,55)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (840 mg, 95%), as a 85:15 mixture of epimers at the position adjacent to the amide (stereochemical assignments tentative). ESI-MS m/z cale. 506.12766, found 507.9 (M+l)⁺.

Step 5:

A solution of methyl rac-(31?,47?,55)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (740 mg, 1.46 mmol) in methanolic ammonia (15 mL of 7 M, 105.0 mmol) was stirred in a sealed vessel at 100 °C for 16 hours. The solution was concentrated in vacuo to give rac-(37?,47?,55)-4-[[3-[2(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl] amino]pyridine-2-carboxamide (700 mg, 98%) as a mixture of epimers at the position adjacent to the amide (stereochemical assignments tentative). ESI-MS m/z cale. 491.12796, found 491.7 (M+l)⁺.

Step 6:

Purification of rac-(37?,47?,55)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifIuoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (400 mg, 0.8Immol) by chiral SFC using a Chiralpak IC column, 5um particle size, 25 cm x 20 mm from Daicel gave:

244

First Eluting Isomer (rt = 3.40 min): re/-(25,37î,4R,55)-4-[[3-[2-(difIuoromethoxy)-4fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide (1, 150 mg, 74%) (stereochemical assignments tentative). *H NMR (500 MHz, Methanol-d4) δ 8.48 (d, J = 5.5 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.90 (dd, J = 5.5, 2.2 Hz, 1H), 7.49 5 (dd, J = 9.0, 6.3 Hz, 1H), 7.01 (dd, J = 9.0, 6.7 Hz, 2H), 7.14 - 6.74 (m, 1H), 5.14 (d, J = 10.3 Hz, 1H), 4.33 (dd, J = 10.3, 7.9 Hz, 1H), 2.83 (p, J = 7.6 Hz, 1H), 1.66 (s, 3H), 0.83 (dd, J = 7.7, 2.3 Hz, 3H) ppm. ESI-MS m/z cale. 491.12796, found 492.2 (M+l)⁺; 490.3 (M-l)-.

Second Eluting Isomer (rt = 4.28 min): The second eluting isomer was purified further by reverse phase préparative HPLC (basic eluent) to give rel-QR,35,45,57?)-4-[[3-[210 (difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (2, 100 mg, 50%) (stereochemical assignments tentative). ‘H NMR (500 MHz, Methanol-d₄) δ 8.49 (d, J = 5.5 Hz, 1H), 8.27 - 8.23 (m, 1H), 7.90 (dd, J = 5.5, 2.2 Hz, 1H), 7.49 (dd, J = 9.1, 6.4 Hz, 1H), 7.06 - 6.99 (m, 2H), 7.16 - 6.69 (m, 1H), 5.14 (d, J = 10.3 Hz, 1H), 4.33 (dd, J = 10.3, 7.9 Hz, 1H), 2.83 (p, J = 7.6 Hz, 1H), 1.66 (d, J = 1.3 Hz, 3H), 0.83 15 (dd, J = 7.6, 2.3 Hz, 3H) ppm. ESI-MS m/z cale. 491.12796, found 492.1 (M+l)⁺.

The following compound was made using a similar method to that described in Example 1, but no SFC séparation step 6 was carried out at the end of the synthesis, and the compound was isolated as a racemate:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
28	rac-(25,37?,42?,5Æ)-4-[[3-[2(difluoromethoxy)-4-fluorophenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide	ESI-MS m/z cale. 491.12796, found 492.0 (M+l)⁺; Rétention time: 3.12 minutes	Ή NMR (500 MHz, Chloroform-d) δ 8.46 (d, J = 5.5 Hz, 1H), 8.05 (dd, J = 5.6, 2.2 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.82 (s, 1H), 7.44 (dd, J = 8.7, 6.1 Hz, 1H), 6.99 (td, J = 8.3, 2.6 Hz, 1H), 6.90 (dd, J = 9.5, 2.5 Hz,

245

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
			1H), 6.54 (t, J = 72.8 Hz, 1H), 5.61 (s, 1H), 5.00 (d, J = 9.3 Hz, 1H), 4.26 (t, J = 8.7 Hz, 1H), 3.08 - 2.93 (m, 1H), 1.43 (s, 3H), 0.74 (d, J = 7.4 Hz, 3H) ppm.

The following compounds were made using a similar method to that described in Example 1, but using methylamine at 40 °C in step 5. The conditions used for the epimerization/hydrolysis step 3 followed the conditions described in Example 11 step 5. The purification in step 6 was conducted by chiral SFC using a Chiralpak AS-H column, 5 pm particle size, 25 cm x 10 mm from Daicel on a Minigram SFC instrument from Berger Instruments:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
29	re/-(25,3Æ,47?,5S)-4-[[3-[2(difluoromethoxy)-4-fluorophenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofu ran-2-carbonyl]amino]-Nmethyl-pyridine-2carboxamide (first eluting peak by SFC on Chiralpak AS-H column, rt = 2.00 min)	ESI-MS m/z cale. 505.14362, found 506.5 (M+l)⁺; 504.5 (Μ-l)’; Rétention time: 3.28 minutes	Ή NMR (500 MHz, Chloroform-d) δ 8.60 (s, 1H), 8.43 (d, J = 5.5 Hz, 1H), 8.12 (dd, J = 5.5, 2.2 Hz, 1H), 8.07 7.98 (m, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.48 (dd, J = 8.8, 6.2 Hz, 1H), 7.00 (td, J = 8.3, 2.6 Hz, 1H), 6.87 (dd, J = 9.3, 2.5 Hz, 1H), 6.53 (d, J = 74.0 Hz, 1H),

246

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
			5.05 (d, J= 11.0 Hz, 1H), 4.09 (dd, J = 11.1, 8.0 Hz, 1H), 3.04 (d, J = 5.1 Hz, 3H), 2.80 (p, J = 7.6 Hz, 1H), 1.70 (s, 3H), 0.86 - 0.75 (m, 3H) ppm.
30	rel-{2R, 35,45,57?)-4-[[3-[2(difluoromethoxy)-4-fluorophenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofu ran-2-carbonyl]amino]-Nmethyl-pyridine-2carboxamide (second eluting peak by SFC on Chiralpak AS-H column, rt = 3.23 min)	ESI-MS m/z cale. 505.14362, found 506.5 (M+l)⁺; 504.5 (Μ-l)'; Rétention time: 3.28 minutes	‘H NMR (500 MHz, Chloroform-d) δ 8.61 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 8.13 (dd, J = 5.6, 2.2 Hz, 1H), 8.04 (s, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.48 (dd, J = 8.8, 6.2 Hz, 1H), 7.00 (td, J = 8.3, 2.5 Hz, 1H), 6.87 (dd, J = 9.2, 2.5 Hz, 1H), 6.53 (d, J = 72.7 Hz, 1H), 5.05 (d, J= 11.1 Hz, 1H), 4.09 (dd, J = 11.1,8.0 Hz, 1H), 3.04 (d, J = 5.0 Hz, 3H), 2.80 (p, J = 7.6 Hz, 1H), 1.721.68 (m, 3H), 0.860.75 (m, 3H) ppm.

247

The following compounds were made using a similar method to that described in Example 1, except that 5-amino-2-fluorobenzamide was used as coupling partner in step 4, and step 5 was omitted. The conditions used for the epimerization/hydrolysis step 3 followed the conditions described in Example 11 step 5. The purification in step 6 was conducted by chiral SFC using a

Chiralpak AS-H column, 5um particle size, 25 cm x 10 mm from Daicel on a Minigram SFC instrument from Berger Instruments:

Cmpd No.	Compound Naine	LC/MS	NMR (shifts in ppm)
31	re/-(25,37?,47?,55)-N-(3- carbamoyl-4-fluoro-phenyl)3-[2-(difluoromethoxy)-4fluoro-phenyl]-4,5-dimethyl- 5- (trifluoromethyl)tetrahydrofu ran-2-carboxamide (first eluting peak by SFC on Chiralpak AS-H column, rt = 1.79 min)	ESI-MS m/z cale. 508.1233, found 507.1 (M-l)'; Rétention time: 3.22 minutes	Ή NMR (500 MHz, Chloroform-d) δ 8.51 (s, 1H), 8.13 (ddd, J = 9.0, 4.5, 2.9 Hz, 1H), 7.90 (dd, J = 6.6,2.9 Hz, 1H), 7.49 (dd, J = 8.8, 6.1 Hz, 1H), 7.10 (dd, J = 11.3,9.0 Hz, 1H), 6.98 (td, J = 8.3, 2.6 Hz, 1H), 6.86 (dd, J = 9.3, 2.6 Hz, 1H), 6.70 (d, J= 12.2 Hz, 1H), 6.68-6.35 (m, 1H), 5.88 (s, 1H), 5.05 (d, J = 11.0 Hz, 1H), 4.09 (dd, J= 11.0, 7.9 Hz, 1H), 2.79 (p, J = 7.6 Hz, 1H), 1.69 (d, J = 1.1 Hz, 3H), 0.84-0.75 (m, 3 H) ppm.
32	rel-(2R, 35,45,57?)-N-(3- carbamoyl-4-fluoro-phenyl)-	ESI-MS m/z cale. 508.1233, found 507.1	‘H NMR (500 MHz, Chloroform-d) δ 8.50

248

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
	3-[2-(difluoromethoxy)-4fluoro-phenyl]-4,5-dimethyl- 5- (trifluoromethyl)tetrahydrofu ran-2-carboxamide (second eluting peak by SFC on Chiralpak AS-H column, rt = 3.07 min)	(M-1)'; Rétention time: 3.22 minutes	(s, 1H), 8.13 (ddd, J = 9.0, 4.4, 2.9 Hz, 1H), 7.90 (dd, J = 6.6, 2.9 Hz, 1H), 7.49 (dd, J = 8.8, 6.2 Hz, 1H), 7.10 (dd, J= 11.2, 9.0 Hz, 1H), 6.98 (ddd, J = 8.8, 7.9, 2.6 Hz, 1H), 6.86 (dd, J = 9.2, 2.5 Hz, 1H), 6.70 (d, J= 12.0 Hz, 1H), 6.68 - 6.32 (m, 1H), 5.86 (s, 1H), 5.05 (d, J= 11.0 Hz, 1H), 4.09 (dd, J= 11.0, 7.9 Hz, 1H), 2.79 (p, J = 7.6 Hz, 1H), 1.69 (d, J = 1.1 Hz, 3H), 0.830.76 (m, 3H) ppm.

The following compounds were made using a similar method to that described in Example 1, but using catalytic 1,2-dibromoethane to activate the magnésium in step 2 and without the séparation of the racemate by chiral SFC in step 6:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
33	rac-(25,3/?,4/?,52?)-4-[[3- (3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofu	ESI-MS m/z cale. 473.1374, found 474.0 (M+l)⁺; Rétention time: 3.19 minutes	‘H NMR (500 MHz, Chloroform-d) δ 8.55 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.07 (dd, J =

249

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
	ran-2- carbonyl]amino]pyridine-2carboxamide		5.5, 2.1 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.82 (s, 1H), 7.107.01 (m, 1H), 6.90 (q, J = 8.7 Hz, 1H), 5.51 (s, 1H), 4.96 (d, J = 9.0 Hz, 1H), 4.24 (t, J = 8.5 Hz, 1H), 4.00 (d, J = 2.7 Hz, 3H), 2.97 (q, J = 7.5 Hz, 1H), 1.42 (s, 3H), 0.72 (d, J = 7.4 Hz, 3H) ppm.
34	rac-(25,3R,45,5/?)-4-[[3(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide	ESI-MS m/z cale. 473.1374, found 474.1 (M+l)⁺; Rétention time: 3.15 minutes	Ή NMR (500 MHz, Chloroform-d) δ 8.55 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.08 (dd, J = 5.5, 2.2 Hz, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.83 (s, 1H), 7.016.86 (m, 2H), 5.55 (s, 1H), 4.74 (d, J = 9.7 Hz, 1H), 3.99 (d, J = 2.3 Hz, 3H), 3.68 (t, J = 11.0 Hz, 1 H), 2.52 (dd, J = 12.1, 6.9 Hz, 1H), 1.63 - 1.58 (m,3H), 1.03 (dd, J = 7.2, 2.1 Hz, 3H) ppm.

250

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
35	rac-(2R,35,4/?,5/?)-4-[[3(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofu ran-2- carbonyl] amino]pyridine-2carboxamide	ESI-MS m/z cale. 473.1374, found 474.0 (M+l)⁺; Rétention time: 3.22 minutes	Ή NMR (500 MHz, Methanol-d4) δ 8.48 (dd, J = 5.5, 0.6 Hz, 1H), 8.24 (dd, J = 2.2, 0.6 Hz, 1H), 7.86 (dd, J = 5.5, 2.2 Hz, 1H), 7.12 (ddd, J = 8.2, 5.6, 2.2 Hz, 1H), 7.02 (ddd, J = 9.8, 8.9, 7.5 Hz, 1H), 4.63 (d,J= 10.4 Hz, 1 H), 3.91 (d, J = 2.2 Hz, 3H), 3.62 (dd, J = 12.0, 10.4 Hz, 1H), 3.35 (s, 1H), 2.91 (dq, J = 11.9, 6.9 Hz, 1H), 1.51 (d, J= 1.1 Hz, 3H), 0.99 (d, J = 6.9 Hz, 3H) ppm.

The following compounds were made using a method similar to that described in Example 1, but using catalytic 1,2-dibromoethane to activate the magnésium in step 2, and without the addition of LiOH/EtOH in step 3. The purification in step 6 was conducted by SFC using a DE AP column, 5 5pm particle size, 25 cm x 21.2 mm from Princeton Chromatography Inc. on an SFC 100 instrument from Waters Corp., followed by chiral SFC using a Chiralpak AS-H column, 5pm particle size, 25 cm x 10 mm from Daicel on a Minigram SFC instrument from Berger Instruments. Compound 3a was purified further by chiral SFC using a Chiralpak OD-H column, 5pm particle size, 25 cm x 10 mm from Daicel on a Minigram SFC instrument from Berger Instruments. Compounds 38 and 39

251 were separated by chiral SFC using a (R,R)-Whelk-Ol column, 5 pm particle size, 25 cm x 21.2 mm from Regis Technologies:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
3a	re/-(27?,35,45,57?)- 4-[[3-(4fluoro-2-methoxy-phenyl)- 4,5-dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide (fïrst eluting isomer by SFC on Chiralpak AS-H column, rt = 1.77 min)	ESI-MS m/z cale. 455.14682, found 456.6 (M+l)⁺ ; 454.7 (M-l) Rétention time: 3.16 minutes	‘H NMR (500 MHz, Chloroform-d) δ 8.71 (s, 1H), 8.44 (d, J = 5.6 Hz, 1H), 8.18 (dd, J = 5.6, 2.2 Hz, 1H), 7.93 (d, J = 2.2 Hz, 1H), 7.85 (s, 1H), 7.35 (dd, J = 8.6, 6.4 Hz, 1H), 6.71 (td, J = 8.4, 2.5 Hz, 1H), 6.61 (dd, J= 10.7, 2.5 Hz, 1H), 5.62 (s, 1H), 5.08 (d, J = 11.3 Hz, 1H), 4.10 (dd, J = 11.2, 7.7 Hz, 1H), 3.81 (s, 3H), 2.81 (p, J = 7.5 Hz, 1H), 1.70 (d, J = 1.2 Hz, 3H), 0.75 (dq, J = 7.4, 2.4 Hz, 3H) ppm.
3b	reZ-(25,37?,47?,55)- 4-[[3-(4fluoro-2-methoxy-phenyl)4,5-dimethyl-5(trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide	ESI-MS m/z cale. 455.14682, found 456.6 (M+l)⁺; 454.7 (M-l)'; Rétention time: 3.16 minutes

252

Cmpd No.	Compound Naine	LC/MS	NMR (shifts in ppm)
	(second eluting isomer by SFC on Chiralpak AS-H column, rt = 2.79 min)
36	rel-(2R, 35,47?, 5S)-4-[[3-(4fluoro-2-methoxy-phenyl)4,5-dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide (first eluting isomer by SFC on Chiralpak AS-H column, rt = 2.94 min)	ESI-MS m/z cale. 455.14682, found 456.6 (M+l)⁺; 454.6 (Μ-l)’; Rétention time: 3.06 minutes	Ή NMR (500 MHz, Methanol-d4) δ 8.49 (d, J = 5.5 Hz, 1H), 8.18 (d, J = 2.1 Hz, 1H), 7.84 (dd, J = 5.5, 2.2 Hz, 1H), 7.30 (dd, J = 8.5, 6.6 Hz, 1H), 6.79 (dd, J= 11.0, 2.5 Hz, 1H), 6.71 (td, J = 8.3, 2.5 Hz, 1H), 4.80 (s, 1H), 3.78 (s, 3H), 3.77 - 3.71 (m, 1H), 2.84 2.70 (m, 1H), 1.60 (d, J = 1.1 Hz, 3H), 1.050.97 (m, 3H) ppm.
37	re/-(25,37?,45,57?)-4-[[3-(4fluoro-2-methoxy-phenyl)4,5-dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl] amino]pyridine-2carboxamide	ESI-MS m/z cale. 455.14682, found 456.6 (M+l)⁺; 454.6 (Μ-l)'; Rétention time: 3.06 minutes	Ή NMR (500 MHz, Chloroform-d) δ 8.56 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.09 (dd, J = 5.5, 2.2 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H), 7.83 (d, J = 4.3 Hz, 1H), 7.13 (dd, J = 8.3, 6.5 Hz, 1H), 6.71 - 6.63 (m, 2H), 5.58 (s, 1H),

253

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
	(second eluting isomer by SFC on Chiralpak AS-H column, rt = 3.66 min)		4.92 (d, J = 9.6 Hz, 1H), 3.82 (s, 3H), 3.54 (t, J = 10.9 Hz, 1H), 2.80-2.67 (m, 1H), 1.62- 1.58 (m, 3H), 1.01 (dt, J = 7.0, 1.9 Hz, 3H) ppm.
38	re/-(25,37î,45,55)-4-[[3-(4- fluoro-2-methoxy-phenyl)4,5-dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl] amino]pyridine-2carboxamide (first eluting isomer by SFC on WhelkOl column, rt = 3.29 min)	ESI-MS m/z cale. 455.14682, found 456.6 (M+l)⁺; 454.7 (M-l)’; Rétention time: 3.13 minutes	‘HNMR(500 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.17 (dd, J = 5.5, 2.2 Hz, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.86 (s, 1H), 7.14 (dd, J = 8.4, 6.4 Hz, 1H), 6.72 - 6.62 (m, 2H), 5.64 (s, 1H), 4.80 (d, J= 10.6 Hz, 1H), 3.78 (s, 3H), 3.30 (t, J = 11.2 Hz, 1 H), 3.06 (dq, J= 13.4, 6.8 Hz, 1H), 1.51 (s, 3H), 0.96 (d, J = 6.8 Hz, 3H) ppm.
39	rel-(2R, 35,47?, 57î)-4-[[3-(4fluoro-2-methoxy-phenyl)4,5-dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2-	ESI-MS m/z cale. 455.14682, found 456.6 (M+l)⁺; 454.6 (M-1)'; Rétention time: 3.13 minutes	‘H NMR (500 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.18 (dd, J = 5.5, 2.2 Hz, 1H), 7.94

254

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
	carbonyl] amino]pyridine-2carboxamide (second eluting isomer by SFC on WhelkOl column, rt = 4.09 min)		(d, J = 2.2 Hz, 1H), 7.87 (s, 1H), 7.16 (dd, J = 8.4, 6.5 Hz, 1H), 6.75 - 6.64 (m, 2H), 5.66 5.61 (m, 1H), 4.83 (d, J = 10.6 Hz, 1H), 3.81 (s, 3H), 3.32 (t, J = 11.2 Hz, 1H), 3.09 (dq, J = 11.8, 6.9 Hz, 1H), 1.53 (s, 3H), 0.99 (d, J = 6.8 Hz, 3 H) ppm.
40	rel-(2R, 35,45,55)-4-[[3-(4fluoro-2-methoxy-phenyl)4,5-dimethyl-5- (trifluoromethyl)tetrahydrofii ran-2- carbonyl]amino]pyridine-2carboxamide (first eluting isomer by SFC on Chiralpak AS-H column, rt= 1.87 min)	ESI-MS m/z cale. 455.14682, found 456.6 (M+l)⁺; 454.6 (Μ-l)’; Rétention time: 3.09 minutes	Ή NMR (500 MHz, Chloroform-d) δ 8.57 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.09 (dd, J = 5.4, 2.2 Hz, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.83 (s, 1H), 7.34 7.27 (m, 1H), 6.70 (td, J = 8.3, 2.5 Hz, 1H), 6.62 (dd, J= 10.8, 2.5 Hz, 1H), 5.60 - 5.56 (m, 1H), 5.01 (d, J = 9.1 Hz, 1H), 4.26 (t, J = 8.6 Hz, 1H), 3.82 (s, 3H), 3.01 (p, J = 7.5 Hz, 1H), 1.41 (s, 3H),

255

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
			0.68 (d, J = 7.4 Hz, 3H) ppm.
41	re/-(25,3R,4R,5R)-4-[[3-(4fluoro-2-methoxy-phenyl)4,5-dimethyl-5(trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide (second eluting isomer by SFC on Chiralpak AS-H column, rt = 2.96 min)	ESI-MS m/z cale. 455.14682, found 456.6 (M+l)⁺; 454.7 (Μ-l)’; Rétention time: 3.09 minutes	Ή NMR (500 MHz, Chloroform-d) δ 8.57 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.09 (dd, J = 5.6, 2.2 Hz, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.85 - 7.80 (m, 1H), 7.30 (dd, J = 8.5, 6.4 Hz, 1H), 6.70 (td, J = 8.3, 2.5 Hz, 1H), 6.62 (dd, J = 10.7, 2.5 Hz, 1H), 5.56 (s, 1H), 5.01 (d, J = 9.1 Hz, 1H), 4.26 (t, J = 8.6 Hz, 1H), 3.82 (s, 3H), 3.01 (p, J = 7.5 Hz, 1H), 1.41 (s, 3H), 0.68 (d, J = 7.4 Hz, 3H) ppm.

The following compounds were made using a method similar to that described in Example 1, but using catalytic 1,2-dibromoethane to activate the magnésium in step 2, and without the addition of LiOH/EtOH in step 3. The purification in step 6 was conducted by SFC using a Lux Cellulose-2 5 column, 5pm particle size, 25 cm x 10 mm from Phenomenex on an SFC 100 instrument from

Waters Corp., on a Minigram SFC instrument from Berger Instruments:

256

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
42	rel-(2R, 35,45,5A)-4-[[3-[2methoxy-3- (trifluoromethyl)phenyl]-4,5dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl] amino]pyridine-2carboxamide (first eluting isomer by SFC on Lux CeIlulose-2 column, rt = 4.18 min)	ESI-MS m/z cale. 505.14362, found 506.1 (M+l)⁺; 504.1 (Μ-l)'; Rétention time: 3.37 minutes	Ή NMR (400 MHz, DMSO-dô) δ 10.73 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.29 (d, J = 2.1 Hz, 1H), 8.06 (s, 1H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.64 (dd, J = 8.1, 1.5 Hz, 1H), 7.61 (s, 1H), 7.38 (t, J = 7.8 Hz, 1H), 5.15 (d, J= 10.2 Hz, 1H), 4.38 (dd, J= 10.2, 7.8 Hz, 1H), 3.84 (s, 3H), 2.91-2.83 (m, 1H), 1.65 (s, 3H), 0.74 (d, J = 7.3 Hz, 3H) ppm.
43	re/-(25,3/?,47?,55)-4-[[3-[2- methoxy-3- (trifluoromethyl)phenyl]-4,5dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl] amino]pyridine-2carboxamide	ESI-MS m/z cale. 505.14362, found 506.1 (M+l)⁺; 504.1 (M-l)*; Rétention time: 3.37 minutes	‘H NMR (400 MHz, DMSO-dô) δ 10.73 (s, 1H), 8.48 (d, J = 5.4 Hz, 1H), 8.29 (d, J = 2.1 Hz, 1H), 8.05 (s, 1H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.67 7.58 (m, 2H), 7.37 (t, J = 7.8 Hz, 1H), 5.15 (d, J = 10.2 Hz, 1H), 4.38

257

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
	(second eluting isomer by SFC on Lux Cellulose-2 column, rt = 4.18 min)		(dd, J= 10.2, 7.8 Hz, 1H), 3.84 (s, 3H), 2.88 (q, J = 7.6 Hz, 1H), 1.65 (s, 3H), 0.74 (d, J = 7.2 Hz, 3H) ppm.

The following compounds were made using a method similar to that described in Example l, but without the addition of LiOH/EtOH in step 3. The amide coupling step 4 was carried out using T3P as an activating agent rather than oxalyl chloride. The purification in step 6 was conducted by

SFC using a Lux i-Cellulose-5 column, 5pm particle size, 25 cm x 10 mm from Phenomenex on an SFC 100 instrument from Waters Corp., on a Minigram SFC instrument from Berger Instruments:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
44	rel-(2R, 35,45,57?)-4-[[3-[3(difluoromethyl)-4-fluoro-2methoxy-phenyl]-4,5dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl] amino]pyridine-2carboxamide (first eluting isomer by SFC on Lux i-Cellulose-5 column, rt = 2.65 min)	ESI-MS m/z cale. 505.14362, found 506.2 (M+l)⁺; 504.2 (M-l)’; Rétention time: 3.16 minutes	Ή NMR (400 MHz, DMSO-dô) δ 10.68 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.05 (s, 1H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.65 - 7.57 (m, 2H), 7.37 - 7.01 (m, 2H), 5.11 (d, J = 10.1 Hz, 1H), 4.294.22 (m, 1 H), 3.81 (s, 3H), 2.78 (q, J = 7.5 Hz, 1H), 1.63 (s, 3H), 0.74 (d, J = 7.2 Hz, 3H) ppm.

258

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
45	re/-(25,3R,4/?,55)-4-[[3-[3(difluoromethyl)-4-fluoro-2methoxy-phenyl]-4,5dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl] amino]pyridine-2carboxamide (second eluting isomer by SFC on Lux i-Cellulose-5 column, rt = 3.16 min)	ESLMS m/z cale. 505.14362, found 506.1 (M+l)⁺; 504.2 (Μ-l)'; Rétention time: 3.16 minutes	*H NMR (400 MHz, DMSO-de) δ 10.67 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.05 (s, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.60 (s, 2H), 7.35 - 7.03 (m, 2H), 5.11 (d, J = 10.2 Hz, 1H), 4.32 - 4.22 (m, 1H), 3.81 (s, 3H), 2.78 (dt, J = 14.9, 7.5 Hz, 1H), 1.63 (s, 3H), 0.74 (d, J = 7.4 Hz, 3H) ppm.

The following compounds were made using a method similar to that described in Example 1, except that methylamine was used in place of ammonia in Step 5. In step 6, purification was performed by chiral SFC using a Chiralpak AS-H column, 5pm particle size, 25 cm x 10 mm from

Daicel on a Minigram SFC instrument from Berger Instruments:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
12	rel-(2R, 35,45,55)-4-[[3-[2(difluoromethoxy)-3,4difluoro-phenyl] -4,5dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2-carbonyl]amino]-N-	ESI-MS m/z found 524.5 (M+l)⁺; Rétention time: 3.33 minutes	Ή NMR (500 MHz, Methanol-di) δ 8.51 (d, J = 5.5 Hz, 1H), 8.27 (d, J = 2.1 Hz, 1H), 7.91 (dd, J = 5.5, 2.2 Hz, 1H), 7.37 - 7.26

259

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
	methyl-pyridine-2- carboxamide (fïrst eluting isomer by SFC)		(m, 2H), 6.97 (td, J = 73.1, 1.1 Hz, 1H), 5.14 (d, J = 10.4 Hz, 1H), 4.41 (dd, J = 10.4, 8.1 Hz, 1H), 2.99 (s, 3H), 2.87 (p, J = 7.6 Hz, 1H), 1.71 (d, J= 1.2 Hz, 3H), 0.97 - 0.84 (m, 3 H) ppm.
13	re/-(25,3A,47?,57?)-4-[[3-[2(difluoromethoxy)-3,4difluoro-phenyl]-4,5dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2-carbonyl]amino]-Nmethyl-pyridine-2carboxamide (second eluting isomer by SFC)	ESI-MS m/z found 524.5 (M+l)⁺; Rétention time: 3.33 minutes	’H NMR (500 MHz, Methanol-dq) δ 8.54 8.49 (m, 1H), 8.27 (d, J = 2.0 Hz, 1H), 7.91 (dd, J = 5.5, 2.2 Hz, 1H), 7.37 - 7.25 (m, 2H), 6.97 (td, J = 73.1, 1.1 Hz, 1H), 5.14 (d, J = 10.3 Hz, 1H), 4.41 (dd, J = 10.4, 8.0 Hz, 1H), 2.99 (s, 3H), 2.87 (p, J = Ί.Ί Hz, 1H), 1.71 (d, J = 1.2 Hz, 3H), 0.93 - 0.86 (m, 3 H) ppm.

260

Example 2 re/-(25,37?,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (4) and re/-(27?,35,57î)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (5)

1) TBSOTf, DCM, Et₃N, 0 °C, 97%

2) 1,1,1-trifluoropropan2-one, TiCI₄, DCM, -78 ⁰

C, 61%

4) Tf₂O, DIPEA, DCM, -78 °C, 100%

Me CF₃O O OEt

N₂

5) ArB(OH)₂, PhMe, K₃PO₄, Pd(PPh₃)₄, 100 °C, 85% _

3) Rh(OAc)₂, PhMe, 100 C, 88%

6) EtOH, 10% Pd/C, H₂ (1 atm), 94%

Àr

7) Cs₂CO₃, EtOH, 50 °C, 96%

8) DCM, DMF (cat.), (COCI)₂, 0 ° C then NEt₃, methyl 4aminopyridine-2carboxylate, 74%

9) 7 M NH₃ in MeOH, 99%

(rac) (rac) (rac)

10) SFC

4, first eluting isomer

5, second eluting isomer

Step 1:

To a solution of ethyl 2-diazo-3-oxo-butanoate (5.0 g, 31.4 mmol) in DCM (50 mL) stirring at 0 °C was added triethylamine (8.05 g, 11.2 mL, 78.8 mmol). TBSOTf (9.24 g, 8.2 mL, 34.3 mmol) was added slowly and the reaction mixture was stirred for 30 mins at 0 °C. The reaction mixture was washed with 30% NaHCO₃ solution (200 mL). The organic layer was separated and washed with water (500 mL) then dried over MgSO4. The solvent was evaporated to give ethyl 3

261

[terZ-butyl(dimethyl)silyl]oxy-2-diazo-but-3-enoate (8.22 g, 97%) which was used in the next step without further purification.

Step 2:

A solution of l,l,l-trifluoropropan-2-one (33.8 g, 27 mL, 301.2 mmol) in DCM (150 mL) was stirred at -78 °C and TiCfi (56.8 g, 33 mL, 299.2 mmol) was added dropwise. The reaction was kept at -78 °C for 10 min before a solution of ethyl 3-[Zer/-butyl(dimethyl)silyl]oxy-2-diazobut-3-enoate (64 g, 236.7 mmol) in DCM (150 mL) was added dropwise. The reaction was kept at 78 °C for 1 hour then a saturated solution of NaHCCh was added and the mixture diluted with DCM. The organic layer was dried over MgSCfi, concentrated in vactio and the residue purified by column chromatography (0 to 30% EtOAc in hexane) to give ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-5methyl-3-oxo-hexanoate (39 g, 61%) as a pale yellow liquid. Ή NMR (400 MHz, Chloroform-d) δ 4.92 (s, 1H), 4.32 (q, J = 7.1 Hz, 2H), 3.63 (d, J = 15.5 Hz, 1H), 2.84 (d, J = 15.5 Hz, 1H), 1.41 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H) ppm.

Step 3:

Rhodium (II) acetate (643 mg, 1.45 mmol) was charged into an oven dried two necked flask. Toluene (970 mL) was added and the solution was stirred at 100 °C for 10 mins. The solution was briefly lifted out of the oil bath whilst a solution of ethyl 2-diazo-6,6,6-trifluoro-5hydroxy-5-methyl-3-oxo-hexanoate (39 g, 145.4 mmol) in a toluene (200 mL) was added dropwise, and the reaction was heated at reflux for 1 hr. The reaction mixture was filtered through filter paper and the fïltrate was concentrated in vactio to give ethyl 5-methyl-3-oxo-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (30.89 g, 88%). ’H NMR (400 MHz, Chloroform-d) δ 4.68 (s, 1H), 4.35-4.17 (m, 2H), 2.89 (d, J= 18.8, 1H), 2.58 (d, J = 18.8, 1H), 1.70 (s, 3H), 1.30 (t, J = 7.2, Hz, 3H) ppm.

Step 4:

Trifluoromethanesulfonic anhydride (6.0 mL, 35.7 mmol) was added dropwise to a solution of ethyl 5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (6.5 g, 27.1 mmol) and DIPEA (14 mL, 80.4 mmol) in DCM (150 mL) at -78 °C and the reaction stirred for 2.5 hours before saturated aqueous NH4CI (75 mL) was added. The mixture was warmed to ambient température, the layers separated, and the aqueous layer extracted with DCM (2 x 30 mL). The combined organic extracts were dried (MgSCk), filtered and concentrated in vactio to give ethyl 2

262 methyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (10.1 g, 100%) which was used directly in the next reaction.

Step 5:

To a stirred solution of (3,4-difluoro-2-methoxy-phenyl)boronic acid (2.0 g, 10.6 mmol) and ethyl 2-methyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (3 g, 7.90 mmol) in toluene (80 mL) was added K3PO4 (13 mL of 2 M aq., 26.0 mmol). The mixture was degassed with N2 for 20 mins before Pd(PPh₃)4 (466 mg, 0.40 mmol) was added and then heated to 100 °C for 1 h. The mixture was filtered by celite pad, the filtrate diluted with water (50 mL) and the aqueous layer extracted with EtOAc (50 x 2 mL). The organic layer was dried (MgSCh), filtered and evaporated. The residue was purified by column chromatography (S1O2, 0-2% EtOAc in hexane) to give ethyl 4-(3,4-difluoro-2-methoxy-phenyl)-2-methyl-2-(trifluoromethyl)-3H-furan-5carboxylate (2.5 g, 85%) as a light-yellow liquid. Ή NMR (400 MHz, Chloroform-d) δ 6.87 (pd, J = 8.8, 6.2 Hz, 2H), 4.15 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.42 (d, J = 17.4 Hz, 1H), 2.93 (d, J = 17.4 Hz, 1H), 1.65 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H) ppm. ESI-MS m/z cale. 366.089, found 367.2 (M+l)⁺.

Step 6:

EtOH (200 mL) was added to ethyl 4-(3,4-difluoro-2-methoxy-phenyl)-2-methyl-2(trifluoromethyl)-3H-furan-5-carboxylate (5.51 g, 15.0 mmol) and Pd/C (10 wt. % loading, 2.2 g, 2.067 mmol). The mixture was degassed and stirred under a balloon of H2 for 96 hours. The catalyst was removed by filtration, the solids washed with EtOH (50 mL) and the filtrate concentrated in vacuo. A further portion of Pd/C (10 wt. % loading, 2.2 g, 2.07 mmol) was added to the residue followed by EtOH (200 mL) and the reaction mixture stirred under a balloon of H2 at ambient température for 24 hours. The catalyst was removed by filtration, the solids washed with EtOH (50 mL) and the filtrate concentrated in vacuo. A further portion of Pd/C (10 wt. % loading, 2.2 g, 2.07 mmol) was added to the residue followed by EtOH (200 mL) and the réaction mixture stirred under a balloon of H2 at ambient température for 4 days. The catalyst was removed by filtration, the solids washed with EtOH (50 mL) and the filtrate concentrated in vacuo to give ethyl rac-(2S,35,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxylate (5.19 g, 94%) as a white solid, and as a single diastereomer. Ή NMR (500 MHz, Chloroform-d) δ 6.89 - 6.86 (m, 1H), 6.82 - 6.77 (m, 1H), 4.93 (d, J = 8.9 Hz, 1H), 4.23 (dt, J =

263

13.0, 7.6 Hz, 1H), 4.08 (d, J = 2.9 Hz, 3H), 3.85 - 3.71 (m, 2H), 2.82 (t, J = 12.5 Hz, 1H), 2.04 (dd, J = 12.0, 6.7 Hz, 1H), 1.53 (s, 3H), 0.94 (t, J = 7.1 Hz, 3H) ppm; ¹⁹FNMR (471 MHz, Chloroform-d) δ -80.15, -136.84 (d, J = 19.4 Hz), -154.77 (d, J = 19.6 Hz) ppm.

Step 7:

Ethyl rac-(25,35,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (5.19 g, 14.09 mmol) was dissolved in éthanol (100 mL). Césium carbonate (7.1 g, 21.8 mmol) was added and the suspension stirred at 50 °C for 2 hours. The reaction mixture was concentrated in vacno and the residue partitioned between IM HCl and MTBE. The layers were separated and the aqueous layer was extracted twice with MTBE. The combined organic extracts were dried (MgSCU), filtered and concentrated in vacno to give rac(25,35,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxylic acid (5.11 g, 96%) as a colourless oil, as a single diastereomer. *H NMR (500 MHz, Chloroform-d) δ 6.99 - 6.96 (m, 1H), 6.92 - 6.87 (m, 1H), 4.68 (d, J = 10.5 Hz, 1H), 4.00 (d, J = 2.7 Hz, 3H), 3.90 (ddd, J = 12.0, 10.6, 8.2 Hz, 1H), 2.58 (t, J = 12.5 Hz, 1H), 2.31 (dd, J = 13.0, 8.2 Hz, 1H), 1.60 (s, 3H) ppm; ¹⁹F NMR (471 MHz, Chloroform-d) δ -81.56, -136.40 (d, J = 19.6 Hz), 153.60 (d, J = 19.5 Hz) ppm. ESI-MS m/z cale. 340.0734, found 339.5 (M-l)'.

Step 8:

To a solution of rac-(25,35,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofiiran-2-carboxylic acid (1.5 g, 4.41 mmol) in DCM (30 mL) cooled to 10 °C was added DMF (5 pL, 0.065 mmol) followed by oxalyl chloride (620 pL, 7.11 mmol). The reaction was stirred for 4 hours, allowing it to warm to ambient température before further oxalyl chloride (300 pL, 3.55 mmol) was added. The reaction was stirred for a further hour before being concentrated in vacno. The residue was dissolved in DCM (30 mL) and the solution cooled in an ice bath. TEA (600 pL, 4.31 mmol) and methyl 4-aminopyridine-2-carboxylate (663.7 mg, 4.36 mmol) were added sequentially and the résultant mixture stirred for 30 mins before being quenched with MeOH and concentrated in vacno. Purification by flash chromatography (40 g S1O2, 0 to 60% ethyl acetate in heptane, loaded in DCM) gave methyl rac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (827.6 mg, 74%). Ή NMR (500 MHz, Chloroform-d) δ 8.63 (d, J = 5.5 Hz, 1H), 8.46 (s, 1H), 8.07 (d, J = 2.1 Hz, 1H), 7.94 (dd, J = 5.5, 2.2 Hz, 1H), 7.00 (ddd, J = 8.0, 5.5, 2.1 Hz, 1H), 6.90 (td, J =

264

9.1, 7.3 Hz, 1H), 4.75 (d, J = 10.7 Hz, 1H), 4.01 (s, 3H), 3.99 (d, J = 2.6 Hz, 3H), 3.83 (td, J = 11.4, 8.3 Hz, 1H), 2.61 (t, J = 12.5 Hz, 1H), 2.34 (dd, J = 13.1, 8.2 Hz, 1H), 1.65 (s, 3H) ppm. ESI-MS m/z cale. 474.1214, found 474.7 (M+l)⁺ and 473.2 (M-l)'.

Step 9:

Methyl rac-(27?,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxylate (1.9 g, 4.01 mmol) was dissolved in methanolic ammonia (20 mL of 7 M, 140.0 mmol) and the reaction stirred at ambient température ovemight. Additional methanolic ammonia (5 mL of 7 M, 35.0 mmol) was added and reaction stirred at ambient température for a further 3 hrs before being concentrated in vacuo to give rac-(27?,35,5.R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (1.94 g, 99%). Ή NMR (500 MHz, Methanol-d4) δ 8.49 (dd, J = 5.5, 0.6 Hz, 1H), 8.26 (dd, J = 2.2, 0.6 Hz, 1H), 7.88 (dd, J = 5.5, 2.2 Hz, 1H), 7.14 (ddd, J = 8.3, 5.7, 2.3 Hz, 1H), 6.99 (ddd, J = 9.9, 8.9, 7.5 Hz, 1H), 4.67 (d, J = 10.3 Hz, 1H), 4.10 - 4.01 (m, 1H), 3.92 (d, J = 2.3 Hz, 3H), 3.35 (s, 3H), 2.62 (t, J = 12.4 Hz, 1H), 2.40 (dd, J = 12.8, 8.2 Hz, 1H), 1.63 (s, 3H) ppm. ESI-MS m/z cale. 459.12173, found 460.2 (M+l)⁺ and 458.3 (M-l)'.

Step 10:

rac-(2R,3S,5R)-4-[[3-(3,4-Difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (1.9 g, 3.89 mmol) was separated by chiral SFC using a (R,R)-Whelk-Ol column, 5pm particle size, 25 cm x 21.2 mm from Regis Technologies to give two single isomers of unknown absolute configuration:

First Eluting Isomer (rt = 5.05 min): re/-(25,37î,5>S)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (4, 724 mg, 38%); ESI-MS m/z cale. 459.12173, found 460.2 (M+l)⁺ and 458.3 (M-l)*. ’H NMR (500 MHz, Methanol-d₄) δ 8.36 (d, J = 5.5 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 7.75 (dd, J = 5.5, 2.2 Hz, 1H), 7.00 (ddd, J = 8.2, 5.6, 2.2 Hz, 1H), 6.86 (td, J = 9.3, 7.5 Hz, 1H), 4.55 (d, J = 10.3 Hz, 1H), 3.92 (ddd, J = 12.2, 10.4, 8.2 Hz, 1H), 3.79 (d, J = 2.3 Hz, 3H), 3.22 (s, 1H), 2.49 (t, J = 12.4 Hz, 1H), 2.27 (dd, J = 12.8, 8.2 Hz, 1H), 1.50 (s, 3H) ppm.

Second Eluting Isomer (rt = 7.36 min): reZ-(2R,35',57?)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (5, 749 mg, 39%); ESI-MS m/z cale. 459.12173, found 460.2 (M+l)⁺ and 458.3 (M-l)’. Ή NMR (500

265

MHz, Methanol-d₄) δ 8.36 (d, J = 5.5 Hz, 1H), 8.13 (d, J = 2.2 Hz, 1H), 7.75 (dd, J = 5.5, 2.2 Hz, 1H), 7.01 (ddd, J = 8.3, 5.6, 2.2 Hz, 1H), 6.86 (td, J = 9.4, 7.5 Hz, 1H), 4.55 (d, J = 10.2 Hz, 1H), 3.92 (ddd, J = 12.0, 10.4, 8.2 Hz, 1H), 3.79 (d, J = 2.3 Hz, 3H), 3.22 (s, 3H), 2.49 (t, J = 12.4 Hz, 1H), 2.27 (dd, J = 12.9, 8.2 Hz, 1H), 1.50 (s, 3H) ppm.

The following compounds were made using a method similar to that described Example 2, except that 5-amino-2-fluorobenzamide was used as coupling partner in step 8, and step 9 was omitted:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
46	re/-(25,3R,5S)-N-(3carbamoyl-4-fluoro-phenyl)3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofu ran-2-carboxamide (first eluting isomer by SFC on WhelkOl column, rt = 0.90 min)	ESI-MS m/z cale. 476.11707, found 477.1 (M+l)⁺; 475.3 (M-1)'; Rétention time: 3.09 minutes	’H NMR (500 MHz, Chloroform-d) δ 8.44 (s, 1 H), 8.18 (ddd, J = 9.0, 4.4, 2.9 Hz, 1H), 7.89 (dd, J = 6.6,2.9 Hz, 1H), 7.10 (dd, J = 11.3, 9.0 Hz, 1H), 7.01 (ddd, J = 8.8, 5.6, 2.2 Hz, 1H), 6.89 (td, J = 9.2, 7.3 Hz, 1H), 6.71 (d, J= 11.8 Hz, 1H), 5.91 (s, 1H), 4.73 (d, J = 10.7 Hz, 1H), 3.97 (d, J = 2.5 Hz, 3H), 3.82 (td, J= 11.4,8.3 Hz, lH),3.49(d, J = 4.4 Hz, 1H), 2.57 (t, J = 12.5 Hz, 1H), 2.32 (dd, J = 13.0,8.2 Hz, 1H), 1.64 (s, 3H)ppm.

266

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
47	rel-(2R,3S,5R)-W(3carbamoyl-4-fluoro-phenyl)3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofu ran-2-carboxamide (second eluting isomer by SFC on WhelkOl column, rt = 1.35 min)	ESI-MS m/z cale. 476.11707, found 477.1 (M+l)⁺; 475.3 (Μ-l)'; Rétention time: 3.09 minutes	Ή NMR (500 MHz, Chloroform-d) δ 8.42 (s, 1H), 8.18 (ddd, J = 9.0, 4.4, 2.9 Hz, 1H), 7.89 (dd, J = 6.6, 2.9 Hz, 1H), 7.11 (dd, J = 11.2, 9.0 Hz, 1H), 7.01 (ddd, J =8.1, 5.5, 2.2 Hz, 1H), 6.89 (td, J = 9.1, 7.3 Hz, 1H), 6.71 (d, J = 11.8 Hz, 1H), 5.88 (s, 1H), 4.73 (d, J = 10.7 Hz, 1 H), 3.97 (d, J = 2.5 Hz, 3H), 3.82 (td, J= 11.4, 8.3 Hz, 1H), 2.57 (t, J = 12.5 Hz, 1 H), 2.32 (dd, J = 13.1, 8.2 Hz, 1H), 1.64 (s, 3H) ppm.

267

Example 3 (25,37?,47?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (6) and (27?,35,45,57?)4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-25 carbonyl]amino]pyridine-2-carboxamide (7)

1) TMSOTf, DCM, Et₃N, 0 °C, 99%

2) 1,1,1-trifluopropan-2one, TiCI₄, DCM, -78 ⁰

C, 67%

Me CF₃O O

ΗοΠΤίΙ °Et ^Ξ N₂

3) Rh(OAc)₂, PhH, 100 °C, 100%

4) Tf₂O, DIPEA, DCM, -78 °C, 97%

(rac)

5) ArB(OH)₂, PhMe, aq. K₃PO₄, Pd(PPh₃)₄,100 °C, 93%

(rac)

6) BBr₃, DCM, 0 °C - RT then DCM, TFA, 45 °C, 78%

7) Activated charcoal, EtOAc then MeOH, Pd(OH)₂, H₂ (60 psi), 99%

8) KOf-Bu, THF, RT, 100%

9) Mel, K₂CO₃, MeCN, 100%

10) LiOH.H₂O, MeOH, H₂O, 99%^

11) DCM, DMF (cat.), (COCI)₂, 0 °C then NEt₃, DMF, methyl 4-

aminopyridine-2carboxylate, DCM, 76%

12) 7N NH₃, MeOH

(^rac) (rac)

6, first eluting isomer

7, second eluting isomer

Step 1:

268

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

Step 2:

To a solution of l,l,l-trifluoropropan-2-one (8 mL, 89.4 mmol) in DCM (80 mL) stirring at 78 °C was added TiCU (70 mL of 1 M in DCM, 70.00 mmol) via cannula. To the resulting solution, a solution of ethyl (Z)-2-diazo-3-trimethylsilyloxy-pent-3-enoate (36.1 g of 31.3 %w/w, 46.6 mmol) in 40 mL of DCM was added dropwise over 15 mins. After 100 mins the reaction was carefully quenched with water, allowing the température to rise slowly, and then extracted with DCM. The combined organic layers were dried (MgSCU), fdtered, and concentrated in vacuo. Purification by flash chromatography (330 g SiCh, 0 to 20% EtOAc in heptane) gave ethyl 2-diazo-6,6,6-trifluoro5-hydroxy-4,5-dimethyl-3-oxo-hexanoate (8.82 g, 67%), which was stored as a solution in toluene. 'HNMR (500 MHz, Chloroform-d) δ 4.33 (q, J = 7.1 Hz, 2H), 4.14 (q, J = 7.0 Hz, IH), 3.98 (s, IH), 1.43 (q, J = 1.2 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H), 1.31 (dq, J = 7.0, 1.4 Hz, 3H) ppm. ESI-MS m/z cale. 282.08273, found 283.1 (M+l)⁺; 281.0 (M-l)’.

Step 3:

A solution of rhodium tetraacetate (245 mg, 0.55 mmol) in benzene (32 mL) was heated at reflux for 10 minbefore a solution of ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxohexanoate (10 g, 35.4 mmol) in benzene (13 mL) was added slowly via addition funnel while refluxing for 60 mins. The mixture was then concentrated in vacuo to give ethyl rac-(47?,57?)-4,5dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (9.0 g, 100%) as a green coloured residue containing residual catalyst, and as a mixture of epimers at the position next to the ester. This material was used without further purification. Ή NMR (500 MHz, Chloroform-d) δ 4.83 269

4.57 (m, 1H), 4.38 - 4.16 (m, 2H), 2.60 (dddd, J = 9.3, 8.2, 5.6, 1.4 Hz, 1H), 1.73 - 1.63 (m, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.24 (ddq, J = 6.4, 4.1, 1.9 Hz, 3H) ppm.

Step 4:

To a stirred solution of ethyl rac-(4R,5JÎ)-4,5-dimethyl-3-oxo-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (48 g, 188.83 mmol) in DCM (400 mL) stirring at 78 °C was added DIPEA (29.680 g, 40 mL, 229.64 mmol). A solution of trifluoromethylsulfonyl trifluoromethanesulfonate (53.440 g, 32 mL, 189.41 mmol) in DCM (200 mL) was added to the reaction mixture at the same température over Ih. The reaction mixture was stirred for 30 mins at 0 °C before being quenched with 100 mL saturated aqueous NaHCCh solution. The organic layer was separated and aqueous layer extracted with DCM (160 mL). The combined organic layers were dried (MgSOY) and concentrated in vacuo to give ethyl rac-(47?,57?)-2,3-dimethyl-2(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (71 g, 97%). Ή NMR (400 MHz, Chloroform-d) δ 4.38-4.32 (m, 2H), 3.29-3.23 (m, 1H), 1.64 (s, 3H), 1.37-1.33 (m, 6H) ppm.

Step 5:

To stirred a solution of ethyl rac-(47?,5J?)-2,3-dimethyl-2-(trifluoromethyl)-4(trifluoromethylsulfonyloxy)-3H-fiiran-5-carboxylate (26 g, 67.311 mmol) in toluene (130.00 mL) was added (3,4-difluoro-2-methoxy-phenyl)boronic acid (14 g, 74.5 mmol) followed by K3PO4 (100 mL of 2 M, 200.00 mmol) under an argon atmosphère. The reaction was degassed before tetrakîs(triphenylphosphine)palladium(0) (4 g, 3.46 mmol) was added. After fiirther degassing, the reaction was heated at 100 °C for 2 hours. The reaction was diluted in water and the aqueous layer extracted with EtOAc (2 xlOO mL). The combined organic layers were concentrated in vacuo. Purification by flash chromatography (S1O2, 0 to 10% EtOAc in heptane) gave ethyl 4-(3,4difluoro-2-methoxy-phenyl)-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (24.4 g, 93%) as a 6:1 diastereomeric mixture, with the major isomer believed to be ethyl rac-(47?,57?)-4-(3,4difluoro-2-methoxy-phenyl)-2,3-dimethyl-2-(trifluoromethyl)-3H-fiiran-5-carboxylate. Major isomer: Ή NMR (400 MHz, Chloroform-d) δ 6.88 - 6.79 (m, 2H), 4.17 - 4.09 (m, 2H), 3.90 (s, 3H), 3.46 (q, J = 7.4 Hz, 1H), 1.67 (s, 3H), 1.12 (t, J = 7.4 Hz, 3H), 1.06 (dd, J = 5.4, 2.7 Hz, 3H) ppm. Minor isomer ’H NMR (400 MHz, Chloroform-d) δ 6.88 - 6.79 (m, 2H), 4.17-4.09 (m, 2H), 3.88(s,

270

3H), 3.76-3.7l(m, 1H), 1.51 (s, 3H), 1.12 (t, J = 7.4 Hz, 3H), 0.99 (dd, J = 5.4, 2.7 Hz, 3H) ppm. ESI-MS m/z cale. 380.1047, found 381.02 (M+l)⁺.

Step 6:

To an ice-cooled solution of ethyl 4-(3,4-difluoro-2-methoxy-phenyl)-2,3-dimethyl-2(trifluoromethyl)-3H-furan-5-carboxylate (110 g, 243.0 mmol) in DCM (360 mL) was added BBr₃(370 mL of 1 M, 370.0 mmol) dropwise. Upon completion the mixture was quenched by addition of water and aqueous sodium bicarbonate solution, the aqueous layer extracted with DCM and the combined organic layers dried (MgSÜ4) and concentrated in vacuo. The residue was dissolved in DCM (430 mL) at ambient température and TFA (40 mL, 519.2 mmol) was added, then the reaction was heated to 45 °C. Upon completion, the mixture was quenched by addition of aqueous sodium bicarbonate solution and the aqueous layer extracted with DCM, dried (MgSO₄) and concentrated in vacuo to give the desired product in a 5:1 mixture of diastereomers. Recrystallization was carried out by solubilizing the crude in the smallest possible amount of DCM and adding a layer of heptane on top of this solution (liquid-liquid diffusion). After approx. 1 hour, 56.5 g (d.r. 97:3 symanti) from the fîrst and second crystallization was obtained, and a further 4.6 g (d.r. 96:4 symanti) from the third crystallization was obtained. The fîrst to third batches were combined to give 6,7-difluorol,2-dimethyl-2-(trifluoromethyl)-lH-furo[2,3-c]chromen-4-one (61 g, 78%), with the major isomer believed to be rac-(15,2R)-6,7-difluoro-l,2-dimethyl-2-(trifluoromethyl)-lH-furo[2,3-c]chromen-4one. ESI-MS m/z cale. 320.04718, found 321.5 (M+l)⁺; 319.6 (M-l)’.

Step 7:

rac-(15,27?)-6,7-Difluoro-l,2-dimethyl-2-(trifluoromethyl)-lH-furo[2,3-c]chromen-4-one (30 g, 93.69 mmol) was dissolved in EtOAc (400 mL) and stirred with activated charcoal (6 g, 499.6 mmol) (0.2 g/g of substrate) at ambient température for 4 hours and 30 minutes. The mixture was filtered through a pad of celite, washing with EtOAc. The filtrate was concentrated in vacuo to give a white solid. The white solid was suspended in MeOH (600 mL) and added to a suspension of Pd(OH)i (13.62 g of 20% w/w, 19.40 mmol) in MeOH (150 mL) in a 2.25 L Pair bottle. The resulting mixture was shaken in the Parr hydrogenator under a hydrogen pressure of 60 psi ovemight. The suspension was filtered through celite under a nitrogen atmosphère, rinsed with MeOH and then with EtOAc, and the resulting filtrate was concentrated in vacuo to give methyl rac(2R,35,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran271

2-carboxylate (32.75 g, 99%). Ή NMR (400 MHz, Methanol-d4) δ 7.05 (ddq, J = 9.4, 5.9, 1.9 Hz, 1H), 6.57 (ddd, J = 10.0, 9.0, 7.6 Hz, 1H), 5.01 (d, J = 6.0 Hz, 1H), 4.34 (dd, J = 8.4, 6.0 Hz, 1H), 3.49 (s, 3H), 3.01 - 2.86 (m, 1H), 1.50 (q, J = 1.2 Hz, 3H), 0.89 (dq, J = 7.6, 1.9 Hz, 3H) ppm. ESIMS m/z cale. 354.08905, found 353.3 (M-l)'.

Step 8:

A solution of methyl rac-(2R,35,45,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (60.8 g, 171.6 mmol) in THF (620 mL) was cooled to 1 °C, and potassium ZerZ-butoxide (65.0472 g, 579.7 mmol) was added over 10 mins, keeping the internai température below 10 °C. The mixture was stirred at 0 °C for a further 5 min, and then the mixture was warmed slightly. When the température had reached 13 °C, the reaction was cooled down again with an ice bath before adding 2 M HCl (365 mL, to pH 1), keeping the internai température below 15 °C. Water (300 mL) was added, the layers were separated, and the aqueous layer was extracted with EtOAc (110 mL). The combined organic extracts were washed with brine (300 mL), dried (MgSCU), filtered and concentrated in vacuo to give rac-(2R,35,45,57?)-3-(3,4difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (58.22 g, 100%). Ή NMR (400 MHz, Methanol-d₄) δ 7.00 (ddd, J = 8.4, 5.6, 2.3 Hz, 1H), 6.69 (ddd, J = 10.1, 8.8, 7.5 Hz, 1H), 4.98 (d, J = 10.5 Hz, 1H), 4.18 (dd, J = 10.5, 7.6 Hz, 1H), 2.83 (p, J = 7.5 Hz, 1H), 1.59 (q, J = 1.2 Hz, 3H), 0.76 (dq, J = 7.2, 2.2 Hz, 3H) ppm. ESI-MS m/z cale. 340.0734, found 339.0 (M-l)'.

Step 9:

To a solution of rac-QR,35,45,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (58.39 g, 171.6 mmol) in acetonitrile (300 mL) was added K2CO3 (82.6 g, 597.7 mmol) and Mel (37 mL, 594.3 mmol). The reaction was heated to 80 °C (intemally température reached 61 °C) for 5 hours before being cooled to ambient température and diluted with DCM (350 mL). The mixture was filtered, washing the fïlter cake with more DCM (350 mL) and the fîltrate was concentrated in vacuo to give methyl rac-(2R,35,45,5R)-3(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (64.7 g, 100%) as an orange oil containing some residual K2CO3. This material was used in the next step without further purification. ’H NMR (400 MHz, Chloroform-d) δ 6.91 (ddd, J = 7.6, 5.7, 1.9 Hz, 1H), 6.85 (td, J = 9.1, 7.2 Hz, 1H), 4.91 (d, J = 10.2 Hz, 1H), 4.13 (dd, J = 10.2, 8.0 Hz, 1H),

272

4.00 (d, J = 2.7 Hz, 3H), 3.71 (s, 3H), 2.72 (p, J = 7.7 Hz, IH), 1.62 (q, J = 1.2 Hz, 3H), 0.76 (dq, J = 7.5, 2.4 Hz, 3H) ppm.

Step 10:

Methyl rac-QR,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydroforan-2-carboxylate (63.2 g, 171.6 mmol) was dissolved in MeOH (500 mL) and water (300 mL). LiOHH₂O (14.8882 g, 354.8 mmol) was added and the résultant mixture stirred at ambient température for 2 hours. The MeOH was removed in vacuo and the mixture was diluted in MTBE (320 mL). 2 M HCl (440 mL) was added to reach pH 1, the layers were separated and the aqueous layer extracted twice with MTBE (100 mL). The combined organic layers were dried (MgSOq), fïltered and concentrated in vacuo to give rac-(2R,35,45,57?)-3-(3,4-difhioro-2methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydroforan-2-carboxylic acid (60.3 g, 99%) as an orange oil. Ή NMR (400 MHz, DMSO-d₆) δ 12.96 (s, IH), 7.40 - 6.82 (m, 2H), 4.96 (dd, J = 15.5, 10.5 Hz, IH), 4.08 (dd, J = 10.4, 7.6 Hz, IH), 3.93 (d, J = 2.2 Hz, 3H), 2.67 (p, J = 7.7 Hz, IH), 1.59 - 1.49 (m, 3H), 0.77 - 0.63 (m, 3H) ppm. ESI-MS m/z cale. 354.08905, found 353.1 (Μι)-Step 11:

To a solution ofrac-(27?,35,45,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifhioromethyl)tetrahydrofuran-2-carboxylic acid (158.6 g, 447.7 mmol) and DMF (135 pL, 1.74 mmol) in DCM (1.5 L) stirring at 0 °C under nitrogen was added oxalyl chloride (79 mL, 905.6 mmol) via dropping formel, over 30 mins. Halfway through addition the ice bath was removed and the mixture allowed to warm ambient température over the remainder of the addition. The mixture was stirred at ambient température for a forther 1 hour before being evaporated in vacuo. The residue was dissolved in DCM (700 mL) and added via dropping formel to a solution of methyl 4aminopyridine-2-carboxylate (81.5 g, 535.7 mmol), DMF (135 pL, 1.744 mmol) and Et₃N (95 mL, 681.6 mmol) in DCM (780 mL) stirring at -10 °C. The rate of addition was controlled so as to keep internai température below 5 °C (~15 mins). Following addition, the mixture was diluted in water (600 mL), the layers were separated and the aqueous phase was forther extracted with DCM (100 mL). Solid formed at the interface between the layers and was collected by filtration to provide fïltered desired product (43.2g). The filtrate was washed further with water (600 mL), dried (MgSC>4), fïltered and concentrated in vacuo. The residue was suspended in MeOH (360 mL) and

273 stirred rapidly for 20 mins. The mixture was filtered and the solid washed with MeOH and dried under vacuum for 30 mins. This material was combined with the previously obtained product to give methyl rac-(2R,35,45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (166.2 g, 76%) as a white solid. Ή NMR (500 MHz, DMSO-d₆) δ 10.74 (s, 1H), 8.57 (d, J = 5.4 Hz, 1H), 8.36 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 5.5, 2.2 Hz, 1H), 7.16 (qd, J = 9.2, 6.3 Hz, 2H), 5.11 (d, J = 10.1 Hz, 1H), 4.25 (dd, J = 10.2, 7.7 Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 3.87 (s, 3H), 2.77 (p, J = 7.6 Hz, 1H), 1.61 (s, 3H), 0.81 - 0.65 (m, 3H) ppm. ESI-MS m/z cale. 488.13705, found 489.6 (M+l)⁺; 487.6 (M-l)'.

Step 12:

Methanolic ammonia (3 L of 7 M, 21.00 mol) was added to methyl rac-(27?,35,45,51?)-4-[[3(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxylate (166 g, 339.9 mmol) and the reaction stirred at ambient température ovemight. The mixture was concentrated in vacuo to give rac-(2R,35,45,57?)-4-[[3(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (173 g) as an off-white solid, which was used in the next step without further purification. ESI-MS m/z cale. 473.1374, found 474.6 (M+l)⁺; 472.6 (M-l)'.

Step 13:

rac-(2R,35,45,57?)-4-[[3-(3,4-difIuoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (670 mg, 1.415 mmol) was purified by chiral SFC (using a (R’R) Whelk O-l column, 3-5 pm particle size, 5.0 cm x 3.0 mm from Regis Technologies with Solvent A: liquid CO₂ [58-60 bar/40 °C; Solvent B: methanol HPLC grade with 20 mM NH3 on a UPC2-SFC instrument from Waters Corp.) to give:

First Eluting Isomer: (25,37?,4/?,55)-4-[[3-(3,4-difluoro-2-mcthoxy-phenyl)-4,5-dimethyI5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (6, 198 mg): Ή NMR (500 MHz, Methanol-d₄) δ 8.52 (d, J = 5.5 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 7.94 (dd, J = 5.5, 2.2 Hz, 1H), 7.16 (ddd, J = 8.2, 5.6, 2.3 Hz, 1H), 7.02 (ddd, J = 9.9, 8.9, 7.5 Hz, 1H), 5.12 (d, J = 10.4 Hz, 1H), 4.37 (dd, J = 10.4, 8.0 Hz, 1H), 4.03 (d, J = 2.2 Hz, 3H), 2.84 (p, J = 7.6 Hz, 1H), 1.70 (d, J = 1.1 Hz, 3H), 0.86 (dq, J = 7.4, 2.4 Hz, 3H) ppm. ESI-MS m/z cale. 473.1374, found 474.6 (M+l)⁺; 472.7 (M-l)'.

274

Second Eluting Isomer: (27î,35,45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (7, 195 mg): ’H NMR (500 MHz, Methanol-d₄) δ 8.39 (d, J = 5.5 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.80 (dd, J = 5.5, 2.0 Hz, 1H), 7.02 (ddd, J = 8.2, 5.7, 2.4 Hz, 1H), 6.88 (ddd, J = 9.9, 8.8, 7.5 Hz, 1H), 5 4.98 (d, J = 10.4 Hz, 1H), 4.23 (dd, J = 10.4, 7.9 Hz, 1H), 3.89 (d, J = 2.2 Hz, 3H), 2.70 (p, J = 7.6

Hz, 1H), 1.56 (d, J = 1.1 Hz, 3H), 0.72 (dq, J = 7.6, 2.4 Hz, 3H) ppm. ESI-MS m/z cale. 473.1374, found 474.6 (M+l)⁺; 472.8 (M-l)'.

The absolute stereochemistry of 6 and 7 was determined by single-crystal X-ray crystallography of 7.

Compound 7—Solid Form A

Crystallization of Compound 7 in methanol at 60 °C produced a crystalline form of Compound 7, which is referred to herein as Form A. Form A was characterized by XRPD, TGA, and DSC analysis.

The XRPD pattem of Form A is depicted in Figure 1, and the corresponding data are summarized in the following table:

Angle (° 20 ± 0.2)	Rel. Intensity (%)
7.3	19.9
9.9	28.3
13.9	100.0
15.7	20.1
19.0	50.4
20.1	31.8
20.3	19.3
25.4	14.7

The TGA thermogram of Form A is depicted in Figure 2 and shows negligible weight loss from ambient température up until thermal dégradation.

275

The DSC thermogram of Form A is depicted in Figure 3 and shows a melting onset of 186 °C with a peak at 187 °C.

Compound 7 — Solid Form B

Compound 7 was dissolved in ethyl acetate (6 volumes) at 68 °C. The mixture was cooled to °C over 1 hour, and n-heptane (6 volumes) was added over 5 hours. The mixture was then cooled to 20 °C over a further 5 hours and held ovemight. The resulting solid material was filtered, washed with heptane (3 volumes), and dried to produce a crystalline form of Compound 7, which is referred to herein as Form B. Form B was characterized by XRPD, solid state NMR (¹³C and ¹⁹F),

TGA, DSC, IR, and single-crystal X-ray analysis.

The XRPD pattern of Form B is depicted in Figure 4, and the corresponding data are summarized in the following table:

Angle (° 20 ± 0.2)	Rel. Intensity (%)
7.6	11.3
9.2	10.5
12.0	10.0
12.8	36.7
14.1	59.3
15.1	24.0
15.2	39.4
16.2	23.9
16.9	31.9
17.6	15.1
18.4	63.1
18.5	100.0
18.7	51.7
19.3	64.2
20.3	64.6

276

Angle (° 20 ± 0.2)	Rel. Intensity (%)
21.7	11.6
22.0	29.3
22.2	29.7
22.9	15.1
23.6	27.3
24.0	10.9
24.2	16.8
25.2	30.0
26.9	15.6
27.0	10.7
27.4	17.0
28.6	10.8
28.9	20.9

The solid State ^l3C NMR spectrum of Form B is depicted in Figure 5, and the corresponding data are summarized in the following table:

Chemical Shift [ppm]	Rel. Intensity (%)
172.5	23.1
172.1	29.4
168.5	18.8
168.3	17.8
168.0	20.1
151.5	36.8
148.3	100.0
147.8	35.0
127.7	83.3
122.7	70.4

277

Chemical Shift [ppm]	Rel. Intensity (%)
116.6	53.1
115.1	44.5
110.6	51.6
86.5	13.0
80.2	60.4
63.2	42.3
44.3	99.1
23.0	51.8
13.1	51.7

The solid State ^l9F NMR spectrum of Form B is depicted in Figure 6, and the corresponding data are summarized in the following table:

Chemical Shift [ppm]	Rel. Intensity
-137.1	12.5
-152.8	5.8

The TGA thermogram of Form B is depicted in Figure 7 and shows negligible weight loss from ambient température up until thermal dégradation.

The DSC thermogram of Form B is depicted in Figure 8 and shows a melting onset of 182 °C with a peak at 183 °C.

