NZ716609B2 - Fused piperidine amides as modulators of ion channels - Google Patents

Abstract

The invention relates to fused piperidine amides useful as inhibitors of ion channels for the treatment of pain. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

Description

(12) Granted patent specificaon (19) NZ (11) 716609 (13) B2 (47) Publicaon date: 2021.12.24 (54) FUSED PIPERIDINE AMIDES AS MODULATORS OF ION LS (51) Internaonal Patent Classificaon(s): C07D 221/04 C07D 401/04 C07D 401/06 C07D 403/06 C07D 405/06 C07D 487/04 C07D 491/044 C07D 491/048C07D 491/056A61K 31/436 A61K 31/472 A61K 31/435 A61K 31/4355A61P 25/04 (22) Filing date: (73) Owner(s): 2014.07.08 VERTEX PHARMACEUTICALS INCORPORATE (23) Complete specificaon filing date: 2014.07.08 (74) Contact: AJ PARK (30) Internaonal Priority Data: US 61/844,499 2013.07.10 (72) Inventor(s): HADIDA-RUAH, Sara, Sabina (86) Internaonal Applicaon No.: ANDERSON, Corey ZHOU, Jinglan UY, Johnny (87) Internaonal Publicaon number: FRIEMAN, Bryan, A.

WO/2015/006280 SILINA, Alina , Dennis, James DENINNO, l, Paul CONROY, Erica, Lynn GROOTHENHUIS, Peter, Diederik Jan PIERRE, e Jean, Denis (57) Abstract: The invenon relates to fused piperidine amides useful as inhibitors of ion channels for the treatment of pain. The invenon also provides pharmaceucally able composions comprising the compounds of the on and methods of using the composions in the treatment of various disorders. 716609 B2 FUSED PIPERIDINE AMIDES AS MODULATORS OF ION CHANNELS CROSS-REFERENCE TO RELATED APPLICATIONS This ation claims the benefit ofUS. Provisional Patent Application No. 61/844,499, filed July 10, 2013, the entire contents of which are hereby incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION The invention relates to compounds useful as inhibitors of ion channels. The invention also provides ceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION Pain is a protective mechanism that allows healthy animals to avoid tissue damage and to prevent r damage to injured tissue. Nonetheless there are many conditions where pain persists beyond its usefulness, or where patients would benefit from inhibition of pain. Voltage-gated sodium channels are believed to play a critical role in pain signaling. This belief is based on the known roles of these ls in normal physiology, pathological states arising from mutations in sodium channel genes, nical work in animal models of disease, and the clinical usefulness ofknown sodium channel modulating agents (Cummins, T. R., Sheets, P.

L., and Waxman, S. G., The roles of sodium channels in nociception: Implications for mechanisms of pain. Pain 131 (3), 243 ; England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin Investig Drugs 17 (12), 1849 (2008); Krafte, D. S. and Bannon, A. W., Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr Opin Pharmacol 8 (1), 50 (2008)).

Voltage-gated sodium channels ) are key biological mediators of electrical ing. NaV’s are the primary mediators of the rapid upstroke of the action potential of many excitable cell types (e. g. neurons, skeletal myocytes, cardiac es), and thus are al for the tion of signaling in those cells (Hille, WO 06280 Bertil, Ion Channels ofExcz'table Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). Because of the role NaV’s play in the initiation and propagation of neuronal signals, antagonists that reduce NaV currents can prevent or reduce neural signaling. Thus NaV channels are considered likely targets in pathologic states Where reduced excitability is predicted to alleviate the clinical symptoms, such as pain, epilepsy, and some cardiac arrhythmias (Chahine, M., Chatelier, A., Babich, 0., and Krupp, J. J., Voltage-gated sodium channels in neurological disorders. CNS Neural Disord Drug Targets 7 (2), 144 (2008)).

The NaV’s form a subfamily of the voltage-gated ion channel super- family and comprises 9 isoforms, designated NaV 1.1 — NaV 1.9. The tissue zations of the nine isoforms vary y. NaV 1.4 is the primary sodium channel of skeletal muscle, and NaV 1.5 is primary sodium channel of cardiac myocytes.

NaV’s 1.7, 1.8 and 1.9 are primarily localized to the peripheral nervous , While NaV’s 1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the central and peripheral nervous s. The functional behaviors of the nine isoforms are similar but distinct in the specifics of their e-dependent and kinetic behavior (Catterall, W. A., Goldin, A. L., and Waxman, S. G., International Union of Pharmacology.

XLVII. Nomenclature and structure-function onships of voltage-gated sodium channels. Pharmacol Rev 57 (4), 397 (2005)).

[0006] NaV channels have been identified as the primary target for some clinically useful pharmaceutical agents that reduce pain (Cummins, T. R., Sheets, P.

L., and Waxman, S. G., The roles of sodium channels in nociception: Implications for mechanisms of pain. Pain 131 (3), 243 (2007)). The local anesthetic drugs such as ine block pain by inhibiting NaV channels. These compounds provide excellent local pain reduction but suffer the drawback of abolishing normal acute pain and sensory inputs. Systemic administration of these nds results in dose limiting side effects that are generally ascribed to block neural channels in the CNS (nausea, sedation, confusion, ataxia). Cardiac side effects can also occur, and indeed these nds are also used as class 1 anti-arrhythmics, presumably due to block of NaV1.5 ls in the heart. Other compounds that have proven effective at reducing pain have also been ted to act by sodium channel blockade ing carbamazepine, lamotragine, and tricyclic antidepressants (Soderpalm, B., WO 06280 nvulsants: aspects of their mechanisms of action. Eur J Pain 6 Suppl A, 3 (2002); Wang, G. K., Mitchell, J ., and Wang, S. Y., Block of persistent late Na+ currents by antidepressant line and tine. JMembr Biol 222 (2), 79 (2008)).

These compounds are likewise dose limited by adverse effects similar to those seen with the local anesthetics. Antagonists that specifically block only the isoform(s) critical for nocioception are ed to have increased efflcacy since the reduction of e effects caused by block of off-target channels should enable higher dosing and thus more te block of target channels isoforms.

Four NaV isoforms, NaV 1.3, 1.7, 1.8, and 1.9, have been cally indicated as likely pain targets. NaV 1.3 is normally found in the pain sensing neurons of the dorsal root ganglia (DRG) only early in development and is lost soon after birth both in humans and in rodents. Nonetheless, nerve ng injuries have been found to result in a return of the NaV 1.3 channels to DRG neurons and this may contribute to the abnormal pain ing in various chronic pain conditions resulting from nerve damage (neuropathic pain). These data have led to the suggestion that pharmaceutical block of NaV 1.3 could be an effective treatment for neuropathic pain. In opposition to this idea, global genetic knockout ofNaV 1.3 in mice does not prevent the development of allodynia in mouse models of neuropathic pain (Nassar, M. A. et al., Nerve injury induces robust allodynia and ectopic discharges in NaV 1.3 null mutant mice. M01 Pain 2, 33 (2006)). It s unknown whether compensatory changes in other ls allow for normal neuropathic pain in NaV 1.3 knockout mice, though it has been reported that knockout ofNaV 1.1 results in drastic upregulation ofNaV 1.3.

The converse effect in NaV 1.3 knockouts might explain these results.

NaV 1.7, 1.8, and 1.9 are highly expressed in DRG neurons, including the neurons whose axons make up the C-flbers and A8 nerve fibers that are believed to carry most pain signals from the nocioceptive terminals to the central nervous system.

Like NaV 1.3, NaV 1.7 expression increases after nerve injury and may contribute to neuropathic pain states. The localization ofNaV 1.7, 1.8, and 1.9 in nocioceptors led to the hypothesis that reducing the sodium currents through these channels might alleviate pain. Indeed, specific interventions that reduce the levels of these channels have proven effective in animal models of pain.

Specific reduction ofNaV 1.7 in rodents by multiple different techniques has resulted in the reduction of observable pain behaviors in model animals. Injection of a viral antisense NaV 1.7 cDNA construct greatly reduces normal pain responses due to inflammation or mechanical injury (Yeomans, D. C. et al., Decrease in inflammatory lgesia by herpes vector-mediated knockdown of NaV 1.7 sodium channels in primary afferents. Hum Gene Ther 16 (2), 271 (2005)).

Likewise, a genetic knockout ofNaV 1.7 in a subset of nociceptor neurons reduced acute and inflammatory pain in mouse models (Nassar, M. A. et al., Nociceptor- specific gene deletion reveals a major role for NaV 1.7 (PNl) in acute and inflammatory pain. Proc Natl Acad Sci U S A 101 (34), 12706 (2004)). Global knockout ofNaV 1.7 in mice leads to death in pups presumably due to a disruption in olfactory-guided feeding. Selective NaV1.7 ablation in both sensory and sympathetic neurons in mice prevents mechanical and l hypersensitivity induced by inflammation and nerve injury, and attenuates normal withdrawal responses to noxious heat (Minett, M.S. et al., Distinct Nav1.7-dependent pain sensations require different sets of y and sympathetic s. Nat Comm 3, 791 (2012)) recapitulating the pain-free phenotype of humans with NaV1.7 loss-of filnction mutations.

Treatments that specifically reduce NaV 1.8 channels in rodent models effectively reduce pain sensitivity. Knockdown ofNaV 1.8 in rats by intrathecal ion of antisense oligodeoxynucleotides reduces neuropathic pain behaviors, while leaving acute pain sensation intact (Lai, J. et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8. Pain 95 (1-2), 143 (2002); Porreca, F. et al., A comparison of the potential role of the otoxin-insensitive sodium channels, PN3/SNS and S2, in rat models of chronic pain. Proc Natl Acad Sci U S A 96 (14), 7640 (1999)). Global genetic knockout ofNaV 1.8 in mice or specific destruction ofNaV 1.8 sing neurons greatly reduces perception of acute mechanical, inflammatory, and visceral pain (Akopian, A. N. et al., The tetrodotoxin-resistant sodium l SNS has a specialized function in pain pathways. Nat Neurosci 2 (6), 541 (1999); Abrahamsen, B. et al., The cell and molecular basis of mechanical, cold, and atory pain. e 321 (5889), 702 (2008); Laird, J. M., Souslova, V., Wood, J. N., and Cervero, F., Deficits in visceral pain and referred lgesia in NaV 1.8 (SNS/PN3)-null mice. J Neurosci 22 (19), 8352 (2002)). In st to the antisense ments in rats, genetic knockout mice appear to p neuropathic pain ors normally after nerve injury (Lai, J. et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8. Pain 95 (1-2), 143 (2002); Akopian, A. N. et al., The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat Neurosci 2 (6), 541 (1999); Abrahamsen, B. et al., The cell and molecular basis of mechanical, cold, and inflammatory pain. e 321 (5889), 702 (2008); Laird, J. M., Souslova, V., Wood, J. N., and Cervero, F., Deficits in visceral pain and referred hyperalgesia in NaV 1.8 (SNS/PN3)-null mice. J Neurosci 22 (19), 8352 (2002)).

NaV 1.9 global knock out mice have decreased sensitivity to inflammation induced pain, despite normal acute, and neuropathic pain behaviors (Amaya, F. et al., The voltage-gated sodium channel Na(v)1.9 is an effector of peripheral atory pain hypersensitivity. sci 26 (50), 12852 (2006); Priest, B. T. et al., Contribution of the tetrodotoxin-resistant voltage-gated sodium channel NaV1.9 to sensory transmission and nociceptive behavior. Proc Natl Acad Sci USA 102 (26), 9382 (2005)). Spinal knockdown ofNaV 1.9 had no apparent effect on pain behavior in rats (Porreca, F. et al., A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain. Proc Natl Acad Sci U S A 96 (14), 7640 (1999)).

The understanding of the role ofNaV channels in human physiology and pathology has been greatly advanced by the discovery and analysis of naturally occurring human mutations. NaV 1.1 and NaV 1.2 mutations result in s forms of epilepsy ara, T., al spectrum of mutations in SCN1A gene: severe myoclonic epilepsy in infancy and related epilepsies. Epilepsy Res 70 Suppl 1, S223 (2006); George, A. L., Jr., ted disorders of voltage-gated sodium channels. .1 Clin Invest 115 (8), 1990 (2005); Misra, S. N., , K. M., and George, A. L., Jr., Impaired NaV1.2 fianction and reduced cell surface expression in benign familial neonatal-infantile seizures. Epilepsia 49 (9), 1535 (2008)). Mutations of the NaV 1.4 cause muscular disorders like paramyotonia congenital t, S., Stemberg, D., Fontaine, B., and Meola, G., Human skeletal muscle sodium channelopathies. Neurol Sci 26 (4), 194 (2005)). NaV 1.5 mutations result in cardiac abnormalities like Brugada Syndrome and long QT syndrome (Bennett, P. B., Yazawa, K., Makita, N., and George, A. L., Jr., lar mechanism for an inherited cardiac arrhythmia.

Nature 376 (6542), 683 (1995); , D. et al., Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation. Circulation 117 (15), 1927 (2008); Wang, Q. et al., SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 80 (5), 805 ).

Recent discoveries have demonstrated that mutations in the gene that encodes the NaV 1.7 l (SCN9A) can cause both enhanced and reduced pain mes. Work by Waxman’s group and others have identified at least 15 mutations that result in enhanced current through NaV 1.7 and are linked to dominant congenital pain syndromes. Mutations that lower the threshold for NaV 1.7 activation cause inherited erythromelalgia (IBM). IBM patients exhibit abnormal burning pain in their extremities. Mutations that interfere with the normal inactivation properties ofNaV 1.7 lead to prolonged sodium currents and cause paroxysmal extreme pain disorder (PEPD). PEPD patients exhibit periocular, perimandibular, and rectal pain symptoms that progresses throughout life (Drenth, J. P. et al., SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels. .1 Invest Dermatol 124 (6), 1333 (2005); Estacion, M. et al., NaV 1.7 gain-of-function mutations as a continuum: A1632E displays physiological changes associated with erythromelalgia and paroxysmal e pain disorder mutations and produces symptoms of both disorders. J ci 28 (43), 11079 (2008)).

NaV 1.7 null mutations in human patients were ly described by several groups (Ahmad, S. et al., A stop codon mutation in SCN9A causes lack of pain sensation. Hum Mol Genet 16 (17), 2114 ; Cox, J. J. et al., An SCN9A channelopathy causes congenital inability to experience pain. Nature 444 (7121), 894 (2006); Goldberg, Y. P. et al., Loss-of—function mutations in the NaV 1.7 gene underlie congenital indifference to pain in le human populations. Clin Genet 71 (4), 311 (2007)). In all cases patients exhibit congenital indifference to pain. These patients report no pain under any stances. Many of these patients suffer dire injuries early in childhood since they do not have the protective, normal pain that helps to prevent tissue damage and develop appropriate protective behaviors. Aside from the striking loss of pain ion and reduced or absent sense of smell (Goldberg, Y. P. et 2014/045675 al., Loss-of-function mutations in the NaV 1.7 gene underlie congenital indifference to pain in multiple human populations. Clin Genet 71 (4), 311 (2007)), these ts appear completely normal. e the normally high expression ofNaV 1.7 in sympathetic neurons (Toledo-Aral, J. J. et al., Identification of PNl, a predominant voltage-dependent sodium channel expressed principally in peripheral neurons. Proc Natl Acad Sci U S A 94 (4), 1527 (1997)) and adrenal chromaf1n cells (Klugbauer, N., Lacinova, L., Flockerzi, V., and Hofmann, F., Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells. EMBO J 14 (6), 1084 (1995)), these NaV 1.7-null patients show no sign of neuroendocrine or sympathetic nervous dysfianction.

The gain ofNaV 1.7 on mutations that cause pain, coupled with the loss ofNaV 1.7 on mutations that abolish pain, provide strong evidence that NaV 1.7 plays an ant role in human pain signaling. The relative good health of NaV 1.7-null patients indicates that ablation ofNaV 1.7 is well tolerated in these patients.

Unfortunately, the efficacy of currently used sodium channel blockers for the disease states bed above has been to a large extent limited by a number of side effects. These side effects include various CNS disturbances such as blurred vision, dizziness, nausea, and sedation as well more ially life ening cardiac arrhythmias and cardiac failure. Accordingly, there remains a need to develop additional Na channel nists, preferably those with higher potency and fewer side effects.

SUMMARY OF THE INVENTION It has now been found that nds of this invention, and pharmaceutically acceptable compositions thereof, are useful as inhibitors of voltage- gated sodium channels. These compounds have the general formula I: B (R 2) o (R 3) p A (R 1) n O N or a pharmaceutically able salt thereof. [0017a] In a particular aspect, the present invention provides a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence, O O O O O ring A is O , O , O , , , O , , D F O D, F , O or ; [FOLLOWED BY PAGE 8a] ring B is ed from a pyridyl, thiazole, pyrimidine, pyrazole, furan, thiophene, pyrrole, oxazole, imidazole, isoxazole, isothiazole, pyridazine, pyrazine F F F Cl F CN ring, , , , , , , , F CF 3 Br N N S N N N N N F O , , , , , , , O O Cl CF 3 S S N N N N N N N , , , , , , , O O O N N N N N F O , , , , or ; [FOLLOWED BY PAGE 8b] O F 3C O O O O O F ring C is ed from CF 3 , F , , OH, O O O Cl O Cl O CF3 CF 3 , , F F , CF 3 , OH , OH , , Cl Cl O O O O O , CF 3 , , HO , , OH , OH , O Cl O O O O O O F F O O F F CF 3 F F , , CF3 , CF3 , CF 3 , F F , O O CF 3 O O O O S O F HO O F OH , , , , F F , , [FOLLOWED BY PAGE 8c] F F 3C CF 3 O O O O O F F F F OH , , F 3C , CF 3 , F F , O CF 3 O NC O O CF 3 , F , F 3C , F F , , O O F O O F O F F , F 3C , OH , CF 3 , F F , Cl Cl F O O O S O F NH O S O F Cl O O CF 3 , , , F , OH , , , WED BY PAGE 8d] Cl O CF 3 O O O O O O O F F , F , , F , F , O O Cl O O O F F , , CF 3 , or ; R1 is C1-C6 alkyl, C1-C6 alkoxy, halo, fluoro-C1-C6 alkyl, fluoro-C1-C6 alkoxy, or oxo; and n is an integer from 0 to 4 inclusive.

These compounds and pharmaceutically acceptable compositions are useful for treating or lessening the ty of a variety of diseases, disorders, or conditions, including, but not limited to, acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, r headaches, trigeminal neuralgia, ic gia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, dipolar disorder, myotonia, arrhythmia, movement ers, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel me, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, cancer pain, , cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress- or exercise induced angina, ations, ension, migraine, or abormal gastro-intestinal motility.

DETAILED DESCRIPTION OF THE INVENTION

[0019] In one aspect, the invention provides compounds of formula I: [FOLLOWED BY PAGE 9] (R1)n or a pharmaceutically acceptable salt thereof, n, independently for each occurrence: ring A is a fused cycloalkyl or heterocycloalkyl ring; ring B is a substituted or unsubstituted aryl or heteroaryl ring; ring C is a substituted or unsubstituted aryl or heteroaryl ring; R1 is C1-C6 alkyl, Cl-C6 alkoxy, halo, fluoro-Cl-C6 alkyl, fluoro-Cl-C6 alkoxy, or oxo; R2 is C 1 -C6 alkyl, C 1 -C6 alkoxy, halo, CN, fluoro-C 1 -C6 alkyl, fluoro-C 1 -C6 alkoxy, N(R7)2, NR7SOZR7, $02117, C02R7, SOZN(R7)2, or (C1-C8)-R8 wherein up to two CH2 units may be replaced with O, CO, CFz, or NR7; R3 is C 1 -C6 alkyl, C 1 -C6 alkoxy, halo, CN, fluoro-C 1 -C6 alkyl, or fluoro-C 1 -C6 alkoxy; n, o, and p are integers from 0 to 4 inclusive; R7 is H, Cl-C6 alkyl, CHFZ, CF3, or C3-C8 cycloalkyl; and R8 is H, CF3, C02R7, OH, aryl, aryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R7)2, NR7COR7, CON(R7)2, CN, or SOZR7.

For purposes of this ion, the chemical ts are fied in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, ito: 1999, and "March’s Advanced Organic Chemistry", 5th Ed., Ed.: Smith, MB. and March, J John Wiley & Sons, New York: ., 2001, the entire contents of which are hereby incorporated by reference.

As described herein, compounds of the invention can optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. The phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” As described herein, the variables in formula I ass specific groups, such as, for example, alkyl or lkyl. Unless otherwise noted, each of the specific groups for the variables can be optionally substituted with one or more tuents of halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. For instance, an alkyl group can be optionally substituted with one or more of halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As an additional example, an aryl group can be optionally substituted with one or more of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. As one of ordinary skill in the art will ize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their ry, 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 ature of 40°C or less, in the e of moisture or other chemically reactive conditions, for at least a week. When two alkoxy groups are bound to the same atom or nt atoms, the two alkoxy groups can form a ring together with the atom(s) to which they are bound.

In general, the term “substituted,” whether preceded by the term nally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. c substituents are described above in the definitions and below in the description of compounds and examples thereof Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. A ring substituent, such as a heterocycloalkyl, can be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one common atom. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those ations that result in the formation of stable or chemically feasible compounds.

The phrase "up to", as used herein, refers to zero or any integer number that is equal or less than the number following the . For e, "up to 3" means any one of 0, l, 2, and 3.

The term "aliphatic", "aliphatic group" or "alkyl" as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is tely saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain l-lO aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other ments, tic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or tituted alkyl, alkenyl, alkynyl groups. The term "cycloaliphatic" or “cycloalkyl” mean a monocyclic arbon, bicyclic, or tricyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic and has a single point of attachment to the rest of the molecule. In some embodiments, "cycloaliphatic" refers to a monocyclic C3-C8 hydrocarbon or bicyclic C8-C12 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members.

Unless ise specified, the term "heterocycle", "heterocyclyl", "heterocycloaliphatic", "heterocycloalkyl" or "heterocyclic" as used herein means non- aromatic, clic, bicyclic, or tricyclic ring systems in which one or more ring atoms in one or more ring s is an independently selected heteroatom.

Heterocyclic ring can be saturated or can contain one or more unsaturated bonds. In some embodiments, the "heterocycle", ocyclyl", "heterocycloaliphatic", ocycloalkyl"or "heterocyclic" group has three to en ring atoms in which one or more ring atoms is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the ring system ns 3 to 7 ring atoms.

The term "heteroatom" means oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H—pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N,N-di-substituted pyrrolidinyl)).

The term "unsaturated", as used , means that a moiety has one or more units of unsaturation but is not aromatic.

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

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

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

The term "alkylidene chain" refers to a straight or ed carbon chain that may be fillly saturated or have one or more units of unsaturation and has two points of attachment to the rest of the molecule.

Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e. g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and cis and trans conformational isomers. Therefore, single stereochemical s as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.

Unless otherwise , all eric forms of the compounds of the ion are within the scope of the invention. Thus, included within the scope of the invention are tautomers of nds of a I.

Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds of formula I, n one or more hydrogen atoms are replaced with deuterium or tritium, or one or more carbon atoms are replaced by a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or sodium channel blockers with an improved therapeutic profile.

In one embodiment, the invention features compounds of a I wherein ring A is a fused cycloalkyl ring, ring B is an aryl ring and ring C is a substituted or unsubstituted aryl; R1 is Cl-C6 alkyl, Cl-C6 alkoxy, halo, fluoro-Cl-C6 alkyl, fluoro-Cl-C6 alkoxy, or oxo; R2 is Cl-C6 alkyl, Cl-C6 alkoxy, halo, CN, fluoro-Cl-C6 alkyl, fluoro-Cl-C6 alkoxy, N(R7)2, NR7SOZR7, SOZR7, C02R7, 7)2, or (Cl-C8)—R8 wherein up to two CH2 units may be replaced with O, CO, CF2, or NR7; R3 is Cl-C6 alkyl, Cl-C6 alkoxy, halo, CN, fluoro-Cl-C6 alkyl, or fluoro-Cl-C6 alkoxy; n, o, and p are integers from 0 to 4 inclusive; R7 is H, Cl-C6 alkyl, CHFZ, CF3, or C3-C8 cycloalkyl; and R8 is H, CF3, C02R7, OH, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R7)2, 7, CON(R7)2, CN, or SOZR7. In another embodiment, R1 is Cl-C6 alkyl, halo, or oxo. In yet another embodiment, R1 is CH3, F, or oxo. In another embodiment, R2 is Cl-C6 alkyl, Cl-C6 alkoxy, fluoro- Cl-C6 alkyl, halo, CN, or (Cl-C8)—R8 wherein up to two CH2 units may be ed with o, co, CFz, or NR7. More specifically, R2 is CH3, OCH3, CF3, F, Cl, Br, CN, OCHzCHzOtBu, OCH2CH(CH3)2. In a further embodiment, R3 is Cl-C6 alkyl. In a further embodiment, R3 is CH3. 53“,}:9 F In some embodiments, ring A18‘?” In other FF\;,F F embodiments, ring B is N , 9 ’N’ CN F JV‘ or JV‘

[0036] In one embodiment, ring C is JIV‘ R4 R4 R5 : :R5 wherein R4 is H, C1-C6 alkyl, Cl-C6 alkoxy, halo, CN, or OH; R5 is H, Cl-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, 0R7, N(R7)2, NR7SOZR7, $02117, C02R7, SOZN(R7)2, fluoro-Cl-C6 alkyl, or fluoro-Cl-C6 alkoxy; R6 is H, Cl-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, 0R7, N(R7)2, NR7SOZR7, SR7, SOR7, $02117, C02R7, NR7COR7,NR7C02R7, CON(R7)2, SOZN(R7)2, C133, OCF3, OCHFZ, heterocycloalkyl, aryl, heteroaryl, or a ht chain, branched, or cyclic (Cl-C8)-R8 or fluoro-(Cl- C8)-R8 wherein up to three CH2 units may be replaced with O, CO, S, SO, 802, or NR7.

[0037] In a further embodiment, two occurrences of R4 and R5, or R5 and R6 together with the s to which they are attached form an ally substituted ring comprising up to 2 heteroatoms.

In a r embodiment, R4 is H, Cl-C6 alkoxy, or halo. R4 may also be H, OCH3, or F. In one ment, R5 is H, Cl-C6 alkyl, Cl-C6 , halo, CN, OH, or fluoro-Cl-C6 alkyl. In another embodiment, R5 is H, CH3, OCH3, F, Cl, CN, OH, or CF3. In certain embodiments, R6 is H, Cl-C6 alkoxy, fluoro-Cl-C6 alkoxy, SOZR7, SOZN(R7)2, or a straight chain, branched, or cyclic (Cl-C8)—R8 or fluoro-(Cl- C8)—R8 n up to three CH2 units may be replaced with O, CO, S, SO, 802, or NR7. In some embodiments, R6 is H, OCHZCHZCFg, OCHZCF(CH3)2, C(CH3)2CH20H, OCHZCHZCH(CH3)2, OCH(CH3)CF3, CH20CH2CH2CF3, C(CH3)20H, zOtBu, CH2C(CH3)20H, OCH(CH3)2, OCH2C(CH3)20H, OCHZCFZCHFZ, 3, OCHZCHZOCFg, OCH(CH3)CF2CHF2, SOZCHFZ, OCHZCFZCHg, OCHZCHZOCHZCFg, OCH2CF3, OCH2C(CH3)3, OCHZCH(CH3)CH2CF3, SOZCHZCHg, 3)CH2CF3, OCHZCFZCHFZ, . In one embodiment, R4 and R5 together with the carbons to which they are attached may also form an optionally substituted ring comprising up to 2 heteroatoms.

In another embodiment, ring C is

[0040] In further embodiments, R5 and R6 together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 heteroatoms.

In one embodiment, ring C is CFs In another embodiment, the invention features compounds of formula I wherein ring A is a fused lkyl ring, ring B is an aryl ring and ring C is a substituted or unsubstituted aryl; R1 is C1-C6 alkyl, Cl-C6 alkoxy, halo, fluoro- Cl-C6 alkyl, fluoro-Cl-C6 alkoxy, or oxo; R2 is Cl-C6 alkyl, Cl-C6 , halo, CN, fluoro-Cl-C6 alkyl, fluoro-Cl-C6 alkoxy, N(R7)2, NR7SOZR7, SOZR7, C02R7, SOZN(R7)2, or (Cl-C8)-R8 n up to two CH2 units may be replaced with O, CO, CF2, or NR7; R3 is Cl-C6 alkyl, Cl-C6 alkoxy, halo, CN, fluoro-Cl-C6 alkyl, or fluoro-Cl-C6 alkoxy; n, o, and p are integers from 0 to 4 inclusive; R7 is H, Cl-C6 alkyl, CHFZ, CF3, or C3-C8 cycloalkyl; and R8 is H, CF3, C02R7, OH, aryl, heteroaryl, lO C3-C8 cycloalkyl, heterocycloalkyl, N(R7)2, NR7COR7, CON(R7)2, CN, or SOZR7. In another embodiment, R1 is Cl-C6 alkyl, halo, or oxo. In yet another embodiment, R1 is CH3, F, or oxo. In another embodiment, R2 is Cl-C6 alkyl, Cl-C6 alkoxy, fluoro-Cl- C6 alkyl, halo, CN, or (Cl-C8)-R8 n up to two CH2 units may be replaced with O, CO, CFz, or NR7. More cally, R2 is CH3, OCH3, CF3, F, Cl, Br, CN, OCHzCHzOtBu, OCH2CH(CH3)2. In a further embodiment, R3 is Cl-C6 alkyl. In a further embodiment, R3 is CH3. In some embodiments, ring A is F F F : CI other embodiments, ringBis ~N‘ JV‘ \N‘ JV‘ JV‘ , , , , , F CN F F F JV" JU‘ or N 9 , In some embodiments, ring C is a pyridyl or quinoline ring. In a further embodiment, ring C is selected from: WO 06280 N N \ \N / NI / /O \ / O\|\ 0 O O\|\ 9% F— OIMWJ N /o ol , F, N/O FNN-\/ N- \/ oi N\oN.\/ G \ N N IN N / \N \ O N\ I / IN 0' N/ \ l/ /O / N o o' (I) F3C NH O O F F 9 9 OH9 9 9 JV" N \ N\ IN N IN I / /? \ / N O \ O 0' 'N |\ O O é N|\ /(|) /N F F / F 00 or 9 F9 O\9FF 9 9 9 and CF3.

In another embodiment, the invention features compounds of formula I wherein ring A is a fused cycloalkyl ring, ring B is a heteroaryl ring and ring C is a substituted or unsubstituted aryl; R1 is C1-C6 alkyl, Cl-C6 alkoxy, halo, fluoro-Cl- C6 alkyl, Cl-C6 alkoxy, or oxo; R2 is Cl-C6 alkyl, Cl-C6 alkoxy, halo, CN, fluoro-Cl-C6 alkyl, fluoro-Cl-C6 alkoxy, N(R7)2, NR7SOZR7, SOZR7, C02R7, SOZN(R7)2, or )-R8 n up to two CH2 units may be replaced with O, CO, CF2, or NR7; R3 is Cl-C6 alkyl, Cl-C6 alkoxy, halo, CN, fluoro-Cl-C6 alkyl, or fluoro-Cl-C6 alkoxy; n, o, and p are integers from 0 to 4 inclusive; R7 is H, Cl-C6 alkyl, CHFZ, CF3, or C3-C8 cycloalkyl; and R8 is H, CF3, C02R7, OH, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R7)2, NR7COR7, )2, CN, or In another embodiment, R1 is Cl-C6 alkyl, halo, or oxo. In yet another embodiment, R1 is CH3, F, or oxo. In another embodiment, R2 is Cl-C6 alkyl, Cl-C6 alkoxy, fluoro-Cl- C6 alkyl, halo, CN, or (Cl-C8)-R8 wherein up to two CH2 units may be replaced with O, CO, CFz, or NR7. More specifically, R2 is CH3, OCHg, CF3, F, Cl, Br, CN, OCHZCHzOtBu, OCH2CH(CH3)2. In a further embodiment, R3 is C1-C6 alkyl. In s.s sS Q m><FF r embodiment, R3 is CH3. In some embodiments, ring A is or . In one ment, ring B is a pyridyl, thiazole, pyrimidine, pyrazole, furan, thiophene, pyrrole, oxazole, imidazole, isoxazole, isothiazole, zine, or pyrazine ring. In I l=\ m \ \ CFs I I /N NTS NTN \o /N /N another embodiment, ring B is N JV‘ N JV‘ JV‘ , , , , , | | Br 0 0 CI CF \ \ \ \ \ 3 | | SW | | | \7”S \ I | /N N / \ N /N /N N / N / N / JV‘ JV‘ JV‘ JV‘ JV‘ JV‘ JV‘ JV‘ , , , , , , , , —l— A I 01 O \ O \ \ \ I I I l“ \ \ I N / /N /N N\ N / F O JV‘ JV‘ JV" JV‘ 01' JV‘ R6 wherein R4 is H, Cl-C6 alkyl, Cl-C6 alkoxy, halo, CN, or OH; R5 is H, Cl-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, 0R7, , NR7SOZR7, SOZR7, C02R7, SOZN(R7)2, fluoro-Cl-C6 alkyl, or fluoro-Cl-C6 alkoxy; R6 is H, Cl-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, 0R7, N(R7)2, NR7SOZR7, SR7, SOR7, SOZR7, C02R7, NR7COR7,NR7C02R7, CON(R7)2, SOZN(R7)2, C133, OCFg, OCHFZ, heterocycloalkyl, aryl, heteroaryl, or a straight chain, branched, or cyclic (Cl-C8)-R8 or fluoro-(Cl- C8)-R8 wherein up to three CH2 units may be replaced with O, CO, S, SO, SOZ, or NR7.