The IR spectrum of Form B is depicted in Figure 9 and includes peaks at 3501, 3356, 1684, 10 1565, 1505, and 1122 cm'¹.

Crystals having Form B were grown for single-crystal X-ray analysis by dissolving 1 mg of Compound 7 material in 500 pL of éthanol, which was allowed to evaporate slowly over several days. The thermal ellipsoid plot, at 50% probability, is depicted in Figure 10, and the unit cell parameters are reported in the following table:

Crystal System:	Orthorhombic
Space Group:	P2i2i2i

278

a(Â)	7.3929(2)
b(Â)	14.5827(4)
c(Â)	18.9312(6)
a(°)	90
β(°)	90
y(°)	90
V(Â³)	2040.94(10)
Z	4
Température	100K

The following compounds were made using a similar method to that of Example 3 and were separated by chiral SFC using a (R,R)-Whelk-Ol column, 5 pm particle size, 25 cm x 21.2 mm from Regis Technologies :

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
8	(25,37?,47?,55)-4-[[3-(2- ethoxy-3,4-difluoro-phenyl)- 4,5-dimethyl-5(trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide (first eluting isomer by SFC, rt = 3.76 min)	ESI-MS m/z found 488.35 (M+l)⁺; Rétention time: 3.355 minutes	Ή NMR (500 MHz, DMSO-dô) δ 10.73 (s, 1H), 8.50 (dd, J = 5.5, 0.6 Hz, 1H), 8.28 (dd, J = 2.2, 0.6 Hz, 1H), 8.06 (d, J = 2.8 Hz, 1H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.62 (d, J = 2.8 Hz, 1H), 7.20-7.15 (m, 2H), 5.11 (d, J = 10.4 Hz, 1H), 4.30 (dd, J = 10.4, 7.5 Hz, 1H), 4.24-4.12 (m, 2H), 2.76 (p, J = 7.5 Hz,

279

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
			1H), 1.62 (s, 3H), 1.36 (t, J = 7.0 Hz, 3H), 0.74 (dd, J = 7.6, 2.4 Hz, 3H) ppm.
9	(2R, 35,45,57?)-4-[[3-(2- ethoxy-3,4-difluoro-phenyl)- 4,5-dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide (second eluting isomer by SFC, rt = 8.22 min)	ESI-MS m/z found 488.35 (M+l)⁺; Rétention time: 3.355 minutes	Ή NMR (500 MHz, DMSO-dô) δ 10.73 (s, 1H), 8.50 (dd, J = 5.5, 0.6 Hz, 1H), 8.28 (dd, J = 2.2, 0.7 Hz, 1H), 8.06 (d, J = 2.8 Hz, 1H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.61 (d, J = 2.8 Hz, 1H), 7.20-7.14 (m, 2H), 5.11 (d, J = 10.4 Hz, 1H), 4.30 (dd, J = 10.4, 7.6 Hz, 1H), 4.24-4.12 (m, 2H), 2.76 (p, J = 7.5 Hz, 1H), 1.62 (s, 3H), 1.36 (t, J = 7.0 Hz, 3H), 0.74 (dd, J = 7.6, 2.4 Hz, 3H) ppm.

Compound 9 — Solid Form A

A crystalline form of Compound 9, referred to herein as Form A, was obtained and was characterized by single-crystal X-ray analysis. Crystals having Form A were grown for single5 crystal X-ray analysis by dissolving ~l mg of Compound 9 material in 350 pL of 10/90 dichloromethane/dichloroethane solution, which was then vapor diffused with pentane over several

280 days. The thermal ellipsoid plot, at 50% probability, is depicted in Figure 11, and the unit cell parameters are reported in the following table:

Crystal System:	Orthorhombic
Space Group:	1222
a(Â)	12.0172(5)
b (A)	15.6682(6)
c(Â)	24.1406(11)
a(°)	90
β(°)	90
y(°)	90
V(Â³)	4545.4(3)
z	8
Température	100K

The following compound was made from (27?,35,45,57?)-3-(3,4-difluoro-2-hydroxy-phenyl)5 4,5-dimethyl-5-(trifluoromethyI)tetrahydrofuran-2-carboxylic acid, which can be obtained by separating the enantiomers of the 6,7-difluoro-l,2-dimethyl-2-(trifluoromethyl)-lH-furo[2,3c]chromen-4-one obtained in Step 6 using the SFC conditions described in Step 1 of Example 23, and using the resulting optically pure material in steps 7 and 8 of Example 3, by a method similar to that described in Steps 9-12 of Example 3, using CD₃I in place of Mel in Step 9:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
26	4-[[(27?,35,45,57î)-3-[3,4- difluoro-2- (trideuteriomethoxy)phenyl]- 4,5-dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide	ESI-MS m/z found 477.6 (M+l)⁺; Rétention time: 3.24 minutes	Ή NMR (500 MHz, DMSO-dô) δ 10.71 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.05 (s, 1H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.60 (s, 1H), 7.17 (dd, J = 9.6,

281

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
			6.2 Hz, 2H), 5.10 (d, J = 10.2 Hz, 1H), 4.26 (dd, J= 10.2, 7.7 Hz, 1H), 2.78 (p, J = 7.6 Hz, 1H), 1.61 (s, 3H), 0.73 (d, J = 7.5 Hz, 3H) ppm.

The following compounds were prepared by methods similar to the methods described herein:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
48	4-(((25,35,45,57?)-3-(3,4- difluoro-2-methoxy-phenyl)- 4,5-dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl] amino]pyridine-2carboxamide		Ή NMR (400 MHz, DMSO-dô) δ 10.29 (s, 1H), 8.42 (d, J = 5.5 Hz, 1H), 8.20 (d, J = 1.5 Hz, 1H), 8.02 (br s, 1H), 7.70 (dd, J = 5.4, 1.9 Hz, 1H), 7.58 (br s, 1H), 7.24-7.17 (m, 1H), 6.99 (q, J = 9.1 Hz, 1H), 5.12 (d, J = 5.9 Hz, 1H), 4.37-4.25 (m, 1H), 3.89 (s, 3H), 2.98 (quin, J = 7.5 Hz, 1H), 1.54 (s, 3H), 0.75 (br d, J = 6.7 Hz, 3H) ppm.

282

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
49	4-[[(27?,37?,45,57î)-3-(3,4difluoro-2-methoxy-phenyl)4,5-dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl] amino]pyridine-2carboxamide		*H NMR (400 MHz, DMSO-dô) δ 10.20 (s, 1H), 8.39 (d, J = 5.5 Hz, 1H), 8.02 (brd, J = 2.1 Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.65 7.53 (m, 1H), 7.48 (dd, J = 2.2, 5.5 Hz, 1H), 7.00 - 6.90 (m, 2H), 4.85 (d, J = 8.9 Hz, 1H), 3.98 (d, J = 2.0 Hz, 3H), 3.93 (dd, J = 9.1, 13.0 Hz, 1H), 2.99 (brqd, J = 6.7, 12.7 Hz, 1H), 1.68 (s, 3H), 0.98 (br d, J = 6.5 Hz, 3H) ppm.
50	4-[[(2R,35,4R,5R)-3-(3,4difluoro-2-methoxy-phenyl)4,5-dimethyl-5(trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide	ESI-MS m/z cale. 473.4, found 474.2 (M+H)⁺; Rétention time: 8.9 minutes	Ή NMR (400 MHz, Chloroform-d) δ 8.83 (s, 1H), 8.45 (d, J= 5.6 Hz, 1H), 8.19 (dd, J= 5.6, 2.3 Hz, 1H), 8.03 (dd, .7=2.2, 0.4 Hz, 1H), 7.84 (brd, J= 3.8 Hz, 1H), 6.98 - 6.88 (m, 2H), 5.80 (br d, J= 3.9 Hz, 1H), 4.68 (d, J = 10.6 Hz, 1H), 3.94

283

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
			(d, J= 2.4 Hz, 3H), 3.41 (t, J= 11.3 Hz, 1H), 2.93 - 2.84 (m, 1H), 1.53 (s, 3H), 0.98 (d, J= 6.8 Hz, 3H) ppm.

Example 4 (25,37î,47î,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (10) and (27?,35,45,57?)5 4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (11)

Me ^f3^C'-,LO 0 1) TMSCBrF₂, KOH, | )—DCM, H₂O, 0 °C then fa/ OH KOf-Bu, t-BuOH, 95% HO-Â^ ^F F frac) _{c e} Me ^h3^bv,O ,O /=\ < \ HN —4 _χΝ F-/° \ Λ ^V^NH2 F _FW ° 10, first eluting isomer Step 1:

2) DCM, DMF (cat.), (COCI)₂, 0 °C then NEt₃, F₃C„y^e _o o DMF, methyl4- \ // aminopyridine-2-carboxylate, DCM, 0 °C to RT, 40% 0* ς Un r T-faffa 3) ^{7N nh}3· ^Me0H· ^97% ^h \ fa/ 4) SFC ^F O _c _ Me ^h3A,r.o o A HN—G N and v— Vnh₂ 11, second eluting isomer

284

To a solution of rac-(2R,35,45,57?)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (9.30 g, 27.33 mmol, prepared as described in Example 3, Step 8) in DCM (50 mL) stirring at 0 °C was added a solution of KOH (18.4 g, 328.0 mmol) in H2O (50 mL) and the solution stirred vigorously. [Bromo(difluoro)methyl]-trimethylsilane (22.5 g, 110.8 mmol) was added and stirring continued at this température. Upon complété consumption of starting material, the mixture was acidified by addition of 1 N HCl, extracted with DCM and concentrated in vacuo. The résultant oil was dissolved in ZerZ-butanol (50 mL) at ambient température and KO/-Bu (7.5 g, 66.84 mmol) was added. After complété conversion the mixture was acidified with 1 N HCl, diluted with DCM, the layers separated and the aqueous layer extracted. The organic phase was washed with water concentrated in vacuo to give rac-(2R,35,45,57?)-3-[2(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxylic acid (10.10 g, 95%) which was used without further purification.

Step 2:

To an ice-cooled solution of rac-(27?,35,45,57î)-3-[2-(difluoromethoxy)-3,4-difluorophenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (10.10 g, 25.88 mmol) in DCM (100 mL) stirring at 0 °C, DMF (400 pL, 5.17 mmol) and oxalyl chloride (4.85 mL, 55.60 mmol) were added. The mixture was warmed to ambient température over 30 min before being concentrated in vacuo. The solids were dissolved in DCM (80 mL) and DMF (400 pL, 5.17 mmol) and the solution added to an ice cooled solution of methyl 4-aminopyridine-2-carboxylate (4.05 g, 26.62 mmol) and NEt3 (4.5 mL, 32.29 mmol) in DCM (80 mL). The reaction was warmed to ambient température over 2 hours then quenched by addition of water (1 drop) and MeOH (2 mL) and concentrated in vacuo. Purification by flash chromatography (4 g S1O2, 0 to 100% EtOAc in Petroleum ether) gave methyl rac-(27?,35,45,57î)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (5.4 g, 40%). ESI-MS m/z cale. 524.1182, found 523.6 (M-l)'.

Step 3:

Methyl rac-(2R,35,45,57?)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (5.50 g, 10.49 mmol) was dissolved in MeOH (300 mL) and methanolic ammonia (300 mL of 3.37 M, 1.01 mol) and stirred at ambient température ovemight before the reaction mixture was concentrated in vacuo to

285 afford rac-(2R,35,45,57?)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (115, 5.18 g, 97%). Ή NMR (500 MHz, Methanol-d₄) δ 8.38 (d, J = 5.6 Hz, 1H), 8.15 (d, J = 2.1 Hz, 1H), 7.79 (dd, J = 5.5, 2.2 Hz, 1H), 7.23 - 7.10 (m, 2H), 6.83 (td, J = 73.1, 1.0 Hz, 1H), 4.99 (d, J = 10.3 Hz, 1H), 4.27 (dd, J = 10.4, 8.1 Hz, 1H), 2.73 (p, J = 7.7 Hz, 1H), 1.56 (d, J = 1.2 Hz, 3H), 0.78 - 0.72 (m, 3H) ppm. ESI-MS m/z cale. 509.11856, found 510.5 (M+l)⁺; 508.6 (M-l)’.

Step 4:

Purification of rac-(27?,35,45,57?)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (82 mg, 0.1562 mmol) by chiral SFC [System: (R,R)-Whelk-Ol column, 5 pm particle size, 25 cm x 21.2 mm from Regis Technologies, MeOH, 20 mM NH3] gave:

First Eluting Isomer: (2S,37?,4/?,5S)-4-[[3-[2-(difIuoromethoxy)-3,4-difluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (10, 23 mg). ’H NMR (500 MHz, Methanol-d₄) δ 8.53 (d, J = 5.5 Hz, 1H), 8.30 (dd, J = 2.2, 0.6 Hz, 1H), 7.93 (dd, J = 5.5, 2.2 Hz, 1H), 7.40 - 7.23 (m, 2H), 6.97 (td, J = 73.1, 1.0 Hz, 1H), 5.14 (d, J = 10.4 Hz, 1H), 4.41 (dd, J = 10.3, 8.1 Hz, 1H), 2.87 (p, J = 7.7 Hz, 1H), 1.71 (d, J = 1.3 Hz, 3H), 0.94 0.81 (m, 3H) ppm. ESI-MS m/z cale. 509.11856, found 510.4 (M+l)⁺; 508.4 (M-l)-.

Second Eluting Isomer: (27?,3S,45,57?)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (11, 28 mg, 70%). ’H NMR (500 MHz, Methanol-d₄) δ 8.53 (d, J = 5.5 Hz, 1H), 8.30 (dd, J = 2.2, 0.6 Hz, 1H), 7.93 (dd, J = 5.5, 2.2 Hz, 1H), 7.40 - 7.23 (m, 2H), 6.97 (td, J = 73.1, 1.0 Hz, 1H), 5.14 (d, J = 10.4 Hz, 1H), 4.41 (dd, J = 10.3, 8.1 Hz, 1H), 2.87 (p, J = 7.7 Hz, 1H), 1.71 (d, J = 1.3 Hz, 3H), 0.94 - 0.81 (m, 3H) ppm. ESI-MS m/z cale. 509.11856, found 510.4 (M+l)⁺, 508.4 (M-l)'.

The absolute stereochemistry of 10 and 11 was determined by single-crystal X-ray crystallography of 11.

Compound 11 — Solid Form A

Compound 11 was suspended in distilled water, the suspension was stirred at 37 °C for 24 hours, at which time the suspension was filter-centrifiiged. The resulting solid was dried at 60 °C

286 ovemight in a vacuum oven to afford a crystalline form of Compound 11, which is referred to herein as Form A. Form A was characterized by XRPD analysis.

The XRPD pattem of Form A is depicted in Figure 12, and the corresponding data are summarized in the following table:

Angle (° 20 ± 0.2)	Rel. Intensity (%)
7.1	12.0
7.3	29.0
10.1	43.2
13.7	100.0
' 14.1	76.7
16.0	23.0
16.3	65.6
17.6	10.3
18.5	17.0
18.9	11.5
20.0	46.5
20.4	18.5
21.5	15.2
23.7	22.9
24.8	27.3
25.7	12.7
26.1	13.9

Compound 11 — Solid Form B

Compound 11 was recrystallized from acetonitrile and dried ovemight to produce a crystalline form of Compound 11, which is referred to herein as Form B. Form B was characterized by XRPD and single-crystal X-ray analysis.

The XRPD pattem of Form B is depicted in Figure 13, and the corresponding data are summarized in the following table:

287

Angle (° 20 ± 0.2)	Rel. Intensity (%)
6.8	36.4
11.5	26.7
13.2	100.0
13.6	18.3
14.4	19.8
15.6	12.0
16.1	40.5
16.3	28.2
17.6	14.0
18.0	13.2
18.8	23.9
19.4	16.6
20.6	48.1
21.3	67.5
22.3	11.2
23.3	10.8
24.2	12.1
27.4	9.8

Crystals having Form A were grown for single-crystal X-ray analysis by concentration of a toluene solution of Compound 11. The thermal ellipsoid plot, at 50% probability, is depicted in Figure 14, and the unit cell parameters are reported in the following table:

Crystal System:	Monoclinic
Space Group:	P2i
a(Â)	12.0863(2)
b(Â)	7.48310(10)
c(Â)	23.9904(4)

288

a(°)	90
β(°)	90.0130(10)
ï(°)	90
V(Â³)	2169.76(6)
Z/Z'	2/0.5
Température	100(2)K

The following compounds were made using a method similar to that described in Example 4, except that 5-amino-2-fluorobenzamide was used in place of methyl 4-aminopyridine-2-carboxylate in Step 2, and Step 3 was omitted. In step 4, purification was performed by chiral SFC using a (R,R)-Whelk-Ol column, 5 pm particle size, 25 cm x 21.2 mm from Regis Technologies:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
14	rel-(2R, 35,45,57?)-N-(3carbamoyl-4-fluoro-phenyl)3-[2-(difluoromethoxy)-3,4difluoro-phenyl]-4,5- dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2-carboxamide (fïrst eluting isomer by SFC)	ESI-MS m/z found 527.1 (M+l)⁺; Rétention time: 3.23 minutes	‘H NMR (500 MHz, Methanol-d4) δ 7.96 (dd, J = 6.5, 2.8 Hz, IH), 7.77 (ddd, J = 9.0, 4.4, 2.8 Hz, IH), 7.35 7.24 (m, 2H), 7.19 (dd, J = 10.5, 9.0 Hz, IH), 6.94 (td, J = 73.1, 1.1 Hz, IH), 5.08 (d, J = 10.5 Hz, IH), 4.36 (dd, J = 10.5, 8.0 Hz, IH), 2.83 (p, J = 7.6 Hz, IH), 1.73- 1.65 (m, 3H), 0.87 (dq, J = 7.4, 2.3 Hz, 3H) ppm.

289

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
15	rel-(2R, 35,45,5Æ)-N-(3carbamoyl-4-fluoro-phenyl)3 -[2-(difluoromethoxy)-3,4difluoro-phenyl]-4,5dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2-carboxamide (second eluting isomer by SFC)	ESI-MS m/z found 527.1 (M+l)⁺; Rétention time: 3.23 minutes	'H NMR (500 MHz, Methanol-di) δ 7.97 (dd, J = 6.5, 2.8 Hz, 1H), 7.78 (ddd, J = 9.0, 4.4, 2.8 Hz, 1H), 7.37 7.24 (m, 2H), 7.20 (dd, J = 10.5, 9.0 Hz, 1H), 6.95 (td, J = 73.1, 1.0 Hz, 1H), 5.09 (d, J = 10.5 Hz, 1H), 4.37 (dd, J =10.5, 8.0 Hz, 1H), 2.84 (p, J = 7.7 Hz, 1H), 1.69 (d, J= 1.2 Hz, 3H), 0.88 (dt, J = 7.4, 2.4 Hz, 3H) ppm.

The following compounds were made using a method similar to that described in Example 4, except that 3-aminobenzamide was used in place of methyl 4-aminopyridine-2-carboxylate in Step 2, and Step 3 was omitted. In step 4, purification was performed by chiral SFC using a Lux

Cellulose-2 column, 5 pm particle size, 25 cm x 10 mm from Phenomenex, Inc.:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
51	re/-(25,37?,47?,55)-N-(3carbamoylphenyl)-3-[2(difluoromethoxy)-3,4difluoro-phenyl]-4,5dimethyl-5-	ESI-MS m/z cale. 508.1233, found 509.1 (M+l)⁺; 507.2 (M-l)-; Rétention time: 3.19 minutes	Ή NMR (500 MHz, DMSO-dô) δ 10.32 (s, 1H), 8.06 (t, J= 1.9 Hz, 1H), 7.93 (s, 1H), 7.77 - 7.74 (m, 1H), 7.58

290

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
	(trifluoromethyl)tetrahydrofu ran-2-carboxamide (first eluting isomer by SFC on Lux Cellulose-2 column, rt = 2.97 min)		(dt, J = 7.8, 1.3 Hz, 1H), 7.51-7.41 (m, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.34 - 7.32 (m, 2H), 7.29 (t, J = 72.2 Hz, 1H), 5.12 (d, J = 10.4 Hz, 1H), 4.28 (dd, J = 10.4, 7.6 Hz, 1H), 2.76 (p, J = 7.3 Hz, 1H), 1.60 (s, 3H), 0.76 (d, J = 6.4 Hz, 3H) ppm.
52	rel-(2R, 35,45,5Λ)-Ν-(3carbamoylphenyl)-3-[2(difluoromethoxy)-3,4difluoro-phenyl]-4,5dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2-carboxamide (second eluting isomer by SFC on Lux Cellulose-2 column, rt = 3.51 min)	ESI-MS m/z cale. 508.1233, found 509.1 (M+l)⁺; 507.2 (M-l)-; Rétention time: 3.18 minutes	Ή NMR (500 MHz, DMSO-dô) δ 8.06 (t, J = 2.0 Hz, 1H), 7.93 (s, 1H), 7.75 (ddd, J = 8.3, 2.3, 1.0 Hz, 1H), 7.58 (dt, J = 7.6, 1.3 Hz, 1H), 7.51 - 7.46 (m, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.35-7.31 (m, 2H), 7.29 (t, J = 71.9 Hz, 1H), 5.12 (d, J = 10.3 Hz, 1H), 4.28 (dd, J= 10.4, 7.6 Hz, 1H), 2.76 (p, J = 7.6 Hz, 1H), 1.60 (s, 3H), 0.76 (d, J = 6.2 Hz, 3H)

291

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
			ppm. Amide NH not observed.

The following compound was made using a method similar to that described in Example 4, except that rac-(2R,35,45,55)-3-(2-(difluoromethoxy)-4-fluoro-3-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used as the starting material for step 2. Rac5 (25,35,45,55)-3-(2-(difluoromethoxy)-4-fluoro-3-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxyIic acid was prepared using methods analogous to those described for other intermediates of this application. The séparation of the racemates at step 4 was not carried out and the compound was isolated as a racemate:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
53	rac-(2S, 3R,4R, 55)-4-[[3-[2(difluoromethoxy)-4-fluoro3-methyl-phenyl]-4,5dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl] amino]pyridine-2carboxamide	ESI-MS m/z cale. 505.14362, found 506.1 (M+l)⁺; 504.2 (Μ-l)'; Rétention time: 3.36 minutes	Ή NMR (500 MHz, DMSO-dô) δ 10.70 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.33 - 8.22 (m, 1H), 8.06 (d, J = 2.6 Hz, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.61 (d, J = 2.8 Hz, 1H), 7.36 (dd, J = 8.8, 6.2 Hz, 1H), 7.26 - 6.90 (m, 2H), 5.10 (d, J = 10.4 Hz, 1H), 4.32 (dd, J = 10.5, 7.5 Hz, 1H), 2.75 (p, J = 7.4 Hz, 1H), 2.18 (d, J = 2.0 Hz, 3H), 1.60 (s, 3H),

292

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
			0.79 - 0.70 (m, 3H) ppm.

The following compounds were made by separating 53 by chiral SFC (Exampe 4, Step 4) using a Chiralpak AS-H column, 5 pm particle size, 25 cm x 10 mm from Daicel on a Minigram SFC instrument from Berger Instruments:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
16	rel-(2R, 35,45,57?)-4-[[3-[2(difluoromethoxy)-4-fluoro3 -methyl-phenyl] -4,5 dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide (first eluting isomer by SFC)	ESI-MS m/z found 506 (M+l)⁺; Rétention time: 3.34 minutes	Ή NMR (500 MHz, Chloroform-d) δ 8.60 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.10 (dd, J = 5.6, 2.3 Hz, 1H), 7.94 (d, J = 2.1 Hz, 1H), 7.83 (s, 1H), 7.31 (dd, J = 8.8, 6.1 Hz, 1H), 7.06 (t, J = 8.7 Hz, 1H), 5.56 (s, 1H), 4.97 (d, J = 11.1 Hz, 1H), 4.18 (dd, J =11.1, 8.0 Hz, 1H), 2.79 (p, J = 7.7 Hz, 1H), 2.25 (d, J = 2.2 Hz, 3H), 1.69 (d, J = 1.1 Hz, 3H), 0.86-0.79 (m, 3H) ppm.
17	re/-(27?,35,45,57?)-4-[[3-[2- (difluoromethoxy)-4-fiuoro- 3-methyl-phenyl]-4,5-	ESI-MS m/z found 507 (M+l)⁺; Rétention time: 3.34 minutes	Ή NMR (500 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.46 (d, J = 5.5

293

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
	dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide (second eluting isomer by SFC)		Hz, 1H), 8.09 (dd, J = 5.5, 2.3 Hz, 1H), 7.93 (d, J = 2.2 Hz, 1H), 7.83 (s, 1H), 7.34 7.29 (m, 1H), 5.54 (s, 1H), 4.96 (d, J= 11.1 Hz, 1H), 4.18 (dd, J = 11.2, 8.1 Hz, 1 H), 2.78 (p, J = 7.7 Hz, 1H), 2.24 (d, J = 2.2 Hz, 3H), 1.69 (d, J= 1.1 Hz, 3H), 0.86 - 0.76 (m, 3H) ppm.

Example 5 (27î,35,45,51î)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide (18)

To a solution of (27?,35,45,57?)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (11, 35 mg,

294

0.06802 mmol) in DCM (1 mL) was added ni-CPBA (50 mg, 0.2028 mmol) in one portion at ambient température. After 16 hours a further portion of zn-CPBA (50 mg, 0.2028 mmol) was added and the reaction stirred for 4 days. The mixture was concentrated in vacuo and the remaining solid purified by silica gel chromatography (4 g, 0 to 100% EA in heptane) to afford (27?,35,45,57?)-4-[[35 [2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide (18, 33 mg, 90%). ’H NMR (500 MHz, Methanol-d4) δ 8.47 (d, J = 3.2 Hz, 1H), 8.18 (d, J = 7.3 Hz, 1H), 7.93 (dd, J = 7.3, 3.2 Hz, 1H), 7.23 -7.12(m, 2H), 6.83 (td, J = 73.1, 1.1 Hz, 1H), 5.00 (d,J= 10.4 Hz, 1H), 4.26 (dd, J = 10.5, 8.1 Hz, 1H), 2.72 (p, J = 7.6 Hz, 1H), 1.56 (s, 3H), 0.75 (dq, J = 4.7, 2.4 Hz, 3H) ppm. ESI-MS m/z cale.

525.11346, found 526.6 (M+l)⁺; 524.7 (M-l)’.

The following compounds were made using a method similar to Example 5, using 5, 7, 9, 26, and 27, respectively, as the starting materials:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
19	(27?,3S,4S,5R)-4-[[3-(3,4difluoro-2-methoxy-phenyl)4,5-dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2-carbonyl]amino]-1 oxido-pyridin-1 -ium-2carboxamide	ESI-MS m/z found 490.5 (M+l)⁺; Rétention time: 3.014 minutes	Ή NMR (500 MHz, DMSO-dô) δ 10.79 (s, 1H), 10.58 (d, J = 4.6 Hz, 1H), 8.52 (d, J = 3.3 Hz, 1H), 8.31 (d, J = 7.2 Hz, 1H), 8.21 (d, J = 4.7 Hz, 1H), 7.87 (dd, J = 7.2, 3.3 Hz, 1H), 7.16 (dd, J = 9.7, 6.5 Hz, 2H), 5.08 (d, J = 10.2 Hz, 1H), 4.24 (dd, J= 10.2, 7.7 Hz, 1 H), 3.94 (d, J = 2.1 Hz, 3H), 2.76 (p, J = 7.6 Hz, 1H), 1.60 (s,

295

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
			3H), 0.72 (dd, J = 7.6, 2.3 Hz, 3H) ppm.
54	re/-(27?,35,57î)-4-[[3-(3,4difluoro-2-methoxy-phenyl)5-methyl-5- (trifluoromethyl)tetrahydrofu ran-2-carbonyl] amino] -1 oxido-pyridin-1 -ium-2carboxamide	ESI-MS m/z cale. 475.11667, found 476.1 (M+l)⁺; 474.0 (M-l)'; Rétention time: 2.82 minutes	Ή NMR (500 MHz, Chloroform-d) δ 11.10 (d, J = 5.2 Hz, 1H), 8.84 (s, 1H), 8.29 (dd, J = 7.2, 3.3 Hz, 1H), 8.25 -8.14(m, 2H), 6.99 (ddd, J = 8.0, 5.6, 1.9 Hz, 1H), 6.94 - 6.86 (m, 1H), 6.15 (s, 1H), 4.77 (d, J = 10.7 Hz, 1H), 3.99 (d, J = 2.6 Hz, 3H), 3.88 - 3.76 (m, 1H), 2.61 (t, J = 12.5 Hz, 1H), 2.34 (dd, J= 13.1, 8.2 Hz, 1H), 1.65 (s, 3H) ppm.
55	(27?,35,45,57?)-4-[[3-(2- ethoxy-3,4-difluoro-phenyl)4,5-dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2-carbonyl]amino]-1 oxido-pyridin-1 -ium-2carboxamide	ESI-MS m/z cale. 503.14795, found 504.5 (M+l)⁺; 502.5 (M-l)'; Rétention time: 3.17 minutes	‘H NMR (500 MHz, DMSO-dô) δ 10.82 (s, 1H), 10.59 (d, J = 4.7 Hz, 1H), 8.53 (d, J = 3.2 Hz, 1H), 8.32 (d, J = 7.2 Hz, 1H), 8.22 (d, J = 4.6 Hz, 1H), 7.88 (dd, J = 7.2, 3.2 Hz, 1H), 7.22 - 7.09 (m, 2H), 5.09 (d, J = 10.4

296

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
			Hz, 1H), 4.28 (dd, J = 10.5, 7.6 Hz, 1H), 4.25 -4.11 (m, 2H), 2.75 (p, J = 7.4 Hz, 1H), 1.61 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H), 0.73 (d, J = 7.1 Hz, 3H) ppm.
56	4-[[(2Æ,35,4S,57?)-3-[3,4difluoro-2- (trideuteriomethoxy)phenyl]4,5-dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2-carbonyl]amino]-1 oxido-pyridin-1 -ium-2carboxamide	ESI-MS m/z cale. 492.15115, found 493.6 (M+l)⁺; 491.6 (Μ-l)'; Rétention time: 3.02 minutes
57	4-[[(2/?,35,45,57?)-3-(3,4difluoro-2-hydroxy-phenyl)4,5-dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2-carbonyl]amino]-1 oxido-pyridin-1 -ium-2carboxamide	ESI-MS m/z cale. 475.11667, found 476.6 (M+l)⁺; 474.4 (Μ-l)'; Rétention time: 2.35 minutes	Ή NMR (500 MHz, Methanol-di) δ 8.58 (d, J = 3.2 Hz, 1H), 8.30 (d, J = 7.2 Hz, 1H), 8.07 (dd, J = 7.2, 3.2 Hz, 1H), 7.03 (ddd, J = 8.4, 5.7, 2.1 Hz, 1H), 6.72 (ddd, J = 10.1,8.8, 7.4 Hz, 1H), 5.12 (d, J = 10.4 Hz, 1H), 4.34 (dd, J = 10.5, 7.8 Hz, 2H), 2.92 (p, 1 = 1.6 Hz, 1H), 1.68 (s, 2H),

297

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
			0.83 (dt, J = 7.5, 2.3 Hz, 3H) ppm; Amide NHandNH₂; alcohol OH not observed.

Compound 19 — Solid Form A

A crystalline form of Compound 19, referred to herein as Form A, was obtained from a suspension of Compound 19 in éthanol, acetonitrile, and water by lyophilization. Form A can also be obtained by précipitation from a methanol solution via addition of heptane antisolvent. Form A was characterized by XRPD, solid State NMR (^l3C and ^l9F), and single-crystal X-ray analysis.

The XRPD pattem of Form A is depicted in Figure 15, and the corresponding data are summarized in the following table:

Angle (° 20 ± 0.2)	Rel. Intensity (%)
6.8	8.8
13.7	100
14.3	11.1
15.2	24.1
16.1	12.2
18.2	51.5
18.3	23.5
19.1	10.0
20.6	10.4
20.8	22.0
22.5	11.6
23.8	13.6
24.0	7.5
25.8	11.8

298

26.3	7.9
26.6	7.7

The solid State ^,3C NMR spectrum of Form A is depicted in Figure 16, and the corresponding data are summarized in the following table:

Chemical Shift [ppm]	Rel. Intensity (%)
171.4	39.1
164.2	29.2
151.8	6.3
149.5	8.2
148.4	44.8
146.6	4.3
144.0	5.4
141.6	86.1
138.7	35.3
126.2	62.8
123.8	59.1
118.0	100.0
112.2	49.2
86.4	19.1
78.8	67.1
63.3	65.2
47.6	71.9
43.8	50.2
23.0	56.9
11.6	58.6

299

The solid State ¹⁹F NMR spectrum of Form A is depicted in Figure 17, and the corresponding data are summarized in the following table:

Chemical Shift [ppm]	Rel. Intensîty
-74.6	2.4
-141.5	12.5
-154.6	8.4

The absolute stereochemistry of Compound 19 was confirmed by single crystal X-ray crystallographic analysis. Crystals having Form A were grown for single-crystal X-ray analysis by dissolving ~1 mg of Compound 19 material in 150 pL of methanol and allowing slow diffusion of heptane antisolvent over several days. The thermal ellipsoid plot, at 50% probability, is depicted in Figure 18, and the unit cell parameters are reported in the following table:

Crystal System:	Monoclinic
Space Group:	P2i
a (À)	11.2266(3)
b(Â)	7.3948(2)
c(Â)	13.1432(4)
a(°)	90
β(°)	100.3980(10)
Y(°)	90
V(Â³)	1073.21(5)
Z/Z'	2/0.5
Température	173(2)K

300

Example 6 re/-(25,37ï,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (20), (25,37?,57?)-4-[[3(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofiiran-25 carbonyl]amino]pyridine-2-carboxamide (21), re/-(27?,3S,57?)-4-[[3-(3-chloro-4-fluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (22), and (22?,35,55)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (23)

CF₃ ^Me

O

1) Tf₂O, DIPEA, _CF Me

DCM, -78 ’C ³

OTf

2) ArBpin, Pd(PPh₃)₂CI₂, NaHCOj, dioxane, 80 °C, 78% over two steps

Ar

3) 1,2-dibromoethane, Mg powder, MeOH, 50 C, 91%

CF₃ ^Me

Ar

4) LIOH, EtOH then Me KOt-Bu, t-BuOH, 88% ^CF3xL-0 .0

5) DCM, DMF (cat.), (COCI)₂ then NEt₃, DMAP, methyl 4aminopyridine-2carboxylate, 0 °C to RT, 97%

7) SFC, 32.1% total ( OK 6) 7 M NH₃ in

Ar MeOH, 92%

nh₂

HN Ar

20, first eluting Isomer

21, second eluting isomer

22, thlrd eluting isomer

23, fourth eluting Isomer

Step 1:

Trifluoromethylsulfonyl trifluoromethanesulfonate (1.53 g, 5.42 mmol) was added dropwise to a solution of ethyl 5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1000 mg, 4.16 mmol) and triethylamine (1.26 g, 12.45 mmol) in DCM (40 mL) stirring at -78 ° C. After 2h, 15 the reaction was quenched by addition of saturated aqueous NaHCCh solution, the layers were separated and the aqueous layer extracted with DCM. The combined organic layers were passed through a phase separator cartridge, filtered and concentrated in vacuo to give ethyl 2-methyl-2(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-fiiran-5-carboxylate (2.7 g, 87% yield) at 50%

301 purity (containing 1 eq. NEts), which was used without further purification. ESI-MS m/z cale. 372.01022, found 373.0 (M+l)⁺.

Step 2:

A mixture of ethyl 2-methyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5carboxylate (2 g, 50% purity with 1 eq. NEt3,2.686 mmol), 2-(3-chloro-4-fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (925.8 mg, 3.231 mmol) and Pd(PPh3)2Ch (97.63 mg, 0.14 mmol) in dioxane (25 mL) and saturated aqueous NaHCCfr (excess) was degassed, refilled with N2 (three times before catalyst addition, then three times after catalyst addition), and heated at 80 °C for 4 hours. The reaction mixture was cooled to ambient température and filtered through a celite cartridge, eluting with EtOAc, then the filtrate concentrated in vacuo. Purification by flash chromatography (40 g S1O2 0 to 20% EtOAc in heptane) gave ethyl 4-(3-chIoro-4-fluoro-2methoxy-phenyl)-2-methyl-2-(trifluoromethyl)-3H-fiiran-5-carboxylate (800 mg, 78%) as a clear oil. ^lH NMR (400 MHz, Chloroform-d) δ 7.12 (dd, J = 8.7, 6.1 Hz, 1H), 6.96 (t, J = 8.5 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 3.52 (d, J = 17.6 Hz, 1H), 2.96 (dt, J = 17.6, 0.9 Hz, 1H), 1.69 (d, J = 1.0 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H) ppm. ESI-MS m/z cale. 382.0595, found 383.3 (M+l)⁺.

Step 3:

A pressure tube was loaded with magnésium powder (770 mg, 31.68 mmol) and purged with nitrogen. To the reaction vessel was added MeOH (12 mL) followed by a solution of ethyl 4-(3chloro-4-fluoro-2-methoxy-phenyl)-2-methyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (600 mg, 1.57 mmol) in MeOH (12 mL) and the resulting solution was degassed with nitrogen. A few drops of 1,2-dibromoethane (12 pL, 0.14 mmol) were added and the reaction mixture was stirred vigorously at 50 °C. After 5 hours the reaction mixture was cooled and quenched by pouring slowly onto a cooled IM solution of HCl. The mixture was stirred for 30 mins until clear. TB ME was added to solution while stirring, the layers separated and the aqueous layer extracted with TBME (x 3). The combined organic layers were passed through a phase separator cartridge and the filtrate concentrated in vacuo to give ethyl 3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (550 mg, 91%), which was used without further purification. ESI-MS m/z cale. 384.07516, found 385.2 (M+l)⁺.

Step 4:

302

Ethyl 3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran2-carboxylate (550 mg, 1.43 mmol) was dissolved in éthanol (25 mL) and LiOH (5 mL of 2 M, 10.00 mmol) was added. The resulting white suspension was stirred at ambient température ovemight before being concentrated in vacuo and then partitioned between EtOAc and IM aqueous HCl. The layers were separated and the organic layer passed through a phase separator cartridge). The filtrate was concentrated in vacuo to give a yellow oil which was dissolved in fôrAbutanol (20 mL). Potassium teri-butoxide (800 mg, 7.129 mmol) was added and the mixture stirred at ambient température ovemight. The reaction mixture was evaporated in vacuo to give potassium 3-(3chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofiiran-2-carboxylate (500 mg, 88%). ESI-MS m/z cale. 356.04385, found 355.2 (M-l)'.

Step 5:

To a solution of potassium 3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (500 mg, 1.40 mmol) in DCM (20 mL) stirring at ambient température was added DMF (25 pL, 0.32 mmol) and oxalyl chloride (415 pL, 4.76 mmol). After 15 mins the reaction mixture was concentrated in vacuo then the residue diluted in DCM (10 mL) and added dropwise over 5 mins to a solution of methyl 4-aminopyridine-2-carboxylate (334 mg, 2.20 mmol), DMAP (16.55 mg, 0.14 mmol) and Et₃N (1.2 mL, 8.61 mmol) in DCM (10 mL) stirring at 0 °C. After 10 mins the reaction was warmed to ambient température and after 40 mins the reaction mixture was diluted with DCM (50 mL) and washed with 2 M HCl solution (50 mL). The organic layer was passed through a phase separator cartridge and the filtrate was concentrated in vacuo to give methyl 4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (670 mg, 97%), which was used without fiirther purification. ESI-MS m/z cale. 490.09186, found 491.1 (M+l)⁺.

Step 6:

Methyl 4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (470 mg, 0.96 mmol) was dissolved in methanolic ammonia (10.00 mL of 2 M, 20.00 mmol) and stirred ovemight at ambient température. The reaction mixture was evaporated in vacuo to give 4-[[3-(3-chloro-4fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine

303

2-carboxamide (420 mg, 92%), which was used without further purification. ESI-MS m/z cale. 475.0922, found 476.4 (M+l)⁺.

Step 7:

(4-[[3-(3-Chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofiiran2-carbonyl]amino]pyridine-2-carboxamide (420 mg, 0.8827 mmol) was separated by chiral SFC [(R,R)-Whelk-Ol column, 5 pm particle size, 25 cm x 21.2 mm from Regis Technologies, MeOH, 20 mM NH₃], followed by further purification of one or more of the fractions by chiral SFC using a Chiralpak IC column, 5 pm particle size, 25 cm x 20 mm from Daicel or a Chiralpak ID column, 5 pum particle size, 25 cm x 20 mm from Daicel to give:

First Eluting Isomer: re/-(25,37î,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (20, 30 mg, 7.1%) (further purified by chiral SFC using Chiralpak IC column). Ή NMR (500 MHz, Chloroform-d) δ 8.92 (s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.21 (dd, J = 5.6, 2.1 Hz, 1H), 8.09 (d, J = 2.2 Hz, 1H), 7.87 (d, J = 4.1 Hz, 1H), 7.26 (dd, J = 8.8, 5.8 Hz, 1H), 7.03 (t, J = 8.4 Hz, 1H), 5.87 5.82 (m, 1H), 4.77 (d, J = 10.6 Hz, 1H), 3.98 (td, J = 11.2, 8.3 Hz, 1H), 3.88 (s, 3H), 2.51 (dd, J = 13.2, 11.7 Hz, 1H), 2.42 (dd, J = 13.2, 8.3 Hz, 1H), 1.69 (s, 3H) ppm. ESI-MS m/z cale. 475.0922, found 476.4 (M+l)⁺; 474.4 (M-l)'.

Second Eluting Isomer: (25,37î,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (21, 29 mg, 6.7%) (further purified by chiral SFC using Chiralpak ID column). *H NMR (500 MHz, Chloroform-d) δ 8.56 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.08 (dd, J = 5.5, 2.2 Hz, 1H), 7.98 (d, J = 2.1 Hz, 1H), 7.86 (d, J = 4.4 Hz, 1H), 7.23 (dd, J = 8.8, 5.8 Hz, 1H), 7.01 (t, J = 8.4 Hz, 1H), 5.86 (d, J = 4.2 Hz, 1H), 4.80 (d, J = 9.7 Hz, 1H), 4.10 - 4.00 (m, 1H), 3.93 (s, 3H), 3.52 - 3.48 (m, 1H), 2.86 (dd, J = 13.9, 8.4 Hz, 1H), 2.16 - 2.07 (m, 1H), 1.64 (s, 2H) ppm. ESI-MS m/z cale. 475.0922, found 476.4 (M+l)⁺; 474.4 (M-l)'.

Third Eluting Isomer: re7-(27î,35,57?)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (22, 42 mg, 9.5%). Ή NMR (500 MHz, Chloroform-d) δ 8.87 (s, 1H), 8.33 (d, J = 5.6 Hz, 1H), 8.08 (dd, J = 5.6, 2.2 Hz, 1H), 7.98 (d, J = 2.2 Hz, 1H), 7.74 (d, J = 4.5 Hz, 1H), 7.12 (dd, J = 8.8, 5.8 Hz, 1H), 6.89 (t, J = 8.4 Hz, 1H), 5.79 (d, J = 4.5 Hz, 1H), 4.63 (d, J = 10.7 Hz, 1H), 3.85 (td, J = 11.2, 8.4

304

Hz, IH), 3.74 (s, 3H), 2.37 (dd, J = 13.2, 11.7 Hz, IH), 2.28 (dd, J = 13.1, 8.4 Hz, IH), 1.55 (s, 3H) ppm. ESI-MS m/z cale. 475.0922, found 476.4 (M+l)⁺; 474.4 (M-l)'.

Fourth Eluting Isomer: (2R,35,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (23, 40 mg, 8.8%).

Ή NMR (500 MHz, Chloroform-d) δ 8.43 (s, IH), 8.35 (d, J = 5.5 Hz, IH), 7.95 (dd, J = 5.5, 2.2 Hz, IH), 7.85 (d, J = 2.2 Hz, IH), 7.73 (d, J = 4.3 Hz, IH), 7.10 (dd, J = 8.8, 5.9 Hz, IH), 6.87 (t, J = 8.4 Hz, IH), 5.76 - 5.71 (m, IH), 4.67 (d, J = 9.7 Hz, IH), 3.97 - 3.87 (m, IH), 3.80 (s, 3H), 2.73 (dd, J = 13.9, 8.4 Hz, IH), 1.98 (dd, J = 13.9, 11.6 Hz, IH), 1.51 (s, 3H) ppm. ESI-MS m/z cale. 475.0922, found 476.4 (M+l)⁺; 474.4 (M-l)-.

Compound 22 — Solid Form A

A crystalline form of Compound 22, referred to herein as Form A, was generated by slow évaporation of a 1:1 2-methyltetrahydrofuran/heptane solution. Form A was characterized by XRPD and solid State NMR (¹³C and ¹⁹F) analysis.

The XRPD pattern of Form A is depicted in Figure 19, and the corresponding data are summarized in the following table:

Angle (° 20 ± 0.2)	Rel. Intensity (%)
7.7	48.9
9.2	95.9
10.4	100
12.9	44.8
13.8	9.9
14.7	13.4
15.7	46.2
16.1	27.4
18.4	46.0
19.8	26.5
21.7	23.6

305

Angle (° 20 ± 0.2)	Rel. Intensity (%)
22.3	13.6
24.0	23.8

The solid state ^,3C NMR spectrum of Form A is depicted in Figure 20, and the corresponding data are summarized in the following table:

Chemical Shift [ppm]	Rel. Intensity (%)
172.6	41.8
167.7	56.7
158.7	14.5
156.8	34.9
151.8	43.8
148.7	65.9
128.6	44.0
126.0	62.1
115.9	77.5
113.1	54.9
112.3	58.0
88.0	60.7
85.5	64.1
62.0	40.7
60.5	52.3
55.6	21.3
43.5	100.0
37.7	22.1
29.6	11.0
21.1	57.3
20.3	62.9

306

The solid State ^l9F NMR spectrum of Form A is depicted in Figure 21, and the corresponding data are summarized in the following table:

Chemical Shift [ppm]	Rel. Intensity
-82.2	11.7
-83.1	12.5
-111.7	1.8
-114.4	3.0

Compound 23 — Solid Form A

A crystalline form of Compound 23, referred to herein as Form A, was generated by slow évaporation of a 1:1 2-methyltetrahydrofuran/heptane solution. Form A was characterized by XRPD, solid State NMR (^,3C and ¹⁹F), and single-crystal X-ray analysis.

The XRPD pattern of Form A is depicted in Figure 22, and the corresponding data are summarized in the following table:

Angle (° 20 ± 0.2)	Rel. Intensity (%)
11.3	5.8
12.2	16.8
13.2	6.9
14.2	22.2
15.2	13.1
15.8	25.5
16.6	10.2
17.2	100
19.3	71.7
21.1	14.4
22.3	37.3
22.8	24.9

307

Angle (° 2Θ ± 0.2)	Rel. Intensity (%)
23.7	7.0
24.6	8.7
25.0	16.7
25.1	19.7
25.9	10.9
27.1	5.3
27.9	13.2
30.6	31.6
34.4	6.7
39.4	11.5

The solid State ^l3C NMR spectrum of Form A is depicted in Figure 23, and the corresponding data are summarized in the following table:

Chemical Shift [ppm]	Rel. Intensity (%)
171.1	60.6
166.7	59.9
156.8	19.4
155.5	27.1
151.9	64.5
149.3	83.3
147.3	56.5
131.5	42.1
123.3	56.1
119.0	49.1
114.2	76.6
112.8	54.0
86.0	98.6

308

Chemical Shift [ppm]	Rel. Intensity (%)
85.0	39.0
61.7	36.4
61.0	54.8
44.4	53.9
41.6	88.6
20.0	100.0

The solid state ¹⁹F NMR spectrum of Form A is depicted in Figure 24, and the corresponding data are summarized in the following table:

Chemical Shift [ppm]	Rel. Intensity
-78.2	12.5
-113.5	3.7
-115.1	4.7

Crystals having Form A were grown for single-crystal X-ray analysis by dissolving ~1 mg of

Compound 23 material in 150 pL of methanol and allowing diffusion of heptane vapor over several days. The thermal ellipsoid plot, at 50% probability, is depicted in Figure 25, and the unit cell parameters are reported in the following table:

Ciystal System:	Monoclinic
Space Group:	P2i
a(Â)	7.8661(3)
b(Â)	7.9167(3)
c(Â)	16.8777(7)
a(°)	90
β(°)	98.487(2)
ï(°)	90
V(Â³)	1039.52(7)
Z	2

309

Température

173(2)K

The following compounds were made using a method similar to that described in Example 6, except that methylamine was used in place of ammonia in Step 7. In step 4, purification was performed by chiral SFC using a (R,R)-Whelk-Ol column, 5 pm particle size, 25 cm x 21.2 mm from Regis Technologies on a Minigram SFC instrument from Berger Instruments:

Cmpd No.	Compound Naine	LC/MS	NMR (shifts in ppm)
58	re/-(25,37?,5S)-4-[[3-(3chloro-4-fluoro-2-methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofu ran-2-carbonyl] amino] -N methyl-pyridine-2carboxamide (first eluting isomer by SFC on WhelkOl column, rt = 3.41 min)	ESI-MS m/z cale. 489.10785, found 490.4 (M+l)⁺; 488.4 (Μ-l)'; Rétention time: 3.21 minutes	Ή NMR (500 MHz, Chloroform-d) δ 8.62 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.18 (dd, J = 5.6, 2.2 Hz, 1H), 8.13 (s, 1H), 7.93 (d, J = 2.2 Hz, 1H), 7.25 (dd, J = 8.8, 5.8 Hz, 1H), 7.07 6.95 (m, 1H), 4.75 (d, J = 10.7 Hz, 1 H), 3.993.85 (m, 1H), 3.89 (s, 3H), 3.06 (d, J = 5.0 Hz, 3H), 2.51 (dd, J = 13.2, 11.7 Hz, 1H), 2.42 (dd, J = 13.2, 8.3 Hz, 1H), 1.68 (s, 3H) ppm.
59	re/-(2R,3S,55)-4-[[3-(3chloro-4-fluoro-2-methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofu ran-2-carbonyl]amino]-N-	ESI-MS m/z cale. 489.10785, found 490.4 (M+l)⁺; 488.4 (Μ-l)^-; Rétention time: 3.17 minutes	’H NMR (500 MHz, Chloroform-d) δ 8.48 (s, 1H), 8.36 (d, J = 5.5 Hz, 1H), 8.08 - 8.00 (m, 2H), 7.86 (d, J =

310

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
	methyl-pyridine-2- carboxamide (second eluting isomer by SFC on WhelkOl column, rt = 3.81 min)		2.2 Hz, 1H), 7.14 (dd, J = 8.8, 5.9 Hz, 1H), 6.92 (dd, J = 8.8, 8.1Hz, 1H), 4.71 (d, J = 9.7 Hz, 1H), 4.01-3.91 (m, 1H), 3.84 (s, 3H), 2.97 (d, J = 5.1 Hz, 3H), 2.77 (dd, J= 13.9, 8.4 Hz, 1H), 2.03 (dd, J = 13.8, 11.7 Hz, 1H), 1.56 (s, 2H) ppm.
60	re/-(2R,3S,5R)-4-[[3-(3chloro-4-fluoro-2-methoxyphenyl)-5-methyl-5- (trifluoromethyl)tetrahydrofii ran-2-carbonyl]amino]-Nmethyl-pyridine-2carboxamide (third eluting isomer by SFC on WhelkOl column, rt = 4.32 min)	ESI-MS m/z cale. 489.10785, found 490.4 (M+l)⁺; 488.4 (Μ-l)’; Rétention time: 3.22 minutes	^lH NMR (500 MHz, Chloroform-d) δ 8.54 (s, 1H), 8.36 (d, J = 5.5 Hz, 1H), 8.09 (dd, J = 5.6, 2.2 Hz, 1H), 8.05 (s, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.16 (dd, J = 8.8, 5.9 Hz, 1H), 6.93 (t, J = 8.4 Hz, 1H), 4.66 (d, J= 10.7 Hz, 1H), 3.85 (td, J= 11.3, 8.4 Hz, 1 H), 3.79 (s, 3H), 2.97 (d, J = 5.0 Hz, 3H), 2.41 (dd, J= 13.2, 11.7 Hz, 1H), 2.32 (dd, J = 13.2, 8.4 Hz, 1H), 1.59 (s, 3H) ppm.

311

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
61	reZ-(25,37?,57?)-4-[[3-(3chloro-4-fluoro-2-methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofu ran-2-carbonyl]amino]-Nmethyl-pyridine-2carboxamide (fourth eluting isomer by SFC on WhelkOl column, rt = 4.93 min)	ESI-MS m/z cale. 489.10785, found 490.4 (M+l)⁺; 488.4 (M-l)'; Rétention time: 3.16 minutes	Ή NMR (500 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.45 (d, J = 5.6 Hz, 1H), 8.12 (dd, J = 5.6, 2.2 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.23 (dd, J = 8.8, 5.8 Hz, 1H), 7.01 (dd, J = 8.7, 8.1 Hz, 1H), 4.80 (d, J = 9.7 Hz, 1H), 4.11-4.01 (m, 1H), 3.93 (s, 3H), 3.06 (d, J = 5.0 Hz, 3H), 2.91 2.82 (m, 1H), 2.162.07 (m, 1H), 1.64 (d, J = 1.1 Hz, 3H) ppm.

312

Example 7 rel-(2R, 35,45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (24) and rel(25,37?,47?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-methyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (25)

1) Trimethylboroxine, K₂CO₃, 2-MeTHF, Pd(amphos)CI₂, 60 'C, 100%

---------->-

2) LiOH.H₂O, MeOH, 89%

3) Ru(bpy)₃CI₂.6H₂O, pyridine, Tf₂O, blue LEDs, 55%

CF₃,„

Me''

4) n-BuLi, l₂, THF, -78’C, 69%

5) Etl, K₂CO₃, DMF, 50 °C, 76%

6) ArB(0H)₂, Pd(dppf)CI₂.DCM, aq. Na₂CO₃, dioxane, 71%

7) Pd(OH)₂, H₂ (60 bar), 60 °C, 58%

CF₃,„

Me''

racemic

9) (COCI)₂, DCM, DMF (cat.), 0 °C-RT then NEt₃, methyl 4-aminopyridine-2carboxylate, 2-MeTHF, 65%

10)7NNH₃, MeOH

11) SFC

8) KOf-Bu, THF, 0 ·

C, 31%

Step 1:

A solution of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (25 g of 50% w/w, 99.57 mmol) and potassium carbonate (21.5 g, 155.6 mmol) in water (40 mL) were added to a solution of methyl 4-bromofuran-2-carboxylate (10 g, 48.78 mmol) in 2-methyltetrahydrofuran (200 mL) and the reaction mixture degassed for 10 mins. Pd(amphos)Clz (1.5 g, 2.12 mmol) was added and the reaction mixture further degassed for 5 mins before the reaction was heated at 60 °C for 4 hours. The reaction was then cooled to ambient température, filtered through a small pad of celite and washed with MTBE (200 mL). The layers were separated and the aqueous layer extracted with MTBE (2 x 20 mL). The combined organic extracts were dried (NazSCh) and carefully concentrated in vacuo (approximately 90 mBar, no heating) to give methyl 4-methylfuran-2-carboxylate (6.836 g, 100%) which was used without any further purification.

Step 2:

313

To a solution of methyl 4-methylfuran-2-carboxylate (10 g, 48.78 mmol) in THF (40 mL), water (40 mL) and MeOH (10 mL) stirring at ambient température was added LÎOH-H2O (12.3 g, 293.11 mmol). The reaction was stirred for 2 hours before MTBE (100 mL) and water (100 mL) were added. The aqueous layer was isolated and treated with 6 N HCl solution to adjust the pH to about 3-4, then extracted with MTBE (2 x 50 mL). The combined organic layers were concentrated in vacuo to afford 4-methylfuran-2-carboxylic acid (5.5 g, 89%) as an off-white solid. ’H NMR (400 MHz, DMSO-dô) δ 12.92 (s, 1H), 7.65 (s, 1H), 7.07 (s, 1H), 2.00 (s, 3H) ppm.

Step 3:

To a solution of 4-methylfuran-2-carboxylic acid (150 mg, 1.19 mmol) in DCE (25 mL) was added tris(2, 2’-bipyridyl)dichlororuthenium(II) hexahydrate (17 mg, 0.023 mmol) and pyridine (288 pL, 3.56 mmol) then triflic anhydride (599 pL, 3.56 mmol) dropwise over 5 mins. The mixture was irradiated with blue LEDs for 2 hours at ambient température stirring at 800 rpm, using a PennPhD Photoreacter m2 (using 450 nm blue LED lights) and an EvoluChem™ PhotoRedOx Box device (using 455 nm blue LED lights) used in parallel. This process was repeated in 5 batches and the crude material combined for purification. The combined reaction mixtures were washed with IM NaCCh (2 x 80 mL) and the organic layer discarded. The combined aqueous layers were acidified to pH 2 using IM HCl and extracted with MTBE (2 x 50 mL). The combined organic layers were washed with brine (20 mL), dried (MgSCL) and concentrated in vacuo. The residue was redissolved in a small amount of diethyl ether and slowly triturated by addition of petroleum ether and allowed to stir. The liquid was decanted to afford 4-methyl-5-(trifluoromethyl)furan-2carboxylic acid (700 mg at 90% purity, 55%) as an off-white solid. *H NMR (400 MHz, DMSO-dô) δ 13.75 (brs, 1H), 7.29 (d, J = 1.2 Hz, 1H), 2.19 (q, J = 2.0 Hz, 3H) ppm. ESI-MS m/z cale. 194.01907, found 193.3 (M-l)‘.

Step 4:

To a solution of 4-methyl-5-(trifluoromethyl)furan-2-carboxylic acid (2.8 g, 14.03 mmol) in THF (40 mL) stirring at -78 °C was added n-BuLi (14 mL of 2.5 M in hexanes, 35.00 mmol). The solution was stirred at -78 °C for 20 mins before a solution of iodine (3.9 g, 15.37 mmol) in THF (5 mL) was added. The mixture was allowed to warm to ambient température, then partitioned between MTBE (80 mL) and water (100 mL). The organic layer was discarded and the aqueous layer acidified to pH 2 with 1 M HCl and extracted with MTBE (2 x 40 mL). The combined organic

314 fractions were washed with brine (20 mL), dried (MgSO₄) and concentrated in vacuo. Purification by flash chromatography (40 g S1O2, 0 to 100% MTBE in petroleum ether) gave 3-iodo-4-methyl-5(trifluoromethyl)furan-2-carboxylic acid (3.1 g, 69%) as an oil. ESI-MS m/z cale. 319.9157, found 319.3 (M-l)-.

Step 5:

To a solution of 3-iodo-4-methyl-5-(trifluoromethyl)furan-2-carboxylic acid (300 mg at 71% purity, 0.6656 mmol) in DMF (5 mL) was added potassium carbonate (276 mg, 2.00 mmol) and iodoethane (160 pL, 2.00 mmol). The mixture was heated at 50 °C for 2 hours then cooled to ambient température and partitioned between MTBE (40 mL) and water (80 mL). The layers were separated and the aqueous layer further extracted with MTBE (30 mL). The combined organic fractions were washed with brine (1 x 20 mL), dried (MgSO₄) and concentrated in vacuo. Purification by flash chromatography (80 g S1O2, 0 to 100% EtOAc in petroleum ether) gave ethyl 3-iodo-4-methyl-5-(trifluoromethyl)furan-2-carboxylate (220 mg at 80% purity, 76%) as an oil. ’H NMR (500 MHz, Chloroform-d) δ 4.42 (dq, J = 20.1, 7.1 Hz, 2H), 2.24 - 2.11 (m, 3H), 1.42 (dt, J = 20.2, 7.1 Hz, 3H) ppm.

Step 6:

To a solution of ethyl 3-iodo-4-methyl-5-(trifluoromethyl)furan-2-carboxylate (500 mg at 71% purity, 1.01 mmol) in dioxane (2 mL) was added (3,4-difluoro-2-methoxy-phenyl)boronic acid (476 mg, 2.533 mmol), Pd(dppf)C12-DCM (83 mg, 0.10 mmol) and aqueous sodium carbonate (2 mL of 2 M, 4.00 mmol). The mixture was heated at 80 °C for 1 hour before being cooled to ambient température and partitioned between MTBE (30 mL) and water (30 mL). The layers were separated and the aqueous layer further extracted with MTBE (10 mL). The combined organic fractions were washed with brine (1 x 20 mL), dried (MgSO₄) and concentrated in vacuo. Purification by flash chromatography (12 g SiCh, 0 to 100% EtOAc in petroleum ether) gave ethyl 3-(3,4-difluoro-2methoxy-phenyl)-4-methyl-5-(trifluoromethyl)furan-2-carboxylate (330 mg at 80% purity, 71%) as an oil. ESI-MS m/z cale. 364.0734, found 365.4 (M+l)⁺.

Step 7:

A solution of ethyl 3-(3,4-difluoro-2-methoxy-phenyl)-4-methyl-5-(trifluoromethyl)furan-2carboxylate (410 mg at 70% purity, 0.7879 mmol) in éthanol (2 mL) was passed through a 70 mm palladium hydroxide (90.52 mg, 0.64 mmol) CatCart® on an H-Cube® at 60 °C and 60 bar pressure

315 of hydrogen. The mixture was recirculated for 30 hours before being concentrated in vacuo to give ethyl rac-(2S,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (300 mg at 75% purity, 58%), which was used in the next step without further purification. ESI-MS m/z cale. 368.1047, found 369.3 (M+l)⁺.

Step 8:

To a solution of ethyl rac-(2S,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4-methyI-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (900 mg at 80% purity, 2.44 mmol) in THF (5 mL) stirring at 0 °C was added KOf-Bu (822 mg, 7.33 mmol). The reaction was stirred for 30 mins before being diluted with MTBE (5 mL) and quenched by addition of 1 M HCl. The layers were separated and the aqueous layer was further extracted with MTBE (5 mL). The combined organic layers were dried (MgSO₄), filtered and concentrated in vacuo to give rac-(25,35,45,55)-3-(3,4difluoro-2-methoxy-phenyl)-4-methyl-5-(trifluoromethyl)tetrahydrofiiran-2-carboxylic acid (500 mg at 52% purity, 31%) as an oil, which was used without further purification. ESI-MS m/z cale. 340.0734, found 339.4 (M-l)’.

Step 9:

To an ice-cooled solution of rac-(2R,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (380 mg at 52% purity, 0.58 mmol) in 2-methyltetrahydrofuran (5 mL) was added a solution of DMF (5 mg, 0.068 mmol) in 2methyltetrahydrofuran and oxalyl chloride (116 pL, 1.330 mmol) dropwise. The mixture was warmed to ambient température over 30 mins then concentrated in vacuo. The residue was redissolved in 2-methyltetrahydrofuran (5 mL) and methyl 4-aminopyridine-2-carboxylate (114 mg, 0.75 mmol) and NEt₃ (162 pL, 1.16 mmol) were added. The mixture was warmed to ambient température over 1 hour before being quenched by the addition of water (10 mL). The layers were separated and the aqueous layer extracted with EtOAc (2x10 mL). The combined organic layers were dried (MgSO₄), filtered and concentrated in vacuo to give methyl rac-(2R,35,45,55)-4-[[3(3,4-difluoro-2-methoxy-phenyl)-4-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxylate (210 mg at 86% purity, 65%). ESI-MS m/z cale. 474.1214, found 475.5 (M+l)⁺.

Step 10 and 11:

316

To a solution of methyl rac-(27?,35,45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-methyl5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (200 mg at 86% purity, 0.42 mmol) in MeOH (2 mL) was added methanolic ammonia (322 pL of 7 M, 2.25 mmol). The mixture was stirred at ambient température for 6 hours before being concentrated in vacuo to afford rac-(2R,35,45,51?)-4-[[3-(3,4-difIuoro-2-methoxy-phenyl)-4-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide. The residue was purified by chiral SFC using a Chiralpak AS-H column, 5 pm particle size, 25 cm x 10 mm from Daicel on a Minigram SFC instrument from Berger Instruments to give:

First Eluting Isomer: rel-(2R,35,45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-methyl5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (24, 60 mg). Ή NMR (500 MHz, Chloroform-d) δ 8.75 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.14 (dd, J = 5.5, 2.2 Hz, 1H), 8.02 (d, J = 2.2 Hz, 1H), 7.85 (s, 1H), 7.10 (ddd, J = 7.9, 5.4, 2.0 Hz, 1H), 6.94 (td, J = 9.2, 7.5 Hz, 1H), 5.60 (s, 1H), 5.07 (d, J = 10.7 Hz, 1H), 4.78 - 4.65 (m, 1H), 4.08 - 3.94 (m, 4H), 3.09 - 2.94 (m, 1H), 0.83 (dt, J = 7.3, 2.0 Hz, 3H) ppm. ESI-MS m/z cale. 459.12173, found 460.2 (M+l)⁺.

Second Eluting Isomer: re/-(25,37?,47?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (25, 68 mg). Ή NMR (500 MHz, Chloroform-d) δ 8.75 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.14 (dd, J = 5.5, 2.2 Hz, 1H), 8.02 (d, J = 2.2 Hz, 1H), 7.85 (s, 1H), 7.10 (ddd, J = 7.9, 5.4, 2.0 Hz, 1H), 6.94 (td, J = 9.2, 7.5 Hz, 1H), 5.60 (s, 1H), 5.07 (d, J = 10.7 Hz, 1H), 4.78 - 4.65 (m, 1H), 4.08 - 3.94 (m, 4H), 3.09 2.94 (m, 1H), 0.83 (dt, J = 7.3, 2.0 Hz, 3H) ppm. ESI-MS m/z cale. 459.12173, found 460.2 (M+l)⁺.

Compound 25 - Solid Form A

Compound 25 was dissolved in a 1:1 mixture of 2-methyltetrahydrofuran and heptane, and the mixture was subjected to slow évaporation of the solvent, producing a crystalline form of Compound 25, which is referred to herein as Form A. Form A was characterized by XRPD and solid State NMR (^,3C and ¹⁹F) analysis.

The XRPD pattern of Form A is depicted in Figure 26, and the corresponding data are summarized in the following table:

317

Angle (° 20 ± 0.2)	Rel. Intensity (%)
3.2	5.43
6.8	29.74
7.9	100
11.0	13.22
11.8	4.16
13.7	26.93
13.8	36.08
15.1	18
15.9	17.42
16.3	16.21
17.5	3.92
18.6	3.77
19.0	8.7
19.5	6.95
21.6	7.98
21.9	6.78
23.2	11.32
27.0	5.04
27.4	24.34
29.4	4.93
30.3	3.29

318

Example 8 (25,35,45,55)-4-[[3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (27)

To a solution of (25,35,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (7, 280 mg, 0.59 mmol) in DCM (6 mL) stirring at 0 °C was added boron tribromide (830.0 pL of 1 M, 0.83 mmol). The mixture was warmed slowly to ambient température and stirred for 24 hours. The mixture was then cooled to 0 °C and additional boron tribromide (400 pL of 1 M, 0.40 mmol) was added. An additional portion of boron tribromide (400 pL of 1 M, 0.40 mmol) was added at 0 °C, after which the mixture was warmed to and stirred at ambient température for 16 hours. Subsequently, water and saturated aqueous sodium bicarbonate solution were added and the mixture was stirred for 30 mins. The aqueous layer was isolated and extracted with DCM, and the combined organic layers were dried and concentrated in vacuo. Purification by flash chromatography (12 g SiCh, 0 to 70% EtOAc in heptane) gave (25,35,45,55)-4-[[3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (162 mg, 60%) (27). ESI-MS m/z cale. 459.12, found 460.7 (M+l)⁺; 458.8 (M-l)‘. Ή NMR (500 MHz, DMSO-A) δ 10.73 (s, 1H), 10.46 (s, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.27 (s, 1H), 8.06 (s, 1H), 7.86 - 7.82 (m, 1H), 7.61 (s, 1H), 7.06 - 7.00 (m, 1H), 6.89 - 6.83 (m, 1H), 5.15 - 5.08 (m, 1H), 4.29 - 4.22 (m, 1H), 2.86 - 2.80 (m, 1H), 1.61 (s, 3H), 0.72 (d, J = 7.2 Hz, 3H) ppm.