WO 06280 In a further embodiment, two occurrences of R4 and R5, or R5 and R6 together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 heteroatoms.

In a further embodiment, R4 is H, C1-C6 alkoxy, or halo. R4 may also be H, OCH3, or F. In one embodiment, R5 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, or Cl-C6 alkyl. In another embodiment, R5 is H, CH3, OCH3, F, Cl, CN, OH, or CF3. In certain embodiments, R6 is H, Cl-C6 alkoxy, fluoro-Cl-C6 alkoxy, SOZR7, SOZN(R7)2, or a straight chain, branched, or cyclic (Cl-C8)—R8 or fluoro-(Cl- C8)—R8 wherein up to three CH2 units may be replaced with O, CO, S, SO, 802, or NR7. In some embodiments, R6 is H, OCH2CH2CF3, OCH2CF(CH3)2, C(CH3)2CHZOH, 2CH(CH3)2, OCH(CH3)CF3, CHzOCHzCHzCFg, C(CH3)ZOH, OCHzCHzOtBu, CH2C(CH3)ZOH, 3)2, OCH2C(CH3)2OH, OCHZCFZCHFZ, OCH2CF3, OCHZCHZOCFg, OCH(CH3)CF2CHF2, SOZCHFZ, ZCHg, OCHZCHZOCHZCFg, OCH2CF3, OCH2C(CH3)3, OCH2CH(CH3)CH2CF3, SOZCHZCHg, OCH(CH3)CH2CF3, OCHZCFZCHFZ, é—owfi g—OWZPHOW: é—ows Ho: Ho]:we, é—l<><:, 3- “Ex: || 13—0 g—E_N]H>’é _0M’é—OE, hF,§—O\—<l—F ,orF . In one ment, R4 and R5 together with the carbons to which they are attached may also form an optionally substituted ring comprising up to 2 atoms.

In another embodiment, ring C is In further embodiments, R5 and R6 together with the carbons to which they are attached form an optionally substituted ring sing up to 2 heteroatoms.

In one embodiment, ring C is CFs In another embodiment, the invention features compounds of formula I wherein ring A is a fused heterocycloalkyl ring, ring B is an aryl ring and ring C is a substituted or unsubstituted aryl; R1 is C1-C6 alkyl, Cl-C6 alkoxy, halo, fluoro-Cl- C6 alkyl, fluoro-Cl-C6 alkoxy, or oxo; R2 is Cl-C6 alkyl, Cl-C6 alkoxy, halo, CN, fluoro-Cl-C6 alkyl, fluoro-Cl-C6 alkoxy, N(R7)2, NR7SOZR7, SOZR7, C02R7, SOZN(R7)2, or (Cl-C8)-R8 n up to two CH2 units may be replaced with O, CO, CF2, or NR7; R3 is Cl-C6 alkyl, Cl-C6 alkoxy, halo, CN, fluoro-Cl-C6 alkyl, or fluoro-Cl-C6 alkoxy; n, o, and p are integers from 0 to 4 inclusive; R7 is H, Cl-C6 alkyl, CHFZ, CF3, or C3-C8 cycloalkyl; and R8 is H, CF3, C02R7, OH, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, , NR7COR7, )2, CN, or SOZR7. In another embodiment, R1 is Cl-C6 alkyl, halo, or oxo. In yet another embodiment, R1 is CH3, F, or oxo. In another embodiment, R2 is Cl-C6 alkyl, Cl-C6 alkoxy, fluoro-Cl- C6 alkyl, halo, CN, or (Cl-C8)-R8 n up to two CH2 units may be replaced with O, CO, CF2, or NR7. More specifically, R2 is CH3, OCH3, CF3, F, Cl, Br, CN, zOtBu, OCHZCH(CH3)2. In a further embodiment, R3 is Cl-C6 alkyl. In further embodiment, R3 is CH3.

[0050] In some embodiments, ring A is EQAE-LK95530,?23/o 53-/o D 2014/045675 FF F CI F embodiments, ring B is N N N JV‘ JV‘ JV‘ CN F JU‘ ,or JV‘ In one embodiment, ring C is wherein R4 is H, C1-C6 alkyl, Cl-C6 alkoxy, halo, CN, or OH; R5 is H, Cl-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, 0R7, N(R7)2, NR7SO2R7, $02117, CO2R7, SO2N(R7)2, fluoro-Cl-C6 alkyl, or fluoro-Cl-C6 alkoxy; R6 is H, Cl-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, 0R7, N(R7)2, NR7SO2R7, SR7, SOR7, $02117, CO2R7, 7,NR7CO2R7, )2, SO2N(R7)2, C133, OCF3, OCHF2, heterocycloalkyl, lO aryl, heteroaryl, or a straight chain, branched, or cyclic (Cl-C8)-R8 or fluoro-(Cl- C8)-R8 wherein up to three CH2 units may be replaced with O, CO, S, SO, SO2, or NR7.

In a further embodiment, two occurrences of R4 and R5, or R5 and R6 together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 heteroatoms.

In a further ment, R4 is H, Cl-C6 , or halo. R4 may also be H, OCH3, or F. In one embodiment, R5 is H, Cl-C6 alkyl, Cl-C6 , halo, CN, OH, or fluoro-Cl-C6 alkyl. In another embodiment, R5 is H, CH3, OCH3, F, Cl, CN, OH, or CF3. In certain embodiments, R6 is H, Cl-C6 alkoxy, fluoro-Cl-C6 alkoxy, SO2R7, SO2N(R7)2, or a straight chain, branched, or cyclic (Cl-C8)—R8 or fluoro-(Cl- C8)—R8 wherein up to three CH2 units may be replaced with O, CO, S, SO, SO2, or NR7. In some embodiments, R6 is H, OCH2CH2CF3, OCH2CF(CH3)2, C(CH3)2CH2OH, OCH2CH2CH(CH3)2, OCH(CH3)CF3, CH2OCH2CH2CF3, C(CH3)2OH, 2OtBu, CH2C(CH3)2OH, OCH(CH3)2, OCH2C(CH3)2OH, 2014/045675 OCHZCFZCHFZ, OCHZCFg, OCHZCHZOCFg, OCH(CH3)CF2CHF2, SOZCHFZ, OCHZCFZCHg, OCHZCHZOCHZCFg, OCHZCFg, OCH2C(CH3)3, OCHZCH(CH3)CH2CF3, SOZCHZCHg, OCH(CH3)CH2CF3, OCHZCFZCHFZ, . In another embodiment, R4 and R5 er with the carbons to which they are attached may also form an optionally substituted ring comprising up to 2 heteroatoms.

[0054] In another embodiment, ring C is In filrther embodiments, R5 and R6 together with the carbons to which they are attached form an ally substituted ring comprising up to 2 heteroatoms.

In one embodiment, ring C is CFs In another embodiment, the invention es compounds of formula I wherein ring A is a fused heterocycloalkyl ring, ring B is an aryl ring and ring C is a substituted or unsubstituted heteroaryl; R1 is Cl-C6 alkyl, Cl-C6 alkoxy, halo, fluoro- Cl-C6 alkyl, fluoro-Cl-C6 alkoxy, or oxo; R2 is Cl-C6 alkyl, Cl-C6 alkoxy, halo, CN, Cl-C6 alkyl, fluoro-Cl-C6 alkoxy, N(R7)2, NR7SOZR7, SOZR7, C02R7, SOZN(R7)2, or (Cl-C8)-R8 wherein up to two CH2 units may be replaced with O, CO, CF2, or NR7; R3 is C1-C6 alkyl, Cl-C6 , halo, CN, fluoro-Cl-C6 alkyl, or fluoro-Cl-C6 alkoxy; n, o, and p are integers from 0 to 4 inclusive; R7 is H, Cl-C6 alkyl, CHFZ, CF3, or C3-C8 cycloalkyl; and R8 is H, CF3, C02R7, OH, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R7)2, NR7COR7, CON(R7)2, CN, or SOZR7. In another embodiment, R1 is Cl-C6 alkyl, halo, or oxo. In yet another embodiment, R1 is CH3, F, or oxo. In another embodiment, R2 is Cl-C6 alkyl, Cl-C6 alkoxy, fluoro-Cl- C6 alkyl, halo, CN, or (Cl-C8)-R8 wherein up to two CH2 units may be replaced with O, CO, CFz, or NR7. More specifically, R2 is CH3, OCHg, CF3, F, Cl, Br, CN, OCHzCHzOtBu, OCH2CH(CH3)2. In a further embodiment, R3 is Cl-C6 alkyl. In 2/0 2’0 further embodiment, R3 is CH3. In some ments, ring A is 3&0), :Loj 2:? 24 é—I iii/OK)??? 21 1’0 D ,SS\/O, g—O, ”\O $5\/O,or JJLO D. Insome ; ;,F F F CI F embodiments, ringBis ~N‘ ~N‘ N JV‘ JV‘ JV‘ , , , , , , CN F N ,or JV‘ In some embodiments, ring C is a pyridyl, lopiperidine, or one ring. In a further embodiment, ring C is selected from: 2014/045675 N N \ \N / NI / /O \ / O\|\ 0 O O\|\ 0&3 F— OIMWJ N /o ol , F, N/O FNN-\/ N- \/ oi N\oN.\/ O JV‘ JV‘ IN N / \N I \ O N\ 0' N/ \ l/ /O / N o o' ('3 F30 NH O O F F 9 9 OH9 9 9 JV" N \ N\ IN N IN I / \ / N o /? \ O 0' 'N |\ O O é N|\ /(|) /N FF / F F9 O\9FF 00 or 9 9 9 9 and CF3.

In another embodiment, the invention features compounds of formula I wherein ring A is a fused heterocycloalkyl ring, ring B is a heteroaryl ring and ring C is a tuted or unsubstituted aryl; R1 is C1-C6 alkyl, Cl-C6 alkoxy, halo, fluoro- Cl-C6 alkyl, fluoro-Cl-C6 alkoxy, or oxo; R2 is Cl-C6 alkyl, Cl-C6 alkoxy, halo, CN, fluoro-Cl-C6 alkyl, fluoro-Cl-C6 , N(R7)2, NR7SOZR7, SOZR7, C02R7, SOZN(R7)2, or (Cl-C8)-R8 n up to two CH2 units may be replaced with O, CO, CF2, or NR7; R3 is Cl-C6 alkyl, Cl-C6 alkoxy, halo, CN, fluoro-Cl-C6 alkyl, or fluoro-Cl-C6 alkoxy; n, o, and p are integers from 0 to 4 inclusive; R7 is H, Cl-C6 alkyl, CHFZ, CF3, or C3-C8 cycloalkyl; and R8 is H, CF3, C02R7, OH, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R7)2, NR7COR7, CON(R7)2, CN, or SOZR7. In r embodiment, R1 is Cl-C6 alkyl, halo, or oxo. In yet another embodiment, R1 is CH3, F, or oxo. In another embodiment, R2 is Cl-C6 alkyl, Cl-C6 alkoxy, fluoro- Cl-C6 alkyl, halo, CN, or (Cl-C8)-R8 wherein up to two CH2 units may be replaced with o, co, CFz, or NR7. More specifically, R2 is CH3, OCH3, c123, F, Cl, Br, CN, OCHZCHzOtBu, OCH2CH(CH3)2. In a further embodiment, R3 is C1-C6 alkyl. In further embodiment, R3 is CH3. In some embodiments, ring A is‘br gm»)’0 é—o 24o §_| “2,70O><, 55\), $530,0r “\O2,0 2 1/0 D §—| D. Inone embodiment, ring B is a pyridyl, thiazole, pyrimidine, pyrazole, furan, thiophene, pyrrole, oxazole, imidazole, isoxazole, isothiazole, zine, or ne ring. In |\ H h |\ |\ CF3 /N NTS NTN \O /N /N another embodiment, ring B is N JV‘ N JV‘ JV‘ , , , , , | | Br 0 0 CI CF \ \ \ \ \ 3 | I S"\\ | | I 7F 3 \ /N N/C|\N /N /N N/ N/ N/ JV‘ J'V‘ N N m JV" , , N, , , , JU‘, + A\ I '\ N\I OI\ N / O\LI\I\O/N /N N\ N / F O JV" JV‘ JV‘ N , , , N,0r

[0059] In one embodiment, ring C is R4 R4 R5 R5 wherein R4 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, or OH; R5 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, 0R7, N(R7)2, NR7SOZR7, soaR7, C02R7, SOZN(R7)2, Cl-C6 alkyl, or fluoro-Cl-C6 alkoxy; R6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, 0R7, N(R7)2, NR7SOZR7, SR7, SOR7, soaR7, C02R7, NR7COR7,NR7C02R7, CON(R7)2, SOZN(R7)2, C133, OCFg, OCHFZ, heterocycloalkyl, aryl, heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R8 or fluoro-(Cl- 2014/045675 C8)-R8 wherein up to three CH2 units may be replaced with O, CO, S, SO, SO2, or NR7.

In a further embodiment, two ences of R4 and R5, or R5 and R6 together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 heteroatoms.

In a further embodiment, R4 is H, Cl-C6 alkoxy, or halo. R4 may also be H, OCH3, or F. In one embodiment, R5 is H, Cl-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, or fluoro-Cl-C6 alkyl. In r embodiment, R5 is H, CH3, OCH3, F, Cl, CN, OH, or CF3. In certain embodiments, R6 is H, Cl-C6 alkoxy, fluoro-Cl-C6 alkoxy, lO SO2R7, SO2N(R7)2, or a straight chain, branched, or cyclic (Cl-C8)—R8 or fluoro-(Cl- C8)—R8 wherein up to three CH2 units may be replaced with O, CO, S, SO, SO2, or NR7. In some ments, R6 is H, OCH2CH2CF3, OCH2CF(CH3)2, C(CH3)2CH2OH, OCH2CH2CH(CH3)2, OCH(CH3)CF3, CH2OCH2CH2CF3, C(CH3)2OH, OCH2CH2OtBu, CH2C(CH3)2OH, OCH(CH3)2, OCH2C(CH3)2OH, OCH2CF2CHF2, OCH2CF3, OCH2CH2OCF3, OCH(CH3)CF2CHF2, SO2CHF2, OCH2CF2CH3, OCH2CH2OCH2CF3, OCH2CF3, CH3)3, OCH2CH(CH3)CH2CF3, SO2CH2CH3, OCH(CH3)CH2CF3, OCH2CF2CHF2, E—owfi é—OfiFg—OW: bows a—om, Hot: é—m, e—l<><:, %- W3: || 3-0 H; _0‘9 F a HE, MHz—w F . In one ment, R4 and R5 together with the carbons to which they are attached may also form an optionally substituted ring comprising up to 2 heteroatoms.

In r embodiment, ring C is In filrther embodiments, R5 and R6 together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 atoms. 05/0 In one embodiment, ring C is CFs

[0064] In one embodiment, the compound has formula IA: or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence, ring B is an aryl or heteroaryl ring; R2 is Cl-C6 alkyl, Cl-C6 , halo, CN, fluoro-Cl-C6 alkyl, fluoro-Cl-C6 alkoxy, N(R7)2, NR7SOZR7, SOZR7, C02R7, SOZN(R7)2, or )—R8 wherein up to two CH2 units may be replaced with O, CO, CFz, or NR7; o is an integer from 0 to 4 inclusive; R5 is H, C1-C6 alkyl, C1- C6 alkoxy, halo, CN, OH, 0R7, N(R7)2, NR7soaR7, soaR7, C02R7, 7)2, fluoro-Cl-C6 alkyl, or fluoro-Cl-C6 alkoxy; R6 is H, Cl-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, 0R7, N(R7)2, NR7soaR7, SR7, SOR7, soaR7, C02R7, NR7COR7,NR7C02R7, CON(R7)2, SOZN(R7)2, CF3, OCFg, OCHFZ, heterocycloalkyl, aryl, heteroaryl, or a straight chain, branched, or cyclic (Cl-C8)-R8 or fluoro-(Cl- C8)-R8 wherein up to three CH2 units may be replaced with O, CO, S, SO, S02, or NR7; R7 is H, C1-C6 alkyl, CHFZ, CF3, or C3-C8 cycloalkyl; and R8 is H, CF3, COZR7, OH, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R7)2, NR7COR7, CON(R7)2, CN, or SOZR7.

In some embodiments, ring B is an aryl ring. In one embodiment, R2 is Cl-C6 alkyl, Cl-C6 , fluoro-Cl-C6 alkyl, halo, CN, or (Cl-C8)-R8 wherein up to two CH2 units may be replaced with O, CO, CF2, or NR7. In another embodiment, R2 is CH3, OCH3, CF3, F, Cl, Br, CN, OCHZCHZOtBu, OCHZCH(CH3)2. In a further ment, ring B is a phenyl ring.

F F F In certain embodiments, ringBis ~N‘ JV‘ N JV‘ , , , , CI F CN F F F JV‘ J'V‘ JV‘ or N 9 9 , In certain embodiments, R5 is H, Cl-C6 alkyl, Cl-C6 alkoxy, halo, CN, OH, or fluoro-Cl-C6 alkyl. In others, R5 is H, CH3, OCH3, F, Cl, CN, OH, or CF3.

Yet in others, R6 is H, Cl-C6 , fluoro-Cl-C6 alkoxy, SOzR7, 7)2, or a straight chain, branched, or cyclic (Cl-C8)-R8 or fluoro-(Cl-C8)-R8 wherein up to three CH2 units may be replaced with O, CO, S, SO, S02, or NR7. R6 may also be H, OCHZCHZCFg, OCH2CF(CH3)2, C(CH3)2CHZOH, OCHZCHZCH(CH3)2, OCH(CH3)CF3, CH20CH2CH2CF3, C(CH3)ZOH, OCHzCHzOtBu, CH2C(CH3)ZOH, 3)2, OCH2C(CH3)ZOH, ZCHFZ, OCH2CF3, OCHZCHZOCFg, OCH(CH3)CF2CHF2, SOZCHFZ, OCH2CF2CH3, 20CH2CF3, OCH2CF3, OCH2C(CH3)3, OCHZCH(CH3)CH2CF3, 802CH2CH3, OCH(CH3)CH2CF3, é—o F EV §—ow F D F, C OCHZCFZCHFZ, F F , 9 a —O § —|S(?-N H é—o é—o g F H >r<I O b F EL F F _OW:| , , F, §_O\_d—F M’F or F In one embodiment, R6 of compound of a IA is selected from: WO 06280 F, and ‘F In some embodiments, ring B is a heteroaryl ring. In one embodiment, R2 is C1-C6 alkyl, C1-C6 alkoxy, fluoro-CI-C6 alkyl, halo, CN, or (C1-C8)-R8 wherein up to two CH2 units may be replaced with O, CO, CF2, or NR7. In another ment, R2 is CH3, OCHg, CF3, F, Cl, Br, CN, OCHZCHzOtBu, OCHZCH(CH3)2.

In a further embodiment, ring B is a pyridyl, thiazole, pyrimidine, pyrazole, filran, thiophene, e, oxazole, imidazole, isoxazole, isothiazole, pyridazine, or pyrazine \ __\ h\ \ I F I /N NTS NTN \o /N ring. In some embodiments, ringB is N JV‘ JV‘ JV‘ , , , , /N /N N / \ N /N /N N / JV‘ N JV‘ JV‘ JV‘ JV‘ JV‘ , , , , , , , + k I F S |\ |\ O O NW)”N / N / 01 |\ |\ .N\ |\ /N /N N\ N / F o N JV‘ JV‘ N,or N.

In certain embodiments, R5 is H, C1-C6 alkyl, Cl-C6 alkoxy, halo, CN, OH, or fluoro-Cl-C6 alkyl. In others, R5 is H, CH3, OCH3, F, Cl, CN, OH, or CF3. Yet in others, R6 is H, Cl-C6 alkoxy, fluoro-Cl-C6 alkoxy, SOZR7, SOZN(R7)2, or a straight chain, branched, or cyclic (Cl-C8)—R8 or fluoro-(Cl-C8)—R8 wherein up to three CH2 units may be replaced with O, CO, S, SO, 802, or NR7. R6 may also be H, OCH2CH2CF3, OCH2CF(CH3)2, C(CH3)2CHzOH, OCHZCHZCH(CH3)2, OCH(CH3)CF3, CH20CH2CH2CF3, C(CH3)ZOH, OCHzCHzOtBu, CH2C(CH3)ZOH, lO OCH(CH3)2, OCH2C(CH3)ZOH, ZCHFZ, 3, OCHZCHZOCFg, OCH(CH3)CF2CHF2, Z, OCHZCFZCHg, OCHZCHZOCHZCFg, OCH2CF3, OCH2C(CH3)3, OCH2CH(CH3)CH2CF3, SOZCHZCHg, OCH(CH3)CH2CF3, é—o Era—Os OCHZCFZCHFZ, fixh F F , , , é—o CF3 who:rig—03340; F F 9 9 9 9 F9 In n embodiments, the compound has formula IE: or a pharmaceutically acceptable salt thereof, n, ndently for each occurrence, R2 is C1-C6 alkyl, Cl-C6 alkoxy, halo, CN, fluoro-Cl-C6 alkyl, fluoro- C1-C6 alkoxy, N(R7)2, NR7SOZR7, SOZR7, C02R7, SOZN(R7)2, or (Cl—C8)—R8 wherein up to two CH2 units may be replaced with O, CO, CF2, or NR7; o is an integer from 0 to 4 inclusive; R5 is H, Cl-C6 alkyl, Cl-C6 alkoxy, halo, CN, OH, 0R7, N(R7)2, NR7SOZR7, SOZR7, C02R7, SOZN(R7)2, fluoro-Cl-C6 alkyl, or fluoro-Cl-C6 alkoxy; R6 is H, C1-C6 alkyl, c3—cs cycloalkyl, C1-C6 alkoxy, halo, CN, OH, 0R7, N(R7)2, NR7SOZR7, SR7, SOR7, SOZR7, C02R7, NR7COR7,NR7C02R7, CON(R7)2, SOZN(R7)2, CF3, OCF3, OCHFz, heterocycloalkyl, aryl, heteroaryl, or a straight chain, branched, or cyclic (Cl-C8)—R8 or fluoro-(Cl-C8)-R8 wherein up to three CH2 units may be ed with O, CO, S, SO, SOZ, or NR7; R7 is H, Cl-C6 alkyl, CHFZ, CF3, or C3-C8 cycloalkyl and R8 is H, CFg, C02R7, OH, aryl, heteroaryl, c3-cs cycloalkyl, heterocycloalkyl, , 7, CON(R7)2, CN, or SOZR7. In further embodiments, R2 is Cl-C6 alkyl, Cl-C6 alkoxy, fluoro-Cl-C6 alkyl, halo, CN, or (Cl-C8)-R8 wherein up to two CH2 units may be replaced with O, CO, CF2, or NR7.

Alternatively, R2 is CH3, OCH3, CFg, F, Cl, Br, CN, OCHZCHZOtBu, OCH2CH(CH3)2. R2 may also be F, C1, or CN. In some embodiments, o is 0, l or 2.

In others, R5 is H, Cl-C6 alkyl, Cl-C6 alkoxy, halo, CN, OH, or Cl-C6 alkyl.

In some ments, R5 is H, CH3, OCH3, F, Cl, CN, OH, or CF3. In certain embodiments, R6 is H, C1-C6 alkoxy, fluoro-Cl-C6 alkoxy, SOZR7, SOZN(R7)2, or a straight chain, branched, or cyclic (Cl-C8)-R8 or fluoro-(Cl-C8)-R8 wherein up to three CH2 units may be replaced with O, CO, S, SO, 802, or NR7. In others, R6 is H, OCHZCHZCFg, OCHZCF(CH3)2, C(CH3)2CH20H, OCHZCHZCH(CH3)2, OCH(CH3)CF3, CHZOCHZCHZCFg, C(CH3)20H, zOtBu, CH2C(CH3)20H, 3)2, CH3)20H, OCHZCFZCHFZ, OCH2CF3, OCHZCHZOCFg, OCH(CH3)CF2CHF2, SOZCHFZ, OCHZCFZCHg, OCHZCHZOCHZCFg, OCH2CF3, OCH2C(CH3)3, OCHZCH(CH3)CH2CF3, SOZCHZCHg, OCH(CH3)CH2CF3, é—o F é—o F OCHZCFZCHFZ, ELF, fig; , WP, é—o CF3 , e—o<><:, Hot: ““9, a—Mx: é-o : 2%,]; “M “W: ml, m “PW E In some embodiments, R6 is selected from: WO 06280 2 § 0/e2 :0; F OH 9 9 9 9 9 9 JV‘ N N JV‘ \ Lb CI CFs O \ \ o o o o O 0 F F $ F F , , 9 a F’ and In some embodiments, the nd has formula IC: 2014/045675 O N 0> or a pharmaceutically able salt thereof, wherein, independently for each occurrence, R2 is C1-C6 alkyl, Cl-C6 alkoxy, halo, CN, fluoro-Cl-C6 alkyl, fluoro- C1-C6 alkoxy, N(R7)2, NR7SOZR7, SOZR7, C02R7, SOZN(R7)2, or (C1-C8)-R8 wherein up to two CH2 units may be replaced with O, CO, CF2, or NR7; o is an integer from 0 to 4 inclusive; R5 is H, Cl-C6 alkyl, Cl-C6 alkoxy, halo, CN, OH, 0R7, N(R7)2, R7, SOZR7, C02R7, SOZN(R7)2, fluoro-Cl-C6 alkyl, or fluoro-Cl-C6 alkoxy; R6 is H, C1-C6 alkyl, c3—cs cycloalkyl, C1-C6 alkoxy, halo, CN, OH, 0R7, N(R7)2, NR7SOZR7, SR7, SOR7, SOZR7, C02R7, 7,NR7C02R7, CON(R7)2, SOZN(R7)2, CF3, OCF3, OCHFz, heterocycloalkyl, aryl, heteroaryl, or a ht chain, branched, or cyclic (Cl-C8)-R8 or fluoro-(Cl-C8)-R8 wherein up to three CH2 units may be replaced with O, CO, S, SO, SOZ, or NR7; R7 is H, Cl-C6 alkyl, CHFZ, CF3, or C3-C8 cycloalkyl; and R8 is H, CF3, COZR7, OH, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R7)2, NR7COR7, CON(R7)2, CN, or SOZR7.

In some embodiments, R2 is Cl-C6 alkyl, Cl-C6 alkoxy, fluoro-Cl-C6 alkyl, halo, CN, or (Cl-C8)-R8 wherein up to two CH2 units may be replaced with O, C0, C12, or NR7. In others, R2 is CH3, OCHg, C133, F, Cl, Br, CN, OCHZCHzOtBu, OCH2CH(CH3)2. In some embodiments, o is 0, l, or 2. In further ments, R5 is H, Cl-C6 alkyl, Cl-C6 alkoxy, halo, CN, OH, or fluoro-Cl-C6 alkyl. Alternatively, R5 is H, CH3, OCHg, F, Cl, CN, OH, or CF3. In some further ments, R6 is H, Cl- C6 alkoxy, fluoro-Cl-C6 alkoxy, SOZR7, SOZN(R7)2, or a straight chain, branched, or cyclic (Cl-C8)-R8 or fluoro-(Cl-C8)-R8 wherein up to three CH2 units may be 2014/045675 replaced with O, CO, S, SO, 802, or NR7. In others, R6 is H, OCHZCHZCFg, (CH3)2, C(CH3)2CH20H, OCHZCHZCH(CH3)2, OCH(CH3)CF3, CHZOCHZCHZCFg, C(CH3)20H, OCHZCHzOtBu, CH2C(CH3)20H, OCH(CH3)2, OCH2C(CH3)20H, OCHZCFZCHFZ, OCH2CF3, OCHZCHZOCFg, OCH(CH3)CF2CHF2, SOZCHFZ, OCHZCFZCHg, OCHZCHZOCHZCFg, 3, OCH2C(CH3)3, OCHZCH(CH3)CH2CF3, SOZCHZCHg, OCH(CH3)CH2CF3, OCHZCFZCHFZ, F In one embodiment, R6 is selected from: WO 06280 WO 06280 ”fie/J WO 06280 \O:\ JV‘ JV‘ :CF3\ F ,Oofé OOLVFLF and F‘FF In one embodiment, the compound is selected from Table 1: Table 1. 2014/045675 I.._x p”!«LVN...

Ln ml. an} nun ma. n....U ... I. ailfl ..1.0%:3 1..”__n15. n.9 nINn RP: GT n vxxlxlnu G a\nnnlnm .Tn. DI .faf FR.. an n.“ .lx. .nlnn .3.g 1.}: .J.A L an \.l H % N .n, an.V an.9 fin,n.

I ]|. manln. 1xnu flflNJ.7...- nun 0 film“ i. _ v..Hany” o GI WO 06280 WO 06280 WO 06280 WO 06280 WO 06280 WO 06280 WO 06280 WO 06280 133--a it}? 12%? m7I WO 06280 .1; «I 2 1 “M HS 1 «“G WO 06280 $24 1.E "$353 WO 06280 WO 06280 1i!“ 15% WO 06280 WO 06280 HE 1 7E! WO 06280 MEE- WO 06280 WO 06280 WO 06280 WO 06280 WO 06280 32$ 12 342 WO 06280 2014/045675 -513 EEG ‘1‘ «A;u... 2014/045675 4“...» \Ifi N(JILbaa 28:3 WO 06280 WO 06280 In another ment, the compound may exist as a racemic mixture of enantiomers according to Table 2: Table 2.

WO 06280 .3—\ WO 06280 WO 06280 WO 06280 3mm 333 , s, 9.36 Djflwlfij,N x,” WO 06280 37mnun WO 06280 WO 06280 WO 06280 .4 4.: 4 415 .3. .52 E WO 06280 WO 06280 WO 06280 WO 06280 %3‘2 4.. an.3 m 453 45E 4m WO 06280 WO 06280 WO 06280 WO 06280 512? WO 06280 LIFNA.»wI/qiaagax,,.,.l"...

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I”. \P. .1127?w. 0I , WO 06280 WO 06280 WO 06280 QC»? WO 06280 WO 06280 512 $13 WO 06280 In another aspect, the invention features a ceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.

In another aspect, the invention features a method of inhibiting a voltage-gated sodium ion l in: a patient; or a ical sample; comprising administering to the patient, or contacting the biological sample, with a compound or composition of the invention. In another embodiment, the voltage-gated sodium ion channel is NaV 1.7.

In another aspect, the invention features a method of treating or lessening the severity of the pain in a subject ed with acute, chronic, neuropathic, or inflammatory pain, arthritis, ne, cluster headaches, trigeminal neuralgia, herpatic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative ers, psychiatric disorders, anxiety, depression, dipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, le sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, hrough pain, postsurgical pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress- or se induced , palpitations, hypertension, migraine, or abormal gastro-intestinal motility, comprising administering an effective amount of a compound or composition of the invention.

In another embodiment, the method is used for treating or lessening the severity of the pain in a subject afflicted with femur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; neuropathic low back pain; myofascial pain syndrome; yalgia; temporomandibular joint pain; chronic Visceral pain, abdominal pain; pancreatic; IBS pain; c and acute he pain; migraine; tension he, including, cluster hes; chronic and acute neuropathic pain, post-herpatic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy d neuropathic pain; radiotherapy-induced athic pain; post-mastectomy pain; l pain; spinal cord injury pain; troke pain; thalamic pain; complex al 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/exercise pain; acute Visceral pain, abdominal pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelVic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory, burn and trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain including sinusitis pain, dental pain; le sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's e pain; bladder and urogenital disease, including, y incontinence; hyperactivity bladder; painfill bladder syndrome; interstitial cyctitis (IC); prostatitis; complex regional pain me (CRPS), type I and type II; widespread pain, paroxysmal extreme pain, pruritis, tinnitis, or angina- induced pain.

The compounds of the invention may be prepared readily using the following methods. Illustrated below in Scheme 1 through Scheme 15 are methods for preparing the compounds of the invention.

Scheme 1 flkokO O O a.) b.) H011". NJLOJ< 0‘8 Ar x HO Arflkok X = Halide, Y = H, D a.) N32C03 (2M), Pd(dppf)C12, DMF; b.) AD-miX-B, methanesulfonarnide, t- BuOH, H20; 0.) BrzCHz or Br2(CD2), NaH, DMF; d.) TFA, DCM.

Scheme 2 ' ©fifi© LQQWQ C.) H a.) BnBr, DIPEA, DCM; b.) diethylzinc, TFA, CHZIZ, DCM; c.) l-chloroethyl chloroformate, DCM, 2.) MeOH (40 CC).

Scheme 3 o o 0 JLoJ< NJLOJ< fl. NJJ\oJ< i. NJ\OJ< 0&0 a. ) HO HO 0% O O OH OTBS OTBS d.) NiOJ< JOL J< f.) N 0 g) _, _, Ar Ar HO HO HO OTBS OMS NJLAr AHo HO O HOkAr X=halide a.) NaBH4, K2C03, MeOH (0 CC); b.) TBSCI, DIPEA, DCM; c.) DMP, sodium onate, DCM; d.) Ar-Mg-X, THF (-78 CC - 25 CC); 6.) tetra-n- butylarnmoniurn fluoride, THF; f.) MsCl, triethylarnine; g) HCl, DCM h.) HATU, triethylamine, DMF; i.) NaH, THF.

Scheme 4 a.) 2-tert-butoxyethanol, NaH, DMF (80 CC).

Scheme 5 ,CbZ N b.) m,CbZ C.) —> —> O —> O 0 HOwX-Jbz CI Cbz d.) m,N e_) CI f_) a% ~N,CbZ o g o L Q 0 O O Cbz = carboxybenzyl a.) -en-l-ol, Xantphos, [C3H5PdCl]2, pyrrolidine-Z-carboxylic acid, DMSO; b.) 4-methylbenzenesulfonic acid, ethylene glycol, PhCHg; c.) l. 03, DCM 2.) NaBH4, MeOH; d.) thionyl chloride, DMF, pyridine, CHC13; e.) l M HCl (aq), EtOH; f.) butyllithium, 2-br0mopyridine, THF (-78 °C - 25 CC) g.) H2 (1 atm), Pd/C, MeOH.

Scheme 6 a.) Pd(PPh3)4, trimethylalumane, THF; b.) TFA, DCM.

WO 06280 Scheme 7 a.) R—OH (R: C1-C6 alkyl or fluoroalkyl), NaH, DMF b.) TFA, DCM.

Scheme 8 i J< N/lkO/l<O / N a) N O b.) c) I ’ —’ o —> Br N O \ I O / \N OH 0 /[< HO NJLO/k d.) N o e.) NH / \N \N \N ‘ I / / N Ar f) O a.) 1) H2 (55 psi), PtOz, HCl, H20 2.) B0020, triethylamine, DCM/MeOH b.) Pd[P(tBu)3]2, LHMDS, toluene; c.) NaBH4, toluene/THF; d.) PPhg, DEAD, THF; 6.) HCl, DCM; f.) ArCOOH, HATU, triethylamine, DMF.

Scheme 9 a.) tetra-butyl-ammonium-HS04, NaOH, C12(CH2)2.

Scheme 10 a.) TFA, DCM; b.) HATU, triethylarnine; c.) H2 (1 atm), Pd/C, iPrOH; d.) oxypropane, [(1R,4S)—7,7-dirnethy1—2-0X0-n0rb0rnan-1 - yl]rnethanesulfonic acid.

Scheme 11 \I C|)TBS \x a.) b.) C) —> —> —> O , Ar A. Ar \\ Ar .,,l/C| \N ’\\\ OTBS OTBS OTBS OTBS \\ —)> \\“ i» \ g ) \ NHZ OH OMS / A Ar Ar A —»“-’ SO —»” “>0 Ar A a.) NaNHz, THF (-78 - 25 CC); b.) TBS-C1, imidazole, DCM; c.) DiBAl-H, DCM (-78 - 25 CC); (1.) NaBH4, MeOH (-10 - 25 CC); 6.) MsCl, DIEA, DCM; WO 06280 f.) NaCN, DMSO; g.) BHg-THF, THF; h.) tetra-n-butylarnmonium fluoride, THF; i.) SOCIZ, DCE.

Scheme 12 micki. :flfiok a.) trimethyl-(trifluorornethyl)silane, NaI, THF (65 CC).

Scheme 13 a.) 1.) NBS, dioxane, 2.) NaOH; b.) NaCN, DMSO (90 0C); c.) BnBr, NaH, DMF; d.) KOH, EtOH; e.) Mel, NaH, DMF; f.) LAH, THF (reflux, 1 min); g.) MsCl, ylamine, DCM; h.) ammonia; formic acid, Pd/C, MeOH (78 CC); i.) DBU, toluene.

Scheme 14 a.) 3-chlorofluoro-benzoic acid, HATU, triethylamine, DMF; b.) 2-tert- butoxyethanol, NaH, DMF.

Scheme 15 R3 JL R3 R2>C HO R4 R2>CN 0 NH Q R1 R1 a.) HATU, triethylamine, DMF.

Uses Formulation and Administration Pharmaceutically acceptable compositions

[0098] As discussed above, the invention provides compounds that are inhibitors of voltage-gated sodium ion channels, and thus the present compounds are useful for the treatment of diseases, disorders, and conditions including, but not limited to acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, atric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, and inence. Accordingly, in another aspect of the invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and ally comprise a ceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these itions optionally further comprise one or more onal therapeutic agents.

It will also be appreciated that n of the compounds of invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically able salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a subject in need is capable of providing, directly or indirectly, a compound as otherwise described , or a metabolite or residue thereof.

[00100] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the s of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are surate with a reasonable /risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is e of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. As used herein, the term “inhibitorily active metabolite or residue thereof’ means that a metabolite or residue thereof is also an inhibitor of a voltage-gated sodium ion 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, l-l9, incorporated herein by reference. ceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion ge. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, te, bisulfate, borate, butyrate, rate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, lfate, heptanoate, hexanoate, hydroiodide, oxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2—naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, ate, picrate, pivalate, propionate, te, succinate, e, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts d from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1_4alkyl)4 salts. This invention also enVisions the quatemization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or sable products may be obtained by such quatemization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as , hydroxide, ylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of the invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, sion or suspension aids, surface active agents, isotonic agents, ning 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) ses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the ation thereof Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable ical effect or otherwise interacting in a rious 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 e, but are not limited to, ion exchangers, a, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated ble fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium de, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl idone, polyacrylates, waxes, hylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl ose, 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 ene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; c acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and ing agents, preservatives and antioxidants can also be present in the composition, according to the nt of the formulator.

Uses ofCompounds and Pharmaceutically Acceptable Compositions In yet another aspect, a method for the treatment or lessening the severity of acute, chronic, neuropathic, or inflammatory pain, tis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, atric disorders such as anxiety and depression, dipolar disorder, myotonia, hmia, nt disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain is provided comprising administering an effective amount of a compound, or a pharmaceutically acceptable composition comprising a compound to a subject in need thereof.

In certain embodiments, a method of treatment or lessening the severity of , cerebral ia, traumatic brain injury, amyotrophic l sclerosis, stress- or exercise induced angina, palpitations, ension, migraine, or abormal gastro-intestinal motility is provided comprising administering an effective amount of a compound, or a pharmaceutically acceptable composition comprising a compound to a subject in need thereof In certain embodiments, a method for the treatment or lessening the severity of acute, chronic, neuropathic, or inflammatory pain is ed comprising stering an effective amount of a nd or a ceutically able composition to a subject in need thereof. In certain other embodiments, a method for the treatment or lessening the severity of radicular pain, sciatica, back pain, head pain, or neck pain is provided comprising administering an effective amount of a compound or a pharmaceutically acceptable composition to a subject in need thereof.

In still other embodiments, a method for the treatment or lessening the severity of severe or intractable pain, acute pain, postsurgical pain, back pain, tinnitis or cancer pain is provided comprising stering an effective amount of a compound or a ceutically acceptable ition to a t in need thereof.

In certain embodiments, a method for the treatment or lessening the severity of femur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; neuropathic low back pain; myofascial pain syndrome; f1bromyalgia; temporomandibular joint pain; chronic visceral pain, including, abdominal; pancreatic; IBS pain; chronic and acute headache pain; migraine; tension headache, including, cluster headaches; chronic and acute neuropathic pain, including, post-herpetic neuralgia; diabetic neuropathy; HIV- associated neuropathy; trigeminal neuralgia; Charcot-Marie Tooth neuropathy; hereditary y neuropathies; peripheral nerve injury; painful neuromas; c proximal and distal discharges; radiculopathy; chemotherapy induced neuropathic pain; herapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome; m pain; intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury/exercise pain; acute al pain, including, abdominal pain; pyelonephritis; appendicitis; ystitis; intestinal obstruction; hernias; etc; chest pain, including, cardiac Pain; pelvic pain, renal colic pain, acute obstetric pain, including, labor pain; cesarean n pain; acute inflammatory, burn and trauma pain; acute ittent pain, including, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain including sinusitis pain, dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; ’s disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry’s disease pain; bladder and urogenital disease, including, urinary incontinence; hyperactivity bladder; painful r me; interstitial cyctitis (IC); or prostatitis; complex regional pain syndrome (CRPS), type I and type II; angina-induced pain is provided, comprising administering an ive amount of a compound or a pharmaceutically acceptable composition to a subject in need thereof.

[00107] In certain embodiments of the invention an “effective amount” of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the ty of one or more of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, ic neuralgia, general neuralgias, sy or epilepsy conditions, egenerative disorders, psychiatric ers such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, ble bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, tinnitis or cancer pain.

The compounds and compositions, according to the method of the invention, may be administered using any amount and any route of administration effective for treating or ing the severity of one or more of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and sion, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sis, irritable bowel syndrome, incontinence, visceral pain, rthritis pain, postherpetic gia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, is or cancer pain. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.

The nds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the invention will be decided by the attending physician within the scope of sound medical nt. The specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the er; the activity of the c compound employed; the specific composition employed; the age, body weight, general , sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in ation or dental with the specific compound 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 itions of this ion can be administered to humans and other animals orally, ly, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, ing on the severity of the infection being treated. In certain embodiments, the nds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, 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, l,3-butylene , 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, ning, flavoring, and perfilming agents.

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

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

In order to prolong the effect of a compound of the ion, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid sion of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by g microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the nd in liposomes or microemulsions that are compatible with body tissues. [001 14] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or rs such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or l cavity and e the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically able excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, e, sucrose, glucose, ol, 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, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution ing agents such as paraffin, f) absorption accelerators such as nary ammonium compounds, g) wetting agents such as, for example, cetyl l and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[00116] 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 c 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 e 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 itions 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 lar weight polethylene glycols and the like.

The active compounds 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 c gs, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, e or starch. Such dosage forms may also comprise, as is normal practice, onal substances other than inert diluents, e.g., tableting ants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a ition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, ally, 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 of this invention include ointments, pastes, creams, lotions, gels, powders, ons, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also plated as being within the scope of this invention. Additionally, the invention contemplates the use of transdermal patches, which have the added advantage of providing lled delivery of a nd to the body. Such dosage forms are ed 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 lled 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 e-gated sodium ion channels. In one embodiment, the compounds and itions of the invention are inhibitors of one or more ofNaVl . l, NaVl.2, NaVl.3, NaVl.4, NaVl.5, , NaVl.7, NaVl.8, or NaVl.9, and thus, without wishing to be bound by any particular theory, the nds and compositions are ularly useful for treating or lessening the severity of a disease, condition, or disorder where tion or hyperactivity of one or more ofNaVl . l , NaVl.2, NaVl.3, NaVl.4, NaVl.5, NaVl.6, NaVl.7, NaVl.8, or NaVl.9 is implicated in the disease, condition, or disorder. When activation or hyperactivity of NaVl.l, NaVl.2, NaVl.3, NaVl.4, NaVl.5, NaVl.6, NaVl.7, NaVl.8, or NaVl.9 is implicated in a particular disease, condition, or disorder, the e, condition, or disorder may also be referred to as a “NaVl.l, NaVl.2, NaVl.3, , NaVl.5, NaVl .6, NaVl .7, NaVl .8 or NaVl .9-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 one or more ofNaVl.l, NaVl .2, NaVl .3, NaVl .4, NaVl .5, NaVl .6, NaVl .7, NaVl .8, or NaVl .9 is implicated in the disease state.

] The activity of a compound utilized in this invention as an inhibitor .l, NaV1.2, NaVl.3, NaVl.4, NaVl.5, NaVl.6, NaVl.7, NaVl.8, or NaVl .9 may be assayed according to methods described generally in the Examples , or according to methods available to one of ordinary skill in the art.

In n exemplary embodiments, compounds of the invention are useful as inhibitors ofNaVl .7 and/or NaVl .8.

It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the invention can be employed in combination therapies, that is, the compounds and ceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired eutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive nd may be administered concurrently with r agent used to treat the same disorder), or they may achieve ent effects (e.g., control of any adverse s). 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 onal therapeutic agents include, but are not limited to: nonopioid analgesics (indoles such as Etodolac, thacin, Sulindac, in; naphthylalkanones such sa Nabumetone; oxicams such as Piroxicam; para-aminophenol derivatives, such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylates such as Asprin, Choline magnesium trisalicylate, Diflunisal; fenamates such as meclofenamic acid, Mefenamic acid; and pyrazoles such as Phenylbutazone); or opioid (narcotic) agonists (such as Codeine, Fentanyl, orphone, hanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, orphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesic approaches may be utilized in conjunction with administration of one or more compounds of the invention. For example, anesthesiologic (intraspinal infilsion, neural blocade), neurosurgical (neurolysis of CNS pathways), timulatory cutaneous electrical nerve stimulation, dorsal column stimulation), physiatric (physical therapy, orthotic devices, rmy), or psychologic (cognitive methods-hypnosis, biofeedback, or behavioral methods) approaches may also be utilized. Additional appropriate eutic agents or approaches are described generally in The Merck Manual, Seventeenth Edition, Ed.

Mark H. Beers and Robert Berkow, Merck Research Laboratories, 1999, and the Food and Drug Administration website, 3§3'_w_}§f_._'§,_‘§iagoy, the entire contents of which are hereby incorporated by reference.

In another embodiment, onal appropriate therapeutic agents are selected from the following: (1) an opioid sic, e. g. morphine, heroin, orphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, odone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine; ] (2) a nonsteroidal antiinflammatory drug (NSAID), e. g. aspirin, diclofenac, diflusinal, etodolac, en, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac; (3) a barbiturate sedative, e. g. bital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal or thiopental; (4) a benzodiazepine having a sedative action, e. g. chlordiazepoxide, clorazepate, diazepam, flurazepam, pam, oxazepam, temazepam or triazolam; (5) a histamine antagonist of the H1 receptor having a sedative action, e. g. hydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;

[00129] (6) a ve such as glutethimide, meprobamate, methaqualone or ralphenazone; (7) a skeletal muscle relaxant, e. g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine; (8) an NMDA receptor antagonist, e. g. dextromethorphan ((+)- 3-hydroxy-N— morphinan) or its lite dextrorphan ((+)—3-hydroxy-N— methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis (phosphonomethyl) dinecarboxylic acid, budipine, EN—323l (MorphiDex(R), a ation formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B nist, e. g. ifenprodil, rodil or (-)-(R) {2-[4-(3-fluorophenyl)hydroxy-l- piperidinyl]-l-hydroxyethyl-3,4- dihydro-2(lH)-quinolinone; (9) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil, or 4-amino-6,7-dimethoxy(5-methane- sulfonamido-l, 2,3,4- tetrahydroisoquinolyl)(2-pyridyl) quinazoline;

[00133] (10) a tricyclic antidepressant, e. g. desipramine, imipramine, amitriptyline or nortriptyline; (ll) an anticonvulsant, e.g. carbamazepine, lamotrigine, topiratmate or valproate; (12) a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-I antagonist, e.g. ([alpha]R,9R)—7-[3,5-bis(trifluoromethyl)benzyl]-8,9, lO,ll - tetrahydromethyl(4- phenyl)-7H-[l ,4]diazocino[2,l-g][l,7]-naphthyridine- 6-l3-dione (TAK-637), 5- [[(2R,3S)[(lR)—l-[3,5-bis(trifluoromethyl)phenyl]ethoxy- 3-(4-fluorophenyl)morpholinyl]-methyl]-l,2-dihydro-3H-l,2,4-triazolone (MK- 869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy(trifluoromethoxy)phenyl]- methylamino]phenylpiperidine (2S,3 S); (13) a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium; (14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, xib, valdecoxib, xib, etoricoxib, or lumiracoxib;

[00138] (15) a coal-tar analgesic, in particular paracetamol; (16) a neuroleptic such as droperidol, chlorproniazine, haloperidol, perphenazine, thioridazine, dazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, serin, iloperidone, perospirone, raclopride, zotepine, unox, asenapine, lurasidone, amisulpride, balaperidone, ore, eplivanserin, osanetant, rinionabant, nieclinertant, Miraxion(R) or sarizotan; (17) a oid receptor t (e.g. resinferatoxin) or antagonist (e.g. capsazepine); (18) a beta-adrenergic such as propranolol;

[00142] (19) a local anaesthetic such as rnexiletine; (20) a corticosteroid such as dexaniethasone; (21) a 5-HT receptor agonist or antagonist, particularly a 5-HTi B/I D agonist such as eletriptan, sumatriptan, iptan, zolniitriptan or rizatriptan; (22) a 5-HT2A receptor antagonist such as R(+)—alpha-(2,3- dimethoxy-phenyl)-l-[2-(4- fluorophenylethyl)]piperidinen1ethanol (MDL- 100907); (23) a cholinergic (nicotinic) analgesic, such as ispronicline (TC- 1734), (E)-N-n1ethyl (3-pyridinyl)buten-l -an1ine (RJR-2403), (R)(2- azetidinylniethoxy)chloropyridine (ABT-S94) or nicotine; (24) Tramadol(R);

[00148] (25) a PDEV tor, such as thoxy(4-n1ethyl-l- piperazinyl-sulphonyl)phenyl]- l-n1ethyln-propyl-l,6-dihydro-7H-pyrazolo[4,3- d]pyrin1idinone (sildenafil), (6R,12aR)- 2,3,6,7,l2,l2a-hexahydron1ethyl(3,4- methylenedioxyphenyl)-pyrazino[2',l':6,l]- pyrido[3,4-b]indole-l,4-dione (IC-3Sl or tadalafil), 2-[2-ethoxy(4-ethyl-piperazin-l-yl-l- sulphonyl)-phenyl]n1ethyl propyl-3H-in1idazo[5,l-f] [l,2,4]triazinone (vardenafil), 5-(5 -acetylbutoxy pyridinyl)ethyl(l-ethylazetidinyl)-2,6-dihydro-7H— pyrazolo[4,3-d]pyrin1idin- 7-one, cetylpropoxypyridinyl)ethyl(l-isopropylazetidinyl)-2,6- o-7H—pyrazolo[4,3-d]pvrin1idinone, 5-[2-ethoxy(4-ethylpiperazin-l- ylsulphonyl)pyridinyl]ethyl[2-methoxyethyl]-2,6-dihydro-7H- pyrazolo[4,3- d]pyrin1idinone, 4-[(3-chloron1ethoxybenzyl)an1ino][(ZS) (hydroxymethyl)pyrrolidin-l -yl]-N-(pyrimidinylmethyl)pyrimidinecarboxamide, 3-(l - methyloxopropyl-6,7-dihydro-lH-pyrazolo[4,3-d]pyrimidinyl)-N-[2-(lmethylpyrrolidinyl )ethyl]propoxybenzenesulfonamide; an alphadelta ligand such as gabapentin, pregabalin, 3 -methyl gabapentin, (l[0t],3[0t],5[0t])(3-amino- methyl-bicyclo[3.2.0]heptyl)-acetic acid, (3S,5R)—3-aminomethyl- yl- heptanoic acid, (3S,5R)aminomethyl-heptanoic acid, (3S,5R)amino- 5- methyl-octanoic acid, (2S,4S)(3-chlorophenoxy)proline, (2S,4S)(3- fluorobenzyl)- proline, [(lR,5R,6S)(aminomethyl)bicyclo[3.2.0]heptyl]acetic acid, 3-(l-aminomethyl- cyclohexylmethyl)-4H-[ l ,2,4]oxadiazolone, C-[ l -(I H- tetrazol-S -ylmethyl)-cycloheptyl]- amine, (3S,4S)-(l-aminomethyl-3,4- dimethyl-cyclopentyl)-acetic acid, (3 S, 5R)- 3-aminomethylmethyl-octanoic acid, (3S,5R)aminomethyl-nonanoic acid, (3S,5R)— 3-aminomethyl-octanoic acid, (3R,4R,5R)-3 -amino-4,5-dimethyl-heptanoic acid and ,5R)amino-4,5- dimethyl-octanoic acid;

[00149] (26) a cannabinoid; ] (27) metabotropic glutamate subtype 1 receptor (mGluR1) antagonist; ] (28) a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl lite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l- fenfluramine, femoxetine, ifoxetine, cyanodothiepin, tine, dapoxetine, nefazodone, cericlamine and trazodone; (29) a enaline (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, mine, tine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and Viloxazine (Vivalan(R)), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)—reboxetine; (30) a dual serotonin-noradrenaline reuptake inhibitor, such as axine, venlafaxine metabolite O-desmethylvenlafaxine, ramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine; WO 06280 (31) an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(l- iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(l-iminoethyl)-amino]ethyl]- oxo-L- cysteine, (l-iminoethyl)amino]ethyl]methyl-L-cysteine, (2S,5Z)- 2-aminomethyl- 7-[(l-iminoethyl)amino]heptenoic acid, 2-[[(lR,3S)amino hydroxy- l-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile; 2-[[(lR,3S) aminohydroxy-l-(5- thiazolyl)butyl]thio]chlorobenzonitrile, )—2-amino [[2-chloro (trifluoromethyl)phenyl]thio]thiazolebutanol, R,3S)—3-amino hydroxy-l-(S-thiazolyl) butyl]thio](trifluoromethyl)-3 pyridinecarbonitrile, 2- [[(lR,3S) aminohydroxy(5-thiazolyl)butyl]thio] chlorobenzonitrile, N—[4- [2-(3-chlorobenzylamino)ethyl]phenyl]thiophenecarboxamidine, or guanidinoethyldisulfide; (32) an acetylcholinesterase inhibitor such as donepezil; (33) a prostaglandin E2 subtype 4 (EP4) antagonist such as 7V- [( {2-[4-(2-ethyl-4,6- dimethyl-lH-imidazo[4,5-c]pyridin-l-yl)phenyl]ethyl} amino)- carbonyl] methylbenzenesulfonamide or 4-[(15)-l-({[5-chloro(3- henoxy)pyridin yl]carbonyl} ethyl]benzoic acid; (34) a leukotriene B4 antagonist; such as l-(3-biphenyl ylmethylhydroxy-chroman yl)-cyclopentanecarboxylic acid (CP- 105696), 5-[2- (2-Carboxyethyl)[6-(4- methoxyphenyl)-5E- hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870, (35) a 5-lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro [4-methoxy-3 ,4,5 ,6- tetrahydro-2H-pyranyl])phenoxy-methyl] -l-methyl quinolone (ZD-2138), or 2,3,5- trimethyl(3 -pyridylmethyl),l ,4-benzoquinone (CV- 6504); (36) a sodium channel blocker, such as lidocaine; (36) a 5-HT3 antagonist, such as ondansetron; and the pharmaceutically acceptable salts and solvates thereof.

In another embodiment, the additional eutic agent is an NaV 1.8 inhibitor. NaV 1.7 and NaV 1.8 ion channels are both highly expressed in the sensory s of the dorsal root ganglion, where pain signals originate, but the distinct functional behavior of the two ls leads them to fulfill ct and complementary roles in neuronal excitability. NaVl .7 controls the general sensitivity of nociceptive neurons, and initiating the painful signal in a nociceptor. NaVl .8 amplifies and sustains the pain signal once it has been initiated. Because of these distinct roles, inhibiting both channels should increase the effectiveness of pain relief.

Preclinical c knockout mice support this idea, as double knockouts ofNaVl .7 and NaVl .8 channels in the sensory DRG neurons surprisingly diminish nociceptive behaviors to a greater degree than knockout of either channel alone.