The following compound was made using a method similar to that described in Example 8, except that (25,35,45,55)- 4-[[3-(4-fluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide was used as the starting

319 material in place of (27?,35,45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
62	(27?,35,45,57?)-4-[[3-(4- fluoro-2-hydroxy-phenyl)- 4,5-dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide	ESI-MS m/z cale. 489.10785, found 490.4 (M+l)⁺; 488.4 (Μ-l)'; Rétention time: 3.21 minutes	Ή NMR (500 MHz, DMSO-î/ô) δ: 10.80 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.26 (d, J = 2.1 Hz, 1H), 8.07 (d, J = 2.9 Hz, 1H), 7.84 (dd, J = 2.2, 5.5 Hz, 1H), 7.62 (d, J = 2.9 Hz, 1H), 7.20 (t, 7= 8.5 Hz, 1H), 6.62 (m, 2H), 5.10 (d, 7= 10.4 Hz, 1H), 4.20 (dd, J = 7.5, 10.5 Hz, 1H), 2.83 (p, J = 7.4 Hz, 1H), 1.59 (br s, 3H), 0.70 (dd,7= 2.8, 7.6 Hz, 3H) ppm. Hydroxyl (OH) proton not observed.

320

Example 9 re/-(25,37?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (63) and re/-(27?,35,5/?)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (64)

1) TiCI₄, DCM, Et₃N, -65 °C then

1,1,1-trifluoro-2butanone, Ti(O/Pr)₄, DCM -65 °C, 51%

Et CF₃O O

HoA/y-Y_OEt

N₂

2) Rh(OAc)₂, PhMe, 100 °C, 97%

3) Tf₂O, DIPEA, DCM, -65 °C, 98%

4) ArBpin, PhMe, MeOH, H₂O, Na₂CO₃, Pd(PPh₃)₄, 80 °C, 61%

5) EtOH, 10% Pd/C, H₂(50 bar), 80 °C, 94%

Âr (rac)

6)KOt-Bu, tBuOH, 99%

7) DCM, DMF (cat.), (COCI)₂, 0 ⁰C then DIPEA, methyl 4aminopyridine-2carboxylate, 56%* 8) 13 M NH₃ in MeOH, 56%

9) SFC

63, first eluting isomer 64, second eluting isomer

Step 1:

To a solution of ethyl 2-diazo-3-oxo-butanoate (12 g, 76.9 mmol) in DCM (420 mL) stirring at -65 °C was added triethylamine (8.71 g, 12 mL, 86.1 mmol) and titanium tetrachloride (85 mL of 1 M, 85.0 mmol). The resulting deep red solution was stirred at -65 °C for 1 hour. A solution of l,l,l-trifluoro-2-butanone (9.75 g, 10.5 mL, 77.4 mmol) and Ti(Oi-Pr)4 (23.1 g, 24 mL, 81.3 mmol) in DCM (100 mL) was added dropwise and the resulting mixture was stirred at -65 °C for 2 hours then allowed to warm to ambient température ovemight. The reaction mixture was quenched

321 with saturated NH4CI solution (200 mL) and extracted with DCM (3 x 150 mL). The combined organic phases were dried over MgSCU, filtered and concentrated in vacuo. Purification by reversephase flash chromatography (Cl8 silica, acetonitrile/water 0-70%) afforded ethyl 2-diazo-5hydroxy-3-oxo-5-(trifluoromethyl)heptanoate ( 11.21 g, 51 %) as a yellow liquid. ’H NMR (400 MHz, DMSO-dô) δ 5.99 (s, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.28 (d, J = 15.4 Hz, 1H), 3.16 (d, J = 15.4 Hz, 1H), 1.84 (dp, J = 25.7, 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H), 0.93 (td, J = 7.5, 1.2 Hz, 3H) ppm; ’⁹FNMR (376 MHz, DMSO-d₆) δ -78.78 ppm. ESI-MS m/z cale. 282.0827, found 282.95 (M+l)⁺.

Step 2:

To a stirred suspension of rhodium(II) acetate (89 mg, 0.2014 mmol) in toluene (90 mL) at 100 °C was added a solution of ethyl 2-diazo-5-hydroxy-3-oxo-5-(trifluoromethyl)heptanoate (5.8 g, 20.1 mmol) in toluene (200 mL). The reaction mixture was stirred at 100 °C for 1 hour before being cooled to ambient température and filtered through a Celite pad, washing with DCM (6 x 50 mL). The combined filtrâtes were concentrated in vacuo to afford ethyl 5-ethyl-3-oxo-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (5.22 g, 97%, mixture of four isomers) as a yellow oil. ’H NMR (400 MHz, DMSO-d₆) δ 4.99 (d, J = 62.3 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.18 2.98 (m, 1H), 2.90 (dd, J = 19.2, 14.4 Hz, 1H), 2.03 - 1.79 (m, 2H), 1.21 (q, J = 7.2 Hz, 3H), 1.05 (td, J = 7.4, 0.9 Hz, 3H), 0.97 (td, J = 7.5, 1.0 Hz, 1H) ppm; ’⁹F NMR (376 MHz, DMSO-d₆) δ 78.68, -79.35 ppm.

Step 3:

To a solution of ethyl 5-ethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (4.25 g, 14.7 mmol) in DCM (120 mL) stirring at -65 °C was added DIPEA (5.79 g, 7.8 mL, 44.8 mmol) and trifluoromethylsulfonyl trifluoromethanesulfonate (5.37 g, 3.2 mL, 19.0 mmol). The resulting orange solution was stirred at -65 °C for 3 hours before being quenched with saturated aqueous NaHCCh solution (80 mL) and extracted with DCM (4 x 60 mL). The combined organic phases were dried over MgSO₄, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (500 mL) and washed with 1 M HCl (5 x 100 mL). The organic phase was dried over Na2SÛ4, filtered and concentrated to afford ethyl 2-ethyl-2-(trifluoromethyl)-4(trifluoromethylsulfonyloxy)-3H-fiiran-5-carboxylate (5.84 g, 98%). ’H NMR (300 MHz, Chloroform-d) δ 4.39 (q, J = 7.2 Hz, 2H), 3.29 (d, J = 17.5 Hz, 1H), 3.09 (d, J = 17.5 Hz, 1H), 2.19

322

-2.01 (m, IH), 1.81 (dd, J = 14.6, 7.4 Hz, IH), 1.39 (t, J = 7.2 Hz, 3H), 1.16 - 1.03 (m, 3H) ppm; ’⁹F NMR (376 MHz, Chloroform-d) δ -73.84, -82.96 ppm.

Step 4:

Ethyl 2-ethyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (5.8 g, 14.3 mmol), 2-(3,4-difluoro-2-methoxy-phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (5.78 g, 21.4 mmol), sodium carbonate (3.78 g, 35.7 mmol), toluene (45 mL), MeOH (4.5 mL) and water (4.5 mL) were placed in a 120 mL glass pressure reactor. The mixture was degassed and purged with argon three times. Pd(PPh₃)4 (1.24 g, 1.07 mmol) was added and the reactor was sealed and the mixture stirred at 80 °C ovemight before being cooled to ambient température, diluted with EtOAc (50 mL) and fïltered through a pad of Celite, washing with EtOAc (6 x 50 mL). Combined filtrâtes were concentrated in vacuo. Purification by flash chromatography (S1O2, 0-5% EtOAc in hexane) gave ethyl 4-(3,4-difluoro-2-methoxy-phenyl)-2-ethyl-2-(trifluoromethyl)-3Hfuran-5-carboxylate (2.7 g, 45%) as a yellow oil. Repurification of mixed fractions by flash chromatography (S1O2, 0-10% EtOAc in hexane) gave ethyl 4-(3,4-difluoro-2-methoxy-phenyl)-2ethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (0.9 g, 16%) as a light-yellow oil. ’H NMR (300 MHz, Chloroform-d) δ 6.97 - 6.82 (m, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.92 (d, J = 2.0 Hz, 3H), 3.32 (d, J = 17.7 Hz, IH), 3.09 (dd, J = 17.7, 1.0 Hz, IH), 2.13 (dq, J = 14.9, 7.5 Hz, IH), 1.82 (dq, J = 14.7, 7.4 Hz, IH), 1.15 (dt, J = 12.4, 7.4 Hz, 6H) ppm; ¹⁹F NMR (376 MHz, Chloroform-d) δ 82.50, -135.66 (ddd, J = 20.2, 9.4, 6.3 Hz), -154.83 - -154.95 (m) ppm. ESI-MS m/z cale. 380.1047, found 381.0 (M+l)⁺.

Step 5:

A solution of ethyl 4-(3,4-difluoro-2-methoxy-phenyl)-2-ethyl-2-(trifluoromethyl)-3H-furan5-carboxylate (240 mg, 0.60 mmol) in éthanol (15 mL) was hydrogenated in an H-cube apparatus using a Pd/C catalytic cartridge at 80 °C and 50 bar, with flow rate of 0.5 ml/min. The mixture was concentrated in vacuo to afford ethyl rac-(2S,35,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (185 mg, 77%, mixture of four isomers) as a white solid; ’H NMR (300 MHz, Chloroform-d) δ 7.06 - 6.71 (m, 2H), 4.95 (d, J = 9.1 Hz, IH), 4.29 4.15 (m, IH), 4.09 (d, J = 2.9 Hz, 3H), 3.82 (dddd, J = 17.9, 10.8, 7.1, 3.7 Hz, 2H), 2.77 (t, J = 12.5 Hz, IH), 2.15 (dd, J = 12.4, 7.3 Hz, IH), 1.93 (dq, J = 13.8, 7.3 Hz, 2H), 1.11 (td, J = 7.6, 1.3 Hz,

323

3H), 0.97 (t, J = 7.2 Hz, 3H) ppm; ¹⁹F NMR (376 MHz, Chloroform-d) δ -76.93, -79.92, -136.98 (ddd, J = 19.4, 9.6, 5.4 Hz), -153.95 (d, J = 12.5 Hz), -154.80 (ddt, J = 19.5, 6.2, 2.9 Hz) ppm.

Step 6:

To a solution of ethyl rac-(25,3S,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (100 mg, 0.25 mmol) in teri-butanol (3 mL) at ambient température was added potassium 2-methylpropan-2-olate (84 mg, 0.75 mmol). The reaction mixture was stirred for 1 hour before being quenched with saturated aqueous NH4CI solution (1 mL) and extracted with EtOAc (3x5 mL). The combined organic layers were dried overNa2SC>4, filtered and concentrated in vacuo to afford rac-(27?,35,57?)-3-(3,4-difluoro-2methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (93 mg, 99%, mixture of four isomers) as a yellow oil. Ή NMR (300 MHz, Chloroform-d) δ 7.02 - 6.83 (m, 2H), 4.68 (d, J = 10.8 Hz, 1H), 3.98 (d, J = 2.6 Hz, 3H), 3.76 (q, J = 10.6 Hz, 1H), 2.55 - 2.33 (m, 2H), 1.95 (dt, J = 14.7, 7.3 Hz, 1H), 1.79 (dq, J = 14.6, 7.4 Hz, 1H), 1.12 (t, J = 7.4 Hz, 3H) ppm; ¹⁹F NMR (376 MHz, Chloroform-d) δ -77.01, -79.71, -79.93, -137.04 (ddd, J = 19.3, 9.5, 5.6 Hz), -153.72 (d, J = 20.7 Hz), -153.92 (ddd, J = 19.5, 5.0, 2.6 Hz), 154.79 (d, J = 19.5 Hz) ppm. ESI-MS m/z cale. 354.089, found 353.4 (M-l)'.

Step 7:

To a solution of rac-(27î,3S,5/?)-3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (290 mg, 0.8186 mmol) in DCM (6 mL) stirring at 0 °C was added a catalytic amount of DMF (15.1 mg, 16 pL, 0.21 mmol) and oxalyl chloride (291 mg, 194 pL, 2.29 mmol). The mixture was stirred at 0 °C for 2 hours then concentrated in vacuo and azeotroped with DCM (3x5 mL). The residue was taken up in DCM (6 mL) and the resulting solution added to ice-cooled solution of methyl 4-aminopyridine-2-carboxylate (137 mg, 0.9004 mmol) and DIPEA (445.20 mg, 0.6 mL, 3.4447 mmol) in DCM (6 mL). The resulting mixture was stirred at 0 °C for 1 hour and then 60 hours at ambient température. The mixture was poured into water (10 mL) and extracted with DCM (3x10 mL). The combined organic layers were dried over Na2SÛ4, filtered and concentrated. Purification using flash chromatography (S1O2, 0 to 60% EtOAc in hexane) gave methyl rac-(27?,35',51?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (223 mg, 56%, mixture of four isomers) as a white foam. *H NMR (300 MHz, Chloroform-d) δ 8.65 (d, J = 5.5 Hz,

324

1H), 8.53 (s, 1H), 8.10 - 8.06 (m, 1H), 7.96 (dd, J = 5.5, 2.2 Hz, 1H), 7.08 - 6.86 (m, 2H), 4.82 (d, J = 10.9 Hz, 1H), 4.03 (s, 3H), 4.00 (d, J = 2.6 Hz, 3H), 3.75 (td, J = 11.1, 9.0 Hz, 1H), 2.63 - 2.38 (m, 2H), 2.18 - 1.84 (m, 2H), 1.24 - 1.12 (m, 3H) ppm; ^l9F NMR (376 MHz, Chloroform-d) δ 76.90, -79.76, -136.20 (ddd, J = 19.2, 9.1, 5.7 Hz), -136.61 (ddd, J = 19.3, 9.4, 5.6 Hz), -153.43 -153.56 (m), -153.95 - -154.06 (m) ppm. ESI-MS m/z cale. 488.1371, found 489.2 (M+l)⁺; 487.1 (M-l)’.

Step 8:

Methyl rac-(22?,35,5J?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (200 mg, 0.41 mmol) was dissolved in methanolic ammonia (2.2 mL of 13 M, 28.6 mmol). The solution was stirred at ambient température ovemight then concentrated in vacuo and the residue azeotroped with MeOH (3x5 mL) to give rac-(2J?,35,57î)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5(trifIuoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (108 mg, 56%, mixture of four isomers) as a light-yellow solid. Ή NMR (300 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.19 (dd, J = 5.6, 2.3 Hz, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.09 - 6.85 (m, 2H), 5.60 (s, 1H), 4.80 (d, J = 10.9 Hz, 1H), 4.00 (d, J = 2.6 Hz, 3H), 3.74 (q, J = 10.8 Hz, 1H), 2.63 - 2.37 (m, 2H), 1.99 (ddt, J = 37.8, 14.5, 7.3 Hz, 2H), 1.18 (t, J = 7.5 Hz, 3H) ppm; ^I9F NMR (376 MHz, Chloroform-d) δ -76.93, -79.78, -136.32 (ddd, J = 19.5, 9.5, 5.8 Hz), 136.69 (ddd, J = 19.3, 9.4, 5.6 Hz), -153.54 (dd, J = 19.1, 6.3 Hz), -154.05 (d, J = 19.6 Hz) ppm. ESI-MS m/z cale. 473.1374, found 474.15 (M+l)⁺; 472.15 (M-l)’.

Step 9:

rac-(27?,3S,5Æ)-4-[[3-(3,4-difluoro-2-methoxy-phenyI)-5-ethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (108 mg, 0.23 mmol) was separated by chiral SFC using a Lux Cellulose-2 column, 5um particle size, 25 cm x 10 mm from Phenomenex, Inc. to give two single isomers of unknown absolute configuration:

First Eluting Isomer (rt = 3.22 min): rel-{2S,37?,5S)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (63, 29 mg, 27%); ESI-MS m/z cale. 473.1374, found 474.4 (M+l)⁺ and 472.4 (M-l)'.

325

Second Eluting Isomer (rt = 4.63 min): reZ-(27?,3S,57?)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (64, 35 mg, 32%); ESI-MS m/z cale. 473.1374, found 474.4 (M+l)⁺ and 472.4 (M-l)'.

The following compounds were made using a method similar to that described in Example 9, 5 except that trimethylacetaldehyde was used as the starting material in place of l,l,l-trifluoro-2butanone in step 1. In step 9, purification was performed by chiral SFC using a (R,R)-Whelk-Ol column, 5 pm particle size, 25 cm x 21.2 mm from Regis Technologies on a Minigram SFC instrument from Berger Instruments:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
65	reZ-(25,37?,55)-4-[[5-tertbutyl-3-(3,4-difluoro-2methoxy- phenyl)tetrahydrofuran-2carbonyl] amino]pyridine-2carboxamide (first eluting isomer by SFC on WhelkOl column, rt = 1.18 min)	ESI-MS m/z cale. 433.1813, found 434.2 (M+l)⁺; 432.3 (M-l)-; Rétention time: 3.23 minutes	Ή NMR (500 MHz, Chloroform-d) δ 8.62 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.18 (dd, J = 5.6, 2.2 Hz, 1H), 8.13 (s, 1H), 7.93 (d, J = 2.2 Hz, 1H), 7.25 (dd, J = 8.8, 5.8 Hz, 1H), 7.07 6.95 (m, 1H), 4.75 (d, J = 10.7 Hz, 1 H), 3.993.85 (m, 1H), 3.89 (s, 3H), 3.06 (d, J = 5.0 Hz, 3H), 2.51 (dd, J = 13.2, 11.7 Hz, 1H), 2.42 (dd, J = 13.2,8.3 Hz, 1H), 1.68 (s, 3H) ppm.
66	rel-(2R,3S,5R)-4-[[5-tertbutyl-3 -(3,4-difluoro-2methoxy-	ESI-MS m/z cale. 433.1813, found 434.2 (M+l)⁺; 432.3 (M-l)-;	*H NMR (500 MHz, Chloroform-d) δ 8.48 (s, 1H), 8.36 (d, J = 5.5

326

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
	phenyl)tetrahydrofuran-2carbonyl] amino]pyridine-2carboxamide (second eluting isomer by SFC on WhelkOl column, rt = 1.68 min)	Rétention time: 3.23 minutes	Hz, 1H), 8.08 - 8.00 (m, 2H), 7.86 (d, J = 2.2 Hz, 1H), 7.14 (dd, J = 8.8, 5.9 Hz, 1H), 6.92 (dd, J = 8.8, 8.1 Hz, 1H), 4.71 (d, J = 9.7 Hz, 1H), 4.01-3.91 (m, 1H), 3.84 (s, 3H), 2.97 (d, J = 5.1 Hz, 3H), 2.77 (dd, J= 13.9, 8.4 Hz, 1H), 2.03 (dd, J = 13.8, 11.7 Hz, 1H), 1.56 (s, 2H) ppm.

327

Example 10 reZ-(2S,37?,5S)-4-[[3-(4-fluoro-2-methoxy-phenyI)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (67) and re/-(27?,35',57?)-4-[[3-(4-fluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (68)

1)Tf₂O. DIPEA, DCM, -78 ’C

2) ArB(OH)₂, PhMe, MeOH, H₂O, Na₂CO₃, Pd(PPh₃)₄, 80 °C, 68% over two steps

Ar

3) EtOH, 10% Pd/C, H₂(1 atm), 93%

5) DCM, DMF (cat.), (COCI)₂ then

NEt₃, methyl 4aminopyridine-2-

Âr

4) KOt-Bu, t-BuOH

Âr carboxylate, DMAP, DCM, 49% _FaC/

6) 7M NH₃ in .

MeOH Âr

NH₂ (rac) 9:1 dr 9:1 dr

7) SFC

67, fîrst eluting isomer

68, second eluting isomer

Step 1:

Triflic anhydride (1.5 mL, 8.92 mmol) was added dropwise to a solution of ethyl 5-methyl-3oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.66 g, 6.91 mmol) and DIPEA (3.6 mL,

20.67 mmol) in DCM (50 mL) stirring at -78 °C. After 3 hours saturated aqueous NalICCh was added, the layers separated and the aqueous layer extracted with DCM. The combined organic layers were dried (MgSCU), filtered and concentrated in vacuo to give ethyl 2-methyl-2-(trifluoromethyl)4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (2.573 g), which was used in the next step without further purification.

Step 2:

328

A solution of ethyl 2-methyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5carboxylate (2.573 g, 6.91 mmol), (4-fluoro-2-methoxy-phenyl)boronic acid (1.84 g, 10.83 mmol), Pd(PPh3)4 (600 mg, 0.52 mmol) and Na₂COj (1.8 g, 16.98 mmol) in PhMe (30 mL), MeOH (3 mL) and H₂O (3 mL) was degassed, then heated at 80 °C for 16 hours. The reaction was cooled to ambient température, diluted with EtOAc, the layers separated and the organic layer washed with brine, dried (MgSO₄), filtered and concentrated in vacuo. Purification by flash chromatography (80 g SiO₂, 0 to 20% EtOAc in petrol) gave ethyl 4-(4-fluoro-2-methoxy-phenyl)-2-methyl-2(trifluoromethyl)-3H-furan-5-carboxylate (1.64 g, 68% over two steps) as a yellow oil. ESI-MS m/z cale. 348.09848, found 349.2 (M+l)⁺.

Step 3:

EtOH (45 mL) was added to a flash containing ethyl 4-(4-fluoro-2-methoxy-phenyl)-2methyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (1.64 g, 4.71 mmol) and Pd/C (500 mg, 0.47 mmol). The mixture was degassed then stirred under a balloon of hydrogen for 24 hours. The mixture was filtered through Celite, washing with EtOH, and concentrated in vacuo. Pd/C (500 mg, 0.47 mmol) was added to the residue, and the mixture was suspended in EtOH (45 mL). The mixture was degassed then stirred under a balloon of hydrogen for 24 hours. The mixture was filtered through Celite, washing with EtOH, and concentrated in vacuo to give ethyl rac-(25,35,57?)-3-(4fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.53 g, 93%) as an off-white solid. ESI-MS m/z cale. 350.11414, found 351.2 (M+l)⁺.

Step 4:

A solution of ethyl rac-(2S,3S,57?)-3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (10 mg, 0.029 mmol) and KOt-Bu (192 mg, 1.711 mmol) in teri-butanol (0.3 mL) was stirred at ambient température for 30 mins. The reaction was diluted in EtOAc and quenched by addition of saturated aqueous NH4C1 solution. This process was repeated a further 19 times and the 20 reactions combined for the rest of the work-up. The layers were separated and the aqueous layer extracted with EtOAc. The aqueous layer was then acidified with 1 M HCl and extracted again. The combined organic layers were dried (MgSO₄), filtered and concentrated in vacuo to give rac-(27?,35,57?)-3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (186 mg) as an orange residue, in an 9:1 diastereomeric ratio, which was taken on to the next step without further purification.

329

Step 5:

To a solution of rac-(27?,3S,57?)-3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (222 mg in 9:1 diastereomeric ratio, 0.69 mmol) in DCM (7.0 mL) was added DMF (10 pL, 0.13 mmol) and oxalyl chloride (200 pL, 2.29 mmol). The reaction was stirred at ambient température for 30 mins before being concentrated in vacuo. The residue was diluted in DCM (5 mL) and added dropwise to a solution of methyl 4-aminopyridine-2carboxylate (160 mg, 1.05 mmol) and Et₃N (500 pL, 3.59 mmol) in DCM (2.0 mL) stirring at 0 °C. DMAP (8 mg, 0.06548 mmol) was added and the reaction stirred at 0 °C for 10 mins, then warmed to ambient température and stirred for a further 16 hours. The reaction mixture was diluted in DCM and washed with 2M HCl solution. The organic layer was dried (MgSCU), filtered and concentrated in vacuo directly onto silica gel. Purification by flash chromatography (40 g SiCh, 0 to 100% EtOAc in petrol) gave methyl rac-(27?,35,57?)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (154 mg, 49%) as a 9:1 mixture of diastereomers. ESI-MS m/z cale. 456.13083, found 457.3 (M+l)⁺; 455.2 (M-l)'.

Step 6:

Methyl rac-(27î,35,5J?)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (154 mg in a 9:1 mixture of diastereomers, 0.34 mmol) was dissolved in methanolic ammonia (2.0 mL of 7 M, 14.00 mmol) and the solution stirred at ambient température ovemight, then the mixture was concentrated in vacuo to give rac-(2J?,35,57?)-4-[[3-(4-fiuoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, as a mixture of diasteromers. ESI-MS m/z cale. 441.13116, found 442.1 (M+l)⁺; 440.3 (M-l)'.

Step 7:

The enantiomers of the major diastereomer of rac-(27?,3S,57?)-4-[[3-(4-fluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide ( 15 mg, 0.03398 mmol) were separated by chiral SFC using a Chiralpak AS-H column, 5um particle size, 25 cm x 21.2 mm from Daicel Corporation to give two single isomers of unknown absolute configuration:

First Eluting Isomer (rt = 1.44 min): re/-(2S,37?,5S)-4-[[3-(4-fluoro-2-mcthoxy-phenyl)-5methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (67, 3.2 mg,

330

42%); ESI-MS m/z cale. 441.13116, found 442.8 (M+l)⁺; 440.8 (M-l)-; Rétention time: 2.98 mins. *H NMR (500 MHz, DMSO-d₆) δ 10.28 (s, 1H), 8.37 (d, J = 5.4 Hz, 1H), 8.08 - 7.94 (m, 2H), 7.56 (s, 1H), 7.54 - 7.45 (m, 1H), 7.20 (t, J = 7.6 Hz, 1H), 6.76 (dd, J = 11.3, 2.5 Hz, 1H), 6.64 (td, J = 8.6, 2.6 Hz, 1H), 5.10 (d, J = 8.4 Hz, 1H), 4.22 - 4.06 (m, 1H), 3.77 (s, 3H), 2.91 (t, J = 12.3 Hz, 5 1H), 2.24 (dd, J = 11.6, 6.7 Hz, 1H), 1.49 (s, 3H) ppm.

Second Eluting Isomer (rt = 1.63 min): reZ-(27î,35,5R)-4-[[3-(4-fluoro-2-methoxy-phenyl)5-methyl-5-(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (68, 4.1 mg, 52%). ESI-MS m/z cale. 441.13116, found 442.8 (M+l)⁺; 440.8 (M-l)'; Rétention time: 2.98 mins.

The following compounds were made using the method described in Example 10, taking forward the minor diastereoisomer formed in step 4. In step 7, purification was performed by chiral SFC using a (R,R)-Whelk-Ol column, 5 pm particle size, 25 cm x 21.1 mm from Daicel on a Minigram SFC instrument from Berger Instruments:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
69	re/-(2R,3R,55)-4-[[3-(4fluoro-2-methoxy-phenyl)-5methyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl] amino]pyridine-2carboxamide (first eluting isomer by SFC on (7?,7?)-Whelk-Ol column, rt = 1.44 min)	ESI-MS m/z cale. 441.13116, found 442.1 (M+l)⁺; 440.2 (M-l)'; Rétention time: 2.85 minutes	Ή NMR (500 MHz, DMSO-dô) δ 10.28 (s, 1H), 8.37 (d, J = 5.4 Hz, 1H), 8.08 - 7.94 (m, 2H), 7.56 (s, 1H), 7.54 - 7.45 (m, 1H), 7.20 (t, J = 7.6 Hz, 1H), 6.76 (dd, J = 11.3,2.5 Hz, 1H), 6.64 (td, J = 8.6, 2.6 Hz, 1H), 5.10 (d, J = 8.4 Hz, 1H), 4.22-4.06 (m, 1H), 3.77 (s, 3H), 2.91 (t, J = 12.3 Hz, 1H), 2.24 (dd,

331

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
			J= 11.6, 6.7 Hz, 1H), 1.49 (s, 3H) ppm.
70	reZ-(2S,3S,5/?)-4-[[3-(4- fluoro-2-methoxy-phenyl)-5methyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl] amino]pyridine-2carboxamide (second eluting isomer by SFC on (/?,/?)-Whelk-O l column, rt = 1.63 min)	ESI-MS m/z cale. 441.13116, found 442.2 (M+l)⁺; 440.7 (M-l); Rétention time: 2.85 minutes

The following compounds were made using the method described in Example 10, except that 2-(4-fluoro-2-methoxy-3-methyl-phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane was used as coupling partner in the Suzuki coupling step 2. In step 4, THF was used as solvent rather than tert5 butanol. In step 7, purification was performed by chiral SFC using a (R,R)-Whelk-Ol column, 5 pm particle size, 25 cm x 21.1 mm from Daicel on a Minigram SFC instrument from Berger Instruments:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
71	reZ-(25,37?,5S)-4-[[3-(4fluoro-2-methoxy-3 -methylphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofu ran-2-	ESI-MS m/z cale. 455.14682, found 456.2 (M+l)⁺; 454.2 (M-l)'; Rétention time: 3.05 minutes

332

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
	carbonyl] amino]pyridine-2carboxamide (first eluting isomer by SFC on (R,R)-Whelk-Ol column, rt = l .05 min)
72	re/-(2R,3S,5R)-4-[[3-(4fluoro-2-methoxy-3 -methylphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide (second eluting isomer by SFC on (R,R)-Whelk-Ol column, rt = 1.73 min)	ESI-MS m/z cale. 455.14682, found 456.2 (M+l)⁺; 454.2 (Μ-l)’; Rétention time: 3.06 minutes	*H NMR (500 MHz, DMSO-dô) δ 10.47 (s, 1H), 8.48 (dd, J = 5.5, 0.6 Hz, 1H), 8.24 (dd, J = 2.2, 0.6 Hz, 1H), 8.04 (d, J = 2.8 Hz, 1H), 7.81 (dd, J = 5.5, 2.2 Hz, 1H), 7.65 - 7.55 (m, 1H), 7.26 (dd, J = 8.7, 6.5 Hz, 1H), 7.02 (t, J = 8.8 Hz, 1H), 4.64 (d, J= 10.1 Hz, 1H), 4.15-4.04 (m, 1H), 3.63 (s, 3H), 2.49 2.46 (m, 1H), 2.33 (t, J = 12.4 Hz, 1H), 2.11 (d, J = 2.0 Hz, 3H), 1.58 (s, 3H) ppm.

The following compounds were made using the method described in Example 10, except that 2-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane was used as coupling partner in the Suzuki coupling step 2 and the conditions used for the

333 epimerization/hydrolysis step 4 are similar to the ones used in Example 2 step 7. In step 7, purification was performed by chiral SFC using a (R,R)-Whelk-Ol column, 5 pm particle size, 25 cm x 21.1 mm from Daicel on a Minigram SFC instrument from Berger Instruments:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
73	reZ-(25',37?,55)-4-[[3-[2(difluoromethoxy)-4-fluorophenyl]-5-methyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide (first eluting isomer by SFC on (R,R)-Whelk-Ol column, rt = 2.61 min)	ESI-MS m/z cale. 477.11234, found 478.6 (M+l)⁺; 476.6 (M-l)’; Rétention time: 3.03 minutes	Ή NMR (500 MHz, DMSO-dô) δ 10.42 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.25 (d,J = 2.2 Hz, 1H), 8.05 (d, J = 2.8 Hz, 1H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.59 (d, J = 2.8 Hz, 1H), 7.56 - 7.49 (m, 1H), 7.42 - 7.07 (m, 3H), 4.69 (d, J = 10.1 Hz, 1H), 4.05 (ddd, J = 11.8, 10.1,8.1 Hz, 1H), 2.57-2.51 (m, 1H), 2.43 (dd,J = 12.8, 8.2 Hz, 1H), 1.57 (s, 3H) ppm.
74	reZ-(2R,35,5R)-4-[[3-[2(difluoromethoxy)-4-fluorophenyl]-5-methyl-5 (trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide	ESI-MS m/z cale. 477.11234, found 478.6 (M+l)⁺; 476.6 (M-l)’; Rétention time: 3.04 minutes

334

Cmpd No.	Compound Name	LC/MS	NMR (shifts în ppm)
	(second eluting isomer by SFC on (R,R)-Whelk-Ol column, rt = 3.32 min)

The following compounds were made using the method described in Example 10, except that (2,4-difluoro-3-methyl-phenyl)boronic acid was used as coupling partner in the Suzuki coupling step 2 and the conditions used for the epimerization/hydrolysis step 4 are similar to the ones used in

Example 1 step 3:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
75	reZ-(2S,3R,5S)-4-[[3-(2,4- difluoro-3-methyl-phenyl)-5methyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl] amino]pyridine-2carboxamide (first eluting isomer by SFC on Chiralpak AS-H column, rt = 2.89 min)	ESI-MS m/z cale. 443.12683, found 444.6 (M+l)⁺; 442.7 (Μ-l)'; Rétention time: 3.12 minutes	Ή NMR (500 MHz, DMSO-dô) δ 10.46 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.26 (d, J = 2.2 Hz, 1H), 8.11-7.99 (m, 1H), 7.80 (dd, J = 5.5, 2.2 Hz, 1H), 7.60 (d, J = 2.8 Hz, 1H), 7.31 (td, J = 8.5, 6.3 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 4.66 (d, J = 10.1 Hz, 1H), 4.073.94 (m, 1H), 2.56 2.44 (m, 2H), 2.12 (s, 3H), 1.57 (s, 3H) ppm.
76	reZ-(27?,3S,57?)-4-[[3-(2,4difluoro-3-methyl-phenyl)-5- methyl-5-	ESI-MS m/z cale. 443.12683, found 444.6 (M+l)⁺; 442.7

335

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
	(trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide (second eluting isomer by SFC on Chiralpak AS-H column, rt = 3.71 min)	(M-l); Rétention time: 3.12 minutes

336

Example 11 rel-(2S,3R,5S)- 4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (77) and rel(2R,3S,5R)- 4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-55 (trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (78)

OTf

1) B₂Pin₂, KOAc, Pd(dppf)CI₂,1,4dioxane, 80°C

2) NalO₄, THF, H₂O, 0 °C to RT then 10 M HCl, 27%overtwo steps

B(OH)₂

3) 1-Bromo-3-ethyl-4fluoro-2-methoxybenzene, PdCI₂(dtbpf), K3PO4, DME, 100°C, 31%

Ar (rac)

4) Pd(OH)₂, EtOH, H₂ (50 psi), 86%

Âr

6) DCM, DMF (cat.), (COCI)₂, 0°C then NEt₃, DMAP, methyl 4aminopyridine-2carboxylate, 0°C to RT, 72% f₃c,„

nh₂

5) Cs₂CO₃, MeOH, 50°C, 75%

7) 7 M NH₃ in MeOH (rac) (rac)

77, fïrst eluting isomer

78, second eluting isomer

Step 1 and 2:

To a stirred solution of ethyl 2-methyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)3H-furan-5-carboxylate (10 g, 26.865 mmol) in 1,4-dioxane (150 mL), Potassium acetate (8 g, 10 81.514 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2dioxaborolane (27 g, 106.32 mmol) were added. The reaction mixture was de-gassed by argon gas then Pd(dppf)Ch (983 mg, 1.3434 mmol) was added to this reaction mixture and heated to 80 °C under argon for 15 min. Reaction was monitored by TLC. Reaction was allowed to room température. Then diluted with EtOAc (500 mL) and water (300 mL). Then filtered through celite 15 bed, two layers were separated and the aqueous layer was extracted with EtOAc (300 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum.

337

The crude product was dissolved in THF (30 mL) and H2O (15 mL), cooled to 0-5 °C. NaICh (17 g, 79.479 mmol) was added in the reaction mixture portion wise and stirred it at room température for 15 min. Then HCl (10 mL of 1 M, 10.000 mmol) was added and reaction mass was stirred for 4 hours. Then reaction mass was diluted with water (200 mL) and EtOAc (500 mL). Layers were separated. Organic layer was washed with brine solution. Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Crude mass was purified by silica gel chromatography using 2-10% EtOAc in hexane to get a yellow solid , this was washed with hexane to get [5-ethoxycarbonyl-2-methyl-2-(trifluoromethyl)-3H-furan-4-yl]boronic acid (2.5 g, 27%) as a white solid. *H NMR (400 MHz, DMSO-dô) δ 8.22 (s, 2H), 4.23 (q, J = 7.1 Hz, 2H), 3.11 (d, J = 18.2 Hz, IH), 2.85 (d, J = 18.24 Hz, IH), 1.49 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H) ppm.

Step 3:

To a stirred solution of l-bromo-3-ethyl-4-fluoro-2-methoxy-benzene (3 g, 12.87 mmol) and [5-ethoxycarbonyl-2-methyl-2-(trifluoromethyl)-3H-furan-4-yl]boronic acid (3.79 g, 14.16 mmol) in DME (15 mL) was added K3PO4 (7.65 g, 36.04 mmol). The mixture was degassed with N₂ gas for 5 mins followed by addition of PdCh(dtbpf) (838.86 mg, 1.29 mmol) and heated to 100 °C for 4 h. The reaction mixture was fïltered through a celite pad, the filtrate was diluted with water (50 mL) and the aqueous layer extracted with EtOAc (100 mL). The organic layer was dried (MgSÜ4), fïltered and evaporated in vacuo. Purification by flash chromatography (S1O2, 0 to 3% EtOAc in hexane) gave ethyl 4-(3-ethyl-4-fluoro-2-methoxy-phenyl)-2-methyl-2-(trifluoromethyl)3H-fiiran-5-carboxylate (1.5 g, 31%) as light yellow liquid. ’H NMR (400 MHz, DMSO-dô) δ 7.1823 (t, J = 7 Hz, IH), 6.9648 (t, J = 8.8 Hz, IH) 4.0401 (q, J = 6.9Hz, 2H), 3.5996 (s, 3H), 3.4321 (d, J = 17.6 Hz, IH), 3.1492 (d, J= 17.6Hz, IH), 2.6211-2.5858 (m, 2H), 1.614 (s, 3H), 1.1339 (t, J = 7.3 Hz, 3H), 1.0159 (t, J = 7 Hz, 3H) ppm. ESI-MS m/z cale. 376.1298, found 377.0 (M+l)⁺.

Step 4:

To a stirred solution of ethyl 4-(3-ethyl-4-fluoro-2-methoxy-phenyl)-2-methyl-2(trifluoromethyl)-3H-furan-5-carboxylate (1.5 g, 3.99 mmol) in éthanol (50 mL) was added Pd(OH)2 (4.5 g, 32.04 mmol). The reaction was stirred at ambient température for 16 hours in a Panshaker under a 50 psi pressure of hydrogen. Reaction mass was fïltered through celite bed, filtrate was evaporated under reduced pressure to get crude compound. Purification by flash chromatography (S1O2, 30% EtOAc in hexane) gave ethyl rac-(2S,3S,57?)-3-(3-ethyl-4-fluoro-2

338 methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofiiran-2-carboxylate (1.3 g, 86%) as a white solid. Ή NMR (400 MHz, DMSO-d₆) δ 7.04 (t, J = 6.9Hz, 1H), 6.92 (t,J = 9Hz, 1H) 4.95 (d, J = 8.9 Hz, 1H), 4.35-4.28 (m, 1H), 3.80 (s, 3H), 3.70-3.59 (m, 2H), 2.63-2.54 (m, 3H), 2.31-2.26 (m, 1H), 1.49 (s, 3H), 1.13 (t, J = 7.3 Hz, 3H), 0.72 (t, J = 7Hz, 3H) ppm. ESI-MS m/z cale. 378.1454, found 379.0 (M+l)⁺.

Step 5:

To a stirred solution of ethyl rac-(25,35,55)-3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.2 g, 3.17 mmol) in MeOH (10 mL) was added césium carbonate (2.07 g, 6.34 mmol). The reaction was stirred at an ambient température for Ih then it was heated at 50 °C for 16 h. The reaction mixture was concentrated in vacno then water (5 mL) was added. The aqueous layer was acidified with IM HCl, to neutral pH. The aqueous layer was extracted in 10% methanol-DCM mixture (2 x 50 mL) and the organic layer was evaporated in vacno to give rac-(25,35,55)-3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1 g, 75%) as a colourless liquid, which was used without further purification. *H NMR (400 MHz, DMSO-dô) δ 12.89 (s, 1H), 7.29-7.25 (m,lH) 6.99 (t, J = 9 Ηζ,ΙΗ), 4.44 (d, J = 10.4, 1H), 3.91-3.88 (m, 1H), 3.70 (s, 3H), 2.64-2.58 (m, 2H), 2.492.42 (m, 1H), 2.27-1.98 (m, 1H), 1.48 (s, 3H), 1.14 (t,J = 7.4Hz, 3H) ppm. ESI-MS m/z cale. 350.1141, found 351.0 (M+l)⁺.

Step 6:

To a solution of rac-(25,35,55)-3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (100 mg, 0.29 mmol) in DCM (2.5 mL) stirring at 0 °C was added DMF (5 pL, 0.065 mmol) and oxalyl chloride (100 pL, 1.15 mmol). After 30 mins the reaction mixture was concentrated in vacno then diluted in DCM (2.3 mL) and added dropwise to a solution of methyl 4-aminopyridine-2-carboxylate (60 mg, 0.39 mmol), DMAP (4 mg, 0.033 mmol) and Et₃N (250 pL, 1.79 mmol) in DCM (2 mL) stirring at 0 °C. After 10 mins the reaction was warmed to ambient température and stirred for 16 h. The reaction mixture was concentrated onto silica gel and purified by flash chromatography (40 g SiCh, 0 to 100 % EtOAc in heptane) to give methyl rac-(25,35,55)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (109 mg, 72%). ESI-MS m/z cale. 484.16214, found 485.8 (M+l)⁺; 483.1 (M-l)’.

339

Step 7:

Methyl rac-(2R,3S,5Æ)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (109 mg, 0.20 mmol) and ammonia (10 mL of 7 M, 70.00 mmol) were stirred at ambient température ovemight. The reaction mixture was concentrated in vacuo to give rac-(2A,35’,57î)-4-[[3-(3-ethyl-4-fluoro-2methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2carboxamide (105 mg, containing 8% of an undesired minor isomer), which was used without further purification. ESI-MS m/z cale. 469.16248, found 470.2 (M+l)⁺; 468.2 (M-l) .

Step 8:

rac-(2Z?,35,57?)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (105 mg, 0.22mmol) was separated by chiral SFC using a Chiralpak AS-H column, 5um particle size, 25 cm x 10 mm from Daicel on a Minigram SFC instrument from Berger Instruments to give two single isomers of unknown absolute configuration:

First Eluting Isomer (rt = 3.22 min): reZ-(2S,3/?,55)-4-[[3-(3-ethyl-4-fluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (77, 22.6 mg, 22%); ESI-MS m/z cale. 469.16248, found 470.2 (M+l)⁺; 468.2 (M-l)’

Second Eluting Isomer (rt = 4.63 min): re/-(21?,3<S',57?)-4-[[3-(3-ethyl-4-fluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (78, 20.7 mg, 20%); ESI-MS m/z cale. 469.16248, found 470.3 (M+l)⁺; 468.2 (M-l)-.

340

Example 12 rac-(27?,35,5/?)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (79)

1)ArB(0H)₂,

Pd(PPh₃)₂CI₂, NaHCO₃, dioxane, 80°C, 97%

4) Cs₂CO₃, EtOH, 50°C then KOt-Bu, EtOH

2) BBr₃, DCM, 0°C, 92%

O

Me F₃C

3) Pd(OH)₂, MeOH, H₂ (60 psi) then Pd/C, EtOH, H₂ (60 psi), 17%

5) K₂CO₃, Mel, MeCN, 80°C, 92%

6) Cs₂CO₃, EtOH, 50°C

7) DCM, DMF (cat.), (COCI)₂ then NEt₃, DMAP, methyl 4aminopyridine-2carboxylate

8) 7 M NH₃ in MeOH, 1% over 5 steps

Step 1:

A mixture of ethyl 2-methyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5carboxylate (1550 mg, 4.16 mmol), (2-fhioro-6-methoxy-phenyl)boronic acid (690 mg, 4.06 mmol) and Pd(PPh3)2Ch (160 mg, 0.23 mmol) in dioxane (35 mL) and saturated aqueous NaHCCh (excess) was degassed and refilled with nitrogen (x 3 before catalyst added, then x 3 with catalyst). The reaction mixture was heated at 80 °C for 24 hours before being cooled to ambient température and concentrated in vacuo. The residue was redisolved in EtOAc and the solution washed with water/brine. The layers were separated and the organic layer filtered through a celite cartridge (10 g), eluting with EtOAc, then concentrated in vacuo to give ethyl 4-(2-fluoro-6-methoxy-phenyl)-2methyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (1.40 g, 97%), which was used without further purification. ESI-MS m/zcalc. 348.09848, found 349.1 (M+l)⁺.

Step 2:

BBr₃ (6.30 mL of 1 M, 6.34 mmol) was added dropwise to an ice-cooled solution of ethyl 4(2-fluoro-6-methoxy-phenyl)-2-methyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (1450 mg, 4.16 mmol) in DCM (5.65 mL). Upon completion, the mixture was quenched with water and sodium bicarbonate solution. The layers were separated and the aqueous layer extracted with DCM. The

341 organic layer was dried (MgSCU) and concentrated in vacuo. The oil was dissolved in DCM (6.75 mL) and stirred at ambient température whilst TFA (1.014 g, 685 pL, 8.90 mmol) was added. The mixture was heated to 45 °C for 30 mins then quenched with sodium bicarbonate solution, extracted with DCM and the organic layer dried (MgSCU) and concentrated in vacuo to give 9-fluoro-2methyl-2-(trifluoromethyl)-l,2-dihydro-4/7-furo[2,3-c]chromen-4-one (1.1 g, 92%) as abrownwaxy solid, which was used without any further purification. Ή NMR (400 MHz, DMSO-de) δ 7.57 - 7.49 (m, IH), 7.39 - 7.19 (m, 2H), 3.86 - 3.59 (m, 2H), 1.72 (d, J = 1.0 Hz, 3H) ppm.

Step 3:

9-fluoro-2-methyl-2-(trifluoromethyl)-l,2-dihydro-477-furo[2,3-c]chromen-4-one (1100 mg, 3.82 mmol) was dissolved in MeOH (50 mL) and this solution added to Pd(OH)2 (3 g, 21.4 mmol) in a 250 mL Pair vessel. The mixture was shaken under 60 psi hydrogen at ambient température ovemight. The reaction mixture was filtered and concentrated in vacuo. The residue was redissolved in éthanol (50 mL) and added to Pd/C (1.1g), then shaken under 60 psi hydrogen at ambient température for 60 hours before being filtered and concentrated in vacuo. Purification by flash chromatography (12 g SiO2, 10 to 40% EtOAc in heptane) gave rac-(27?,3aS,9b5)-9-fluoro-2methyl-2-(trifluoromethyl)-l,2,3a,9b-tetrahydro-477-furo[2,3-c]chromen-4-one (190 mg, 17%), which was used without further purification. ESI-MS m/z cale. 290.0566, found 291.1 (M+l)⁺.

Step 4:

Césium carbonate (430 mg, 1.32 mmol) was added to a stirred suspension of rac(27?,3aS,9b5)-9-fluoro-2-methyI-2-(trifluoromethyl)-l,2,3a,9b-tetrahydro-4Z/-furo[2,3-e]chromen-4one (190 mg, 0.65 mmol) in éthanol (4 mL) and the mixture heated at 50 °C for 2 hours. The reaction was cooled to ambient température and concentrated in vacuo. The residue was redissolved in éthanol (4 mL) and potassium ter/-butoxide (4 eq.) was added. The reaction was stirred ovemight before being quenched with IM aqueous HCl (5 mL), diluted with EtOAc (10 mL) and the layers separated. The aqueous layer was extracted with EtOAc (3x10 mL), and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give rac-(2Æ,35,57?)-3-(2-fluoro6-hydroxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (200 mg) as a white solid, which was used without further purification.

Step 5:

342

To a solution of rac-(25,3S,55)-3-(2-fluoro-6-hydroxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (200 mg, 0.65 mmol) in acetonitrile (2 mL) was added K2CO3 (380 mg, 2.75 mmol) and Mel (263 mg, 1.85 mmol). The reaction was heated to 80 °C for 6 hours in a sealed reaction vessel, then cooled to ambient température, diluted in DCM and filtered. The filtrate was carefully concentrated in vacuo using a cold water bath to give methyl rac(25,35,55)-3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxylate (200 mg) as a yellow oil, which was used without further purification.

Step 6:

Methyl rac-(25,35,55)-3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (200 mg, 0.59 mmol) was added to a stirred suspension of césium carbonate (390 mg, 1.19 mmol) in éthanol (4 mL) and the mixture heated at 50 °C for 2 hours. The reaction was cooled to ambient température and concentrated in vacuo. The residue was dissolved in IM aqueous HCl (5 mL) and EtOAc (10 mL) and the layers separated. The aqueous layer was extracted with EtOAc (3x10 mL) and the combined organic extracts were dried (MgSO₄), filtered and concentrated in vacuo to give rac-(2A,3S,55)-3-(2-fluoro-6-methoxy-phenyl)5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (190 mg) as a white solid, which was used in the next step without further purification. ESI-MS m/z cale. 322.08282, found 321.1 (M-l)'.

Step 7:

To a solution of rac-(27?,35,55)-3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (190 mg, 0.59 mmol) in DCM (10 mL) stirring at ambient température was added DMF (4.6 pL, 0.059 mmol) and oxalyl chloride (160 pL, 1.83 mmol). After 15 mins the reaction mixture was concentrated in vacuo, the residue diluted in DCM (3 mL) and added dropwise over 5 mins to an ice-cooled solution of methyl 4-aminopyridine-2carboxylate (90 mg, 0.59 mmol) , DMAP (3.7 mg, 0.030 mmol) and NEt₃ (250 pL, 1.79 mmol) in DCM (5 mL). After warming to ambient température ovemight the reaction mixture was diluted with DCM (50 mL) and washed with 2M HCl solution (50 mL). The organic layer was passed through a phase separator cartridge and the filtrate concentrated in vacuo to give methyl rac(25,3S,55)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxylate (250 mg), which was used without further purification. ESIMS m/z cale. 456.13083, found 457.1 (M+l)⁺.

343

Step 8:

Methyl rac-(2/?,35,5/?)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (250 mg, 0.55 mmol) was dissolved in methanolic ammonia (10 mL of 7 M, 70.00 mmol) and stirred at ambient température for 6 hours. The solution was concentrated in vacuo before being purified fraction lynx (Ammonia shallow 5 gradient, in DMSO loading solvent) to give rac-(21?,35,57î)-4-[[3-(2-fIuoro-6methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide (79, 3.2 mg, 1% over 5 steps). ’H NMR (400 MHz, Chloroform-d) δ 8.61 (s, 1H), 8.47 (d, J = 5.6 Hz, 1H), 8.19 (dd, J = 5.6, 2.2 Hz, 1H), 7.97 - 7.87 (m, 2H), 7.26 (td, J = 8.4, 6.6 Hz, 1H), 10 6.81 - 6.70 (m, 2H), 5.64 (s, 1H), 5.12 (d, J = 10.7 Hz, 1H), 4.05 (td, J = 11.5, 8.2 Hz, 1H), 3.87 (s,

3H), 3.10 (t, J = 12.4 Hz, 1H), 2.14 (dd, J = 12.6, 8.1 Hz, 1H), 1.66 (s, 3H) ppm. ESI-MS m/z cale. 441.13116, found 442.1 (M+l)⁺; 440.3 (M-l)*.

344

Example 13 rel-(2R,3S,5S)- 4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (80), rel-(2R,3S,5R)- 4[[3-(3_>4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-25 carbonyl]amino]pyridine-2-carboxamide (81), rel-(2S,3R,5S)- 4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (82) and rel-(2S,3R,5R)- 4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (83)

3) Tf₂O, DIPEA, DCM. -78’C, 92%

1) 4,4,4-trifluorobutan-2one, TiCI₄, DCM, -78C, 50%

2) Rh(OAc)₂, PhH, 100°C, 67%

5) 10% Pd/C, EtOH, H₂(1 atm), 69%

4) ArBpin, sat aq.

Me NaHCO₃, Pd(PPh₃)₂CI₂,

P₃C—Y-O ,9 dioxane, 80 C, 35%

----------*~ ( OEt OTf

7) DCM. DMF (cat.), (COCI)₂ then NEt₃, DMAP, methyl 4aminopyridine-26) KOf-Bu, f-BuOH. ζ 98%_______

OEt

F₃C

Me ,0 carboxylate, 0°C to RT, 85% (rac) (rac)

9) SFC, 43%

-, ^oh8) NH₃, MeOH, 88% Ar

(rac)

83, third eluting Isomer (firstSFC)

82, first eluting peak (first SFC); second eluting Isomer (second SFC)

80, first eluting peak 81, second eluting isomer (firstSFC); (first SFC) first eluting Isomer (second SFC)

Step 1:

TiCh (20 mL of 1 M, 20.0 mmol) and EtjN (2.77 mL, 19.9 mmol) were added sequentially and dropwise to a solution of ethyl 2-diazo-3-oxo-butanoate (2.47 mL, 17.89 mmol) in DCM (100 mL) in a three-necked flask, stirring at -78 °C . After 1 h, a solution of Ti(OiPr)4 (5.6 mL, 19.0

345 mmol) and 4,4,4-trifluorobutan-2-one (2.33 g, 18.5 mmol) in DCM (20 mL) was added to the mixture via dropping tunnel. After a further 5 hours the reaction was quenched by the addition of saturated aq. NH4CI solution. The aqueous layer was separated and extracted (DCM) and the combined organics washed with brine, dried (MgSOq) and concentrated in vacuo. Purification (80 g S1O2, 0 to 20% EtOAc in heptane) gave ethyl 2-diazo-7,7,7-trifluoro-5-hydroxy-5-methyl-3-oxoheptanoate (2.5 g, 50%) as a colourless oil. ’H NMR (400 MHz, Chloroform-d) δ 4.32 (q, J = 7.1 Hz, 2H), 4.17 - 4.08 (m, 1H), 3.31 (d, J = 17.2 Hz, 1H), 3.09 (d, J = 17.2 Hz, 1H), 2.63 - 2.37 (m, 2H), 1.42 (d, J = 1.2 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H) ppm.

Step 2:

A suspension of rhodium tetraacetate (68 mg, 0.15 mmol) in benzene (60 mL) was heated at 100 °C for 10 mins. A solution of ethyl 2-diazo-7,7,7-trifluoro-5-hydroxy-5-methyl-3-oxoheptanoate (2500 mg, 8.858 mmol) in benzene (22 mL) was then added dropwise via dropping tunnel. After 2 hours the reaction was cooled to ambient température, filtered through celite, washing with DCM, and concentrated in vacuo. Purification by flash chromatography (40 g S1O2, 0 to 20% EtOAc in heptane) gave ethyl 5-methyl-3-oxo-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2carboxylate (1.5 g, 67%) as a colourless oil, in a 1:1 mixture of diastereomers. Ή NMR (400 MHz, Chloroform-d) δ 4.67 - 4.55 (m, 1H), 4.38 - 4.18 (m, 2H), 2.86 - 2.66 (m, 2H), 2.65 - 2.49 (m, 2H), 1.57 (dd, J = 52.9, 1.1 Hz, 3H), 1.32 (td, J = 7.1, 2.4 Hz, 3H)ppm.

Step 3:

Trifluoromethylsulfonyl trifluoromethanesulfonate (2.18 g, 7.72 mmol) was added to a solution of ethyl 5-methyl-3-oxo-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carboxylate (1.50 g, 5.90 mmol) and DIPEA (2.3 g, 17.8 mmol) in DCM (50 mL) stirring at -78 °C . After 4 hours saturated aq. NaHCOj solution was added, the layers separated and the aqueous layer extracted with DCM, dried (MgSÜ4) and concentrated in vacuo to give ethyl 2-methyl-2-(2,2,2-trifluoroethyl)-4(trifluoromethylsulfonyloxy)-3H-fiiran-5-carboxylate (2.1 g, 92%), which was used without any further purification.

Step 4:

A mixture of ethyl 2-methyl-2-(2,2,2-trifluoroethyl)-4-(trifluoromethylsulfonyloxy)-3Hfuran-5-carboxylate (850 mg, 2.20 mmol), 2-(3,4-difluoro-2-methoxy-phenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane (715 mg, 2.647 mmol) and Pd(PPhj)2C12 (80 mg, 0.11 mmol) in dioxane (20

346 mL) and saturated aqueous NaHCCh (2 mL) was degassed extensively and heated at 80 °C. After 4 hours the reaction mixture was cooled to ambient température and filtered through a celite cartridge washing with EtOAc, then concentrated in vacuo. The residue was purified by flash chromatography (40 g S1O2, 0 to 20% EtOAc in heptane) to give ethyl 4-(3,4-difluoro-2-methoxy-phenyl)-2-methyl2-(2,2,2-trifluoroethyl)-3H-furan-5-carboxylate (290 mg, 35%) as a clear oil. ESI-MS m/z cale. 380.1047, found 381.2 (M+l)⁺.

Step 5:

EtOH (10 mL) was added to a mixture of ethyl 4-(3,4-difluoro-2-methoxy-phenyl)-2-methyl2-(2,2,2-trifluoroethyl)-3H-furan-5-carboxylate (290 mg, 0.7625 mmol) and Pd/C (10 wt. % loading, 1000 mg, 0.94 mmol). The mixture was degassed and stirred under a balloon of hydrogen ovemight. Further Pd/C (10 wt. % loading, 1000 mg, 0.94 mmol) was added, the mixture degassed and stirred under a balloon of hydrogen for a further 20h. The mixture was passed through a celite cartridge rinsing with DCM, and the filtrate concentrated in vacuo and purified by column chromatography (12g S1O2, 0 to 40% EtOAc/Hexanes) to give ethyl rac-(25,35',57?)-3-(3,4-difluoro2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carboxylate (200 mg, 69%). Ή NMR (400 MHz, Methanol-d₄) δ 6.95 - 6.81 (m, 2H), 4.86 (d, J = 8.5 Hz, 1H), 4.27 - 4.15 (m, 1H), 4.09 (d, J = 2.7 Hz, 3H), 3.84 - 3.63 (m, 2H), 3.00 - 2.86 (m, 1H), 2.88 - 2.73 (m, 1H), 2.51 (t, J = 12.8 Hz, 1H), 2.15 - 2.05 (m, 1H), 1.47 (d, J = 1.5 Hz, 3H), 0.85 (t, J = 7.1 Hz, 3H) ppm. ESI-MS m/z cale. 382.12036, found 383.3 (M+l)⁺.

Step 6:

A solution of ethyl rac-(25',35',57?)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2trifluoroethyl)tetrahydrofuran-2-carboxylate (75 mg, 0.20 mmol) and potassium ZerZ-butoxide (65 mg, 0.58 mmol) in ZerZ-butanol (2.2 mL) were stirred at ambient température for 6h before being quenched with saturated aq. NH4CI solution and diluted with EtOAc. The layers were separated and the aqueous layer and extracted with EtOAc. The aqueous layer was then acidified with IM HCl and extracted with further EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to afford rac-(2R,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(2,2,2-trifluoroethyl)tetrahydrofuran-2-carboxylic acid (68 mg, 98%) which was used without further purification. ESI-MS m/z cale. 354.08905, found 355.0 (M+l)⁺; 352.9 (M-l) '.

Step 7:

347

To a solution of rac-(27?,3S,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2trifluoroethyl)tetrahydrofuran-2-carboxylic acid (60 mg, 0.17 mmol) in DCM (5 mL) was added DMF (3 pL, 0.04 mmol) and oxalyl chloride (50 pL, 0.57 mmol). After 15 mins at ambient température the reaction was concentrated in vacuo. The residue was diluted in DCM (2 mL) and added dropwise to a solution of methyl 4-aminopyridine-2-carboxylate (40 mg, 0.26 mmol), DMAP (2 mg, 0.016 mmol) and Et₃N (150 pL, 1.08 mmol) in DCM (1 mL) stirring at 0 °C. After 10 mins at this température, the reaction was warmed to ambient température and stirred for a further 40 mins before being diluted in DCM (50mL) and washed with 2M HCl solution (50 mL). The organic layer was passed through a phase separator cartridge and concentrated in vacuo to give methyl rac(27?,35,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxylate (70 mg, 85%), which was used without further purification. ESI-MS m/z cale. 488.13705, found 489.3 (M+l)⁺; 487.3 (M-l)*.

Step 8:

Methyl rac-(27?,35,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (70 mg, 0.14 mmol) was stirred in methanolic ammonia (2 mL of 7 M, 14.00 mmol) at ambient température ovemight. Further methonolic ammonia (2 mL of 7 M, 14.00 mmol) was added and the reaction left for 6 hours before being concentrated in vacuo to give a mixture of rac-(27î,35,5S)-4-[[3-(3,4-difluoro-2methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide and rac-(2J?,35,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (60 mg, 88%), which was used without further purification. ESI-MS m/z cale. 473.1374, found 474.3 (M+l)⁺; 472.3 (M-l)*.

Step 9:

The mixture of rac-(2Æ,35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide and rac-(27?,35,5Æ)-4-[[3(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide obtained in Step 8 (60 mg, 0.1267 mmol) was separated by chiral SFC using a (R,R)-Whelk-Ol column, 5 pm particle size, 25 cm x 21.2 mm from Regis Technologies on a Minigram SFC instrument from Berger Instruments to give:

348

First Eluting Isomers (rt = 0.91 min): a mixture of both reZ-(2R,3S,5S)-4-[[3-(3,4-difluoro2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide (80) and re/-(25',3R,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (82), that needed further séparation.

Second Eluting Isomer (rt = 1.29 min): re/-(2R,3S,57?)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (81, 9.9 mg, 16.5%). Ή NMR (500 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.34 (d, J = 5.5 Hz, 1H), 8.06 (dd, J = 5.5, 2.2 Hz, 1H), 7.79 (d, J = 2.2 Hz, 1H), 7.72 (d, J = 4.1 Hz, 1H), 6.87 (ddd, J = 8.1, 5.5, 2.1 Hz, 1H), 6.77 (td, J = 9.1, 7.2 Hz, 1H), 5.60 - 5.55 (m, 1H), 4.51 (d, J = 10.0 Hz, 1H), 3.87 (d, J = 2.4 Hz, 3H), 3.80 (q, J = 9.8 Hz, 1H), 2.48 (dddd, J = 26.3, 15.2, 11.0, 4.2 Hz, 2H), 2.22 (d, J = 9.8 Hz, 2H), 1.45 (s, 3H) ppm. ESI-MS m/z cale. 473.1374, found 474.4 (M+l)⁺; 472.4 (M-l)'.

Third Eluting Isomer (rt — 1.45 min): reZ-(2S',3R,5R)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (83, 4.8 mg, 8%). Ή NMR (500 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.33 (d, J = 5.5 Hz, 1H), 7.95 7.89 (m, 1H), 7.84 (s, 1H), 7.72 (s, 1H), 6.87 (s, 1H), 6.81 - 6.72 (m, 1H), 5.46 (s, 1H), 4.53 (d, J = 10.3 Hz, 1H), 3.85 (d, J = 2.4 Hz, 3H), 3.66 (q, J = 10.5 Hz, 1H), 2.50 - 2.39 (m, 3H), 2.01 (t, J = 12.4 Hz, 1H), 1.47 (s, 3H) ppm. ESI-MS m/z cale. 473.1374, found 474.4 (M+l)⁺; 472.4 (M-l)\

The fîrst eluting peak was further separated by chiral SFC using a Lux Cellulose-2 column, 5 pm particle size, 25 cm x 10 mm from Phenomenex, Inc. to give two single isomers of unknown absolute configuration:

First Eluting Isomer (rt = 4.05 min): reZ-(27î,3S,55)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (80, 3.6 mg, 6%). *H NMR (500 MHz, Chloroform-d) δ 8.76 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.09 (dd, J = 5.5, 1.9 Hz, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.93 (s, 1H), 7.02 (ddd, J = 8.0, 5.5,2.1 Hz, 1H), 6.91 (td, J = 9.1, 7.3 Hz, 1H), 5.62 (s, 1H), 4.68 (d, J = 10.4 Hz, 1H), 4.00 (d, J = 2.5 Hz, 3H), 3.81 (td, J = 11.0, 8.2 Hz, 1H), 2.65 - 2.54 (m, 3H), 2.21 - 2.12 (m, 1H), 1.62 (s, 3H) ppm. ESI-MS m/z cale. 473.1374, found 474.3 (M+l)⁺; 472.4 (M-l)-.

Second Eluting Isomer (rt = 4.39 min): rel-[2S,3R,5S)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

349 (82, 7 mg, 11.7%). Ή NMR (500 MHz, Chloroform-d) δ 8.72 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.21 (dd, J = 5.6, 2.0 Hz, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.89 (s, 1H), 7.02 (ddd, J = 8.1, 5.5, 2.1 Hz, 1H), 6.91 (td, J = 9.1, 7.2 Hz, 1H), 5.68 (s, 1H), 4.66 (d, J = 9.9 Hz, 1H), 4.02 (d, J = 2.4 Hz, 3H), 4.02 3.90 (m, 1H), 2.63 (dddd, J = 26.4, 15.2, 11.0, 4.2 Hz, 2H), 2.36 (d, J = 9.7 Hz, 2H), 1.59 (s, 3H) ppm. ESI-MS m/z cale. 473.1374, found 474.4 (M+l)⁺; 472.4 (M-l)'.

The following compounds were made using a method similar to that described in Example 13, except that 3,3-difluoro-butan-2-one was used as the starting material in place of 4,4,4trifIuorobutan-2-one in step 1. In step 6, éthanol was used as solvent rather than ZerZ-butanol:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
84	re/-(2Æ,3S,5S)-4-[[5-(l,ldifluoroethyl)-3-(3,4difluoro-2-methoxy-phenyl)5-methyl-tetrahydrofuran-2carbonyl] amino]pyridine-2carboxamide (first eluting peak by SFC on WhelkOl column, rt= 1.18 min; first eluting isomer by SFC on Lux Cellulose-2 column, rt = 2.35 min)	ESI-MS m/z cale. 455.14682, found 456.6 (M+l)⁺; 454.7 (M-l)’; Rétention time: 3.01 minutes	Ή NMR (500 MHz, Chloroform-d) δ 8.40 (dd, J = 5.4, 2.4 Hz, 1H), 8.21-8.05 (m, 1H), 7.92 (q, J = 2.4 Hz, 1H), 7.01 (td, J = 5.9, 2.9 Hz, 1H), 6.94 6.73 (m, 1H), 4.59 (dd, J = 10.6, 2.8 Hz, 1H), 3.89 (q, J = 2.3 Hz, 3H), 3.85 (dd, J = 8.9, 5.7 Hz, 1H), 2.62-2.49 (m, 1H), 2.16 (dt, J = 12.7, 5.4 Hz, 1H), 1.70 (td, J= 19.0,2.9 Hz, 3H), 1.51 (d, J = 2.9 Hz, 3 H) ppm.
85	re/-(2S,3R,5S)-4-[[5-(I,l- difluoroethyl)-3 -(3,4difluoro-2-methoxy-phenyl)-	ESI-MS m/z cale. 455.14682, found 456.6 (M+l)⁺; 454.7	‘H NMR (500 MHz, Chloroform-d) δ 8.30 (dd, J = 5.6, 1.9 Hz,

350

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
	5-methyl-tetrahydrofuran-2carbonyl]amino]pyridine-2carboxamide (first eluting peak by SFC on WhelkOl column, rt = 1.18 min; second eluting isomer by SFC on Lux Cellulose-2 column, rt = 3.69 min)	(M-l)'; Rétention time: 2.89 minutes	1H), 7.73 (s, 1H), 7.69 - 7.64 (m, 1H), 6.75 6.63 (m, 1H), 6.60 (tdd, J = 9.2, 7.1,2.0 Hz, 1H), 4.80 - 4.74 (m, 1H), 4.36 (dddd, J = 12.4, 9.5, 7.1,2.0 Hz, 1H), 4.03 (t, J = 2.6 Hz, 3H), 2.62 - 2.47 (m, 1H), 1.95 (ddd, J = 12.5, 7.3, 1.7 Hz, 1H), 1.77 (td, J= 19.4, 2.1 Hz, 3H), 1.44 (d, J = 1.9 Hz, 3H) ppm.
86	re/-(2Z?,35,5R)-4-[[5-(l,ldifluoroethyl)-3-(3,4difluoro-2-methoxy-phenyl)5-methyl-tetrahydrofuran-2carbonyl]amino]pyridine-2carboxamide (second eluting isomer by SFC on WhelkOl column, rt = 1.39 min)	ESI-MS m/z cale. 455.14682, found 456.6 (M+l)⁺; 454.7 (M-l)'; Rétention time: 2.89 minutes	Ή NMR (500 MHz, Methanol-cU) δ 8.25 (d, J = 5.6 Hz, 1H), 7.69 (d, J = 2.1 Hz, 1H), 7.61 (dd, J = 5.5, 2.2 Hz, 1H), 6.64 (ddd, J = 8.0, 5.6, 1.9 Hz, 1H), 6.55 (td, J = 9.2, 7.2 Hz, 1H), 4.74 (dd, J = 9.9, 1.2 Hz, 1H), 4.344.25 (m, 1H), 3.97 (d, J = 2.6 Hz, 3H), 2.50 (t, J = 12.7 Hz, 1H), 1.91 (dd, J= 12.5, 7.1 Hz,

351

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
			1H), 1.72 (t, J= 19.5 Hz, 3H), 1.39 (s, 3H) ppm.
87	re/-(25,3R,5R)-4-[[5-(l,ldifluoroethyl)-3-(3,4difluoro-2-methoxy-phenyl)5-methyl-tetrahydrofuran-2carbonyl] amino]pyridine-2carboxamide (third eluting isomer by SFC on WhelkOl column, rt = 1.81 min)	ESI-MS m/z cale. 455.14682, found 456.2 (M+l)⁺; 454.1 (M-l)’; Rétention time: 2.98 minutes	Ή NMR (500 MHz, Chloroform-d) δ 8.33 (d, J = 5.5 Hz, 1H), 8.05 (dq, J = 4.4, 2.3 Hz, 1H), 7.80 (d, J = 2.2 Hz, 1H), 6.93 (ddd, J = 8.1, 5.5, 2.1 Hz, 1H), 6.77 (td, J = 9.2, 7.4 Hz, 1H), 4.51 (d, J = 10.6 Hz, 1 H), 3.833.67 (m, 4H), 3.14 3.06 (m, 1H), 3.04 (s, 2H), 2.49 (t, J= 12.4 Hz, 1H), 2.12-2.04 (m, 1H), 1.64 (d, J = 19.0 Hz, 2H), 1.43 (s, 3 H) ppm.