In another embodiment, the additional appropriate therapeutic agent is an NaV 1.8 inhibitor selected from the following: 2-(4-fluorophenoxy)—N—(2- 0x0- 1 ,2-dihydropyridinyl)benzamide; 2-(4-fluorophenoxy)-N-(2-oxo-l ,2- dihydropyridinyl)(trifluoromethyl)benzamide; 2-(4-fluorophenoxy)-N—(6-oxo- l ,6-dihydropyridinyl)benzamide; 2-(4-fluorophenoxy)-N—(2-oxo- l ,2- dihydropyridinyl)(trifluoromethyl)benzamide; 2-(4-fluorophenoxy)-N—(6-oxo- l,6-dihydropyridinyl)(trifluoromethyl)benzamide; 2-(2,4-difluorophenoxy)—N— (2-oxo- l ydropyridinyl)(trifluoromethyl)benzamide; 2-(4-(2- methoxyethoxy)phenoxy)-N-(2-oxo- l ydropyridinyl) (trifluoromethyl)benzamide; N—(2-oxo-l ,2-dihydropyridinyl)phenoxy (trifluoromethyl)benzamide; 2-(4-fluoromethylphenoxy)-N-(2-oxo-l ,2- dihydropyridinyl)(trifluoromethyl)benzamide; N—(2-oxo- l ,2-dihydropyridin (o-tolyloxy)(trifluoromethyl)benzamide; N—(2-oxo- l ,2-dihydropyridinyl)- 2-(p-tolyloxy)(trifluoromethyl)benzamide; ro(2,4-difluorophenoxy)-N—(2- 0x0- 1 ,2-dihydropyridinyl)benzamide; ro(2-chlorofluorophenoxy)-N-(2- 0x0- 1 ,2-dihydropyridinyl)benzamide; 4-chloro(4-fluorophenoxy)-N—(2-oxo- l ,2- dihydropyridinyl)benzamide; 4-chloro(4-fluoromethoxyphenoxy)-N-(2-oxo- l,2-dihydropyridinyl)benzamide; 4-chloro(2-fluoromethylphenoxy)-N—(2- 0x0- 1 ,2-dihydropyridinyl)benzamide; 4-chloro(2-chlorofluorophenoxy)-N-(2- 0x0- 1 ydropyridinyl)benzamide; 4-chloro(2,6-difluorophenoxy)-N-(2—oxo- l,2-dihydropyridinyl)benzamide; ro(4-fluoromethylphenoxy)-N—(2- 0x0- 1 ,2-dihydropyridinyl)benzamide; 4-cyano(4-fluorophenoxy)-N—(2-oxo-l ,2- dihydropyridinyl)benzamide; 4-cyano(4-fluoromethoxyphenoxy)—N—(2-oxo- l,2-dihydropyridinyl)benzamide; 4-cyano(4-fluoromethylphenoxy)-N—(2-oxo- 1 ,2-dihydropyridiny1)benzarnide; 2-(2,4-diflu0rophenoxy)-N-(2-oxo- 1 ,2- opyridinyl)(trifluoromethyl)benzamide; yan0phenoxy)-N—(2-ox0- 1,2-dihydr0pyridinyl)(triflu0rornethyl)benzamide; 2-(2,6-diflu0rophenoxy)—N— (2-0X0-1 ,2-dihydropyridinyl)(trifluoromethyl)benzarnide; N—(2-0X0- 1 ,2- dihydropyridiny1)(p-toly10xy)—5-(trifluoromethyl)benzamide; N—(2-0X0- 1 ,2- dihydropyridinyl)(0-t01y10xy)(triflu0r0rnethyl)benzamide; 2-(2-chlor0 fluorophenoxy)-N-(2-oxo-1 ,2-dihydropyridiny1)(trifluoromethyl)benzarnide; 2- (4-fluororneth0xyphenoxy)-N—(2-0X0- 1 ,2-dihydropyridinyl)-5 - oromethyl)benzamide; 2-(4-flu0r0rnethy1phenoxy)-N-(2-0X0-1 ,2- dihydropyridinyl)(triflu0r0methyl)benzarnide; N—(2-0X0- 1 ,2-dihydropyridin yl)phenoxy(trifluorornethyl)benzamide; 2—(2,4-difluor0phenoxy)-N—(2-oxo- 1 ,2- dihydropyridiny1)-5 -(trifluor0rnethoxy)benzarnide; 2—(2,6-difluor0phenoxy)-N—(2- 0x0- 1 ,2-dihydropyridiny1)-5 uor0rnethoxy)benzarnide; N—(2-0X0- 1 ,2- dihydropyridiny1)(p-t01y10xy)—5-(trifluoromethoxy)benzarnide; N—(2-0X0- 1 ,2- dihydropyridiny1)(0-t01yloxy)(triflu0rornethoxy)benzamide; 2-(2-ch10r0 fluorophenoxy)-N-(2-oxo-1 ,2-dihydropyridiny1)(trifluorornethoxy)benzarnide; 2- (4-fluorophenoxy)—N—(2-oxo- 1 ydropyridinyl)(trifluoromethoxy)benzamide; 2-(2-fluor0methylphenoxy)-N-(2-0X0- 1 ,2-dihydropyridinyl)-5 - oromethoxy)benzamide; 2-(4-fluor0methylphenoxy)-N-(2-0X0- 1 ,2- dihydropyridinyl)(trifluor0rnethoxy)benzarnide; N—(2-0X0-1 ,2-dihydropyridin yl)phen0xy(trifluorornethoxy)benzarnide; 2-(4-fluor0-2—rnethoxyphenoxy)-N-(2- 0x0- 1 ,2-dihydropyridiny1)-5 -(trifluor0rnethoxy)benzarnide; 2-(4-flu0r0phenoxy)-N— (2-0X0-1 ,2-dihydr0pyridiny1)—6-(trifluoromethyl)benzamide; 2-(4-ethoxyphenoxy)- N—(2-0X0-1 ,2-dihydr0pyridiny1)(trifluorornethyl)benzarnide; 2-(4- yphenoxy)—N—(2-OXO- 1 ,2-dihydropyridinyl)(trifluorornethyl)benzamide; 2-(2-ethoxyphenoxy)-N-(2-0X0-1 ,2-dihydropyridiny1)-5 - (trifluoromethyl)benzamide; 2-(2-rnethoxyrnethy1phenoxy)—N—(2-0X0- 1 ,2- dihydropyridinyl)(trifluoromethyl)benzamide; 2—(2-fluor0methoxyphenoxy)- N—(2-0X0-1 ,2-dihydropyridiny1)(trifluoromethyl)benzarnide; 2-(2—ch10r0 methoxyphenoxy)—N—(2-OXO- 1 ,2-dihydropyridinyl)(trifluorornethyl)benzamide; 2-(4-chlorornethy1phenoxy)-N—(2-ox0-1 ,2-dihydropyridinyl)-5 - (trifluoromethyl)benzamide; 2-(4-ch10r0fluor0phen0xy)-N—(2-0X0- 1 ,2- dihydropyridinyl)(trifluoromethyl)benzamide; 2—(5-fluor0methoxyphenoxy)- N—(2-0X0-1 ydropyridiny1)(trifluoromethyl)benzarnide; N-(2-0X0-1 ,2- dihydropyridiny1)(4-pr0p0xyphenoxy)(trifluor0rnethyl)benzamide; 2-(3- fluororneth0xyphenoxy)-N-(2-0X0-1 ,2-dihydropyridinyl)-5 - (trifluoromethyl)benzamide; uor0methoxyphenoxy)-N-(2-0X0- 1 ,2- dihydropyridinyl)(trifluoromethyl)benzamide; 2-(5-flu0r0rnethy1phenoxy)-N— (2-0X0-1 ydropyridinyl)(trifluoromethyl)benzarnide; u0r0-5 - methoxyphenoxy)—N—(2-OXO- 1 ydropyridinyl)(trifluorornethyl)benzamide; 2-(4-ch10r0phenoxy)—N—(2—oxo-1 ,2-dihydropyridinyl)-5 - (trifluoromethyl)benzamide; 2-(3-flu0r0rneth0xyphenoxy)-N-(2-0X0- 1 ,2- dihydropyridinyl)(trifluoromethyl)benzamide; N—(6-ch10r00X0- 1 ,2- dihydropyridiny1)(4-fluor0rnethy1phenoxy)—5-(triflu0rornethyl)benzarnide; 2- rornethy1phenoxy)—N—(6-methy1—2—oxo- 1 ,2-dihydropyridinyl)-5 - (trifluoromethyl)benzamide; N—(2-0X0-1 ,2-dihydropyridiny1)—2-(2- propoxyphenoxy)—5-(trifluoromethyl)benzamide; 2-(4-rnethoxymethylphenoxy)-N- (2-oxo- 1 ,2-dihydropyridinyl)-5 -(trifluorornethyl)benzamide; 2-(2- isopropoxyphenoxy)-N—(2-oxo- 1 ,2-dihydropyridiny1)-5 - (trifluoromethyl)benzamide; 2-(2-ch10r0phenoxy)—N—(2—oxo-1 ,2-dihydropyridinyl)(trifluorornethyl)benzamide; 5-ch10r0(2-ch10r0fluorophenoxy)—N—(2-oxo- 1 ,2- dihydropyridiny1)benzarnide; 5-ch10r0(4-fluor0phenoxy)-N—(2-oxo- 1 ,2- dihydropyridiny1)benzarnide; 5-chloro(4-fluor0methylphenoxy)-N-(2-0X0- 1 ,2-dihydropyridiny1)benzarnide; 5-ch10r0(2,4-difluor0phenoxy)—N—(2-0X0- 1 ,2- dihydropyridiny1)benzarnide; 5-ch10ro(4-fluor0-2—rnethoxyphenoxy)-N-(2-0X0- 1 ,2-dihydropyridiny1)benzarnide; 5 -ch10r0(3-flu0r0rneth0xyphenoxy)-N—(2- 0x0- 1 ,2-dihydropyridiny1)benzarnide; N—(2-0X0- 1 ,2-dihydropyridiny1)(4- (trifluorornethoxy)phenoxy)(trifluoromethyl)benzamide; N—(2-0X0- 1 ,2- dihydropyridinyl)(triflu0r0rnethyl)—2-(4-(trifluorornethy1)phenoxy)benzamide; N—(2-0X0-1 ,2-dihydr0pyridiny1)(2-(trifluoromethoxy)phenoxy)-5 - (trifluoromethyl)benzamide; 2-(2-(difluorornethoxy)phenoxy)-N-(2-ox0-1 ,2- dihydropyridinyl)(trifluoromethyl)benzamide; 2-(2-ch10r0fluorophenoxy)-N— (2-0X0-1 ,2-dihydr0pyridiny1)—4-(trifluoromethyl)benzamide; 2-(4-chlorophenoxy)- X0-1 ,2-dihydr0pyridiny1)(trifluorornethyl)benzarnide; N-(2-0X0-1 ,2- dihydropyridiny1)(4-(trifluoromethoxy)phenoxy)(trifluorornethyl)benzamide; N—(2-0X0-1 ,2-dihydr0pyridiny1)(2-(trifluorornethoxy)phenoxy) (trifluoromethyl)benzamide; 2-(3-flu0r0rneth0xyphenoxy)-N-(2-0X0- 1 ,2- dihydropyridiny1)(trifluoromethyl)benzamide; 2-(4-(difluorornethoxy)phenoKy)- N—(2-0X0-1 ,2-dihydr0pyridiny1)(trifluorornethyl)benzarnide; 2-(2- (difluoromethoxy)phenoxy)-N-(2-0X0-1 ,2-dihydropyridiny1) (trifluoromethyl)benzamide; 2-(2-fluor0methoxyphenoxy)-N-(2-0X0- 1 ,2- opyridiny1)(trifluoromethyl)benzamide; uor0phenoxy)-N-( 1 -(2- hydroxyethy1)oxo-1 ,2-dihydr0pyridinyl)(triflu0rornethyl)benzarnide; 2-(4- fluorornethylphenoxy)-N—(5-rnethyl0X0- 1 ,2-dihydropyridiny1) (trifluoromethyl)benzamide; u0r0rneth0xyphenoxy)-N-(2-0X0- 1 ,2- dihydropyridinyl)(trifluoromethy1)benzarnide; 2-(4-fluorophenoxy)-N—(2-0X0- 1,2—dihydr0pyridiny1)—4-(perflu0roethyl)benzamide; 2-(3-flu0r0 methoxyphenoxy)—N—(2-OXO- 1 ,2-dihydr0pyridinyl)(perfluoroethyl)benzarnide; N—(2-0X0-1 ,2-dihydropyridiny1)-5 -(trifluor0rnethyl)(2,3 ,4- trifluorophenoxy)benzamide; N—(2-0X0-1 ,2-dihydropyridinyl)-5 -(trifluor0rnethyl)- 2-(2,3 ,5 -trimethylphenoxy)benzarnide; 2-(2,3-difluor0methylphenoxy)-N-(2-0X0- 1 ,2-dihydr0pyridiny1)(trifluorornethyl)benzarnide; N-(2-0X0-1 ,2-dihydr0pyridin- 4-y1)-5 -(trifluoromethy1)(2,4,5-trimethylphenoxy)benzamide; 0-N—(2-0X0- 1 ,2-dihydr0pyridinyl)(2,3 ,5 -trirnethylphenoxy)benzamide; 5-fluor0-N—(2-0X0- 1,2-dihydropyridinyl)phenoxybenzarnide; yc10pr0pylphenoxy)flu0r0-N— (2-0X0-1 ,2-dihydropyridiny1)benzarnide; 2-(4-(tert-butoxy)phenoxy)—5-fluor0-N—(2— 0x0- 1 ,2-dihydropyridiny1)benzamide; 2-(4-ethoxyphenoxy)flu0r0-N—(2-0X0- 1 ,2- opyridiny1)benzarnide; 5-flu0r0(4-isopr0pylphenoxy)-N-(2-0X0-1 ,2- opyridiny1)benzarnide; 5-fluor0-N—(2-0X0- 1 ,2-dihydropyridiny1)—2-(4- propoxyphenoxy)benzamide; 5-fluoro-N—(2-oxo- 1 ,2-dihydropyridiny1)(4- (trifluorornethoxy)phenoxy)benzamide; 5-flu0r0(4-(2-rneth0xyethy1)phenoxy)-N- (2-0X0-1 ,2-dihydr0pyridiny1)benzamide; 2-(2-chlororneth0xyphenoxy)—5-fluor0- N—(2-0X0-1 ,2-dihydropyridiny1)benzarnide; 5-fluoro(4-methoxyphenoxy)-N—(2- 0x0- 1 ,2-dihydropyridiny1)benzarnide; 5-fluoro-N-(2-0X0-1 ,2-dihydropyridinyl)- 2—(2,4,5 -trimethylphenoxy)benzarnide; 2-(4-fluoromethy1phenoxy)—N—(2-0x0- 1 ,2- dihydropyridinyl)(triflu0r0methyl)benzarnide; 5-flu0r0-N—(2-0X0- 1 ,2- opyridinyl)(4-(2,2,2-triflu0roethoxy)phenoxy)benzamide; 2-(4- (cyclopropylrnethoxy)phenoxy)—5-fluoro-N—(2-oxo- 1 ,2-dihydropyridin yl)benzarnide; 4-ch10r0(2-ch10r0fluorophenoxy)fluor0-N-(2-0X0-1 ,2- dihydropyridiny1)benzarnide; 2-(2-ch10r0flu0r0rneth0xyphenoxy)-N-(2-0X0- 1,2-dihydropyridiny1)(trifluoromethyl)benzarnide; u0r0 methoxyphenoxy)—N—(2-OXO- 1 ,2-dihydr0pyridinyl)(perfluoroethyl)benzarnide; 2- (4-flu0r0methy1phenoxy)—N—(2-0xo- 1 ydropyridiny1) (perfluoroethyl)benzarnide; 4,5-dichlor0(4-fluor0phen0xy)-N—(2-oxo- 1 ,2- dihydropyridiny1)benzarnide; chlor0(4-flu0r0rneth0xyphenoxy)—N—(2- 0x0- 1 ,2-dihydropyridiny1)benzarnide; 4,5 -dichlor0-2—(3-flu0r0 yphenoxy)-N-(2-0X0- 1 ,2-dihydr0pyridiny1)benzamide; 2-(isopenty10xy)—N— (2-0X0-1 ,2-dihydr0pyridiny1)—4-(trifluorornethyl)benzarnide; 2-isobut0xy-N—(2-0X0- 1 ,2-dihydr0pyridinyl)(triflu0rornethyl)benzarnide; 2-((2R)—bicyc10[2.2. 1]heptan- 2-y10xy)-N—(2-ox0- 1 ,2-dihydr0pyridiny1)—4-(trifluorornethyl)benzarnide; 2-((1- methylcyc10pr0py1)rnethoxy)—N—(2-oxo- 1 ,2-dihydr0pyridiny1) (trifluoromethyl)benzamide; 10pentylrnethoxy)-N—(2-0X0- 1 ,2-dihydr0pyridin yl)(trifluor0methyl)benzamide; N-(2-0X0-1 ,2-dihydropyridiny1) ((tetrahydrofilrany1)rneth0xy)(trifluoromethyl)benzarnide; 2-cyc10but0xy-N—(2- 0x0- 1 ,2-dihydropyridiny1)(triflu0r0rnethyl)benzamide; N—(2-0X0- 1 ,2- dihydropyridinyl)(4,4,4-triflu0r0butoxy)(triflu0r0rnethy1)benzamide; 2-((2,2- dimethylcyc10pr0py1)rnethoxy)—N—(2-0X0- 1 ,2-dihydr0pyridiny1) (trifluoromethy1)benzarnide; 2-((1R,5 S)—bicyclo [3. 1 .0]hexany10xy)—N—(2-0X0- 1 ,2- dihydropyridiny1)(trifluoromethyl)benzarnide; 2-((2,2- difluorocyclopropyl)methoxy)-N-(2-oxo- 1 ,2-dihydropyridiny1)—4- (trifluoromethyl)benzamide; 2-(bicyclo[2.2. 1]heptan-Z-y10xy)-N—(2-0X0- 1 ,2- dihydropyridiny1)(trifluoromethyl)benzamide; 2-(cyc10hexy10xy)—N—(2-oxo- 1 ,2- dihydropyridiny1)(trifluoromethyl)benzamide; 4-ch10r0-N—(2-0X0- 1 ,2- dihydropyridinyl)(4,4,4-triflu0r0butoxy)benzamide; 2-(cyclopentylrnethoxy)-N— (2-0X0-1 ,2-dihydropyridiny1)—5-(trifluoromethyl)benzarnide; 2-isobutoxy-N—(2-0X0- 1 ,2-dihydr0pyridiny1)(trifluorornethyl)benzarnide; N-(2-0X0-1 ,2-dihydr0pyridin- 4-y1)-5 -(trifluor0rnethy1)(3 ,3 ,3 -trifluor0propoxy)benzamide; N-(2-0X0-1 ,2- dihydropyridinyl)(4,4,4-trifluor0butoxy)(trifluorornethyl)benzamide; 2-((2,2- dimethylcyc10pr0py1)rnethoxy)—N—(2-0X0- 1 ,2-dihydropyridinyl)-5 - (trifluoromethyl)benzamide; 2-(cyc10pentylrnethoxy)-N—(2-0X0- 1 ,2-dihydr0pyridin yl)(trifluorornethoxy)benzamide; 2-(cyc10hexy10xy)—N—(2-oxo- 1 ,2-dihydr0pyridin- 4-y1)(trifluoromethoxy)benzamide; N—(2-0X0- 1 ,2-dihydropyridinyl)-5 - orornethoxy)(3 ,3 ,3 -trifluor0propoxy)benzamide; N—(2-0X0- 1 ,2- dihydropyridiny1)(4,4,4-trifluorobutoxy)(trifluoromethoxy)benzamide; 2- ((2,2-dimethylcyclopropyl)methoxy)-N-(2-0X0- 1 ,2-dihydropyridinyl)-5 - (trifluoromethoxy)benzamide; 4-(tert-buty1)-N—(2-oxo-1 ,2-dihydr0pyridinyl)((6- (trifluoromethyl)pyridinyl)oxy)benzarnide; t-buty1)-N—(6-0X0-1 ,6- dihydropyridiny1)((6-(trifluoromethyl)pyridiny1)0xy)benzarnide; 4-chlor0-N- - 1 ,2-dihydropyridiny1)((6-(trifluorornethyl)pyridin-3 y)benzarnide; N—(2-0X0-1 ,2-dihydropyridiny1)(trifluor0rnethyl)((6-(trifluoromethyl)pyridinyl)oxy)benzarnide; N-(6-0X0-1 ,6-dihydropyridin-3 -y1)(trifluorornethyl)((6- (trifluorornethyl)pyridiny1)0xy)benzarnide; 2-((6-rnethylpyridiny1)oxy)-N—(2- oxo-l ,2-dihydr0pyridiny1)—4-(trifluorornethyl)benzamide; methylpyridin-3 - yl)0xy)-N—(2-0X0- 1 ,2-dihydr0pyridiny1)(trifluorornethyl)benzarnide; 4-(tertbuty1 )-N-(1 -rnethy1—2-oxo- 1 ,2-dihydr0pyridiny1)((6-(trifluorornethyl)pyridin-3 - yl)oxy)benzarnide; 4-(tert-buty1)-N—(1-rnethy1—6-0X0-1 ,6-dihydropyridin-3 -y1)((6- (trifluorornethyl)pyridiny1)0xy)benzarnide; 2-((2-rnethylpyridiny1)oxy)-N—(2- oxo-l ,2-dihydropyridiny1)—5-(trifluoromethyl)benzamide; methylpyridin-3 - yl)0xy)-N-(2-0X0-1 ydropyridiny1)—5-(trifluorornethoxy)benzamide; 2-(2,4- ophenoxy)-N—(2-oxo-1 ,2-dihydropyridinyl)-4,6- bis(trifluoromethyl)benzarnide; 2-(4-fluoromethy1phenoxy)—N—(2-oxo- 1 ,2- dihydropyridinyl)-4,6-bis(trifluorornethyl)benzamide; 2-(4-fluor0 methoxyphenoxy)-N-(2-0X0- 1 ,2-dihydr0pyridinyl)-4,6- bis(trifluoromethyl)benzamide; 2-(4-fluorophenoxy)-N—(2-oxo- 1 ,2-dihydr0pyridin yl)-4,6-bis(trifluoromethyl)benzamide; N—(2-ox0-1 ,2-dihydropyridiny1)phenoxy- 4,6-bis(trifluorornethyl)benzarnide; 2-(4-fluoro(hydroxymethyl)phenoxy)-N-(2-oxo- 1,2-dihydropyridiny1)(trifluoromethyl)benzarnide; 2-(4-flu0r0 methoxyphenoxy)—N—(2-OXO- 1 ,2-dihydr0pyridiny1)(trifluoromethyl)benzarnide; 2-((5-flu0r0hydr0xybenzyl)oxy)-N—(2-0X0-1 ,2-dihydr0pyridiny1) (trifluoromethyl)benzamide; 5-flu0r0-N—(2-0X0- 1 ,2-dihydropyridiny1)(4-(4,4,4- trifluorobutoxy)phenoxy)benzamide, or combinations thereof.

In another embodiment, the additional appropriate therapeutic agent is an NaV 1.8 inhibitor ed from the following: 3-(4-fluorophenoxy)—N—(3- sulfamoylphenyl)quinoxalinecarboxamide; 3-(4-fluoromethoxyphenoxy)-N—(3- sulfamoylphenyl)quinoxalinecarboxamide; N—(3-sulfamoylphenyl)(4- (trifluoromethoxy)phenoxy)quinoxaline-Z-carboxamide; 3-(2-chloro methoxyphenoxy)-N—(3-sulfamoylphenyl)quinoxalinecarboxamide; 3-(2,4- difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxalinecarboxamide; 3-(2-chloro fluorophenoxy)-N—(3-sulfamoylphenyl)quinoxalinecarboxamide; 3-(3-fluoro methoxyphenoxy)-N—(3-sulfamoylphenyl)quinoxalinecarboxamide; 3-(2,4- dimethoxyphenoxy)—N—(3-sulfamoylphenyl)quinoxalinecarboxamide; 3-(4-chloro methylphenoxy)-N—(3-sulfamoylphenyl)quinoxalinecarboxamide; 3-(2- (difluoromethoxy)phenoxy)-N-(3-sulfamoylphenyl)quinoxalinecarboxamide; 3-(4- chloromethoxyphenoxy)-N—(3-sulfamoylphenyl)quinoxalinecarboxamide; 3-(2- fluoromethoxyphenoxy)-N—(3-sulfamoylphenyl)quinoxalinecarboxamide; 3- phenoxy-N—(3-sulfamoylphenyl)quinoxalinecarboxamide; uoro methylphenoxy)-N—(3-sulfamoylphenyl)quinoxalinecarboxamide; N—(3- sulfamoylphenyl)(4-(2,2,2-trifluoroethoxy)phenoxy)quinoxalinecarboxamide; 3- (4-fluoromethoxyphenoxy)-N-(3-(N-methylsulfamoyl)phenyl)quinoxaline carboxamide; 4-(3 -(4-(trifluoromethoxy)phenoxy)quinoxalinecarboxamido)benzoic acid; 5-(3-(4-fluorophenoxy)quinoxalinecarboxamido)picolinic acid; 5-(3-(4-fluoro- 2-methylphenoxy)quinoxalinecarboxamido)picolinic acid; 5-(3- phenoxyquinoxaline-Z-carboxamido)picolinic acid; 5-(3-(2-fluoro methoxyphenoxy)quinoxalinecarboxamido)picolinic acid; 5-(3-(4-(2,2,2- roethoxy)phenoxy)quinoxalinecarboxamido)picolinic acid; 4-chloro methoxyphenoxy)quinoxalinecarboxamido)picolinic acid; 5-(3-(2— (difluoromethoxy)phenoxy)quinoxalinecarboxamido)picolinic acid; 5-(3-(4-chloro- 2-methylphenoxy)quinoxalinecarboxamido)picolinic acid; 5-(3-(2,4- dimethoxyphenoxy)quinoxalinecarboxamido)picolinic acid; 5-(3-(3-fluoro methoxyphenoxy)quinoxalinecarboxamido)picolinic acid; 2-chloro fluorophenoxy)quinoxalinecarboxamido)picolinic acid; 5-(3-(2,4- difluorophenoxy)quinoxalinecarboxamido)picolinic acid; 5-(3-(2-chloro methoxyphcnoxy)quinoxalinccarboxamido)picolinic acid; 5-(3-(4- (trifluororncthoxy)phcnoxy)quinoxalinc-Z-carboxarnido)picolinic acid; 5-(3-(4-flu0r0- 2-mcthoxyphcnoxy)quinoxalinc-Z-carb0xarnido)picolinic acid; 4-(3 -(4- (trifluororncthoxy)phcnoxy)quinoxalinc-Z-carboxarnido)picolinic acid; 4-(3-(4-fluor0- oxyphcnoxy)quinoxalinc-Z-carb0xarnido)picolinic acid; 3-(4-flu0r0phcn0xy)- N—(2-0X0-1 ,2-dihydr0pyridiny1)quin0xalinccarboxarnidc; 3 -(3-(4-flu0r0 methoxyphcnoxy)quinoxalinccarboxarnido)bcnzoic acid; 2—(3-(4-flu0r0 methoxyphcnoxy)quinoxa1inccarboxamido)thiaz016carboxy1ic acid; 3-(4-fluor0- 2-mcth0xyphcnoxy)-N—(1H-1,2,4-triaz01—3-y1)quinoxalinc-Z-carb0xarnidc; 2-(3 -(4- fluoromcthoxyphcnoxy)quinoxalinccarboxarnido)oxazolccarboxylic acid; 3 - (4-flu0r0rncthoxyphcnoxy)—N—( 1 H-pyraz01y1)quinoxalinc-Z-carb0xarnidc; 3 -(4- fluoro-Z-mcthoxyphcnoxy)-N-( 1 H-tctrazol-S-y1)quin0xalinccarb0xarnidc; N—( 1 H- bcnzo [d] [ 1 ,2,3 ]triaz01—5 -y1)-3 oromcthoxyphcnoxy)quinoxalinc-Z- carboxarnidc; 3-(4-fluororncthoxyphcnoxy)-N-( 1 H-pyraz01y1)quin0xalinc carboxamidc; 3-(4-fluororncthoxyphcnoxy)—N—(2-(hydr0xyrncthyl)- 1H- bcnzo[d]irnidaz01—5-y1)quinoxalinccarb0xamidc; N—(3 ctraz01—5 cny1)-3 - (4-flu0r0mcthoxyphcnoxy)quinoxalinc-Z-carboxamidc; 3-(4-fluoro methoxyphcnoxy)—N—(3-(methylsulfonyl)phcnyl)quinoxa1inccarboxarnidc; 3 -(4- fluororncth0xyphcnoxy)-N—(1H-indaz01y1)quinoxa1inccarb0xarnidc; 3 -(4- fluoro-Z-mcthoxyphcnoxy)-N-( 1 H-indazol-S-y1)quinoxalinc-Z-carb0xarnidc; N—( 1 H- d]irnidaz01—6-y1)—3-(4-fluororncthoxyphcnoxy)quinoxalinc-Z-carb0xarnidc; N—(4-cyan0pyridin-2—y1)(4-flu0r0rncthoxyphcnoxy)quinoxalinc-Z-carb0xarnidc; N—(6-cyanopyridin-3 -y1)(4-flu0r0rncthoxyphcnoxy)quinoxalinc-Z-carb0xarnidc; N—(S-cyanopyridinyl)(4-flu0r0rncthoxyphcnoxy)quinoxalinc-Z-carb0xarnidc; 3 -(4-fluor0mcthoxyphcnoxy)-N-(pyridiny1)quinoxalinccarb0xarnidc; 3 -(4- fluoro-Z-mcthoxyphcnoxy)-N-(pyridin-3 -y1)quinoxalinc-Z-carb0xarnidc; N—(4- cyanophcnyl)(4-fluororncthoxyphcnoxy)quinoxalinc-Z-carboxarnidc; N—(3- cyanophcny1)(4-fluororncthoxyphcnoxy)quinoxalinccarboxarnidc; 3 -(4- fluoro-Z-mcthoxyphcnoxy)-N-(2-oxo-2,3-dihydr0-1H-bcnz0[d]irnidaz01—5 - yl)quinoxalinccarb0xarnidc; N—(4-carbarn0ylphcnyl)(4-fluor0 methoxyphcnoxy)quin0xa1inccarb0xarnidc; N—(3-carbarn0y1phcnyl)(4-fluor0 methoxyphcnoxy)quinoxalinccarb0xarnidc; 2-(4-flu0rophcnoxy)-N-(3- sulfamoylphenyl)quinolinecarboxamide; 2-(4-fluoromethoxyphenoxy)—N—(3- sulfamoylphenyl)quinolinecarboxamide; 2-(3-fluoromethoxyphenoxy)—N—(3- sulfamoylphenyl)quinolinecarboxamide; 2-(4-fluoromethylphenoxy)—N—(3- sulfamoylphenyl)quinolinecarboxamide; 2-phenoxy-N—(3- sulfamoylphenyl)quinolinecarboxamide; 2—(2,4-difluorophenoxy)—N—(3- sulfamoylphenyl)quinolinecarboxamide; 2-(2-chlorofluorophenoxy)—N—(3- sulfamoylphenyl)quinolinecarboxamide; N—(3-sulfamoylphenyl)—2-(4-(2,2,2- trifluoroethoxy)phenoxy)quinolinecarboxamide; N—(3-sulfamoylphenyl)(4- (trifluoromethoxy)phenoxy)quinolinecarboxamide; 2-(2-chloro methoxyphenoxy)-N—(3-sulfamoylphenyl)quinolinecarboxamide; uoro methoxyphenoxy)—N—(3-sulfamoylphenyl)quinolinecarboxamide; 2-(4-chloro methylphenoxy)-N—(3-sulfamoylphenyl)quinolinecarboxamide; 2-(2,4- dimethoxyphenoxy)—N—(3-sulfamoylphenyl)quinolinecarboxamide; 2-(4-chloro methoxyphenoxy)—N—(3-sulfamoylphenyl)quinolinecarboxamide; 2-(2- romethoxy)phenoxy)-N-(3-sulfamoylphenyl)quinolinecarboxamide; 4-(2- (2,4-difluorophenoxy)quinolinecarboxamido)benzoic acid; 4-(2-(4-fluoro methylphenoxy)quinolinecarboxamido)benzoic acid; 4-(2-(2- romethoxy)phenoxy)quinolinecarboxamido)benzoic acid; 4-(2-(2,4- dimethoxyphenoxy)quinolinecarboxamido)benzoic acid; 5-(2-(2-chloro fluorophenoxy)quinolinecarboxamido)picolinic acid; 5-(2-(2,4- difluorophenoxy)quinolinecarboxamido)picolinic acid, or combinations thereof In r embodiment, the additional appropriate therapeutic agent is an NaV 1.8 inhibitor selected from the following: 4-(2-(2—chloro fluorophenoxy)(perfluoroethyl)benzamido)benzoic acid; 4-(2-(2,4- difluorophenoxy)(perfluoroethyl)benzamido)benzoic acid; 4-(2-(4-fluoro methylphenoxy)—4-(perfluoroethyl)benzamido)benzoic acid; 4-(2-(2—chloro fluorophenoxy)(trifluoromethyl)benzamido)benzoic acid; 4-(2-(4-fluoro methylphenoxy)—4-(trifluoromethyl)benzamido)benzoic acid; 2,4- difluorophenoxy)(trifluoromethyl)benzamido)benzoic acid; 4- (trifluoromethoxy)phenoxy)(trifluoromethyl)benzamido)benzoic acid; 4-(2-(2,4- difluorophenoxy)-4,6-bis(trifluoromethyl)benzamido)benzoic acid; 4-(2-(4-fluoro phenoxy)-4,6-bis(trifluoromethyl)benzamido)benzoic acid; 4-(2-(4-fluoro 2014/045675 methoxyphcnoxy)—4,6-bis(triflu0r0rncthy1)bcnzamido)bcnzoic acid; 4-(2-(4- fluorophcnoxy)-4,6-bis(trifluororncthyl)bcnzamido)bcnzoic acid; 4-(4,5-dich10r0(4- fluororncth0xyphcnoxy)bcnzarnido)bcnzoic acid; 4-(4,5-dich10r0(4- fluorophcnoxy)bcnzarnido)bcnzoic acid; 4-(4,5-dichlor0(4-fluor0 methylphcnoxy)bcnzamido)bcnzoic acid; 4-(4,5-dichloro phcnoxybcnzarnido)bcnzoic acid; 4-(4,5-dichlor0(2-fluor0 methoxyphcnoxy)bcnzamido)bcnzoic acid; 4-(4,5-dichlor0(4-(2,2,2- rocthoxy)phcnoxy)bcnzarnido)bcnzoic acid; 4-(4,5-dich10r0(4-chlor0 methoxyphcnoxy)bcnzamido)bcnzoic acid; 4-(4,5-dich10r0(2- (difluororncthoxy)phcnoxy)bcnzarnido)bcnzoic acid; 4-(4,5-dich10r0(4-chloro methylphcnoxy)bcnzarnido)bcnzoic acid; 4-(4,5-dich10r0(2,4- dirncthoxyphcnoxy)bcnzarnido)bcnzoic acid; 4-(4,5-dichloro(3-flu0ro methoxyphcnoxy)bcnzamido)bcnzoic acid; 4-(4,5-dich10r0(2-chlor0 fluorophcnoxy)bcnzarnido)bcnzoic acid; 4-(4,5-dich10r0(2,4- difluorophcnoxy)bcnzarnido)bcnz0ic acid; 4-(4,5-dich10r0(2-chloro yphcnoxy)bcnzamido)bcnzoic acid; 4-(4,5-dich10r0(4- (trifluoromcthoxy)phcnoxy)bcnzamido)bcnzoic acid; 4-(2-(4-flu0r0 methoxyphcnoxy)—4-(pcrfluorocthyl)bcnzarnido)bcnzoic acid; 4-(2-(4-flu0r0 methylphcnoxy)(trifluoromcthyl)bcnzamid0)bcnzoic acid; 4-(2-(4-flu0r0 methylphcnoxy)—5-(trifluoromcthyl)bcnzamid0)bcnzoic acid; 5-(4,5-dich10r0(4- fluorophcnoxy)bcnzarnido)pic01inic acid; 5-(4,5-dich10r0(4- (isopcntyloxy)phcnoxy)bcnzarnido)picolinic acid; 5-(4,5-dich10r0(4-flu0ro phcnoxy)bcnzarnido)picolinic acid; 5-(4,5-dich10r0-2— phenoxybcnzamido)picolinic acid; 5-(4,5-dich10r0(2-flu0ro methoxyphcnoxy)bcnzarnido)pic01inic acid; 5-(4,5-dichlor0(4-(2,2,2- trifluorocthoxy)phcnoxy)bcnzamid0)picolinic acid; 5-(4,5-dich10r0(4-chloro yphcnoxy)bcnzarnido)picolinic acid; -dich10r0(2- (difluoromcthoxy)phcnoxy)bcnzamido)pic01inic acid; 5-(4,5-dich10r0(4-chloro methylphcnoxy)bcnzarnido)picolinic acid; 5-(4,5-dich10r0(2,4- dimcthoxyphcnoxy)bcnzamido)picolinic acid; 5-(4,5-dich10r0(3-flu0ro methoxyphcnoxy)bcnzarnido)picolinic acid; 5-(4,5-dich10r0(2-chloro fluorophcnoxy)bcnzarnido)pic01inic acid; 5-(4,5-dich10r0(2,4- difluorophcnoxy)bcnzarnido)pic01inic acid; 5-(4,5-dich10r0(2-chloro methoxyphcnoxy)bcnzarnido)picolinic acid; 5-(4,5-dich10r0(4- (trifluororncthoxy)phcnoxy)bcnzarnido)picolinic acid; 5-(2-(2—rncth0xyphcnoxy)—4,6- bis(trifluororncthyl)bcnzarnido)pic0linic acid; 5-(2-(4-rncthoxyphcnoxy)-4,6- bis(trifluororncthyl)bcnzarnido)pic0linic acid; 5-(2-(4-fluor0rncthylphcnoxy)-4,6- ifluororncthyl)bcnzarnido)pic0linic acid; 5-(2-(4-fluor0rncthoxyphcnoxy)-4,6- bis(trifluororncthyl)bcnzarnido)pic0linic acid; 5-(2-(2,4-dirncthoxyphcnoxy)—4,6- bis(trifluororncthyl)bcnzarnido)pic0linic acid; 5-(2-(4-fluorophcnoxy)-4,6- ifluororncthyl)bcnzarnido)pic0linic acid; 5-(4,5-dich10r0(4-fluoro methoxyphcnoxy)bcnzarnido)picolinic acid; 5-(4-(tcrt-butyl)(4-flu0r0-2— methoxyphcnoxy)bcnzarnido)picolinic acid; 5-(4-(tcrt-buty1)—2-(4-fluor0-2— phcnoxy)bcnzarnido)pic0linic acid; 5-(4-(tcrt-butyl)—2-(4- fluorophcnoxy)bcnzarnido)pic01inic acid; 5-(2-(4-fluorophcnoxy)bcnzamid0)picolinic acid; 5-(2-(4-flu0r0phcnoxy)(trifluororncthy1)bcnzarnido)picolinic acid; 5-(2-(4- fluor0rncthoxyphcnoxy)(triflu0rorncthyl)bcnzarnido)picolinic acid; 2— fluorophcnoxy)(trifluororncthyl)bcnzarnido)picolinic acid; 5-flu0r0- 2-mcthoxyphcnoxy)(trifluororncthyl)bcnzarnido)picolinic acid; 5-(2-(2— (difluororncthoxy)phcnoxy)(trifluororncthy1)bcnzamido)picolinic acid; 5-(2-(4- ch10rorncthylphcnoxy)(triflu0r0rncthy1)bcnzamido)picolinic acid; 5-(2-(2— methoxyphcnoxy)—5-(trifluor0rncthyl)bcnzarnido)picolinic acid; 5-(2-(2— chlorophcnoxy)(trifluororncthyl)bcnzarnido)picolinic acid; 5-(2-(2— isopropoxyphcnoxy)(triflu0r0rncthyl)bcnzarnido)pic0linic acid; 5-(2-(2,4- dimcthoxyphcnoxy)(trifluororncthyl)bcnzarnido)picolinic acid; 5-(2-(4-ch10r0 methoxyphcnoxy)—5-(trifluoromcthyl)bcnzarnido)picolinic acid; 5-(2-(4-rncthoxy methylphcnoxy)—5-(triflu0r0rncthy1)bcnzamido)picolinic acid; 5-(2-(2-ch10r0 methoxyphcnoxy)—5-(trifluor0rncthyl)bcnzarnido)picolinic acid; 5-(2-(3-flu0r0 methoxyphcnoxy)—5-(trifluor0rncthyl)bcnzarnido)picolinic acid; 5-(2-phcnoxy (trifluororncthyl)bcnzarnido)picolinic acid; 5-(2-(4-fluorophcnoxy) (trifluororncthyl)bcnzamid0)picolinic acid; 5-(2-(4-flu0rorncth0xyphcnoxy) (pcrfluorocthyl)bcnzarnido)picolinic acid; 5-(2-(4-fluorophcnoxy) (pcrfluorocthyl)bcnzarnido)picolinic acid; 5-(2-(2-ch10r0flu0r0phcnoxy)—6- (trifluororncthyl)bcnzarnido)picolinic acid; 5-(2-(4-flu0r0rncthylphcnoxy) (trifluoromethyl)benzamido)picolinic acid; 5-(4,5-dichloro(4-fluoro methoxyphenoxy)benzamido)picolinic acid, or combinations thereof.

The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that eutic agent as the only active agent. ably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount ly present in a composition comprising that agent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptable itions thereofmay also be incorporated into compositions for coating an implantable l device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the invention, in another aspect, includes a composition for coating an implantable device comprising a compound 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 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 l preparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible ric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be r covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the ition. r aspect of the invention relates to inhibiting one or more .1, NaV1.2, , NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, or NaV1.9, activity in a biological sample or a subject, which method comprises administering to the subject, or contacting said biological sample with a compound of formula I or a ition sing said compound. The term gical sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied al obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or ts thereof.

Inhibition of one or more ofNaVl . l, NaVl .2, NaVl .3, NaVl .4, NaVl .5, NaVl .6, NaVl .7, NaVl .8, or NaV1.9, 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 ion channels in biological and ogical phenomena; and the comparative evaluation ofnew sodium ion channel inhibitors.

EXAMPLES General methods. 1H NMR (400 MHz or 300 MHz) and 13c NMR (100 MHz) spectra were obtained as solutions in deuterioacetonitrile (CD3CN), chloroform-d (CDClg), deuteromethanol (MeOD-d4), or dimethyl sulfoxide-D6 . Mass spectra (MS) were ed using an Applied tems API EX LC/MS system ed with a Phenomenex 50 X 4.60 mm luna-5u C18 column. The LC/MS eluting system was 1-99% or 10-99% acetonitrile in H20 with 0.035% v/v trifluoroacetic acid, 0.035% v/v formic acid, 5 mM HCl or 5 mM ammonium formate using a 3 or 15 min linear nt and a flow rate of 12 mL/min. Silica gel chromatography was performed using silica gel-60 with a particle size of 230-400 mesh. Pyridine, DCM (CHzClz), tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile (ACN), methanol (MeOH), and l,4-dioxane were from Aldrich Sure-Seal bottles kept under dry nitrogen. All reactions were stirred ically unless otherwise noted. [(3aR,7aR)—7a-phenyl-3a,4,6,7—tetrahydr0-[1,3]dioxolo[4,5- c]pyridinyl]-[3-meth0xy[2-(triflu0r0meth0xy)eth0xy]phenyl]methanone Step 1: tert-butyl 4-phenyl—3,6-dihydr0-2H-pyridine—1- carboxylate 0 AOL J< JJ\OJ< NaZCO3 (2M), Pd(dppf)C|2 N O D I A solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-3,6-dihydro- idinecarboxylate (10.0 g, 32.3 mmol) and bromobenzene (5.1 g, 3.4 mL, 32.3 mmol) in DMF (30 mL), was treated with sodium carbonate (16.2 mL of 2 M, 32.3 mmol) in water. The reaction mixture was purged with nitrogen and treated with Pd(dppf)Clz (1.2 g, 1.6 mmol). The reaction mixture was stirred at 80 CC for 1 h.

Volatiles were removed under reduced re at 70 oC. The remaining residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The mixture was filtered to remove emusifying solids. The organic layer was r washed with saturated s NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting brown oil was purified by silica gel column chromatography: 120 gram silica gel column, 0-40% ethyl acetate/hexane gradient over 30 min to afford tert-butyl yl-3,6-dihydro-2H-pyridinecarboxylate (8.13 g, mmol, 97%) as a clear colorless oil. ESI-MS m/z calc. 259.2, found 260.3 (M+1)+; Retention time: 2.05 min (3 min run).

The following compounds were prepared using the procedure reported above: Aryl Halide Product tert-butyl 4-(3 ,5 rophenyl)-3 ,6-dihydro- 1-bromo-3 ,5-difiuoro-benzene 2H-pyridinecarboxylate tert-butyl 4-(3-fiuorophenyl)-3 ,6-dihydro-2HBromofluoro-benzene pyridinecarboxylate tert-butyl 4-(4-fiuorophenyl)-3 ,6-dihydro-2Hbromofiuoro-benzene pyr1d1ne-_ _ 1 xylate tert-butyl 4-(6-bromopyridyl)-3 ,6-dihydro- bromopyridine. 2H-pyridinecarboxylate tert-butyl 4-(2,5-difluorophenyl)-3 ,6-dihydro- 2-brorno-1 uoro-benzene 2H-pyridinecarb0xylate tert-butyl 4-(3-chlor0pyridy1)-3 ,6-dihydro- 2-brorno-3 -chloro-pyridine idinecarb0xylate tert-butyl 4-(3 0xypyridin 2-br0rn0rneth0xyoxid0-pyridiniurn iurny1)-3 ,6-dihydro-2H-pyridine carboxylate tert-butyl 4-pyrirnidinyl-3 ,6-dihydro-2H- 2-br0m0pyrirnidine pyridinecarb0xylate utyl 4-(3-flu0r0-2—pyridyl)-3 ,6-dihydro- 2-ch10r0flu0r0-pyridine 2H-pyridinecarb0xylate tert-butyl 4-(1 -rnethy1pyrazol-3 -y1)-3 ,6br0rn0rnethy1—pyrazole dihydro-ZH-pyridinecarb0xylate tert-butyl 4-(3-cyanopheny1)—3 ,6-dihydro-2H- nobenzonitrile pyridinecarb0xylate tert-butyl 4-(2-rnethylthiazoly1)-3 ,6- 4-br0rnornethy1—thiazole dihydro-ZH-pyridinecarb0xylate tert-butyl 4-thiaz01—4-yl-3 ,6-dihydro-2H- 4-brom0thiazole pyridinecarb0xylate tert-butyl 4-phenyl-3 ,6-dihydro-2H-pyridine- bromobenzene l-carboxylate tert-butyl 4-(3-chloropheny1)-3 ,6-dihydro-2Hbrorno-3 -chloro-benzene necarb0xylate tert-butyl 4-(2,3-difluorophenyl)-5 ,6- l-bromo-2,3-difluoro-benzene dihydropyridine- l (2H)—carboxylate tert-butyl 4-(2,5-difluorophenyl)-3 ,6-dihydro- 2-bromo- l ,4-difluoro-benzene 2H-pyridine- l xylate tert-butyl 6-(trifluoromethyl)—5',6'-dihydro- 2-bromo(trifluoromethyl)pyridine [2,4'-bipyridine]— l '(2'H)-carboxylate tert-butyl 4-[4-(trifluoromethyl)—2-pyridyl]- 2-bromo(trifluoromethyl)pyridine 3 ,6-dihydro-2H-pyridine- l -carboxylate utyl 4-(6-chloromethoxypyridyl)— 2,6-dichloromethoxy-pyridine 3 ,6-dihydro-2H-pyridine- l -carboxylate tert-butyl 6-bromo-5',6'-dihydro-[2,4'- 2,6-dibromopyridine b1pyr1d1ne]. . . - l -carboxylate Step 2: tert-butyl (3R,4R)—3,4-dihydr0xyphenyl- piperidine-l-carboxylate NJKOJ< l AD—mix-B, methanesulfonamide, , H20; Methanesulfonamide (917 mg, 9.6 mmol) was dissolved in a solution of water (54 mL) and utanol (54 mL). AD-mix-B (7.6 g, 9.6 mmol) was added, and the mixture was allowed to stir at rt for 5 min before cooling to 0 CC. To the mixture was added utyl 4-phenyl-3,6-dihydro-2H-pyridine-l-carboxylate (2.5 g, 9.6 mmol) in one portion, and the reaction mixture was allowed to continue stirring at 0 0C for 8 h. Sodium sulfite (6 g) was added, and the mixture was allowed to stir at rt for an additional 30 min and was extracted with ethyl acetate (2X 75 mL). The combined organic layers were washed with aqueous l N NaOH (l X 75 mL)., dried over sodium e, filtered and concentrated under reduced pressure to a yellow- orange oil. It was purified by silica gel column chromatography: 40 gram silica gel column, 0-30% ethyl acetate/hexane gradient over 30 min; product eluted at 25% to provide tert-butyl (3R,4R)—3,4-dihydroxyphenyl-piperidinecarboxylate (1.6 g, 58%) as a white solid. 1H NMR (400 MHz, CDClg) 8 7.48 (dt, J = 3.1, 1.8 Hz, 2H), 7.44 - 7.35 (m, 2H), 7.33 - 7.27 (m, 1H), 4.26 - 4.12 (m, 1H), 4.11 - 4.01 (m, 1H), 3.95 (d, J = 11.7 Hz, 1H), 3.22 - 3.08 (m, 1H), 3.07 - 2.93 (m, 1H), 2.71 (s, 1H), 1.96 - 1.79 (m, 2H), 1.64 (t, J = 18.5 Hz, 1H), 1.55 - 1.44 (m, 9H). ESI-MS m/z calc. 293.2, found 294.5 (M+1)+; ion time: 1.32 min (3 min run).

[00174] The following compounds were prepared using the procedure reported above: Product sor tert-butyl (3R,4R)—3 ,4-dihydroxy(3 ,5 - tert-butyl 4-(3 ,5 -difluorophenyl)—3 ,6- ophenyl)-pyridine- 1 xylate dihydro-2H-pyridinecarboxylate tert-butyl (3R,4R)-3,4-dihydroxy(3- tert-butyl 4-(3 -fluorophenyl)-3 ,6- fluorophenyl)-piperidinecarboxylate dihydro-2H-pyridinecarboxylate tert-butyl (3R,4R)-3 ydroxy—4-(4_ tert-butyl 4-(4-fluorophenyl)—3 ,6- fluorophenyl)-piperidinecarboxylate dihydro-2H-pyridinecarboxylate tert-butyl (3R,4R)-3 ,4-dihydroxy-(6-bromo- tert-butyl 4-(6-bromopyridyl)—3 ,6- 2-pyridyl)-piperidinecarboxylate dihydro-2H-pyridinecarboxylate tert-butyl (3R,4R)—3 ,4-dihydroxy(2,5 - tert-butyl 4-(2,5-difluorophenyl)—3 ,6- difluorophenyl)-piperidinecarboxylate dihydro-2H-pyridinecarboxylate tert-butyl (3R,4R)-3,4-dihydroxy(3- tert-butyl 4-(3-chloropyridyl)-3 ,6- chloropyridyl)-piperidine-1 xylate dihydro-2H-pyridinecarboxylate tert-butyl (3R,4R)-3,4-dihydroxy(3- tert-butyl 4-(3 -rneth0xy0xid0-pyridinmethoxyoxido-pyridin-1 -iurny1)- 1-iurn—2-y1)—3 ,6-dihydr0-2H-pyridine piperidinecarb0xylate carboxylate tert-butyl (3R,4R)—3 ,4-dihydr0xy tert-butyl 4-pyrirnidinyl-3 ,6-dihydr0- din-Z-y1—piperidinecarb0xylate 2H-pyridine-1 -carb0xylate tert-butyl )-3,4-dihydroxy(3- tert-butyl 4-(3-fluoropyridyl)-3 ,6- fluoropyridyl)-piperidinecarb0xylate dihydro-ZH-pyridinecarb0xylate tert-butyl (3R,4R)-3 ydr0xy(1- tert-butyl 4-(1 -rnethy1pyrazol-3 -y1)-3 ,6- methylpyrazoly1)-piperidine dihydro-ZH-pyridinecarb0xylate carboxylate tert-butyl (3R,4R)-3,4-dihydroxy—4-(3_ utyl 4-(3 -cyanophenyl)-3 ydro- cyanophenyl)—piperidinecarb0xylate 2H-pyridine-1 -carb0xylate tert-butyl (3R,4R)-3 ,4-dihydr0xy(2- tert-butyl 4-(2-methylthiazolyl)-3 ,6- methylthiazo1—4-y1)-piperidine dihydro-ZH-pyridinecarb0xylate carboxylate tert-butyl (3R,4R)-3 ,4-dihydr0xythiazol- tert-butyl 4-thiaz01—4-yl-3 ,6-dihydro-2H- 4-y1—piperidine- 1 xylate necarb0xylate tert-butyl (3R,4R)-3 ,4-dihydr0xyphenyl- tert-butyl 4-pheny1—3 ,6-dihydro-2H- piperidinecarb0xylate pyridinecarb0xylate tert-butyl (3R,4R)-3,4-dihydroxy(3- tert-butyl 4-(3-chloropheny1)-3 ,6- chlorophenyl)-piperidinecarb0xylate dihydro-ZH-pyridinecarb0xylate tert-butyl (3R,4R)—3 ,4-dihydr0xy(2,3 - tert-butyl -difluoropheny1)-5,6- difluorophenyl)-piperidine-1 -carb0xylate dihydropyridine- 1 (2H)-carb0xylate tert-butyl )—3 ,4-dihydr0xy(2,5 - tert-butyl -difluoropheny1)-3,6- difluorophenyl)-piperidine-1 -carb0xylate dihydro-ZH-pyridinecarb0xylate 2014/045675 tert-butyl 6-(trifluoromethyl)-5',6'- tert-butyl (3R,4R)—3,4-dihydroxy d1hydro-[2,4'-b1pyridine]-l'(2'H)—_ _ (trifluoromethyl)-piperidine- l -carboxylate carboxylate tert-butyl (3R,4R)—3,4-dihydroxy[4- tert-butyl 4-[4-(trifluoromethyl) oromethyl)—2-pyridyl] -piperidine- l - pyridyl]-3 ,6-dihydro-2H-pyridine- l - carboxylate carboxylate tert-butyl (3R,4R)-3,4-dihydroxy(6- tert-butyl 4-(6-chloromethoxy chloromethoxypyridyl)-piperidine- l - pyridyl)-3 ,6-dihydro-2H-pyridine- l - carboxylate carboxylate tert-butyl (3R,4R)—4-(6-bromopyridinyl)- tert-butyl 6-bromo-5',6'-dihydro-[2,4'- 3 ,4-dihydroxypiperidine- l -carboxylate bipyridine] -l '(2'H)—carboxylate Step 3: tert-butyl (3aR,7aR)—7a-phenyl—3a,4,6,7— tetrahydro-[1,3] dioxolo[4,5-c]pyridine-S-carboxylate iokO o BrzCHz, NaH, On", NAok DMF O In a 100 mL flask equipped with a nitrogen inlet, utyl (3R,4R)-3,4-dihydroxyphenyl-piperidine-l-carboxylate (l .3 g, 4.5 mmol) was dissolved in DMF (7 mL). The solution was cooled to 0 0C before the addition of sodium hydride (395 mg, 9.86 mmol) (60 wt% dispersion in mineral oil). The reaction mixture was allowed to stir at 0 CC for 20 min before the addition of omethane (344 uL, 4.94 mmol). Following addition, the 0 OC ice bath was d, and the reaction e was allowed to stir at rt for 20 h. Water and saturated aqueous NaCl (total volume of 50 mL) were added and the product was extracted with ethyl acetate (2X 30 mL). The organic layers were ed, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained oil (1.76 grams) was ved in DCM and purified by silica gel column chromatography (80 g column): 0-lO% ethyl acetate/hexane gradient over 25 min, then 10-40% over 15 min. The pure fractions were combined and concentrated to provide tert-butyl (3aR,7aR)—7a-phenyl-3a,4,6,7- tetrahydro-[l,3]dioxolo[4,5-c]pyridinecarboxylate (1.0 g, 73%) as a colorless Viscous oil. 1H NMR (400 MHz, CDClg) 8 7.42 - 7.34 (m, 4H), 7.33 - 7.25 (m, 1H), 5.25 (s, 1H), 4.84 (s, 1H), 4.29 (s, 1H), 3.95 (d, J = 13.0 Hz, 1H), 3.59-3.50 (m, 2H), 3.43 (td, J = 12.3, 3.9 Hz, 1H), 2.15 - 1.91 (m, 2H), 1.50 (s, 9H). ESI-MS m/z calc. 305.2, found 306.0 (M+1)+; Retention time: 1.74 min (3 min run).

The following compounds were prepared using the procedure reported above: Product Precursor tert-butyl (3 aR,7aR)—7a-(3 ,5 - utyl )-3 ,4-d1hydroxy(3 ,5 -_ d1fluorophenyl)-3a,4,6,7-tetrahydro-. . . . difluorophenyl)-pyridine- 1 xylate [1 ,3]dloxolo[4,5-c]pyr1d1necarboxylate tert-butyl (3 aR,7aR)—7a-(3-fluorophenyl)- tert-butyl (3R,4R)-3 ,4-dihydroxy(3- 3a,4,6,7-tetrahydro-[1,3]d10xolo[4,5-_ henyl)-piperidinecarboxylate d1necarboxylate. . tert-butyl (3 aR,7aR)—7a-(4-fluorophenyl)- tert-butyl (3R,4R)-3 ,4-dihydroxy—4-(4_ 3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- fluorophenyl)-piperidinecarboxylate d1necarboxylate. . tert-butyl (3aR,7aR)—7a-(6-bromo tert-butyl (3R,4R)—3 ,4-dihydroxy-(6- pyridyl)-3 a,4,6,7-tetrahydro- bromopyridyl)-piperidine [1 ,3]dioxolo[4,5 -c]pyridine-5 -carboxylate carboxylate utyl (3 aR,7aR)-7a-(2,5 - . tert-butyl (3R,4R)-3 ,4-d1hydroxy(2,5 - d1fluorophenyl)-3a,4,6,7-tetrahydrod1fluorophenyl )-p1per1d1necarboxylate. . . . [1 ,3]dloxolo[4,5-c]pyr1d1necarboxylate. . . tert-butyl (3 aR,7aR)—7a-(3 -chloro tert-butyl (3R,4R)-3 ,4-dihydroxy(3 - pyridyl)-3 a,4,6,7-tetrahydro- chloropyridyl)-piperidine [1 ,3]dioxolo[4,5 idine-5 -carboxylate ylate tert-butyl (3 aR,7aR)-7a-(3-methoxy-1 - _ _ _ _ tert-butyl (3R,4R)-3 ,4-dihydroxy(3 - ox1do-pyr1d1n1umyl)-3 a,4,6,7- methoxypyridiniumyl)- tetrahydro-[ 1 ,3 ] dioxolo [4,5 -c]pyridine-5 - p1per1d1necarboxylate_ _ _ carboxylate tert-butyl (3 aR,7aR)—7apyrimidinyl- tert-butyl (3R,4R)-3 ,4-dihydr0xy piperidine-3a,4,6,7-tetrahydropyrimidin-Z-yl-piperidine-1 -carb0xylate [1 ,3]dioxolo[4,5-c]pyridinecarboxy1ate tert-butyl (3 aR,7aR)-7a-(3-fluor0 tert-butyl (3R,4R)-3 ,4-dihydr0xy(3- pyridyl)-piperidine-3a,4,6,7-tetrahydrofluoropyridy1 )-piperidinecarb0xylate [1 ,3]dioxolo[4,5-c]pyridinecarboxy1ate tert-butyl (3 aR,7aR)-7a-(1 -rnethy1pyrazol- tert-butyl (3R,4R)-3 ,4-dihydr0xy(1- 3-y1)-piperidine-3a,4,6,7-tetrahydro- methylpyrazoly1)-piperidine-1 - [1 ,3]dioxolo[4,5-c]pyridinecarboxy1ate carboxylate utyl (3aR,7aR)-7a-(3-cyan0phenyl)- tert-butyl (3R,4R)-3 ,4-dihydroxy—4-(3_ 3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- cyanophenyl)-piperidine-1 -carb0xylate c]pyridinecarboxylate utyl (3 aR,7aR)-7a-(2-methylthiazol- tert-butyl (3R,4R)-3 ,4-dihydr0xy(2- 4-y1)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- methylthiazoly1)-piperidine c]pyridinecarboxylate carboxylate tert-butyl (3 aR,7aR)-7a-thiazolyltert-butyl )-3 ,4-dihydr0xy 3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- thiazoly1-piperidinecarb0xylate c]pyridinecarboxylate tert-butyl (3aR,7aR)-7a-phenyl-3a,4,6,7- tert-butyl (3R,4R)-3 ,4-dihydr0xy ydro-[ 1 ,3 ] dioxolo [4,5 -c]pyridine-5 - -piperidinecarb0xylate carboxylate utyl (3aR,7aR)-7a-(3-chlor0phenyl)- tert-butyl (3R,4R)-3 ,4-dihydr0xy(3- 3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- chlorophenyl)-piperidine-1 -carb0xylate c]pyridinecarboxylate tert-butyl (3aR,7aR)-7a-(2,3- tert-butyl (3R,4R)-3 ydroxy(2,3- difluorophenyl)—3a,4,6,7-tetrahydrodifluorophenyl )-piperidine- 1 xylate [1 ,3]dioxolo[4,5-c]pyridinecarboxy1ate tert-butyl aR)-7a-(2,5- tert-butyl (3R,4R)-3 ,4-dihydroxy(2,5- difluorophenyl)—3a,4,6,7-tetrahydrodifluorophenyl )-piperidinecarb0xylate [1 ,3]dioxolo[4,5-c]pyridinecarboxy1ate tert-butyl (3aR,7aR)-7a-(trifluoromethyl)- _ tert-butyl (3R,4R)-3 ,4-dihydroxy 3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- (trifluoromethyl)-piperidine- 1 xylate c]pyr1d1necarboxylate. . tert-butyl (3aR,7aR)-7a--[4— tert-butyl (3R,4R)-3 ,4-dihydroxy[4- (trifluoromethyl)pyridyl]-3a,4,6,7- (tr1fluoromethyl)pyr1dyl]-p1per1d1ne-. . . . . 1 - tetrahydro-[ 1 ,3 ] dioxolo [4,5 -c]pyridine-5 - carboxylate carboxylate tert-butyl (3aR,7aR)—7a-(6-chloro utyl (3R,4R)-3,4-dihydroxy(6- methoxypyridyl)—3a,4,6,7-tetrahydro- chloromethoxypyridyl)-piperidine- [l,3]dioxolo[4,5-c]pyridinecarboxylate 1-carboxylate (3 aR,7aR)-tert-butyl bromopyridin- tert-butyl (3R,4R)(6-bromopyridin 2-yl)tetrahydro-[1 ,3]dioxolo [4,5 - . . yl)-3 ,4-dihydroxypiperidinecarboxylate c]pyr1d1ne-5(6H)-carboxylate Step 4: (3aR,7aR)—7a-phenyl—4,5,6,7—tetrahydro-3aH- [1,3]di0xolo[4,5-c]pyridine OJ< TFA Olin.

[00179] A solution of tert-butyl (3aR,7aR)-7a-phenyl-3a,4,6,7- tetrahydro-[l,3]dioxolo[4,5-c]pyridinecarboxylate (980 mg, 3.2 mmol) in DCM (8 mL) was d with 2,2,2-trifluoroacetic acid (2.5 mL). The reaction mixture was stirred at rt for 1.5 h. The on mixture was diluted with DCM (40 mL) and quenched by the addition of aqueous 1 N NaOH (50 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (3 aR,7aR)—7a-phenyl-4,5,6,7-tetrahydro-3aH-[ 1 ,3]dioxolo[4,5-c]pyridine (608 mg, 93.2%) as a pale brown oil that solidified upon standing . 1H NMR (400 C13)8 7.45 (dt, J = 3.0, 1.8 Hz, 2H), 7.42 - 7.33 (m, 2H), 7.33 - 7.27 (m, 1H), .28 (d, J = 0.9 Hz, 1H), 5.05 (d, J = 0.8 Hz, 1H), 4.20 (dd, J = 5.7, 4.8 Hz, 1H), 3.16 (dd, J = 13.4, 4.6 Hz, 1H), 3.07 - 2.94 (m, 2H), 2.83 (dt, J = 12.6, 5.3 Hz, 1H), 2.15 - 1.90 (m, 2H), 1.78 (s, 1H). ESI-MS m/z calc. 205.1, found 206.4 ; Retention time: 0.45 min (3 min run).

] The following compounds were prepared using the procedure reported above: Product Precursor (3 aR,7aR)—7a-(3,5-difluoropheny1)- tert-butyl (3 aR,7aR)-7a-(3,5- 3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- difluoropheny1)-3a,4,6,7-tetrahydro- c]pyridine [1 ,3]dioxolo[4,5 -c]pyridine-5 -carboxy1ate utyl (3aR,7aR)-7a-(3-fluoropheny1)— (3 aR,7aR)—7a-(3-fluoropheny1)—3a,4,6,7- 3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- tetrahydro- [1 ,3 ] dioxolo [4,5 -c]pyridine c]pyridinecarboxy1ate tert-butyl (3aR,7aR)-7a-(4-fluoropheny1)— (3 aR,7aR)—7a-(4-fluoropheny1)—3a,4,6,7- 3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- tetrahydro- [1 ,3 ] dioxolo [4,5 -c]pyridine c]pyridinecarboxy1ate (3 aR,7aR)—7a-(6-brornopyridy1)— tert-butyl (3 aR,7aR)—7a-(6-brorno ,7-tetrahydro-[1,3]dioxolo[4,5- pyridy1)-3 a,4,6,7-tetrahydroc ]pyridine [1 ,3]dioxolo[4,5 idine-5 -carboxy1ate (3 aR,7aR)—7a-(2,5-difluoropheny1)- tert-butyl (3aR,7aR)-7a-(2,5- 3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- difluoropheny1)-3a,4,6,7-tetrahydro- c]pyridine [1 ,3]dioxolo[4,5 -c]pyridine-5 -carboxy1ate (3 aR,7aR)-7a-(3-chloropyridy1)- tert-butyl (3 aR,7aR)-7a-(3-chloro 3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- pyridy1)-3 7-tetrahydroc ]pyridine [1 ,3]dioxolo[4,5 -c]pyridine-5 -carboxy1ate tert-butyl (3 )-7a-(3 -n1ethoxy (3 aR,7aR)-7a-(3-n1ethoxyoxidooxido-pyridin- 1 2-y1)—3 a,4,6,7- pyridiniun1y1)-3 a,4,6,7-tetrahydro- ydro-[ 1 ,3 ] dioxolo [4,5 -c]pyridine-5 - [1 ,3]dioxolo[4,5-c]pyridine carboxylate (3 aR,7aR)-7apyrin1idiny1— tert-butyl (3 aR,7aR)—7apyrin1idiny1— piperidine-3a,4,6,7-tetrahydro- piperidine-3 a,4,6,7-tetrahydro- [1 ,3]dioxolo[4,5-c]pyridine [1 ,3]dioxolo[4,5 -c]pyridine-5 -carboxy1ate (3 aR,7aR)—7a-(3-fluor0pyridy1)— tert-butyl (3 aR,7aR)—7a-(3-flu0r0 piperidine-3a,4,6,7-tetrahydr0- pyridy1)-piperidine-3a,4,6,7-tetrahydro- [1 ,3]di0X010[4,5-c]pyridine [1 ,3]dioxolo[4,5 -c]pyridine-5 -carb0xy1ate (3 )-7a-(1 -rnethy1pyraz01yl)- tert-butyl (3aR,7aR)-7a-(1-rnethy1pyraz01- piperidine-3a,4,6,7-tetrahydro- 3-y1)-piperidine-3a,4,6,7-tetrahydr0- [1 ,3]di0X010[4,5-c]pyridine [1 ,3]dioxolo[4,5 -c]pyridine-5 xy1ate tert-butyl (3 )-7a-(3 -cyanopheny1)- (3 aR,7aR)-7a-(3-cyanopheny1)—3a,4,6,7- 3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- ydro- [1 ,3]diox010[4,5 -c]pyridine c]pyridinecarboxy1ate (3 aR,721R)-7a-(2-methy1thiaz01yl)- tert-butyl (3aR,721R)-7a-(2-methylthiaz01 3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- y1)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- c]pyridine c]pyridinecarboxy1ate tert-butyl (3aR,7aR)-7a-thiaz01y1- (3 aR,7aR)—7a-thiaz01y1-3 a,4,6,7- 3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- tetrahydro- [1 ,3]diox010[4,5 -c]pyridine c]pyridinecarboxy1ate tert-butyl (3aR,7aR)—7a-pheny1-3a,4,6,7- (3 aR,7aR)-7a-pheny1-4,5,6,7-tetrahydro- tetrahydro-[ 1 ,3]diox010[4,5 -c]pyridine-5 - 3aH-[1,3]di0x010[4,5-c]pyridine carboxylate tert-butyl (3aR,7aR)-7a-(3-chlor0pheny1)- (3 aR,7aR)-7a-(3-ch10r0pheny1)—3a,4,6,7- 3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- tetrahydro- [1 ,3]diox010[4,5 -c]pyridine c]pyridinecarboxy1ate (3 aR,7aR)—7a-(2,3-difluor0pheny1)- tert-butyl (3aR,7aR)-7a-(2,3- 3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- difluorophenyl)-3a,4,6,7-tetrahydr0- c]pyridine [1 xolo[4,5 -c]pyridine-5 -carb0xy1ate (3 aR,7aR)—7a-(2,5-difluor0pheny1)- utyl (3aR,7aR)-7a-(2,5- 3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- difluorophenyl)-3a,4,6,7-tetrahydr0- dine [1 ,3]dioxolo[4,5 -c]pyridine-5 -carb0xy1ate tert-butyl (3 )—7a-(trifluoromethyl)- (3 aR,7aR)-7a-(triflu0r0rnethy1)—3a,4,6,7- 3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- tetrahydro- [1 ,3]diox010[4,5 -c]pyridine c]pyridinecarboxy1ate tert-butyl (3 aR,7aR)—7a--[4- (3 aR,7aR)-7a--[4-(trifluoromethyl) (trifluoromethyl)pyridyl]-3a,4,6,7- pyridyl]-3a,4,6,7-tetrahydrotetrahydro- [1 ,3 ] o [4,5 -c]pyridine-5 - [1 ,3]dioxolo[4,5-c]pyridine ylate (3 aR,7aR)-7a-(6-chloromethoxy tert-butyl (3 aR,7aR)-7a-(6-chloro pyridyl)-3a,4,6,7-tetrahydro- methoxypyridyl)-3a,4,6,7-tetrahydro- [1 ,3]dioxolo[4,5-c]pyridine [1 ,3]dioxolo[4,5-c]pyridinecarboxylate tert-butyl (3aR,7aR)-7a-(pyridinyl)- (3 aR,7aR)—7a-(pyridinyl)hexahydro- 3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- [1 ,3]dioxolo[4,5-c]pyridine c]pyridinecarboxylate 6-(4-flu0r0phenyl)azabicyclo[4.1.0]heptane Step 1: 6-phenylazabicyclo[4.1.0]heptane BnBr DIPEA INAQ ] 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (2.1 g, 11.6 mmol was dissolved in DMF (15 mL), and DIPEA (1.5 g, 2.0 mL, 11.6 mmol) was added. A solution of benzylbromide (2.0 g, 1.4 mL, 11.6 mmol) in DMF (5 mL) was added dropwise. After 5 min of stirring at rt, the solvent was removed under d re. The remaining oil was dissolved in ethyl acetate (75 mL) and washed with saturated aqueous NaCl (1 X 75 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude t was purified by silica gel column chromatography: 40 gram silica gel column, 0-15% methanol/DCM gradient over 30 min with 1% aqueous ammonium hydroxide to afford 1-benzyl(4- fluorophenyl)-3,6-dihydro-2H-pyridine (3.1 g, 100%) was ed as a brownish-red oil. 1H NMR (400 MHz, CDClg) 5 7.40 = 7.5, 4.0, 1.7 Hz, - 7.31 (m, 6H), 7.27 (ddd, J 1H), 7.03 = 5.0, 1.7 Hz, 1H), 3.64 (s, 2H), 3.16 (dd, J = 6.0, - 6.94 (m, 2H), 6.00 (dt, J 2.9 Hz, 2H), 2.71 (t, J = 5.7 Hz, 2H), 2.58 - 2.48 (m, 2H). ESI-MS m/z calc. 267.1, found 268.4 (M+1)+; Retention time: 1.09 min (3 min run).

The following compounds were prepared using the procedure reported above: Product Precursor 1-benzylphenyl-3 ,6-dihydro-2H-pyridine 4-phenyl- 1,2,3,6-tetrahydropyridine 1-benzyl(4-fluorophenyl)-3 ,6-dihydro-2H- luorophenyl)-1,2,3 ,6-tetrahydropyridine pyr1'd'1ne Step 2: 3-benzylphenyl—3-azabicyclo[4.1.0]heptane N/\© —,F/©§:)\ldiethylzinc, TFA, CHZIZ /\© A solution of diethylzinc (39.7 mL of 15 %w/V, 48.1 mmol) in toluene was added to anhydrous DCM (25 mL) at 0 OC. TFA (3.7 mL, 48.1 mmol) in DCM (12 mL) was added, and the ing slightly gelatinous mixture was allowed to stir for 20 min at 0 CC. Diiodomethane (4.1 mL, 50.5 mmol) in DCM (12 mL) was slowly added dropwise and the reaction mixture was stirred at 0 0C for 20 min forming white . A solution of l-benzyl(4-fluorophenyl)—3,6-dihydro-2H- pyridine (3.2 g, 12.0 mmol) in DCM (12 mL) was added at 0 CC, and the reaction e was d to stir at rt for 45 min. The reaction mixture was carefully quenched with the addition of saturated aqueous ammonium chloride solution (125 mL). The organic layer was then washed with l N HCl (l X 100 mL) and saturated aqueous sodium onate solution (1 X 100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under d pressure. The remaining oil was purified by silica gel column chromatography: 40 gram silica gel column, 0-30% ethyl acetate/DCM gradient over 25 min; product eluted at 10% while the quaternary side-product eluted at 25%. Pure fractions were combined and concentrated to provide 3-benzyl(4-fluorophenyl)—3-azabicyclo[4.l.0]heptane (1.5 g, 44%) as an orange oil. 1H NMR (400 MHz, CDC13)5 7.37 - 7.29 (m, 4H), 7.27 - 7.19 (m, 3H), 6.98 - 6.90 (m, 2H), 3.54 - 3.41 (m, 2H), 2.85 = 13.5, - 2.71 (m, 2H), 2.34 - 2.18 (m, 2H), 2.09 (tdd, J 9.0, 6.6 Hz, 2H), 1.34 (dtd, J = 8.9, 5.6, 2.0 Hz, 1H), 0.92 (dt, J = 9.1, 4.1 Hz, 2H).

ESI-MS m/z calc. 281.2, found 282.5 (M+1)+; Retention time: 1.13 min (3 min run).

The following compounds were ed using the procedure reported above: Product sor 3 -benzylphenyl-3 -azabicyclo [4. 1.0]heptane 1-benzylphenyl-3 ,6-dihydro-2H-pyridine 3-benzyl-(4-fluorophenyl) 1-benzyl(4-fluorophenyl)-3,6-dihydro-2H- azabicyclo[4. 1 .0]heptane pyridine Step 3: 6-(4-flu0r0phenyl)—3-azabicyclo[4.1.0]heptane 1. )1 c—hloroethyl N/\©—>2.)MeOH (40 oroformate, DCM NH F F A on of 1-chloroethyl chloroformate (3.8 g, 2.8 mL, 26.3 mmol) in DCM (3 mL) at 0 CC was treated dropwise with a solution of 3-benzyl(4- fluorophenyl)azabicyclo[4.1.0]heptane (1.5 g, 5.3 mmol) in DCM (6 mL). The reaction mixture was allowed to stir at rt for 30 min. Methanol (25 mL) was added to the solution, and it was stirred at 40 0C for 30 min. The volatiles were d under reduced pressure, and the remaining solid was suspended in aqueous 1 N HCl (75 mL).

The suspension was extracted with ethyl acetate (1 X 75 mL). The aqueous layer was adjusted to pH 12 with the addition of aqueous 1 N NaOH (100 mL). The resulting cloudy white suspension was extracted with ethyl e (2 X 75 mL). The final organic layers were combined, dried over sodium , filtered and concentrated under reduced pressure to provide 6-(4-fluorophenyl)—3-azabicyclo[4.1.0]heptane (0.8 g, 79%) as a clear yellow oil that crystallized upon standing. 1H NMR (400 MHz, CDC13)5 7.26 = 12.8, 5.7 Hz, 1H), 3.08 - 7.19 (m, 2H), 6.99 - 6.91 (m, 2H), 3.36 (dd, J (d, J = 12.7 Hz, 1H), 2.75 = 12.8, 6.3, 4.2 Hz, 1H), 1.96 - 2.58 (m, 2H), 2.02 (ddd, J - 1.86 (m, 1H), 1.42 - 1.20 (m, 2H), 0.95 (dd, J = 9.3, 4.4 Hz, 1H), 0.81 (dd, J = 5.5, 4.8 Hz, 1H). ESI-MS m/z calc. 191.1, found 192.4 (M+1)+; Retention time: 0.58 min (3 min run).