352

Example 14 reZ-(25,37?,47î,55)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (88) and reZ(27?, 35,45,57?)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (89)

1) MeOH, Pd(OH)₂, H₂(55 psi), 95%

2) 2-bromopropane, K₂CO₃, DMF, 60 °C

3) KOt-Bu, f-BuOH, 94%

(rac)

4) DCM, DMF (cat), (COCI)₂, 0 °C then NEt₃, DMAP, methyl 4aminopyridine-2carboxylate, DCM, 40%

5) NH₃, MeOH, 100%

(rac)

6) SFC, 55%

88, first eluting isomer

89, second eluting isomer

Step 1:

MeOH (620 mL) was added into a Pair shaker flask shaker containing rac-(15,27?)-6,7difluoro-l,2-dimethyl-2-(trifluoromethyl)-l,2-dihydro-477-furo[2,3-c]chromen-4-one (32.3 g, 100.9 mmol) and Pd(OH)2 (24 g, 34.18 mmol). The mixture was degassed and repressurised to 55 psi H2, and left to shake for 2 days. The mixture was filtered, washing the catalyst with DCM followed by EtOAc and methanol, and the filtrate concentrated in vacuo to give methyl rac-(25,35,45,57?)-3-(3,4difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (34 g, 95%). Ή NMR (500 MHz, Methanol-cU) δ 7.05 (ddt, J = 9.1, 7.5, 2.0 Hz, 1H), 6.57 (ddd, J = 10.1, 9.0, 7.6 Hz, 1H), 5.01 (d, J = 6.0 Hz, 1H), 4.34 (dd, J = 8.5, 6.0 Hz, 1H), 3.49 (s, 3H), 2.93 (h, J = 7.4 Hz, 1H), 1.50 (d, J = 1.2 Hz, 3H), 0.89 (dd, J = 7.6, 1.9 Hz, 3H) ppm. ESI-MS m/z cale. 354.08905, found 353.6 (M-l)'.

Step 2:

2-bromopropane (210 pL, 2.24 mmol) was added to a solution of methyl rac-(2S,35,45,57?)3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

353 (260 mg, 0.73 mmol) and K2CO3 (305 mg, 2.21 mmol) in DMF (3.7 mL). The reaction was heated at 60 °C for 2 hours before further 2-bromopropane (210 pL, 2.24 mmol) was added. After a further 2 hours stirring at 60 °C the reaction was cooled to ambient température and diluted with NH4CI solution. The layers were separated and the aqueous layer extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to afford methyl rac-(2S,35,45,5Æ)-3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (271 mg) as an oil which was used without further purification.

Step 3:

To a solution of methyl rac-(25,35,45,57?)-3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (270 mg, 0.68 mmol) in ZerZ-butanol (5 mL) strring at ambient température was added potassium ZerZ-butoxide (155 mg, 1.38 mmol). The reaction was stirred for 2 hours before being diluted in EtOAc and quenched by the addition of IM HCL The layers were separated and the aqueous layer extracted with EtOAc. The combined organic layers were dried (MgSÜ4), filtered and concentrated in vacuo to give rac-(27?,35,45,57?)-3-(3,4difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (246 mg, 94%) as a yellow residue. ESI-MS m/z cale. 382.12036, found 381.6 (M-l)'.

Step 4:

To a solution of rac-(27?,35,45,57?)-3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (246 mg, 0.64 mmol) in DCM (6 mL) stirring at 0 °C was added DMF (5 pL, 0.065 mmol) and oxalyl chloride (170 pL, 1.95 mmol). After 30 mins the reaction was concentrated in vacuo and the residue diluted in DCM (4 mL). This solution was added dropwise to a solution of methyl 4-aminopyridine-2-carboxylate (145 mg, 0.95 mmol) and Et3N (450 pL, 3.229 mmol) in DCM (2 mL) stirring at 0 °C. DMAP (7 mg, 0.057 mmol) was added and the reaction stirred at this température for 10 mins before being warmed to ambient température and stirred ovemight. The reaction mixture was diluted with DCM and washed with IM HCl solution. The organic layers were dried (MgSCU), filtered and concentrated in vacuo, directly onto silica gel. Purification by flash chromatography (24 g SiO₂, 0 to 100% EtOAc in petrol) gave methyl rac-(2R,35,45,5/?)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5354 (trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (133 mg, 40%). ESI-MS m/z cale. 516.16833, found 517.7 (M+l)⁺; 515.8 (M-l)’.

Step 5:

Methyl rac-(27?,35,45,57?)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (133 mg, 0.26 mmol) was stirred in methanolic ammonia (8 mL of 7 M, 56.00 mmol) at ambient température ovemight. The reaction mixture was concentrated in vacuo to give rac-(2R,35,45,57?)-4-[[3-(3,4-difluoro-2isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide (130 mg, 100%). ESI-MS m/z cale. 501.1687, found 502.6 (M+l)⁺.

Step 6:

rac-(2R,35,45,57?)-(4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (130 mg, 0.26 mmol) was separated by chiral SFC using a (R,R)-Whelk-Ol column, 5 pm particle size, 25 cm x 21.2 mm from Regis Technologies on a Minigram SFC instrument from Berger Instruments to give:

First Eluting Isomers (rt = 0.84 min): rel-(2S,3R,4R,5S)- 4-[[3-(3,4-difluoro-2-isopropoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (88, 38 mg, 29%). ESI-MS m/z cale. 501.1687, found 502.2 (M+l)⁺; 500.2 (M-l)'.

Second Eluting Isomer (rt = 1.29 min): rel-(2R,3S,4S,5R)- 4-[[3-(3,4-difluoro-2isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide (89, 34.2 mg, 26%). ’H NMR (500 MHz, DMSO-de) δ 10.74 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.26 (d, J = 2.2 Hz, 1H), 8.05 (d, J = 2.6 Hz, 1H), 7.80 (dd, J = 5.5, 2.2 Hz, 1H), 7.61 (d, J = 2.8 Hz, 1H), 7.20 - 7.10 (m, 2H), 5.09 (d, J = 10.5 Hz, 1H), 4.62 - 4.51 (m, 1H), 4.30 (dd, J = 10.5, 7.5 Hz, 1H), 2.74 (p, J = 7.5 Hz, 1H), 1.61 (s, 3H), 1.35 (d, J = 6.1 Hz, 3H), 1.22 (d, J = 6.1 Hz, 3H), 0.71 (d, 3H) ppm. ESI-MS m/z cale. 501.1687, found 502.2 (M+l)⁺; 500.2 (M-l)’.

355

Example 15 reZ-(25,3/?,47?,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (90) and reZ-(2.Æ,35,45,57?)-4-[[3-(3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (91)

OTf

1)ArB(OH)₂, PhMe, aq. K3PO4, Pd(PPh₃)₄,100°C^ 98%— (rac)

2) Pd(OH)₂, MeOH, H₂ (1 atm), 99%^

4) DCM, DMF (cat.), (COCI)₂, 0°C then DIPEA, methyl 4-aminopyridine-2carboxylate, 75%

Âr (rac)

3) KOt-Bu, tBuOH, RT, 85%

(^rac) (rac)

Ar

5) NH₃ in MeOH

6) SFC, 12% over _F;jC Me two steps

NH₂ and

90, first eluting isomer 91, second eluting isomer

Step 1:

To a degassed solution of ethyl rac-(47?,57?)-4,5-dimethyl-5-(trifluoromethyl)-3(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (2 g, 4.85 mmol) in toluene (25 mL) was added K3PO4 (8.5 mL of 2 M, 17.00 mmol) and (3,4-difluorophenyl)boronic acid (860 mg, 10 5.45 mmol). The mixture was further degassed for 10 mins before tetrakis(triphenylphosphine)palladîum(0) (285 mg, 0.25 mmol) was added. The reaction was stirred at 100 °C for 2 hours before the solvent was removed in vacuo and the residue diluted with water. The aqueous layer was extracted with EtOAc (3 x 100 mL) and the combined organic layers were dried (MgSÛ4) and concentrated in vacuo. Purification by flash chromatography (SiO2, 2 to 5%

EtOAc in hexane) gave ethyl rac-(45,57?)-3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)4,5-dihydrofuran-2-carboxylate (1.7 g, 98%) as a colourless oil. Ή NMR (400 MHz, DMSO-dô) δ

356

7.55 - 7.38 (m, 2H), 7.21 (ddt, J = 8.4, 4.1, 1.6 Hz, 1H), 4.20 - 3.98 (m, 2H), 3.78 (q, J = 7.3 Hz, 1H), 1.63 (s, 3H), 1.08 (t, J = 7.1 Hz, 3H), 1.02 (d, J = 5.64 Hz, 3H) ppm. ESI-MS m/z cale. 350.0941, found 351.0 (M+l)⁺.

Step 2:

Pd/C (10 wt. % loading, 456 mg, 0.43 mmol) was added to a solution of ethyl rac-(4S,5R)-3(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (1.00 g, 2.86 mmol) in EtOH (50 mL) and the mixture vacuum degassed. The flask was refilled with hydrogen and a balloon of hydrogen was bubbled through the solution over 5 mins. The reaction was stirred under a balloon of hydrogen at ambient température for 3 hours before the balloon was refreshed and the bubbling repeated. The reaction was then left stirring under a balloon of hydrogen for 3 days. The reaction mixture was filtered through celite and the filtrate dried in vacuo to give ethyl rac-(2S, 35,45,5R)-3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxylate (1000 mg, 99%) as a colourless oil which crystallised on standing. *H NMR (500 MHz, Chloroform-d) δ 7.11 - 7.02 (m, 1H), 6.97 (dt, J = 10.0, 8.2 Hz, 1H), 6.94 - 6.89 (m, 1H), 4.76 (d, J = 5.8 Hz, 1H), 3.96 (ttt, J = 10.8, 7.1, 3.8 Hz, 2H), 3.60 (dd, J = 8.5, 5.8 Hz, 1H), 2.71 (p, J = 7.8 Hz, 1H), 1.50 - 1.40 (m, 3H), 0.89 (t, J = 7.1 Hz, 3H), 0.79 (dq, J = 7.6, 1.9 Hz, 3H) ppm.

Step 3:

A solution of ethyl rac-(2S,35,45,57?)-3-(3,4-difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.26 g, 3.58 mmol) and KOi-Bu (801 mg, 7.14 mmol) in ZerZ-butanol (34 mL) was stirred at ambient température for 16 hours. The reaction was diluted with EtOAc and acidified to pH 2 with 1 M HCl. The aqueous layer was further extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to give rac-(2R,35,45,5R)-3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran2-carboxylic acid (1.22 g, 76%) as a pale yellow oil. 'H NMR (500 MHz, Chloroform-d) δ 7.17 (dt, J = 10.0, 8.3 Hz, 1H), 7.07 (ddd, J = 11.3, 7.4, 2.3 Hz, 1H), 6.97 (ddd, J = 8.5, 3.9, 1.8 Hz, 1H), 4.93 (d, J = 9.6 Hz, 1H), 3.96 - 3.86 (m, 1H), 2.64 (p, J = Ί.Ί Hz, 1H), 1.29 (s, 3H), 0.85 (dq, J = 7.4, 2.3 Hz, 3H) ppm. ESI-MS m/z cale. 324.0785, found 323.1 (M-l)*.

Step 4:

Oxalyl chloride (28 pL, 0.32 mmol) was added to a solution of rac-(27?,35,45,5R)-3-(3,4difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (50 mg, 0.13

357 mmol) in DCM (1 mL) and DMF (5 pL, 0.065 mmol) stirring at 0 °C, and the mixture was warmed to ambient température over 30 min before being concentrated in vacuo. The residue was azeotroped using toluene and the residue dissolved in DCM (1 mL). To this new solution was added DIPEA (46 pL, 0.26 mmol) and methyl 4-aminopyridine-2-carboxylate (20.4 mg, 0.13 mmol) and the reaction stirred at ambient température for 1 hour. The réaction was quenched by addition of MeOH and the mixture evaporated in vacuo. Purification by reverse phase préparative HPLC (basic eluent) gave methyl rac-(2R,35,45,57?)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (45 mg, 75%). Ή NMR (500 MHz, Chloroform-d) δ 8.66 (d, J = 5.5 Hz, 1H), 8.56 (s, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.95 (dd, J = 5.5, 2.2 Hz, 1H), 7.20 (dt, J = 10.0, 8.3 Hz, 1H), 7.16 - 7.10 (m, 1H), 7.08 - 6.98 (m, 1H), 5.00 (d, J = 10.4 Hz, 1H), 4.03 (s, 3H), 3.91 (dd, J = 10.3, 8.5 Hz, 1H), 2.67 (p, J = 7.7 Hz, 1H), 1.71 (d, J = 1.1 Hz, 3H), 0.88 (dt, J = 7.3, 2.4 Hz, 3H) ppm; ^,9F NMR (471 MHz, Chloroform-d) δ 74.42, -136.68 (d, J = 21.4 Hz), -138.88 (d, J = 21.4 Hz) ppm. ESI-MS m/z cale. 458.1265, found 459.2 (M+l)⁺.

Step 5:

Methyl rac-(2R,35,45,57?)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (45 mg, 0.098 mmol) dissolved in methanolic ammonia (3 mL of 7 M, 21.00 mmol) and MeOH (2.5 mL) and stirred at ambient température for 2.5 hours. The reaction was heated at 50 °C for 1 hour 40 mins before further methanolic ammonia (3 mL of 7 M, 21.00 mmol) was added. After a further 20 mins the reaction was concentrated in vacuo. Purification by préparative reverse phase HPLC (basic eluent) gave rac-(2R,35,45,57?)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (15 mg). ESI-MS m/z cale. 443.12683, found 444.2 (M+l)⁺; 442.2 (M-l)-.

Step 6:

rac-(2R,35,45,5/?)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide was separated by chiral SFC using a (R,R)-Whelk-Ol column, 5 pm particle size, 25 cm x 21.2 mm from Regis Technologies to give two single isomers of unknown absolute configuration:

358

First Eluting Isomer (rt = 0.64 min): reZ-(25,3Z?,47?,55)-4-[[3-(3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (90, 2 mg, 5%). Ή NMR (500 MHz, DMSO-d₆) δ 10.63 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.8 Hz, 1H), 7.84 (dd, J = 5.5, 2.2 Hz, 1H), 7.71 - 7.55 (m, 1H), 7.48 (ddd, J = 12.3, 5 7.8, 2.2 Hz, 1H), 7.42 (dt, J = 10.8, 8.6 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 5.11 (d, J = 9.6 Hz, 1H),

4.18 (dd, J = 9.7, 7.6 Hz, 1H), 2.76 (p, J = 7.5 Hz, 1H), 1.62 (s, 3H), 0.83 - 0.64 (m, 3H) ppm. ESIMS m/z cale. 443.12683, found 444.2 (M+l)⁺; 442.2 (M-l)’.

Second Eluting Isomer (rt = 1.29 min): reZ-(2Z?,35,45,52?)-4-[[3-(3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (91, 3 mg, 10 7%). Ή NMR (500 MHz, DMSO-d₆) δ 10.65 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.30 (d, J = 2.1 Hz,

1H), 8.06 (d, J = 2.9 Hz, 1H), 7.84 (dd, J = 5.5, 2.2 Hz, 1H), 7.60 (d, J = 2.9 Hz, 1H), 7.48 (ddd, J = 12.1, 7.7, 1.8 Hz, 1H), 7.42 (dt, J = 10.7, 8.6 Hz, 1H), 7.20 (dd, J = 9.5, 3.5 Hz, 1H), 5.12 (d, J = 9.7 Hz, 1H), 4.18 (dd, J = 9.7, Ί.Ί Hz, 1H), 2.76 (p, J = 7.4 Hz, 1H), 1.62 (s, 3H), 0.75 (dd, J = 7.4, 2.4 Hz, 3H) ppm. ESI-MS m/z cale. 443.12683, found 444.2 (M+l)⁺; 442.2 (M-l)'.

359

Example 16 re/-(25,37?,47?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (92) and rel(2R, 35,45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-55 (trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (93)

) TBSOTf, DCM, Et₃N, 0 °C. 96%

2) 1,1,1-trifluoropropan2-one, T1CI4. DCM, -78 °C, 48%

Me. CF₃O O ^ΗθζΧΥ]| ^OEt

Ét N₂ (rac)

3) Rh(OAc)₂, PhMe, 100°C,86%

4) Tf₂O, DIPEA, DCM, 0 °C, 65%

OTf

5) ArB(OH)₂, aq. K3PO4, Pd(PPh₃)₄, PhMe, 100 °C, 62%

6) BBr₃, DCM, 0 °C, 98%

7) DCM, TFA, 50^C, 82% (rac) (rac)

8) Pd(OH)₂, MeOH, H₂(55 psi), 70%

9) KOf-Bu, EtOH, 97% 10) Mel, K₂CO₃, MeCN, 80 °C, 28%

11) KOt-Bu, EtOH, 97%

Ar (rac)

12) DCM, DMF (cat.), (COCI)₂ then NEt₃, DMAP, methyl 4aminopyridine-2carboxylate, DCM, 73% f₃c,,

13) 7N NH₃, MeOH, 35% Et'

NH₂

(rac) (rac)

92, first eluting isomer

93, second eluting isomer

Step 1:

360

To a stirred solution of ethyl 2-diazo-3-oxo-hexanoate (5 g, 24.47 mmol) in DCM (50 mL) stirring at 0 °C was added TEA (6.5340 g, 9 mL, 64.57 mmol). [7er/-butyl(dimethyl)silyl] trifluoromethanesulfonate (8.6250 g, 7.5 mL, 32.63 mmol) was added very slowly and the reaction mixture was stirred for 30 mins at 0 °C. The reaction mixture was washed with saturated aqueous NaHCCh solution (50 mL) and the organic layer dried (MgSCU) and concentrated in vacuo to give ethyl (Z)-3-[rerr-butyl(dimethyl)silyl]oxy-2-diazo-hex-3-enoate (7 g, 96%) which was used without fiirther purification. *H NMR (400 MHz, DMSO-dô) δ 5.16 (t, J = 7.3Hz, 1 H), 4.18 (q, J = 7.1 Hz, 4H), 2.04-2.11 (m, 3H), 1.21 (t,J = 8 Hz, 3H), 0.92 (s, 9H), 0.12 (s, 6H) ppm.

Step 2:

To a stirred solution of 1,1,1 -trifluoropropan-2-one (70 g, 624.72 mmol) in DCM (448 mL) stirring at -78 °C was added TiCL (617 mL of 1 M, 617.00 mmol) very slowly. A solution of ethyl (Z)-3-[ter/-butyl(dimethyl)silyl]oxy-2-diazo-hex-3-enoate (150 g, 452.33 mmol) in DCM (152 mL, pre-dried over MgSÛ4) was added and the reaction stirred for 1 hour at this température. The reaction mixture was quenched with water (260 mL), the layers separated and the organic layer washed with fiirther water (200mL), dried (MgSCU) and concentrated in vacuo to give ethyl rac(47?,57?)-2-diazo-4-ethyl-6,6,6-trifluoro-5-hydroxy-5-methyl-3-oxo-hexanoate (66 g, 48%) as a light reddish liquid which was used without fiirther purification. Ή NMR (400 MHz, DMSO-dô) δ 6.17 (s,lH), 4.21-4.27(m,2H), 4.1(d,J = 9.2Hz,lH),1.77-1.82 (m,lH) 1.64-1.68 (m,lH), 1.29 (s, 3H), 1.24 (t,J = 7Hz,3H), 0.83 (t,J = 7.4Hz,3H) ppm. ESI-MS m/z cale. 296.0984, found 297.1 (M+l)⁺.

Step 3:

To a stirred solution of rhodium(II) acetate (985 mg, 2.23 mmol) in toluene (340 mL) stirring at 100 °C was added a solution of ethyl rac-(47?,57?)-2-diazo-4-ethyl-6,6,6-trifluoro-5-hydroxy-5methyl-3-oxo-hexanoate (66 g, 219.23 mmol) in toluene (1320 mL) slowly over 1 hour. Upon complété consumption of starting material the reaction mixture was filtered through celite and concentrated in vacuo to afford ethyl rac-(4/?,5/?)-4-ethyl-5-methyl-3-oxo-5(trifluoromethyl)tetrahydrofiiran-2-carboxylate (53 g, 86%) as a light yellow liquid which was used without fiirther purification. Ή NMR (400 MHz, DMSO-dô) δ 4.79 (s, 1H), 4.20-4.13 (m, 2H), 2.95 (t, J = 4Hz, 1H), 1.66 (s, 3H), 1.49 - 1.41 (m, 2H), 1.20-1.14(m, 3H), 1.06 (t, J = 3.7Hz, 3H) ppm.

Step 4:

361

To a stirred solution of ethyl rac-(47?,57?)-4-ethyl-5-methyl-3-oxo-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (53 g, 187.71 mmol) in DCM (340 mL) stirring at 0 °C was added DIPEA (28.196 g, 38 mL, 218.16 mmol) followed by a solution of trifluoromethanesulfonic anhydride (63.840 g, 38 mL, 226.27 mmol) in DCM (190 mL) dropwise over 20 mins. After addition the reaction was quenched by addition of cool water and diluted in hexane. The organic layer was washed with saturated aqueous sodium bicarbonate solution and concentrated in vacuo. Purification by flash chromatography (SiO₂, 0 to 1% EtOAc in hexane) gave ethyl rac-(47?,57?)-4-ethyl-5-methyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5dihydrofuran-2-carboxylate (50 g, 65%). ’H NMR (400 MHz, Chloroform-d) δ 4.36 (q, J = 7.1 Hz, 2H), 3.01 (t, J = 6.9 Hz, 1H), 1.92 - 1.75 (m, J = 7.1 Hz, 2H),1.64 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H), 1.07 (t, J = 7.5 Hz, 3H) ppm.

Step 5:

To a stirred solution of (3,4-difluoro-2-methoxyphenyl) boronic acid (28 g, 148.99 mmol) and ethyl rac-(47?,57?)-4-ethyl-5-methyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5dihydrofuran-2-carboxylate (50 g, 122.41 mmol) in toluene (1000 mL) was added K3PO4 (188 mL of 2 M, 376.00 mmol). The mixture was degassed with N₂ gas for 20 mins before Pd(PPhj)4 (7.2 g, 6.23 mmol) was added and the reaction heated to 100 °C for 1 hour. The reaction mixture was filtered through celite, the filtrate was diluted with water (500 mL), and the aqueous layer was extracted with EtOAc (2 x 750 mL). The combined organic layers were dried (MgSCk) and concentrated in vacuo. Purification by flash chromatography (SiO₂, 0 to 2% EtOAc in hexane) gave ethyl rac-(4S,57?)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)-4,5dihydrofuran-2-carboxylate (30.82 g, 62%) as a light yellow liquid. Ή NMR (400 MHz, Chloroform-d) δ 6.91 - 6.76 (m, 2H), 4.12 (qq, J = 6.8, 3.6 Hz, 2H), 3.90 (d, J = 2.2 Hz, 3H), 3.32 (t, J = 7.0 Hz, 1H), 1.72 (s, 3H), 1.63-1.68 (m, 1H), 1.46 (dq, J = 14.6, 7.3 Hz, 1H), 1.11 (t, J = 7.1 Hz, 3H), 0.78 (t, J = 7.4 Hz, 3H) ppm. ESI-MS m/z cale. 394.1204, found 395.2 (M+l)⁺.

Step 6:

To a solution of ethyl rac-(4S,57?)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethyl-5-methyl-5(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (30.8 g, 78.11 mmol) in DCM (275 mL) stirring at 0 °C was added BBn (100 mL of 1 M, 100.0 mmol) over 35 mins. The reaction mixture was stirred at this température for 1 hour then quenched at this température by the slow addition of a mixture of

362 water (110 mL) and satutared aqueous sodium bicarbonate solution (110 mL). The layers were separated and the aqueous layer extracted with DCM (2 x 100 mL) and the combined organic extracts washed with water (100 mL), dried (MgSCh), fdtered and concentrated in vacno to give ethyl rac-(4S,55)-3-(3,4-difluoro-2-hydroxyphenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)-4,5dihydrofuran-2-carboxylate (29.1 g, 98%) as an orangey-brown, powdery solid. Ή NMR (500 MHz, Chloroform-d) δ 6.85 (ddd, J = 8.8, 5.7, 2.2 Hz, 1H), 6.77 (ddd, J = 9.6, 8.8, 7.3 Hz, 1H), 5.87 (s, 1H), 4.30 - 4.12 (m, 2H), 3.44 - 3.33 (m, 1H), 1.84 - 1.74 (m, 3H), 1.74 - 1.63 (m, 1H), 1.60 - 1.46 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H), 0.82 (t, J = 7.4 Hz, 3H) ppm. ESI-MS m/z cale. 380.1047, found 381.2 (M+l)⁺; 379.0 (M-l)-.

Step 7:

TFA (11.8 mL, 153.2 mmol) was added to a solution of ethyl rac-(4S,55)-3-(3,4-difluoro-2hydroxyphenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (29.1 g, 76.52 mmol) was dissolved in DCM (200 mL) stirring at ambient température. The mixture was heated at 50 °C for 1 hour 45 mins before being cooled to ambient température and quenched with saturated aqueous sodium bicarbonate solution (800 mL). The layers were separated, the aqueous layer extracted with DCM (3 x 200 mL), and the combined organic extracts dried (MgSCL) and concentrated in vacno. The residue was re-dissolved in DCM (50 mL) and heptane (100 mL) was layered on top. The mixture was allowed to stand at ambient température ovemight and the résultant solid isolated by filtration, washing with a minimum of heptane. The filtrate was concentrated in vacno, redissolved in DCM and heptane layered on top. The mixture was allowed to stand at ambient température ovemight and the résultant second crop of solid isolated by filtration, washing with a minimum of heptane. The crops were combined to give rac-( 15,25)-1-ethyl-6,7-difluoro-2methyl-2-(trifluoromethyl)-lH-furo[2,3-c]chromen-4-one (21.0 g, 82%) as a fluffy white solid. Ή NMR (500 MHz, Chloroform-d) δ 7.22 - 7.07 (m, 2H), 3.49 (dd, J = 7.3, 4.5 Hz, 1H), 2.16 - 1.92 (m, 2H), 1.66 (q, J = 1.1 Hz, 3H), 1.06 - 0.96 (m, 3H) ppm; ¹⁹FNMR (471 MHz, Chloroform-d) δ 74.15, -133.57 (d, J = 20.1 Hz), -153.89 (d, J = 20.1 Hz) ppm. ESI-MS m/z cale. 334.06284, found 335.1 (M+l)⁺; 333.1 (M-l)'.

Step 8:

Pd(OH)2 (27 g of 10 %w/w, 19.23 mmol) was added to a Parr vessel containing a solution of rac-( 15,25)-1 -ethyl-6,7-difluoro-2-methyl-2-(trifluoromethyl)-1 H-furo[2,3 -c]chromen-4-one (21 g,

363

62.83 mmol) in MeOH (460 mL) that had first been left to sonicate for 15 mins at 45 °C to get material into solution. The flask was evacuated and refïlled with H₂ three times before being shaken under 55 psi of hydrogen for 24 h. The catalyst was removed by filtration through celite under a blanket of nitrogen, washing with EtOH. The filtrate was concentrated in vacuo to give methyl rac(25,35, 45,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (16.2 g, 70%) as a fluffy white solid, in a mixture of diastereomers, also containing 5% of the acid side-product. ESI-MS m/z cale. 368.1047, found 368.9 (M+l)⁺; 367.2 (M-l)-.

Step 9:

Methyl rac-(2S,35,45,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (1000 mg, 2.616 mmol) was dissolved in éthanol (35 mL) and KOi-Bu (1.21 g, 10.78 mmol) was added. The reaction mixture was stirred at ambient température ovemight before being concentrated in vacuo and the residue partitioned between EtOAc and IM HCl. The layers were separated and the organic layer passed through a phase separator cartridge and concentrated in vacuo to give rac-(2R,35,45,57?)-3-(3,4-difluoro-2-hydroxyphenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (900 mg, 97%). ESIMS m/z cale. 354.08905, found 356.3 (M+l)⁺.

Step 10:

To a solution of rac-(2R,35,45,57?)-3-(3,4-difluoro-2-hydroxy-phenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1 g, 2.823 mmol) in acetonitrile (6 mL) was added K₂CO₃ (1.65 g, 11.94 mmol) and Mel (1.6 g, 11.27 mmol). The mixture was heated in a sealed vial at 80 °C for 6 hours before being diluted with DCM, filtered and the filtrate carefully concentrated in vacuo (cold water bath). Purification by flash chromatography (24g SiO₂, 10 to 55% EtOAc in heptane) gave methyl rac-(2R,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (300 mg, 28%). *H NMR (400 MHz, DMSO-dô) δ 7.17 - 7.08 (m, 2H), 5.13 (d, J = 6.1 Hz, 1H), 4.27 (dd, J = 8.7, 6.1 Hz, 1H), 3.89 (d, J = 1.5 Hz, 3H), 3.36 (s, 3H), 2.75 (ddd, J = 10.5, 8.6, 4.2 Hz, 1H), 1.54 - 1.48 (m, 3H), 1.52 - 1.36 (m, 1H), 0.73 (t, J = 7.3 Hz, 3H) ppm.

Step 11:

364

To a solution of ethyl rac-(27?,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (300 mg, 0.78 mmol) in EtOH (10 mL) was added KOz-Bu (363 mg, 3.24 mmol). The reaction was stirred at ambient température ovemight, then concentrated in vacuo. The residue was partitioned between EtOAc and IM HCl and the layers separated. The organic layer was passed through a phase separator cartridge and the filtrate evaporated in vacuo to give rac-(27?,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (300 mg), which was used without any further purification. *H NMR (400 MHz, DMSO-de) δ 7.26—7.10 (m, 2H), 4.79 ( d , J = 9.0 Hz, 1H), 4.17 (t, J = 9. 2 Hz, 1H), 3.92( d, J= 1.9 Hz, 3H), 1.58-1.48 (m, 3H), 1.45-1.31 (m, 1H), 1.301.02 (m, 2H), 0.50 (t, J = 7.3 Hz, 3H) ppm.

Step 12:

To a solution of rac-(2R,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (300 mg, 0.81 mmol) in DCM (15 mL) was added DMF (6.4 pL, 0.083 mmol) and oxalyl chloride (216 pL, 2.48 mmol). The mixture was stirred at ambient température for 15 mins then concentrated in vacuo. The residue was diluted in DCM (3 mL) and added dropwise to a solution of methyl 4-aminobenzoate (185 mg, 1.22 mmol), DMAP (5 mg, 0.041 mmol) and NEt₃ (350 pL, 2.51 mmol) in DCM (5 mL) stirring at ambient température. The mixture was stirred for 16 hours then diluted in DCM (50 mL) and washed with 2 M HCl (50 mL). The organic layers were passed through a phase separator cartridge and concentrated in vacuo to give methyl rac-(2R,35,45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (300 mg, 73%), which was used without further purification. ESI-MS m/z cale. 502.1527, found 503.2 (M+l)⁺.

Step 13:

Methyl rac-(2R,35,45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (300 mg, 0.5971 mmol) was dissolved in methanolic ammonia (500 mL of 2 M, 1.00 mol). The reaction was stirred for 16 hours at ambient température before being concentrated in vacuo. Purification by flash chromatography (24 g SiCh, 0 to 100% EtOAc in heptane, loaded in DCM) gave rac-(2R,35,45,57?)4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2365 carbonyl]amino]pyridine-2-carboxamide (116, 107.1 mg, 35%) as a white solid. ’H NMR (500 MHz, DMSO-dô) δ 10.65 (s, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 2.5 Hz, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.61 (d, J = 2.4 Hz, 1H), 7.25 - 7.16 (m, 2H), 4.94 (d, J = 8.8 Hz, 1H), 4.34 (t, J = 9.0 Hz, 1H), 3.91 (d, J = 1.8 Hz, 3H), 2.63 - 2.60 (m, 1H), 1.63 (s, 3H), 1.47 1.41 (m, 1H), 1.27-1.21 (m, 1H), 0.54 (t, J = 7.3 Hz, 3H) ppm; ^,9F NMR (471 MHz, DMSO-d6) δ 72.26, -138.00 (d, J = 21.2 Hz),

-154.96 (d, J = 21.2 Hz) ppm. ESI-MS m/z cale. 487.15305, found 488.4 (M+l)⁺.

Step 14:

rac-(27?,35,45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (245 mg, 0.480 mmol) was separated by chiral SFC using a (R,R)-Whelk-Ol column, 5 pm particle size, 25 cm x 21.2 mm from Regis Technologies to give two single isomers of unknown absolute configuration:

First Eluting Isomer (rt = 0.96 min): reZ-(25,37î,47?,55)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide (92, 78.6 mg, 67%). ’H NMR (500 MHz, DMSO-d₆) δ 10.65 (s, 1H), 8.50 (dd, J = 5.5, 0.6 Hz, 1H), 8.28 (dd, J = 2.2, 0.6 Hz, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.62 - 7.61 (m, 1H), 7.25 - 7.16 (m, 2H), 4.94 (d, J = 8.8 Hz, 1H), 4.34 (t, J = 9.1 Hz, 1H), 3.91 (d, J = 1.8 Hz, 3H), 2.65 - 2.60 (m, 1H), 1.63 (s, 3H), 1.48 - 1.39 (m, 1 H), 1.28 - 1.19 (m, 1H), 0.54 (t, J = 7.3 Hz, 3H) ppm; ¹⁹F NMR (471 MHz, DMSO-d₆) δ -72.26, -138.00 (d, J = 21.3 Hz), -154.96 (d, J = 21.4 Hz) ppm. ESI-MS m/z cale. 487.15305, found 488.5 (M+l)⁺.

Second Eluting Isomer (rt = 2.07 min): reZ-(2Z?,35,45,5Z?)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide (93, 87.5 mg, 74%). ’H NMR (500 MHz, DMSO-d₆) δ 10.65 (s, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.28 (d, J = 2.1 Hz, 1H), 8.06 (d, J = 2.1 Hz, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.61 (d, J = 2.9 Hz, 1H), 7.25 - 7.16 (m, 2H), 4.94 (d, J = 8.8 Hz, 1H), 4.34 (t, J = 9.0 Hz, 1H), 3.91 (d, J = 1.8 Hz, 3H), 2.65 - 2.60 (m, 1H), 1.63 (s, 3H), 1.48 - 1.40 (m, 1 H), 1.28 - 1.19 (m, 1H), 0.54 (t, J = 7.3 Hz, 3H) ppm; ’⁹FNMR (471 MHz, DMSO-d₆) δ -72.26 , -138.00 (d, J = 21.2 Hz), -154.96 (d, J = 21.4 Hz) ppm. ESI-MS m/z cale. 487.15305, found 488.8 (M+l)⁺.

The following compounds were made using a method similar to that described in Example 16, except that ethyl 4-cyclopropyl-2-diazo-3-oxo-butanoate was used as the starting material in

366 place of ethyl 2-diazo-3-oxo-hexanoate in step 1. In step 8, 1 atm of pressure of hydrogen was used rather than 55 psi. The conditions used for the saponification step 11 are similar to those used in Example 3 step 10. In step 14, purification was performed by chiral SFC using a Lux Cellulose-2 column, 5 pmparticle size, 25 cm x 10 mm from Phenomenex, Inc. to give two single isomers of unknown absolute configuration:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
94	re/-(25,37?,4R,55)-4-[[4cyclopropyl-3-(3,4-difluoro2-methoxy-phenyl)-5 methyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide (first eluting peak by SFC on Lux Cellulose-2 column, rt = 2.32 min)	ESI-MS m/z cale. 499.15305, found 500.1 (M+l)⁺; 498.2 (Μ-l)'; Rétention time: 3.32 minutes	*H NMR (500 MHz, DMSO-de) δ 10.69 (s, IH), 8.49 (d, J = 5.5 Hz, IH), 8.27 (d, J = 2.1Hz, IH), 8.05 (d, J = 2.6 Hz, IH), 7.83 (dd, J = 5.5, 2.2 Hz, IH), 7.61 (s, IH), 7.24 (t, J = 7.5 Hz, IH), 7.20 -7.11 (m, IH), 5.14 (d, J = 10.4 Hz, IH), 4.31 (dd, J= 10.3, 8.3 Hz, IH), 3.92 (d, J= 1.9 Hz, 3H), 1.88 (dd, J = 11.6, 8.2 Hz, IH), 1.58 (s, 3H), 0.63 (s, IH), 0.45 (d,J= 13.7 Hz, IH), 0.20 (q, J = 4.7 Hz, IH), -0.04--0.17 (m, IH), -0.48 (dd, J = 9.6, 5.0 Hz, lH)ppm.
95	rel-(2R, 35,45,57?)-4-[[4- cyclopropyl-3-(3,4-difluoro-	ESI-MS m/z cale. 499.15305, found	Ή NMR (500 MHz, DMSO-dô) δ 10.77 (s,

367

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
	2-methoxy-phenyl)-5methyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl] amino]pyridine-2carboxamide (second eluting peak by SFC on Lux Cellulose-2 column, rt = 3.59 min)	500.6 (M+l)⁺; 498.7 (Μ-l)'; Rétention time: 3.32 minutes	1H), 8.58 (d, J = 5.5 Hz, 1H), 8.36 (d, J = 2.1 Hz, 1H), 8.14 (d, J = 2.8 Hz, 1H), 7.91 (dd, J = 5.5, 2.2 Hz, 1H), 7.69 (d, J = 2.8 Hz, 1H), 7.32 (ddd, J = 8.1,5.8, 1.8 Hz, 1H), 7.29 - 7.20 (m, 1H), 5.23 (d, J = 10.4 Hz, 1H), 4.40 (dd, J= 10.4, 8.2 Hz, 1H), 4.01 (d, J = 1.9 Hz, 3H), 1.96 (dd, J= 11.7, 8.3 Hz, 1H), 1.67 (s, 3H), 0.71 (s, 1H), 0.51 (td, J = 8.6, 4.6 Hz, 1H), 0.28 (dt, J= 10.0, 5.0 Hz, 1H), 0.06 - -0.06 (m, 1H), -0.40 (dd, J = 9.7, 4.9 Hz, 1H) ppm.

368

Example 17 rel-(2R, 35,4/?, 55)- 4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (96), re/-(25,37?,45,57?)- 4-[[3-(3,45 difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (97), reZ-(25,37?,47?,55)- 4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide (98) and rel-QR,3S,45,57?)- 4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (99)

1)TBSOTf, DCM, c Me θ O

Et₃N, 0 °C, 96% V II Π

---------► OEt

2) 1,1-difluoropropan-2- one, TiCI₄, DCM. ²

-78°C, 43% (_rac)

OTf (rac)

5) ArB(OH)j, aq. NaHCO₃, Pd(PPh₃)₂CI₂, PhMe, 80°C, 50%

7) KOt-Bu, EtOH, 79%

3) Rh(OAc)₂, PhMe, 100°C, 84% _uc„Me 4) Tf₂O, DIPEA, ^Η|·2^υ'-.1-Ο O DCM, -78°C

Me'' θ® O (rac)

6) Pd/C, H₂ (1 atm), EtOH then Pd(OH)₂, EtOH, H₂ (1 atm), 99%

8) DCM, DMF (cat), (COCI)₂ then NEt₃, DMAP, methyl 4aminopyridine-2carboxylate, DCM

(rac) (rac)

9) 7M NH₃, MeOH, 34% over two steps

96, diastereoisomer 1, first 97, diastereoisomer 1, second eluting isomer eluting Isomer

98, diastereoisomer 2, first eluting isomer

99, diastereoisomer 2, second eluting isomer

Step 1:

To a solution of ethyl 2-diazo-3-oxo-pentanoate (30 g, 172.77 mmol) in DCM (300 mL) stirring at 0 °C was added EtsN (45.999 g, 64 mL, 450.03 mmol). TBSOTf (55.223 g, 49 mL,

369

204.73 mmol) was added slowly and the mixture was stirred for 30 mins at the same température. The reaction mixture was diluted with 30% aqueous NaHCCh solution (200 mL), the layers separated and the organic layer washed with water (500 mL), dried (MgSO₄) and concentrated in vacuo to give ethyl rac-(Z)-3-[ZerZ-butyl(dimethyl)silyl]oxy-2-diazo-pent-3-enoate (48 g, 98%), which was used without further purification.

Step 2:

To a solution of l,l-difluoropropan-2-one (14 g, 148.84 mmol) in DCM (100 mL) stirring at -78 °C was added dropwise TiCl₄ (28.545 g, 16.5 mL, 150.49 mmol) and ethyl (Z)-3-[ZerZbutyl(dimethyl)silyl]oxy-2-diazo-pent-3-enoate (20 g, 73.964 mmol). The reaction was stirred at this température for 30 mins before diluting in water. The layers were separated and the aqueous layer extracted with DCM (2 x 100 mL). The combined organic layers were washed with water and brine, nad concentrated in vacuo. Purification by flash chromatography (SiCh) gave ethyl rac-(4R,5R)-2diazo-6,6-difluoro-5-hydroxy-4,5-dimethyl-3-oxo-hexanoate (8.5 g, 43%) as a liquid. Ή NMR (400 MHz, CDCh) δ 5.74 (t, J = 56.12 Hz, 1H), 4.31(q, J = 14.24 Hz, 2H), 3.97-3.93 (m, 1H), 3.67 (s, 1H), 1.34 (d, J = 7.16 Hz, 3H), 1.30 (s, 3H), 1.26-1.23 (m, 3H) ppm.

Step 3:

A solution of rhodium(II) acetate (3 mg, 0.0068 mmol) in toluene was stirred at 100 °C for 30 mins before a solution of ethyl rac-(4R,5R)-2-diazo-6,6-difluoro-5-hydroxy-4,5-dimethyl-3-oxohexanoate (120 mg, 0.45 mmol) in toluene was added. The mixture was stirred at his température for 45 mins then cooled to ambient température and filtered. The filtrate was concentrated in vacuo to give ethyl rac-(4R,5R)-5-(difluoromethyl)-4,5-dimethyl-3-oxo-tetrahydrofuran-2-carboxylate (90 mg, 84%) as a light brown liquid, which was used without further purification. *H NMR (400 MHz, CDCh) δ 5.66 (t, J = 54.62 Hz, 1H), 4.70 (s, 1H), 4.30-4.22 (m, 2H), 2.54-2.46 (m, 1H), 1.71 (s, 3H), 1.38-1.28 (m, 6H) ppm.

Step 4:

Triflic anhydride (1.85 mL, 11.00 mmol) was added dropwise to a solution of ethyl rac(47?,57?)-5-(difluoromethyl)-4,5-dimethyl-3-oxo-tetrahydrofuran-2-carboxylate (2000 mg, 8.47 mmol) and NEt3 (3.55 mL, 25.47 mmol) in DCM (40 mL) with stirring at -78 °C. After 2 hours, saturated aqueous NaHCCh was added, the layers separated and the aqueous layer extracted with DCM. The combined organic layers were passed through a phase separator cartridge and

370 concentrated in vacuo to give ethyl rac-(4R,5R)-5-(difluoromethyl)-4,5-dimethyl-3(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (3.8 g), containing some NEt₃, which was used as such in the next step, without any further purification. ESI-MS m/z cale. 368.0353, found 369.2 (M+l)⁺.

Step 5:

A mixture of ethyl rac-(4R,5R)-5-(difluoromethyl)-4,5-dimethyl-3(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (3250 mg, 8.83 mmol), (3,4difluoro-2-methoxy-phenyl)boronic acid (2.0 g, 10.64 mmol) and saturated aqueous NaHCO₃(excess) in dioxane (80 mL) was degassed and refilled with nitrogen. Pd(PPh₃)2Ch (321 mg, 0.46 mmol) was added and the mixture further degassed. The reaction was heated at 80 °C for 4 hours then cooled to ambient température and concentrated in vacuo. The residue was disolved in EtOAc, washed with water and brine, and the organic layer filtered through a Celite (10 g), washing with EtOAc, and concentrated in vacuo. Purification by flash chromatography (40 g SiO2, 20 to 40% EtOAc in heptane, Ioaded in DCM) gave ethyl rac-(45',5R)-3-(3,4-difluoro-2-methoxyphenyl)-5(difluoromethyl)-4,5-dimethyl-4,5-dihydrofuran-2-carboxylate (1.6 g, 50%) as a clear oil. Ή NMR (400 MHz, DMSO-dô) δ 7.23 - 7.10 (m, 1H), 7.10 - 6.97 (m, 1H), 6.51 - 6.13 (m, 1H), 4.12 - 3.95 (m, 2H), 3.82 (dd, J = 5.4, 1.8 Hz, 3H), 3.36 (m, 1H), 1.47 (d, J = 1.4 Hz, 3H), 1.31 - 1.14 (m, 3H), 1.08 - 0.82 (m, 3H) ppm. ESI-MS m/z cale. 362.11414, found 363.3 (M+l)⁺.

Step 6:

EtOH (20 mL) was added to a flask containing ethyl rac-(45,57?)-3-(3,4-difluoro-2methoxyphenyl)-5-(difluoromethyl)-4,5-dimethyl-4,5-dihydrofuran-2-carboxylate (300 mg, 0.83 mmol) and Pd/C (900 mg, 0.85 mmol). The mixture was degassed and then stirred under a balloon of hydrogen for 3 days. The reaction mixture was filtered through Celite, washed with EtOH, and the filtrate was concentrated in vacuo. To the residue was added Pd(OH)2/C (20% wt, 1 équivalent) and EtOH (20 mL) and the mixture degassed and stirred under a balloon of hydrogen ovemight. The mixture was filtered through Celite and the filtrate concentrated in vacuo to give a mixture of isomers of ethyl 3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carboxylate (300 mg, 99%). ESI-MS m/z cale. 364.12976, found 365.1 (M+l)⁺.

Step 7:

371

To a solution of a mixture of isomers of ethyl 3-(3,4-difluoro-2-methoxy-phenyl)-5(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carboxylate (300 mg, 0.82 mmol) in EtOH (10 mL) was added KOi-Bu (380 mg, 3.39 mmol). The mixture was stirred at ambient température ovemight then concentrated in vacuo. The residue was partitioned between EtOAc and IM HCl, the layers separated and the organic layer passed through a phase separator cartridge. The filtrate was concentrated in vacuo to give a mixture of isomers of 3-(3,4-difluoro-2-methoxy-phenyl)-5(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carboxylic acid (220 mg, 79%) as a colourless oil. ESI-MS m/z cale. 336.09848, found 335.1 (M-l)'.

Step 8 and 9:

To a solution of a mixture of isomers of 3-(3,4-difluoro-2-methoxy-phenyl)-5(difluoromethyl)-4,5-dimethyI-tetrahydrofuran-2-carboxylic acid (220 mg, 0.65 mmol) in DCM (6 mL) was added DMF (5 pL, 0.065 mmol) and oxalyl chloride (180 pL, 2.06 mmol). The reaction was stirred at ambient température for 2 hours then concentrated in vacuo. The residue was dissolved in DCM (3 mL) and added dropwise over 5 mins to a solution of methyl 4-aminopyridine2-carboxylate (150 mg, 0.99 mmol), DMAP (4 mg, 0.033 mmol) and NEt3 (280 pL, 2.01 mmol) in DCM (5 mL) stirring at ambient température. The mixture was stirred ovemight then evaporated in vacuo. The residue was dissolved in methanolic ammonia (7M, 5 mL) and the solution stirred at ambient température ovemight before being evaporated in vacuo. Purification by reverse phase préparative HPLC (basic eluent) gave two diastereomers of rac-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide (100 mg total, 34%) in a 1:1 ratio. ESI-MS m/z cale. 455.14682, found 456.1 (M+l)⁺; 454.1 (Μ-l)'.

Step 10:

The two seperated diastereomers of rac-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (100 mg, 0.2196 mmol) were each further purified by chiral SFC using a (R,R)-Whelk-Ol column, 5 pm particle size, 25 cm x 21.2 mm from Regis Technologies to give single isomers of unknown absolute configuration:

First Eluting Isomer of Diastereoisomer 1 (rt = 4.45 min): reZ-(25,35,45,5S)-4-[[3-(3,4difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2372 carbonyl]amino]pyridine-2-carboxamide (96, 16.9 mg). Ή NMR (400 MHz, Chloroform-d) δ 8.86 (s, IH), 8.41 (d, J = 5.6 Hz, IH), 7.98 (dd, J = 5.5, 2.1 Hz, IH), 7.90 (d, J = 2.4 Hz, 2H), 6.79 - 6.67 (m, 2H), 5.87 (s, IH), 5.80 (t, IH), 4.92 (d, J = 9.9 Hz, IH), 4.11 (s, IH), 4.04 (d, J = 2.4 Hz, 3H), 2.55 (dq, J = 13.8, 7.1 Hz, IH), 1.65 (t, J = 1.6 Hz, 3H), 1.12 (dd, J = 7.0, 1.6 Hz, 3H) ppm. ESI-MS m/z cale. 455.14682, found 456.1 (M+l)⁺ ; 454.1 (M-l)'.

Second Eluting Isomer of Diastereoisomer 1 (rt = 5.00 min): rel-(2S.3R,4S,5R)-4-[[3(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (97, 16.5 mg). *H NMR (400 MHz, Chloroform-d) δ 8.72 (s, IH), 8.38 (d, J = 5.5 Hz, IH), 8.03 (dd, J = 5.5, 2.2 Hz, IH), 7.90 (d, J = 2.1 Hz, IH), 7.82 - 7.76 (m, IH), 6.91 - 6.77 (m, 2H), 5.77 (t, J = 54.4 Hz, IH), 5.62 (d, J = 4.3 Hz, IH), 4.62 (d, J = 9.7 Hz, IH), 3.89 (d, J = 2.3 Hz, 3H), 3.57 (ddd, J = 12.1, 9.7, 2.2 Hz, IH), 2.38 (dqd, J = 14.3, 7.1, 2.8 Hz, IH), 1.42 (d, J = 1.7 Hz, 3H), 0.93 (dd, J = 7.2, 1.2 Hz, 3H) ppm. ESI-MS m/z cale. 455.14682, found 456.1 (M+l)⁺; 454.1 (M-l)-.

First Eluting Isomer of Diastereoisomer 2 (rt = 3.34 min): Γβ/-(25,37?,47?,55)-4-[[3-(3,4difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (98, 17.8 mg). Ή NMR (400 MHz, Chloroform-d) δ 8.84 (s, IH), 8.41 (d, J = 5.5 Hz, IH), 7.98 (dd, J = 5.8, 2.1 Hz, IH), 7.90 (d, J = 2.2 Hz, 2H), 6.77 - 6.69 (m, 2H), 5.85 (d, J = 4.3 Hz, IH), 5.80 (t, J = 54.5 Hz, IH), 4.92 (d, J = 10.0 Hz, IH), 4.11 (t, J = 11.1 Hz, IH), 4.03 (d, J = 2.4 Hz, 3H), 2.55 (dq, J = 14.0, 7.1 Hz, IH), 1.65 (t, J = 1.6 Hz, 3H), 1.16 - 1.08 (m, 3H) ppm. ESI-MS m/z cale. 455.14682, found 456.1 (M+l)⁺; 454.1 (M-l)’.

Second Eluting Isomer of Diastereoisomer 2 (rt = 4.00 min): rel-(2R,3S,4S,5R)-4-[[3(3,4-difluoro-2-methoxy-phenyI)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (99, 18.1 mg). Ή NMR (400 MHz, Chloroform-d) δ 8.81 (s, IH), 8.47 (d, J = 5.5 Hz, IH), 8.11 (dd, J = 5.5, 2.2 Hz, IH), 7.99 (dd, J = 2.3, 0.6 Hz, IH), 7.87 (d, J = 4.4 Hz, IH), 7.01 - 6.86 (m, 2H), 5.80 (t, J = 54.3 Hz, IH), 5.74 (s, IH), 4.71 (d, J = 9.7 Hz, IH), 3.98 (d, J = 2.3 Hz, 3H), 3.66 (ddd, J = 12.1, 9.7, 2.2 Hz, IH), 3.50 (s, 3H), 2.54 - 2.40 (m, IH), 1.02 (dd, J = 7.2, 1.1 Hz, 3H) ppm. ESI-MS m/z cale. 455.14682, found 456.1 (M+l)⁺; 454.1 (M-l)’.

373

Example 18 rac-(2S, 3S, 4R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (100), rel-(2S,3R,4S)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (101) and rel5 (27?,3S,4/?)-4-[[3-(3,4-difIuoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (102)

1) Acetone, T1CI4, DCM, -78°C, 30%

----------HO

(rac)

2) Rh(OAc)₂, PhMe, 100°C

(4 stereoisomers'}

3) Tf₂O, DIPEA, DCM, -78°C, 80%

4) ArB(OH)₂, PhMe, EtOH, aq. K3PO4, Pd(dppf)CI₂, 100 °C, 82% _

6) KOt-Bu, THF, 0°C, 71%

5) Pd/C, EtOH, H₂(250 psi), 70%

(rac) (rac) (rac) (rac)

7) (COCI)₂, DCM, DMF (cat.), 0°C to RT then DIPEA, methyl 4aminopyridine-2carboxylate, DCM, 0°C toRT, 81%

(rac)

101, first eluting isomer

102, second eluting isomer major diastereoisomer

Step 1:

To a solution of acetone (5.3 mL, 71.54 mmol) in DCM (100 mL) stirring at -78 °C was added dropwise TiCU (12.90 g, 7.5 mL, 68.01 mmol). The reaction was stirred at this température for 10 mins before a solution of ethyl (£)-3-[tert-butyl(dimethyl)silyl]oxy-2-diazo-pent-3-enoate (15 g, 52.738 mmol) in DCM (100 mL) was added dropwise. The reaction was stirred at -78 °C for 1 hour then quenched by addition of saturated aqueous NaHCOj. The mixture was diluted with DCM, the layers separated and the organic layer dried (MgSCU) and concentrated in vacuo. Purification by flash chromatography (SiC>2, 0 to 30% EtOAc in hexane) gave ethyl rac-2-diazo-5-hydroxy-4,5dimethyl-3-oxo-hexanoate as a pale yellow liquid. (3.6 g, 30%). Ή NMR (400 MHz, Chloroform-d)

374 δ 4.29 (q, J = 7.1 Hz, 2H), 3.69 (q, J = 7.0 Hz, 1H), 3.46 (br.s, 1H), 1.32 (t, J = 7.1 Hz, 3H), 1.26 (s, 3H) 1.24- 1.15 (m, 6H) ppm.

Step 2:

A solution of rhodium (II) acetate (64 mg, 0.14 mmol) in toluene (36 mL) was heated at 100 °C for 10 minutes, then the heating removed and a solution of ethyl rac-2-diazo-5-hydroxy-4,5dimethyl-3-oxo-hexanoate (6.58 g, 28.83 mmol) in toluene (95 mL) was added dropwise. The reaction was heated at reflux for 1 hour then fïltered through Celite and the fïltrate concentrated in vacuo to give ethyl rac-4,5,5-trimethyl-3-oxo-tetrahydrofuran-2-carboxylate, which was used without further purification.

Step 3:

To a solution of ethyl rac-4,5,5-trimethyl-3-oxo-tetrahydrofuran-2-carboxylate (2.83 g, 14.13 mmol) in DCM (5 mL) stirring at -78 °C was added DIPEA (3.1 mL, 17.80 mmol). A solution of triflic anhydride (4.20 g, 2.5 mL, 14.89 mmol) in DCM (5 mL) was added dropwise over 20 mins. Upon complété addition the reaction was diluted with DCM and water, the layers separated and the organic layer dried (MgSO₄) and concentrated in vacuo to give ethyl rac-2,2,3-trimethyl-4(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (3.76 g, 80%) as a brown liquid. *H NMR (400 MHz, Chloroform-d) δ 4.33 (q, J = 7.1 Hz, 2H), 2.93 (q, J = 7.1 Hz, 1H), 1.45 (s, 3H), 1.38 1.30 (m, 6H), 1.14 (d, J = 7.1 Hz, 3H) ppm.

Step 4:

To a solution of ethyl rac-2,2,3-trimethyl-4-(trifluoromethylsulfonyloxy)-3H-furan-5carboxylate (3.1 g, 8.03 mmol) in toluene (19 mL) and EtOH (9.5 mL) was added (3,4-difluoro-2methoxy-phenyl)boronic acid (2.1 g, 11.17 mmol) and K₃PO₄ (13 mL of 2 M, 26.00 mmol). The reaction was purged with argon for 20 mins before [1,1*bis(diphenylphosphino)ferrocene]dichloropalladium(II) (197 mg, 0.24 mmol) was added and the mixture stirred at 100 °C for 16 hours. The reaction was concentrated in vacuo and the residue diluted in EtOAc (150 mL). The layers were separated and the organic layer was concentrated in vacuo. Purification by flash chromatography (S1O2, 0 to 50% EtOAc in hexane) gave ethyl rac-4(3,4-difluoro-2-methoxy-phenyl)-2,2,3-trimethyl-3H-furan-5-carboxylate (2.16 g, 82%) as a light yellow liquid. ‘H NMR (400 MHz, Chloroform-d) δ 6.89 - 6.72 (m, 2H), 4.26 - 4.01 (m, 2H), 3.88

375 (d, J = 1.9 Hz, 3H), 3.07 (q, J = 7.2 Hz, 1H), 1.49 (s, 3H), 1.36 (s, 3H), 1.10 (t, J = 7.2 Hz, 3H), 0.89 (d, J = 7.2 Hz, 3H) ppm.

Step 5:

A solution of ethyl rac-4-(3,4-difluoro-2-methoxy-phenyl)-2,2,3-trimethyl-3H-furan-5carboxylate (1 g, 3.06 mmol) in EtOH (40 mL) was degassed for 10 mins before Pd/C (500 mg, 4.70 mmol) was added. The reaction was stirred under a 250 psi pressure of hydrogen for 16 hours, at ambient température, then filtered through Celite and the fdtrate concentrated in vacno. Purification by flash chromatography (SiCh, 5% ethyl acetate in hexane) gave a mixture of isomers of ethyl 3(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carboxylate (700 mg, 70%) as a white solid. Ή NMR (400 MHz, Chloroform-d) δ 6.84 - 6.73 (m, 2H), 4.70 (d, J = 9.2 Hz, 1H), 4.03 (d, J = 2.3 Hz, 3H), 3.83 - 3.70 (m, 2H), 3.45 - 3.26 (m, 1H), 2.46 (q, J = 13.5 Hz, 1H), 1.51 (s, 3H), 1.18 (s, 3H), 0.88 - 0.76 (m, 6H) ppm.

Step 6:

To a solution of a mixture of isomers of ethyl 3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5trimethyl-tetrahydrofuran-2-carboxylate (600 mg, 1.83 mmol) in THF (10 mL) stirring at 0 °C was added KOi-Bu (862 mg, 7.68 mmol). The reaction was stirred at this température for 9 hours then quenched by addition of 2N HCl. The layers were separated and the aqueous layer extracted with EtOAc and water. The organic layer was dried (NaiSCh) and concentrated in vacno. Purification by flash chromatography (SiCh, 0 to 100% EtOAc in hexane) gave a mixture of isomers of 3-(3,4difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carboxylic acid (390 mg, 71%).

Step 7:

Oxalyl chloride (105 pL, 1.20 mmol) was added to a solution of a mixture of isomers of3(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carboxylic acid (120 mg, 0.40 mmol) and DMF (5 pL, 0.065 mmol) in DCM (3 mL) stirring at 0 °C. The mixture was warmed to ambient température over 30 mins, then concentrated in vacno. The residue was dissolved in DCM (2 mL) and the solution cooled to 0 °C before methyl 4-aminopyridine-2-carboxylate (100 mg, 0.66 mmol) and DIPEA (235 pL, 1.35 mmol) were added. The reaction was stirred ovemight, allowing to warm to ambient température, then quenched with water (20 mL) and the layers separated. The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organics layers were dried (MgSO4), filtered and concentrated in vacno. Purification by flash chromatography (12 g SiO?, 0 to

376

15% MeOH in DCM) gave methyl 4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxyIate (140 mg, 81%) as a colourless oil, containing an inseperable mixture of diastereomers. ESI-MS m/z cale. 434.1653, found 435.5 (M+l)⁺; 433.5 (M-l)'.

Step 8 and 9:

A solution of a mixture of diastereomers of methyl 4-[[3-(3,4-difluoro-2-methoxy-phenyl)4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (140 mg, 0.32 mmol) in methanolic ammonia (9 mL of 7 M, 63.00 mmol) was stirred at ambient température ovemight, then concentrated in vacuo. Purification by flash chromatography (SiOi, 0-10% MeOH in DCM) followed by reverse phase préparative HPLC (basic eluent) gave two diastereomers:

First Eluting minor diastereoisomer: rac-(23?,37î,4S)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (100, 17 mg, 12%). Ή NMR (500 MHz, Chloroform-d) δ 8.68 (s, 1H), 8.31 (d, J = 5.5 Hz, 1H), 7.83 (s, 1H), 7.78 (s, 1H), 7.67 (d, J = 2.2 Hz, 1H), 6.60 (dd, J = 9.0, 6.1 Hz, 2H), 5.58 (s, 1H), 4.57 (d, J = 10.1 Hz, 1H), 3.98 (s, 3H), 3.85 (d, J = 11.0 Hz, 1H), 2.17 - 2.10 (m, 1H), 1.47 (s, 3H), 1.18 (s, 3H), 0.83 (d, J = 6.8 Hz, 3H) ppm. ESI-MS m/z cale. 419.16565, found 420.5 (M+l)⁺; 418.5 (M-l)’.

Second Eluting major diastereoisomer: rac-(27?,35',4_JR)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (62 mg, 46%). Ή NMR (500 MHz, Chloroform-d) δ 8.80 (s, 1H), 8.37 (d, J = 5.5 Hz, 1H), 8.12 (dd, J = 5.5, 2.2 Hz, 1H), 7.84 (d, J = 2.2 Hz, 1H), 7.81 - 7.73 (m, 1H), 6.90 (ddd, J = 8.8, 5.7, 2.1 Hz, 1H), 6.85 (s, 1H), 5.64 (s, 1H), 4.43 (d, J = 9.7 Hz, 1H), 3.91 - 3.84 (m, 3H), 3.47 (dd, J = 11.9, 9.7 Hz, 1H), 2.15 (dq, J = 11.9, 6.9 Hz, 1H), 1.37 (s, 3H), 1.20 (s, 3H), 0.75 (d, J = 6.9 Hz, 3H) ppm.

The enantiomers of the major diasteromer rac-(2??,35,42î)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (62 mg, 0.15 mmol) were separated by chiral SFC using a Chiralpak AS-H column, 5um particle size, 25 cm x 10 mm from Daicel on a Minigram SFC instrument from Berger Instruments to give two single isomers of unknown absolute configuration:

First Eluting Isomer (rt = 2.09 min): rel-(2S,3R,4S)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5,5-trimethyl-tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (101, 19 mg, 31%). ‘H NMR (500 MHz, Chloroform-d) δ 8.80 (s, 1H), 8.37 (d, J = 5.5 Hz, 1H), 8.12 (dd, J = 5.5,

377

2.2 Hz, IH), 7.84 (d, J = 2.2 Hz, 1H), 7.81 - 7.73 (m, IH), 6.90 (ddd, J = 8.8, 5.7, 2.1 Hz, 1H), 6.85 (s, IH), 5.64 (s, IH), 4.43 (d, J = 9.7 Hz, IH), 3.91 - 3.84 (m, 3H), 3.47 (dd, J = 11.9, 9.7 Hz, IH), 2.15 (dq, J = 11.9, 6.9 Hz, IH), 1.37 (s, 3H), 1.20 (s, 3H), 0.75 (d, J = 6.9 Hz, 3H) ppm. ESI-MS m/z cale. 419.16565, found 420.3 (M+l)⁺; 418.3 (M-l)'.

Second Eluting Isomer (rt = 2.87 min): rel-(2R,3S,4Z?)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (102, 16 mg, 26%). ’H NMR (500 MHz, Chloroform-d) δ 8.80 (s, IH), 8.37 (d, J = 5.5 Hz, IH), 8.12 (dd, J = 5.5, 2.2 Hz, IH), 7.84 (d, J = 2.2 Hz, IH), 7.81 - 7.73 (m, IH), 6.90 (ddd, J = 8.8, 5.7, 2.1 Hz, IH), 6.85 (s, IH), 5.64 (s, IH), 4.43 (d, J = 9.7 Hz, IH), 3.91 - 3.84 (m, 3H), 3.47 (dd, J = 11.9, 9.7 Hz, IH),

2.15 (dq, J = 11.9, 6.9 Hz, IH), 1.37 (s, 3H), 1.20 (s, 3H), 0.75 (d, J = 6.9 Hz, 3H) ppm. ESI-MS m/z cale. 419.16565, found 420.3 (M+l)⁺; 418.3 (M-l)‘.

378

Example 19 re/-(27?,35,47?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (103), reZ-(25,37?,45)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (104), rel5 (2/?,35,45)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (105) and reZ-(25,37?,4A)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (106)

3) [lr(OMe)(1,5-cod)]₂, BBBPY, heptane, then B₂pin₂, 80°C then DIPEA,

1) Cs₂CO₃, MeOH, O’C, 90%

2) 170-180’C, 79%

8) KOt-Bu, THF, 100%

4) NiCI₂6H₂O, NaBH₄, THF,-40°C, 88% ,

5) DIBAL, DCM, -78°C, 97%

6) AcjO, DMAP, DCM, 70%

7) TMSCN, BF₃OEt₂,78°C to RT then NaOMe, MeOH, 30%

(rac)

9) DCM, DMF (cat.), (COCI)₂, 0°C then methyl 4aminopyridine-2-

11) SFC (rac)

103, first eluting peak (fîrst SFC); first eluting isomer (second SFC)

105, second eluting isomer (first SFC)

106, thlrd eluting Isomer (first SFC)

104, first eluting peak (first SFC); second eluting isomer (second SFC)

Step 1:

A solution of 3-hydroxy-3-methyl-butan-2-one (39 g, 381.86 mmol) and dimethyl propanedioate (25 g, 21.74 mL, 189.23 mmol) in MeOH (550 mL) was cooled to 0 °C and stirred under nitrogen. CS2CO3 (127 g, 389.79 mmol) was added and the mixture was stirred ovemight. The

379 reaction was then cooled to 0 °C and HCl (630 mL of 1 M, 630.00 mmol) was added. The reaction mixture was concentrated to remove the MeOH, and then EtOAc (800 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 500 mL) and the combined organic layers dried (Na₂SO₄) and concentrated in vacuo. The residue was triturated with n-pentane to give 4,5,5-trimethyl-2-oxo-furan-3-carboxylic acid (29 g, 90%) as a off-white solid. ’H NMR (400 MHz, DMSO-dô) δ 13.13 (s, 1H), 2.28 (s, 3H), 1.42 (s, 6H) ppm.

Step 2:

4,5,5-trimethyl-2-oxo-fiiran-3-carboxylic acid (17 g, 99.904 mmol) was heated at 170 “ΟΙ 80 °C for 4 hours then cooled to ambient température. Purification by flash chromatography (SiO₂, 15% EtOAc in hexane) gave 4,5,5-trimethylfiiran-2-one (10 g, 79%) as an off-white solid. Ή NMR (400 MHz, DMSO-dô) δ 5.81 (s, 1 H), 2.03 (s, 3H), 1.38 (s, 6H) ppm. ESI-MS m/z cale. 126.0681, found 127.6 (M+l)⁺.

Step 3:

A mixture of (l,5-cyclooctadine)(methoxy)iridium(I) dimer (1.2 g, 1.81 mmol) and 4,4-diZer/-butyl-2,2'-bipyridine (1.6 g, 5.96 mmol) in n-heptane (50 mL) was degassed and stirred for 15 mins under nitrogen. A solution of 4,5,5-trimethylfuran-2-one (15 g, 118.90 mmol) and bis(pinacolato)diboron (31.8 g, 125.23 mmol) in n-heptane (190 mL) was degassed and stirred under nitrogen for 5 mins and then added to the first solution. The résultant reaction mixture was heated at 80 °C for 2 hours then cooled to ambient température. DIPEA (46.75 g, 63 mL, 361.69 mmol) was added to a solution of l-bromo-3,4-difluoro-2-methoxy-benzene (39.8 g, 178.46 mmol) in TPGS-750-M (40.0 g, 40 mL of 2 %w/v, 69.59 mmol) and THF (240 mL) and the mixture was degassed and stirred under nitrogen for 10 mins. This was added to the cooled reaction mixture followed by PdCh(dtbpf) (3 g, 4.60 mmol), and the résultant mixture was stirred ovemight at ambient température. The mixture was diluted with water (200 mL) and extracted with EtOAc (2 x 700 mL).The combined organic layers were washed with brine (200 mL), dried (Na₂SO₄) and concentrated in vacuo. Purification by flash chromatography (SiO2, 3 to 5% EtOAc in hexane) gave 3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-furan-2-one (19 g, 58%) as a white solid. Ή NMR (400 MHz, DMSO-d₆) δ 7.25 - 7.23 (m, 1H), 7.10-7.07 (m, 1H), 3.81 (d, J = 1.72 Hz, 3H), 1.93 (s, 3H), 1.49 (s, 6H) ppm. ESI-MS m/z cale. 268.0911, found 269.2 (M+l)⁺.

Step 4:

380

To a solution of 3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-furan-2-one (4.2 g, 15.66 mmol) in MeOH (170 mL) and THF (34 mL) stirring at -40 °C was added NÎC12.6H2O (3.8 g, 15.99 mmol) and NaBH4 (3 g, 79.30 mmol). The resulting mixture was stirred for 5 mins before further NÏC12.6H2O (3.8 g, 15.99 mmol) and NaBH» (3 g, 79.30 mmol) was added. Upon full conversion the reaction was quenched by the addition of saturated aqueous NH4CI and the aqueous layer extracted with DCM (2 x 50 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give rac-3-(3,4-difIuoro-2-methoxy-phenyl)-4,5,5-trimethyI-tetrahydrofuran-2-one (3.72 g, 88%) as a 1:1.4 mixture of diasteromers. ESI-MS m/z cale. 270.10675, found 271.4 (M+l)⁺.

Step 5:

To a solution of rac-3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2one (3.8 g, 14.06 mmol) in DCM (55 mL) stirring at -78 °C was added DIBAL (17 mL of 1 M, 17.00 mmol). The mixture was stirred at this température until complété reaction was observed, then quenched by the addition of saturated ammonium chloride solution (20 mL) and Rochelle's sait (30% w/w solution). The mixture was diluted with DCM (20 mL) and vigorously stirred for Ih at ambient temperaure. The layers were separated and the organic layers dried (MgSCM) and concentrated in vacuo to give rac-3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyltetrahydrofuran-2-ol (3.70 g, 97%), which was used without further purification.

Step 6:

To a solution of rac-3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-ol (3.7 g, 13.59 mmol) in DCM (40 mL) was added DMAP (850 mg, 6.96 mmol) and acetic anhydride (5.3 mL, 56.17 mmol). The reaction was stirred at ambient température ovemight then quenched by addition of saturated aqueous sodium bicarbonate solution (50 mL). The mixture was stirred vigorously for 30 mins then the layers were separated. The aqueous layer was extracted with DCM (20 mL) and the combined organic extracts were dried (MgSCU) and concentrated in vacuo. Purification by flash chromatography (S1O2) gave rac-[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5trimethyl-tetrahydrofuran-2-yl] acetate (3.0 g, 70%) as a mixture of stereoisomers. Data for desired diastereomer: Ή NMR (500 MHz, Chloroform-d) δ 6.91 (d, J = 1.4 Hz, IH), 6.86 - 6.76 (m, 2H), 3.91 (d, J= 1.7 Hz, 3H), 2.92 (qd, J = 7.0, 1.4 Hz, IH), 2.10 (s, 3H), 1.37 (s, 3H), 1.37 (s, 3H), 1.01 (d, J = 7.0 Hz, 3H), 0.91 - 0.86 (m, IH) ppm. ESI-MS m/z cale. 314.13297, found 256.6 (M-OAc)⁺.

Step 7:

381

To a solution of rac-[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2yl] acetate (3 g, 9.544 mmol) in DCM (90 mL) stirring at -78 °C was added trimethylsilyl cyanide (3.3 mL, 24.75 mmol) and diethyloxonio(trifluoro)boranuide (3.7 mL, 29.98 mmol) . The mixture was stirred at this température for 30 mins then allowed to warm to ambient température. Upon completion the mixture was quenched with saturated aqueous sodium bicarbonate solution, the layers separated and the aqueous layer extracted with DCM (3 x 30 mL). The combined organic layers were dried (NajSCh) and concentrated in vacuo. The residue was dissolved in DCM and filtered through Celite, then concentrated in vacuo. NaOMe (30 mL of 0.5 M in methanol, 15.00 mmol) was added to the residue and the résultant solution stirred at ambient température ovemight before being quenched by addition of a saturated solution of citric acid. The mixture was stirred at ambient température until complété conversion of the amidate was observed, then extracted with DCM (2 x 30 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give methyl rac-3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carboxylate (900 mg, 30%), which was used in the next step without further purification. ESI-MS m/z cale.

314.13297, found 315.6 (M+l)⁺. ’

Step 8:

To a solution of methyl rac-3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyltetrahydrofuran-2-carboxylate (440 mg, 1.40 mmol) in THF (5.4 mL) was added KOt-Bu (630 mg, 5.61 mmol) and the mixture stirred at ambient température. Upon completion, the reaction was quenched by addition of water and the aqueous layer washed with DCM. The aqueous phase was acidified with IM HCl and extracted with DCM. The organic layer was evaporated in vacuo to give rac-3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carboxylic acid (420 mg, 100%) in a 1:1.4 ratio of diastereomers. ESI-MS m/z cale. 300.1173, found 299.6 (M-l)'.

Step 9: '>

To a solution of rac-3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2carboxylic acid (105 mg, 0.35 mmol) in DCM (1.2 mL) stirring at 0 °C was added DMF (3 pL, 0.039 mmol) and oxalyl chloride (65 pL, 0.75 mmol). The mixture was warmed to ambient température over 30 mins then concentrated in vacuo. The residue was dissolved in DCM (600 pL) and the résultant solution added to a solution of methyl 4-aminopyridine-2-carboxylate (64 mg, 0.42 mmol) and NEt₃ (68 pL, 0.49 mmol) in DCM (600 pL) stirring at 0 °C. The reaction was warmed to

382 ambient température over 2 hours, quenched by addition of water ( 1 drop) and MeOH (2 mL), and the solution concentrated in vacuo. Purification by flash chromatography (SiO₂) gave methyl rac-4[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxylate (110 mg, 72%). ESI-MS m/z cale. 434.1653, found 435.5 (M+l)⁺; 433.6 (M-l)‘.

Step 10:

Methyl rac-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxylate (110 mg, 0.2532 mmol) was dissolved in methanolic ammonia (6 mL of 4 M, 24.00 mmol) and the solution stirred at ambient température. Upon complété conversion the mixture was concentrated in vacuo to give rac-4-[[3-(3,4-difluoro-2methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide ( 100 mg, 94%) as a mixture of diasteromers. ESI-MS m/z cale. 419.16565, found 420.5 (M+l)⁺; 418.7 (M-l)’.

Step 11:

rac-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (85 mg, 0.20 mmol) was separated by chiral SFC using a Lux i-Cellulose-5 column, 5 pm particle size, 25 cm x 10 mm from Phenomenex, Inc. to give:

First Eluting Isomers (rt = 4.84 min): a mixture of both re/-(27?,35,42?)-4-[[3-(3,4-difluoro2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (103) and re/-(25,3R,45)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (104), that needed fiirther séparation.

Second Eluting Isomer (rt = 5.23 min): re/-(2R,35,45)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (105, 10.2 mg). ‘H NMR (500 MHz, DMSO-d₆) δ 10.46 (s, 1H), 8.47 (d, J = 5.6 Hz, 1H), 8.35 (d, J = 2.2 Hz, 1H), 8.08 - 8.05 (m, 1H), 7.87 (dd, J = 5.5, 2.2 Hz, 1H), 7.63 - 7.59 (m, 1H), 7.22 - 7.11 (m, 2H), 4.87 (d, J = 8.5 Hz, 1H), 4.22 (t, J = 8.1 Hz, 1H), 3.91 (d, J = 1.8 Hz, 3H), 2.35 (p, J = 7.4 Hz, 1H), 1.40 (s, 3H), 1.20 (s, 3H), 0.59 (d, J = 7.3 Hz, 3H) ppm. ESI-MS m/z cale. 419.16565, found 420.6 (M+l)⁺; 418.5 (M-l)’.

Third Eluting Isomer (rt = 5.67 min): re/-(2S,3R,4R)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (106, 14.4 mg). Ή NMR (500 MHz, DMSO-d₆) δ 10.32 (broad s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.34 (d, J = 2.2

383

Hz, 1H), 8.04 (d, J = 2.7 Hz, 1H), 7.85 (dd, J = 5.5, 2.2 Hz, 1H), 7.58 (d, J = 2.9 Hz, 1H), 7.26 - 7.11 (m, 2H), 4.87 (d, J = 8.6 Hz, 1H), 4.22 (t, J = 8.1 Hz, 1H), 3.91 (d, J = 1.8 Hz, 3H), 2.35 (p, J = 7.3 Hz, 1H), 1.40 (s, 3H), 1.20 (s, 3H), 0.59 (d, J = 7.3 Hz, 3H) ppm. ESI-MS m/z cale. 419.16565, found 420.6 (M+l)⁺; 418.6 (M-l) -,

The first eluting peak was further separated by chiral SFC using a Chiralpak AS-H column, 5 pm particle size, 25 cm x 10 mm from Daicel on a Minigram SFC instrument from Berger Instruments:

First Eluting Isomer (rt = 2.27 min): reZ-(27î,35',4Z?)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (103, 6 mg). Ή NMR (500 MHz, DMSO-d₆) δ 10.24 (s, 1H), 8.47 (d, J = 5.6 Hz, 1H), 8.35 (d, J = 2.1 Hz, 1H), 8.08 (s, 1H), 7.87 (dd, J = 5.5, 2.2 Hz, 1H), 7.65 - 7.61 (m, 1H), 7.26 (ddd, J = 8.3, 5.9, 1.9 Hz, 1H), 7.18 (td, J = 9.4, 7.5 Hz, 1H), 4.53 - 4.44 (m, 1H), 3.83 (d, J = 1.4 Hz, 3H), 3.70 - 3.59 (m, 1H), 2.19 (dq, J = 11.8, 6.8 Hz, 1H), 1.37 (s, 3H), 1.20 (s, 3H), 0.78 (d, J = 6.8 Hz, 3H) ppm. ESI-MS m/z cale. 419.16565, found 420.6 (M+l)⁺; 418.5 (M-l)’.

Second Eluting Isomer (rt = 3.22 min): reZ-(25,3Æ,4S)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (104, 5.4 mg). ’H NMR (500 MHz, DMSO-d₆) δ 10.19 (s, 1H), 8.46 (dd, J = 5.7, 1.7 Hz, 1H), 8.33 (d, J = 2.1 Hz, 1H), 8.04 (s, 1H), 7.86 (dt, J = 5.7, 1.9 Hz, 1H), 7.58 (s, 1H), 7.26 (dd, J = 8.6, 6.2 Hz, 1H), 7.23 - 7.14 (m, 1H), 4.46 (dd, J = 9.4, 1.6 Hz, 1H), 3.83 (d, J = 1.5 Hz, 3H), 3.63 (ddd, J = 11.2, 9.3, 1.7 Hz, 1H), 2.19 (dtd, J = 12.6, 7.6, 5.9 Hz, 1H), 1.37 (d, J = 1.7 Hz, 3H), 1.20 (d, J = 1.7 Hz, 3H), 0.77 (dd, J = 6.9, 1.7 Hz, 3H) ppm. ESI-MS m/z cale. 419.16565, found 420.6 (M+l)⁺; 418.5 (M-l)'.

384

Example 20 reZ-(25,37?,47?,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (107) and reZ-(2A,35,45,55)-4-[[3-(3,4-difluoro-2methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (108)

1) BuLi, l₂, THF, -78°C, 48%

2) K₂CO₃, Etl, 50 °C, 71%

3) ArB(OH)₂, Pd(PPh₃)₄, Na₂CO₃, dioxane, H₂O, 80°C, 70%

CO₂Et

4) Pd(OH)₂, H₂ (60 bar), EtOH, 60°C, 62%

Γ \CO₂Et

Me''' Ar

5) KOf-Bu, THF, 0°C, 66%

(rac) (rac)

6) Methyl 4aminopyridine-2carboxylate, 1methylimidazole, TCFH, MeCN, 65%

7) 7N NH₃, MeOH 8) SFC

Step 1:

To a solution of 4,5-dimethylfuran-2-carboxylic acid (1 g, 7.14 mmol) in THF (15 mL) stirring at -78 °C was added n-BuLi (6.56 mL of 2.5 M, 16.40 mmol) dropwise. The solution was stirred at this température for 30 mins before a solution of h (2.35 g, 9.26 mmol) in THF (10 mL) was added. The mixture was warmed to ambient température then partitioned between MTBE (30 mL) and water (30 mL). The organic layer was discarded, and the aqueous layer acidified to pH 2 by addition of 1 N HCl and extracted with MTBE (2 x 20 mL). The combined organic layers were washed with brine (10 mL), dried (MgSCL) and concentrated in vacuo to give 3-iodo-4,5-dimethylfiiran-2-carboxylic acid (950 mg, 48%), which was used without further purification. ESI-MS m/z cale. 265.944, found 265.3 (M-l)*.

385

Step 2:

To a solution of 3-iodo-4,5-dimethyl-furan-2-carboxylic acid (900 mg, 3.38 mmol) in DMF (5 mL) was added K2CO3 (1.40 g, 10.13 mmol) and iodoethane (811 pL, 10.14 mmol). The reaction was stirred at 50 °C for 2 hours before being cooled to ambient température and partitioned between MTBE (30 mL) and water (30 mL). The aqueous layer was further extracted with MTBE (20 mL) and the combined organic fractions were washed with brine (20 mL), dried (MgSO₄) and concentrated in vacuo. Purification by flash chromatography (12 g S1O2, 0 to 100% EtOAc in Petroleum ether) gave ethyl 3-iodo-4,5-dimethyl-furan-2-carboxylate (800 mg, 71%) as a white solid. ESI-MS m/z cale. 293.97528, found 295.3 (M+l)⁺.

Step 3:

To a solution of ethyl 3-iodo-4,5-dimethyl-furan-2-carboxylate (700 mg, 2.38 mmol) in dioxane (6 mL) was added (3,4-difluoro-2-methoxy-phenyl)boronic acid (492 mg, 2.62 mmol), Pd(PPh3)₄ (343 mg, 0.30 mmol), Na2CO₃ (3.57 mL of 2 M, 7.14 mmol) and water (2 mL). The mixture was heated to 80 °C for 2 hours then cooled to ambient température and partitioned between EtOAc (30 mL) and water (30 mL). The aqueous layer was further extracted with EtOAc (50 mL) and combined organic layers were washed with brine (20 mL), dried (MgSO₄) and concentrated in vacuo. Purification by flash chromatography (12 g S1O2, 0 to 100% EtOAc in petroleum ether) gave ethyl 3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-furan-2-carboxylate (520 mg, 70%) as a white solid. Ή NMR (500 MHz, Chloroform-d) δ 6.97 - 6.82 (m, 2H), 4.22 (q, J = 7.1 Hz, 2H), 3.81 (d, J = 2.0 Hz, 3H), 2.37 (d, J = 0.8 Hz, 3H), 1.80 (d, J = 0.8 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H) ppm. ESI-MS m/z cale. 310.10165, found 311.4 (M+l)⁺.

Step 4:

A solution of ethyl 3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-furan-2-carboxylate (350 mg, 1.128 mmol) in éthanol (2 mL) was circulated through a 70 mm Pd(OH)2 catalyst cartridge on an H-cube apparatus at 60 °C under 60 bar pressure of hydrogen for 48 hours before being concentrated in vacuo to give ethyl rac-(2S,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5dimethyl-tetrahydrofuran-2-carboxylate (245 mg, 62%). Ή NMR (500 MHz, Chloroform-d) δ 7.19 - 7.08 (m, IH), 6.72 (td, J = 9.3, 7.6 Hz, IH), 4.55 (d, J = 6.1 Hz, IH), 4.25 (dq, J = 9.1, 6.6 Hz, IH), 4.19 - 4.02 (m, IH), 4.02 - 3.81 (m, 5H), 2.79 (ddt, J = 16.4, 8.9, 7.4 Hz, IH), 1.27 - 1.04 (m, 3H),

386

0.86 (t, J = 7.1 Hz, 3H), 0.55 (d, J = 7.4 Hz, 3H) ppm. ESI-MS m/z cale. 314.13297, found 315.4 (M+l)⁺.

Step 5:

To a solution of ethyl rac-QS,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyltetrahydrofuran-2-carboxylate (400 mg, 1.27 mmol) in THF (5 mL) stirring at 0 °C was added KOzBu (428 mg, 3.81 mmol). The reaction was stirred for 30 mins before being diluted in MTBE (5 mL) and quenched by addition of 1 M HCl. The aqueous layer was extracted with MTBE (5 mL) and the combined organic layers were dried (MgSCL), fdtered and concentrated in vacuo to give rac(2R,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyI)-4,5-dimethyl-tetrahydrofuran-2-carboxylic acid (270 mg, 66%) as an oil. ESI-MS m/z cale. 286.10165, found 285.4 (M-l)’.

Step 6:

To a solution ofrac-(27?,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyltetrahydrofuran-2-carboxylic acid (100 mg, 0.3493 mmol) in MeCN (2 mL) was added methyl 4aminopyridine-2-carboxylate (63 mg, 0.41 mmol), 1-methylimidazole (100 pL, 1.26 mmol) and TCFH (117 mg, 0.42 mmol). The solution was stirred at ambient température for 16 hours then diluted with EtOAc (10 mL) and water (10 mL). The organic layer was dried (MgSOq) and concentrated in vacuo to give methyl rac-(2J?,35,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (95 mg, 65%) as a white solid, which was used without further purification. ESI-MS m/z cale. 420.1497, found 421.5 (M+l)⁺.

Step 7 and 8:

To a solution of methyl rac-(27?,35,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (95 mg, 0.23 mmol) in MeOH (1 mL) was added methanolic ammonia (322 pL of 7 M, 2.25 mmol). The mixture was stirred at ambient température for 6 hours before being concentrated in vacuo to give rac-(2R,35,45,55)-4-[[3(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyI]amino]pyridine-2carboxamide.

rac-(2R,35,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide was separated by chiral SFC using a Chiralpak AS-H column, 5um particle size, 25 cm x 10 mm from Daicel on a Minigram SFC instrument from Berger Instruments:

387

First Eluting Isomer (rt = 1.84 min): rel-(2S,3R,4R,5/?)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (107, 28 mg, 29%). Ή NMR (500 MHz, Chloroform-d) δ 8.96 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.23 (dd, J = 5.6, 2.3 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.89 (s, 1H), 7.12-7.09 (m,lH), 7.02 - 6.83 (m, 1H), 5.58 (s, 5 1H), 4.86 (d, J = 9.7 Hz, 1H), 4.57 - 4.41 (m, 1H), 4.10 - 3.84 (m, 4H), 2.56 (dt, J = 13.5, 6.8 Hz,

1H), 1.35 (d, J = 6.4 Hz, 3H), 0.67 (d, J = 7.2 Hz, 3H) ppm. ESI-MS m/z cale. 405.15002, found 406.3 (M+l)⁺.

Second Eluting Isomer (rt = 3.28 min): rel-(2R,3S,4S,55)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (108, 28 mg, 10 30%). Ή NMR (500 MHz, Chloroform-d) δ 8.96 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.23 (dd, J = 5.6,

2.3 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.89 (s, 1H), 7.12-7.09 (m,lH), 7.02 - 6.83 (m, 1H), 5.58 (s, 1H), 4.86 (d, J = 9.7 Hz, 1H), 4.57 - 4.41 (m, 1H), 4.10 - 3.84 (m, 4H), 2.56 (dt, J = 13.5, 6.8 Hz, 1H), 1.35 (d, J = 6.4 Hz, 3H), 0.67 (d, J = 7.2 Hz, 3H) ppm. ESI-MS m/z cale. 405.15002, found 406.3 (M+l)⁺.

388

Example 21 re/-(25,37?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (109) and re/-(27?,35,57?)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (110)

1) BuLi, DIPA, THF, -75°C then CO₂ (s), MTBE, -78°C to RT, 83%

3) ArB(OH)₂, Pd(PPh₃)₂CI₂, aq. NaHCO₃, dioxane, 50°C

-

4) Ru(BPY)₃ 6H₂O, pyridine, Tf₂O, DCE, hu, 72%

2) Etl, K₂CO₃, 65°C, 74%

Ar

5) Pd(OH)₂/C, EtOH, H₂, (1 atm), 95%

(rac)

7) Methyl 4aminopyridine-2carboxylate, 1methylimidazole, TCFH, MeCN, 36%

8) 7M NH₃, MeOH

9) SFC, 20% over two steps

6) Cs₂CO₃, MeOH, 50°C, 98%

109, first eluting isomer 110, second eluting isomer

Step 1:

To a solution of diisopropylamine (2.3 mL, 16.41 mmol) in THF (15 mL) stirring at -78 °C was added butyllithium (6 mL of 2.5 M, 15.00 mmol), keeping the température below -65 °C. The reaction mixture was stirred at -75 °C for 30 mins before a solution of 3-bromofuran (2 g, 13.61 mmol) in THF (10 mL) was added dropwise, again keeping the température below -65 °C. The mixture was stirred at -78 °C for 30 mins before being added slowly to a pre-cooled (to -78 °C) mixture of dry ice (600 mg, 13.63 mmol) and MTBE (25 mL). Further dry ice was added during the

389 addition. The mixture was allowed to warm to ambient température over 2 hours before being carefully added to water (50 mL). The layers were separated and the aqueous phase extracted with MTBE (x 2). The aqueous phase was acidified to pH 3 with 1 M HCl and again extracted with MTBE (x 3). The combined organic extracts were dried (Na₂SO₄), fïltered and concentrated in vacuo to give 3-bromofuran-2-carboxylic acid (2.17 g, 83%) as a white solid. Ή NMR (500 MHz, Chloroform-d) δ 7.57 (d, J = 1.9 Hz, 1H), 6.66 (d, J = 1.8 Hz, 1H) ppm.

Step 2:

To a solution of 3-bromofuran-2-carboxylic acid (2.17 g, 11.36 mmol) in DMF (25 mL) was added potassium carbonate (4.7 g, 34.01 mmol) and ethyliodide (2.7 mL, 33.76 mmol). The reaction mixture was heated to 65 °C for 40 mins then allowed to cool and stirred over the weekend. The reaction mixture was fïltered, washing with EtOAc and then the filtrate diluted with water. The layers were separated and the aqueous layer extracted with EtOAc. The combined organic layers were washed with water (x 5) then dried (Na₂SO4), fïltered and concentrated in vacuo. The residue was dissolved in EtOAc and adsorbed onto diatomaceous earth (Telos nm). Purification by flash chromatography (24 g SiO₂, 0 to 50% EtOAc in heptane) gave ethyl 3-bromofuran-2-carboxylate (1.8322 g, 74%) as a white solid. ’H NMR (500 MHz, Chloroform-d) δ 7.50 (d, J = 1.9 Hz, 1H), 6.60 (d, J = 1.8 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H) ppm.

Step 3:

A mixture of ethyl 3-bromofuran-2-carboxylate (1.55 g, 7.08 mmol), (3,4-difluoro-2methoxy-phenyl)boronic acid (1.45 g, 7.72 mmol), Pd(PPh3)Cl₂ (98 mg, 0.14 mmol) and NaHCOi (5 mL) in dioxane (20 mL) was heated at 50 °C for 1 hour before being cooled to ambient température and diluted with EtOAc and water. The layers were separated and the aqueous phase was extracted with EtOAc (4 x). The combined organic extracts were washed with brine, dried (MgSO4), fïltered and concentrated in vacuo. The residue was dissolved in EtOAc and adsorbed onto diatomaceous earth (Telos nm). Purification by flash chromatography (24 g SiO₂, 0 to 20% EtOAc in heptane) gave ethyl 3-(3,4-difluoro-2-methoxy-phenyl)furan-2-carboxylate (1.5105 g, 76%) as a clear oil. Ή NMR (500 MHz, Chloroform-d) δ 7.59 (d, J = 1.7 Hz, 1H), 7.07 (ddd, J = 8.8, 5.9, 2.3 Hz, 1H), 6.90 (ddd, J = 9.6, 8.8, 7.3 Hz, 1H), 6.57 (d, J = 1.8 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.82 (d, J = 2.0 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H) ppm. ESI-MS m/z cale. 282.07037, found 283.4 (M+l)⁺.

390

Step 4:

To a solution of ethyl 3-(3,4-difluoro-2-methoxy-phenyl)furan-2-carboxylate (200 mg, 0.71 mmol) in DCE (25 mL) was added tris(2,2’-bipyridyl)dichlororuthenium(II) hexahydrate (11 mg, 0.015 mmol). The reaction mixture was degassed with nitrogen and pyridine (172 pL, 2.13 mmol) was added followed by trifluoromethylsulfonyl trifluoromethanesulfonate (358 pL, 2.13 mmol) dropwise over 10 mins. The mixture was irradiated with blue LEDs (Penn PhD photoreactor M2 and the Blue LED Hepatochem) for 2 hours stirring at ambient température (100 rpm). This process was repeated 13 times, and the crude mixtures combined for work up. The combined mixture was washed with water and brine and the organic layer dried (MgSCU) and concentrated in vacno. Purification by flash chromatography (24g SiCfr, 0 to 20% EtOAc in heptane) gave ethyl 3-(3,4difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)furan-2-carboxylate (2.39 g, 72%) as a clear oil that solidifies on standing. Ή NMR (500 MHz, Chloroform-d) δ 7.07 (ddd, J = 8.8, 5.8, 2.3 Hz, 1H), 6.97 - 6.87 (m, 2H), 4.31 (q, J = 7.1 Hz, 2H), 3.88 (d, J = 2.5 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H) ppm. ESI-MS m/z cale. 350.05774, found 351.4 (M+l)⁺.

Step 5:

A solution of ethyl 3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)furan-2carboxylate (2.29 g, 6.538 mmol) in éthanol (200 mL) was added to Pd(OH)2/C (920 mg of 20 %w/w, 1.310 mmol) and the mixture degassed with nitrogen. The mixture is stirred under a balloon pressure of hydrogen for 18 hours before further Pd(OH)2 (920 mg of 20 %w/w, 1.310 mmol) was added, the mixture degassed with nitrogen and then stirred under a balloon pressure of hydrogen for 18 hours. The mixture was filtered through celite, washing with éthanol, and the filtrate concentrated in vacno to give ethyl rac-(2S,35,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (3.2 g, 95%). Ή NMR (500 MHz, Chloroform-d) δ 6.91 - 6.75 (m, 2H), 4.88 (d, J = 8.8 Hz, 1H), 4.49 (dp, J = 11.9, 6.0 Hz, 1H), 4.15 - 4.03 (m, 4H), 3.88 - 3.70 (m, 2H), 2.66 (td, J = 12.5, 10.7 Hz, 1H), 2.31 (dt, J = 11.9, 5.9 Hz, 1H), 0.93 (t, J = 7.1 Hz, 3H) ppm. ESI-MS m/z cale. 354.08905, found 355.0 (M+l)⁺.

Step 6:

To a solution of ethyl rac-(25,35,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5(trifluoromethyl)tetrahydrofiiran-2-carboxylate (3.2 g, 6.233 mmol) in MeOH (100 mL) was added césium carbonate (4 g, 12.28 mmol). The mixture was heated at 50 °C for 16 hours before being

391 concentrated in vacuo. The residue was partitioned between EtOAc and IM HCl, the layers separated and the organic layer passed through a phase separator and concentrated in vacuo to give rac-(27?,35,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1.9947 g, 98%) as a yellow oil. Ή NMR (500 MHz, Chloroform-d) δ 6.96 (ddd, J = 8.8, 5.5, 2.2 Hz, 1H), 6.88 (td, J = 9.1, 7.2 Hz, 1H), 4.70 - 4.59 (m, 2H), 4.00 (d, J = 2.7 Hz, 3H), 3.92 - 3.78 (m, 1H), 2.68 - 2.54 (m, 1H), 2.35 - 2.25 (m, 1H) ppm. ESI-MS m/z cale. 326.05774, found 325.0 (M-l)-.

Step 7:

To a solution of rac-(27î,35,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (80 mg, 0.25 mmol) in MeCN (3 mL) was added methyl 4-aminopyridine-2-carboxylate (44 mg, 0.29 mmol). 1-methylimidazole (70 mg, 0.8526 mmol) and TCFH (82 mg, 0.29 mmol) were added and the reaction stirred at ambient température for 16 hours. The reaction mixture was partitioned between EtOAc (10 mL) and water (10 mL), the layers separated and the aqeuous layer further extracted with EtOAc (10 mL). The combined organic layers were washed with brine (10 mL), dried (MgSO₄) and concentrated in vacuo to give methyl rac-(2??,35,57î)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxylate (70 mg, 36%), which was used without further purification. ESI-MS m/z cale. 460.10577, found 461.6 (M+l)⁺.

Step 8 and 9:

To a solution of methyl rac-(27?,35,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (50 mg, 0.11 mmol) in MeOH (1 mL) was added methanolic ammonia (155 pL of 7 M, 1.1 mmol) and the mixture stirred at ambient température ovemight before being concentrated in vacuo to give rac-(27?,35,52?)-4-[[3(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide.

rac-(27?,35,57î)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide was separated by chiral SFC using a (R,R)-Whelk-Ol column, 5um particle size, 25 cm x 21.2 mm from Regis Technologies to give two single enantiomers of unknown absolute configuration:

392

First Eluting Isomer (rt = 0.75 min): re/-(2S,37?,5S)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (109, 5 mg, 10%). Ή NMR (500 MHz, Chloroform-d) δ 8.57 (s, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.13 (dd, J = 5.5, 2.3 Hz, 1H), 8.00 (d, J = 2.2 Hz, 1H), 7.84 (s, 1H), 7.11 - 7.00 (m, 1H), 6.99 - 6.84 (m, 1H), 5.56 (s, 5 1H), 4.76 (d, J = 10.2 Hz, 1H), 4.73 - 4.56 (m, 1H), 4.02 (d, J = 2.6 Hz, 3H), 3.83 (q, J = 10.4 Hz,

1H), 2.70 (dt, J = 13.0, 7.7 Hz, 1H), 2.42 (td, J = 12.1, 8.8 Hz, 1H) ppm. ESI-MS m/z cale. 445.1061, found 446.5 (M+l)⁺.

Second Eluting Isomer (rt = 1.15 min): rel-(2R,3S,57?)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (110, 5 mg, 10 10%). Ή NMR (500 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.13 (dd, J = 5.5,

2.2 Hz, 1H), 8.00 (d, J = 2.5 Hz, 1H), 7.84 (s, 1H), 7.03 (t, J = 6.4 Hz, 1H), 6.93 (q, J = 8.8 Hz, 1H), 5.56 (s, 1H), 4.76 (d, J = 10.2 Hz, 1H), 4.69 (q, J = 7.3 Hz, 1H), 4.02 (d, J = 2.6 Hz, 3H), 3.91 - 3.70 (m, 1H), 2.70 (dt, J = 13.0, 7.7 Hz, 1H), 2.42 (td, J = 12.2, 8.8 Hz, 1H) ppm. ESI-MS m/z cale. 445.1061, found 446.5 (M+l)⁺.

The following compounds were made using the method described in Example 21, except that (4-fluoro-2-methoxy-3-methyl-phenyl)boronic acid was used as coupling partner in the Suzuki coupling step 3 and the conditions used for the amide formation step 7 are similar to those used in Example 14 step 4:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
111	re/-(25,3R,5S)-4-[[3-(4fluoro-2-methoxy-3 -methylphenyl)-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl] amino]pyridine-2carboxamide	ESI-MS m/z cale. 441.13116, found 442.5 (M+l)⁺; 440.6 (Μ-l)’; Rétention time: 2.95 minutes

393

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
	(first eluting isomer by SFC on (R,R)-Whelk-Ol column, rt = 0.82 min)
112	rel-(/2R, 35,57?)-4-[[3-(4fluoro-2-methoxy-3 -methylphenyl)-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide (second eluting isomer by SFC on (R,R)-Whelk-Ol column, rt = 1.38 min)	ESI-MS m/z cale. 441.13116, found 442.3 (M+l)⁺; 440.3 (Μ-l)'; Rétention time: 2.96 minutes	Ή NMR (500 MHz, DMSO-dô) δ 10.53 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.26 (d, J = 2.2 Hz, 1H), 8.05 (d, J = 2.8 Hz, 1H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.60 (d, J = 2.8 Hz, 1H), 7.31 (dd, J = 8.7, 6.5 Hz, 1H), 7.02 (t, J = 8.8 Hz, 1H), 5.03 -4.91 (m, 1H), 4.59 (d, J = 9.4 Hz, 1H), 4.053.95 (m, 1H), 3.59 (s, 3H), 2.77 (dt, J= 12.5, 7.4 Hz, 1H), 2.16-2.04 (m, 4H) ppm.

394

Example 22

4-[[(27?, 35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (113)

1) n-BuLi, propanoyl chloride, THF, -65°C

4) (/Pr)₂NH, n-BuLi, THF, fert-butyl acetate, -65°C to RT, 16%

O

N.

O

2) TiCI₄, DCM, DIPEA, -5°C then NMP, isobutyraldéhyde, 100% azidosulfonylphen yl)acetamide, MeCN, NEt₃, 0°C to RT, 89%

9) Pd/C, H₂(1 atm), 84%

F 10) KOt-Bu, t-BuOH, 35°C, then LiOH, RT

F 12) 7M NH₃, MeOH, 41%

3) NaOMe, MeOH, 0°C to RT, 73%

6) Rh(OAc)₂, PhMe, 60°C, 90%

O

11) (COCI)₂, DMF, DCM, 0°C then methyl 47) Tf₂O, DIPEA, DCM, -65 °C to -40°

C, 88%

8) ArBpin, Pd(dppf)CI₂ DCM Na₂CO₃, H₂O, dioxane, 80°C, 14% aminopyridine-2carboxylate, Et₃N, DMAP, DCM, 51%

113

Step 1:

To a solution of (47î)-4-benzyloxazolidin-2-one (29.7 g, 164.26 mmol) in THF (297 mL) cooled to -65 °C was added n-BuLi (65.7 mL of 2.5 M, 164.2 mmol) dropwise, keeping the température at -65 °C. The resulting mixture was stirred at -65 °C for 30 min before propanoyl chloride (17.059 g, 16.247 mL, 180.69 mmol) was added dropwise. The mixture was stirred at -65 10 °C for 1 hour and then allowed to warm to ambient température ovemight. The mixture was quenched by addition of saturated aqueous NH₄C1 solution (300 mL) and the aqueous layer extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with saturated

395 aqueous NaHCOj solution (300 mL) and brine (200 mL), dried (MgSO₄), filtered and evaporated in vacuo to give (47?)-4-benzyl-3-propanoyl-oxazoIidin-2-one (39 g, 100%) as a colorless oil. Ή NMR (300 MHz, Chloroform-d) δ 7.46 - 7.14 (m, 5H), 4.69 (ddt, J = 9.5, 6.9, 3.4 Hz, 1H), 4.27 - 4.15 (m, 2H), 3.32 (dd, J = 13.4, 3.3 Hz, 1H), 2.98 (qd, J = 7.3, 5.9 Hz, 2H), 2.80 (dd, J = 13.4, 9.6 Hz, 1H), 1.23 (t, J = 7.4 Hz, 3H) ppm. ESI-MS m/z cale, mass 233.105, found, 233.95 [M+l]⁺.

Step 2:

To a solution of (47î)-4-benzyl-3-propanoyl-oxazolidin-2-one (13.12 g, 56.25 mmol) in DCM (130 mL) cooled to 0 °C was added titanium tetrachloride (59 mL of 1 M in DCM, 59.00 mmol). The resulting mixture was stirred at 0 °C for 15 mins before DIPEA (8.1620 g, 11 mL, 63.15 mmol) was addded and the mixture stirred at this température for 40 mins. NMP (5.5512 g, 5.4 mL, 55.999 mmol) was added and the reaction stirred for 10 mins at ambient température before isobutyraldéhyde (4.2660 g, 5.4 mL, 59.16 mmol) was added and the mixture was stirred at 0 °C for 1 hour and then at ambient température ovemight. The mixture was quenched with a mixture of water (50 mL) and saturated aqueous NH4CI solution (50 mL) and extracted with DCM (3 x 100 mL). The combined organic extracts were dried (Na2SÛ4), filtered and concentrated in vacuo. Purification by flash chromatography (SiCh, 0 to 20% EtOAc to hexane) gave (47?)-4-benzyl-3[(27?,35)-3-hydroxy-2,4-dimethyl-pentanoyl]oxazolidin-2-one (16 g, 86%) as a light yellow oil. *H NMR (300 MHz, Chloroform-d) δ 7.44 - 7.16 (m, 5H), 4.72 (ddt, J = 9.4, 6.9, 3.3 Hz, 1H), 4.30 4.17 (m, 2H), 3.99 (qd, J = 7.0, 2.6 Hz, 1H), 3.56 (dd, J = 8.6, 2.6 Hz, 1H), 3.28 (dd, J = 13.4, 3.4 Hz, 1H), 2.90 (d, J = 3.4 Hz, 1H), 2.81 (dd, J = 13.4, 9.4 Hz, 1H), 1.75 (dp, J = 8.5, 6.6 Hz, 1H), 1.27 (d, J = 7.0 Hz, 3H), 1.06 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H) ppm. ESI-MS m/z cale. 305.1627, found 306.05 (M+l)⁺.

Step 3:

To a solution of (47?)-4-benzyl-3-[(22?,3S)-3-hydroxy-2,4-dimethyl-pentanoyl]oxazolidin-2one (100 g, 301.27 mmol) in MeOH (750 mL) stirring at 0 °C was added sodium methoxide (19.609 g, 83 mL of 25 %w/w in methanol, 90.74 mmol). The mixture was stirred for 30 mins at ambient température before being quenched with saturated aqueous NH4CI solution (300 mL) and the aqueous layer extrated with DCM (3 x 200 mL). The combined organic layers were dried (Na₂SO₄), filtered and concentrated in vacuo. Purification by flash column chromatography (S1O2, 10 to 20% diethyl ether in hexane) gave methyl (27?,35)-3-hydroxy-2,4-dimethyl-pentanoate (40.24 g, 73%) as

396 a colorless liquid, containing 12% hexane by weight. 'H NMR (300 MHz, Chloroform-d) δ 3.73 (s, 3H), 3.59 (dt, J = 7.9, 3.9 Hz, IH), 2.70 (qd, J = 7.2, 3.6 Hz, IH), 2.45 (dd, J = 4.1, 1.8 Hz, IH), 1.69 (ddd, J = 13.3, 8.0, 6.7 Hz, IH), 1.21 (d, J = 7.2 Hz, 3H), 1.03 (d, J = 6.6 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H) ppm.

Step 4:

To a solution of diisopropylamine (67.146 g, 93 mL, 663.56 mmol) in THF (1 L) cooled to 65 °C was added n-BuLi (228 mL of 2.5 M in hexanes, 570 mmol). The mixture was stirred for 30 mins at -65 °C before a solution of terZ-butyl acetate (66.143 g, 77 mL, 569.42 mmol) in THF (100 mL) was added dropwise followed by solution of methyl (2R,35)-3-hydroxy-2,4-dimethylpentanoate (40 g, 189.75 mmol) in THF (100 mL). The mixture was stirred for 1 hour at -50 °C and then allowed to warm to ambient température ovemight. The reaction was quenched by addition of ice-water (800 mL) and extracted with DCM (3 x 400 mL). The combined organic layers were washed with saturated NaHCCh (500 mL), water (2 x 500 mL), dried (Na2SÛ4), fïltered and evaporated in vacuo. Purification by reverse phase flash chromatography (SiCh Cl 8, acetonitrile/water 0 to 60%) gave ZerZ-butyl (47?,5S)-5-hydroxy-4,6-dimethyl-3-oxo-heptanoate (7.95 g, 16%) as a yellow oil. Ή NMR (300 MHz, Chloroform-d) δ 3.62 (dt, J = 8.7, 3.2 Hz, IH), 3.54 3.39 (m, 2H), 2.88 (qd, J = 7.2, 2.8 Hz, IH), 2.57 (d, J = 3.7 Hz, IH), 1.71 (ddt, J = 13.3, 8.6, 6.7 Hz, IH), 1.49 (s, 9H), 1.17 (d, J = 7.2 Hz, 3H), 1.05 (d, J = 6.5 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H) ppm.

Step 5:

To a solution of N-(4-azidosulfonylphenyl)acetamide (10.33 g, 43.00 mmol) in acetonitrile (160 mL) was added ter/-butyl (47?,5S)-5-hydroxy-4,6-dimethyl-3-oxo-heptanoate (7.9 g, 30.72 mmol). The mixture was cooled to 0 °C and triethylamine (9.29 g, 12.8 mL, 91.84 mmol) was added. The reaction mixture was warmed to ambient température and stirred ovemight before being concentrated. Purification by flash chromatography gave Zeri-butyl (4J?,55)-2-diazo-5-hydroxy-4,6dimethyl-3-oxo-heptanoate (7.58 g, 89%) as a yellow oil. Ή NMR (300 MHz, Chloroform-d) δ 3.78 (qd, J =7.1,2.5 Hz, 1 H), 3.54 (dt, J = 8.6, 2.7 Hz, IH), 3.10 (d, J = 2.8 Hz, IH), 1.81-1.66 (m, IH), 1.55 (s, 9H), 1.16 (d, J = 7.1 Hz, 3H), 1.05 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H) ppm. ESI-MS m/z cale. 270.158, found 271.1 (M+l)⁺.

Step 6:

397

To a suspension of rhodium (II) acetate (134 mg, 0.30 mmol) in toluene (25 mL) stirring at 60 °C was added a solution of ZerZ-butyl (47?,55)-2-diazo-5-hydroxy-4,6-dimethyl-3-oxo-heptanoate (8.63 g, 30.33 mmol) in toluene (78 mL). The mixture was stirred at 60 °C for 1 hour, then cooled to ambient température, filtered through filter paper and concentrated in vacuo to give ZerZ-butyl (47?,55)-5-isopropyl-4-methyl-3-oxo-tetrahydrofuran-2-carboxylate (7.34 g, 90%) as a light yellow oil.

Step 7:

To a solution of Ze/'Z-butyl (47?,55)-5-isopropyl-4-methyl-3-oxo-tetrahydrofuran-2carboxylate (500 mg, 2.06 mmol) in DCM (15 mL) stirring at a cooled -65 °C was added DIPEA (1.1 mL, 6.32 mmol) and trifluoromethylsulfonyl trifluoromethanesulfonate (0.45 mL, 2.67 mmol). The reaction mixture was stirred for 2 hours at -65 °C before further trifluoromethylsulfonyl trifluoromethanesulfonate (0.45 mL, 2.66 mmol) was added. The mixture was stirred at -60 °C for 1 hour and then further DIPEA (0.4 mL, 2.30 mmol) and trifluoromethylsulfonyl trifluoromethanesulfonate (0.45 mL, 2.66 mmol) were added and the mixture was stirred for 1 hour at -60 °C and 1 hour at -40 °C. The mixture was quenched with saturated aqueous NaHCCh solution (15 mL) and the aqueous layer extracted with DCM (3x10 mL). The combined organic layers were dried (MgSOq), filtered and evaporated in vacuo. The residue was dissolved in EtOAc (30 mL) and washed with IM HCl (3 x 30 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give ZerZ-butyl (2S,37?)-2-isopropyl-3-methyl-4-(trifluoromethylsulfonyloxy)-2,3dihydrofuran-5-carboxylate (676 mg, 88%) as a brown oil, which was used without further purification.

Step 8:

A mixture of crude ZerZ-butyl (25,37?)-2-isopropyl-3-methyl-4-(trifluoromethylsulfonyloxy)2,3-dihydrofuran-5-carboxylate (676 mg, 1.81 mmol), 2-(3,4-difluoro-2-methoxy-phenyl)-4,4,5,5tetramethyl-l,3,2-dioxaborolane (731 mg, 2.71 mmol) and sodium carbonate (478 mg, 4.51 mmol) in dioxane (13.5 mL) and water (3.5 mL) in a pressure glass reactor was degassed by bubbling argon through it for 15 mins. Next Pd(dppf)Ch.DCM (206 mg, 0.2523 mmol) was added and the reactor was sealed. The reaction mixture was stirred at 80 °C ovemight before being cooled to ambient température, diluted with EtOAc (20 mL), filtered through celite and concentrated in vacuo. Purification by flash chromatography gave ZerZ-butyl (25,35)-4-(3,4-difIuoro-2-methoxy

398 phenyl)-2-isopropyl-3-methyl-2,3-dihydrofuran-5-carboxylate (107 mg, 14%) as a yellow oil. Ή NMR (300 MHz, Chloroform-d) δ 6.98 - 6.74 (m, 2H), 4.14 (dd, J = 10.2, 8.0 Hz, IH), 3.92 (d, J = 1.8 Hz, 3H), 3.18-2.99 (m, IH), 2.14 (dp, J = 10.1, 6.4 Hz, IH), 1.30 (s, 9H), 1.19 (d, J = 6.5 Hz, 3H), 0.97 (dd, J = 7.8, 6.8 Hz, 6H) ppm; ^,9F NMR (376 MHz, Chloroform-d) δ -136.92 - -137.21 (m), -155.04 - -155.40 (m) ppm.

Step 9:

Ethanol (3.5 mL) was added to a mixture of ZerZ-butyl (25,35)-4-(3,4-difluoro-2-methoxyphenyl)-2-isopropyl-3-methyl-2,3-dihydrofuran-5-carboxylate (118 mg, 0.32 mmol) and Pd/C (Degussa, wet, 350 mg, 0.33 mmol). The mixture was degassed and stirred under a balloon of hydrogen for 4 days before being filtered through celite, washing with EtOAc. The filtrate was concentrated in vacuo to give ZerZ-butyl (25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5isopropyl-4-methyl-tetrahydrofiiran-2-carboxylate (100 mg, 84%). Ή NMR (400 MHz, Chloroform-d) δ 7.11 - 7.03 (m, IH), 6.83 - 6.75 (m, IH), 4.45 (d, J = 7.9 Hz, IH), 4.23 (t, J = 8.3 Hz, IH), 3.93 (d, J = 1.5 Hz, 3H), 3.49 (dd, J = 9.9, 6.9 Hz, IH), 2.76 - 2.63 (m, IH), 1.97 - 1.83 (m, IH), 1.15 (s, 9H), 1.13 (d, J = 6.5 Hz, 3H), 0.90 (d, J = 6.5 Hz, 3H), 0.70 (d, J = 7.4 Hz, 3H) ppm.

Step 10:

TerZ-butyl (25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyltetrahydroftiran-2-carboxylate (100 mg, 0.27 mmol) and potassium ZerZ-butoxide (60 mg, 0.53 mmol) were mixed in ZerZ-butanol (2.6 mL) and stirred at ambient température. After 1 hour the reaction was heated to 35 °C. After 2 hours at this température the reaction was cooled to ambient température, LiOH (400 pL of 2 M, 0.80 mmol) was added and the reaction stirred at ambient température for 16 h. The reaction was diluted with EtOAc and quenched with 1 M aqueous HCl. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to afford (2Λ,35,45,55)-3-(3,4-difluoro-2methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofiiran-2-carboxylic acid (100 mg) as a white solid, which was used without further purification.

Step 11:

To a solution of (2R,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyltetrahydrofuran-2-carboxylic acid (100 mg, 0.3181 mmol) in DCM (3 mL) stirring at 0 °C was added DMF (5 pL, 0.065 mmol) and oxalyl chloride (90 pL, 1.03 mmol). After 30 mins the reaction

399 mixture was concentrated in vacuo. The residue was diluted in DCM (2 mL) and the solution added dropwise to a solution of methyl 4-aminopyridine-2-carboxylate (75 mg, 0.4929 mmol) and Et₃N (300 pL, 2.15 mmol) in DCM (1.5 mL) stirring at 0 °C. DMAP (5 mg, 0.041 mmol) was added and the reaction stirred at this température for 10 mins before being warmed to ambient température and stirred for 16 h. The reaction mixture was diluted with DCM and washed with 1 M HCl solution, the organic layer dried (MgSO₄), filtered and concentrated in vacuo directly onto silica. Purification by flash chromatography (24 g SiO₂, 0 to 100% EtOAc in petrol) gave methyl 4-[[(27?,35,45,55)-3-(3,4difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxylate (73 mg, 51%). ESI-MS m/z cale. 448.18097, found 449.2 (M+l)⁺; 447.3 (M-l)-.

Step 12:

Methyl 4-[[(27?,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (73 mg, 0.1628 mmol) was stirred in methanolic ammonia (5 mL of 7 M, 35.00 mmol) at ambient température ovemight. The reaction mixture was concentrated in vacuo and purified by chiral SFC using a Chiralpak AS-H column (5 pm particle size, 25 cm x 10 mm from Daicel) on a Minigram SFC instrument from Berger Instruments to remove a minor diastereomer to give 4-[[(27?,35,45,55)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (113, 30.5 mg, 41%). ’H NMR (500 MHz, DMSO-d₆) δ 10.34 (s, 1H), 8.47 (d, 1H), 8.25 (d, J = 2.2 Hz, 1H), 8.05 (d, J = 2.8 Hz, 1H), 7.85 (dd, J = 5.5, 2.2 Hz, 1H), 7.59 (d, J = 2.8 Hz, 1H), 7.25 - 7.10 (m, 2H), 4.87 (d, J = 10.1 Hz, 1H), 4.09 (dd, J = 10.2, 5.8 Hz, 1H), 3.95 - 3.84 (m, 4H), 3.29 (s, 1H), 1.78 1.61 (m, 1H), 1.07 (d, J = 6.4 Hz, 3H), 0.86 (d, J = 6.6 Hz, 3H), 0.58 (d, J = 7.0 Hz, 3H) ppm. ESIMS m/z cale. 433.1813, found 434.2 (M+l)⁺; 432.3 (M-l)’.

400

Example 23

6-[[(27?,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (114)

2) Pd(OH)₂/C, H₂ (40 psi). MeOH, 100%

5) LiOH, THF MeOH, H₂O (rac)

8) 2-MeTHF, DMF (cat.), (COCI)₂, 0°C then TEA, methyl 6aminopyridine-2carboxylate, 83°/^

7) 1M HCl, MTBE, 99%

114

Step 1:

rac-(15,27?)-6,7-difluoro-l,2-dimethyl-2-(trifluoromethyl)-l,2-dihydro-4H-furo[2,3c]chromen-4-one (1348 g, 4.366 mol) was separated by chiral SFC using a (R,R)-Whelk-Ol column, 5 pm particle size, 15 cm x 3 cm from Regis Technologies on a MultiGram III SFC instrument from Berger Instruments to give:

401

First Eluting Isomer (rt = 1.85 min): (17Î,25)-6,7-difluoro-l,2-dimethyl-2(trifluoromethyl)-l,2-dihydro-4H-furo[2,3-c]chromen-4-one (only an analytical sample was collected). Ή NMR (400 MHz, DMSO-d₆) δ 7.57 (ddd, J = 9.0, 5.5, 2.0 Hz, 1H), 7.51 (ddd, J = 10.3, 9.0, 7.0 Hz, 1H), 4.03 (q, J = 7.2 Hz, 1H), 1.65 (s, 3H), 1.45 (dt, J = 6.9, 2.2 Hz, 3H) ppm. ESI-MS m/z cale. 320.04718, found 321.3 (M+l)⁺; 319.4 (M-l)'.

Second Eluting Isomer (rt = 2.38 min): (15,27?)-6,7-Difluoro-l,2-dimethyl-2(trifluoromethyl)-l,2-dihydro-477-furo[2,3-c]chromen-4-one (366.99 g, 26%). Ή NMR (400 MHz, DMSO-dô) δ 7.57 (ddd, J = 9.0, 5.5, 2.0 Hz, 1H), 7.50 (ddd, J = 10.3, 9.0, 7.0 Hz, 1H), 4.03 (q, J = 7.2 Hz, 1H), 1.65 (s, 3H), 1.45 (dt, J = 6.9, 2.2 Hz, 3H) ppm. ESI-MS m/z cale. 320.04518, found 321.4 (M+l)⁺; 319.4 (M-l)'.

Step 2:

A solution of (15,27?)-6,7-DifIuoro-l,2-dimethyl-2-(trifIuoromethyl)-l,2-dihydro-4Hfuro[2,3-c]chromen-4-one (0.89 kg, 2.78 mol) and 20% palladium hydroxide on carbon (50% wet, 0.39 kg, 0.278 mol) in MeOH (12 L) was stirred under a 40 psi pressure of hydrogen ovemight. An increase in the reaction température to 37 °C was observed after reacting ovemight and the mixture was cooled to 24 °C and hydrogénation was continued for a total of 48 hours. The mixture was filtered through celite, washing with MeOH (20 L) and the fïltrate was concentrated in vacuo. The residue was dissolved in toluene (4 L) and concentrated in vacuo, and this process repeated. The residue was dried under vacuum at 40 °C ovemight to give methyl (25,35,45,57?)-3-(3,4-difluoro-2hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.0 kg at 91% purity, 100%) as a beige solid. Ή NMR (400 MHz, DMSO-d₆) 10.20 (br s, 1H), 6.94 (br t, J = 7.4 Hz, 1H), 6.79-6.69 (m, 1H), 5.10 (d, J = 6.0 Hz, 1H), 4.20 (dd, J = 6.1, 8.2 Hz, 1H), 3.43 (s, 3H), 2.94 (quin, J = 7.7 Hz, 1H), 1.46 (s, 3H), 0.77 (br d, J = 6.8 Hz, 3H) ppm.

Step 3:

Potassium carbonate (2.0 kg, 14.4 mol) and iodomethane (800 mL, 12.8 mol) were sequentially added to a solution of methyl (25,35,45,57?)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.0 kg, 2.82 mol) in acetonitrile (10 L) under nitrogen stirring at ambient température. After stirring ovemight, additional iodomethane (120 mL, 2 mmol) was added. After stirring ovemight, additional iodomethane (60 mL, 0.85 mmol) was added and the mixture was stirred for 3 days. The reaction mixture was diluted with MTBE (30 L),

402 treated with celite (1 kg) and filtered through a bed of celite (1 kg) washing with MTBE (10 L). The filtrate was filtered a second time through celite (1 kg) washing with MTBE (4 L) and the filtrate concentrated in vacuo. The residue was dissolved in toluene (4 L) and concentrated in vacuo, and this process repeated. The residue was dried under vacuum at 40 °C ovemight to give methyl (25,35,45,55)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-diniethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxylate (0.99 kg at 90% purity, 95%) as a brown solid. ‘H NMR (400 MHz, DMSO-de) 7.147.00 (m, 2H), 5.14 (d, J = 6.0 Hz, 1H), 4.15 (dd, J = 6.2, 8.4 Hz, 1H), 3.88 (d, J = 1.7 Hz, 3H), 2.97 (quin, J = 7.8 Hz, 1H), 1.48 (s, 3H), 0.72 (br d, J = 6.6 Hz, 3H) ppm.

Step 4 and 5:

Sodium methoxide (25% in methanol, 65 mL, 0.28 mol) was added to a solution of methyl (25,35,45,55)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofiiran2-carboxylate (0.98 kg, 2.66 mol) in THF (10 L) stirring at ambient température under nitrogen. After 5 hours, MeOH (1 L), water (IL) and lithium hydroxide monohydrate (0.168 kg, 4.0 mol) were sequentially added and the mixture was stirred ovemight. The reaction mixture was poured into IM HCl (4.4 L, 4.4 mol) then extracted with MTBE (20 L). The aqueous layer was further extracted with MTBE (2 x 5 L) and the combined organic layers washed with brine (2 L), dried (NaiSCh) then treated with activated carbon (50 g, 5% w/w) with stirring for 1 h. The mixture was filtered through celite, washing with MTBE (2 x 4 L) and the filtrate concentrated in vacuo. The residue was dissolved in toluene (4 L) and concentrated in vacuo, then dissolved in MTBE (4 L) and concentrated in vacuo again to give (25,35,45,55)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1.06 kg at 77.7% purity) as an amber oil, which was used without further purification.

Step 6:

Crade (25,35,45,55)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (2.09 kg at 77% purity, 4.54 mol) was dissolved in MTBE (25 L) in a 100 L Chemglass reactor then stirred at 84 rpm at ambient température. A mixture of (5)-l-phenylethylamine (0.704 kg, 5.81 mol) and MTBE (2 L) was added to the reactor, followed by additional MTBE to give a total volume of 30 L in the reactor. After 2 hours additional MTBE (2 L) was added to the reaction and after a total of 3.5 hours the mixture was filtered, washing with MTBE (2 L). The reactor was rinsed with MTBE (4 L), which was used to rinse the

403 solids, which were then compressed and dried on the Büchner funnel for 2 hours. The solid product cake was loosened then dried under a stream of nitrogen and under vacuum ovemight on the Büchner funnel. The isolated solids were dried in a convection oven at 40 °C for 24 hours to give (27î,35,45,57?)-3-(3,4-Difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran2-carboxylic acid (7?)-l-phenylethan-l-amine sait (1.86 kg at 95.7% purity, 74% over 3 steps) as an off-white solid. Ή NMR, 400 MHz, DMSO-d₆) 8.34 (br s, 2H), 7.46-7.41 (m, 2H), 7.36-7.27 (m, 3H), 7.16-7.11 (m, IH), 7.10-7.03 (m, IH), 4.58 (d, J = 9.9 Hz, IH), 4.23 (q, J = 6.7 Hz, IH), 3.99 (dd, J = 7.8, 9.8 Hz, IH), 3.90 (d, J = 2.0 Hz, 3H), 2.60 (quin, J = 7.5 Hz, IH), 1.50 (s, 3H), 1.40 (d, J = 6.7 Hz, 3H), 0.71-0.59 (m, 3H) ppm.

Step 7:

To a suspension of (2R,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (17?)-l-phenylethanamine sait (10.6 g, 22.29 mmol) in MTBE (250 mL) was added HCl (200 mL of 2 M, 400.0 mmol). The layers were separated and the organic layer was washed with water (200 mL), dried (MgSCU), filtered and concentrated in vacuo to give (2R,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (8.4 g, 99%) as an oil. Ή NMR (400 MHz, Chloroform-d) δ 6.96 (ddd, J = 7.9, 5.6, 2.0 Hz, IH), 6.88 (td, J = 9.2, 7.3 Hz, IH), 4.96 (d, J = 10.5 Hz, IH), 4.15 (dd, J = 10.5, 8.0 Hz, IH), 4.02 (d, J = 2.8 Hz, 3H), 2.74 (p, J = 7.6 Hz, IH), 1.64 (t, J = 1.2 Hz, 3H), 0.79 (dq, J = 7.4, 2.3 Hz, 3H) ppm.

Step 8:

To an ice cooled solution of (2R,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (63 mg, 0.1672 mmol) in 2methyltetrahydrofuran (0.6 mL) was added DMF (1.8880 mg, 2 pL, 0.0258 mmol) followed by carefully addition of oxalyl chloride (37.830 mg, 26 pL, 0.2980 mmol). The reaction mixture was warmed up to room température and stirred for 1 hr. The reaction mixture was concentrated in vacuo and the residue dissolved in 2-methyltetrahydrofuran (0.6 mL). To this was added methyl 6aminopyridine-2-carboxylate (25 mg, 0.1643 mmol) and triethylamine (34.122 mg, 47 pL, 0.3372 mmol). The resulting mixture was stirred at room température for 1 hour. The reaction mixture was quenched with water (5 mL) and partitioned with ethyl acetate (10 mL). The layers were separated and the organic phase was washed with brine (5 mL), dried (sodium sulfate), filtered and

404 concentrated under reduced pressure. Purification by flash chromatography (Biotage Isolera, 12 g SiliaSep 25 pm Silicycle flash cartridge, 0 to 100% ethyl acetate in heptane) gave methyl 6[[(27?, 35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (72 mg, 83%) as a pale yellow glassy oil. ‘H NMR (400 MHz, Chloroform-d) δ 9.04 (s, 1H), 8.37 (dd, J = 8.2, 1.1 Hz, 1H), 7.87 (dd, J = 7.6, 0.9 Hz, 1H), 7.84-7.75 (m, 1H), 7.09-7.04 (m, 1H), 6.88 (td, J = 9.2, 7.5 Hz, 1H), 5.00 (d, J = 11.0 Hz, 1H), 4.12-4.06 (m, 1H), 3.99 (d, J = 3.4 Hz, 3H), 3.97 (d, J = 3.0 Hz, 3H), 2.762.68 (m, 1H), 1.69 (s, 3H), 0.82-0.69 (m, 3H) ppm. ESI-MS m/z cale. 488.1371, found 489.14 (M+l)⁺.

Step 9:

A solution of methyl 6-[[(27?,35,45,5/?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (72 mg, 0.1388 mmol) in ammonia (7 M in methanol) (1 mL of 7 M, 7.0000 mmol) was stirred at room température ovemight and then concentrated in vacuo to give a colourless oil. Purification by flash chromatography (Biotage Isolera, 12 g SiliaSepC18 Monomeric 25 pm Silicycle flash cartridge, 30 to 90% acetonitrile containing 0.1% ammonium hydroxide in water containing 0.1% ammonium hydroxide). Fractions containing product were freeze dried to give 6-[[(27?,35,45,57î)-3-(3,4difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (114, 24.5 mg, 36%) as a white solid. Ή NMR (400 MHz, Chloroform-d) δ 8.85 (s, 1H), 8.31 (dd, J = 8.2, 0.7 Hz, 1H), 7.97 (dd, J = 7.6, 0.7 Hz, 1H), 7.84 (t, J = 7.9 Hz, 1H), 7.59 (s, 1H), 7.12-7.08 (m, 1H), 6.90 (td, J = 9.2, 7.5 Hz, 1H), 5.62 (s, 1H), 5.03 (d, J = 11.0 Hz, 1H), 4.11 (dd, J = 10.9, 8.1 Hz, 1H), 3.99 (d, J = 2.7 Hz, 3H), 2.79-2.70 (m, 1H), 1.71 (s, 3H), 0.81-0.78 (m, 3H) ppm. ESI-MS m/z cale. 473.1374, found 474.15 (M+l)⁺.

The following compounds were made using the method described in Example 23, except that different coupling partners were used in the amide coupling step 8:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
117	6-[[(27?,35,45,5R)-3-(3,4- difluoro-2-methoxy-phenyl)- 4,5-dimethyl-5-	ESI-MS m/z cale. 474.1326, found 475.48 (M+l)⁺;	Ή NMR (400 MHz, Chloroform-d) δ 9.64 (s, 1H), 9.17 (d, J = 0.5

405

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
	(trifluoromethyl)tetrahydrofii ran-2- carbonyl] amino]pyrazine-2carboxamide	Rétention time: 2.4 minutes	Hz, 1H), 8.85 (s, 1H), 7.39 (s, 1H), 7.10-7.04 (m, 1H), 6.92 (td, J = 9.2, 7.4 Hz, 1H), 5.70 (s, 1H), 5.07 (d, J = 11.0 Hz, 1H), 4.13 (dd, J = 11.0, 8.2 Hz, 1H), 4.01 (d, J = 3.0 Hz, 3H), 2.81-2.73 (m, 1H), 1.71 (s, 3H), 0.81-0.78 (m, 3H) ppm.
118	5-[[(272,35,45,572)-3-(3,4- difluoro-2-methoxy-phenyl)- 4,5-dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl] amino]pyridine-3 carboxamide	ESI-MS m/z cale. 473.1374, found 474.46 (M+l)⁺; Rétention time: 2.24 minutes	Ή NMR (400 MHz, Chloroform-d) δ 8.88 (d, J = 2.3 Hz, 1H), 8.80 (d, J = 1.8 Hz, 1H), 8.60 (s, 1H), 8.49 (t, J = 2.2 Hz, 1H), 7.10-7.06 (m, 1H), 6.90 (td, J = 9.2, 7.5 Hz, 1H), 6.32 (br. s, 1H), 5.88 (br. s, 1H), 5.04 (d, J= 11.0 Hz, 1H), 4.11 (dd, J = 11.1,8.1 Hz, 1H), 4.01 (d, J = 3.0 Hz, 3H), 2.80-2.70 (m, 1H), 1.69 (s, 3H), 0.80-0.74 (m, 3H) ppm.

406

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
119	4-[[(27?,3S,45,5R)-3-(3,4difluoro-2-methoxy-phenyl)4,5-dimethyl-5(trifluoromethyl)tetrahydrofu ran-2-carbonyl]amino]-5methyl-pyridine-2carboxamide	ESI-MS m/z cale. 487.153, found 488.13 (M+l)⁺; Rétention time: 2.54 minutes	Ή NMR (400 MHz, Chloroform-d) δ 8.89 (s, 1H), 8.58 (s, 1H), 8.32 (s, 1H), 7.71 (s, 1H), 7.12-7.08 (m, 1H), 6.90 (td, J = 9.2, 7.5 Hz, 1H), 5.54 (s, 1H), 5.05 (d, J = 11.0 Hz, 1H), 4.08 (dd, J = 11.0, 7.8 Hz, 1H), 4.00 (d, J = 3.0 Hz, 3H), 2.802.72 (m, 1H), 2.32 (s, 3H), 1.68 (d, J = 0.7 Hz, 3H), 0.78 (td, J = 4.9, 2.4 Hz, 3H) ppm.
120	2-[[(2R,35,45,5R)-3-(3,4difluoro-2-methoxy-phenyl)4,5-dimethyl-5(trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-4carboxamide	ESI-MS m/z cale. 473.1374, found 474.1 (M+l)⁺; Rétention time: 2.37 minutes	Ή NMR (400 MHz, Chloroform-d) δ 9.05 (s, 1H), 8.45 (d, J = 5.0 Hz, 1H), 8.42 (s, 1H), 7.55 (dd, J = 5.0, 1.6 Hz, 1H), 7.12-7.08 (m, 1H), 6.94-6.87 (m, 1H), 6.24 (s, 1H), 5.68 (s, 1H), 5.03 (d,J= 11.2 Hz, 1H), 4.10 (dd, J = 11.0, 8.2 Hz, 1H), 3.99 (d, J = 3.0 Hz, 3H), 2.78-2.70 (m, 1H), 1.69

407

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
			(s, 3H), 0.80-0.77 (m, 3H) ppm.
121	6-[[(27?,35,4S,57?)-3-(3,4difluoro-2-methoxy-phenyl)4,5-dimethyl-5(trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyrimidine4-carboxamide	ESI-MS m/z cale. 474.1326, found 475.17 (M+l)⁺; Rétention time: 2.3 minutes	'HNMR (400 MHz, Chloroform-d) δ 9.22 (brs, 1H), 8.67 (d, J = 5.5 Hz, 1H), 8.27 (d, J = 5.5 Hz, 1H), 7.81 (br s, 1H), 7.07-7.03 (m, 1H), 6.90 (dd, J = 16.9, 8.7 Hz, 1H), 5.85 (brs, 1H), 5.02 (d, J= 11.0 Hz, 1H), 4.07 (dd, J = 11.0, 8.7 Hz, 1H), 3.99 (d, J= 1.8 Hz, 3H), 2.77-2.69 (m, 1H), 1.69 (s, 3H), 0.78 (d, J = 6.4 Hz, 3 H) ppm.