The following compounds were prepared using the procedure reported above: Product Precursor 6-(4-fluorophenyl) 3-benzylphenyl azabicyclo[4. 1 .0]heptane azabicyclo[4. 1 .0]heptane 3-benzyl-(4-fluorophenyl) 6-phenylazabicyclo[4. 1 .0]heptane azabicyclo[4. 1 .0]heptane (ZS,4S)-tert-butyl 4-methoxytri- 2-[(ZS,4S)methyl (tr1deuteriomethoxy)p1per1dyl]th1azole. . . . . deutero-methyl(thiazolyl)piperidine- 1-carboxylate (4-is0pr0p0xymethylphenyl)(6-phenyl—7—0xa azabicyclo[4.2.0] 0ctanyl)—methan0ne Step 1: tert—butyl 3-[[tert-butyl(dimethyl)silyl]oxymethyl]- 4-0x0-piperidine—l-carboxylate Nioko JL J< 1. NaBH4, K2003, MeOH (0 °C) N o o O 2. TBSCI, DIPEA, DCM 3. DMP, NaHCO3, DCM o o OTBS ] To a solution of Ol-tert-butyl O3-ethyl 4-oxopiperidine-1,3- dicarboxylate (5 g, 18.4 mmol) in methanol (50 mL) at 0 0C was added sodium borohydride (1.74 g, 46.1 mmol) portionwise over 15 min. The reaction e was stirred at 0 0C for 30 min and was trated under reduced re. The resulting e was diluted with water and adjusted to pH 3 with 1N HCl. The mixture was extracted with ethyl acetate (3x) and the combined organic layers were dried over sodium sulfate and concentrated under d pressure to afford tert-butyl 4-hydroxy- 3-(hydroxymethyl)piperidinecarboxylate (4.1 g) as a white solid.

In a 250 mL round bottom flask ning tert-butyl 4- y(hydroxymethyl)piperidine-l-carboxylate (2.0 g, 8.6 mmol) was added dichoromethane (50.0 mL) followed by triethylamine (2.8 mL, 20 mmol). tert- Butyldimethylsilyl chloride (1.5 g, 10.2 mmol) was added portionwise and the reaction mixture was allowed to stir at rt ovn. The reaction e was almost complete by lcms. The reaction mixture was quenched with saturated aqueous ammonium chloride and saturated aqueous NaCl and extracted with dichloromethane. The organic layer was seperated and dried over sodium sulfate and then concentrated under reduced pressure. The crude product was used in the next step without purification.

] To a 250 mL round bottom flask containing crude tert-butyl 3- [[tert—butyl(dimethyl)silyl]oxymethyl]hydroxy-piperidine-l-carboxylate (2.4 g) was added DCM (24 mL) and sodium bicarbonate (2.0 g, 20.4 mmol). The reaction mixture was cooled to 0 0C for 5 min and Dess-Martin periodane (3.6 g, 8.5 mmol) was added.

The reaction mixture was stirred for 3 h while warming to rt. The on e was filtered and trated under reduced pressure to dryness. The crude product was purified Via silica gel chromatography (0-50%) DCM:ethyl acetate to provide tert- butyl 3-[[tert-butyl(dimethyl)silyl]oxymethyl]oxo-piperidine- l -carboxylate (l .7 g, 71%) as a clear yellow oil. ESI-MS m/z calc. 343.5, found 344.4 (M+1)+; Retention time: 2.47 min (3 min run).

[00196] Step 2: tert-butyl 4-hydr0xy(methylsulfonyloxymethyl)— 4-phenyl-piperidine—l-carboxylate NJkOJ<0 fl J< 1.Ph-Mg-X,THF(—78°C-25°C) N O O 2. TBAF, THF OH 3. MSCI, TEA OTBS To a 100 mL round bottom flask was added tert—butyl 3-[[tert- butyl(dimethyl)silyl]oxymethyl]oxo-piperidine-l-carboxylate (1.0 g, 2.9 mmol) and THF (9 mL). The mixture was cooled to -78 CC and phenyl magnesium chloride (1.46 ml, 2 M, 2.9 mmol) was added dropwise and the reaction mixture was allowed to warm to rt over 1h. The on mixture was quenched with saturated s um chloride and extracted with ethyl acetate (3x). The organic layers were separated, dried over sodium sulfate, and concentrated under reduced pressure to provide tert-butyl 3- [[tert-butyl(dimethyl)silyl]oxymethyl]hydroxyphenyl-piperidinecarboxylate as a clear colorless oil which was diluted with THF (9 mL). The mixture was treated with tetra-n-butylammonium e (4.4 mL of 1 M, 4.4 mmol) and the reaction mixture was allowed to stir at rt for 10 min. The on mixture was quenched with water and extracted with ethyl acetate (3x). The organic layers were seperated, dried over sodium sulfate, and concentrated under reduced pressure to afford tert-butyl 4- hydroxy(hydroxymethyl)phenyl-piperidinecarboxylate which was dissolved in dichoromethane (9 mL) and treated with triethylamine (0.81 mL, 5.8 mmol), and methanesulfonyl chloride (0.23 mL, 2.9 mmol). The reaction mixture was quenched with water and extracted with dichoromethane (3x). The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude on mixture was purified Via silica gel chromatography 0%-25% ethyl acetate in dichoromethane to afford tert-butyl 4-hydroxy(methylsulfonyloxymethyl)phenyl-piperidine carboxylate (0.7 g, 63%) as a pale yellow oil. ESI-MS m/z calc. 385.5, found 386.3 (M+1)+; Retention time: 1.80 min (3 min run).

Step 3: (4-hydroxyphenylpiperidyl)methyl methanesulfonate ii J< N O HCI, DCM NH OH OH OMS OMS To a 100 mL round bottom flask was added dichoromethane (10 mL), and HCl (0.45 mL of 4 M, 1.83 mmol) and the reaction mixture was d to stir at rt for 4 h. The on mixture was concentrated under reduced pressure to afford (4-hydroxyphenylpiperidyl)methyl methanesulfonate hloride (596 mg) which used in the next reaction without purification. ESI-MS m/z calc. 285.1, found 286.3 (M+1)+; Retention time: 0.92 min (3 min run).

[00200] Step 4: (4-hydr0xy(4-is0pr0p0xymethylbenzoyl)—4- phenylpiperidinyl)methyl methanesulfonate HATU, TEA, DMFkQ/KEN: To a vial was added the 4-isopropoxymethyl-benzoic acid (39 mg, 0.2 mmol), HATU (76 mg, 0.2 mmol), DMF (2 mL), and triethylamine (0.7 mL, 5 mmol) and the reaction e was allowed to stir for 10 min at rt. A solution of (4-hydroxy(4-isopropoxymethylbenzoyl)phenylpiperidinyl)methyl methanesulfonate (57 mg, 0.2 mmol) dissolved in DMF (1 mL) was added and the reaction mixture was d to stir for 15 min. The reaction was quenched with ted aqueous NaCl and extracted with ethyl acetate. The ethyl acetate layer was further rinsed with saturated aqueous NaCl (3x) to remove any DMF. The organic layers were dried over sodium sulfate, concentrated under reduced pressure, and used in the next on without further purification. ESI-MS m/z calc. 461.6, found 462.1 (M+l)+; Retention time: 1.93 min (3 min run).

The following compounds were prepared using the procedure reported above: Product (4-hydroxy(4-isopropoxy-3 - (4-hydroxypheny1—3 _ methylbenzoyl) 4-ISOpropoxy-3 _. p1per1dyl)methyl. . phenylpiperidinyl)methyl -benzoic acid methanesulfonate methanesulfonate (4-hydroxy(5-isopropoxy _ _ 5-isopropoxy (4-hydroxyphenyl methyl-pyr1d1necarboxyl) methyl-pyridine piperidyl)methyl phenylpiperidinyl)methyl carboxylic acid methanesulfonate methanesulfonate (4-hydroxy(3 -methoxy(2- . oxy(2- (4-hydroxyphenyl (tr1fluoromethoxy)ethoxy)benzoyl (trifluoromethoxy)eth piperidyl)methyl )4- . -ph 1 eny :p1 n-3 -y1)methy1 oxy)benzoic acid methanesulfonate met anesuIfonate (4-hydroxy(2-fluoromethy1- 4-(2-fiuoromethy1— (4-hydroxypheny1—3- propoxy)—3-methoxy-benzoy1)—4- propoxy)—3-methoxy- p1per1dy1)methy1_ _ piperidiny1)methy1 benzoic acid methanesulfonate methanesu1fonate (4-hydroxy-1 -(quinoline (4-hydroxypheny1—3 - qu1nohnecarboxy11c. . . carboxyl)pheny1p1per1d1n. . . p1per1dy1)methy1. . ac1'd hy1 methanesu1fonate methanesu1fonate (4-hydroxy- 1 thoxy 3-methoxy[(3R)- (4-hydroxypheny1—3- [(3R)-tetrahydrofuran-3 -y1]oxy- benzoy1)pheny1p1per1d1n. . . tetrahydrofi1ran piperidy1)methy1 y1]oxy-benzoic acid methanesu1fonate y1)methy1 methanesu1fonate Step 5: (4-isopr0p0xymethylphenyl)(6-phenyloxa azabicyclo[4.2.0] 3-yl)—methan0ne O O Q)? NaH N)UorT ©3§N)U OMS A Vial containing the (4-hydroxy(4-isopropoxy methylbenzoy1)pheny1piperidiny1)methy1 methanesu1fonate (92 mg, 0.2 mmol) in THF (1.5 mL) was treated with NaH in mineral oil (60%, 8 mg, 0.2 mmol). The reaction mixture was stirred at rt for 1h, filtered and purified by reverse phase HPLC (1-99%) ACN:H20 with no modifier) to afford (4-isopropoxymethy1pheny1)(6- pheny1oxaazabicyclo[4.2.0]octany1)-methanone (13 mg, 18%). 1H NMR (400 MHz, MeOD) 5 7.47 - 7.22 (m, 7H), 6.99 (t, J = 9.1 Hz, 1H), 4.72 - 4.54 (m, 2H), 4.46 - 4.03 (m, 2H), 3.99 - 3.74 (m, 2H), 3.66 (dd, J = 25.7, 12.9 Hz, 1H), 3.09 (t, J = 15.9 Hz, 1H), 2.57 — 2.25 (m, 1H), 2.21 (d, J = 7.8 Hz, 3H), 1.34 (d, J = 5.8 Hz, 6H). ESI-MS m/z ca1c. 365.5, found 366.5 ; Retention time: 1.95 min (3 min run).

The ing compounds were prepared using the procedure reported above: Product Precursor (4-isopropoxyn1ethy1pheny1)(6-pheny1 roxy(4-isopropoxy-3 - azabicyclo[4.2.0]octanyl)— methylbenzoyl)pheny1piperidin-3 - methanone yl)n1ethy1 methanesulfonate (4-hydroxy(5-isopropoxy (5 -isopropoxyn1ethy1-pyridine -pyridinecarboxyl) carboxy1)-(6-pheny1oxa phenylpiperidin-3 -y1)n1ethy1 azabicyclo[4.2.0]octany1)—n1ethanone methanesulfonate (3 -rnethoxy(2- (4-hydroxy(3-n1ethoxy(2- (trifluoromethoxy)ethoxy)benzoy1)—(6- (trifluoromethoxy)ethoxy)benzoy1)- pheny1oxaazabicyclo[4.2.0]octanyl) 4-pheny1piperidin-3 -y1)n1ethy1 methanone esulfonate (4-hydroxy-1 -(2-fluoron1ethy1— (4-(2-fluoron1ethy1—propoxy)—3-n1ethoxy- propoxy)n1ethoxy-benzoyl) benzoyl)-(6-pheny1oxa phenylpiperidin-3 -y1)n1ethy1 azabicyclo[4.2.0]octany1)—n1ethanone methanesulfonate (4-hydroxy-1 -(quinolinecarboxy1)— quinolinecarboxy1)-(6-pheny1oxa 4-pheny1piperidin-3 -y1)n1ethy1 azabicyclo[4.2.0]octany1)—n1ethanone methanesulfonate (4-hydroxy(3-n1ethoxy[(3R)n1ethoxy-4 -[(3R)-tetrahydrofuran-3 - tetrahydrofuranyl]oxy-benzoyl) yl]oxy-benzoyl)-(6-pheny1—7-oxa phenylpiperidin-3 -y1)n1ethy1 azabicyclo[4.2.0]octany1)—n1ethanone methanesulfonate

[00206] (3aR,7aR)—tert—butyl 7a-(pyridin-Z-yl)tetrahydr0- [1,3]dioxolo[4,5-c]pyridine-5(6H)—carboxylate WO 06280 AOL J< Pd/C, H2 O (1 atm) EtOH A solution of tert-butyl (3 aR,7aR)—7a-(6-bromopyridyl)- 3a,4,6,7-tetrahydro-[l,3]dioxolo[4,5-c]pyridinecarboxylate (342 mg, 0.88 mmol) was dissolved in absolute ethanol (10 mL) and stirred under nitrogen before the addition of 10% palladium on carbon (473 mg, 0.44 mmol). The on mixture was evacuated and put under hydrogen gas (1 atm) for 2 h. The reaction mixture was filtered through a pad of celite, rinsed with DCM, and concentrated under reduced pressure to provide tert—butyl (3 aR,7aR)-7a-(2-pyridyl)-3a,4,6,7-tetrahydro- [l,3]dioxolo[4,5-c]pyridinecarboxylate (266 mg, 99%) as a clear yellow-brown oil. 1H NMR (400 MHz, CDC13)5 8.99 (s, 1H), 8.44 (s, 1H), 8.09 (s, 1H), 7.91 (s, 1H), .35 (s, 1H), 5.13 (s, 1H), 4.72 (s, 1H), 4.23 (s, 1H), 4.07 (d, J = 15.1 Hz, 1H), 3.60 (s, 2H), 2.80 (s, 1H), 2.20 (d, J = 14.4 Hz, 1H), 1.49 (s, 9H).ESI-MS m/z calc. 306.2, found 307.5 (M+l)+; Retention time: 1.1 min, (3 min run). [(3aR,7aR)—7a-(3-flu0r0pyridyl)—3a,4,6,7—tetrahydr0- [1,3]dioxolo[4,5-c]pyridin-S-yl]-(3-chlor0flu0r0-phenyl)methan0ne 2-ter1—butoxyethanol, NaH DMF (80 °C), A In a vial, 2-tert-butoxyethanol (155 mg, 1.31 mmol) was ved in DMF (500 uL). NaH (52 mg, 1.31 mmol) (60% oil sion) was added in small portions and the suspension was stirred at rt for 25 min. [(3aR,7aR)-7a-(3- fluoropyridyl)-3 a,4,6,7-tetrahydro-[ l ,3 ] dioxolo [4,5 -c]pyridin-5 -yl] -(3 -chloro fluoro-phenyl)methanone (50 mg, 0. 13 mmol) as a solution in DMF (100 uL) was added and the reaction mixture was stirred at 80 CC for lh. The reaction mixture was quenched by the addition of water and the e was extracted with DCM (3x). The combined extracts were dried over sodium sulfate and the volatiles were removed under d re. The material was dissolved in DMF (lmL) and purified by preparative HPLC using HCl as a modifier. Evaporation of the volatiles provided [(3 aR,7aR)-7a-[3-(2-tert-butoxyethoxy)pyridyl]-3a,4,6,7-tetrahydro- [1 ,3]dioxolo [4,5 -c]pyridin-5 -yl] -[4-(2-tert-butoxyethoxy)-3 -chloro-phenyl]methanone (38 mg, 46.5%) as a colorless glass. ESI-MS m/z calc. 576.3, found 577.0 (M+1)+; Retention time: 1.48 min (3 min run). 7a-(pyridinyl)octahydrofuro[3,2-c]pyridine [0021 1] Step 1: benzyl 3-allyl0x0-piperidinecarb0xylate 0&0N/CbZ propenol, Xantphos, m,Cbz dCI]2, pyrrolidine-Z-carboxylic acid 0 DMSO A mixture of benzyl 4-oxopiperidinecarboxylate (14.0 g, 60.0 mmol), -enol (3.4 mL, 50 mmol), idinecarboxylic acid (1.7 g, .0 mmol) and (5-diphenylphosphanyl-9,9-dimethyl-xanthenyl)-diphenyl- phosphane (1.45 g, 2.5 mmol) in DMSO (100 mL) was purged with nitrogen for 5 min.

The mixture was treated with 1,3-diallyl-dichloro-dipalladacyclobutane (457 mg, 1.25 mmol) and heated at 75 0C for 72 h. The reaction mixture was cooled to rt and filtered through celite (ethyl acetate). The filtrate was repartitioned between ethyl acetate and water. The aqueous layer was ted with ethyl acetate (2x). The combined organic layers were washed with water (3x), dried over MgSO4, filtered and concentrated to s. The crude material was purified by column chromatography (0-10% ethyl acetate-hexanes) to provide benzyl 3-allyloxo-piperidinecarboxylate (11.5 g, 84.1%). ESI-MS m/z calc. 273.3, found 274.5 (M+1)+; Retention time: 1.72 min (3 min run).

Step 2: benzyl 6-(2-hydr0xyethyl)—1,4-di0xa ro[4.5]decane—S-carboxylate \ N/CbZ 1. pTSA, ethylene glycol, PhCH3 O :1 SS’BIID-IE,MMeOH How/CMO£0 ] To a solution of benzyl loxo-piperidinecarboxylate (6.0 g, 22.0 mmol) in toluene (100 mL) was added ethylene glycol (1.4 g, 1.2 mL, 22.0 mmol) followed by the addition of 4-methylbenzenesulfonic acid-(water) (0.6 mL, 3.3 mmol). The reaction mixture was equipped with a Dean-Stark trap and heated at reflux overnight. The reaction mixture was cooled to rt, washed with saturated sodium bicarbonate (2x), saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to dryness. The crude material benzyl 6-allyl-1,4-dioxaazaspiro[4.5]decane carboxylate was used directly in next step without further purification.

A solution of benzyl 6-allyl-1,4-dioxaazaspiro[4.5]decane- 8-carboxylate (3.2 g, 10.0 mmol) in DCM (30 mL) was cooled to -78 0C. Ozone was bubbled through the solution for 10 min until a light blue color persisted. The blue on was then d with en gas for 10 min to remove the excess of ozone.

MeOH (30 mL) was added followed by the addition of sodium borohydride (380 mg, .0 mmol). The reaction mixture was stirred at rt for 5 min, and was repartitioned between ethyl e and water. The aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated to s. The crude material was purified by column tography (30-40% ethyl e-hexanes) to provide benzyl 6-(2- hydroxyethyl)-1,4-dioxaazaspiro[4.5]decanecarboxylate (1.7 g, 53%). ESI-MS m/z calc. 321.4, found 322.5 (M+1)+; Retention time: 1.44 min (3 min run).

Step 3: Step 4: benzyl 10-(2-chloroethyl)—1,4-dioxa azaspiro [4.5] decane—8-carb0xylate HO“as —» noa N,Cbz SOCIZ, DMF, ne, CI N,Cbz O c0

[00217] To a solution of benzyl 10-(2-hydroxyethyl)-1,4-dioxa azaspiro[4.5]decanecarboxylate (320 mg, 1.0 mmol) in chloroform (10 mL) was added thionyl chloride (290 uL, 4.0 mmol) followed by the addition of a drop of pyridine and a drop of DMF. The reaction mixture was heated at reflux for 1 h, concentrated to dryness and purified by column chromatography (10-20% ethyl acetate-hexanes) to provide benzyl 10-(2-chloroethyl)-1,4-dioxa azaspiro[4.5]decanecarboxylate (140 mg, 41%) as a colorless oil. ESI-MS m/z calc. 339.8, found 340.5 (M+1)+; Retention time: 1.89 min (3 min run).

Step 4: benzyl 7a-(2-pyridyl)—2,3,3a,4,6,7— hexahydrofuro[3,2-c]pyridine-S-carboxylate 0' NOW 1. HCI (aq), EtOH N’ O —> </ O 2. butyllithium, 2-bromopyridine O THF (—78 °c - 25 °C) \ I N To a solution of benzyl lO-(2-chloroethyl)-l,4-dioxa azaspiro[4.5]decanecarboxylate (68 mg, 0.2 mmol) in EtOH (2 mL) was added aqueous HCl (1 mL of l M, 1.0 mmol). The reaction mixture was heated in a sealed Vial at 70 0C for 3 h. The volume was reduced to U3. The residue was repartitioned n ethyl acetate and water. The s layer was extracted with ethyl acetate (2x). The combined c layers were washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to dryness to afford crude benzyl 3-(2- chloroethyl)oxo-piperidine-l-carboxylate which was used ly in next step without filrther purification.

A solution of 2-bromopyridine (49 mg, 0.31 mmol) in THF (5 mL) was cooled to -78 0C and treated with ithium (10 mg, 0.16 mmol) (1M in hexanes) se under an argon atmosphere. The reaction mixture was stirred at -78 0C for 30 min and crude benzyl 3-(2-chloroethyl)oxo-piperidine-l-carboxylate (46 mg, 0.16 mmol) in THF (1 mL) was added dropwise. The reaction mixture was allowed to warm to rt and stirred over for 72 h. The reaction mixture was quenched with ted aqueous um chloride. The aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by column chromatography (20-30% ethyl acetate-hexanes) to provided benzyl 7a-(2-pyridyl)-2,3,3a,4,6,7-hexahydrofuro[3,2-c]pyridinecarboxylate. ESIMS m/z calc. 338.4, found 339.3 (M+l)+; Retention time: 1.28 min (3 min run).

Step 5: 7a-(2-pyridyl)—3,321,4,5,6,7—hexahydr0-2H-fur0[3,2- c]pyridine ’Cbz H2 (1 atm), Pd/C NH M OHe / N / A solution of benzyl 7a-(2-pyridyl)-2,3,3a,4,6,7- hexahydrofi1ro[3,2-c]pyridinecarboxylate (22 mg, 0.06 mmol) in MeOH (5 mL) was WO 06280 purged with nitrogen for 5 min. The mixture was treated with 10% palladium on carbon (14 mg, 0.013 mmol). The mixture was the evacuated and put under a en atmosphere (balloon) at rt. The Pd-catalyst was removed via filtration and washed with MeOH. The solvent was removed under reduced pressure affording crude 7a-(2-pyridyl)-3,3a,4,5,6,7-hexahydro-2H-furo[3,2-c]pyridine which was used directly in next step without further purification. ESI-MS m/z calc. 204.3, found 205.3 (M+1)+; Retention time: 0.184 min (3 min run). (3aR,7aR)-7a-(6-methylpyridyl)—4,5,6,7-tetrahydr0-3aH- [1,3]di0xolo[4,5-c]pyridine OJ< a.) Pd(PPh3)4, (CH3)3AI, THF b.) TFA, DCM A flask ning tert-butyl (3aR,7aR)-7a-(6-bromo pyridyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridinecarboxylate (84 mg, 0.22 mmol) in THF (1 mL) was treated with Pd(PPh3)4 (126 mg, 0.11 mmol). The mixture was purged with nitrogen and trimethylalumane (31 mg, 42 uL, 0.44 mmol) was added. The solution was heated to 70 0C over 16 h. Water (1 ml) was added and e was extracted with EtOAc (3x). The organic layers were combined and washed with 1 ml of saturated s NaCl, dried over sodium sulfate, concentrated, providing the tert-butyl (3 aR,7aR)-7a-(2-pyridyl)—3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- c]pyridinecarboxylate as a yellow oil which was treated with a 1:1 mixture of TFA/DCM (1 mL). The reaction mixture was allowed to stir for 1 h and was concentrated under d pressure to provide (3aR,7aR)-7a-(6-methylpyridyl)- 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridine, which was used in the next step without fiarther purification. ESI-MS m/z calc. 220.1, found 221.1 (M+1)+; Retention time: 0.228 min (3 min run).

[00225] 7a-(6-isobut0xypyridyl)—4,5,6,7—tetrahydr0-3aH— [1,3]di0xolo[4,5-c]pyridine OJ< a.) 2-methylpropanol, NaH, DMF b.) TFA, DCM A solution of 2-methylpropanol (240 uL, 2.60 mmol) in DMF (1 mL) was d with sodium hydride (104 mg, 2.6 mmol)(60% dispersion in mineral oil) at 0 0C. The reaction mixture was allowed to stir for 5 min and tert-butyl (3 aR,7aR)—7a-(6-bromopyridyl)-3 a,4,6,7-tetrahydro-[1 ,3]dioxolo[4,5-c]pyridine carboxylate (100 mg, 0.26 mmol) in DMF (0.5 mL) was added. The reaction mixture was allowed to stir at rt for 16 h. Water (lml) was added and mixture was extracted with ethyl acetate (3x). The organic layers were combined and washed with saturated aqueous NaCl, dried over sodium sulfate, and concentrated to afford crude tert-butyl (3 aR,7aR)—7a-(2-pyridyl)-3 a,4,6,7-tetrahydro-[ 1 ,3 ]dioxolo [4,5 -c]pyridine-5 - carboxylate as a yellow oil. The crude product was treated with a 1 ml of 1 :1 e TFA/DCM and the reaction mixture was allowed to stir for 1 h. The on e was concentrated under d pressure to afford 7a-(6-isobutoxypyridyl)-4,5,6,7- tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridine as yellow oil (50 mg, 51%). ESI-MS m/z calc. 278.3, found 279.2 (M+1)+; Retention time: 0.23 min (3 min run). (3-meth0xy(2-(triflu0romethoxy)ethoxy)phenyl)((syn)— 7a-(pyridinyl)hexahydrofuro[3,4-c]pyridin-5(3H)-yl)methanone Step 1: (syn)—tert—butyl 1-0x0hexahydr0fur0[3,4- c]pyridine-5(3H)-carb0xylate / 1. H2 (55 psi), PtOz, HCI, H20 N N102 O I O 2. BOCZO, TEA, DCM/MeOH o 0 A solution of 3H-furo[3,4-c]pyridinone (3.2 g, 23.7 mmol) in HCl (17 mL of 1 M, 17 mmol) and water (17 mL) in a Parr shaker was d with PtOz (700 mg, 3.1 mmol). The mixture was hydrogenated at 55 psi overnight. The catalyst was ed off and the filtrate was concentrated to afford a yellow oil. The resulting oil was diluted with DCM (237 mL) and MeOH (35 mL) and was treated with TEA (8.3 mL, 59.2 mmol) followed by Boc-anhydride (5.7 g, 26.1 mmol). The 2014/045675 reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water and ted with DCM (3 x). The combined organics were dried (Na2S04), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (Si02-24 g, 30-100 % hexanes) afforded (syn)-tert—butyl 1- oxohexahydrofiaro[3,4-c]pyridine-5(3H)-carboxylate (3.1 g, 93%). 1H NMR (400 MHz,CDC13)8 4.27 (dd, J = 9.4, 5.6 Hz, 1H), 3.97 (dd, J = 9.5, 2.0 Hz, 2H), 3.73 (s, 1H), 2.96 - 2.76 (m, 3H), 2.72-2.68 (m, 1H), 2.01 (dq, J = 13.9, 3.6 Hz, 1H), 1.90-1.82 (m, 1H), 1.44 (s, 9H). ESI-MS m/z calc. 241.1, found 242.5 (M+1)+; Retention time: 1.34 min. (3 min run).

[00230] Step 2: tert-butyl 1-0x0-7a-(2-pyridyl)—3a,4,6,7—tetrahydr0- 3H-fur0[3,4-c]pyridine-S-carboxylate Nick Br N\ / NJKOJ< Pd[P(tBu)3]2, LHMDS, O toluene \ N ] In an oven dried flask was added tert-butyl 1-oxo- 3,3a,4,6,7,7a-hexahydrofuro[3,4-c]pyridinecarboxylate (60 mg, 0.25 mmol) which was put under an inert atmosphere (nitrogen) and diluted with toluene (300 uL). The mixture was treated with Pd[P(tBu)3]2 (6.3 mg, 0.012 mmol) and LiHMDS (300 uL of 1 M, 0.30 mmol), ed by 2-bromopyridine (36 uL, 0.37 mmol). The reaction e was warmed to 50 OC and stirred for 20 h. The reaction e was cooled to rt, diluted with saturated aqueous ammonium chloride and extracted with ethyl e (3x). The combined organics were washed with saturated aqueous NaCl, dried (Na2S04), filtered, and concentrated under reduced pressure. Purification by reverse phase HPLC (1-100% ACN/HZO) afforded tert—butyl 1-oxo-7a-(2-pyridyl)-3a,4,6,7- tetrahydro-3H-fi1ro[3,4-c]pyridinecarboxylate (30 mg, 38%) 1H NMR (400 MHz, CDC13)5 8.57 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.73 (td, J = 7.8, 1.8 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.25 (ddt, J = 4.9, 2.9, 2.5 Hz, 1H), 4.33 (dd, J = 9.2, 6.4 Hz, 1H), 4.03 (dd, J = 9.2, 4.2 Hz, 1H), 3.93 (dd, J = 13.9, 5.4 Hz, 1H), 3.63 - 3.49 (m, 2H), 3.29- 3.23 (m, 2H), 2.26 (ddd, J = 14.0, 5.2, 4.0 Hz, 1H), 2.20 - 2.06 (m, 1H), 1.47 (s, 9H).

ESI-MS m/z calc. 318.2, found 319.1 (M+1)+; Retention time: 1.59 min (3 min run).

Step 3: tert—butyl 3,4-bis(hydr0xymethyl)—4-(2- pyridyl)piperidine-l-carboxylate O OH N/U\OJ< NaBH4 HO NAOJ< THF, e I C” A solution of tert-butyl 1-oxo-7a-(2-pyridyl)-3a,4,6,7- tetrahydro-3H-fi.1ro[3,4-c]pyridinecarboxylate (0.56 g, 1.76 mmol) in THF (6.5 mL) and toluene (2 mL) was treated with lithium borohydride (153 mg, 7.0 mmol). The reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to 0 oC and diluted with DCM and ethyl acetate. The reaction mixture was quenched with ted aqueous ammonium chloride and 1 M HCl and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate. The mixture was extracted with DCM (3x) and the combined organics were dried (Na2S04), filtered, and trated under reduced pressure. Purification by flash column chromatography (Si02-24 g, 40-100 % ethyl acetate-DCM) afforded utyl 3 ,4-bis(hydroxymethyl)(2-pyridyl)piperidine carboxylate (400 mg, 70.5%). 1H NMR (400 MHz, CDClg) 5 8.52 (dd, J = 4.9, 0.9 Hz, 1H), 7.83 = 8.2 Hz, 1H), 7.22 (ddd, J = 7.5, 4.9, 0.9 Hz, 1H), - 7.67 (m, 1H), 7.40 (d, J 4.29 - 2.73 (m, 10H), 2.28 (s, 1H), 2.00 - 1.88 (m, 1H), 1.73 (ddd, J = 14.0, 4.7, 3.5 Hz, 1H), 1.49 (s, 9H). ESI-MS m/z calc. 322.2, found 323.5 (M+1)+; Retention time: 1.02 min (3 min run).

Step 4: tert-butyl 7a-(2-pyridyl)—1,3,3a,4,6,7— hexahydrofuro[3,4-c]pyridine-S-carboxylate O OH HO Nick PPh3, DEAD O / A solution of utyl 3,4-bis(hydroxymethyl)(2-pyridyl)piperidinecarboxylate (400 mg, 1.24 mmol) and nylphosphine (391 mg, 1.49 mmol) in THF (12.4 mL) was cooled to 0 oC. The reaction mixture was stirred for 1 h at 0 oC. The reaction mixture was allowed to warm to rt and was concentrated under reduced pressure.

Purification by flash column chromatography (Si02-4 g, 30-100 % EtOAc-hexanes) afforded tert-butyl pyridyl)-1 ,3 ,3 a,4,6,7-hexahydrofuro [3 ,4-c]pyridine-5 - carboxylate (354 mg, 93.7%). ESI-MS m/z calc. 304.2, found 305.3 (M+1)+; Retention time: 1.2 min (3 min run).

Step 5: (3-meth0xy(2- (triflu0r0methoxy)eth0xy)phenyl)(7a-(pyridinyl)hexahydrofuro[3,4-c]pyridin- (3H)—yl)methan0ne o F O no“ Jk J< F>r $0 N O F N O\ 0 O o F HATU,TEA,DMF 0/\/ \fl N / F 1‘“ I A solution of tert-butyl 7a-(2-pyridyl)-1,3,3a,4,6,7- hexahydrofi1ro[3,4-c]pyridinecarboxylate (52 mg, 0.17 mmol) in DCM (0.5 mL) was treated with hydrogen chloride (500 uL of 4 M, 2.00 mmol) in dioxane. The on mixture was stirred for 1 h and was concentrated under reduced pressure. The resulting crude t was diluted with DMF (0.7 mL) and treated with HATU (78 mg, 0.21 mmol) and 3-methoxy[2-(trifluoromethoxy)ethoxy]benzoic acid (48 mg, 0.17 mmol). The mixture was treated with triethylamine (95 uL, 0.68 mmol) and d for 1 h. The reaction mixture was filtered and purified by reverse phase HPLC (Water, HCl-modifier, 1-100% ACN/HZO, 30 min) to afford (3-methoxy(2- (trifluoromethoxy)ethoxy)phenyl)(7a-(pyridinyl)hexahydrofuro [3 yridin- (3H)-yl)methanone (HCl salt) (25 mg, 29%) 1H NMR (400 MHz, C6D6) 5 8.53 (s, 1H), 7.21 = 7.7 Hz, 2H), 6.57 (d, J = 8.1 Hz, 1H), 4.15 - 7.04 (m, 3H), 6.78 - 6.65 (m, J = 8.2 Hz, 1H), 3.81 - 3.91 (m, 4H), 3.86 (d, J - 3.70 (m, 4H), 3.68 - 3.58 (m, 2H), 3.37 (s, 3H), 3.18 - 2.95 (m, 2H), 2.27 - 1.98 (m, 2H). ESI-MS m/z calc. 466.17157, found 467.2 (M+1) MS m/z calc. 466.2, found 467.2 (M+1): Retention time: 0.964 min (3 min run).

[00237] tert—butyl (4aS,8aS)—8a-phenyl-2,3,4a,5,7,8-hexahydr0- [1,4]dioxino[2,3-c]pyridinecarb0xylate OJ< Bu4N+ HSO4', NaOH A solution of tert-butyl (3R,4R)-3,4-dihydroxyphenyl- piperidinecarboxylate (200 mg, 0.68 mmol) and tetrabutylammonium hydrogensulfate (66 mg, 0.19 mmol) in roethane (5 mL) was treated with NaOH (5 mL of 50 %w/w in water). The reaction mixture was stirred at 35 OC overnight and was cooled to rt and diluted with water and EtOAc. The organic layer was ted and the mixture was extracted with ethyl acetate (3 X 100 mL). The combined organics were washed with saturated aqueous NaCl, dried (Na2S04), d, and trated under reduced pressure. Purification by flash column chromatography (Si02-12 g, 0- 100 % ethyl acetate-hexanes) afforded tert-butyl (4aS,8aS)—8a-phenyl-2,3,4a,5,7,8- hexahydro-[1,4]dioxino[2,3-c]pyridinecarboxylate (86 mg, 40%) 1H NMR (400 MHz,CDC13)8 7.55 = 11.9, 9.4, 4.2 Hz, 1H), - 7.27 (m, 5H), 4.34 (s, 1H), 4.01 (ddd, J 3.95 = 11.8, 3.3 Hz, 1H), 3.37 - 3.80 (m, 2H), 3.74 - 3.61 (m, 2H), 3.46 (dt, J - 3.23 (m, 2H), 2.12 (d, J = 14.3 Hz, 1H), 1.77 - 1.62 (m, 1H), 1.48 (s, 9H). ESI-MS m/z calc. 319.2, found 320.3 (M+1) ; Retention time: 1.83 min (3 min run). [(3aR,7aR)—2,2-dimethyl-7a-(2-pyridyl)—3a,4,6,7—tetrahydr0 [1,3]di0x010 [4,5-c]pyridinyl]-[3-meth0xy[2- (trifluoromethoxy)eth0xy]phenyl]methan0ne Step 1: [(3R,4R)—4-(6-br0m0pyridyl)—3,4-dihydr0xy piperidyl]-[3-meth0xy[2-(triflu0r0meth0xy)eth0xy]phenyl]methan0ne HO’”'- NJLOJ< 1. TFA, DCM 2. HATU, TEA, DMF Br “<1“/\/0 F O jF<F Step 1: To a 100 mL round bottom flask was added tert-butyl (3R,4R)(6-bromopyridyl)-3,4-dihydroxy-piperidinecarboxylate (1.0 g, 2.7 mmol) and DCM (9 mL) followed by TFA (3 mL, 39 mmol). After 1 h, the reaction mixture was trated under reduced pressure and used in the next step without purification.

Step 2: To a 100 mL round bottom flask was added 3-methoxy- 4-[2-(trifiuoromethoxy)ethoxy]benzoic acid (976 mg, 3.48 mmol), HATU (1.0 g, 2.7 mmol), DMF (10 mL), and triethylamine (1.9 mL, 13.4 mmol). The reaction mixture was allowed to stir at rt for 10 min. The amine from Step 1: was dissolved in DMF (3 mL) and added to the reaction e se. The reaction e was allowed to stir at rt for 15 min. The reaction mixture was quenched with saturated aqueous NaCl, extracted with ethyl acetate (3x), and the ed organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude reaction mixture was purified via silica gel tography 0%-75% ethyl acetate in DCM to provide [(3R,4R)(6-bromopyridyl)-3 ,4-dihydroxypiperidyl]-[3-methoxy [2- (trifiuoromethoxy)ethoxy]phenyl]methanone (1.4 g, 97%) as a thick yellow oil. ESIMS m/z calc. 534.1, found 535.3 (M+1)+; Retention time: 1.78 min (3 min run).

[00243] Step 2: [(3R,4R)-3,4-dihydroxy(2-pyridyl)—l-piperidyl]- [3-meth0xy[2-(trifluoromethoxy)eth0xy]phenyl] methanone To a 250 mL round bottom flask was added wet Pd/C (1.4 g, 1.3 mmol) and isopropanol (10 mL). The mixture was purged with nitrogen for 10 min and treated with a solution of [(3R,4R)—4-(6-bromopyridyl)-3,4-dihydroxy piperidyl]-[3-methoxy[2-(trifluoromethoxy)ethoxy] phenyl]methanone (1.4 g, 2.6 mmol) in isopropanol (10 mL). The mixture was evacuated and put under en (1 atm, balloon). The reaction mixture was allowed to stir at 45 CC overnight. The reaction mixture was filtered and the filter cake was washed with DCM and isopropanol. The solvent was removed and the product was isolated as a white foam. 1H NMR (400 MHz, MeOD) 8 8.53 (ddd, J = 4.9, 1.7, 1.0 Hz, 1H), 7.86 - 7.80 (m, 1H), 7.78 (dt, J :80, 1.2 Hz, 1H), 7.29 (ddd, J = 7.3, 4.9, 1.4 Hz, 1H), 7.14 (s, 1H), 7.09 - 7.03 (m, 2H), 4.55 (d, J = 46.0Hz, 1H), 4.40 - 4.33 (m, 2H), 4.29 (q, J = 4.1 Hz, 2H), 4.18 (s, 1H), 3.89 (s, 3H), 3.74 (d, J = 25.1 Hz,1H), 3.47 (dd, J = 22.6, 21.0 Hz, 1H), 3.27 - 3.03 (m, 1H), 2.23 (s, 1H), 1.64 (t, J = 50.8 Hz, 1H). ESI-MS m/z calc. 456.4, found 457.5 (M+1)+; Retention time: 1.32 min (3 min run).

Step 3: [(3aR,7aR)—2,2-dimethyl—7a-(2-pyridyl)—3a,4,6,7— tetrahydro-[1,3]di0x010[4,5-c]pyridin-S-yl]-[3-meth0xy[2-(triflu0r0meth0xy) ethoxy]phenyl]methan0ne 0\ oxypropane ONOXF (7,7-dimethyI-2_oxo_ F norbornanyl) methanesulfonic acid To a Vial was added [(3R,4R)-3,4-dihydroxy(2-pyridyl) piperidyl]-[3-methoxy[2-(trifluoromethoxy)ethoxy]phenyl]methanone (45 mg, 0.10 mmol) and dichoromethane (1 mL). [(1R,4S)—7,7-dimethyloxo-norboman yl]methanesulfonic acid (2.3 mg, 0.01 mmol) was added followed by 2,2- dimethoxypropane (36 uL, 0.30 mmol). The reaction e was heated at 45 CC for 4h. The reaction mixture was filtered and purified Via HPLC (1%-99%) ACN:H2O with no r to afford [(3aR,7aR)-2,2-dimethyl-7a-(2-pyridyl)-3a,4,6,7-tetrahydro- [1 ,3]dioxolo [4,5 -c]pyridin-5 -yl]- [3 -methoxy [2-(trifiuoromethoxy) ethoxy]phenyl]methanone (4.2 mg, 8.6%) as a white solid. ESI-MS m/z calc. 496.2, found 497.2 (M+1)+; Retention time: 1.19 min (3 min run). (1 S,6R)—6-(2-pyridyl)—3-azabicyclo[4.1.0]heptane

[00248] Step 1: )(hydr0xymethyl)—1-(2- pyridyl)cyclopropanecarbonitrile N O \\ Q/CI _ NaNH2, THF (—78 — 25 °C) \ /N To a suspension of sodium amide (8.6 g, 199.3 mmol) in anhydrous THF (225 mL) under nitrogen at -25 CC (external temp) was added dropwise a on of 2-(2-pyridyl)acetonitrile (10.7 g, 90.6 mmol) in anhydrous THF (50 mL) over 15 min. The cooling bath was removed and stirring was continued at rt for 2.5 h. A solution of (2S)(chloromethyl)oxirane (21 mL, 272 mmol) in anhydrous THF (20 mL) was added at -25 CC in one portion. The resulting reaction e was heated at 35 CC for 16 h and then at 50 CC for 20 h. After cooling to rt the reaction mixture was poured into aqueous saturated aqueous ammonium chloride (100 mL), diluted with ted aqueous NaCl (200 mL) and extracted with ethyl acetate (4 X 250 mL). The combined organic phases were washed with saturated aqueous NaCl (250 mL), dried over MgSO4 and concentrated. Purification using silica gel chromatography (330 g silica, 10-30% ethyl acetate in DCM, 60 min) ed (1R,2S)(hydroxymethyl)(2-pyridyl)cyclopropanecarbonitrile (5.4 g, 34%) as a yellow-orange solid. 1H NMR (400 MHZ, DMSO) 5 8.51 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.57 (dt, J = 7.9, 0.9 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 5.03 (t, J = 5.2 Hz, 1H), 3.84 (dt, J = 11.9, 5.0 Hz, 1H), 3.49 (ddd, J = 11.9, 8.4, 5.5 Hz, 1H), 2.13 (dd, J = 7.5, 5.1 Hz, 1H), 1.85 (dd, J = 8.9, 4.6 Hz,1H), 1.66 (dd, J = 7.5, 4.7 Hz, 1H). ESI-MS m/z calc. 174.1, found 175.1 (M+1)+; Retention time: 0.39 min (3 min run).

[00250] Step 2: (1R,2S)[[tert-butyl(dimethyl)silyl]0xymethyl] (2-pyridyl)cyclopropanecarbonitrile To a on of (1R,2S)(hydroxymethyl)(2- pyridyl)cyclopropane itrile (5.4 g, 31.3 mmol) and imidazole (4.3 g, 62.5 mmol) in anhydrous DCM (65 mL) at 0 CC was added tert-butyl-chloro-dimethyl-silane (4.9 g, 32 mmol) in portions over 5 min. The cooling bath was removed and stirring was continued at rt for 45 min. The reaction mixture was poured into saturated aqueous ammonium chloride (100 mL), the phases were separated, and the aqueous phase was extracted with DCM (3 X 100 mL). The combined organic extracts were dried over MgSO4, ed, and concentrated in vacuo. Purification using silica gel chromatography (330 g silica, 0-10% ethyl acetate in hexane, 35 min) ed (1R,2S)[[tert-butyl(dimethyl)silyl]oxymethyl](2- pyridyl)cyclopropanecarbonitrile (8.2 g, 91%) as a colorless oil. 1H NMR (400 MHz, DMSO) 5 8.45 (d, J = 4.7 Hz, 1H), 7.78 (dd, J = 7.7, 1.7 Hz, 1H), 7.52 (d, J = 7.9 Hz, 2014/045675 1H), 7.26 (dd, J = 6.8, 4.9 Hz, 1H), 4.03 (dd, J = 11.6, 4.6 Hz, 1H), 3.62 (dd, J = 11.6, 8.5 Hz, 1H), 2.12 (qd, J = 8.5, 4.6 Hz, 1H), 1.81 (dd, J = 8.9, 4.7 Hz, 1H), 1.68 (dd, J = 7.4, 4.7 Hz, 1H), 0.80 (s, 9H), 0.00 (s, 3H), -0.02 (s, 3H). ESI-MS m/z calc. 288.2, found 289.5 (M+1)+; Retention time: 2.0 min (3 min run).

Step 3: (1R,2S)—2-[[tert-butyl(dimethyl)silyl] 0xymethyl] (2-pyridyl)cyclopropanecarbaldehyde OTBS DiBAI-H, DCM (—78 - 25 °C) A solution of (1R,2S)[[tert- butyl(dimethyl)silyl]oxymethyl](2-pyridyl)cyclopropanecarbonitrile (6.2 g, 21 mmol) in anhydrous DCM (62 mL) at -78 0C under nitrogen was added dropwise to a on of DIBAL-H (1M in toluene) (32 mL of 1 M, 32 mmol) over 10 min. Stirring was continued at -78 0C for 1 h, followed by 1.5 h at rt. After cooling to -78 0C the reaction e was quenched with isopropanol (62 mL) and d to warm up to rt. Dichloromethane (300 mL) and 50% aqueous saturated Rochelle’s salt on (100 mL) was added, the phases were separated, and the organic phase was washed with 50% aqueous saturated Rochelles salt solution (2 X 100 mL). The combined aqueous phases were re-extracted with DCM (150 mL). All combined organic phases were washed with water (100 mL) and saturated aqueous NaCl (100 mL), dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (330 g silica, 0-20% MeOH in DCM, 40 min) afforded (1R,2S)—2-[[tert- butyl(dimethyl)silyl]oxymethyl](2-pyridyl)cyclopropanecarbaldehyde (2.7 g, 44%) as a yellow oil. 1H NMR (400 MHz, DMSO) 5 9.75 (s, 1H), 8.49 (dd, J = 4.8, 0.8 Hz, 1H), 7.82 - 7.70 (m, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 4.04 (dd, J = 11.5, 5.7 Hz, 1H), 3.62 (dd, J = 11.5, 9.0 Hz, 1H), 2.28 (qt, J = 40.3, 20.1 Hz, 1H), 1.85 (dd, J = 7.4, 4.4 Hz, 1H), 1.78 (dd, J = 8.6, 4.4 Hz, 1H), 0.87 - 0.71 (s, 9H), -0.00 (d, J = 1.8 Hz, 6H). ESI-MS m/z calc. 291.2, found 292.3 (M+1)+; Retention time: 1.34 min (3 min run).

Step 4: [(1R,2S)—2-[[tert-butyl(dimethyl)silyl]0xymethyl] (2-pyridyl)cyclopr0pyl]methanol OTBS OTBS NaBH4, MeOH (-10 - 25 °C) To a on of (lR,2S)—2-[[tert- butyl(dimethyl)silyl]oxymethyl](2-pyridyl)cyclopropanecarbaldehyde (3.6 g, 12.4 mmol) in anhydrous MeOH (100 mL) at -10 0C under nitrogen was added NaBH4 (470 mg, 12.4 mmol) in portions over 5 min. Stirring was continued at rt for 45 min, and the reaction mixture was cooled to 0 oC and quenched by addition of water (5 mL). Ethyl acetate (250 mL) and saturated aqueous sodium onate (100 mL) were added, the phases were separated, and the s phase was extracted with ethyl acetate (150 mL). The combined c extracts were washed with saturated aqueous NaCl (100 mL), dried over MgSO4 and concentrated to afford S)[[tert- butyl(dimethyl)silyl]oxymethyl](2-pyridyl)cyclopropyl]methanol (3.6 g, 99%) as a yellow oil. 1H NMR (400 MHz, DMSO) 5 8.42 - 8.32 (m, 1H), 7.68 - 7.58 (m, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.14 - 7.03 (m, 1H), 4.42 - 4.37 (m, 1H), 3.97 - 3.92 (m, 1H), 3.88 = 8.7, 3.8 Hz, 1H), 0.85 (dd, J = - 3.68 (m, 3H), 1.75 - 1.56 (m, 1H), 1.30 (dd, J 6.2, 3.9 Hz, 1H), 0.80 (s, 9H), 0.00 (s, 3H), -0.02 (s, 3H). ESI-MS m/z calc. 293.2, found 294.5 (M+1)+; Retention time: 1.16 min (3 min run).

Step 5: [(1R,ZS)[[tert-butyl(dimethyl)silyl] 0xymethyl] idyl)cyclopr0pyl] methyl methanesulfonate OTBS OTBS MsCI, DIEA DCM OMS

[00257] [(1R,2S)—2-[[tert-butyl(dimethyl)silyl]oxymethyl](2- pyridyl)cyclopropyl]methanol (1.5 g, 5.2 mmol) was dissolved in DCM (24 mL), cooled to -10 0C, then treated with DIEA (1.1 mL, 6.3 mmol) and dropwise with MsCl (450 uL, 5.7 mmol). The reaction mixture was stirred at 0 0C for 1.5 h then allowed to warm to rt. The reaction mixture was concentrated and purified by silica gel chromatography (80 g silica, 0-50% ethyl acetate/hexane) to provide [(1R,2S)[[tert- butyl(dimethyl)silyl]oxymethyl] (2-pyridyl)cyclopropyl]methyl methanesulfonate (1.6 g, 84%) as a colorless oil. 1H NMR (400 MHz, DMSO) 8 8.48 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.74 (td, J = 7.8, 1.8 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.20 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 4.86 (d, J = 10.8 Hz, 1H), 4.71 (d, J =10.8 Hz, 1H), 3.92 (dd, J = 11.6, 6.1 Hz, 1H), 3.83 (dd, J = 11.5, 7.3 Hz, 1H), 3.19 (s, 3H), 1.84 (dt, J = 13.7, 6.7 Hz, 1H), 1.52 (dd, J = 8.8, 4.3 Hz, 1H), 1.18 (dd, J = 6.6, 4.4 Hz, 1H), 0.86 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H).

Step 6: 2-[(1R,2S)[[tert—butyl(dimethyl)silyl]0xymethyl]- 1-(2-pyridyl)cyclopr0pyl] itrile OTBS NaCN, DMSO A mixture of [(1R,2S)[[tert- butyl(dimethyl)silyl]oxymethyl] (2-pyridyl)cyclopropyl]methyl esulfonate (870 mg, 2.34 mmol) and NaCN (126 mg, 2.58 mmol) in anhydrous DMSO (8.7 mL) under a nitrogen atmosphere was stirred at rt overnight for 16 h. The reaction e was diluted with ethyl acetate (200 mL) and washed with 50% saturated sodium bicarbonate on (100 mL), water (100 mL), and saturated aqueous NaCl (100 mL).

The organic layer was dried over MgSO4 and concentrated. Purification by silica gel chromatography (120 g silica, 10-50% ethyl acetate/hexane) afforded 2-[(1R,2S) [[tert—butyl(dimethyl)silyl]oxymethyl](2-pyridyl)cyclopropyl]acetonitrile (518 mg, 73.1%) as a colorless oil. 1H NMR (400 MHz, DMSO) 8 8.44 (dd, J = 4.8, 0.9 Hz, 1H), 7.73 = 8.1Hz, 1H), 7.18 - 7.67 (m, 1H), 7.26 (d, J - 7.13 (m, 1H), 3.99 - 3.86 (m, 1H), 3.72 (dd, J = 11.6, 7.8 Hz, 1H), 3.14 (d, J = 17.3 Hz, 1H), 3.05 (d, J =17.3 Hz,1H), 1.66 (dt, J = 14.4, 7.2 Hz, 1H), 1.36 (dd, J = 9.2, 4.6 Hz, 1H), 0.99 (dd, J = 6.6, 4.6 Hz, 1H), 0.55 (s, 9H), -0.00 (s, 3H), -0.02 (s, 3H). ESI-MS m/z calc. 302.2, found 303.3 (M+1)+; Retention time: 1.52 min (3 min run).

Step 7: 2-[(1R,2S)[[tert—butyl(dimethyl)silyl]0xymethyl]- 1-(2-pyridyl)cyclopr0pyl]ethanamine OTBS To a solution of 2-[(lR,2S)[[tert- butyl(dimethyl)silyl]oxymethyl](2-pyridyl)cyclopropyl]acetonitrile (250 mg, 0.83 mmol) in anhydrous THF (7.5 mL) at 0 0C under nitrogen was added a solution of -tetrahydrofilran complex (2.5 mL of 1 M, 2.5 mmol) in THF dropwise over 5 min. The resulting mixture was heated at reflux for 2 h. After cooling to 0 CC, MeOH (0.75 mL) was added carefully, and the mixture was heated again at reflux for 1 h.

After cooling to rt the reaction mixture was concentrated, the residue redissolved in DCM (50 mL), washed with water (30 mL), saturated aqueous NaCl (30 mL), dried over MgSO4 and concentrated. Purification using silica gel chromatography (40 g silica, 0-20% MeOH in DCM with 2%triethylamine, 30 min) ed 2-[(1R,2S) [[tert—butyl(dimethyl)silyl]oxymethyl] (2-pyridyl)cyclopropyl]ethanamine (124 mg, 49%) as a ess oil. 1H NMR (400 MHz, DMSO) 8 8.47 (d, J = 4.5 Hz, 1H), 7.75 - 7.68 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.24 - 7.12 (m, 1H), 4.07 - 3.85 (m, 1H), 3.63 - 3.55 (m, 1H), 3.00 - 2.90 (m, 1H), 2.87 - 2.75 (m, 3H), 2.40 - 2.16 (m, 1H), 2.16 - 1.95 (m, 1H), 1.64 - 1.55 (m, 1H), 1.32 - 1.26 (m, 1H), 0.85 (s, 9H), 0.81 - 0.73 (m, 1H), 0.06 (s, 3H), 0.03 (s, 3H). ESI-MS m/z calc. 306.2, found 307.3 (M+1)+; Retention time: 1.04 min (3 min run).

Step 8: [(1S,2R)—2-(2-amin0ethyl)(2- l)cyclopr0pyl] methanol OTBS To a solution of 2-[(lR,2S)[[tert- butyl(dimethyl)silyl]oxymethyl]-l-(2-pyridyl)cyclopropyl]ethanamine (124 mg, 0.40 mmol) in ous THF (2.5 mL) under nitrogen at rt was added a solution of tetra-n- butylammonium fluoride (0.4 mL of 1 M, 0.40 mmol) in THF dropwise over 5 min.

The reaction mixture was continued to stir at rt for 2.5 h. Additional tetra-n- butylammonium fluoride (50 [LL of 1 M, 0.05 mmol) in THF was added, and the reaction mixture was continued to stir at rt for 30 min. The reaction mixture was concentrated and purified using silica gel chromatography (24 g silica, 0-20% MeOH in DCM w/2.5% triethylamine, 20 min). After concentation of product fractions the residue was coconcentrated under reduced pressure with acetonitrile (3 X 10 mL) to remove traces of triethylamine to afford [(1 S,2R)(2-aminoethyl)(2- pyridyl)cyclopropyl]methanol (54 mg, 69%) ESI-MS m/z calc. 192.1, found 193.5 (M+1)+; Retention time: 0.26 min (3 min run).

] Step 9: (1S,6R)—6-(2-pyridyl)—3-azabicyclo[4.1.0]heptane NH2 SOCI2, DCE To a suspension of [(1S,2R)—2-(2-aminoethyl)(2- pyridyl)cyclopropyl]methanol (54 mg, 0.28 mmol) in anhydrous DCE (2.5 mL) under nitrogen at 0 0C was added SOClz (25 uL, 0.34 mmol) dropwise. The resulting reaction mixture was stirred at rt for 4 h. After cooling to 0 CC additional SOClz (102 uL, 1.40 mmol). The on e was concentrated, dissolved in water (20 mL), and ed to basic pH with 3.75 M aqueous NaOH The aqueous phase was extracted with DCM (5 X 40 mL) and the combined organic extracts were dried over MgSO4, filtered, and concentrated to afford crude (1 S,6R)(2-pyridyl) azabicyclo[4.1.0]heptane (42 mg, 86%). ESI-MS m/z calc. 174.2, found 175.1 (M+1)+; Retention time: 0.368 min (3 min run). tert-butyl 7,7-diflu0r0(2-pyridyl)—3- yclo[4.1.0]heptane—3-carb0xylate o o (CH3)3CF3Si, Nal, NJLOJ< F NJLOJ< | —> ,N THF (65 °C) I FN \ / \ To a 4 ml Vial charged with a ic stirbar was added tert- butyl 4-(2-pyridyl)-3,6-dihydro-2H-pyridinecarboxylate (235 mg, 0.90 mmol), sodium iodide (45 mg, 0.30 mmol) and ous THF (1.5 mL) in under nitrogen atmosphere. To this was added trimethyl-(trifiuoromethyl)silane (470 uL, 3.2 mmol).

The on vessel was sealed and heated to 65 0C for 17 h. The les were removed under reduced pressure and the resulting. residue was purified by flash chromatography on silica gel (24 g column) using a gradient t (0 to 60 % over min) in hexanes to provide tert-butyl 7,7-difiuoro(2-pyridyl) azabicyclo[4.1.0]heptanecarboxylate (64 mg, 22.4%) as a brown viscous oil. 1H NMR (400 MHz, CDC13)5 8.56 (d, J = 4.3 Hz, 1H), 7.68 (td, J = 7.7, 1.8 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.20 (ddd, J = 7.5, 4.9, 1.0 Hz, 1H), 3.91 (br s, 1H), 3.80 (br s, 1H), 3.70-3.40 (br m, 1H), 3.25-3.00 (br m, 1H), 2.60-2.50 (m, 1H), 2.34 (br s, 1H), 2.21 - 2.05 (m, 1H), 1.47 (s, 9H). ESI-MS m/z calc. 310.1, found 311.0 (M+1)+; Retention time: 1.02 min (3 min run). tert—butyl (1R,6R)—6-(2-pyridyl)—8-0xa azabicyclo[4.2.0] 0ctanecarb0xylate (racemic) Step 1: utyl 6-(2-pyridyl)—7—oxa azabicyclo[4.1.0]heptanecarb0xylate Nioj<O 1.) NBS, dioxane, H20 2.) NaOH A solution of tert-butyl 4-(2-pyridyl)-3,6-dihydro-2H-pyridine- 1-carboxylate (15.1 g, 58.1 mmol) in oxane (100 mL), and water (150 mL) was treated with N-bromosuccinimide (15.5 g, 87.1 mmol). The reaction e was d to stir at rt for 1 h. An aqueous solution of sodium hydroxide (116 mL of 1 M, 116 mmol) was added, and the reaction mixture was stirred for an additional 15 min.

The mixture was extracted with ethyl acetate (3>< 75 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure.

The resulting orange oil was purified by silica gel column chromatography: 220 gram silica gel column, 0-40% ethyl acetate/hexane gradient; product eluted at 20% to provide tert-butyl 6-(2-pyridyl)oxaazabicyclo[4.1.0]heptanecarboxylate (11.5 g, 72%) as a clear yellow oil. 1H NMR (400 MHz, CDClg) 5 8.58 (d, J = 4.1 Hz, 1H), 7.70 (td, J = 7.8, 1.8 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.22 (ddd, J = 7.5, 4.8, 1.1Hz, 1H), 3.90 (dt, J = 24.8, 14.3 Hz, 2H), 3.66 (s, 1H), 3.30 (d, J = 2.4 Hz, 2H), 2.83 (s, 2014/045675 1H), 2.16 (s, 1H), 1.47 (s, 9H). ESI-MS m/z calc. 276.1, found 277.3 (M+1)+; Retention time: 0.96 min (3 min run).

Step 2: provide tert-butyl 4-cyanohydroxy(2- pyridyl)piperidine-l-carboxylate NaCN DMSO (90 ”C) To a solution of tert-butyl 6-(2-pyridyl)oxa azabicyclo[4.1.0]heptanecarboxylate (14.4 g, 52.2 mmol) in DMSO (216 mL) was added potassium cyanide (10.2 g, 157 mmol). The reaction mixture was heated at 90 0C for 24 h, cooled to rt, and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with water (3x), saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to dryness. Purification by flash column chromatography (SiOz-80 g, 0-100 % ethyl acetate-hexanes) afforded tert—butyl ohydroxy(2-pyridyl)piperidine carboxylate (3.5 g, 22 %). ESI-MS m/z calc. 303.2, found 304.1 (M+1)+; Retention time: 1.48 min (3 min run).

] Step 3: tert-butyl (3R,4R)—3-benzyloxycyan0(2- l)piperidine-l-carboxylate HO,,,,, Niok BnBr, NaH NEIIIIDMF To a solution of tert-butyl 4-cyanohydroxy(2- pyridyl)piperidinecarboxylate (2.2 g, 7.1 mmol) in DMF (20 mL) was added sodium hydride (340 mg, 8.5 mmol). The reaction mixture was stirred at rt for 15 min and was d with benzylbromide (1.0 mL, 8.5 mmol). The reaction mixture was d at rt overnight and then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl e (3x), and the combined organic layers were washed with water (3x), saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated to dryness. The crude material was purified by column chromatography (0-20% ethyl 2014/045675 acetate-hexanes) to provide tert-butyl (3R,4R)benzyloxycyano(2- pyridyl)piperidinecarboxylate (2.6 g, 93%). ESI-MS m/z calc. 393.5, found 394.5 (M+1)+; Retention time: 2.14 min (3 min run).

Step 4: t—butyl O4-methyl (3R,4S)benzyloxy(2- pyridyl)piperidine-1,4-dicarb0xylate B 0n ” ll J< OJ< 1. KOH, EtOH O\ N O 2. Mel, NaH, DMF To a solution of tert-butyl 3-benzyloxycyano(2- l)piperidinecarboxylate (2.4 g, 6.1 mmol) in EtOH (20 mL) was added KOH (20 mL of 50 %w/w in water). The on mixture was heated at 120 0C for 25 h and the layers were separated. The aqueous layer was extracted with ethyl acetate (3x) and the combined organic layers were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated to dryness. The crude product 3-benzyloxy-l-tert- butoxycarbonyl(2-pyridyl)piperidinecarboxylic acid (2.4 g, 5.8 mmol) was dissolved in DMF (30 mL) and was treated with sodium hydride (349 mg, 8.7 mmol)(60% dispersion in mineral oil). The reaction mixture was stirred at rt for 15 min and was treated with iodomethane (543 uL, 8.73 mmol). The reaction mixture was stirred at rt for 2 h and was ioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3x), the combined organic layers were washed with water (3x), saturated aqueous NaCl, dried (MgSO4), d and concentrated to s.

The crude material was purified by column chromatography (0-20% EtOAc-Hex) to provide 0tert-butyl O4-methyl (3R,4S)—3 -benzyloxy(2-pyridyl)piperidine-1 ,4- dicarboxylate (1.1 g, 44%). ESI-MS m/z calc. 426.5, found 427.5 (M+1)+; Retention time: 2.13 min (3 min run).

Step 5: tert-butyl (3R,4R)—3-benzyloxy (methylsulfonyloxymethyl)(2-pyridyl)piperidine—l-carboxylate 0\ ‘- NJJ\O 3;:- 1. LAH, THF 2. MSCI, TEA, DCM Step 1: To a refluxing on of Ol-tert-butyl O4-methyl (3R,4S)benzyloxy(2-pyridyl)piperidine-1,4-dicarboxylate (1.1 g, 2.6 mmol) in THF (30 mL) was added lithium aluminum hydride (1.5 mL of 2 M in THF, 3.1 mmol). The mixture was heated at reflux for 1 min and was cooled to 0 oC. The reaction mixture was quenched sequentially with water (5 drops), 15% aqueous NaOH (5 drops) and water (15 drops). The resulting white precipitate was removed via filtation and washed with EtOAc. The filtrate was dried over MgSO4, d and concentrated to dryness. The crude material was used ly in next step withour further purification. To a solution of tert—butyl 3-benzyloxy(hydroxymethyl)(2- pyridyl)piperidine-l-carboxylate (200 mg, 0.50 mmol) in DCM (10 mL) was added ylamine (210 uL, 1.51 mmol) followed by the addition of methanesulfonyl chloride (58 uL, 0.75 mmol). The reaction mixture was stirred at rt for 5 min, diluted with DCM, washed with water (3x), dried over MgSO4, d and concentrated to dryness. The crude material was d by column chromatography to provide tert- butyl (3R,4R)—3-benzyloxy(methylsulfonyloxymethyl)(2-pyridyl)piperidine carboxylate (210 mg, 88%). ESI-MS m/z calc. 386.5, found 387.5 (M+1)+; Retention time: 1.34 min (3 min run).

] Step 6: tert-butyl (3R,4R)—3-hydroxy (methylsulfonyloxymethyl)(2-pyridyl)piperidine-l-carboxylate AOJ<O O NH3, formic acid HO/,,,, NLOJ< —,MsO \lln.

Pd/C, MeOH To a on of tert-butyl 3-benzyloxy (methylsulfonyloxymethyl)(2-pyridyl)piperidinecarboxylate (200 mg, 0.42 mmol) in MeOH (20 mL) was added ammonium formate (530 mg, 8.4 mmol) and 10% Pd/C (92 mg, 0.09 mmol). The reaction mixture was heated at reflux for 10 min. The catalyst was removed via filtration through celite and washed with MeOH. The filtrate was concentrated to dryness. The residue was purified by column chromatography to provide tert-butyl (3R,4R)—3-hydroxy(methylsulfonyloxymethyl)(2- pyridyl)piperidine-l-carboxylate (105 mg, 65%) ESI-MS m/z calc. 386.5, found 387.5 (M+1)+; Retention time: 1.34 min (3 min run).