The following compound was made using a method similar to that described in Example 23, except that ethyl 4-amino-5-fluoropyridine-2 carboxylate was used as coupling partner in the amide formation step 8 in place of methyl 6-aminopyridine-2-carboxylate and in step 9, the product was further purified by MD AP (XBridge Cl 8, 19 x 150 mm, 5 pm) using acetonitrile and water containing 0.1% ammonium hydroxîde (30-80% over 10 minutes) before freeze drying:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
122	4-[[(2/?,3S,4S,5/?)-3-(3,4- difluoro-2-methoxy-phenyl)- 4,5-dimethyl-5-	ESI-MS m/z cale. 491.128, found 492.1	Ή NMR (400 MHz, Chloroform-d) δ 9.10 (d, J = 6.4 Hz, 1H),

408

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
	(trifluoromethyl)tetrahydrofu ran-2-carbonyl]amino]-5fluoro-pyridine-2carboxamide	(M+l)⁺; Rétention time: 2.57 minutes	8.85 (s, IH), 8.37 (d, J = 1.8 Hz, 1H), 7.61 (s, 1H), 7.10-7.06 (m, 1H), 6.94-6.87 (m, 1H), 5.48 (s, 1H), 5.05 (d, J = 11.0 Hz, 1 H), 4.08 (dd, J = 10.8, 8.0 Hz, 1H), 4.00 (d, J = 3.0 Hz, 3H), 2.76 (t, J = 7.8 Hz, 1H), 1.68 (s, 3H), 0.800.77 (m, 3H) ppm.

The following compound was made using a method similar to that described in Example 23, except step 9 was omitted and 5-amino-2-fluorobenzamide was used as a coupling partner in step 8:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
123	(2R, 35,45,5R)-N-(3carbamoyl-4-fluoro-phenyl)3 -(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofu ran-2-carboxamide	ESI-MS m/z cale. 490.1327, found 491.43 (M+l)⁺; Rétention time: 2.5 minutes	‘H NMR (400 MHz, Chloroform-d) δ 8.55 (s, 1H), 8.16 (qd, J = 4.5, 3.0 Hz, 1H), 7.89 (q, J = 3.2 Hz, 1H), 7.12-7.04 (m, 2H), 6.88 (td, J = 9.2, 7.6 Hz, 1H), 6.77-6.69 (m, 1H), 5.92 (s, 1H), 5.00 (d, J = 11.0 Hz, 1 H), 4.07 (dd, J= 10.9, 8.1 Hz, 1H), 3.99 (d, J = 2.7

409

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
			Hz, 3H), 2.77-2.70 (m, 1H), 1.68 (s, 3H), 0.790.76 (m, 3H) ppm.

The following compound was made using a method similar to that described in Example 23, except that methyl 5-deuterio-4-aminopyridine-2-carboxylate was used in place of methyl 6aminopyridine-2-carboxylate in Step 8. Purification was performed by normal phase chromatography (Biotage Isolera, 12 g, SiliaSep 25 pm Silicycle flash cartridge) using heptane-ethyl acetate (0 to 100%).

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
124	5-deuterio-4- [[(2Æ,3S,4S,5/?)-3-(3,4- difluoro-2-methoxy-phenyl)- 4,5-dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide	ESI-MS m/z cale. 474.1437, found 475.15 (M+l)⁺; Rétention time: 2.51 minutes	Ή NMR (400 MHz, Chloroform-d) δ 8.73 (brs, 1H), 8.45 (s, 1H), 7.95 (s, 1H), 7.88 (brs, 1H), 7.10-7.06 (m, 1H), 6.93-6.87 (m, 1H), 5.63 (brs, 1H), 5.02 (d,J = 11.0 Hz, 1H), 4.08 (dd, J = 11.0, 8.2 Hz, 1H), 3.99 (d, J = 2.7 Hz, 3H), 2.79-2.71 (m, 1H), 1.68 (s, 3H), 0.80-0.77 (m, 3H) ppm.

410

Example 24

4-(((25,35,45,55)-3-(3,4-difIuoro-2-methoxy-phcnyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide (126)

Âr

1)2-MeTHF, DMF (cat.), (COCI)₂, 0°C then NH₄OH in THF, 0°C - RT 98%

2) Pd(OAc)₂, Cs₂CO₃, Xantphos, 2-MeTHF, methyl 4chloro-3-fluoropyridine-2-

3) 7 M NH₃ in MeOH, 36%

126

Step 1:

To an ice cooled solution of (25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (99 mg, 0.2571 mmol) (see Example 23, step 7) in 2-methyltetrahydrofuran (1 mL) was added DMF (1.8880 mg, 2 pL, 0.0258 mmol) followed by careful addition of oxalyl chloride (58.200 mg, 40 pL, 0.4585 mmol). The reaction mixture warmed to room température and stirred for 1 hr. The reaction mixture was concentrated in vacuo and the residue dissolved in 2-methyltetrahydrofuran (0.4 mL). To this, was added ammonium hydroxide (28% w/w) (360.00 mg, 0.4 mL of 28 %w/v, 10.272 mmol). The resulting mixture was stirred at room température for 1.5 hr. The reaction mixture was quenched with water (10 mL) and partitioned with ethyl acetate (15 mL). The layers were separated and the organic phase was washed with brine (10 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure to give (25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran2-carboxamide (105 mg, 98%) as a pale yellow oil. 'H NMR (400 MHz, DMSO-dô) δ 7.51 (s, 1H), 7.35-7.31 (m, 1H), 7.16-7.12 (m, 2H), 4.82 (d, J = 10.8 Hz, 1H), 4.06-4.00 (m, 1H), 3.93 (d, J = 2.3 Hz, 3H), 2.69-2.62 (m, 1H), 1.55 (s, 3H), 0.67 (dd, J = 7.3, 2.1 Hz, 3H) ppm.

411

Step 2:

(27?,35,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide (100 mg, 0.2354 mmol), methyl 4-chloro-3-fluoropyridine-2-carboxylate (144 mg, 0.2583 mmol), Pd(OAc)2 (11 mg, 0.0490 mmol), césium carbonate (153 mg, 0.4696 mmol) and Xantphos (55 mg, 0.0951 mmol) were suspended in 2-MeTHF (2 mL) and heated to 100 °C for 16 hrs. The reaction was diluted with ethyl acetate (5 mL) and washed with water (5 mL), followed by brine (5 mL). The organic layer was dried (sodium sulfate), filtered and concentrated in vacuo. Purification by flash chromatography (Biotage Isolera, 12 g SiliaSep 25 pm Silicycle flash cartridge, loaded from DCM, 0 to 100% ethyl acetate in heptane) to give methyl 4-[[(27?,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxylate (42 mg, 29%) as a pale yellow oil. ESI-MS m/z cale. 506.1276, found 507.5 (M+l)⁺.

Step 3:

A mixture of methyl 4-(((272,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxylate (37 mg, 0.0599 mmol) and ammonia (7 M in methanol) (1 mL of 7 M, 7.0000 mmol) in methanol (0.5 mL) was stirred for 1 h and then concentrated in vacuo. Purification by MD AP (XBridge Cl 8, 19 x 150 mm, 5 pm) using acetonitrile and water containing 0.1% ammonium hydroxide (30-80% over 10 minutes) to give 4-(((272,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide (126, 5.9 mg, 20%) as a white solid. ‘H NMR (400 MHz, Chloroform-d) δ 9.09 (br s, 1H), 8.46 (t, J = 5.3 Hz, 1H), 8.26 (d, J = 5.5 Hz, 1H), 7.69 (br s, 1H), 7.11-7.07 (m, 1H), 6.94-6.87 (m, 1H), 5.53 (br s, 1H), 5.04 (d, J = 11.0 Hz, 1H), 4.06 (dd, J = 11.3, 7.7 Hz, 1H), 4.00 (d, J = 2.7 Hz, 3H), 2.79-2.71 (m, 1H), 1.68 (s, 3H), 0.80-0.78 (m, 3H) ppm. ESI-MS m/z cale. 491.128, found 492.13 (M+l)⁺.

The following compounds were made using a method similar to that described in Example 24, except that different coupling partners were used in the amide coupling step 2 and, for compounds 128 and 127, the purification in step 3 was conducted by reverse phase chromatography (Biotage Isolera, 12 g, SiliaSepC18 Monomeric 25 pm Silicycle flash cartridge) using a gradient of acetonitrile containing 0.1% ammonium hydroxide and water containing 0.1% ammonium hydroxide before freeze drying:

412

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
128	4-[[(2R,35,45,5R)-3-(3,4difluoro-2-methoxy-phenyl)4,5-dimethyl-5(trifluoromethyl)tetrahydrofu ran-2-carbonyl]amino]-6methyl-pyridine-2carboxamide	ESI-MS m/z cale. 487.153, found 488.12 (M+l)⁺; Rétention time: 2.58 minutes	Ή NMR (400 MHz, Chloroform-d) δ 8.75 (s, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.90 (d, J = 2.7 Hz, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.117.07 (m, 1H), 6.90 (td, J = 9.2, 7.5 Hz, 1H), 5.68 (d, J = 3.9 Hz, 1H), 5.02 (d, J= 11.0 Hz, 1H), 4.08 (dd, J = 11.2, 8.0 Hz, 1H), 4.00 (d, J = 2.7 Hz, 3H), 2.79-2.71 (m, 1H), 2.50 (d, J = 4.4 Hz, 3H), 1.69 (s, 3H), 0.80-0.78 (m, 3H) ppm.
127	4-[[(2R,35,45,5R)-3-(3,4difluoro-2-methoxy-phenyl)4,5-dimethyl-5(trifluoromethyl)tetrahydrofu ran-2-carbonyl]amino]-6fluoro-pyridine-2carboxamide	ESI-MS m/z cale. 491.128, found 492.41 (M+l)⁺; Rétention time: 2.66 minutes	Ή NMR (400 MHz, Chloroform-d) δ 8.77 (brs, 1H), 7.91 (d, J = 1.8 Hz, 1H), 7.76 (s, 1H), 7.51 (brs, 1H), 7.08-7.04 (m, 1H), 6.94-6.87 (m, 1H), 5.56 (br s, 1H), 5.02 (d, J = 11.0 Hz, 1H), 4.06 (dd, J = 11.2, 8.0 Hz, 1H), 4.00 (d, J = 2.7 Hz,

413

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
			3H), 2.79-2.71 (m, IH), 1.68 (s, 3H), 0.80-0.77 (m, 3H) ppm.
128	4-[[(27?,3S,4S,57?)-3-(3,4difluoro-2-methoxy-phenyl)4,5-dimethyl-5(trifluoromethyl)tetrahydrofu ran-2-carbonyl]amino]-3methyl-pyridine-2carboxamide	ESI-MS m/z cale. 487.153, found 488.17 (M+l)⁺; Rétention time: 2.42 minutes	Ή NMR (400 MHz, Chloroform-d) δ 8.88 (brs, IH), 8.37 (d, J = 5.5 Hz, IH), 8.32 (d, J = 5.5 Hz, IH), 7.93 (br s, IH), 7.12-7.08 (m, IH), 6.91 (dd, J= 16.7, 8.9 Hz, IH), 5.54 (brs, IH), 5.06 (d, J = 11.0 Hz, IH), 4.08 (dd, J = 11.0, 7.8 Hz, IH), 4.00 (d, J = 2.7 Hz, 3H), 2.80-2.75 (m, IH), 2.71 (s, 3H), 1.69 (s, 3H), 0.80 (dd, J = 7.3, 1.8 Hz, 3 H) ppm.
129	3-deuterio-4- [[(2Æ,3S,4S,5/?)-3-(3,4difluoro-2-methoxy-phenyl)- 4,5-dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl] amino]pyridine-2carboxamide	ESI-MS m/z cale. 474.1437, found 475.21 (M+l)⁺; Rétention time: 2.48 minutes	‘H NMR (400 MHz, Chloroform-d) δ 8.77 (s, IH), 8.44 (dd, J = 10.8, 4.8 Hz, IH), 8.188.12 (m, IH), 7.86 (s, IH), 7.10-7.06 (m, IH), 6.90 (td, J = 9.2, 7.3 Hz, IH), 5.66 (s, IH), 5.02 (d, J= 11.0 Hz,

414

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
			1H), 4.08 (dd, J= 11.0, 8.2 Hz, 1H), 3.99 (d, J = 2.7 Hz, 3H), 2.792.70 (m, 1H), 1.68 (s, 3H), 0.80-0.77 (m, 3H) ppm.
130	6-deuterio-4- [[(272,35,45,572)-3-(3,4- difluoro-2-methoxy-phenyl)- 4,5-dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl] amino]pyridine-2carboxamide	ESI-MS m/z cale. 474.1437, found 475.19 (M+l)⁺; Rétention time: 2.5 minutes	Ή NMR (400 MHz, Chloroform-d) δ 8.67 (brs, 1H), 8.15 (d, J = 2.3 Hz, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.84 (br s, 1H), 7.10-7.06 (m, 1H), 6.90 (td, J = 9.2, 7.3 Hz, 1H), 5.59 (brs, 1H), 5.01 (d, J = 11.0 Hz, 1H), 4.07 (dd, J = 11.2, 8.0 Hz, 1H), 3.99 (d, J = 2.7 Hz, 3H), 2.78-2.71 (m, 1H), 1.68 (s, 3H), 0.80-0.77 (m, 3H) ppm.

415

Example 25 reZ-(25,37î,42î,55)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (131), rel(27?,35,45,5Z?)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-55 (trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (132), rel(27î,35,4Æ,5₁S)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (133) and rel(25,37?,4S,51î)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (134)

F₃C„^Me

(rac)

Me OTf

1) B₂Pin₂, KOAc, Pd(dppf)CI₂,1,4dioxane, 80°C, 95% _c _ Me

ΥψΟ ,O

F₃C,^Me

Me'

(rac)

2) 1-Bromo-3,4difluoro-2methylbenzene, K3PO4,1,4-dioxane, Pd(dppf)CI₂DCM,

OEt 100°C, 67%

B-o

(rac)

4)KOt-Bu, 2- p r Me MeTHF, 5°C, 71% D

5) 2-MeTHF, DMF (cat.), (COCI)₂, 0°C then TEA, methyl 4aminopyridine-2carboxylate, 56%^

Me'

F₃C„^Me

Me Ar (rac)

3) Mg, 1,2 dibromoethane (cat), 70°C, 76%

Ar =

f₃c,.

Me

NH₂ 7) SFC (rac) . OH 6) 7 M NH₃ in

Âr MeOH, 49%

OMe Âr (rac)

]θ 131, first eluting isomer 132, second eluting isomer 133, third eluting isomer 134, fourth eluting isomer

Step 1:

To a 3 neck 1 litre flask hooked up with a thermometer and air condenser is added ethyl rac(4Z?,57?)-4,5-dimethyl-5-(trifluoromethyI)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-215 carboxylate (42 g, 108.7 mmol) and 1,4-dioxane (500 mL). The mixture was stirred and degassed

416 and flushed with nitrogen. KOAc (32 g, 326.1 mmol) was added followed by bis(pinacolato)diboron (32 g, 126.0 mmol). The reaction mixture was evacuated and back filled with nitrogen (x3). Pd(dppf)Ch (4 g, 5.467 mmol) was added to this reaction mixture which was heated to 60 °C first then when stable, the température was increased to 80 °C (to avoid exotherm). The reaction was allowed to proceed with stirring at 80 °C under nitrogen for 20 hours. The reaction mixture was then cooled to ambient température and diluted with ethyl acetate (300 mL) and water (100 mL). The mixture was filtered through a pad of celite, washing several times with ethyl acetate until no more product came off (5 x 100 ml). The filtrate is then separated, and the aqueous layer was extracted with ethyl acetate twice (100 mL). The combined organic layers were dried and filtered using Whatman 1PS hydrophobie phase separator filter paper. The filtrâtes were concentrated in vacuo to give 47 g of a brown oil. The crude product (47 g) was absorbed onto diatomaceous earth (Telos nm) and passed through a Florisil (magnésium silicate) pad, washing with 100% heptane until no more product came off (4 fractions in total). The filtrâtes were combined and concentrated in vacuo to give ethyl rac-(45,57?)-4,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (47 g, 95%) as a thick viscous yellow oil. Ή NMR (500 MHz, Chloroform-d) δ 4.33 - 4.23 (m, 2H), 3.27 - 3.18 (m, IH), 1.55 (d, J = 1.1 Hz, 3H), 1.32 (s, 12H), 1.28 (d, J = 2.3 Hz, 2H), 1.24 (s, 3H) ppm. ESI-MS m/z cale. 364.1669, found 365.3 (M+l)⁺.

Step 2:

To a solution of rac-(45,57î)-4,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (3 g, 7.414 mmol), l-bromo-3,4-difluoro-2methyl-benzene (1.4 g, 6.763 mmol) and Pd(dppf)C12.CH2C12 (350 mg, 0.4286 mmol) in 1,4dioxane (60 mL), was added an aqueous solution of K3PO4 (8 mL of 2 M, 16.00 mmol). The mixture was degassed and placed under a nitrogen atmosphère. The reaction was stirred at 100 °C for 2 hours. The mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted 3 times with ethyl acetate. The organics were combined, dried and filtered using Whatman 1PS hydrophobie phase separator filter paper. The filtrâtes were concentrated in vacuo to give a brown oil. Purification by flash chromatography (RF combiflash companion, 24 g pre-packed gold silica column, 0 to 100% EtOAc in heptane gave ethyl rac-(4S,57î)-3-(3,4-difluoro-2-methylphenyl)4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (2.21 g, 67%) as a pale yellow

417 oil. Ή NMR (500 MHz, Methanol-di) δ 7.10 (dt, J = 10.3, 8.4 Hz, 1H), 6.90 (s, 1H), 4.14 - 4.00 (m, 2H), 3.54 (d, J = 8.2 Hz, 1H), 2.19 (d, J = 2.7 Hz, 3H), 1.70 (d, J = 1.2 Hz, 3H), 1.09 (dq, J = 7.5, 2.4 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H) ppm. ESI-MS m/z cale. 364.10977, found 365.2 (M+l)⁺.

Step 3:

A pressure tube was loaded with magnésium powder (200 mg, 8.229 mmol) and purged with nitrogen. To the reaction vessel was added a solution of ethyl rac-(4S,57?)-3-(3,4-difluoro-2methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (2.02 g, 5.545 mmol) in MeOH (30 mL). The mixture was degassed and placed under a nitrogen atmosphère. A few drops of 1,2-dibromoethane (5 pL, 0.05802 mmol) were added. The reaction mixture was stirred vigorously and heated at 70 °C for 6 hrs.

A further 3 consecutive portions of magnésium powder (200 mg, 8.229 mmol) were added followed by a drop of 1,2-dibromoethane (5 pL, 0.05802 mmol). The mixture was stirred ovemight at 70 °C for 88 hours. The reaction mixture was cooled to 0 °C prier to opening the pressure vessel. The cooled mixture is added dropwise to a cooled beaker containing 1 M HCl. The reaction was stirred at 0 °C for 30 minutes until ail Mg solids dissolved. The mixture was concentrated in vacuo to remove the MeOH. The remaining aqueous solution was extracted with ethyl acetate (x3). The combined organic extracts were dried and filtered using a Whatman 1PS hydrophobie phase separator filter paper. The filtrâtes were concentrated in vacuo to give methyl rac-(2S,35,45,57?)-3(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.487 g, 76%) as the major diastereomer as a colourless oil. ESI-MS m/z cale. 352.10977, found 353.0 (M+l)⁺.

Step 4:

To a cooled solution of methyl rac-(25,35,45,5R)-3-(3,4-difluoro-2-methylphenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.487 g, 4.221 mmol) in2-Me-THF (20 mL) was added potassium ZerZ-butoxide (1.4 g, 12.48 mmol) (internai température increased to ~5 °C) and the reaction was stirred for 1 hour at ambient température. The reaction mixture colour tumed yellow on addition of potassium Z-butoxide. The reaction was diluted with ethyl acetate and 1 N NaOH. The aqueous layer was separated. The organics were washed further with IM NaOH (x2). The combined organic layers were dried and filtered using a Whatman 1PS hydrophobie phase separator filter paper. The filtrâtes were concentrated in vacuo to give rac-(2R,3S,4S,5R)-3-(3,4418 difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1.01 g, 71%) as the major diastereomer as a colourless oil. ESI-MS m/z cale. 338.09415, found 337.0 (Μι)-Step 5:

To a solution of rac-(2R,35,45,57?)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (200 mg, 0.591 mmol) and DMF (2 pL, 0.026 mmol) in 2-methyl-tetrahydrofuran (4.8 mL) stirring at 0 °C under nitrogen was added oxalyl chloride (154.2 mg, 106.0 pL, 1.215 mmol). The mixture was warmed up to room température over 30 minutes. The reaction mixture was concentrated in vacuo and the residue dissolved in 2-methyltetrahydrofuran (4.8 mL). This solution was added to an ice cooled solution of methyl 4aminopyridine-2-carboxylate (110.7 mg, 0.728 mmol) and TEA (278.6 mg, 383.7 pL, 2.753 mmol) in 2-methyl-tetrahydrofuran (4.8 mL). The resulting mixture was stirred and warmed to ambient température over 18 hrs. The reaction mixture was quenched with water (5 mL) and the layers separated. The aqueous layer was extracted with EtOAc (2x10 mL). The combined organics extracts were dried and filtered using a Whatman 1PS hydrophobie phase separator filter paper. The filtrâtes werer concentrated in vacuo to give an oil. Purification by flash chromatography (RF combiflash companion, 4 g pre-packed silica column, 0-50% EtOAc:EtOH (3:1) containing 2% NH4OH in heptane) gave methyl rac-(27?,35,45,57?)-4-[[3-(3,4-difluoro-2-methyI-phenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (235 mg, 59%) as the major diastereomer. ESI-MS m/z cale. 472.14215, found 473.3 (M+l)⁺; 471.3 (M-l)'.

Step 6:

Methyl rac-(2R,35,45,57?)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (235 mg, 0.4975 mmol) was taken up in a solution of ammonia (1 mL of 7 M, 7.000 mmol) in methanol (10 mL) and stirred at room température for 2 hours. The reaction mixture was concentrated in vacuo to give rac(2R,35,45,57?)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (221.4 mg, 49%) as the major diastereomer as a yellow oil. ESI-MS m/z cale. 457.1425, found 458.4 (M+l)⁺; 456.4 (M-l)'.

Step 7:

419 rac-(2R, 35,45,57?)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (221.4 mg, 49%) was purified by chiral SFC using a Chiralpak IG column, 5um particle size, 25 cm x 10 mm from Daicel on a Minigram SFC instrument from Berger Instruments followed by reversed phase HPLC-MS using a X-bridge Cl8 OBD column (150 x 19 mm, 5 mm particle size) from Waters (using gradient elution over 16.0 minutes; mobile phase A = H2O (0.1% ammonium hydroxide), mobile phase B — CH3CN. Flow rate =19 mL/min; injection volume = <2000pL, column température = 25 °C) to give:

First Eluting Isomer (rt = 3.93 min): reZ-(25,37?,47?,55)-4-[[3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide (131, 4.1 mg, 14%). Ή NMR (500 MHz, DMSO-d₆) δ 10.71 (s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.81 (d, J = 5.5 Hz, 1H), 7.59 (s, 1H), 7.26 (q, J = 9.0 Hz, 1H), 7.18 (dd, J = 9.0, 4.3 Hz, 1H), 5.16 (d, J = 10.4 Hz, 1H), 4.19 (dd, J = 10.5, 7.5 Hz, 1H), 2.85 (p, J = 7.5 Hz, 1H), 2.28 (d, J = 2.1 Hz, 3H), 1.64 (s, 3H), 0.71 - 0.66 (m, 3H) ppm. ESI-MS m/z cale. 457.1425, found 458.2 (M+l)⁺; 456.2 (M-l)’.

Second Eluting Isomer (rt = 4.33 min): rel-QR,35,45,57?)-4-[[3-(3,4-difluoro-2-methyIphenyI)-4,5-dimethyl-5-(trifluoromethyI)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (132, 3.6 mg, 13%). Ή NMR (500 MHz, DMSO-d₆) δ 10.69 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.27 (d, J = 2.2 Hz, 1H), 8.04 (s, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.59 (s, 1H), 7.26 (q, J = 9.0 Hz, 1H), 7.17 (dd, J = 8.9, 4.3 Hz, 1H), 5.16 (d, J = 10.5 Hz, 1H), 4.19 (dd, J = 10.4, 7.6 Hz, 1H), 2.85 (p, J = 7.5 Hz, 1H), 2.27 (d, J = 2.2 Hz, 3H), 1.63 (s, 3H), 0.73 - 0.62 (m, 3H) ppm. ESI-MS m/z cale. 457.1425, found 458.2 (M+l)⁺; 456.2 (M-l)‘.

Third Eluting Isomer (rt = 5.05 min): reZ-(27?,35,47?,55)-4-[[3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyI-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (133, 2.4 mg, 8%). ESI-MS m/z cale. 457.1425, found 458.2 (M+l)⁺; 456.2 (M-l)’.

Fourth Eluting Isomer (rt = 6.87 min): reZ-(25,37?,45,57î)-4-[[3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (134, 2.2 mg, 8%). ESI-MS m/z cale. 457.1425, found 458.2 (M+l)⁺; 456.2 (M-l)'.

The following compounds were made using the method described in Example 25, except that the conditions used for the Suzuki coupling step 2 were similar to the ones used in Example 11 step

420 starting with l-bromo-4-(difluoromethyl)-3-fluoro-2-methoxy-benzene. The réduction step 3 was conducted with Pd(OH)₂ using an atmospheric pressure of hydrogen in conditions similar to those described in Example 11 step 4. In step 7, purification was performed by chiral SFC using â Chiralart Amylose-SA column, 5 pm particle size, 25 cm x 20 mm from YMC Co., Ltd on a

Minigram SFC instrument from Berger Instruments:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
135	re/-(25,37?,47?,55)-4-[[3-[4(difluoromethyl)-3-fluoro-2methoxy-phenyl] -4,5- dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2- carboxamide (first eluting isomer by SFC on Chiralart Amylose-SA column, rt = 3.36 min)	ESI-MS m/z cale. 505.14362, found 506.3 (M+l)⁺; 504.3 (M-l); Rétention time: 3.28 minutes
136	rel-(2R, 35,45,57?)-4-[[3-[4(difluoromethyl)-3-fluoro-2methoxy-phenyl]-4,5- dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2- carboxamide (second eluting isomer by SFC on Chiralart AmyloseSA column, rt = 4.40 min)	ESI-MS m/z cale. 505.14362, found 506.3 (M+l)⁺; 504.3 (M-l)’; Rétention time: 3.28 minutes

421

Example 26 re/-(25,37î,47î,55)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (137) and rel(2R, 35,45,57?)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-55 (trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (138)

OTf (rac)

1) ArB(OH)₂, Na₂CO₃, Pd(PPh₃)₄, PhMe, MeOH, H₂O 80°C, 72%

(rac)

2) Pd/C, EtOH, H₂(1 atm), 93%

3) KOf-Bu, THF.^T

4) DCM, DMF (cat ), (COCI)₂, 0°C then NEt₃, DMF, methyl 4aminopyridine-2carboxylate, DCM, 37% over two steps

5) 7N NH₃, MeOH

(rac) (rac)

137, first eluting isomer 138, second eluting isomer

Step 1:

A mixture of ethyl rac-(47?,57?)-4,5-dimethyl-5-(trifluoromethyl)-3(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (3.48 g, 9.00 mmol), [2-methoxy10 6-(trifluoromethyl)-3-pyridyl]boronic acid (1.977 g, 8.95 mmol), Na₂CO₃ (1.9 g, 17.93 mmol) and Pd(PPh₃)4 (520 mg, 0.45 mmol) in PhMe (50 mL), MeOH (5 mL) and water (5 mL) was degassed before being heated at 80 °C for 16 hours. The mixture was cooled to ambient température and diluted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and

422 concentrated in vacuo. Purification by flash chromatography (40 g SiCh, 0 to 30% EtOAc in petrol) gave ethyl rac-(45,57î)-3-(2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-4,5-dimethyl-5(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (2.67 g, 72%) as a colourless oil. ESI-MS m/z cale. 413.10617, found 414.6 (M+l)⁺.

Step 2:

EtOH (50 mL) was added to rac-(45,5J?)-3-(2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-4,5dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (2.16 g, 5.226 mmol) and Pd/C (wet, Degussa, 5.2 g, 4.89 mmol). The mixture was degassed and stirred under a balloon of hydrogen for 16 hours before being filtered through celite, washing with methanol. The filtrate was concentrated in vacuo. Pd/C (wet, Degussa, 5.2 g, 4.89 mmol) was added to the residue and the mixture resuspended in EtOH (50 mL). The mixture was degassed and stirred under a balloon of hydrogen for 16 hours before being filtered through celite, washing with methanol. The filtrate was concentrated in vacuo to give a mixture of diastereomers including ethyl rac-(25,35,45,57?)-3-(2methoxy-6-(trifluoromethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxylate (2.01 g, 93%) as an off-white solid. ESI-MS m/z cale. 415.12183, found 416.7 (M+l)⁺.

Step 3:

To a solution of ethyl rac-(25,35,45,52?)-3-(2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate obtained from Step 2 (2.01 g, 4.84 mmol) in THF (32 mL) was added potassium terZ-butoxide (1.63 g, 14.53 mmol). The reaction was stirred for 3 days, then diluted with EtOAc and quenched with 1 M HCl. The aqueous layer was extracted with EtOAc, and the combined organic layers dried (MgSO4), filtered and concentrated in vacuo to give a mixture of diastereomers including rac-(2R,35,45,57?)-3-(2-methoxy-6(trifluoromethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2-carboxylic acid (2.09 g), which was used without fiirther purification.

Step 4:

To a solution of rac-(27?,35,45,52?)-3-(2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid obtained from Step 3 (500 mg, 1.29 mmol) in DCM (11 mL) stirring at 0 °C was added DMF (10 pL, 0.13 mmol) and oxalyl chloride (340 pL, 3.90 mmol). The reaction mixture was concentrated in vacuo and the residue disolved in DCM (8 mL) and added dropwise to a solution of methyl 4-aminopyridine-2-carboxylate (300 mg,

423

1.97 mmol) and EtjN (1000 pL, 7.18 mmol) in DCM (4 mL) stirring at 0 °C. DMAP (15 mg, 0.1228 mmol) was added and the reaction stirred at this température for 10 mins before being warmed to ambient température. After stirring ovemight the reaction mixture was diluted in DCM and washed with 1 M HCl solution. The organic layer was dried (MgSCU), filtered and concentrated in vacuo, directly onto silica gel. Purification by flash chromatography (40 g SiO2, 0 to 100% EtOAc in petrol) gave a mixture of diastereomers including methyl rac-(2R,35,45,57?)-4-[[3-[2-methoxy-6(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]pyridine-2-carboxylate (252 mg, 37%). ESI-MS m/z cale. 521.13855, found 522.6 (M+l)⁺; 520.7 (M-l)’.

Step 5:

Methyl rac-(2R,35,45,57?)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate obtained from Step 4 (252 mg, 0.4833 mmol) was dissolved in methanolic ammonia (15 mL of 7 M, 105.0 mmol) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to give a mixture of diastereomers including rac-(2R,35,45,57?)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (250 mg).

Step 6:

rac-(2R,35,45,57?)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxamide obtained from Step 5 (250 mg, 0.4937 mmol) was separated by chiral SFC using a (R,R)-Whelk-Ol column, 5 pm particle size, 25 cm x 21.2 mm from Regis Technologies to give:

First Eluting Isomers (rt = 1.04 min and 1.10 min): a mixture of two stereoisomers of 4[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, which were not purified further.

Second Eluting Isomers (rt = 1.28 min and 1.34 min): a mixture of two stereoisomers of 4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide. Further séparation steps are listed below.

Third Eluting Isomer (rt = 1.52 min): a stereoisomer of 4-[[3-[2-methoxy-6(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, that was not characterized further.

424

Fourth Eluting Isomer (rt = 1.93 min): rel-(2R,3S,4S,5R)- 4-[[3-[2-methoxy-6(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (138, 26.4 mg, 10%). *H NMR (500 MHz, DMSO-dô) δ 10.64 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.30 (dd, J = 2.2, 0.6 Hz, 1H), 8.05 (d, J = 2.8 Hz, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.85 (dd, J = 5.5, 2.2 Hz, 1H), 7.60 (d, J = 2.9 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 5.25 (d, J = 9.5 Hz, 1H), 4.22 (t, 1H), 3.96 (s, 3H), 2.93 (p, J = 7.5 Hz, 1H), 1.63 (s, 3H), 0.76 - 0.66 (m, 3H) ppm. ESI-MS m/z cale. 506.1389, found 507.6 (M+l)⁺; 505.7 (M-l)-.

The second eluting peak was further separated by chiral SFC using a Chiralpak AS-H column, 5 pm particle size, 25 cm x 10 mm from Daicel on a Minigram SFC instrument from Berger Instruments to give:

First Eluting Isomer (rt = 3.01 min): rel-(2S,3R,4R,5S)- 4-[[3-[2-methoxy-6(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (137, 18.4 mg, 7%). ESI-MS m/z cale. 506.1389, found 507.5 (M+l)⁺; 505.5 (M-l)'.

Second Eluting Isomer (rt = 4.09 min): a stereoisomer of 4-[[3-[2-methoxy-6(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, that was not characterized further.

The following compound was made using the method described above, except that the conditions used for the Suzuki coupling step 1 were similar to the ones used in Example 13 step 4 starting with 4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2(trifluoromethyl)pyridine. The réduction step 2 was conducted using 5 atm of hydrogen. The chiral SFC séparation step 6 was not carried out and the product was isolated as a pair of enantiomers:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
139	rac-(2R, 35,45,5Æ)-4-[[3-[4- methoxy-6-(trifluoromethyl)- 3-pyridyl]-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2-	ESI-MS m/z cale. 506.1389, found 507.1 (M+l)⁺; Rétention time: 2.327 minutes	‘H NMR (301 MHz, Chloroform-d) δ 8.71 (s, 1H), 8.64 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.16 (dd, J = 5.5, 2.1 Hz, 1H), 7.93 (d, J

425

Cmpd No.	Compound Naine	LC/MS	NMR (shifts in ppm)
	carbonyl] amino]pyridine-2carboxamide		= 2.1 Hz, 1H), 7.84 (br s, 1H), 7.18 (s, 1H), 5.63 (brs, 1H), 5.24 (d, J = 10.7 Hz, 1H), 4.13 (dd, J= 10.8, 8.1 Hz, 1H), 3.97 (d, J = 5.2 Hz, 3H), 2.85 (t, J = 7.6 Hz, 1H), 1.70 (s, 3H), 0.80 (d, J = 5.5 Hz, 3H) ppm.

426

Example 27 rel-(2R, 35,45,57?)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (140) and rel(25,372,472,55)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-55 (trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (141)

3) 3-bromo-6(difluoromethyl)-2-

OTf (rac)

1) B₂Pin₂, KOAc, _M

Pd(dppf)CI₂,1,4- F₃C,7^e _{o 0}dioxane, 80’C, 95% \ \ (/ methoxy-pyridine, K₂CO₃,1,4-dioxane, water, Pd(PPh₃)₄, 100°C, 67% _c _ Me 4) Pd(OH)₂, MeOH,

O h₂ (60 psi), 68%

2) NalO₄, THF, H₂O, ^Me RT then 1 M HCl, 54%

Ar

OEt /^B'OH HO

OEt 5)KOt-Bu, 2MeTHF, RT, 100%

Me' \ Ar

(rac) (rac) (rac)

140, first eluting isomer 141, second eluting isomer

Step 1: To a 3 neck 1 litre flask hooked up with a thermometer and air condenser is added ethyl rac-(4R,572)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfbnyl)oxy)-4,5dihydrofuran-2-carboxylate (42 g, 108.7 mmol) and 1,4-dioxane (500 mL). The mixture was stirred and degassed and flushed with nitrogen. KOAc (32 g, 326.1 mmol) was added followed by bis(pinacolato)diboron (32 g, 126.0 mmol). The reaction mixture was evacuated and back filled with nitrogen (x3). Pd(dppf)Ch (4 g, 5.467 mmol) was added to this reaction mixture which was heated to 60 °C first then when stable, the température was increased to 80 °C (to avoid exotherm). The reaction was allowed to proceed with stirring at 80 °C under nitrogen for 20 hours. The reaction mixture was then cooled to ambient température and diluted with ethyl acetate (300 mL) and water

427 (100 mL). The mixture was filtered through a pad of celite, washing several times with ethyl acetate until no more product came off (5 x 100 ml). The filtrate is then separated, and the aqueous layer was extracted with ethyl acetate twice (100 mL). The combined organic layers were dried and filtered using Whatman 1 PS hydrophobie phase separator filter paper. The filtrâtes were concentrated in vacuo to give 47 g of a brown oil. The crude product (47 g) was absorbed onto diatomaceous earth (Telos nm) and passed through a Florisil (magnésium silicate) pad, washing with 100% heptane until no more product came off (4 fractions in total). The filtrâtes were combined and concentrated in vacuo to give ethyl rac-(4S,55)-4,5-dimethyl-3-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (47 g, 95%) as a thick viscous yellow oil. ‘H NMR (500 MHz, Chloroform-d) δ 4.33 - 4.23 (m, 2H), 3.27 - 3.18 (m, 1H), 1.55 (d, J = 1.1 Hz, 3H), 1.32 (s, 12H), 1.28 (d, J = 2.3 Hz, 2H), 1.24 (s, 3H) ppm. ESI-MS m/z cale. 364.1669, found 365.3 (M+l)⁺.

Step 2:

ethyl rac-(45,55)-4,5-dimethyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (47 g) was dissolved in a 1:2 mixture of water (50 mL) and THF (100 mL). Sodium periodate (50 g, 233.8 mmol) was added and the reaction was stirred for 1 hour at ambient température. The reaction mixture was cooled with an ice bath. 1M HCl (60 mL) was added and reaction mixture was stirred for 60 mins (a white solid précipitâtes). The mixture was diluted with water (50 mL) and ethyl acetate (100 mL). A white solid was filtered and washed with ethyl acetate. The filtrate was washed with sodium thiosulphate (shaken vigorously at every wash to remove traces of iodine) (3 x 50 ml) followed by a brine solution. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum (keeping water bath at room temp). A cream solid (23 g) was obtained and triturated with cold heptane to afford rac-((45,55)-2-(ethoxycarbonyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5dihydrofuran-3-yl)boronic acid (16.66 g, 54%) as a white solid. *H NMR (500 MHz, Chloroform-d) δ 6.84 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 3.18 (q, J = 7.3 Hz, 1H), 1.51 (d, J = 1.2 Hz, 3H), 1.39 (t, J = 7.1 Hz, 3H), 1.32 (dq, J = 7.2, 2.4 Hz, 3H) ppm. ESI-MS m/z cale. 282.08865, found 281.2 (M-l)'

Step 3:

428

To a solution of rac-((45,57?)-2-(ethoxycarbonyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5dihydrofuran-3-yl)boronic acid (902 mg, 3.79 mmol) and Pd(PPh₃)4 (82 mg, 0.071 mmol) in dioxane (20 mL) was added an aqueous solution of K₂CO₃ (3.5 mL of 2 M, 7.000 mmol). The reaction was initially stirred at 100 °C for 2 hours, then at 115 °C for 3 hours. A further 30 mg of Pd(PPh₃)4 was added and the mixture was stirred for a further 30 mins at reflux. The mixture was partitioned between water and ethyl acetate. The aqueous layer was washed twice more with ethyl acetate. The combined organic phases were washed with brine, dried (MgSO₄) and concentrated in vacuo. Purification by flash chromatography (SiO₂, 0 to 25% EtOAc in heptane) gave ethyl rac(45,57î)-3-(6-(difluoromethyl)-2-methoxypyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)-4,5dihydrofuran-2-carboxylate (1.05 g, 75%) as a colourless oil. Ή NMR (500 MHz, Chloroform-d) δ 7.61 (d, J = 7.5 Hz, 1H), 7.22 (d, J = 7.4 Hz, 1H), 6.52 (t, J = 55.6 Hz, 1H), 4.23 - 4.07 (m, 2H), 3.96 (s, 3H), 3.63 (q, J = 7.4 Hz, 1H), 1.70 (d, J = 1.1 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H), 1.06 (dq, J = 7.3, 2.2 Hz, 3H) ppm. ESI-MS m/z cale. 395.1156, found 396.3 (M+l)⁺.

Step 4:

A solution of ethyl rac-(45,57?)-3-(6-(difluoromethyl)-2-methoxypyridin-3-yl)-4,5-dimethyl5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (250 mg, 0.632 mmol) in MeOH (50 mL) was added to Pd(OH)₂ (475 mg of 20 %w/w, 0.67 mmol) under nitrogen in a Parr flask. The flask was connected to the Parr shaker and put under an atmosphère of hydrogen (60 psi, 4 bar). The reaction was shaken at ambient température ovemight. The reaction mixture was carefully filtered through a pad of celite. The collected filtrâtes were concentrated in vacuo to give a ~1:1 mixture of diastereomers of ethyl rac-(45,57?)-3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (170 mg, 68%). ESI-MS m/z cale. 397.13126, found 398.2 (M+l)⁺.

Step 5:

To a solution of ethyl rac-(4S,5R)-3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (160 mg, 0.4027 mmol) in 2-MeTHF (6 mL) was added KOz-Bu (95 mg, 0.8466 mmol) and the reaction was stirred at ambient température for 30 minutes. The reaction was quenched by addition of a 2M HCl solution. Ethyl acetate was added. The separated organic layer was washed with brine, dried (MgSCU), filtered and concentrated in vacuo to give rac-(45,57?)-3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5429 (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (150 mg, 100%) as a colourless oil, one of the diastereoisomers being the major component. ESI-MS m/z cale. 369.09995, found 368.1 (M-l)’.

Step 6:

To a solution of rac-(45,55)-3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (150 mg, 0.4062 mmol) and methyl 4aminopyridine-2-carboxylate (79 mg, 0.5192 mmol) in ethyl acetate (3 mL) was added TEA (170 pL, 1.220 mmol) and T3P (325 pL of 50 %w/w, 0.5460 mmol). The reaction was stirred at 50 °C for 3 hours. The reaction mixture was diluted with water and ethyl acetate. The aqueous layer was further extracted with ethyl acetate. The combined organics were washed with brine, dried (MgSCU), filtered and concentrated in vacno. Purification by flash chromatography (SiCh, 75% EtOAc in heptane) gave the main diastereoisomer methyl rac-(2R,35,45,55)-4-[[3-[6-(difluoromethyl)-2methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxylate (70 mg, 34%) as a colourless oil. Ή NMR (500 MHz, Chloroform-d) δ 8.63 (d, J = 5.5 Hz, 1H), 8.58 (d, J = 10.2 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.91 (dd, J = 5.5, 2.2 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 6.52 (t, J = 55.6 Hz, 1H), 5.10 (d, J = 11.1 Hz, 1H), 4.05 (dd, J = 11.1, 7.8 Hz, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 2.92 (q, J = 7.6 Hz, 1H), 1.72 (d, J = 2.9 Hz, 3H), 0.77 (dt, J = 7.5, 2.3 Hz, 3H) ppm. ESI-MS m/z cale. 503.14795, found 504.4 (M+l)⁺; 502.3 (M-l)'.

Step 7:

rac-(2R,35,45,57?)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (70 mg, 0.1390 mmol) was dissolved in methanolic ammonia (3 mL of 7 M, 21.00 mmol) and stirred at ambient température ovemight. The reaction mixture was concentrated in vacno to give rac-(2R,35,45,5Æ)-4[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide (26 mg, 38%). ESI-MS m/z cale. 488.1483, found 489.3 (M+l)⁺; 487.3 (M-l)’.

Step 8:

rac-(2R,35,45,57î)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (26 mg, 0.053 mmol) was separated by chiral SFC using a Lux i-Cellulose-5 column, 5 pm particle size, 25 cm x 10 mm from Phenomenex, Inc. on a Minigram SFC instrument from Berger Instruments to give:

430

First Eluting Isomer (rt = 4.12 min): rel-QR,35,45,5R)-4-[[3-[6-(difluoromethyl)-2methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide (140, 8.2 mg). Ή NMR (500 MHz, Methanol-ch) δ 8.48 (d, J = 5.6 Hz, 1H), 8.27 (d, J = 2.2 Hz, 1H), 7.91 (dd, J = 5.5, 2.2 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 6.59 (t, J = 55.5 Hz, 1H), 5.19 (d, J = 10.1 Hz, 1H), 4.26 (t, J = 9.0 Hz, 1H), 4.00 (s, 3H), 2.95 (p, J = 7.6 Hz, 1H), 1.67 (s, 3H), 0.79 (dd, J = 7.7, 2.6 Hz, 3H) ppm; amide NH and NH2 protons not observed. ESI-MS m/z cale. 488.1483, found 489.4 (M+l)⁺; 487.3 (M-l)’.

Second Eluting Isomer (rt = 4.71 min): reZ-(25,3R,47?,55)-4-[[3-[6-(difluoromethyI)-2methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide (141, 10.1 mg). Ή NMR (500 MHz, Methanol-iU) δ 8.52 (d, J = 5.7 Hz, 1H), 8.38 (d, J = 2.1 Hz, 1H), 7.99 (dd, J = 5.8, 2.2 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 6.59 (t, J = 55.5 Hz, 1H), 5.22 (d, J = 10.1 Hz, 1H), 4.33 - 4.23 (m, 1H), 4.00 (s, 3H), 2.96 (p, J = 7.6 Hz, 1H), 1.68 (d, J = 1.4 Hz, 3H), 0.80 (dq, J = 7.4, 2.3 Hz, 3H) ppm; amide NH and NH2 protons not observed. ESI-MS m/z cale. 488.1483, found 489.3 (M+l)⁺; 487.3 (M-l)’.

The following compounds were made using a similar method to that described in Example 27, except that 2-bromo-3-methoxypyridine was used in place of 3-bromo-6-(difluoromethyl)-2methoxy-pyridine in step 3 and the conditions used for the réduction step 4 were similar to the ones used in Example 1 step 2. In step 8, purification was performed by chiral SFC using a Chiralpak IC column for 142 and 143 and using a Chiralcel OD-H column for 144 and 145, 5 pm particle size, 25 cm x 20 mm from Daicel on a Minigram SFC instrument from Berger Instruments:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
142	reZ-(2S,37?,4R,5S)-4-[[3-(3methoxy-2-pyridyl)-4,5dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl] amino]pyridine-2carboxamide	ESI-MS m/z cale. 438.1515, found 440.3 (M+l)⁺; 437.2 (M-l)‘; Rétention time: 2.84 minutes	Ή NMR (500 MHz, Methanol-d4) δ 8.46 (d, J = 5.5 Hz, 1H), 8.22 (d, J = 2.1 Hz, 1H), 8.13 (dd, J = 4.8, 1.3 Hz, 1H), 7.88 (dd, J = 5.5, 2.2 Hz, 1H), 7.38 (dd, J = 8.3, 1.4 Hz,

431

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
	(first eluting peak by SFC on Chiralpak IC column, rt = 1.84 min)		IH), 7.28 (dd, J = 8.3, 4.8 Hz, IH), 5.61 (d, J = 10.4 Hz, IH), 4.39 (dd, J = 10.4, 7.6 Hz, IH), 3.91 (s, 3H), 3.01 (p, J = 7.5 Hz, IH), 1.62 (d, J = 1.4 Hz, 3H), 0.73 (dq, J = 7.6, 2.4 Hz, 3H) ppm.
143	rel-(2R, 35,45,5Λ)-4-[[3-(3methoxy-2-pyridyl)-4,5dimethyl-5- (trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide (second eluting peak by SFC on Chiralpak IC column, rt = 2.20 min)	ESI-MS m/z cale. 438.1515, found 440.1 (M+l)⁺; 437.2 (M-l)'; Rétention time: 2.84 minutes	‘H NMR (500 MHz, Methanol-d4) δ 8.46 (d, J = 5.5 Hz, IH), 8.22 (d, J = 2.2 Hz, IH), 8.13 (dd, J = 4.8, 1.3 Hz, IH), 7.88 (dd, J = 5.5, 2.2 Hz, IH), 7.38 (dd, J = 8.4, 1.4 Hz, IH), 7.28 (dd, J = 8.3, 4.8 Hz, IH), 5.61 (d, J = 10.4 Hz, IH), 4.39 (dd, J= 10.4, 7.5 Hz, IH), 3.91 (s, 3H), 3.01 (p, J = 7.5 Hz, IH), 1.62 (d, J = 1.5 Hz, 3H), 0.73 (dq, J = 7.5, 2.3 Hz, 3H) ppm.
144	rel-(2S, 3R,4R, 55)-4-[[3-(3methoxy-2-methyl-4-	ESI-MS m/z cale. 452.16714, found	‘H NMR (500 MHz, Chloroform-d) δ 8.68

432

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
	pyridyl)-4,5-dimethyl-5 (trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide (first eluting peak by SFC on Chiralcel OD-H column, rt = 4.26 min)	453.2 (M+l)⁺; 451.3 (M-l)'; Rétention time: 2.64 minutes	(s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.36 (d, J = 5.3 Hz, 1H), 8.21-8.12 (m, 1H), 7.98 (t, J = 1.6 Hz, 1H), 7.86 (s, 1H), 7.32 (s, 1H), 5.60 (s, 1H), 5.07 (d, J= 10.5 Hz, lH),4.22(t, J = 9.5 Hz, 1H), 3.83 (d, J = 1.9 Hz, 3H), 2.86 (p, J = 7.9 Hz, 1H), 2.68 (s, 3H), 1.72 (s, 3H), 0.94 - 0.74 (m, 3H) ppm.
145	rel-(2R, 35,45,57?)-4-[[3-(3methoxy-2-methyl-4pyridyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofu ran-2- carbonyl]amino]pyridine-2carboxamide (second eluting peak by SFC on Chiralcel OD-H column, rt = 5.04 min)	ESI-MS m/z cale. 452.16714, found 453.3 (M+l)⁺; 451.3 (M-l)’; Rétention time: 2.64 minutes	Ή NMR (500 MHz, Chloroform-d) δ 8.62 (s, 1H), 8.41 (d, J = 5.5 Hz, 1H), 8.29 (d, J = 5.4 Hz, 1H), 8.04 (dd, J = 5.6, 2.2 Hz, 1H), 7.90 (d, J = 2.2 Hz, 1H), 7.76 (s, 1H), 7.31 (s, 1H), 5.52 (d, J = 4.4 Hz, 1H), 4.99 (d, J = 10.4 Hz, 1H), 4.14 (t, J = 9.5 Hz, 1H), 3.76 (s, 3H), 2.79 (p, J = 7.9 Hz, 1H), 2.64 (s, 3H),

433

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
			1.63 (s, 3H), 0.75 (dt, J = 7.3, 2.4 Hz, 3H) ppm.

Example 28

4-[[(27?,35,45,57?)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (146)

1) K₂CO₃, BnBr, DMF, RT, 56%

2) ΚΟί-Bu, 2-MeTHF, 5°C, 100%

3) T₃P, EtOAc, TEA, then methyl 4aminopyridine-2carboxylate, 657^

4) 107o Pd/C, EtOH, H₂, (1 atm), 607o

5) Cs₂CO₃, 1,1difluoro-3(iodomethyl)cyclob utane, DMF 47%

6)7 M NH₃ in MeOH, 49%

Step 1:

To a stirred mixture of methyl (25,35,45,57î)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (13.5 g, 38.107 mmol) and potassium carbonate (6.85 g, 49.564 mmol) in N,N-dimethylformamide (50 mL) at room température, was added benzyl bromide (9.7784 g, 6.8 mL, 57.172 mmol). The reaction mixture was stirred ovemight at room température. A further portion of benzyl bromide (3.3074 g, 2.3 mL, 19.338 mmol) was added and the stirring was continued for 6 hrs. A further portion of potassium carbonate (2.6 g, 18.812 mmol) and benzyl bromide (3.3074 g, 2.3 mL, 19.338 mmol) were added and reaction mixture was stirred ovemight. The reaction mixture was diluted with water (100 mL) and extracted

434 with diethyl ether (3 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried (NaiSCh), fïltered and concentrated in vacuo. Purification by flash chromatography (SiO₂, 0 to 50% EtOAc in heptane) gave a 2:3 mixture of methyl and benzyl (25,35,45,57?)-3-(2-benzyloxy3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (12.2 g) as a yellow oil, which was used without further purification in the next step.

Step 2:

To a stirred mixture of 2:3 methyl and benzyl (25,35,45,57?)-3-(2-benzyloxy-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.5 g, 1.3007 mmol) in 2methyl tetrahydrofuran (5 mL), was added potassium ZerZ-butoxide (438 mg, 3.9033 mmol) at 0 °C under argon. The reaction mixture was stirred at 0 °C for 15 min then room température for 30 min. The reaction mixture was diluted with diethyl ether (20 mL) and acidified with aqueous hydrochloric acid (2 M solution). The aqueous phase was extracted with diethyl ether (20 mL) and the combined organic extracts were washed with brine (20 mL), dried (Na₂SO4), fïltered and concentrated in vacuo. Purification by reverse phase chromatography (Biotage Isolera, 120 g, SiliaSep C18 Monomeric 25 pm Silicycle flash cartridge) using acetonitrile containing 0.1% ammonium hydroxide and water containing 0.1% ammonium hydroxide (0:100 to 100:0) gave (27?,35,45,57î)-3-(2-benzyloxy-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (760 mg) as a white solid. ’H NMR (400 MHz, chloroform-d) δ 7.37-7.33 (m, 5H), 6.99-6.87 (m, 2H), 5.23 (d, J = 11.0 Hz, 1H), 5.07 (d, J = 11.0 Hz, 1H), 4.83 (d, J= 11.0 Hz, 1H), 3.91 (dd, J= 11.0, 7.8 Hz, 1H), 2.44 (dd, J = 15.3, 7.6 Hz, 1H), 1.37 (s, 3H), 0.66 (dd, J = 7.3, 2.3 Hz, 3H) ppm; alcohol OH not observed. ESI-MS m/z cale. 430.1204, found 429.04 (M-l)*.

Step 3:

To a solution of (27?,35,45,57î)-3-(2-benzyloxy-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (3.3 g, 5.378 mmol) in ethyl acetate (20 mL) was added methyl 4-aminopyridine-2-carboxylate (1.22 g, 8.018 mmol), TEA (2.24 mL, 16.07 mmol) and T3P (6.4 mL, 21.52 mmol). The mixture was stirred at ambient température for 4 hours. The reaction mixture was partitioned between ethyl acetate (30ml) and water (60ml). The organic layer was separated and washed with water (1 x 50 ml) and brine (1 x 20 mL), dried (MgSO4), fïltered and concentrated in vacuo. Purification by flash chromatography (24 g pre-packed SiO₂, with 0-100%

435

EtOAc/petroleum ether) gave the product methyl 4-[[(27?,35,45,57?)-3-(2-benzyloxy-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (2.3 g, 65%) as an oil. ESI-MS m/z cale. 564.16833, found 565.1 (M+l)⁺.

Step 4:

A mixture of methyl 4-[[(27?,35,45,57?)-3-(2-benzyloxy-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (1.5 g, 2.438 mmol) and palladium on carbon 10% (75 mg, 0.705 mmol) in éthanol (20 mL) was stirred under an atmosphère of hydrogen gas (1 atm, balloon) for 3.5 hrs. The reaction mixture was filtered through celite and concentrated in vacuo to give a solid which was triturated with heptane, filtered and dried in vacuo. The solid was dissolved in dichloromethane/methanol (9:1, 50 mL) and a saturated aqueous solution of sodium hydrogencarbonate (50 mL). The aqueous phase was extracted with dichloromethane/methanol (9:1, 2 x 50 mL). The combined organic extracts were washed with water (50 mL), dried (NaiSCL), filtered and concentrated in vacuo. The solid was triturated with heptane to give methyl 4-[[(27?,35,45,5J?)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyI]amino]pyridine-2-carboxylate (1.07 g, 60%) as a beige solid. Ή NMR (400 MHz, DMSO-d₆) δ 11.23 (br s, 1H), 10.82 (br s, 1H), 8.52 (d, J = 5.3 Hz, 1H), 8.29 (d, J = 1.5 Hz, 1H), 7.78 (q, J = 2.5 Hz, 1H), 6.91 (s, 1H), 6.65 (s, 1H), 5.17 (d, J = 9.9 Hz, 1H), 4.14 (t, J = 8.8 Hz, 1H), 3.83 (s, 3H), 2.81-2.72 (m, 1H), 1.55 (s, 3H), 0.67 (d, J = 6.9 Hz, 3H) ppm. ESI-MS m/z cale. 474.1214, found 475.15 (M+l)⁺.

Step 5:

To a solution of methyl 4-[[(27?,35,45,57?)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (100 mg, 0.2108 mmol) in DMF (2 mL) was added l,l-difluoro-3-(iodomethyl)cyclobutane (244 mg, 1.052 mmol) and césium carbonate (103 mg, 0.3161 mmol). The mixture was stirred at ambient température for 48 hrs. The reaction mixture was partitioned between TBME (10ml) and water (10ml). The aqueous layer was further extracted with TBME (lOmL). The combined organic fractions were washed with brine (1 x lOmL), dried (MgSCh), filtered and concentrated in vacuo to yield the crude product methyl 4-[[(2R,35,45,51?)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxylate (80 mg, 47%). ESI-MS m/z cale. 578.16516, found 579.2 (M+l)⁺.

436

Step 6:

To a solution of methyl 4-[[(2R,35,45,5R)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxylate (80 mg, 0.1383 mmol) in methanol (1 mL) was added methanolic ammonia (500 pL of 7 M, 3.500 mmol) and the mixture stirred at ambient température ovemight. The mixture was concentrated in vacuo and the product was purified by reverse phase préparative (basic eluent) to give 4-[[(2R, 35,45,57?)-3-[2-[(3,3-difhiorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (146, 39 mg, 49%). Ή NMR (500 MHz, DMSO-d₆) δ 10.73 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.28 (d, J = 2.1 Hz, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.61 (d, J = 2.9 Hz, 1H), 7.23 - 7.16 (m, 2H), 5.12 (d, J = 10.3 Hz, 1H), 4.26 (dt, J = 10.4, 6.5 Hz, 2H), 4.14 (dd, J = 9.8, 6.5 Hz, 1H), 2.79 - 2.66 (m, 3H), 2.65 - 2.45 (m, 3H), 1.61 (s, 3H), 0.76 - 0.64 (m, 3H) ppm. ESI-MS m/z cale. 563.1655, found 564.2 (M+l)⁺.

Example 29

4-[[(27?,35,45,5/?)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (147)

3) DCM, DMF (cat.),

2) KOf-Bu, THF, 5°C, 22%

1)K₂CO₃, bromocyclobutane, p q Me MeCN/DMF, 75°C, ³ '' Ρ°>

30% L ,

Me'''

Alkyl

F

(COCI)₂, 0°C then TEA, methyl 4aminopyridine-2carboxylate. 45%^ 4)7 M NH₃ in MeOH, 17%

Step 1 and 2:

To a solution of methyl (2R,35,45,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5 (trifluoromethyl)tetrahydrofuran-2-carboxylate (200 mg, 0.5645 mmol) in a mixture of MeCN (2 mL) and DMF (1 mL) was added K2CO3 (250 mg, 1.809 mmol) and bromocyclobutane (200 mg, 1.481 mmol). The mixture was heated to 75°C in a sealed vial for 90 min. Upon completion the

437 mixture was diluted with DCM and partitioned with water. The organic phase was dried (MgSCh), filtered and concentrated in vacuo. Purification by flash chromatography gave methyl (2R, 35,45,57?)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (70 mg, 30%). This was immediately taken in THF (1 mL) and potassium teri-butoxide (60 mg, 0.5347 mmol) was added at ambient température. The mixture is diluted with DCM (10 mL) and partitioned with a saturated solution of ammonium chloride (10 mL). The organics were separated, dried (MgSCL), filtered and concentrated in vacuo to give (2R,35,45,57?)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (50 mg, 22%), which was used without further purification. ESI-MS m/z cale. 394.12036, found 393.5 (M-l)'.

Step 3 and 4:

Oxalyl chloride (30 pL, 0.3439 mmol) was added dropwise to a stirred solution of (2R,3S,4S,5R)-3 - [2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5 (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (50 mg, 0.1268 mmol) and DMF (2 pL, 0.02583 mmol) in DCM (500 pL) at ambient température. The mixture was stirred for 30 min. Upon complété acid chloride formation, the solution was concentrated in vacuo and the residue dissolved in DCM (300 pL). The obtained solution was added to a stirred solution of methyl 4-aminopyridine2-carboxylate (25 mg, 0.1643 mmol) and TEA (30 pL, 0.2152 mmol) in DCM (300 pL) at ambient température and allowed to stir for 2 hrs. The mixture was quenched with 100 pL of methanol and purifîed by flash chromatography to afford methyl 4-[[(27?,35,45,57?)-3-[2-(cyclobutoxy)-3,4difIuoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxylate (30 mg, 45%). ESI-MS m/z cale. 528.16833, found 527.6 (M+l)⁺.

The residue was taken up in methanolic ammomia (4 mL of 7 M, 28.00 mmol) and stirred at ambient température until complété conversion. Purification by flash chromatography gave 4[[(27?,35,45,57?)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (147, 13 mg, 17%). ’H NMR (500 MHz, DMSO-d₆) δ 10.73 (s, IH), 8.49 (d, J = 5.5 Hz, IH), 8.27 (d, J = 2.3 Hz, IH), 8.05 (d, J = 2.6 Hz, IH), 7.82 (dd, J = 5.5, 2.2 Hz, IH), 7.63 - 7.55 (m, IH), 7.15 (t, J = 6.4 Hz, 2H), 5.09 (d, J = 10.4 Hz, IH), 4.65 (p, J = 7.3 Hz, IH), 4.28 (dd, J = 10.5, 7.5 Hz, IH), 2.77 (h, J = 7.8 Hz, IH), 2.36 - 2.22 (m, 2H), 2.14 (ddt, J = 35.2, 19.5, 10.2 Hz, 2H), 1.70 (dd, J = 11.7, 9.0 Hz, IH),

438

1.62 (s, 3H), 1.48 (dtd, J = 18.2, 10.3, 7.8 Hz, 1H), 0.72 (d, J = 7.1 Hz, 3H) ppm. ESI-MS m/z cale.

513.1687, found 514.6 (M+l)⁺and 512.5 (M-l)-.

Example 30

4-[[(27?,35,45,57?)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (148)

1) NIS.DMSO, MeOH, RT, 93%

2) Mel, K₂CO₃, MeCN, 97%

3)iPrMgCI.LiCI, THF, D₂O, -78° C, 82%

4) KOtBu, THF, 0°C, 98%

-

5) DCM, DMF (cat.), (COCI)₂, 0 °C then TEA, methyl 4aminopyridine-2carboxylate, 25%

6)7 M NH₃ in MeOH, 14%

Step 1:

DMSO (80 pL, 1.127 mmol) and NIS (1.7 g, 7.556 mmol) were added to a stirred solution of 10 methyl (25,35,45,57?)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (2.2 g, 6.210 mmol) in MeOH (20 mL) at ambient température. The mixture was stirred at ambient température under air for 30 min. Upon completion, the mixture was concentrated in vacuo. Purification by flash chromatography gave methyl (25,35,45,57î)-3-(3,4-difluoro-2-hydroxy-5-iodo-phenyl)-4,5-dimethyl-515 (trifluoromethyl)tetrahydrofuran-2-carboxylate (2.78 g, 93%). ^lH NMR (500 MHz, Chloroform-d) δ 7.49 (dt, J = 6.4, 2.1 Hz, 1H), 5.56 (d, J = 4.9 Hz, 1H), 4.81 (d, J = 5.9 Hz, 1H), 4.16 (dd, J = 8.3, 5.9 Hz, 1H), 3.60 (s, 3H), 2.75 (p, J = Ί.Ί Hz, 1H), 1.45 (d, J = 1.2 Hz, 3H), 0.90 - 0.85 (m, 3H) ppm. ESI-MS m/z cale. 479.9857, found 481.1 (M+l)⁺ and 479.1 (M-l)'.

439

Step 2:

K2CO3 (2.5 g, 18.09 mmol) and Mel (1 mL, 16.06 mmol) were added to a solution of methyl (25,35,45,57î)-3-(3,4-difluoro-2-hydroxy-5-iodo-phenyl)-4,5-dimethyl-5(trifluoromethyI)tetrahydrofuran-2-carboxylate (2.8 g, 5.831 mmol) in MeCN (25 mL). The mixture was heated to 75°C in a sealed vial for 90 min. The mixture was diluted in DCM and partitioned with an aqueous saturated solution of NaCl. The organic extracts were dried (MgSOy), fïltered and concentrated in vacuo to afford methyl (25,35,45,57?)-3-(3,4-difluoro-5-iodo-2-methoxy-phenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (2.8 g, 97%). ’H NMR (500 MHz, Chloroform-d) δ 7.53 (dq, J = 6.5, 1.5 Hz, IH), 4.80 (d, J = 6.1 Hz, IH), 4.11 (dd, J = 8.5, 5.8 Hz, IH), 3.88 (d, J = 2.4 Hz, 3H), 3.56 (s, 3H), 2.73 (p, J = 8.4, 7.8 Hz, IH), 1.45 (d, J = 1.1 Hz, 3H), 0.80 (dd, J = 7.4, 1.9 Hz, 3H) ppm. ESI-MS m/z cale. 494.00134, found 495.2 (M+l)⁺.

Step 3:

iPrMgCl.LiCl (100 pL of 1.3 M, 0.1300 mmol) was added dropwise to a stirred solution of methyl (25,35,45,57?)-3-(3,4-difluoro-5-iodo-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (70 mg, 0.1416 mmol) in THF (1.5 mL) at -78 °C. The resulting mixture was stirred at -78 °C for 10 min. The resulting mixture was quenched at -78 °C with a solution of D2O (0.1 mL, 5.542 mmol) in THF (1.5 mL). The reaction mixture was allowed to warm up to ambient température, diluted with DCM and partitioned with brine. The organic layer was separated, dried (MgSCU), fïltered and concentrated in vacuo to afford methyl (25,35,45,5R)-3(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxylate (43 mg, 82%). Ή NMR (500 MHz, Chloroform-d) δ 7.16 (d, J = 5.8 Hz, IH), 4.87 (d, J = 6.1 Hz, IH), 4.23 (dd, J = 8.6, 6.1 Hz, IH), 3.94 (d, J = 2.0 Hz, 3H), 3.54 (s, 3H), 2.82 (p, J = 7.8 Hz, IH), 1.53 (s, 3H), 0.86 (dt, J = 7.6, 1.9 Hz, 3H) ppm.

Step 4:

Potassium ZerZ-butoxide (120 mg, 1.069 mmol) was added to a stirred solution of methyl (25,35,45,57?)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (100 mg, 0.2708 mmol) in THF (1.5 mL) atroom température. After 5 minutes, the mixture was quenched by the addition of a saturated solution of ammonium chloride (3 mL) and diluted with DCM (3 mL). The aqueous phase was washed with DCM (5 mL), acidifïed with 1 N HCl to pH 0 and extracted with DCM (2x10 mL). The combined

440 organic extracts were dried (MgSO₄), filtered and concentrated in vacuo to afford (2/?,35,45,5/?)-3(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2carboxylic acid (95 mg, 99%), which was used in the next step without further purification. ESI-MS m/z cale. 355.09534, found 354.2 (M-l)’.

Step 5 and 6:

Oxalyl chloride (70 pL, 0.8024 mmol) was added dropwise to a stirred solution of (22?, 35,45,57?)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (90 mg, 0.2533 mmol) and DMF (3 pL, 0.03874 mmol) in DCM (1000 pL) at ambient température. The mixture was stirred at room température for 30 min. Upon activation completion, the mixture was concentrated in vacuo and re-dissolved in DCM (500 pL). This obtained solution was added to a stirring solution of methyl 4-aminopyridine2-carboxylate (50 mg, 0.3286 mmol) and triethylamine (50 pL, 0.3587 mmol) in DCM (500 pL) at ambient température. Upon complété conversion, the mixture was quenched with 0.1 mL of MeOH. Purification by flash chromatography gave methyl 4-[[(27?,35,45,52?)-3-(5-deuterio-3,4-difluoro-2methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxylate (31 mg, 25%), which was used as is in the next step. ESI-MS m/z cale. 489.14334, found 490.4 (M+l)⁺; 488.4 (M-l)'.

Methyl 4-[[(27?,35,45,57?)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate (31 mg) was taken in a methanolic solution of ammonia (8.5 mL of 7 M, 59.50 mmol) and stirred at ambient température until complété conversion to the corresponding amide. The final compound was lyophilized from MeCN:Water 3:1 to provide 4-[[(27î,35,45,57î)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (148, 17.4 mg, 14%, 93% isotopic purity for D). ’H NMR (500 MHz, DMSO-d₆) δ 10.70 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.05 (s, 1H), 7.83 (dd, J = 5.6, 2.2 Hz, 1H), 7.60 (s, 1H), 7.17 -7.12 (m, 1H), 5.10 (d, J = 10.2 Hz, 1H), 4.26 (dd, J = 10.2, 7.7 Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.77 (p, J = 7.5 Hz, 1H), 1.61 (s, 3H), 0.73 (d, J = 7.4 Hz, 3H) ppm. ESI-MS m/z cale. 474.14368, found 475.4 (M+l)⁺; 473.4 (M-l)‘.

441

Example 31

4-[[(25,35,45,55)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran2-carbonyl]amino]pyridine-2-carboxamide (149)

4) Pd(OAc)₂, Cs₂CO₃, Xantphos, 2-MeTHF, methyl 4bromopyridine-2carboxylate 90°C 47%

1) 7 M NH₃ in MeOH, 87% -----►

2) Tf₂O, pyridine, DCM, 0°C, 72%

3) VinylBpin, PhMe, aq. Cs₂CO₃, RuPhosPd-G3, 80°C, 307^

Step 1:

To a solution of methyl (25,35,45,55)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.3 g, 3.670 mmol) in methanol (5 mL) was added methanolic ammonia (10 mL of 7 M, 70.00 mmol) and the mixture was stirred at ambient température for 14 hours. The mixture was concentrated in vacuo to give (25,35,45,55)-3-(3,410 difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide ( 1.2 g, 87%) as a white solid. ESI-MS m/z cale. 339.0894, found 340.2 (M+l)⁺.

Step 2:

To a solution of (25,35,45,55)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carboxamide (1.2 g, 3.537 mmol) in DCM (10 mL) cooled with 15 an ice-bath was added pyridine (572 pL, 7.072 mmol) followed by trifluoromethylsulfonyl trifluoromethanesulfonate (4.59 mL of 1 M, 4.590 mmol) in portions over 5 mins. The reaction mixture was allowed to warm up to ambient température and was partitioned between DCM (20 ml) and water (20 ml). The organic phase was washed with brine (1x10 mL), dried (MgSO₄), filtered

442 and concentrated in vacuo. Purification by flash chromatography (12 g SiO₂, 0 to 100% EtOAc in heptane) gave [6-[(27?,35,45,57?)-2-carbamoyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-3yl]-2,3-difluoro-phenyl] trifluoromethanesulfonate (1.2 g, 72%) as a white solid. ESI-MS m/z cale. 471.03867, found 472.2 (M+l)⁺.

Step 3:

A mixture of [6-[(27?,35,45,57?)-2-carbamoyl-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-3-yl]-2,3-difluoro-phenyl] trifluoromethanesulfonate (200 mg, 0.4243 mmol), 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (130 mg, 0.8441 mmol), césium carbonate (276 mg, 0.8471 mmol) and RuPhos-Pd-G3 (35 mg, 0.04185 mmol) was suspended in toluene (2 mL) and water (0.2 mL). The suspension was degassed (N₂/vac 3 cycles) and heated to 80 °C for 5 hours. The reaction mixture was cooled down to ambient température and partitioned between TB ME (20 ml) and water (20 ml). The aqueous layer was further extracted with TBME (10 mL). The combined organic extracts were washed with brine (1x10 mL), dried (MgSCfi), filtered and concentrated in vacuo. Purification by flash chromatography (12 g SiO₂, 0 to 100% EtOAc in heptane) gave (27?,35,45,57?)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide (50 mg, 30%) as a white solid. 'H NMR (500 MHz, Chloroform-d) δ 7.13 (ddd, J = 17.3, 8.3, 3.3 Hz, 2H), 6.63 - 6.51 (m, 2H), 5.75 - 5.63 (m, 3H), 4.94 (d, J = 10.6 Hz, 1H), 3.99 (dd, J = 10.7, 8.1 Hz, 1H), 2.62 (p, J = 7.7 Hz, 1H), 1.61 (s, 3H), 0.76 (d, J = 7.6 Hz, 3H) ppm. ESI-MS m/z cale. 349.1101, found 350.2 (M+l)⁺.

Step 4:

Methyl 4-bromopyridine-2-carboxylate (35 mg, 0.1620 mmol), Xantphos (20 mg, 0.03457 mmol), césium carbonate (85 mg, 0.2609 mmol), Pd(OAc)₂ (4 mg, 0.01782 mmol) and (27?,35,45,57î)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamide (30 mg, 0.08589 mmol) were combined in dioxane (3 mL). The suspension was degassed (N₂/vac 3 cycles) and heated at 90 °C under nitrogen for 4 hours. The reaction mixture was cooled down to ambient température and partitioned between TBME (10 ml) and water (10 ml). The aqeuous layer was further extracted with TBME (10 mL). The combined organic layers were washed with brine (1x10 mL), dried (MgSCk), filtered and concentrated in vacuo. Purification by column chromatography (12 g SiO₂, 0 to 100% EtOAc in heptane gave methyl 4-[[(27î,35,45,57î)-3(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2

443 carbonyl]amino]pyridine-2-carboxylate (20 mg, 47%) as a white solid. ESI-MS m/z cale. 484.14215, found 485.4 (M+l)⁺.

Step 5:

To a solution of methyl 4-[[(27?,35,45,57?)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-55 (trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]pyridine-2-carboxylate (8 mg, 0.01651 mmol) in methanol (1 mL) was added methanolic ammonia (235 pL of 7 M, 1.645 mmol) and the mixture was stirred at ambient température for 14 hours. The mixture was concentrated in vacuo.

Purification by reverse phase préparative HPLC (Waters Sunfire Cl8, 10 pM, 100 Â column, gradient 0% - 100% B (solvent A: 0.1% NH3 in water; solvent B: MeCN) over 14 minutes at 25 mL/min) gave 4-[[(27?,35,45,57?)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5(trifluoromethyI)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide 149 (2.5 mg, 31%). Ή NMR (500 MHz, Methanol-tfi) δ 8.50 (dd, J = 5.5, 0.6 Hz, 1H), 8.26 (dd, J = 2.2, 0.6 Hz, 1H), 7.91 (dd, J = 5.5, 2.2 Hz, 1H), 7.24 - 7.13 (m, 2H), 6.76 (dd, J = 17.8, 11.6 Hz, 1H), 5.81 - 5.64 (m, 2H), 5.14 (d, J = 10.4 Hz, 1H), 4.33 (dd, J = 10.4, 8.0 Hz, 1H), 2.77 (p, J = 7.7 Hz, 1H), 1.66 (d, J = 1.2

Hz, 3H), 0.82 (dq, J = 7.4, 2.3 Hz, 3H) ppm. ESI-MS m/z cale. 469.1425, found 470.4 (M+l)⁺.

4-[[(2R,35,45,57?)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide can be obtained by hydrogénation of compound 149 (e.g., Pd/C, H₂).

444

Example 32 rel-(2R, 35,45,57?)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide (150) and re/-(25,37?,47î,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-55 (trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide (151)

1) (COCI)₂, DCM, DMF (cat.), 0°C to RT

then TEA, 2-bromo-5methyl-pyridin-4amine, DCM, 0°C to RT, 43%

(rac) (rac)

2) CO, TEA, Pd(dppf)CI₂DCM, MeOH, _ DMF, 80°C

(rac)

150, first eluting isomer

151, second eluting isomer

Step 1:

To an ice cooled solution of rac-(2R,35,45,57?)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (90 mg, 0.2306 mmol) (see

Example 4, Step 1) in DCM (1.2 mL) was added oxalyl chloride (45 pL, 0.5159 mmol) and the mixture was stirred and warmed up to room température over 30 min after which time full conversion to acid chloride was observed. The reaction mixture was concentrated in vacuo. The residue, dissolved in DCM (750 pL) and DMF (8 pL, 0.1033 mmol) was added to an ice cooled solution of 2-bromo-5-methyl-pyridin-4-amine (46 mg, 0.2459 mmol) and TEA (40 pL, 0.2870 mmol) in DCM (750 pL). The resulting mixture was stirred and warmed to ambient température over 2 hours. The reaction mixture was quenched with 1 drop of water and MeOH (2 mL) and concentrated in vacuo. Purification by flash chromatography (4g SiO₂, 0 to 100 % EtOAc in hexames) gave rac-(27?,35,45,57î)-N-(2-bromo-5-methyl-4-pyridyl)-3-[2-(difluoromethoxy)-3,4

445 difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (55 mg, 43%). ESI-MS m/z cale. 558.0389, found 561.4 (M+l)⁺; 559.5 (M-l)‘.

Step 2 and 3:

A suspension of rac-(2R,35,45,57î)-N-(2-bromo-5-methyl-4-pyridyl)-3-[2(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamide (50 mg, 0.08940 mmol), Pd(dppf)Ch^-DCM (7 mg, 0.008572 mmol) and TEA (30 pL, 0.2152 mmol) in DMF (700 pL) and MeOH (300 pL). CO was bubbled through the reaction mixture, the vessel sealed and heated to 80 °C for 20 hours. The reaction mixture was concentrated in vacuo to give methyl rac-(27?,35,45,57?)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxylate, which was used as is in the next step. ESI-MS m/z cale. 538.13385, found 539.6 (M+l)⁺; 537.7 (M1)'.

Methyl rac-(2R,35,45,57?)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxylate (40 mg, 0.07429 mmol) was taken in a methanolic solution of ammonia (2.4 mL of 7 M, 16.80 mmol) in MeOH (2.4 mL). The mixture was stirred at ambient température. Upon completion, the mixture was concentrated in vacuo. Purification by flash chromatography gave rac-(27?,35,45,57?)-4-[[3-[2(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-methyl-pyridine-2-carboxamide (22 mg, 57% over 2 steps). ESI-MS m/z cale. 523.1342, found 524.5 (M+l)⁺; 522.6 (M-l)'.

Step 4:

rac-(2R,35,45,57?)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide (20 mg, 0.038 mmol) was separated by chiral SFC using a Chiralpak AS-H column, 5 pm particle size, 25 cm x 10 mm from Daicel on a Minigram SFC instrument from Berger Instruments to give:

First Eluting Isomer (rt = 2.12 min): re/-(27?,35,45,52î)-4-[[3-[2-(difluoromethoxy)-3,4difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methylpyridine-2-carboxamide (150, 9 mg, 44%). Ή NMR (400 MHz, Methanol-cU) δ 8.51 - 8.42 (m, 2H), 7.46 - 7.36 (m, IH), 7.29 (td, J = 9.4, 7.6 Hz, IH), 6.95 (td, J = 73.1, 1.2 Hz, IH), 5.23 (d, J = 10.8 Hz, IH), 4.35 (dd, J = 10.8, 7.9 Hz, IH), 2.86 (p, J = 7.6 Hz, IH), 2.31 (s, 3H), 1.72 (d, J = 1.1 Hz,

446

3H), 0.89 (dq, J = 7.5, 2.4 Hz, 3H) ppm. ESI-MS m/z cale. 523.1342, found 524.4 (M+l)⁺; 522.4 (M-l)-.

Second Eluting Isomer (rt = 3.44 min): re/-(25,37?,4R,5S)-4-[[3-[2-(difluoromethoxy)-3,4difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl5 pyridine-2-carboxamide (151, 7 mg, 35%). Ή NMR (400 MHz, Methanol-ch) δ 8.54 - 8.42 (m, 2H), 7.41 (ddd, J = 9.0, 5.4, 2.3 Hz, 1H), 7.29 (td, J = 9.4, 7.6 Hz, 1H), 6.95 (td, J = 73.0, 1.1 Hz, 1H), 5.23 (d, J = 10.8 Hz, 1H), 4.35 (dd, J = 10.8, 7.9 Hz, 1H), 2.86 (p, J = 7.6 Hz, 1H), 2.31 (s, 3H), 1.72 (d, J = 1.1 Hz, 3H), 0.89 (dq, J = 7.5, 2.4 Hz, 3H) ppm. ESI-MS m/z cale. 523.1342, found 524.4 (M+l)⁺; 522.4 (M-l)‘.

Examnle 33

4-[[(27?, 35,45,57?)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (152)

4) DMF (cat.), DCM, (COCI)₂, 0°C to RT then TEA, methyl 4aminopyridine-2carboxylate

5) 7 M NH₃ in MeOH, 13% over 3 steps

152

Step 1:

NCS (1 g, 7.489 mmol) and DMSO (80 pL, 1.127 mmol) were added to a solution of methyl (25,35,45,57?)-3-(3,4-difIuoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran

447

2-carboxylate (2 g, 5.645 mmol) in MeOH (18 mL) at room température and under air. The mixture was stirred until complété conversion. The reaction mixture was concentrated in vacuo. Purification by flash chromatography gave methyl (25,35,45,57?)-3-(5-chloro-3,4-difluoro-2-hydroxy-phenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (2.05 g, 93%). ’H NMR (500 MHz, Chloroform-d) δ 7.23 - 7.19 (m, 1H), 5.44 (d, J = 4.8 Hz, 1H), 4.81 (d, J = 5.9 Hz, 1H), 4.19 (dd, J = 8.4, 5.8 Hz, 1H), 3.57 (s, 3H), 2.81 - 2.71 (m, 1H), 1.46 (d, J = 1.3 Hz, 3H), 0.90 - 0.85 (m, 3H) ppm. ESI-MS m/z cale. 388.05008, found 386.9 (M-l)’.

Step 2:

Potassium carbonate (2 g, 14.47 mmol) and iodomethane (650 pL, 10.44 mmol) were added to a mixture of methyl (25,35,45,57?)-3-(5-chloro-3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.9 g, 4.888 mmol) in MeCN (20 mL) in a sealed tube. The mixture was heated to 75 °C for 2h. The mixture was diluted with water/brine 1:1 (20 mL) and extracted with DCM. The organic extracts were dried (MgSCU), filtered and concentrated in vacuo. Purification by flash chromatography gave methyl (25,35,45,57?)-3-(5-chloro-3,4-difluoro-2methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.85 g, 94%) as a yellow crystalline solid. Ή NMR (500 MHz, Chloroform-d) δ 7.30 (ddq, J = 7.6, 3.0, 1.6 Hz, 1H), 4.87 (d, J = 5.9 Hz, 1H), 4.21 (dd, J = 8.6, 6.0 Hz, 1H), 3.94 (d, J = 2.1 Hz, 3H), 3.61 (s, 3H), 2.82 (p, J = 7.8 Hz, 1H), 1.52 (d, J = 1.3 Hz, 3H), 0.87 (dq, J = 7.7, 2.0 Hz, 3H) ppm.

Step 3:

Potassium ZerZ-butoxide (450 mg, 4.010 mmol) was added to a stirred solution of methyl (25,35,45,57?)-3-(5-chIoro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carboxylate (800 mg, 1.986 mmol) in THF (40 mL) at 0 °C. The mixture was stirred until complété conversion. The reaction mixture was quenched by addition of a saturated solution of ammonium chloride (3 mL) and partitioned with DCM (3 mL). The aqueous phase extracted with DCM (5 mL), and the pH was adjusted to 0 by addition of a 1 N solution of HCl. The aqueous phase was extracted twice with DCM (2x10 mL). The combined organic extracts were dried (MgSCfi), filtered and concentrated concentrated in vacuo to give (27?,35,45,57?)3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxylic acid, which was used in the next step without further purification. ESI-MS m/z cale. 388.05008, found 386.9 (M-l)’.

448

Step 4 and 5:

Oxalyl chloride (130 pL, 1.490 mmol) was added dropwise to a stirred solution of (272,35,45,57?)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxyIic acid (250 mg, 0.643 mmol) and DMF (7 pL, 0.090 mmol) in DCM (2.5 mL). The reaction mixture was stirred at ambient température for 30 min. The solution was concentrated in vacuo. The residue was dissolved in DCM (1.5 mL) and added to a solution of methyl 4-aminopyridine-2-carboxylate (130 mg, 0.8544 mmol) and TEA (130 pL, 0.9327 mmol) in DCM (1.5 mL) at ambient température. The reaction mixture was stirred for 2h. The mixture was quenched by addition of methanol (100 pL). Purification by flash chromatography gave methyl 4-[[(272,35,45,572)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate which was used in the next step without further purification. ESI-MS m/z cale. 522.0981, found 523.0 (M+l)⁺;521.0 (M-l)'

Methyl 4-[[(272,35,45,572)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate was taken in a methanolic solution of ammonia (20 mL of 7 M, 140.0 mmol) and stirred at ambient température. Upon completion, the mixture was concentrated in vacuo and freeze-dried (MeCN:water, 3:1) to give 4-[[(272,35,45,572)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide 152 (45 mg, 13%). Ή NMR (500 MHz, DMSO-d₆) δ 10.62 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 3.0 Hz, 1H), 7.86 (dd, J = 5.6, 2.3 Hz, 1H), 7.62 (d, J = 3.0 Hz, 1H), 7.42 (dd, J = 7.7, 2.4 Hz, 1H), 5.18 (d, J = 9.9 Hz, 1H), 4.24 (dd, J = 10.1, 7.6 Hz, 1H), 3.97 (d, J = 2.4 Hz, 3H), 2.78 (p, J = 7.4 Hz, 1H), 1.62 (s, 3H), 0.76 (dd, J = 7.6, 2.2 Hz, 3H) ppm. ESI-MS m/z cale. 507.09842, found 508.0 (M+l)⁺;506.1 (M-l)’.

449

Intermediate A

3,3-Difluorobutan-2-one

1)A/,ODimethylhydroxyla mine hydrochloride, DIPEA, EDC.HCI, HOBt. DCM. RT.^ 51%

2) MeMgBr(1:3 THF in Toluene), Toluene, -78°C, 53%

Step 1:

To a stirred solution of 2,2-difluoropropanoic acid (100 g, 908.60 nunol) in DCM (1000 mL) was added DIPEA (348.74 g, 470 mL, 2.6983 mol) at 25 °C. The reaction mixture was stirred for 15 minutes. EDC.HCI (209 g, 1.0902 mol) and HOBt (147 g, 1.0879 mol) were added and the reaction mixture was stirred for 15 minutes at 25 °C. ΛζΟ-Dimethylhydroxylamine hydrochloride (133 g, 1.3635 mol) was added to the reaction which was stirred for 16 hrs. Water was added and the mixture was extracted with DCM (2 x 200 ml ). The combined organic layers were washed with water (2 x 200 ml) and brine (200 ml). Purification by distillation under vacuo (192-196 °C) gave 2,2-difluoro-N-methoxy-N-methyl-propanamide (70.5 g, 51%) as a colourless oil. ’H NMR (400 MHz, Chloroform-d) δ 3.72 (s, 3H), 3.24 (s, 3H), 1.81 (t, J = 19.20 Hz, 3H) ppm.

Step 2:

MeMgBr (1:3 THF in toluene) (489 mL of 1.4 M, 684.60 mmol) was slowly added dropwise to a stirred solution of 2,2-difluoro-N-methoxy-N-methyl-propanamide (70 g, 457.14 mmol) in toluene (350 mL) at -78 °C. The reaction mixture was stirred for 2 hours at -78 °C. The mixture was quenched by addition of HCl (685 mL of 2 M, 1.3700 mol) at 0 °C. Cold water was added. The organic layer was washed with water. Purification by distillation (100 °C) gave 3,3-difluorobutan-2one (26.3 g, 53%). ’H NMR (400 MHz, Chloroform-d) δ 2.33 (s, 3H), 1.69 ( t, J = 19.12 Hz, 3H) ppm.

450

Intermediate B

2-[2-(Difluoromethoxy)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane

B

Step 1:

l-Bromo-2-(difluoromethoxy)-4-fluoro-benzene (10 g, 41.49 mmol), bis(pinacol)diboron (11.00 g, 43.32 mmol) and Potassium acetate (12.00 g, 122.3 mmol) were mixed in dry DMF (100 mL). The mixture was degassed (Vac/Nz 3 cycles). Pd(dppf)C12^-DCM (3.4g, 4.163 mmol) was added, and the reaction mixture was degassed (Vac/N2 3 cycles). The reaction mixture was heated to 110 °C for 18 hours. The reaction mixture was diluted with water (300 mL) and EtOAc (150 mL), stirred for 30 min, filtered through a pad of celite, washing with EtOAc. The organic phase was separated and washed with water (2 xl50 ml) and brine (2 x 150 ml), dried (MgSO4), filtered and concentrated in vacuo. Purification on a pad of florisil (200g, 0 to 10% DCM in hexanes) gave 2-[2(difluoromethoxy)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaboroIane (8.43 g, 71%) as a yellow oil. *H NMR (500 MHz, DMSO-d6) δ 7.71 (dd, J = 8.4, 7.3 Hz, 1H), 7.28-7.96 (m, 3 H), 1.28 (s, 12 H); ¹⁹FNMR (471 MHz, DMSO-d6) δ -82.70 (d, J = 74.5 Hz), -106.63 (s) ppm.

The following intermediates were made using a method similar to that described in Intermediate B except that 1,4-dioxane was used as the solvent in place of DMF:

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
M	2-[2-(difluoromethoxy)-4fluoro-3 -methyl-phenyl] 4,4,5,5-tetramethyl-l ,3,2dioxaborolane		*H NMR (400 MHz, DMSO-dô) δ 7.57 ( t, J=7.76 Hz, 1H ),7.17 (t, J=8.72 Hz, 1H), 6.95 (t, J= 75.08 Hz, 1H)

451

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
			2.16 (s, 3H) 1.32 (s, 12H) ppm.
N	4-methoxy-5-(4,4,5,5tetramethyl-1,3,2dioxaborolan-2-yl)-2(trifluoromethyl)pyridine

Intermediate C 2-(3-(Difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane 1) HBPin, TEA,V Z ? Pd(PPh₃)₂CI₂, 1.4-/ ' /OAk dioxane, 1OO°C, 53%'b

AQ* FF

F F

C

Step 1:

To a solution of l-bromo-3-(difluoromethyI)-4-fluoro-2-methoxy-benzene (1.60 g, 6.274 mmol) and Pd(PPh₃)2Ch (200 mg, 0.2849 mmol) in 1,4-dioxane (25 mL) was added 4,4,5,5tetramethyl-l,3,2-dioxaborolane (1.6 mL, 11.03 mmol) and TEA (2.5 mL, 17.94 mmol). The mixture was degassed by bubbling nitrogen through for 5 minutes. The reaction was heated at 100 10 °C in a sealed vial for 3 hours. The reaction was concentrated in vacuo and loaded onto solid support. Purification by flash chromatography (0 to 25 % EtOAc in heptane) gave 2-[3(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.15g, 53%) as a white solid. Ή NMR (400 MHz, Chloroform-d) δ 7.84 (ddt, J = 8.2, 6.9, 1.2 Hz, 1H), 6.99 (td, J = 53.9, 1.1 Hz, 1H), 6.91 (dd, J = 9.7, 8.5 Hz, 1H), 3.90 (s, 3H), 1.36 (s, 12H). ESI-MS m/z cale. 302.1301, Rétention time: 1.03 minutes.

452

Intermediate D

2-(3-Chloro-4-fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane

F

D

Step 1:

An oven dried 500 ml three necked flask was flanked with a condenser and a thermometer. Magnésium (321 mg, 13.21 mmol) tumings were added. The flask was evacuated three times with vac/Nî and then left under vacuum for thirty minutes while the flask was heated to 65 °C. Using a nitrogen flushed needle, THF (12.5 mL) was added to the flask and the mixture was flushed once again with nitrogen. lodine (3 mg, 0.01182 mmol) was added to the reaction. The mixture was stirred at 65 °C until the reaction tumed into a clear pale yellow colour (~1 hour). The mixture was taken off the heat. Pinacolborane (1.74 g, 13.60 mmol) was added dropwise. Gas évolution was observed. A solution of l-bromo-3-chloro-4-fluoro-2-methoxy-benzene (2500 mg, 10.44 mmol) in THF (12.5 mL) was added dropwise. The reaction mixture was left to cool to ambient température over 30 minutes and stirred for 1.5 h at ambient température. The reaction mixture was added carefully dropwise to a stirred solution of 1 M HCl (50 ml) (vigorous effervescence observed) and left to stand for 10 minutes until ail the Mg solids had dissolved. The mixture was diluted with TBME. The aqueous layer was separated and extracted with TBME (x2), passed through a phase separator cartridge and concentrated in vacno to give 2-(3-chloro-4-fluoro-2-methoxy-phenyl)4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2.8152 g, 94%). Ή NMR (500 MHz, DMSO-d₆) δ 7.57 (dd, J = 8.4, 7.0 Hz, 1H), 7.24 - 7.15 (m, 1H), 3.81 (s, 3H), 1.30 (s, 12H). ESI-MS m/z cale. 286.09433, found 287.0 (M+l)+; Rétention time: 1.06 minutes.

The following intermediate was made using a method similar to that described in Intermediate D using l-bromo-4-fluoro-2-methoxy-3-methyl-benzene as starting material:

453

Cmpd No.	Compound Name	LC/MS	NMR (shifts in ppm)
O	2-(4-fluoro-2-methoxy-3 methyl-phenyl)-4,4,5,5tetramethyl-1,3,2dioxaborolane		‘H NMR (400 MHz, DMSO-dô) δ 7.44 (t, J = 7.9 Hz, 1H), 6.93 (t, J = 8.7 Hz, 1H), 3.72 (s, 3H), 2.11 (d, J = 2.1 Hz, 3H), 1.29 (s, 12H) ppm. ¹⁹FNMR(376 MHz, DMSO-de) δ 110.32 (ddt, J = 9.5, 7.3, 2.2 Hz) ppm.

Intermediate E (4-Fluoro-2-methoxy-3-methylphenyl)boronic acid

1) NBS, /PrNH₂, DCM, -78°C, 90%

2) Mel, K₂CO₃, Acetone, RT, 76% ---------->►

1) B(O/Pr)₃, Mg, l₂, THF, RT then -78°

C, 55% —------->►

E

Step 1:

Isopropylamine (23.460 g, 34.5 mL, 396.89 mmol) was slowly added to a stirred solution of 3-fluoro-2-methyl-phenol (50 g, 396.42 mmol) in DCM (2.5 L). The reaction mixture was cooled to -78 °C. N-bromosuccinimide (NBS) (70 g, 393.29 mmol) was added portion wise over 2 hrs 10 min and the mixture was stirred for a further 30 min. The mixture was warmed up to 25 °C. 2N HCl (500 ml) was added and the mixture was stirred for 15 min. The organic layer was separated and

454 concentrated in vacuo, keeping the water bath at 15 °C. Hexane (500 ml) was added to the residue and the mixture was stirred for 10 min. The mixture was filtered and the liquors were concentrated in vacuo, keeping the water bath at 15 °C to give 6-bromo-3-fluoro-2-methyl-phenol (73 g, 90%) as a light brown oil. ’H NMR (400MHz, Chloroform-d) δ 7.24-7.21 (m, 1H), 6.55 (t, J = 8.8Hz, 1H), 5.61 (s, 1H), 2.20 (s, 3H) ppm.

Step 2:

To a stirred solution of 6-bromo-3-fluoro-2-methyl-phenol (40 g, 195.10 mmol) in acetone (400 mL) at ambient température was added potassium carbonate (135 g, 976.80 mmol). The reaction mixture was stirred for 10 min at 25 °C. Methyl iodide (39 g, 17.105 mL, 274.77 mmol) was added dropwise over 10 min and the mixture was stirred for 16 hrs at 25 °C. The reaction mixture was filtered and the solid residues washed with acetone (50 ml). The mother liquors were concentrated at 15 °C under reduced pressure. Hexane (200 ml) was added and the mixture was stirred for 15 minutes. The solid was collected and washed with hexane (8 ml). The mother liquors were concentrated under reduced pressure at 15 °C. Purification by distillation (520 mmHg, 192-196 °C) gave l-bromo-4-fluoro-2-methoxy-3-methyl-benzene (32.4 g, 76%). ’HNMR (400 MHz, Chloroform-d) δ 7.33-7.30 (m, 1H), 6.72 (t, J = 8.7 Hz, 1H), 3.80 (s, 3H), 2.23 (s, 3H) ppm.

Step 3:

lodine (50 mg, 0.1970 mmol) was added at 25 °C to a stirred mixture of Mg tumings (5 g, 205.72 mmol) in THF (50 ml). The mixture was stirred until the reaction tumed into a clear pale yellow colour. l-bromo-4-fluoro-2-methoxy-3-methyl-benzene (2.5 g, 11.4 mmol) was added dropwise at ambient température. When reaction initiation was observed, the remaining solution of l-bromo-4-fluoro-2-methoxy-3-methyl-benzene (22.5g ,102.71 mmol) in THF (200 ml) was added dropwise. The mixture was stirred for 40 minutes. Reaction was cooled down to -78 °C and triisopropylborate (64.385 g, 79 mL, 342.34 mmol) was added dropwise. The mixture was warmed up to ambient température and stirred for 16 hrs. The reaction was quenched by addition of a 2N aqueous solution of HCl (25 ml) and stirred for 15 minutes. The mixture was diluted with water (125 ml) and extracted with ethyl acetate (2 x 250 ml). The organic layer was separated, washed with water (250 ml), dried (NaiSCh) and concentrated in vacuo. Hexane (2 5 ml) was added to the residue at 0 °C and the mixture was stirred for 5 minutes. The resulting solid was

455 filtered, washed with 10 ml of chilled hexane and dried to give (4-fluoro-2-methoxy-3-methylphenyl)boronic acid (11.5 g, 55%). Ή NMR (400MHz, DMSO-d₆) δ 7.96 (br s, 2H), 7.32 (t, J = 8.0 Hz, 1H ), 6.88 (t, J = 8.7 Hz, 1H), 3.75 (s, 3H), 2.11 (s, 3H) ppm.

Intermediate F l-Bromo-3-ethyl-4-fluoro-2-methoxy-benzene

1) Potassium vinyltrifluoroborate,

Pd(dppf)CI₂.DCM, K₂CO₃, water, 1,4- HO dioxane, 90°C, 72%

2) 10% Pd/C, EtOH, H₂ (1 atm), 93%

-

F

3) NBS, /PrNH₂, DCM, -10°C, 55%

4) Mel, K₂CO₃, DMF, 0°C to RT, 94%

Step 1:

Pd(dppf)Ch.DCM (7.5 g, 9.1840 mmol) was added to a stirred mixture of 2-bromo-3-fluorophenol (25 g, 130.89 mmol), potassium vinyltrifluoroborate (52 g, 388.20 mmol) and K2CO3 (55 g, 397.96 mmol) in a mixture of 1,4-dioxane (250 mL) and water (25 mL). The mixture was degassed by bubbling through nitrogen gas for 15 minutes. The mixture was heated to 90 °C for 16h. The reaction mixture was filtered through a pad of celite. The collected mother liquors were diluted with water (300 mL). The aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried (MgSO₄), filtered and concentrated in vacuo. Purification by flash chromatography (S1O2, 0-1 % EtOAc in hexanes) gave 3-fluoro-2-vinyl-phenol (14.5 g, 72%) as a colourless oil. Ή NMR (400 MHz, Chloroform-d) δ 7.06 (q, J = 8.16 Hz, 1H), 6.80-6.73 (m, 1H), 6.66-6.61 (m, 2H), 5.88 (d, J = 18.04, 1H), 5.60 (d, J = 11.7, 1H), 5.48 (s, 1H) ppm.

Step 2:

Palladium on carbon (2.9 g, 10 %w/w, 2.3877 mmol) was added to a stirred solution of 3fluoro-2-vinyl-phenol (14.5 g, 94.470 mmol) in éthanol (145 mL). The mixture was degassed by

456 bubbling through nitrogen gas for 10 minutes. The reaction mixture was stirred under a balloon pressure of hydrogen for 6h. The mixture was filtered through celite, washing with éthanol, and the filtrate concentrated in vacuo. Purification by flash chromatography (SiO₂, 0-1 % EtOAc in hexanes) gave 2-ethyl-3-fluoro-phenol (13 g, 93%) as a colourless oil. Ή NMR (400 MHz, Chloroform-d) δ 7.0 (q, J = 7.96 Hz, 1H), 6.62 (t, J = 8.7 Hz, 1H), 6.54 (d, J = 8.08 Hz, 1H), 4.90 (br s, 1H), 2.66 (q, J = 7.24 Hz, 2H), 1.17 (t, J = 7.52 Hz, 3H) ppm.

Step 3:

NBS (14 g, 78.659 mmol) was added portion wise to a stirred solution of 2-ethyl-3-fiuorophenol (13 g, 88.117 mmol) and isopropylamine (4.6920 g, 6.9 mL, 79.377 mmol) in DCM (274 mL) at -10 °C. The reaction mixture was stirred for 15 minutes. The reaction was quenched by addition of a 2N aqueous solution of HCl. The mixture was extracted with DCM (2 x 500 mL). The combined organic layers were dried (Na₂SÛ4) and concentrated in vacuo. Purification by flash chromatography (SiO₂, 0-1 % EtOAc in hexanes) gave 6-bromo-2-ethyl-3-fluoro-phenol (11 g, 55%) as a colourless oil. ’H NMR (400 MHz, Chloroform-d) δ 7.23 (dd, J = 4.76 Hz, J = 5.8 Hz, 1H), 6.55 (t, J = 8.72 Hz, 1H), 5.6 (d, J = 1.64 Hz, 1H), 2.74 (q, J = 7.08 Hz, 2H), 1.16 (t, J = 7.4 Hz, 3 H) ppm.

Step 4:

Methyl iodide (13.680 g, 6 mL, 96.379 mmol) was added dropwise at 0 °C to a stirred solution of 6-bromo-2-ethyl-3-fluoro-phenol (11 g, 48.208 mmol) and K₂CO₃ (16.5 g, 119.39 mmol) in DMF (110 mL). The reaction mixture was stirred for 12h at ambient température. The mixture was diluted with ice water (250 mL). The aqueous phase was extracted with hexane (3 x 500 mL). The organic layer was separated, dried (MgSCH), filtered and concentrated in vacuo. Purification by flash chromatography (SiO₂, 0-1 % EtOAc in hexanes) gave l-bromo-3-ethyl-4-fluoro-2-methoxybenzene (11g, 94%) as a colourless oil. Ή NMR (400 MHz, Chloroform-d) δ 7.32 (dd, J = 6.08 Hz, J = 6.04 Hz 1H), 6.72 (t, J = 8.84 Hz, 1H), 3.84 (s, 3H), 2.70 (q, 2H), 1.18 (t, J = 7.52 Hz, 3H) ppm.

457

Intermediate G

3-Bromo-6-(difluoromethyl)-2-methoxypyridine

3) Mel, K₂CO₃, DMF, RT, 64%

1) NaOMe, MeOH, 0°C to1QO°C, 70%

2) KMnO₄, ^fBuOH, water, 70°C, 49%_>

6) DAST, DCM, -20 °C to RT, 65% ---------!-------->

4) DIBAL, DCM, 78°C to RT, 91% ' --------------*>

Br

5) MnO₂, DCM, RT, 77% —^:------->►

Step 1:

Sodium methoxide (20 mL of 25 %w/v solution in MeOH, 92.552 mmol) was added at 0 °C to a stirred solution of 3-bromo-2-chloro-6-methyl-pyridine (8 g, 38.747 mmol) in MeOH (50 mL) in a sealed tube. The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried (NazSOq), filtered and concentrated in vacuo to give 3-bromo-2-methoxy-6-methyl-pyridine (5.5 g, 70%) as a colourless oil. 'H NMR (400 MHz, DMSO-dô) δ 7.82 (d, J = 7.7 Hz, 1H), 6.76 (d, J = 7.7 Hz, 1H), 3.88 (s, 3H), 2.35 (s, 3H) ppm. ESIMS m/z cale. 200.9789, found 202.01 (M+l)⁺; Rétention time: 1.69 minutes.

Step 2:

KMnO₄ (13 g, 82.261 mmol) was added at ambient température to a stirred solution of 315 bromo-2-methoxy-6-methyl-pyridine (5.5 g, 27.221 mmol) in ZerZ-butanol (150 mL) and water (300 mL). The reaction mixture was heated at 70 °C for 16 h. The reaction mixture was quenched by addition of a IM aqueous solution of HCl (80 mL). The resulting mixture was stirred for 30 min,

458 filtered and washed with EtOAc (2 x 100 mL). The mother liquors were extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with a 0.5 N aqueous solution of NaOH (2 x 100 mL). The aqueous layer was collected, acidified by addition of a 12N aqueous solution of HCl and extracted with DCM (2 x 100 mL). The combined organic extracts were washed with brine, dried (Na₂SÜ4), filtered and concentrated in vacuo to give 5-bromo-6-methoxy-pyridine-2-carboxylic acid (3.1 g, 49%) as white solid. Ή NMR (400 MHz, DMSO-d₆) δ 13.27 (br s, 1H), 8.19 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 3.98 (s, 3H) ppm. ESI-MS m/z cale. 230.9531, found 232.0 (M+l)⁺; Rétention time: 1.34 minutes.

Step 3:

Sodium carbonate (1.5 g, 14.153 mmol) was added to a stirred solution of 5-bromo-6methoxy-pyridine-2-carboxylic acid (3 g, 12.929 mmol) in DMF (40 mL). Methyl iodide (3.8760 g, 1.7 mL, 27.308 mmol) was then added and the mixture was stirred at ambient température for 16 h. The reaction mixture was quenched by addition of ice cold water (50 mL). The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (2 x 100 mL), brine (50 mL), dried (Na₂SÛ4), filtered and concentrated in vacuo to give methyl 5bromo-6-methoxy-pyridine-2-carboxylate (2.02 g, 63%) as an off-white solid. 'H NMR (400 MHz, DMSO-de) δ 8.22 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 3.98 (s, 3H), 3.87 (s, 3H) ppm. ESIMS m/z cale. 244.9688, found 246.1 (M+l)⁺; Rétention time: 3.21 minutes.

Step 4:

Diisobutylaluminum hydride (14 mL of 25 %w/v solution in toluene, 24.610 mmol) was added at -78 °C to a stirred solution of methyl 5-bromo-6-methoxy-pyridine-2-carboxylate (2 g, 8.128 mmol) in DCM (80 mL). The reaction mixture was stirred at ambient température for 1 h. The reaction mixture was quenched by addition of a saturated aqueous solution of sodium tartrate (50 mL). The mixture was stirred for 30 min then extracted with DCM (3 x 100 mL). The combined organic layers were dried (Na₂SC>4), filtered and concentrated in vacuo to give (5-bromo-6-methoxy2-pyridyl)methanol (1.62 g, 91%) as a white solid. Ή NMR (400 MHz, DMSO-dô) δ 7.99 (d, J = 7.8 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 5.45 (t, J = 11.8 Hz, 1H), 4.45 (d, J = 5.9 Hz, 2H), 3.89 (s, 3H) ppm. ESI-MS m/z cale. 216.9738, found 218.0 (M+l)⁺; Rétention time: 2.93 minutes.

Step 5:

459

MnO₂ (8 g, 92.021 mmol) was added to a stirred solution of (5-bromo-6-methoxy-2pyridyl)methanol (1.6 g, 7.3378 mmol) in DCM (80 mL). The reaction mixture was stirred at ambient température for 16 h. The reaction mixture was filtered and concentrated in vacuo to give 5bromo-6-methoxy-pyridine-2-carbaldehyde (1.22 g, 77%) as off-white solid. Ή NMR (400 MHz, DMSO-de) δ 9.88 (s, 1H), 8.29 (d, J = 7.7 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 4.03 (s, 3H) ppm.

Step 6:

DAST (1.9740 g, 1.5 mL, 12.246 mmol) was slowly added at -20 °C to a stirred solution of 5-bromo-6-methoxy-pyridine-2-carbaldehyde (1.2 g, 5.5547 mmol) in DCM (30.000 mL). The reaction mixture was stirred at ambient température for 16 h. The reaction mixture was quenched by addition of ice-water. The pH of the solution was adjusted to 8-10 by addition of solid sodium hydrogen carbonate. The organic phase was collected, washed with water and brine, dried (Na2SO₄), filtered and concentrated in vacuo. Purification by flash chromatography (SiCh, 100% hexanes) gave 3-bromo-6-(difluoromethyl)-2-methoxy-pyridine (900 mg, 65%) as pale yellow oil. *H NMR (400 MHz, DMSO-de) δ 8.22 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 7.03 - 6.75 (m, 1H), 3.96 (s, 3H) ppm.

Intermediate H

Ethyl 4-amino-5-fluoropicolinate

1) (Boc)₂O, TEA, 2) Pd(dppf)CI₂,

DCM, 15°C to 30° TEA, EtOH, CO

C, 70%_______(60 psi), 65°C, 68% \ocHN^^Br 3) TFA, DCM, RT^

H

Step 1:

TEA (66.17g) was added to a mixture of 2-bromo-5-fluoropyridin-4-amine (25g, 0.131 mol) in DCM (250 mL) at 25-30 °C under a nitrogen atmosphère. The reaction mixture was cooled down to 15-20 °C. Boc anhydride (57.13g, 0.262 mol) was slowly added over 15 to 30 min. A 3 to 5° exotherm was observed. The température was raised to 25-30 °C and maintained for 24-36h. Further TEA (13.23g, 0.131 mol) and Boc anhydride (14.27g, 0.065 mol) were added and the mixture was stirred for a further 12-18h at 25-30 °C. The reaction mixture was quenched by slow addition of

460 water (250 mL) at 10-20 °C over l-2h. The aqueous layer was separated and extracted with DCM (125 mL x 2). The combined organic extracts were washed with a 10% aqueous solution of NaCl (250 mL), dried ( NazSOY), filtered and concentrated in vacuo. EtOAc (25 ml) was added to the brown colour solid and the mixture was stirred for 10-15 min at 25-30 °C. Hexane (50.0mL) was slowly added at 25-30 °C, which caused a solid to precipitate. The mixture was stirred for 30 to 45 min at 25-30 °C. The solid was filtered, washed with hexane (12.5 mL) and dried under vacuum for 2-3h at 40-45 °C to give ZerZ-butyl (2-bromo-5-fluoropyridin-4-yl)carbamate (26.68g, 70% yield). Ή NMR (400 MHz, Chloroform-d) δ 8.33 (d, J = 6.0 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 6.91 (br s, 1H), 1.56 (s, 9H)ppm.

Step 2:

Pd(dppf)Cb (7.54g, 10.3 mmol) and TEA (15.64g, 154.5 mmol) were added to a mixture of ZerZ-butyl (2-bromo-5-fluoropyridin-4-yl)carbamate (15g, 51.25 mmol) in éthanol (300 mL) at 25-30 °C under nitrogen atmosphère in a Pair bottle. The resulting mixture was shaken in the Pair hydrogenator under a carbon monoxide pressure of 60 psi at 75-80 °C for 16-20h. The reaction mixture was cooled down to 25-30 °C. The mixture was filtered through a pad of celite and washed with éthanol (150 mL). The filtrâtes were concentrated concentrated in vacuo at 40-45 °C. Purification by flash chromatography (SiCh, 0 to 10% EtOAc in hexanes) gave ethyl 4-((ZerZbutoxycarbonyl)amino)-5-fluoropicolinate (10g, 68%). 'HNMR (400 MHz, Chloroform-d) δ 8.92 (d, J = 6.4 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 6.95 (br s, 1H), 4.46 (q, J = 7.2 Hz, 2H), 1.56 (s, 9H), 1.43 (t, J = 7.2 Hz, 3H) ppm.

Step 3:

Ethyl 4-((ZerZ-butoxycarbonyl)amino)-5-fluoropicolinate (14g, 49.25 mmol) was stirred at ambient température in a mixture of TFA (56 mL) and DCM (140 mL). Upon reaction completion, the mixture was concentrated in vacuo and the pH of the solution was adjusted to 8-9 by addition of a saturated solution of sodium bicarbonate. The aqueous phase was extracted with ethyl acetate. The organic extracts were concentrated in vacuo to give ethyl 4-amino-5-fluoropicolinate (7.53g, 83%). ‘H NMR (400 MHz, DMSO-d₆) δ 8.17 (d, J = 3.2 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H), 6.50 (br s, 1H), 4.26 (q, J = 6.8 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H) ppm. ESI-MS m/z cale. 184.0648, found 184.84 (M+l)⁺.

461

Intermediate I

Methyl 4-chloro-6-fluoropicolinate

O

I

Step 1:

To a stirred mixture of methyl 4-chloropyridine-2-carboxylate (625 mg, 3.643 mmol) in acetonitrile (15 mL) was added silver fluoride (1.7 g, 11.655 mmol) in one portion at room température. The reaction mixture was stirred at room température for 18 h. Additional silver fluoride (530 mg, 3.634 mmol) was added and the stirring was continued for an additional 24 h. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (50 mL) and ethyl acetate (50 mL) and filtered through a pad of Celite. The organic extracts were washed with brine (20 mL), dried (NaiSCh) and concentrated in vacuo. Purification by flash chromatography (25g SiO₂, 0 to 100% EtOAc in heptane) gave methyl 4-chloro-6-fluoropicolinate (200 mg, 28%) as a white solid. Ή NMR (400 MHz, Chloroform-d) δ 8.03 (dd, J = 1.4, 0.9 Hz, 1H), 7.18 (dd, J = 2.7, 1.8 Hz, 1H), 4.00 (s, 3H) ppm.

Intermediate J

Methyl 4-aminopicolinate-5-d

Step 1:

A mixture of methyl 4-amino-5-iodo-pyridine-2-carboxylate (1 g, 3.5965 mmol), K2CO3 (0.5 g, 3.6178 mmol) and palladium on carbon (200 mg, 5 %w/w, 0.0940 mmol) in methanol-d4 (8 mL) was stirred at room température under an atmosphère of deuterium gas (balloon) for 20 h. The mixture was filtered through Celite, washing with methanol and concentrated in vacuo to give a

462 white solid. Purification by reverse phase chromatography (Biotage Isolera, 30 g, SiliaSep Cl8 Monomeric 25 pm Silicycle flash cartridge, 0 to 100% acetonitrile containing 0.1% ammonium hydroxide in water containing 0.1% ammonium hydroxide) to give methyl 4-amino-5-deuteriopyridine-2-carboxylate (77 mg, 13%) as a white solid. Ή NMR (400 MHz, DMSO-dô) δ 8.03 (s, 1H), 7.18 (s, 1H), 6.29 (br s, 2H), 3.77 (s, 3H) ppm. ESI-MS m/z cale. 153.0649, found 154.08 (M+l)⁺.

Intermediate K

Methyl 4-chloropicolinate-3-iZ

1) D₂O, 2,2,6,6tetramethylpiperidi 2) SOCI₂, DMF, 75 ne, BuLi, THF, -50 AA AA

JJLxiH °Gtn0°G, 51% ► LJL.OH ^RT’^{38 Z}°----Λ JL .OMe π I H ci n

O DO DO

K

Step 1:

A solution of 2,2,6,6-tetramethylpiperidine (3.442 g, 4.147 mL, 24.369 mmol) in THF (40 mL) was cooled to -50 °C. BuLi (1.6M in hexanes) (20.307 mL of 1.6 M, 32.492 mmol) was added dropwise over 10 min. The reaction mixture was stirred for 5 min, then pyridine-2-carboxyIic acid (1 g, 8.1229 mmol) was added. After stirring for 10 min, the reaction mixture was allowed to warm to 0 °C and deuterium oxide (813.40 mg, 0.813 mL, 40.614 mmol) was added. The reaction mixture was stirred for 30 min. The mixture was concentrated in vacuo to give a pale brown solid which was stirred in a 9:1 mixture of DCM and MeOH (20 mL) for 30 min. The solid was filtered and the filtrâtes concentrated in vacuo to give a first crop of 3-deuteriopyridine-2-carboxylic acid (353 mg, 32%) . The solid was subjected a second time to the same treatment to give a second crop of 3deuteriopyridine-2-carboxylic acid (214 mg, 19%). ’H NMR (400 MHz, Methanol-d4) δ 8.53 (q, J = 2.1 Hz, 1H), 7.87 (dd, J = 7.3, 1.4 Hz, 1H), 7.43 (dd, J = 7.6, 4.8 Hz, 1H) ppm. 93% deuterium incorporation observed by NMR.

Step 2:

463

DMF (47.200 mg, 0.05 mL, 0.6457 mmol) was added at 45 °C to a solution of thionyl chloride (1.957 g, 1.2 mL, 16.451 mmol). 3-deuteriopyridine-2-carboxylic acid (400 mg, 3.0617 mmol) was added and the reaction mixture was heated at 75 °C for 16 h. The reaction mixture was cooled to room température and toluene was added (1 mL). The mixture was concentrated in vacuo and the same process was repeated. Methanol was added and the mixture was stirred at room température for 30 minutes then concentrated in vacuo. The residue was partitioned between a saturated aqueous solution of sodium hydrogen carbonate (3 mL) and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (Biotage Isolera, 25 g, SiliaSep 25 pm Silicycle flash cartridge, 30% to 100% ethyl acetate in heptane) gave methyl 4chloro-3-deuterio-pyridine-2-carboxylate (210 mg, 38%) as a pale brown solid. Ή NMR (400 MHz, Chloroform-d) δ 8.64 (d, J = 5.0 Hz, 1H), 7.49 (d, J = 5.0 Hz, 1H), 4.02 (s, 3H) ppm.

Intermediate L

Methyl 4-chloropicolinate-6-iZ

Step 1:

A mixture of 2-carboxypyridine 1-oxide (2.94 g, 21.135 mmol) and sodium deuteroxide (5 mL of 40 %w/v solution in water, 46.493 mmol) in deuterated water (5 mL) was stirred at 80 °C for 4 h. The reaction mixture was cooled to ambient température. The mixture was poured into concentrated hydrochloric acid (6 mL) at 0 °C and the solid collected by filtration. The filtrate was acidified to pH 1 with concentrated hydrochloric acid and additional solid collected by filtration. The solids were combined to give 2-carboxypyridine l-oxide-6-i7 (2.08 g, 67%) as a white solid. Ή NMR (400 MHz, DMSO-d₆) δ 18.67 (s, 1H), 8.28 (dd, J = 7.6, 2.3 Hz, 1H), 7.91-7.85 (m, 2H) ppm. 95% deuterium incorporation observed by NMR.

Step 2:

464

POCh (822.50 mg, 0.5 mL, 5.3642 mmol) was added to a stirred mixture of toluene (2.5 mL) and DMF (5 mL) at room température. The mixture was cooled to 0 °C and 2-carboxypyridine l-oxide-6-ίΖ (150 mg, 1.0170 mmol) was added. The reaction mixture was stirred for 5 min at 0 °C then, for a further 18 h at ambient température. The mixture was concentrated in vacuo to approximately 50% of its volume. Methanol (5 mL) was added, and the mixture was again concentrated in vacuo to approximately 50% of its volume. The obtained solution was added to an aqueous saturated solution of NaHCCh (20 mL) and extracted with ethyl acetate (3x10 mL). The organic extracts were washed with brine (10 mL), dried (NazSCh), filtered and concentrated in vacuo. The crude material was combined with another batch of the same scale. Purification by flash chromatography (Biotage Isolera, 12 g, SiliaSep 25 pm Silicycle flash cartridge, 0 to 50% ethyl acetate in heptane) gave methyl 4-chloropicoIinate-6-i/ (29 mg, 14%) as a colourless oil. Ή NMR (400 MHz, Chloroform-d) δ 8.14 (d, J = 1.5 Hz, IH), 7.49 (s, IH), 4.01 (s, 3H) ppm. ESI-MS m/z cale. 172.015, found 173.01 (M+l)⁺; Rétention time: 1.15 minutes.

Example 34

E-VIPR Assav Detecting and Measuring Nay Inhibition Properties

Sodium ion channels are voltage-dependent proteins that can be activated by inducing membrane voltage changes by applying electric fields. The electrical stimulation instrument and methods of use, referred to as E-VIPR, are described in International Publication No. WO 2002/008748 A3 and C.-J. Huang et al. Characterization of voltage-gated sodium channel blockers by electrical stimulation and fluorescence détection of membrane potential, 24 Nature Biotech. 43946 (2006), both of which are incorporated by reference in their entirety. The instrument comprises a microtiter plate handler, an optical System for exciting the coumarin dye while simultaneously recording the coumarin and oxonol émissions, a waveform generator, a current- or voltagecontrolled amplifier, and parallel electrode pairs that are inserted into assay plate wells. Under integrated computer control, this instrument passes user-programmed electrical stimulus protocols to cells within the wells of the microtiter plate.

16-20 hours prior to running the assay on E-VIPR, HEK cells expressing a truncated form of human Nav 1.8 with full channel activity were seeded into microtiter 384-welI plates, pre

465 coated with matrigel, at a density of 25,000 cells per well. 2.5-5% KIR2.1 Bacmam virus was added to the final cell suspension before seeding into cell plates. HEK cells were grown in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% FBS (Fêtai Bovine Sérum, qualified; Sigma #F4135), 1% NEAA (Non-Essential Amino Acids, Gibco #11140), 1% HEPES (Gibco #15630), 1% Pen-Strep (Penicillin-Streptomycin; Gibco #15140) and 5 pg/ml Blasticidin (Gibco #R210-01). Cells were expanded in vented cap cell culture flasks, with 90-95% humidity and 5% CO₂.

Reagents and Stock Solutions:

100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO Compound Plates: Corning 384-well Polypropylene Round Bottom #3656 Cell Plates: 384-well tissue culture treated plates (Greiner #781O91-1B) 2.5-5% KIR 2.1 Bacmam virus (produced in-house), prepared as described in Section 3.3 of J. A. Fomwald et al., Gene Expression in Mammalian Cells Using BacMam, a Modified Baculovirus System, 1350 Methods in Molecular Biology 95-116 (2016), the entire contents of which are incorporated by reference. The concentration used can be dépendent on viral titer of each batch.

mM DiSBAC6(3), a voltage sensitive oxonol acceptor (CAS number 169211-44-3; 5[3-( 1,3-dihexylhexahydro-4,6-dioxo-2-thioxo-5-pyrimidinyl)-2-propen-1 -ylidene]-1,3dihexyldihydro-2-thioxo-4,6(lH,5H)-pyrimidinedione), in dry DMSO. The préparation of DiSBACô(3) is analogous to that of DiSBAC4(3) as described in Voltage Sensing by Fluorescence Résonance Energy Transfer in Single Cells, Gonzalez, J.E. and Tsien, R.Y. (1995) Biophys. J. 69, 1272-1280.

mM CC2-DMPE, a commercially available membrane-bound coumarin phospholipid FRET donor (ThermoFisher Scientific catalog number K1017, CAS number 393782-57-5;

tetradecanoic acid, l,l'-[(lR)-l-[8-(6-chloro-7-hydroxy-2-oxo-2H-l-benzopyran-3-yl)-3-hydroxy-3oxido-8-oxo-2,4-dioxa-7-aza-3-phosphaoct-l-yl]-l,2-ethanediyl] ester) was prepared in dry DMSO. See also, Improved indicators of cell membrane potential that use fluorescence résonance energy transfer, Gonzalez, J.E. and Tsien, R.Y. (1997) Chem. Biol. 4, 269-277.

Voltage Assay Background Suppression Compound (VABSC-1) is prepared in H2O (89363 mM, range used to maintain solubility)

466

Human Sérum (HS, Millipore #S1P1-O1KL, or Sigma SLBR5469V and SLBR5470V as a 50%/50% mixture, for 25% assay final concentration)

Bathl Buffer:

Sodium Chloride 160 mM (9.35 g/L), Potassium Chloride, 4.5 mM (0.335 g/L), Glucose 10 mM (1.8 g/L), Magnésium Chloride (Anhydrous) 1 mM (0.095 g/L), Calcium Chloride 2 mM (0.222 g/L), HEPES 10 mM (2.38 g/L) in water.

Na/TMA Cl Bathl Buffer:

Sodium Chloride 96 mM (5.61 g/L), Potassium Chloride 4.5 mM (0.335 g/L), Tétraméthylammonium (TMA)-Cl 64 mM (7.01 g/ L), Glucose 10 mM (1.8 g/L), Magnésium Chloride (Anhydrous) 1 mM (0.095 g/L), Calcium Chloride 2 mM (0.222 g/L) HEPES 10 mM (2.38 g/L) in water.

Hexyl Dye Solution (2X concentration):

Bathl Buffer containing 0.5% β-cyclodextrin (made fresh prior to each use, Sigma &C4767), 8 μΜ CC2-DMPE and 2 pM DiSBAC6(3). The solution was made by adding 10% Pluronic F127 stock equal to combined volumes of CC2-DMPE and DiSBACe(3). The order of préparation was first mix Pluronic and CC2-DMPE, then add DiSBACô(3), then while vortexing add Bathl/p-Cyclodextrin.

Compound Loading Buffer (2X concentration): Na/TMA Cl Bathl Buffer containing HS (omitted in experiments run in the absence of human sérum (HS))50%, VABSC-1 1 mM, BSA 0.2 mg/ml (in Bath-1), KC1 9 mM, DMSO 0.75%.

Assay Protocol (7 key Steps):

1) To reach the final concentration in each well, 400 nL of each compound was prespotted (in neat DMSO) into polypropylene compound plates at 250x desired final concentration from an intermediate stock concentration of 0.075 mM, in an 11 point dose response, 3-fold dilution, resulting in a top dose of 300 nM final concentration in the cell plate. Vehicle control (neat DMSO), and positive control (an established Navl.8 inhibitor, 25 pM final in assay in DMSO) were added manually to the outermost columns of each plate respectively. The compound plate was backfilled with 45 pL per well of Compound Loading Buffer resulting in a 250 fold dilution of

467 compound following a 1:1 transfer of compound into the cell plate (see Step 6). Final DMSO concentration for ail wells in the assay was 0.625% (0.75% DMSO was supplemented to the Compound Loading Buffer for a final DMSO concentration of 0.625%). This assay dilution protocol was adjusted to enable a higher dose range to be tested in the presence of HS or if the final assay volume was altered.

2) Hexyl Dye Solution was prepared.

3) Cell plates were prepared. On the day of the assay, the media was aspirated, and the cells were washed three times with 80 pL of Bath-1 buffer, maintaining 25 pL residual volume in each well.

4) 25 pL per well of Hexyl Dye Solution was dispensed into the cell plates. The cells were incubated for 20 minutes at room température or ambient conditions in darkness.

5) 45 pL per well of Compound Loading Buffer was dispensed into compound plates.

6) The cell plates were washed three times with 80 pL per well of Bath-1 Buffer, leaving 25 pL of residual volume. Then 25 pL per well from compound plate was transferred to each cell plate. The mixture was incubated for 30 minutes at room temperature/ambient conditions.

7) The cell plate containing compound was read on E-VIPR using the current-controlled amplifier to deliver stimulation wave puises using a symmetrical biphasic waveform. The userprogrammed electrical stimulus protocols were 1.25-4 Amps and 4-6 millisecond puise width (dépendent on electrode composition) were delivered at 10 Hz for 10 seconds. A pre-stimulus recording was performed for each well for 0.5 seconds to obtain the un-stimulated intensities baseline. The stimulatory waveform was followed by 0.5 seconds of post-stimulation recording to examine the relaxation to the resting State. Ail E-VIPR responses were measured at 200 Hz acquisition rate.

Data Analysis:

Data were analyzed and reported as normalized ratios of émission intensities measured in the 460 nm and 580 nm channels. The response as a function of time was reported as the ratios obtained using the following formula:

(intensity 460 nm )

R(_t)= --------------------------------------------468 (intensity 580 nm)

The data were further reduced by calculating the initial (Ri) and final (Rf) ratios. These were the average ratio values during part or ail of the pre-stimulation period and during sample points during the stimulation period. The fluorescence ratio (Rf/Ri) was then calculated and reported 5 as a fimction of time.

Control responses were obtained by performing assays in the presence of the positive control, and in the absence of pharmacological agents (DMSO vehicle négative control). Responses to the négative (N) and positive (P) Controls were calculated as above. The compound antagonist % activityJ was then defined as:

X-N

A =------------- x 100

P-N where X is the ratio response of the test compound. Using this analysis protocol, dose response curves were plotted and IC50 values were generated for varions compounds of the présent invention as reported below in Tables 1 and 2.

Table 1. IC50 Values of Compounds of the Invention Generated in the Presence of Human Sérum in the E-VIPR Assay (A = IC50 < 0.01 μΜ; B = 0.1 μΜ > IC₅o > 0.01 μΜ; C = 1 μΜ > IC₅o > 0.1 μΜ; D = IC50 > 1 μΜ)

Cmpd #	IC50 (μΜ)
1	B
2	C
3a	D
3b	A
4	D
5	B

469

Cmpd #	IC₅₀ (μΜ)
6	D
7	A
8	D
9	A
10	D
11	A
12	D
13	B
14	D
15	A
16	D
17	A
18	A
19	A
20	D
21	D
22	B
23	B
24	D
25	A
26	A

470

Cmpd #	IC_SO (μΜ)
27	B
28	B
29	D
30	C
31	D
32	A
33	C
34	D
35	C
36	D
37	C
38	D
39	C
40	D
41	B
44	A
45	B
46	D
47	B
51	D
52	A

471

Cmpd #	ICso (μΜ)
53	A
54	C
55	A
56	A
57	D
58	D
59	D
60	B
61	C
63	D
64	B
65	D
66	C
67	D
68	B
69	D
70	D
71	D
72	B
73	D
74	B

472

Cmpd #	IC50 (μΜ)
75	D
76	C
77	D
78	B
79	D
80	D
81	C
82	D
83	C
84	D
85	D
86	D
87	C
88	D
89	A
90	D
91	C
92	D
93	A
94	A
95	D

473

Cmpd #	IC50 (μΜ)
96	D
97	D
98	D
99	D
100	D
101	D
102	D
103	D
104	D
105	B
106	D
107	D
108	C
109	D
110	C
111	D
112	C
113	B
115	A
116	A
137	D

474

Cmpd #	IC50 (μΜ)
138	B
146	B
150	D
151	B

Table 2. IC50 Values of Compounds of the Invention Generated in the Absence of Human Sérum in the E-VIPR Assay (A = IC50 < 0.01 μΜ; B = 0.1 μΜ > IC₅o > 0.01 μΜ; C = 1 μΜ > IC₅o > 0.1 μΜ; D = IC50 > 1 μΜ)

Cmpd #	IC50 (μΜ)
42	A
43	C
50	B
114	B
117	B
118	A
119	A
120	B
121	A
122	A
123	A
124	A
126	A

475

Cmpd #	ICso (μΜ)
127	A
128	A
128	B
129	A
131	D
132	A
133	B
134	C
135	D
136	A
139	D
140	B
141	D
147	A
148	A
149	A
152	A

Many modifications and variations of the embodiments described herein may be made without departing from the scope, as is apparent to those skilled in the art. The spécifie embodiments described herein are offered by way of example only.

Claims

1. A compound of formula (I) i ^v4a

Χ³Λ . · x^4c

I » or a pharmaceutically acceptable sait thereof, wherein:

X^2a is N, N⁺-O', or C-R^2a;

X^4a is N, N⁺-O', or C-R^4a;

X^5a is N, N⁺-0‘, or C-R^5a;

X^6a is N, N⁺-0‘, or C-R^6a;

each R is independently H or Ci-Cô alkyl;

R^2a, R^4a, R^5a, and R^6a are each independently H, halo, Ci-Ce alkyl, or Ci-Cô haloalkyl;

R^5bl and R^5b2 are each independently H, Ct-Cô alkyl, Cj-Cô cycloalkyl, or Ci-Cô haloalkyl;

X^3c is N or C-R^3c;

X^4c is N or C-R^4c;

X^5c is N or C-R^5c;

X^6c is N or C-R^6c;

R^2c is H, OH, halo, Ci-Cô alkyl, Cî-Cô alkenyl, Ci-Cô haloalkyl, Ci-Cô alkoxy, Ci-Cô haloalkoxy, or

-L’-L²-(C3-Cô cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo;

L¹ is a bond or O;

L² is a bond or Ci-Cô alkylene;

R^3c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl;

R^4c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl;

R^5c is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl; and

R⁶⁰ is H, halo, Ci-Cô alkyl, or Ci-Cô haloalkyl;

provided that no more than two of X^2a, X^4a, X^5a, and X^6a are N or N⁺-O'; and provided that no more than one of X^3c, X^4c, X^5c, and X⁶⁰ are N.

2-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-4-carboxamide,

2-[[(25,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-4-carboxamide,

2-[[(25,35,4Æ,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-4-carboxamide,

2-(((25,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-4-carboxamide,

567

2-(((27?,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyI-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-4-carboxamide,

2-(((25,35,47î,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyI]amino]pyridine-4-carboxamide,

2-(((25,37?,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-4-carboxamide,

2-(((27?,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-4-carboxamide,

2-(((25,37?, 47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-4-carboxamide,

2-([(27î,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-4-carboxamide,

2-[[(27?,3Æ,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-4-carboxamide,

2-(((25,37?,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-4-carboxamide,

2-[[(27?,35,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-4-carboxamide,

2-[[(27?,37î,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-4-carboxamide,

2-[((27î,37?,47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-4-carboxamide,

2-([(27?,37?,47î,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydroiuran-2carbonyl]amino]pyridine-4-carboxamide,

2-carbamoyl-4-((2R,3S,4S,5R)-3-(3,4difluoro-2-hydroxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

527

2-carbamoyl-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2(methoxy-d₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide (2S,3R,4R,5S)-A/-(3-carbamoyIphenyl)-3(3,4-difluoro-2-isopropoxyphenyl)-4,5dimethyI-5-(trifluoromethyl)tetrahydrofuran-2carboxamide

(2R₁3S,4S_l5R)-/V-(3-carbamoylphenyl)-3(3,4-difluoro-2-isopropoxyphenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamide

2-carbamoyl-4-((2R,3S,4S,5R)-3-(2-ethoxy-3₁4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

516

(2S,3R,4R,5S)-A/-(3-carbamoylphenyI)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamide (2R,3S,4S,5R)-A/-(3-carbamoylphenyl)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamide

2-carbamoyl-4-((2S₁3R,4R,5S)-3-(2-ethoxy-3₁4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2S,3R,5S)-3-(3,4-difIuoro-2methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2R,3S,5R)-3-(3,4-difluoro-2methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2S₁3S,4S,5R)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethy!)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2R,3S,4S₁5R)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran2-carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2S,3R,4S,5R)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2S,3S,4R,5R)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran2-carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2S,3S,4S,5S)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran2-carboxamido)pyridine 1-oxide

498

2-carbamoyl-4-((2R,3R,4S,5R)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2R,3S,4S,5S)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2S,3R,4S,5S)-3-(2(difluoromethoxy)-3₎4-difluorophenyl)-4,5dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2S,3S,4R,5S)-3-(2(difluoromethoxyFS^-difluorophenylH.Sdimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

497

2-carbamoyl-4-((2R,3R,4R,5R)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyI-4-((2R,3R,4S₁5S)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2R,3S,4R,5S)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2R,3R,4R,5S)-3-(2(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifiuoromethyi)tetrahydrofuran2-carboxamido)pyridine 1-oxide

2-carbamoyi-4-((2S,3S,4S,5S)-3-(3₁4-difluoro2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyi)tetrahydrofuran-2carboxamido)pyridine 1-oxide

490

Q} F ^F2-carbamoyl-4-((2S,3S,4R,5R)-3-(3,4-difluoro2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide > O r^N'° ^f ₃ ^c yV h g / X F ^F 2-carbamoyl-4-((2R,3S,4S₁5R)-3-(3,4difluoro-2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide ? O r^N yÿVAT’ ³ Z\__/ ° _D3c' 4-((2R,3R_l4R,5S)-3-(3,4-difluoro-2-(methoxyc/3)phenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide ^F3^VJh g o—\ / ¹ r^\ V ^F 2-carbamoyl-4-((2S,3R,4S,5R)-3-(3_t4-difluoro-2methoxyphenyI)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide 0 r^N'⁰ _c ^Ar^NH2 ^F3^ \__/ H g / M F ^F 2-carbamoyl-4-((2S,3S₁4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide 0 r^N ³ / ° ^D3C' 4-((2S,3R,4R₁5S)-3-(3,4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

491

2-carbamoyl-4-((2R,3S,4R,5R)-3-(3₁4difluoro-2-methoxyphenyi)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2R,3S,4S,5S)-3-(3,4-difluoro2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2S,3R,4R,5R)-3-(3.4-difluoro2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2-carbamoyl-4-((2S,3R,4S,5S)-3-(3,4difluoro-2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

2. The compound of claim 1, or a pharmaceutically acceptable sait thereof, wherein:

477

X^2a is C-R^2a;

X^5a is C-R^5a;

X^6a is C-R^6a;

R^4bl and R*^b2 are each independently H, Ci-Ce alkyl, or Ci-Cô haloalkyl;

3-deuterio-4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

3-deuterio-4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydroftxran-2carbonyl]amino]pyridine-2-carboxamide,

3-deuterio-4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]pyridine-2-carboxamide,

3-deuterio-4-[[(27?,35,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

577

3-deuterio-4-[[(25,37?, 4R, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

3-deuterio-4-[[(27?,35,47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]pyridine-2-carboxamide,

3-deuterio-4-[[(27?,37î,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

3-deuterio-4-[[(25,37?,47?,5ZÎ)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydroiuran-2carbonyl]amino]pyridine-2-carboxamide,

3-deuterio-4-[[(27?,35,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

3-deuterio-4-[[(27?,37î,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

3-deuterio-4-[[(27?, 37?, 47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

3-deuterio-4-[[(27?,37î,47î,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoroniethyl)tetrahydroiuran-2carbonyl]amino]pyridine-2-carboxamide,

3. The compound of claim 1 or 2, wherein the compound has formula (I-A)

l-A or a pharmaceutically acceptable sait thereof.

4-[[(25,35,45,55)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide.

4-[[(2S,35,45,51?)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, or

4-[[(25,35,4Æ,55)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,3R,4S,55)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(22?,35,45,55)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(2S,35,47?,57?)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(2S,3Æ,4S,5Æ)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(27î,35,45,52?)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,3Æ,4Æ,5S)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyI]amino]pyridine-2-carboxamide,

4-[[(27?,35,4Æ,55)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(222,322,45,55)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

594

4-[[(25,322,422,522)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(222,35,422,522)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(222,322,45,522)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(222,322,422,55)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(222,372,422,57?)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,35,45,55)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,35,45,572)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,35,422,55)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydroftiran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,322,45,55)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(222,35,45,55)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydroftiran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,35,422,522)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,322,45,522)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydroiuran-2carbonyl]ammo]pyridine-2-carboxamide,

4-[[(22?,35,45,52?)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,37î,47î,55)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

593

4-[[(27?,35,47î,5S)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(27?,37î,45,55)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,37?,47î,57î)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(27î,35,47?,57î)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(27?,37?,45,57?)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(27?,37?,47?,55)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(27?,37?,47?,57?)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,35,45,55)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,37?,47?,57?)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (27?,37?,47?,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (27?,37?,45,57?)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (27?,35,47?,57?)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (25,37?,47?,57?)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (27?,37?,45,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (27?,35,47?,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (25,37?, 47?, 55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (27?,35,45,57?)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (25,37?,45,57?)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-methyl-pyridine-2-carboxamide,

592 (25,35,47?,57?)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (27?,35,45,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (25,37?,45,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-methyl-pyridme-2-carboxamide, (25,35,47?,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (25,35,45,57?)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-methyl-pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-methyl-pyridine-2-carboxamide,

4-[[(25,35,45,57?)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,35,47?,55)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,37?,45,55)-3-(3,4-difIuoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(2Æ,35,45,55)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

591

4-[[(25,35,47?,5R)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,37?,45,57?)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(22?,35,45,5Æ)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,3R, 4R, 55)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(2Æ, 35,4R, 55)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(2Æ, 3R,45,55)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,37?,47?,57?)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxatnide,

4-[[(2Æ,35,4Æ,5Æ)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(2Æ,3Æ,45,53?)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(2Æ, 3R, 4R, 55)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridme-2-carboxamide,

4-[[(27?,3Z?,4/?,5Æ)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,35,45,55)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,35,45,57?)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,35,4/?,55)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyI-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

590

4-[[(25,37?,4S,55)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(22?,3S,45,55)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,35,4/?,5Z?)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,37?,45,57?)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(2Æ,35,4S,52?)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,3Æ,4/?,5S)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(22?,35,4/?,55)-3-(5-deuterio-3₎4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(22?,32?,4S,5S)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,37?,4/?,5Æ)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(27?,35,42?₎52?)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(27?,3Æ,4S,5Æ)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(2Æ,37?,4J?,55)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(2Æ,37?,47?,57?)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-(((25,35,45,55)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydroiuran-2carbonyl]amino]pyridine-2-carboxamide,

589

4-(((25,35,45,5Z?)-3-(2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-(((25,35,47?,55)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]pyridine-2-carboxamide,

4-(((25,37?,45,55)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(27î,35,45,55)-3-(2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-(((25,35,47?,57?)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluorc>methyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-(((25,3Æ,45,5Æ)-3-(2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-([(22?,35,45,5Æ)-3-(2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-(((25,3Æ,4Z?,55)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(22?,35,4Æ,55)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(27?,3Æ,45,55)-3-[2-(cyclobutoxy)-3,4-difluoiO-phenyl]-4,5-dimethyl-5-(trifluorOmethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-(((25,3Æ,4Æ,5Æ)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dirnethyl-5-(trifluoroinethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(27?,3S,4/?,57?)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(22?,3Æ,45,52?)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

4-[[(27?,37?,47?,55)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

588

4-[[(27?,37?,47?,57?)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]atnino]pyridine-2-carboxamide,

4-[[(25,35,45,55)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,35,45,57?)-3-[2-[(3,3-difluorocyclobutyI)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,35,47?,55)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,37?,45,55)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide,

4-[[(27?,35,45,55)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,35,47?, 57?)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyI-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,37?,45,57?)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide,

4-[[(27?,35,45,57?)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydroftiran-2-carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,37?,47?,55)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide,

4-[[(27?,35,47?,55)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide,

4-[[(27?,37?,45,55)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide,

4-[[(25,37?,47?,57?)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide,

4-[[(2Æ, 35,42?, 5/?)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide,

587

4-[[(2Æ,37?,45,52?)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide,

4-[[(27?,37?,47?,55)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide,

4-[[(27?,37?,47?,57?)-3-[2-[(3,3-diiluorocyclobutyl)methoxy]-3,4-difluoiO-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyI]amino]pyridine-2-carboxamide,

4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-3-methyl-pyridine-2-carboxamide,

4-[[(25,35,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-3-methyl-pyridine-2-carboxamide,

4-[[(25,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-3-methyl-pyridine-2-carboxamide,

4-[[(25,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-3-methyl-pyridine-2-carboxamide,

4-[[(27?, 35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-3-methyl-pyridine-2-carboxamide,

4-[[(25,35,47î,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-3-methyl-pyridine-2-carboxamide,

576

4-[[(25,37?,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-3-methyl-pyridme-2-carboxamide,

4-[[(27?,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-3-methyl-pyridine-2-carboxamide,

4-[[(25,37?, 47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-3-methyl-pyridine-2-carboxamide,

4-[[(27?,35,47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-3-methyl-pyridme-2-carboxamide,

4-[[(27?,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-3-methyl-pyridine-2-carboxamide,

4-[[(25,37î,47?,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-3-methyl-pyridine-2-carboxamide,

4-[[(27?,35,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-3-methyl-pyridine-2-carboxamide,

4-[[(27î,37?,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-3-methyl-pyridine-2-carboxamide,

4-[[(27?, 37?, 47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-3-methyl-pyridine-2-carboxamide,

4-[[(27?,37?,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-3-methyl-pyridine-2-carboxamide,

4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-methyl-pyridine-2-carboxamide,

4-[[(25,35,45,52?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-methyl-pyridine-2-carboxamide,

4-[[(25, 35,47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-methyl-pyridine-2-carboxamide,

4-[[(25,322,45,55)-3-(3,4-difluoro-2-methoxy-pbenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-methyl-pyridine-2-carboxamide,

575

4-[[(222,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]-6-methyl-pyridine-2-carboxamide,

4-[[(25,35,422,522)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-methyl-pyridine-2-carboxamide,

4-[[(25,3/?,45,522)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-methyl-pyridine-2-carboxamide,

4-[[(222,35,45,5/2)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-methyl-pyridine-2-carboxamide,

4-[[(25,322,422,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-methyl-pyridine-2-carboxamide,

4-[[(222,35,422,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-methyl-pyridine-2-carboxamide,

4-[[(222,322,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-methyl-pyridine-2-carboxamide,

4-[[(25,322,422,522)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-methyl-pyridine-2-carboxamide,

4-[[(222,35,422,522)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-methyl-pyridine-2-carboxamide,

4-[[(2/2,322,45,522)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-methyl-pyridine-2-carboxamide,

4-[[(222,3/2,422,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-methyl-pyridine-2-carboxamide,

4-[[(2/2,3/2,42?,5/2)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-methyl-pyridine-2-carboxamide,

4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-fluoro-pyridine-2-carboxamide,

4-[[(25,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]ammo]-6-fluoro-pyridine-2-carboxamide,

574

4-[[(25,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-fluoro-pyridine-2-carboxamide,

4-[[(25,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyI-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]-6-fluoro-pyridine-2-carboxamide,

4-[[(27?,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-fluoro-pyridine-2-carboxamide,

4-[[(25,35,47?, 57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-fluoro-pyridine-2-carboxamide,

4-[[(25,37î,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-fluoro-pyridine-2-carboxamide,

4-[[(27?,35,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-fluoro-pyridine-2-carboxamide,

4-[[(25,37?,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-fluoro-pyridine-2-carboxamide,

4-[[(27?,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-fluoro-pyridine-2-carboxamide,

4-[[(27?,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-fluoro-pyridine-2-carboxamide,

4-[[(25,37?,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-fluoro-pyridine-2-carboxamide,

4-[[(27?,35,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-fluoro-pyridine-2-carboxamide,

4-[[(27?,37?,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-fluoro-pyridine-2-carboxamide,

4-[[(27?, 3R, 4R, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-6-fluoro-pyridine-2-carboxamide,

4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]-6-fluoro-pyridine-2-carboxamide,

573

4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-3-fluoro-pyridine-2-carboxamide,

4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyI-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-3-fluoro-pyridine-2-carboxamide,

4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-3-fluoro-pyndine-2-carboxamide,

4-[[(27?,32?,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-3-fluoro-pyridine-2-carboxamide,

572

4-[[(27î,3Æ,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-3-fluoro-pyridine-2-carboxamide,

4-[[(27?,3Æ,4ZÎ,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-3-fluoro-pyridine-2-carboxamide,

4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-fluoro-pyridine-2-carboxamide, (22?,32î,42?,52î)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (22?,32?,42?,55)-N-(3-carbamoyl-4-iluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (22?,32î,45,52î)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (22?,35,47?, 5Æ)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,32?,42?,52?)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (22?,32î,45,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (22?,35,42?,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide,

570 (25,32?,42?,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R, 35,45,52?)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,32?,45,52î)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,35,42?,52?)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (22?,35,45,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,32?,45,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,35,42?, 55)-N-(3-carbamoyI-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,35,45,52î)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,35,45,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide,

4-[[(25,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-fluoro-pyridine-2-carboxatnide,

4-[[(25,35,42?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-fluoro-pyridine-2-carboxamide,

4-[[(25,32?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-fluoro-pyridine-2-carboxamide,

4-[[(22?, 35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-fluoro-pyridine-2-carboxamide,

4-[[(25,35,42?,52î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-fluoro-pyridine-2-carboxamide,

4-[[(25,37?,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-fluoro-pyridine-2-carboxamide,

4-[[(22?,35,45,52î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]-5-fluoro-pyridine-2-carboxamide,

569

4-[[(25,32?, 422,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-fluoro-pyridine-2-carboxamide,

4-[[(22?,35,42?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-fluoro-pyridine-2-carboxamide,

4-[[(22?,32?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]atnino]-5-fluoro-pyridine-2-carboxamide,

4-[[(25,32?,42?,52?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-fluoro-pyridine-2-carboxamide,

4-[[(22?,35,42?,52î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-fluoro-pyridine-2-carboxamide,

4-[[(22?,32î,45,52?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-fluoro-pyridine-2-carboxamide,

4-[[(22?,32?,42?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]-5-fluoro-pyridine-2-carboxamide,

4-[[(22?,32?,42?,52?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-fluoro-pyridine-2-carboxamide,

4-(((25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]-5-methyl-pyridine-2-carboxamide,

4-(((25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-methyl-pyridine-2-carboxamide,

566

4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-methyl-pyridine-2-carboxamide,

4-[[(25, 3R, 4R, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-5-methyl-pyridine-2-carboxamide,

4-[[(2Æ,37î,42?,52î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyI)tetrahydrofuran-2carbonyl]amino]-5-methyl-pyridine-2-carboxamide,

565

4-[[(25,35,45,55)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide, (2Æ,37?,42?,52?)-4-[[3-(3-chloro-4-fluoro-2-niethoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2Æ,3Æ,4Æ,55)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2Æ,37?,45,57?)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide,

544 (27?,35,4/?,5Æ)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyI)-5-methyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (25,3Æ,4/?,57?)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyI)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (27?,37?,45,55)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofùran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (27?,35,47?,55)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (25,37?,47?,55)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (27?,35,45,57?)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (25,37?,45,5Z?)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (25,35,4Z?,5Z?)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (22?,35,45,55)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyI-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (25,37î,45,55)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (25,35,4Æ,55)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (25,35,45,5Æ)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (22?,37î,4Æ,52?)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

545 (27?,3/?,47?,55)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4₎5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,3Z?,45,57?)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,35,4/?,57?)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,37?,47?,5/?)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,37?,45,55)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,35,4/?,55)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,37?,47?,55)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2/?,35,45,5/?)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,3Æ,45,52?)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,47?, 5Æ)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27î,35,45,55)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,37?,45,55)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,47?,55)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,57?)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

546 (25,35,45,55)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,3Æ,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,37?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2Æ,35,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,37?,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,3/?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,37?,57?)-4-[[5-Zer/-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (2/?,37?,55)-4-[[5-ZerZ-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (2Æ,35,5Æ)-4-[[5-/£?r/-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (25,35,57?)-4-[[5-/er/-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (27?,35,55)-4-[[5-Zer/-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide,

547 (25,37?,55)-4-[[5-/ez7-butyI-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyI]amino]pyridine-2carboxamide, (2S,3S,5Æ)-4-[[5-ter/-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]ammo]pyridine-2carboxamide, (25,35,55)-4-[[5-/erZ-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (2Æ,3Æ,5Æ)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,37?,55)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyI-5-(trifIuoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (22?,35,5Æ)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,3/?,5/?)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2Z?,35,55)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,37?,55)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,57?)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,55) -4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2Æ,3Æ,5/?)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,35,55)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,35,5Z?)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

548 (25,3/?,5/?)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2Æ,3S,5S)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-rnethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,3Æ,5S)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofaran-2carbonyl]atnino]pyridine-2-carboxamide, (25,3S,5Z?)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2S,3S, 5S)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyI)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2/?,3Æ,5Æ)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxatnide, (27?,3/?,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2R,3S, 5/?)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2S,3Æ,5Z?)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,35',5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2S',32î,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridme-2-carboxamide, (2S,3S,57?)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]atnino]pyridine-2-carboxamide, (2S',3S,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxatnide, (2Æ,3Æ,5Æ)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

549 (27?,37?,55)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,35,57?)-4-((3-(2,4-difluoro-3-methyI-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,37?,57?)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2R, 35,55) -4-((3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,37?,55)-4-((3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,57?)-4-([3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,55)-4-((3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,37?,57?)-4-[(3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27î,37î,55)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,35,57?)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,37?,57?)-4-([3-(3-ethyI-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifIuoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2R,35,55) -4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,3R,55)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,5Æ)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

550 (25,35,55)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,55)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,55)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,55)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,55)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,55)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyI]amino]pyridine-2-carboxamide, (25,35,55)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,55)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,55)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

551 (25,3Æ,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2Æ,3Æ,5R)-4-[[5-(l,l-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2/?,3/?,5S)-4-[[5-(l,l-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofiiran-2carbonyl]amino]pyridine-2-carboxamide, (2Æ,3S,5Æ)-4-[[5-(l,l-difluoroethyl)-3-(3,4-difluoiO-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2S,3Æ,5Æ)-4-[[5-(l,l-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2Æ,3S,5S)-4-[[5-(l,l-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2S,3Æ,5S)-4-[[5-(l,l-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,5Æ)-4-[[5-(l,l-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2S,3S,5S)-4-[[5-(l,l-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2R,3R,4R, 5/?)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyI)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2/?,37?,4Z?,5S)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyI)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2Æ,3Z?,45,5Æ)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

552 (2/?,35,4/î,5Æ)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,3R,4R,57?)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,37?,45,55)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,35,47?,55)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,3Æ,42?,55)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (22î,35,45,52?)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,32?,45,52?)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,42?,57?)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2R, 35,45,5S)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,3Æ,45,55)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,42?,55)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,57?)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,3/?,47?,57?)-4-[[3-(3,4-difluorophenyI)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

553 (25,35,45,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydroforan-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

554 (25,35,45,55)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine2-carboxamide, (27?,37?,47?,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2Æ,3Æ,4Æ,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,37?,45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydroiuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,35,4Z?,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,37?,47?,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,37?,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-inethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,35,4/?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,37?,47?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2Z?,35,45,52?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,37?, 45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,4Æ,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2Æ,35,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,37?,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

555 (25,35,4/?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-rnethyl-5-(trifluorornethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2Æ,3Æ,47?,5Æ)-4-[[4-cyclopropyl-3-(3₎4-difluoro-2-methoxy-phenyl)-5-methyI-5-(trifluorornethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,37?,47?,55)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,32?,45,57?)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,35,47?,57?)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,37?,47?,57?)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyI)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,37?,45,55)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2R, 35,47?, 55)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,37?,47?,55)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,35,45,57?)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,37?,45,57?)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,47î,52î)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

556 (25,35,45,55)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trinuoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

557 (25,37?,4S,52?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,3S,4/?,5Z?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,3S,45,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,32?,45,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4ZÎ,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,52?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,3S,45,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoroinethyl)-4,5-dimethyl-tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2Æ,3Æ,5Æ)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (2/î,3Æ,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (27?,3S,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyI]amino]pyridine-2carboxamide, (25,3/?,5/?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyI-tetrahydrofiiran-2-carbonyl]amino]pyridine-2carboxamide, (27?,3S,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (2S,3Z?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (2S,3S,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide,

558 (2S,35,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (2Æ,3Æ,4Æ,5/?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (2Æ,3/?,4Æ,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (2Æ,32?,4S,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (27?,3S,4Æ,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (25,32î,4Æ,5Æ)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyI-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (2R,3Æ,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (27?,3S,47?,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (25,37?,47?,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (2Æ,35,45,5Æ)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (25,3Z?,45,5/?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (25,3S,4/?,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (27?,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (25,37?,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide,

559 (25,35,4Æ,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (25,35,45,5/?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (25,35,45,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (27?,32?,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (2??,37?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyI)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (27?,35,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (25,37?,57?)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (27?,35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (25,3Z?,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridinc-2carboxamide, (25,35,5Æ)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (25,35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2carboxamide, (2Æ,3/?,52?)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2Æ,37?,55)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,35,5Æ)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

560 (25,3Æ,5Æ)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,35,55)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,3Æ,55)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,57?)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,55)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2Æ,3Æ,4Æ,5Æ)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine2-carboxamide, (2R, 3R, 4R, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofiiran-2-carbonyl]amino]pyridine2-carboxamide, (2/?,3Æ,45,5Æ)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine2-carboxamide, (2Æ,35,47?,5Z?)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyI-tetrahydrofuran-2-carbonyl]amino]pyridine2-carboxamide, (25,3Æ,4Z?,5Æ)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine2-carboxamide, (2R,3R,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine2-carboxamide, (2R, 35,4R, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine2-carboxamide, (25,3R, 4R, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine2-carboxamide, (22?,35,45,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyI-tetrahydrofuran-2-carbonyl]amino]pyridine2-carboxamide,

561 (25,3R, 45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine2-carboxamide, (25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine2-carboxamide, (25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine2-carboxamide, (25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine2-carboxamide, (25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine2-carboxamide, (25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine2-carboxamide, (25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine2-carboxamide,

4-[[(25,35,45,52?)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide,

4-[[(25,35,4Æ, 55)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-1 -oxido-pyridin-1 -iutn-2-carboxamide,

4-[[(25,3R,45,55)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide,

4-[[(2Z?,35,45,55)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide,

4-[[(25,35,47?,57?)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide,

4-[[(25,37?,45,5Æ)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide,

4-[[(2Æ,35,45,5Æ)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoroniethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide,

4-[[(25,3Æ,4Æ,55)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide,

4-[[(2Æ,35,4Æ,55)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide,

4-[[(2Λ,3Λ,45,55)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide,

4-[[(25,322,422, 522)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide,

543

4-[[(222,35,422,522)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide,

4-[[(222,322,45,572)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide,

4-[[(222, 3R, 4R, 55)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide,

4-[[(22?,3Æ,4Æ,522)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide,

4-[[(25,35,45,55)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide,

4-[[(25,35,45,5Æ)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide,

4-[[(2S,3S,4Z?,55)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide,

4-[[(25,3Æ,45,55)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide,

4-[[(27?,3S,4S,55)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofùran-2carbonyl]amino]-l -oxido-pyridin-1 -ium-2-carboxamide,

4-[[(2S,3S,47?,57?)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide,

4-[[(25,3Z2,45,5/?)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide,

4-[[(2Æ,35,45,5Æ)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide,

4-[[(25,37?,47?,55)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxatnide,

4-[[(27?,35,4Æ,55)-3-(3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide,

542

4-[[(2R,32?,45,55)-3-(3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide,

4-(((25,37?,4R,5Æ)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydroftiran-2carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide,

4-[[(22?,35,4Æ,5R)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide,

4-[[(22?,3Æ,45,52?)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide,

4-[[(27?,37?,4/?,55)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide,

4-[[(27?,37?,4Æ,5/?)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide,

4-((2R,3S,4S,5R)-3-(3-methoxy-2methylpyridin-4-yl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide (2Æ,3Æ,42?,5Æ)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxaniide, (2Æ,32?,42?,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2Æ,3Æ,45,5Æ)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (22î,35,4Æ,5Æ)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (25,37?,47?,5Æ)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (27?,3Z?,4S,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dirnethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (2Æ,3S,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4₎5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide,

534 (25,35,45,55)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyI]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydroftiran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-N-methyl-pyridine-2-carboxamide, (25,35,45,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,35,45,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carboxamide, (25,35,45,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofùran-2-carboxamide, (25,35,45,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,35,45,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide,

535 (27?,3Æ,45,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2J?,3S,4Æ,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,37?,4Z?,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R,3S,4S, 5A)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3Æ,45,5Z?)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3S,4Æ,5Æ)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydroftiran-2-carboxamide, (2Æ,3S,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofiiran-2-carboxamide, (2S,37?,4S,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2S,3S,4Æ,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,3S,4S, 5Z?)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyI]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,35,45,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2Æ,3R,4Æ,5Æ)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2Æ,3Æ,4Æ,5S)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,3Z?,45,5J?)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

536 (2/?,35,47?,57?)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,3/?,42?,5ZÎ)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,3Z?,45,55)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2/?,35,4/?,55)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,37?,4??,55)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimcthyI-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2Æ,35,45,5/?)-4-[[3-[2-rnethoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carbonyl]amino]pyridine-2-carboxamide, (25,37?,45,57?)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,47?,5/?)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2/?,35,45,55)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,37?,45,55)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,47?,55)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,52î)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyI]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2R,3/?,47?,5??)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide,

537 (2R,3R, 4/?,55)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2^,3/?,45,5Æ)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2K,3S,42?,5/?)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (25,3/?,42?,5/?)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2/?,3Æ,45,55)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (22?,35,4Æ,55)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (25,3/?,47?,55)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R, 35,45,5Æ)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydroftiran-2-carbonyl]amino]pyridine-2-carboxamide, (25,37?,45,5/?)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (25,35,4Æ,5Æ)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (2R,35,45,5S)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyI-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (25,3R,45,55) -4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (25,35,47?,55)-4-[[3-[3-(difluoromethyl)-4-fluoiO-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (25,35,45,57?)-4-[[3-[3-(difluoromethyl)-4-fIuoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide,

538 (25,35,45,55)-4-[[3-[3-(difluoromethyl)-4-fIuoro-2-methoxy-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, (27?,32?,57?)-N-(3-carbamoyl-4-fIuoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (27?,3Z?,55)-N-(3-carbamoyI-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (27?,35,57?)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,3Z?,52?)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (27?,35,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,37?,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluorc)-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,35,5Z?)-N-(3 -carbamoyl-4-fluoro-phenyl)-3 -(3,4-difluoro-2-methoxy-phenyl)-5 -methyl-5 (trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,35,55)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (22?,37?,47?,57î)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (27?,37?,47?,55)-N-(3-carbamoylphenyl)-3-[2-(difluorc)methoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (27?,37?,45,5Æ)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (2R, 35,42?, 57?)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,32?,42?,5Æ)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide,

539 (2R, 35,45,55)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,35,45,55)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,35,45,55)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,35,45,55)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,35,45,55)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,35,45,55)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,35,45,55)-N-(3-carbamoylphenyI)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,35,45,55)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,35,45,55)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,35,45,55)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,35,45,55)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide, (25,35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]1 -oxido-pyridin-1 -ium-2-carboxamide, (25,35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-loxido-pyridin-1 -ium-2-carboxamide, (25,35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-loxido-pyridin-1 -ium-2-carboxamide,

540 (2S,37?,57?)-4-[[3-(3,4-difIuoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-loxido-pyridin-1 -ium-2-carboxamide, (2/?₎35,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofiiran-2-carbonyl]amino]-loxido-pyridin-1 -ium-2-carboxamide, (2S’,3Æ,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-loxido-pyridin-1 -ium-2-carboxamide, (2S,3S,5Æ)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]arnino]-loxido-pyridin-1 -ium-2-carboxamide, (25,3S,55)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-loxido-pyridin-1 -ium-2-carboxamide, (2Æ,37?,42?,52?)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide, (22?,37?,4Z?,55)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofùran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide, (27?,37?,4S,57?)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide, (22î,35,42?,57?)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide, (2S,3Æ,4Æ,5Æ)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide, (27?,3/?,4S,5S)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide, (22î,35,4/?,5S)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide, (25,32?,42?,55)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide, (2Æ,35,4S,5Æ)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide,

541 (25,37?,45,57?)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide, (25,35,4/?,5Æ)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide, (27?,3S,45,55)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide, (25,3Æ,45,55)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide, (25,35,47?,55)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide, (25,35,45,5/?)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyI-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-1 -oxido-pyridin-1 -ium-2-carboxamide, (25,35,45,55)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]-l-oxido-pyridin-l-ium-2-carboxamide,

4-((2R,3S,4S,5R)-3-(3methoxypyridin-2-yl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

533

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethy!-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide-6-d

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pico!inamide-3-cf ²H

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamidojpicolinamide-5-d

O

4-((2R,3S,4S,5R)-3-(5-chloro-3,4-difIuoro2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5S)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-5-methylpicolinamide

532

F

4-((2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-5-methylpicolinannide

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl-5-d)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-«2R,3S,4S,5R)-3-(2-cyclobutoxy-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

531

4-((2R,3S,4S,5R)-3-(2-((3,3difluorocyclobutyl)methoxy)-3,4-difIuorophenyl)-4,5dimethyl-5-(trifIuoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(6-(difluoromethyl)-2methoxypyridin-3-yl)-4,5-dimethyI-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5S)-3-(6-(difIuoromethyl)-2methoxypyridin-3-yl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S_t4S,5R)-3-(2-ethyl-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5S)-3-(4-methoxy-6(trifIuoromethyI)pyridin-3-yl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(4-methoxy-6(trifIuoromethyl)pyridin-3-yl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

530

nh₂ cf₃

CF₃

4-((2S,3R,4R,5S)-3-(2-methoxy-3(trifluoromethyl)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(3-(difluoromethyl)-4fluoro-2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

529

F

F F

4-((2S.3R.4R,5S)-3-(4-(difluoromethyl)-3fluoro-2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R₁4S,5R)-3-(3,4-difluoro-2methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R,5S)-3-(3₁4-difluoro-2methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S.5R)-3-(3,4-difluoro-2methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R₁3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-5-fluoropicolinamide

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-5-methylpicolinamide

4-((2R,3S,4S,5S)-3-(3₁4-difIuoro-2methoxyphenyl)-5-isopropyl-4methyltetrahydrofuran-2carboxamido)picolinamide

526

4-((2R,3S,5R)-3-(4-fluoro-2-methoxy3-methylphenyl)-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,5S)-3-(3,4-difluoro-2methoxyphenyl)-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5S)-3-(3,4-difluoro-2methoxyphenyl)-4,5dimethyltetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5R)-3-(3,4-difIuoro-2methoxyphenyl)-4,5dimethyltetrahydrofuran-2carboxamido)picolinamide

525

4-((2R,3S,4S)-3-(3,4-difluoro-2methoxyphenyl)-4,5,5trimethyltetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R₁4R)-3-(3,4-difluoro-2methoxyphenyI)-4,5,5trimethyltetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R)-3-(3,4-difluoro-2methoxyphenyl)-4,5,5-trimethyltetrahydrofuran2-carboxamido)picolinamide

4-((2S,3R,4S)-3-(3,4-difluoro-2-methoxyphenyI)4,5,5-trimethyltetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4S)-3-(3,4-difluoro-2methoxyphenyl)-4,5,5trimethyltetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4R)-3-(3,4-difluoro-2-methoxyphenyl)4,5₁5-trimethyltetrahydrofuran-2carboxamido)picolinamide

524

4-((2R.3S,4S,5R)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-/V-methylpicolinamide (2S,3R,4R.5S)-/V-(3-carbamoyl-4-fluorophenyl)3-(2-(difluoromethoxy)-4-fluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamide

(2R,3S,4S,5R)-/V-(3-carbamoyl-4-fluorophenyl)3-(2-(difluoromethoxy)-4-fluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamide

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-5-(difluoromethyl)-4,5dimethyltetrahydrofuran-2carboxamido)pico1inamide

4-((2S,3R,4R,5S)-3-(3,4-difluoro-2methoxyphenyl)-5-(difluoromethyl)-4,5dimethyltetrahydrofuran-2carboxamido)picolinamide

523

4-((2S,3R,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-5-(difluoromethyl)-4,5dimethyltetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R,5S)-3-(3,4-difluoro-2methoxyphenyl)-5-(difluoromethyl)-4,5dimethyltetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S₁5R)-3-(3,4-difluoro-2methoxyphenyl)-4-ethyl-5-methyl-5(trifIuoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S₁3R,4R,5S)-3-(3,4-difluoro-2methoxyphenyl)-4-ethyl-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

522

4-((2S,3R,4R,5S)-3-(3₁4-difluorophenyl)4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,5R)-3-(3,4-difluoro-2-methoxyphenyl)5-(1,1-difluoroethyl)-5-methyltetrahydrofuran-2carboxamido)picolinamide

521

4-((2R,3S,5S)-3-(3,4-difluoro-2-methoxyphenyl)5-(1,1-difIuoroethyl)-5-methyltetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,5R)-3-(3₁4-difluoro-2methoxyphenyl)-5-methyl-5-(2,2,2trifluoroethyl)tetrahydrofuran-2carboxamido)picolinamide

520

4-((2R,3S,5S)-3-(3,4-difluora-2methoxyphenyl)-5-methyl-5-(2,2,2trifluoroethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,5R)-3-(2-fluoro-6methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pico!inamide

4-((2S,3R,5S)-3-(2-fluoro-6methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

519

4-((2R,3S,5R)-3-(2-(difIuoromethoxy)-4f!uorophenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

F F

4-((2R,3S,5R)-3-(4-fluoro-2-methoxy-3methylphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,5S)-3-(4-fluoro-2-methoxy-3methylphenyl)-5-methyI-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

518

4-((2R,3R,5S)-3-(4-fIuoro-2-methoxyphenyl)5-methyl-5-(trifluoromethyl)tetrahydrofuran2-carboxamido)picolinamide

4-((2R,3S,5R)-3-(4-fluoro-2-methoxyphenyl)5-methyl-5-(trifIuoromethyl)tetrahydrofuran2-carboxamido)picolinamide

4-((2R,3S₁5R)-5-(fert-butyl)-3-(3,4-difluoro2-methoxyphenyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R₁5S)-3-(3,4-difluoro-2methoxyphenyl)-5-ethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,5R)-3-(3-chloro-4-fluoro-2methoxyphenyl)-5-methyI-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-/V-methylpicolinamide

517

4-((2R,3S,5R)-3-(3-chloro-4-fluoro-2methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-A/-methylpicolinamide

4-((2R,3S,5S)-3-(3-chloro-4-fluoro-2methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamido)A/-methylpicolinamide

4-((2S,3R,5S)-3-(3-chloro-4-fluoro-2methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-A/-methylpicolinamide

4-((2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

515

4-((2S_I3R,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4R,5R)-3-(3,4-difluoro-2-hydroxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4S,5S)-3-(3,4-difluoro-2-hydroxyphenyl)4₁5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

HO

4-((2R,3S,4S,5S)-3-(3,4-difluoro-2-hydroxyphenyl)4₁5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5R)-3-(3,4-difluoro-2-hydroxyphenyl)4,5-dimethy!-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

514

4-((2S,3R,4S,5S)-3-(3₁4-difluoro-2-hydroxyphenyI)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4R,5S)-3-(3,4-difluoro-2hydroxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4R,5R)-3-(3₁4-difluoro-2-hydroxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4S,5S)-3-(3,4-difluoro-2-hydroxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R,5S)-3-(3,4-difluoro-2-hydroxyphenyI)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

513

4-((2R,3R,4R,5S)-3-(3,4-difluoro-2-hydroxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)4-methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)4-methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2 S, 3 S,4R, 5R)-3-(3,4-difl uoro-2-methoxyphenyl)4-methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R,5R)-3-(3,4-difluoro-2methoxyphenyl)-4-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

512

4-((2R₁3S,4S,5S)-3-(3,4-difluoro-2methoxyphenyl)-4-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)4-methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4R,5S)-3-(3,4-difluoro-2methoxyphenyl)-4-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R₁3R,4R,5R)-3-(3,4-difluoro-2-methoxyphenyl)4-methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

511

4-((2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)4-methyl-5-(trifIuoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5S)-3-(3₁4-difluoro-2methoxyphenyl)-4-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4R,5S)-3-(3₁4-difluoro-2-methoxyphenyl)4-methyI-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(2-(difluoromethoxy)-4fluoro-3-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

510

4-((2S,3S_I4S,5S)-3-(2-(difluoromethoxy)-4fluoro-3-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4S,5R)-3-(2-(difluoromethoxy)-4fluoro-3-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R,5R)-3-(2-(difluoromethoxy)-4fIuoro-3-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5S)-3-(2-(difluoromethoxy)-4fluoro-3-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

509

4-((2S,3S,4R,5S)-3-(2-(difluoromethoxy)-4fluoro-3-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrafuran-2carboxamido)picolinamide

4-((2R,3R,4R.5R)-3-(2-(difluoromethoxy)-4-fluoro3-methylphenyl)-4,5-dimethyl-5(trifluoramethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4S,5S)-3-(2-(difluoromethoxy)-4-fluoro-3methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R₁5S)-3-(2-(difluoromethoxy)-4fluoro-3-methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

508

4-((2R,3S,4S,5R)-3-(2-ethoxy-3₁4-difluorophenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4S,5R)-3-(2-ethoxy-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyI)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4R,5R)-3-(2-ethoxy-3,4-difluorophenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4S₁5S)-3-(2-ethoxy-3,4-difluorophenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

507

4-((2R,3R,4S,5R)-3-(2-ethoxy-3,4-difluorophenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S₁4R,5R)-3-(2-ethoxy-3,4-difluorophenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5S)-3-(2-ethoxy-3.4-difluorophenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R.4S₁5S)-3-(2-ethoxy-3₁4-difluorophenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4R,5S)-3-(2-ethoxy-3,4-difluorophenyl)4,5-dimethyl-5-(trifluoromethyI)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4R.5R)-3-(2-ethoxy-3,4-difluorophenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R_t4S,5S)-3-(2-ethoxy-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

506

4-((2R,3S,4R,5S)-3-(2-ethoxy-3,4difluorophenyl)-4,5-dimethyl-5(trifl uoromethyl)tetrahyd rof u ra n-2carboxamido)picolinamide

4-((2S,3S,5R)-3-(3-chIoro-4-fluoro-2methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

(2R,3R,4R,5S)-/V-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifIuoromethyl)tetrahydrofuran-2carboxamide (2S,3R,4R,5S)-/V-(3-carbamoyl-4-fluorophenyl)3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamide

503

(2R,3S,4R,5S)-/V-(3-carbamoyl-4-fluorophenyl)3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamide (2R,3R,4S,5S)-/V-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide

(2R,3R,4R,5R)-A/-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide (2S,3S,4R,5S)-/V-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide

(2S,3R,4S,5S)-/\/-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide (2S,3R,4R,5R)-/V-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide

504

(2R,3S,4S,5S)-/V-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide (2R,3S,4R,5R)-/V-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide

(2R,3R,4S.5R)-/V-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide (2S,3S,4S,5S)-/V-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide

(2S,3S,4R.5R)-N-(3-carbamoyl-4fIuorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide (2S,3R,4S,5R)-A/-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difIuorophenyI)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide

505

(2R,3S,4S,5R)-A/-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide (2S,3S,4S,5R)-A/-(3-carbamoyl-4fluorophenyl)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamide

4-((2S,3R,5R)-3-(3-chloro-4-fluoro-2methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahyd rof u ra n-2carboxamido)picolinamide

4-((2S,3S,5S)-3-(3-chloro-4-fluoro-2methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,5R)-3-(3-chloro-4-fluoro-2methoxyphenyl)-5-methyl-5(trifl uoromethy l)tetrahyd rof u ran-2carboxamido)picolinamide

502

4-((2R,3S,5S)-3-(3-chloro-4-f1uoro-2methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,5S)-3-(3-chloro-4-fluoro-2methoxyphenyI)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S₁4S,5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-/V-methylpicolinamide

4-((2R,3S.4S,5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-/V-methylpicolinamide

4-((2S,3R,4S,5R)-3-(2-(difluoromethoxy)S^-difluorophenylJ^S-dimethyl-S(trifluoromethyl)tetrahydrofuran-2carboxamido)-/V-methylpicolinamide

501

4-((2S,3S_I4R_l5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifIuoromethyl)tetrahydrofuran-2carboxamido)-M-methylpicolinamide

4-((2S₁3S,4S,5S)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-A/-methylpicolinamide

4-((2R,3R₁4S,5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-/V-methylpicolinamide

4-((2R_t3S₁4R₁5R)-3-(2-(difluoramethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-/V-methylpicolinamide

4-((2R,3S,4S,5S)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-A/-methylpicolinamide

4-((2S,3R,4R,5R)-3-(2-(difluoromethoxy)3,4-difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-A/-methyIpicolinamide

500

4-((2S,3R,4S,5S)-3-(2-(difluoromethoxy)3,4-difluorophenyI)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-A/-methylpicolinamide

4-((2S,3S₁4R,5S)-3-(2-(difluoromethoxy)3,4-difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-A/-methylpicolinamide

4-((2R,3R,4R,5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-A/-methylpicolinamide

4-((2R,3R,4S,5S)-3-(2-(difluoromethoxy)-3₁4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-A/-methylpicolinamide

4-((2R,3S,4R,5S)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-/V-methylpicolinamide

4-((2S,3R,4R₁5S)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyi-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-A/-methylpicolinamide

499

4-((2R,3R_I4R,5S)-3-(2-(difluoromethoxy)-3₁4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-/V-methylpicolinamide

4-((2S,3S,4S₁5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

496

4-((2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4S,5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4R,5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethy!-5(trifluoromethyl)tetrahyd rof u ran-2carboxamido)picolinamide

4-((2R,3R,4S,5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R₁5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

495

4-((2R,3S₁4S,5S)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5R)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4S,5S)-3-(2-(difIuoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4R,5S)-3-(2-(difluoromethoxy)-3₁4difIuorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4S,5S)-3-(2-(difluoromethoxy)-3.4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

494

4-((2R,3S,4R,5S)-3-(2-(difluoromethoxy)-3.4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4R,5S)-3-(2-(difluoromethoxy)-3,4difluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4S_l5R)-3-(3₁4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4S,5R)-3-(3₁4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

493

4-((2S,3S,4R,5R)-3-(3,4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,4S,5S)-3-(3₁4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R₁3R,4S,5R)-3-(3,4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R₁5R)-3-(3₁4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5S)-3-(3,4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

492

4-((2S₁3S,4R,5S)-3-(3,4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4R,5R)-3-(3,4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R_l4S₁5S)-3-(3_l4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R₁5S)-3-(3,4-difluoro-2-(methoxyd₃)phenyl)-4,5-dimethyI-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S₁3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

488 ³ Z\___X ^H ° ° / z=A F F 2-carbamoyl-4-((2R,3R,4R,5S)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyi)tetrahydrofuran-2carboxamido)pyridine 1-oxide 9 o JV° _c λΑΑΐ* ^FsC/-y ^h O o-\ / / aA F F 2-carbamoyl-4-((2R,3S,4R,5S)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2- carboxamido)pyridine 1-oxide 9 O fa'N'⁰ _c ^NHz ^3C Z\___X ^H ° / t=A F F 2-carbamoyl-4-((2R,3R,4R,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide ^FaCz~\ ^H ° F F 2-carbamoyl-4-((2S,3R,4R,5S)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide o _c .Y/iMr^NHz o-\ / ¹ rfa F F 2-carbamoyl-4-((2R,3R,4S,5S)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyi-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide O J^N° _C >0^ΛνΆ^ΝΗ! fa-. ^H ° o-\ / / aA F F 2-carbamoyl-4-((2S,3S,4F?,5S)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyridine 1-oxide

489

4-((2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxyphenyl)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4S,5R)-3-(3,4-difIuoro-2-methoxyphenyI)4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R,5R)-3-(3,4-difluoro-2methoxyphenyI)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

487

4-((2S,3R,4R,5R)-3-(3,4-difluoro2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4R,5R)-3-(3,4-difluoro2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4S,5S)-3-(3,4-difluoro2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

486

4-((2R,3S,4R,5S)-3-(3₁4-difluoro-2-methoxyphenyl)4₁5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4R,5S)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamidojpicolinamide

4-((2S,3S,4S,5R)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S₁5R)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

485

4-((2S,3S,4S,5S)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4S,5R)-3-(2-(difIuoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R,5R)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5S)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5R)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

484

4-((2S,3R,4S,5S)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,4R,5R)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4R,5S)-3-(2-(difluoromethoxy)-4fluorophenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

483

4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxypheny!)-5methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,5R)-3-(3,4-difluoro-2-methoxyphenyI)-5methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5methyI-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

482

4-((2R,3S,5S)-3-(3,4-difluora-2-methoxyphenyl)-5methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5methyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S,4S,5R)-3-(4-fluoro-2-methoxyphenyI)4₁5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3S₁4R.5R)-3-(4-fluoro-2-methoxyphenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

481

4-((2R,3R,4S,5R)-3-(4-fIuoro-2-methoxyphenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2R,3S₁4S,5S)-3-(4-fluoro-2-methoxyphenyl)-4,5dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

4-((2S,3R,4R,5R)-3-(4-fluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran2-carboxamido)picolinamide

4-((2R,3R,4S,5S)-3-(4-fluoro-2methoxyphenyl)-4,5-dimethyl-5(trifl uoromethy ijtetrahyd rofu ra n2-carboxamido)picolinamide

480

4-((2S,3R,4R,5S)-3-(4-fluoro-2methoxyphenyl)-4,5-dimethyl-5(trifl uoromethy ijtetrahyd rofu ra n2-carboxamido)picolinamide

4. The compound of claim 1 or 2, wherein the compound has formula (I-B)

l-B or a pharmaceutically acceptable sait thereof.

5 optionally wherein:

595 (i) the crystalline solid form is Form A;

optionally wherein Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 thêta ± 0.2) of 9.9, 13.9, 15.7, and 19.0; and/or optionally wherein Form A is characterized by a DSC thermogram having a melting onset of 186 °C with a peak at 187 °C; or (ii) the crystalline solid form is Form B, optionally wherein Form B is characterized by one or more of:

(a) an XRPD pattern having diffractions at angles (degrees 2 thêta ± 0.2) of 12.8, 14.1, 15.2, 18.5, and 20.3; and/or (b) a solid State ⁿC NMR spectrum having peaks at Chemical shifts of 172.5, 172.1, 168.5, 168.3,168.0, 151.5,148.3,147.8, 127.7, 122.7,116.6,115.1, 110.6, 86.5, 80.2, 63.2,44.3, 23.0, and 13.1 ppm or a solid State ^l9F NMR spectrum having peaks at Chemical shifts of -137.1 and -152.8 ppm; and/or (c) a DSC thermogram having a melting onset of 182 °C with a peak at 183 °C; and/or (d) an IR spectrum having peaks at 3501, 3356, 1684, 1565, 1505, and 1122 cm¹; and/or (e) an orthorhombic crystal System, as determined by single-crystal X-ray analysis; and/or (f) a unit cell, as determined by single-crystal X-ray analysis, of the following dimensions: a=7.3929(2) Â; b=14.5827(4) Â; c=l 8.9312(6) Â; α=90°; β=90°; andy=90°; and/or (g) being obtainable by dissolving the compound in ethyl acetate and then crystallizing the compound by adding n-heptane as an antisolvent.

5-deuterio-4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxatnide,

5-deuterio-4-[[(25,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

5-deuterio-4-[[(25,35,47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

5-deuterio-4-[[(25,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetraliydrofuran-2carbonyl]amino]pyridine-2-carboxatnide,

5-deuterio-4-[[(27?,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

5-deuterio-4-[[(25,35,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

5-deuterio-4-[[(25,37?,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

5-deuterio-4-[[(27?,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

5-deuterio-4-[[(25,37?,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

5-deuterio-4-[[(27?, 35,4R, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

5-deuterio-4-[[(27?,37?,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

5-deuterio-4-[[(25,32î,42?,52?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

571

5-deuterio-4-[[(22?,35,42?,52?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

5-deuterio-4-[[(22?,32?,45,52î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

5-deuterio-4-[[(22?,32?,42?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

5-deuterio-4-[[(22?,32î,42?,52?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

5-(((25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-3-carboxamide,

5-(((25,35,45,52?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]atnino]pyridine-3-carboxamide,

5-(((25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydroftiran-2carbonyl]amino]pyridine-3-carboxamide,

5-(((25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridme-3-carboxamide,

5-(((25, 35,4R, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]ammo]pyridine-3-carboxamide,

5-(((25,37?, 45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-3-carboxamide,

5-(((25,37?,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-3-carboxamide,

5-[[(2Z?,35,4/?,57?)-3-(3,4-difIuoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-3-carboxamide,

5-[[(2/?,37?,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-3-carboxamide,

564

5-[[(27?,37?,47?, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-3-carboxamide,

5-[[(27î,37î,47î,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-3-carboxamide,

5. The compound of any one of daims 1-4, or a pharmaceutically acceptable sait thereof, wherein X^4a is C-R^4a; and R^4a is H or halo; or wherein X^4a is N.

478

5 R^5bl and R^5b2 are each independently H, Ci-Cô alkyl, or Ci-Cô haloalkyl;

X^3c is C-R^3c;

X^4c is C-R^4c;

X^5c is C-R^5c;

X^6c is C-R^6c; and

6-deuterio-4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]atnino]pyridine-2-carboxamide, (27?,37?,47î,57î)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27î,37î,47?,55)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27î,37?,45,57?)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27î,35,47î,57?)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,37?,47?,57?)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

579 (22?,37?,4S,5S)-4-[[3-(3,4-difluoro-2-methyI-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,3S,47?,55)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2S,37?,47?,5S)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,35,45,57?)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifIuoromethyI)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2S,37?,4S,57?)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,47?,57?)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2/?,35,4S,5S)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,37?,4S,55)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,42?,5S)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,3S,45₎5/?)-4-[[3-(3,4-difluoro-2-methyl-phenyI)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2S,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (22?,32?,42?,57?)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide, (23?,32?,4Æ,55)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide, (2J?,3Æ,45,5/?)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide,

580 (2Z?,35,47?,52?)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide, (25,37î,47î,57?)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide, (2Z?,37?,45,55)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide, (2R, 3S,4R, 5S) -4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide, (25,37?,42?,55)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide, (27î,35,45,57?)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide, (25,37?,45,57?)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide, (25,35,47î,52î)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide, (22?,35,45,55)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide, (25,37?, 45,55)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide, (25,35,47?,55)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide, (25,35,45,57î)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)

581 tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,5S)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,3S,45,55)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,4S,5S)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,3S,45,55)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,5S)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,4S,55)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2S,35,45,55)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,3S,4S,55)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyI-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,5S)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

582 (25,35,45,55)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,3S,4S,55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

583 (25,37?,45,55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,47?,55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,57?)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,37?,47?,57?)-4-[[3-[6-(difluoromethyI)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,37?,47?,55)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (272,37?,45,57?)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (272,35,472,57?)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,372,472,57?)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,37?,45,55)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (272,35,47?,55)-4-[[3-[6-(difluoromethyl)-2-inethoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,37?,472,55)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (27?,35,45,57?)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,372,45,57?)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

584 (25,35,45,55)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyI]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]pyridine-2-carboxamide, (2R, 3R,4R, 55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (2R, 35,45,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

585 (25,35,45,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyI)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

586 (22?,35,42?,55)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,37?,42?,55)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (22?,35,45,52?)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyI)tetrahydrofuran-2carbonyI]amino]pyridine-2-carboxamide, (25,32î,45,52î)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydroftiran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,42?,52?)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]pyridine-2-carboxamide, (2R, 35,45,55) -4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,32?,45,55)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,4Æ,55)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dirnethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide, (25,35,45,52î)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]ammo]pyridine-2-carboxamide, (25,35,45,55)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

6-deuterio-4-[[(25,35,45,57î)-3-(3,4-difiuoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

6-deuterio-4-[[(25,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

6-deuterio-4-[[(25,37î,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

6-deuterio-4-[[(27?,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

6-deuterio-4-[[(25,35,47?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

6-deuterio-4-[[(25,37î,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

6-deuterio-4-[[(27?,35,45,57î)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyI-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

6-deuterio-4-[[(25,37?, 4R, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

6-deuterio-4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]pyridine-2-carboxamide,

578

6-deuterio-4-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

6-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]pyrimidine-4-carboxamide,

6-[[(25,35,45,52?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrimidine-4-carboxamide,

6-[[(25,35,42?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrimidine-4-carboxamide,

6-[[(25,32î,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrimidine-4-carboxamide,

6-[[(22?,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]pyrimidine-4-carboxamide,

6-[[(25,35,4Z?,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrimidine-4-carboxamide,

568

6-[[(25,32?,45,5Z?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrimidine-4-carboxamide,

6-[[(2Æ,35,45,5Æ)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrimidine-4-carboxamide,

6-[[(25,3R, 4R, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrimidine-4-carboxamide,

6-[[(2Æ, 35,4R, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrimidine-4-carboxamide,

6-[[(2Æ,3/?,45,55)-3-(3,4-difluoro-2-rnethoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrimidine-4-carboxamide,

6-[[(25,3Æ,4Æ,5Æ)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrimidine-4-carboxatnide,

6-[[(2Æ,35,47?,57?)-3-(3,4-difluorc>-2-methoxy-phenyl)-4,5-dirnethyl-5-(trifluorornethyl)tetrahydrofuran-2carbonyl]amino]pyrimidine-4-carboxamide,

6-[[(2Æ,3Æ,45,5Æ)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrimidine-4-carboxamide,

6-[[(2Æ, 3R, 4R, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrimidine-4-carboxamide,

6-[[(2Æ, 3R, 4R, 572)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrimidine-4-carboxamide,

6-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrazine-2-carboxamide,

6-[[(25,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrazine-2-carboxamide,

6-[[(25,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrazine-2-carboxamide,

6-[[(25,3R,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrazine-2-carboxamide,

6-[[(27î,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrazine-2-carboxamide,

6-[[(25,35,47î,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrazine-2-carboxamide,

6-[[(25,37?,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrazine-2-carboxamide,

6-[[(27?,35,45,57?)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrazine-2-carboxamide,

6-[[(25,3R, 4R, 55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrazine-2-carboxamide,

6-[[(27?,35,47?,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrazine-2-carboxamide,

6-[[(27?,37?, 45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyrazine-2-carboxamide,

563

6-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2carbonyl]amino]pyridine-2-carboxamide,

6-[[(25,35,45,55)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofiiran-2carbonyl]amino]pyridine-2-carboxamide,

562

6-((2R,3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)pyrazine-2-carboxamide

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable sait thereof, wherein each R is H or CH3;

optionally wherein each R is H.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable sait thereof, wherein X^2a is C-R^2a; and R^2a is H, halo, or Ci-Cô alkyl;

optionally wherein X^2a is C-R^2a; and R^2a is H.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable sait thereof, wherein X^5a is C-R^5a; and R^5a is H, halo, or Ci-Cô alkyl;

optionally wherein X^5a is C-R^5a; and R^5a is H.

9 OA J i ^f3^c' \_Γ nh₂ '' AA ° ° M F ^F (2R,3S,4S,5R)-/V-(3-carbamoyl-4-fluorophenyl)3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl5-(trifluoromethyl)tetrahydrofuran-2carboxamide 5 O γοΟ Γ nh₂ ' AA ⁰ LM F ^F 4-((2R,3S,4S,5R)-3-(3₁4-difluoro-2methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2carboxamido)-6-methylpicolinamide 5 O \/θΟ Γ fl ^F3^CJJ h fY NH₂' /⁼⁼\ ⁰,0-0 F ^F 4-((2R,3S,4S,5R)-3-(3₁4-difluoro-2methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2carboxamido)-3-methylpicolinamide 0 ΟΟχ II f N ^f3^c' N ^γΑ._ΝΗ₂ >=\ ^F 0 /° M F ^F 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-3-fluoropicolinamide F o ^F3C _NH ·, π [T ' 7⁼⁼\ ° /° M F ^F 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)-6-fluoropicolinamide - ⁰ Y-/ H ^\-NH₂ -O ⁰ F^”' ^F 4-((2S_I3R,4R_I5S)-3-(3,4-difluoro-2methylphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2carboxamido)picolinamide

528

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable sait thereof, wherein X^6a is

C-R^6a; and R^6a is H, halo, or Ci-C₆ alkyl;

optionally wherein X^6a is C-R^6a; and R^6a is H.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable sait thereof, wherein R^4bland R^4b2 are each independently H, Ci-Cô alkyl, or C3-C6 cycloalkyl;

optionally wherein R^4bl and R^4b2 are each independently H or Ci-Cô alkyl; or optionally wherein R^4bl and R^4b2 are each independently H or CHj; or optionally wherein R^4bl is Ci-Cô alkyl, and R^4b2 is H; or optionally wherein R^4bl is H, and R^4b2 is Ci-Cô alkyl; or optionally wherein R^4bl is CH3, and R^4b2 is H; or optionally wherein R^4bl is H, and R^4b2 is CH3.

10 R^2c is H, OH, halo, Ci-Cô alkyl, Ci-Cô haloalkyl, Ci-Cô alkoxy, or Ci-Cô haloalkoxy.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable sait thereof, wherein R^5bland R^5b2 are each independently H, Ci-Cô alkyl, or Ci-Cô haloalkyl;

optionally wherein R^5bl and R^5b2 are each independently Ci-Cô alkyl or Ci-Cô haloalkyl; or optionally wherein R^5bI and R^5b2 are each independently H, CH3, or CF3; or optionally wherein R^5bI is Ci-Cô alkyl, and R^5b2 is Ci-Cô haloalkyl; or optionally wherein R^5bl is Ci-Cô haloalkyl, and R^5b2 is Ci-Cô alkyl; or optionally wherein R^5bl is CH3, and R^5b2 is CF3; or optionally wherein R^5bl is CF3, and R^5b2 is CH3.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable sait thereof, wherein R^2cis OH, Ci-Cô alkoxy, or Ci-Cô haloalkoxy.

479

13. The compound of any one of daims 1-12, or a pharmaceutically acceptable sait thereof, wherein X^3cis C-R^3c;

optionally wherein R^3c is H, halo, or Ci-Cô alkyl.

14.1 , 16.3, and 20.0; and/or (b) a monoclinic crystal System, as determined by single-crystal X-ray analysis; and/or (c) a P2i space group, as determined by single-crystal X-ray analysis; and/or (d) a unit cell, as determined by single-crystal X-ray analysis, of the following dimensions: a=12.0863(2) Â; b=7.48310(10) Â; c=23.9904(4) Â; α=90°; β=90.0130(10)°; andy=90°; or (ii) the crystalline solid form is Form B, optionally wherein Form B is characterized by an XRPD pattem having diffractions at angles (degrees 2 thêta ± 0.2) of 6.8, 13.2, 16.1, 20.6, and 21.3.

14. The compound of any one of daims 1-13, or a pharmaceutically acceptable sait thereof, wherein X^4c5 is C-R^4c; and R^4c is H, halo, or Ci-Cô haloalkyl;

optionally wherein R^4c is halo.

15. The compound of any one of daims 1-14, or a pharmaceutically acceptable sait thereof, wherein X^5cis C-R^5c; and R^5c is H or halo;

optionally wherein R^Sc is H.

10

16. The compound of any one of daims 1-15, or a pharmaceutically acceptable sait thereof, wherein X^6c is C-R^6c; and R^6c is H or halo;

optionally wherein R^6c is H.

17. The compound of claim 1, or a pharmaceutically acceptable sait thereof, wherein the compound is selected from

18. The compound of claim 1, or a pharmaceutically acceptable sait thereof, wherein the compound is selected from

(2S,3R,5S)-A/-(3-carbamoyl-4-fluorophenyl)-3-(3,4difluoro-2-methoxyphenyl)-5-methyl-5(trifluoromethyI)tetrahydrofuran-2-carboxamide (2R,3S,5R)-/V-(3-carbamoyl-4-fluorophenyl)-3-(3,4difluoro-2-methoxyphenyl)-5-methyl-5(trifluoromethyl)tetrahydrofuran-2-carboxamide

19. The compound of claim 1.

20. The compound of claim 19, wherein the compound has formula

21.

The compound of claim 20, wherein the compound is in crystalline solid form;

22. The compound of claim 19, wherein the compound has formula

23. The compound of claim 22, wherein the compound is in crystalline solid form;

optionally wherein the crystalline solid form is Form A, optionally wherein Form A is characterized by one or more of:

(a) an orthorhombic crystal System, as determined by single-crystal X-ray analysis; and/or (b) an 1222 space group, as determined by single-crystal X-ray analysis; and/or

596 (c) a unit cell, as determined by single-crystal X-ray analysis, of the following dimensions: a=12.0172(5) A; b=15.6682(6) Â; c=24.1406(ll) Â; α=90°; β=90°; andy=90°.

24. The compound of claim 19, wherein the compound has formula

25. The compound of claim 24, wherein the compound is in crystalline solid form; optionally wherein:

(i) the crystalline solid form is Form A, optionally wherein Form A is characterized by one or more of:

(a) an XRPD pattem having diffractions at angles (degrees 2 thêta ± 0.2) of 10.1, 13.7,

26. The compound of claim 19, wherein the compound has formula

27. The compound of claim 26, wherein the compound is in crystalline solid form;

597 (a) an XRPD pattem having diffractions at angles (degrees 2 thêta ± 0.2) of 13.7, 15.2, and 18.2; and/or (b) a solid State ^I3C NMR spectrum having peaks at Chemical shifts of 171.4, 141.6, 118.0,

112.2, 23.0, and 11.6 ppm or a solid State ¹⁹F NMR spectrum having peaks at Chemical shifts of-74.6, -141.5, and -154.6 ppm; and/or (c) a monoclinic crystal System, as determined by single-crystal X-ray analysis; and/or (d) a P2i space group, as determined by single-crystal X-ray analysis; and/or (e) a unit cell, as determined by single-crystal X-ray analysis, of the following dimensions: a=l 1.2266(3) Â; b=7.3948(2) Â; c=13.1432(4) Â; a=90°; β=100.3980(1)°; andy=90°.

28. The compound of claim 19, wherein the compound has formula _{c r} Me °λ ^f3^cxLo o Vnh₂

T >X /=\ HN—ά _ZN /° 71 ^C' F , wherein the compound has the absolute stereochemistry of the third eluting isomer when a mixture of racemic diastereomers (epimeric at the 5-position) is separated by chiral SFC using a 25 cm x 21.2 mm (R,R)-WHELK-O® 1(1-(3,5-dinitrobenzamido)-1,2,3,4-tetrahydrophenanthrene modified 5 pm silica) column.

29. The compound of claim 28, wherein the compound is in crystalline solid form; optionally wherein the crystalline solid form is Form A;

optionally wherein Form A is characterized by an XRPD pattem having diffractions at angles (degrees 2 thêta ± 0.2) of 9.2, 10.4, and 15.7; and/or optionally wherein Form A is characterized by a solid State ^I3C NMR spectrum having peaks at Chemical shifts of 167.7, 126.0, 115.9,43.5, and 20.3 ppm or a solid State ^I9F NMR spectrum having peaks at Chemical shifts of -82.2, -83.1, -111.7, and -114.4 ppm.

598

30. The compound of claim 19, wherein the compound has formula

31. The compound of claim 30, wherein the compound is in crystalline solid form;

(a) an XRPD pattern having diffractions at angles (degrees 2 thêta ± 0.2) of 17.2, 19.3, and 22.3; and/or (b) a solid State ¹³C NMR spectrum having peaks at Chemical shifts of 171.1, 149.3, 123.3, 41.6, and 20.0 ppm or a solid state ^l9F NMR spectrum having peaks at Chemical shifts of-78.2, -113.5, and -115.1 ppm; and/or (c) a monoclinic crystal System, as determined by single-crystal X-ray analysis; and/or (d) a P2i space group, as determined by single-crystal X-ray analysis; and/or (e) a unit cell, as determined by single-crystal X-ray analysis, of the following dimensions: a=7.8661(3) Â; b=7.9167(3) Â; c=16.8777(7) Â; α=90°; β=98.487(2)°; andy=90°.

32. The compound of claim 19, wherein the compound has formula

wherein the compound has the absolute stereochemistry of the second eluting isomer when a racemic mixture of enantiomers is separated by chiral SFC using a 25 cm x 10 mm CHIRALPAK® AS-H (amylose tris-[(S)α-methylbenzylcarbamate] coated on 5 pm silica) column.

33. The compound of claim 32, wherein the compound is in crystalline solid form;

optionally wherein the crystalline solid form is Form A;

optionally wherein Form A is characterized by an XRPD pattern having diffractions at angles (degrees 2 thêta ± 0.2) of 6.8, 7.9, and 13.8.

599

34. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of daims 1-18, or a pharmaceutically acceptable sait thereof, or the compound of any one of daims 19-33 and one or more pharmaceutically acceptable carriers or vehicles.

35. A pharmaceutical composition comprising the compound of any one of daims 1-18, or a pharmaceutically acceptable sait thereof, or the compound of any one of daims 19-33 and one or more pharmaceutically acceptable carriers or vehicles.

36. A compound of any one of daims 1-18, or a pharmaceutically acceptable sait thereof, the compound of any one of daims 19-33, or the pharmaceutical composition of daim 34 or 35 for use in inhibiting a voltagegated sodium channel in a subject;

optionally wherein the voltage-gated sodium channel is Navl.8.

37. A compound of any one of daims 1-18, or a pharmaceutically acceptable sait thereof, the compound of any one of daims 19-33, or the pharmaceutical composition of daim 34 or 35 for use in treating or lessening the severity in a subject of chronic pain, gut pain, neuropathie pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, viscéral pain, multiple sclerosis, CharcotMarie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia.

38. The compound, pharmaceutically acceptable sait thereof, or pharmaceutical composition of daim 37, wherein the compound, pharmaceutically acceptable sait thereof, or pharmaceutical composition is for us in treating or lessening the severity in the subject of neuropathie pain;

optionally wherein:

the neuropathie pain comprises post-herpetic neuralgia; or the neuropathie pain comprises small fîber neuropathy or idiopathic small-fiber neuropathy, or the neuropathie pain comprises diabetic neuropathy. .

39. The compound, pharmaceutically acceptable sait thereof, or pharmaceutical composition of daim 37, wherein the compound, pharmaceutically acceptable sait thereof, or pharmaceutical composition is for use in treating or lessening the severity in the subject of musculoskeletal pain;

optionally wherein the musculoskeletal pain comprises osteoarthritis pain.

40. The compound, pharmaceutically acceptable sait thereof, or pharmaceutical composition of daim 37, wherein the compound, pharmaceutically acceptable sait thereof, or pharmaceutical composition is for use in treating or lessening the severity in the subject of acute pain;

optionally wherein the acute pain comprises acute post-operative pain.

600

41. The compound, pharmaceutically acceptable sait thereof, or pharmaceutical composition of claim 37, wherein the compound, pharmaceutically acceptable sait thereof, or pharmaceutical composition is for use in treating or lessening the severity in the subject of postsurgical pain;

optionally wherein:

the postsurgical pain comprises bunionectomy pain; or the postsurgical pain comprises hemiorrhaphy pain; or the postsurgical pain comprises abdominoplasty pain.

42. The compound, pharmaceutically acceptable sait thereof, or pharmaceutical composition of claim 37, wherein the compound, pharmaceutically acceptable sait thereof, or pharmaceutical composition is for use in treating or lessening the severity in the subject of viscéral pain.

43. A compound of any one of daims 1-18, or a pharmaceutically acceptable sait thereof, the compound of any one of daims 19-33, or the pharmaceutical composition of claim 34 or 35 for use in treating or lessening the severity in a subject of pain.

44. The compound, pharmaceutically acceptable sait thereof, or pharmaceutical composition of any one of daims 36-43, wherein the compound, pharmaceutically acceptable sait thereof, or pharmaceutical composition is for administration concurrently with, prior to, or subséquent to treatment with one or more additional therapeutic agents.

45. A compound of any one of daims 1-18, or a pharmaceutically acceptable sait thereof, the compound of any one of daims 19-33, or the pharmaceutical composition of claim 34 or 35, for use as a médicament.