Step 7: tert-butyl (1R,6R)—6-(2-pyridyl)—8-0xa azabicyclo[4.2.0] 0ctane—3-carb0xylate To a on of tert-butyl (3R,4R)—3-hydroxy (methylsulfonyloxymethyl)(2-pyridyl)piperidinecarboxylate (100 mg, 0.26 mmol) in toluene (6 mL) was added DBU (46 uL, 0.31 mmol) The reaction mixture was heated at 120 0C for 16 h, d with ethyl acetate, washed with water (3x), dried over MgSO4, filtered, and concentrated to dryness. The crude material was purified by column chromatography to provide tert-butyl (1R,6R)—6-(2-pyridyl)—8-oxa azabicyclo[4.2.0]octanecarboxylate (42 mg, 56 %). 1H NMR (400 MHz, CDClg) 5 8.59 (ddd, J = 4.9, 1.7, 0.9 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.19 (ddd, J = 7.5, 4.9, 0.8 Hz, 1H), 7.09 (t, J = 8.7 Hz, 1H), 5.39 = 6.1 Hz, 1H), 4.72 (d, - 5.23 (m, 1H), 4.99 (t, J J = 6.0 Hz, 1H), 4.18 = 22.2, 15.4, 1.9 Hz, 1H), 2.20 - 3.78 (m, 3H), 3.47 (ddd, J - 2.07 (m, 2H), 1.48 (t, J = 10.4 Hz, 10H). ESI-MS m/z calc. 290.2, found 291.5 (M+1)+; Retention time: 1.17 min. (3 min run). utyl (3aR,7aR)—7a-(4-methoxy-Z-pyridyl)—3a,4,6,7— tetrahydro-[1,3]dioxolo[4,5-c]pyridine-S-carboxylate oj< H2(1 atm), Pd/C TEA, EtOH ] In a 100 mL round bottom flask equipped with a septa, tert- butyl (3 aR,7aR)-7a-(6-chloromethoxypyridyl)-3 a,4,6,7-tetrahydro- [1,3]dioxolo[4,5-c]pyridinecarboxylate (1.09 g, 2.94 mmol) and triethylamine (410 uL, 2.94 mmol) were dissolved in ethanol (20 mL). Palladium (156 mg, 0.15 mmol)(10% on carbon) was added, and the mixture was degassed by bubbling nitrogen gas. The reaction mixture was usly stirred under hydrogen atmosphere on) for 5 h. The suspension was degassed by bubbling nitrogen. The catalyst was removed 2014/045675 by filtration through a pad of celite. The solid was thoroughly washed with ethanol.

The e was trated under reduce pressure to provide a the crude product.

Purification by flash chromatography on silica gel (40 g column) using a gradient of AcOEt (0-100% over 20 min). ed tert-butyl (3aR,7aR)-7a-(4-methoxy pyridyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridinecarboxylate (907 mg, 91.7%) as a colorless oil that started to crystallize upon standing. ESI-MS m/z calc. 336.2, found 337.0 (M+1)+; Retention time: 1.64 min (3 min run). ] 6-eth0xy[2-(trifluoromethoxy)eth0xy]pyridine carboxylic acid

[00286] Step 1: 6-ch10r0hydroxy-pyridine—Z-carbonitrile \ Zn(CN)2, Pd(PPh3)4 OH I I | N/ CI DMF N/ N// CI 2-chloroiodo-pyridinol (2.0 g, 7.8 mmol) was dissolved in DMF (15 mL), and dicyanozinc (0.7 g, 5.9 mmol) was added. Nitrogen gas was bubbled through the reaction mixture before and after the addition of triphenylphosphine palladium (0) (0.6 g, 0.55 mmol). The reaction vessel was sealed under nitrogen and heated under microwave irradiation at 100 CC for 30 min. Volatiles were removed under reduced pressure. The remaining oil was dissolved in ethyl acetate (100 mL) and washed with water (100 mL) ed by saturated aqueous NaCl (2 X 100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to provide a crystalline solid. Purification by silica gel column chromatography: 40 gram silica gel , 0-50% ethyl acetate/hexane gradient over 20 min; provided 6-chlorohydroxy-pyridine carbonitrile (0.8 g, 63%) as a crystalline yellow-white solid. 1H NMR (400 MHz, CDC13)8 7.65 = 8.2 Hz, 1H). ESI-MS m/z calc. 154.0, found - 7.59 (m, 1H), 7.42 (d, J 155.0 (M+1)+; Retention time: 0.72 min (3 min run).

] Step 2: methyl 6-chlor0hydroxy-pyridine—2-carboxylate OH OH \ HCI,MeOH \ | | N// CI /0 N/ CI 6-chlorohydroxy-pyridinecarbonitrile (7.1 g, 45.8 mmol) was dissolved in methanol (25 mL), and a solution of HCl (100 mL of 4 M, 400.0 mmol) in dioxane was added. The reaction mixture was stirred in a pre-heated 80 oC oil bath for 36 h. Additional ol and HCl/dioxane was sequentially added to help ss the reaction. Volatiles were removed under reduced pressure to obtain a yellow solid which was filtered through a plug of silica gel. The filtrate was concentrated and dissolved in 1,4-dioxane (50 mL) at 65 oC. Hot hexane (75 mL) was added to the on, and the resulting slurry was allowed to slowly cool to rt. The crystalline solids were ted by vacuum ion, rinsing with hexane. 1H NMR (400 MHz,CDC13)8 8.07 (d, J = 8.3 Hz, 1H), 7.47 - 7.40 (m, 1H), 6.13 (s, 1H), 3.98 (s, 3H). ESI-MS m/z calc. 187.0, found 188.3 (M+1)+; Retention time: 0.36 min (3 min run).

Step 3: methyl 6-chloro[2- (trifluoromethoxy)eth0xy]pyridine-Z-carboxylate OH CF3SO3(CH2)20CF3 \ O\/\OJ<F —>/O | NaH DMF N/ CI ] A solution of methyl 6-chlorohydroxy-pyridine carboxylate (2.5 g, 13.3 mmol) in DMF (15 mL) was treated slowly with sodium hydride (0.5 g, 12.6 mmol) (60 wt% dispersion in mineral oil) portionwise. The reaction mixture was allowed to stir at rt for 15 min and cooled to -10 CC prior to the slow dropwise addition of neat 2-(trifluoromethoxy)ethyl trifiuoromethanesulfonate (4.5 g, 17.3 mmol) over 5 min. An exotherm was observed during addition. The reaction mixture was then allowed to slowly warm to rt and stirred for 1 h. Water (10 mL) was added, and the mixture was concentrated under reduced pressure. The remaining residue was resuspended in water (75 mL) and extracted with ethyl acetate (3>< 75 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The remaining solid was briefly stirred in DCM (50 mL), and the remaining white solids were removed by vacuum filtration. The filtrate was again concentrated under reduced pressure and purified by silica gel column chromatography: 80 gram silica gel column, 0-40% ethyl e/hexane gradient over 30 min; t eluted at 30%. Pure fractions were combined and concentrated to afford methyl 6-chloro[2-(trifluoromethoxy)ethoxy]pyridine carboxylate (2.9 g, 74%) as a light brown crystalline solid. 1H NMR (400 MHz, CDClg) 5 8.10 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 4.45 - 4.38 (m, 2H), 4.36 (dd, J = 5.8, 3.4 Hz, 2H), 3.98 (s, 3H). ESI-MS m/z calc. 299.0, found 300.4 (M+1)+; Retention time: 1.47 min (3 min run).

] Step 4: 6-eth0xy[2-(trifluoromethoxy)eth0xy]pyridine carboxylic acid F F o\/\O)<FF F NaOEt, EtOH \ \ o\/\OJ<F | | /0 N/ HO CI 1,4-dioxane, H20 N/ OEt O 0 A solution of methyl 6-chloro[2- (trifluoromethoxy)ethoxy]pyridinecarboxylate (250 mg, 0.83 mmol) in 1,4-dioxane was treated with sodium ethanolate (2.0 mL of 21 %w/v, 6.2 mmol) and water (50 uL, 2.78 mmol). The on mixture was heated under microwave irradiation at 100 CC for 1 h. The reaction mixture was partioned between ethyl acetate (75 mL) and water (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced re. The crude product was purified by UV-triggered reverse- phase HPLC: 10-99% acetonitrile/water gradient over 15 min to e 6-ethoxy [2-(trifluoromethoxy)ethoxy]pyridinecarboxylic acid (18 mg, 7.3%) as a light brown foaming solid. 1H NMR (400 MHZ, CDClg) 5 7.82 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 4.36 (dt, J = 15.8, 4.1 Hz, 4H), 1.49 (t, J = 7.1 Hz, 3H). ESI-MS m/z calc. 295.1, found 296.4 (M+1)+; Retention time: 1.38 min (3 min run).

[00294] The following compounds were prepared using the procedure reported above.

Product Precursor 6-ethoxy[2- _ _ . . . methyl 6-chlorohydroxy-pyr1d1ne- (tr1fluoromethoxy)ethoxy]pyr1d1ne 2-carboxylate carboxylic acid oxy[2- methyl rohydroxy-pyr1d1ne-. . (trifluoromethoxy)ethoxy]pyridine 2-carboxylate carboxylic acid 5-(2-flu0r0methyl-prop0xy)meth0xy-pyridine carboxylic acid Step 1: methyl 6-chloro(2-hydroxymethyl- y)pyridinecarboxylate HOJVC' H ICIOH\ /O\"/[NICI\ 0% K2C03, MeOH O 0 A solution of methyl 6-chlorohydroxy-pyridine carboxylate (1.6 g, 8.3 mmol) in methanol (1.5 mL) was treated with finely ground potassium carbonate (4.6 g, 33.0 mmol). The reaction mixture was heated to 80 oC and 1-chloromethyl-propanol (1.7 mL, 16.5 mmol) was added. The reaction mixture was heated at 80 OC overnight. The on e was concentrated under reduced pressure. The remaining residue was suspended in water (75 mL) and extracted with ethyl acetate (2 X 75 mL). c layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was purified by silica gel column tography: 40 gram silica gel column, 0-30% ethyl acetate/hexane gradient over 25 min to afford methyl 6-chloro(2-hydroxymethyl- propoxy)pyridinecarboxylate (1.2 g, 54%) was obtained as a colorless solid. 1H NMR (400 MHz, CDC13)5 8.09 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 2H), 1.41 (s, 6H). ESl-MS m/z calc. 259.1, found 260.2 (M+1)+; Retention time: 0.99 min (3 min run).

Step 2: methyl 6-chloro-S-(2-flu0r0methylpropoxy )pyridinecarboxylate OH F \ 0* deoxofluor \ 0* I —> I /O N/ CI DCM /O N CI 0 0 A solution of methyl 6-chloro(2-hydroxymethyl- propoxy)pyridinecarboxylate (500 mg, 1.93 mmol) in DCM, and 2-methoxy-N—(2- methoxyethyl)-N-(trifluorosulfanyl)ethanamine (391 uL, 2.12 mmol) was slowly added at rt. A water bath was used to maintain the reaction mixture near rt. After 2 h, the reaction mixture was diluted with DCM (75 mL) and washed with water (1 X 75 mL). The aqueous layer was further extracted with DCM (2>< 75 mL). All organic layers were ed, dried over sodium sulfate, d and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography: 12 gram silica gel , 0-40% ethyl acetate/hexane gradient over min to provide methyl 6-chloro(2-fluoromethyl-propoxy)pyridine carboxylate (170 mg, 34%) was obtained as a clear colorless oil that crystallized upon standing. 1H NMR (400 MHz, CDClg) 5 8.08 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 4.09 (d, J = 16.5 Hz, 2H), 3.98 (s, 3H), 1.60 - 1.52 (m, 6H). ESI-MS m/z calc. 261.1, found 262.2 (M+1)+; Retention time: 1.41 min (3 min run).

Step 3: 5-(2-flu0r0methyl-propoxy)methoxy-pyridine— 2-carb0xylic acid /O\[([NICI\ 0% NaOMe/MeOH \ 0% 1,4-dioxane, H20 N/ 0M9 O 0 A solution of methyl 6-chloro(2-fluoromethyl- propoxy)pyridinecarboxylate (170 mg, 0.65 mmol) in oxane (2 mL) was treated with sodium ide (3.00 mL of 0.5 M, 1.500 mmol) in methanol followed by water (50 uL, 2.78 mmol). The on mixture was heated by ave irradiation at 100 0C for 1 h, then at 120 0C for 30 min. Volatiles were removed under reduced pressure, and the remaining solid was dissolved in water (20 mL) and adjusted to pH 2 with the addition of aqueous 1 N HCl solution. The resulting on was extracted with DCM (3>< 50 mL). Organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to a clear colorless oil.

Purification by reverse-phase HPLC (1-99% acetonitrile water gradient over 15 min) provided 5-(2-fluoromethyl-propoxy)methoxy-pyridinecarboxylic acid. ESI- MS m/z calc. 243.1, found 244.3 (M+1)+; Retention time: 1.14 min (3 min run). 5-(2-flu0r0methyl-prop0xy)meth0xy-pyridine—2- carboxylic acid K2C03, H20, EtOH (80 °C) 0%“ /O\fl/(:£ HO 2.) NaOH, H20, EtOH (40 °C) 0 0 A mixture of 1-chloromethyl-propanol (10 mL, ), 4- hydroxymethyl-benzoic acid (2.0 g, 13.2 mrnol), K2C03 (7.3 g, 52.7 mmol), H20 (6.0 mL) and ethanol (60 mL) was heated at 80 CC overnight. The reaction mixture was cooled to rt, partitioned between 1N NaOH and EtOAc and the layers ted.

The c layer was washed with 1N NaOH (2x) and the combined aqueous layers were washed with EtOAc. The combined organics were concentrated under reduced pressure and diluted with EtOH (15 mL). The mixture was treated with H20 (2 mL) and NaOH (1.0 g, 26.3 mmol). The on mixture was stirred at 40 CC for 4 h. The reaction mixture was poured into 1N NaOH and extracted with ether (2x). The pH was brought to 2-3 with 6N HCl and the aqueous material was extracted with EtOAc (3x).

The organics were combined, washed with saturated aqueous NaCl, dried (NaZSO4), filtered, and evaporated to dryness. The material was triturated with ether to provide 4-(2-hydroxymethyl-propoxy)methyl-benzoic acid (2.2 g, 75%) as a white solid. 1H NMR (400 MHz, DMSO) d 7.75 (dd, J = 8.5, 2.0 Hz, 1H), 7.73 - 7.70 (m, 1H), 6.96 (d, J = 8.6 Hz, 1H), 4.67 (s, 1H, OH), 3.76 (s, 2H), 2.20 (s, 3H), 1.22 (s, 6H). ESI-MS m/z calc. 224.1, found 225.5 (M+1)+; Retention time: 1.06 min (3 min run).

The following compounds were prepared using the procedure reported above. t Precursor 4-(2-hydroxymethylpropoxy) methyl 4-(2-hydroxymethylpropoxy)- benzoic acid 3-methylbenzoate ydroxymethylpropoxy) methyl 4-(2-hydroxymethylpropoxy)- methoxybenzoic acid oxybenzoate 4-(2-hydroxymethylpropoxy) methyl 4-(2-hydroxymethylpropoxy)- chlorobenzoic acid 3-chlorobenzoate 6-methyl[2-(trifluoromethoxy)eth0xy]pyridine carboxylic acid ] Step 1: methyl 6-methyl[2- (trifluoromethoxy)eth0xy]pyridine-Z-carboxylate <FF OH CF3803(CH2)ZOCF3 \ O / NaH DMF / N A solution of methyl 5-hydroxymethyl-pyridine ylate (2.0 g, 12.1 mmol) in DMF (12 mL) was cooled to 0 0C before the slow on of sodium hydride (0.5 g, 11.5 mmol) (60 wt% sion in mineral oil). The reaction mixture was allowed to stir at rt for 10 min before it was cooled to -10 oC. 2- (trifluoromethoxy)ethyl trifluoromethanesulfonate (4.1 g, 15.8 mmol) was slowly added neat to the reaction mixture over 5 min. An exotherm was observed during the addition. The reaction mixture was allowed to stir at rt for l h. Water (50 mL) was added to the reaction mixture, and it was concentrated under reduced pressure. The remaining solid was partitioned between ethyl acetate (75 mL) and water (75 mL).

The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude t was purified by silica gel column chromatography: 5-20% ethyl acetate/hexane gradient providing methyl 6-methyl [2-(trifluoromethoxy)ethoxy]pyridinecarboxylate (1.6 g, 48%) as a light brown crystalline solid. 1H NMR (400 MHz, CDClg) 5 8.02 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 4.38 (dd, J = 5.6, 3.5 Hz, 2H), 4.30 - 4.26 (m, 2H), 3.98 (s, 3H), 2.57 (s, 3H). ESI-MS m/z calc. 279.1, found 280.3 (M+l)+; Retention time: 1.29 min (3 min run).

Step 2: 6-methyl[2-(trifluoromethoxy)eth0xy]pyridine carboxylic acid F F F F /O N/ HO MeOH, H20 N/ O 0 To a solution of methyl 6-methyl[2- (trifluoromethoxy)ethoxy]pyridinecarboxylate (1.6 g, 5.9 mmol) in methanol (10 mL) was added a solution of sodium hydroxide (2.3 g, 58.7 mmol) in water (5 mL).

The reaction mixture was stirred at 45 CC for 30 min. After cooling to rt, it was acidified to pH 5 with the addition of an aqueous 1 N HCl solution. The mixture was extracted with DCM (3>< 50 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 6-methyl- -[2-(trifluoromethoxy)ethoxy]pyridinecarboxylic acid (1.5 g, 94%) as a white powder. 1H NMR (400 MHz, CDClg) 5 8.07 (d, J = 8.4 Hz, 1H), 7.24 (t, J = 10.5 Hz, 1H), 4.39 (d, J = 3.9 Hz, 2H), 4.29 (t, J = 13.6 Hz, 2H), 2.53 (s, 3H). ESI-MS m/z calc. 265.1, found 266.3 (M+1)+; Retention time: 0.78 min (3 min run). 5-(2-hydr0xymethyl-prop0xy)meth0xy-pyridine—2- carboxylic acid.

Odell /Oj((N\/[CI1,4-dioxane, H20NaOMe/MeOH H’OWKQIOMe\ 0%“| O 0 To a solution of methyl 6-chloro(2-hydroxymethyl- y)pyridinecarboxylate (200 mg, 0.77 mmol) in 1,4-dioxane (1 mL) was added a solution of sodium methoxide (3 mL of 0.5 M, 1.5 mmol) in methanol, followed by water (50 uL, 2.8 mmol). The reaction mixture was heated under microwave irradiation at 100 0C for 1 h. Volatiles were removed under d pressure, and the remaining solid was dissolved in water (20 mL) and adjusted to pH 2 with the addition of aqueous 1 N HCl solution. The resulting solution was extracted with DCM (3 X 50 mL) and the c layers were combined, dried over sodium sulfate, ed and concentrated under reduced pressure to provide a colorless oil.

Purification by reverse-phase HPLC (1-99% acetonitrile water nt over 15 min) provided 5-(2-hydroxymethyl-propoxy)methoxy-pyridinecarboxylic acid (49 mg, 24%). 1H NMR (400 MHz, CDClg) 5 7.84 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 4.06 (s, 3H), 3.89 (s, 2H), 1.39 (s, 6H). ESI-MS m/z calc. 241.1, found 242.3 (M+1)+; ion time: 0.77 min (3 min run). 2-(triflu0r0meth0xymethyl)—2,3-dihydr0-1,4-benz0di0xine- 6-carb0xylic acid

[00313] Step 1: methyl 2-(methylsulfanylcarbothioyloxymethyl)-2,3- WO 06280 dihydro-1,4-benz0di0xine—6-carb0xylate (DJ/\OH csz, (Bu4N)2-SO4, o /O OfOJLs/ CH3I, NaOH (aq) o 0 o [003 14] To methyl 2-(hydroxymethyl)-2,3-dihydro- 1 ,4-benzodioxine carboxylate (0.9 g, 4.0 mmol) and utylammonium sulfate (186 uL of 50 %w/v, 0.16 mmol) under N2 was added NaOH (8 mL of 50 %w/v in H20, 100.0 mmol) nwise. The viscous mixture was stirred for 10 min and CS2 (7.2 mL, 120.0 mmol) was added dropwise followed by iodomethane (18.8 g, 132.5 mmol) . The viscous biphasic e was stirred overnight, diluted with water (20 mL), and the c layer was separated. The aqueous mixture was extracted with dichloromethane (3 x 20 mL). The combined organics were washed with saturated aqueous NaCl (2 x 10 mL), dried over MgSO4, evaporated and purified by column chromatography to provide methyl 2-(methylsulfanylcarbothioyloxymethyl)-2,3-dihydro-1,4- benzodioxinecarboxylate. 1H NMR (400 MHZ, CDClg) 5 7.64 - 7.54 (m, 2H), 6.99 - 6.89 (m, 1H), 4.83 (qd, J = 11.8, 5.2 Hz, 2H), 4.69 = 11.6, - 4.60 (m, 1H), 4.37 (dd, J 2.4 Hz, 1H), 4.14 (dd, J = 11.6, 6.8 Hz, 1H), 3.88 (s, 3H), 2.59 (s, 3H).

Step 2: methyl 2-((triflu0r0meth0xy)methyl)—2,3- dihydrobenz0[b] [1,4]dioxine—6-carb0xylate 8 NR Br F i / 0)—N F o Br \Br 0 O S OkF /O /O O HF-pyridine, O O OBr

[00316] To a suspension of 5,5-dimethyl-1,3-dibromohydantoin (860 mg, 3.0 mmol) in DCM (5 mL) was added pyridine (hydrofluoric acid) (870 uL of 70 %w/w, 6.0 mmol) at -78 0C dropwise under Ar. The reaction mixture was stirred at -78 0C for 5 min and treated with methyl 2-(methylsulfanylcarbothioyloxymethyl)-2,3- dihydro-l,4-benzodioxinecarboxylate (157 mg, 0.50 mmol) in DCM (2 mL) dropwise. The reaction mixture was stirred at -78 0C for 15 min. The cooling bath was removed and the reaction mixture was d to warm to rt and the mixture was stirred at rt overnight. Water was added and the mixture was extracted with DCM (2x).

The combined organic layers were dried over MgSO4, filtered and concentrated to dryness. The crude al was purified by column cromatography ) to provide methyl 5 ,6,8-tribromo(trifiuoromethoxymethyl)-2,3-dihydro- l ,4- benzodioxinecarboxylate (180 mg, 68%). 1H NMR (400 MHz, CDClg) 8 4.58 (d, J = 6.5 Hz, 1H), 4.47 (dd, J = 11.8, 2.5 Hz, 1H), 4.24 (tdd, J = 10.1, 8.4, 4.1 Hz, 3H), 3.97 (s, 3H).

Step 3: methyl 2-((triflu0r0meth0xy)methyl)—2,3- dihydrobenzoébfll,4] dioxinecarb0xylate Br :onAOkF F Ammonium formate Pd/C, EtOH 0 B::Oj/\ To a solution of methyl 5,6,8-tribromo oromethoxymethyl)-2,3-dihydro-1,4-benzodioxinecarboxylate (3.1 g, 5.8 mmol) in EtOH (100 mL) was added ammonium e (3.1 g, 49.2 mmol) and 10% palladium/carbon (620 mg, 0.58 mmol). The reaction mixture was heated at reflux for 30 min. The catalyst was removed via filtration and washed with EtOH. The filtrate was concentrated to dryness. The resulting residue was repartitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3x). The combined c layers were washed with saturated aqueous NaCl, dried over MgSO4, d and concentrated to dryness to provide methyl 2-(trifiuoromethoxymethyl)-2,3-dihydro- 1,4-benzodioxinecarboxylate (1.5 g, 88%). The crude material was used directly in next step without filrther purification. 1H NMR (400 MHZ, CDClg) 5 7.64 - 7.53 (m, 2H), 7.02 - 6.88 (m, 1H), 4.50 (dd, J = 6.0, 2.0 Hz, 1H), 4.34 (dd, J = 11.7, 2.4 Hz, 1H), 4.26 - 4.08 (m, 3H), 3.88 (s, 3H).

Step 4: 2-(triflu0r0meth0xymethyl)—2,3-dihydr0-1,4- benzodioxinecarb0xylic acid o NaOH okF /O\H/©:O MeOH H20 To a solution of methyl 2-(trifiuoromethoxymethyl)-2,3- dihydro-1,4-benzodioxinecarboxylate (165 mg, 0.56 mrnol) in MeOH (3 mL) was added NaOH (113 mg, 2.82 mmol) in water (1 mL). The reaction mixture was stirred ar rt for 72 h, diluted with H20, and acidified using 1 N HCl to pH ~2. The resulting precipitate was collected via vacuum filtration and washed with cold water to provide fluoromethoxymethyl)-2,3-dihydro-1,4-benzodioxinecarboxylic acid (140 mg, 89.1%). 1H NMR (400 MHz, CDC13)5 7.67 (td, J = 4.5, 2.0 Hz, 2H), 7.04 - 6.88 (m, 1H), 4.52 (td, J = 7.8, 2.4 Hz, 1H), 4.36 (dd, J = 11.7, 2.4 Hz, 1H), 4.28 - 4.07 (m, 3H). ] 4-(2-flu0r0methyl-pr0p0xy)methyl-benz0ic acid ] Step 1: methyl 4-(2-flu0r0methyl-propoxy)—3-methyl- benzoate Owl—I 0% We: deoxofluor —M» ”Yer O 0 A solution of methyl 4-(2-hydroxymethyl-propoxy) methyl-benzoate (4.0 g, 16.8 mmol) was dissolved in DCM (40 mL) and treated with deoxy-fluor (3.4 mL, 18.5 mmol) slowly while a water bath was used to keep the reaction mixture near rt. The reaction mixture was allowed to stir at rt for 2 h, diluted with DCM (35 mL), and washed with water (75 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced presssure. The crude product was purified by silica gel column chromatography: 80 gram silica gel , 0-10% ethyl acetate/hexane gradient over 30 min; providing methyl 4-(2-fluoro methyl-propoxy)methyl-benzoate (2.5 g, 62%) as a clear colorless oil. 1H NMR (400 C13)8 7.90 = 8.5 Hz, 1H), 3.99 (d, J = 16.5 - 7.83 (m, 2H), 6.80 (d, J Hz, 2H), 3.88 (s, 3H), 2.28 (s, 3H), 1.52 (d, J = 21.4 Hz, 6H). ESI-MS m/z calc. 240.1, found 241.4 (M+1)+; Retention time: 1.86 min (3 min run).

Step 2: 4-(2-flu0r0methyl-pr0p0xy)methyl-benz0ic acid O\/kF NaOH x O HO H20, MeOH \n/(ZO O 0 To a on of methyl 4-(2-fluoromethyl-propoxy) methyl-benzoate (2.5 g, 10.4 mmol) dissolved in methanol (2 mL) was added a solution of sodium hydroxide (1.2 g, 31.1 mmol) in water (6 mL). The reaction mixture was allowed to stir at 55 CC for 30 min. The ing clear solution was concentrated under reduced pressure. The obtained white solid was redissolved in water (50 mL) and washed with ethyl acetate (1 X 50 mL). The s layer was ed to pH 2 with the on of aqueous 1 N HCl solution, resulting in a cloudy white suspension. The mixture was extracted with ethyl acetate (2 X 75 mL) and the combined organics were dried over sodium e, d and concentrated under reduced pressure to provide 4-(2-fluoromethyl-propoxy)methyl-benzoic acid (1.9 g, 81%) as a white solid. 1H NMR (400 MHz, CDClg) 8 7.96 (dd, J = 8.5, 2.2 Hz, 1H), 7.92 (d, J = 1.4 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 4.01 (d, J = 16.5 Hz, 2H), 2.30 (s, 3H), 1.54 (d, J = 21.4 Hz, 6H). ESI-MS m/z calc. 226.1, found 453.3 (M+1)+; Retention time: 1.53 min (3 min run). 3-meth0xy(2-(trifluor0meth0xy)eth0xy)benz0ic acid Step 1: methyl 3-meth0xy[2- (trifluoromethoxy)eth0xy] benzoate CF3803(CH2)ZOCF3 O\/\o)<F / 0M9 /O NaH, DMF OMe 0 0 A 100 mL RB flask was fitted with a teflon stirrer bar, a magnetic stirrer, a cooling bath and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with 60% sodium hydride (1.1 g, 26.7 mmol) in mineral oil and cooled to 0 0C with an ice bath. The vessel was then charged with N,N— dimethylformamide (35 ml) via syringe and stirring was commenced. The vessel was then charged with methyl 4-hydroxymethoxy-benzoate (4.9 g, 26.7 mmol) as a solid in 4 equal portions over 20 min resulting in slight g. The reaction mixture was d for 20 min and then treated with 2-(trifluoromethoxy)ethyl trifluoromethanesulfonate (14.0 g, 26.7 mmol) neat via canula over 10 min. The cooling bath was removed and the reaction mixture was continued to stir and allowed to warm to rt. The reaction mixture was heated to 40 0C for 30 min, After cooling to rt the on mixture was poured onto crushed ice (150 g). The mixture was diluted with water (150 ml) and then transferred to a separatory flannel and partitioned with ethyl acetate (250 ml). The organic was removed and the aqueous layer was extracted with ethyl acetate (2 x 100 ml). The combined organics were washed with 0.1 M NaOH aqueous solution (2 X 150 ml), saturated aqueous sodium chloride (4 x 150 ml), dried over sodium sulfate (250 g), and d through a glass fiit r funnel. The filtrate was concentrated under reduced pressure. Purification by flash column chromatography 220 g, 0-20 % ethyl acetate-hexanes) afforded methyl 3- methoxy[2-(trifluoromethoxy)ethoxy]benzoate (7.5 g, 95%). 1H NMR (400 MHz, CDC13)5 7.68 (dd, J = 8.4, 2.0 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 4.41 = 8.3, 5.3, 2.7 Hz, 4H), 3.94 (s, 3H), 3.92 (s, 3H). - 4.29 (m, J The following compounds were prepared using the procedure reported above.

Product Precursor methyl 3-methoxy[2- Methyl 4-hydroxymethoxy-benzoate (trifluoromethoxy)ethoxy]benzoate. methyl 3-methyl[2- Methyl 4-hydroxymethyl-benzoate (tr1fluoromethoxy)ethoxy]benzoate. methyl 3-chloro(2- Methyl 4-hydroxychloro-benzoate (tr1fluoromethoxy)ethoxy)benzoate_ methyl 3-fluoro[2- Methyl 4-hydroxyfiuoro-benzoate (trifluoromethoxy)ethoxy]benzoate methyl 3-chloromethoxy(2- methyl 3-chlorohydroxy (trifluoromethoxy)ethoxy)benzoate methoxybenzoate Step 2: 3-methoxy(2-(trifluor0meth0xy)eth0xy)benz0ic acid <FF NaOH O\/\O F 0 HO / OMe MeOH. H20 OMe O O

[00331] A solution of methyl 3-methoxy[2- (trifluoromethoxy)ethoxy]benzoate (5.1 g, 17.5 mmol) in methyl alcohol (24 mL) was treated with aqueous sodium ide (96.1 mL of 1 M, 96.1 mmol). The reaction mixture was heated to 50 0C for 1 h (reaction mixture became homogeneous during this time). After cooling to rt the methyl alcohol was removed under reduced pressure. The ing aqueous mixture was treated with cold 37 wt.% HCl until pH~1 which resulted in the formation of a precipitate. The solid was collected by vacuum filtration in a glass frit r funnel and washed with water (2 x 150 ml).

The material was further dried under vacuum to e 3-methoxy(2- (trifluoromethoxy)ethoxy)benzoic acid (4.3 g, 88 %) as a white solid. 1H NMR (400 MHz,DMSO)512.73(s, 1H), 7.55 (dd, J = 8.4, 2.0 Hz, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 4.43 (dd, J = 5.3, 3.0 Hz, 2H), 4.38 - 4.24 (m, 2H), 3.82 (s, 3H). ESI-MS m/z calc. 280.1, found 281.1 (M+1)+; Retention time: 0.52 min (3 min run).

The following compounds were prepared using the procedure reported above.

Product Precursor 3-methoxy(2- methyl 3-methoxy[2- (trifluoromethoxy)ethoxy)benzoic acid (trifluoromethoxy)ethoxy]benzoate 3-methyl(2- methyl 3-methyl[2- (trifluoromethoxy)ethoxy)benzoic acid (trifluoromethoxy)ethoxy]benzoate l 3 -chloro(2- methyl 3-chloro(2- oromethoxy)ethoxy)benzoic acid (trifluoromethoxy)ethoxy)benzoate 3-fluoro[2- methyl o[2- (trifluoromethoxy)ethoxy]benzoic acid (trifluoromethoxy)ethoxy]benzoate 3-chloromethoxy(2- methyl 3-chloromethoxy(2- (trifluoromethoxy)ethoxy)benzoic acid (trifluoromethoxy)ethoxy)benzoate 3-methyl(2,2,2-triflu0r0eth0xy)benzoic acid Step 1: methyl 3-methyl(2,2,2-triflu0r0eth0xy)benz0ate F F OH Br\XF o\)<FF / /O Cscos, DMF O 0 To a solution of methyl 4-hydroxymethyl-benzoate (1.6 g, mmol) in DMF (20 mL) was added cesium carbonate (2.7 g, 20.0 mmol) and 2- bromo-l,1,1-trifiuoro-ethane (1.8 mL, 20.0 mmol). The reaction e was heated at 80 0C overnight and was recharged with 2-bromo-1,1,1-trifiuoro-ethane (1 mL, 11 mmol) and heated at 80 0C overnight. The reaction mixture was recharged again with 2-bromo-1,1,1-trifluoro-ethane (2 mL, 22 mmol) and heated at 80 0C for 6 h. The reaction mixture was quenched and partitioned between ethyl e and water. The aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with water (3x), 1N aqueous NaOH, saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to dryness. The crude material was used directly in next step t further purification. ESI-MS m/z calc. 248.2, found 249.3 (M+l)+; Retention time: 2.02 min (3 min run).

Step 2: 3-methyl(2,2,2-triflu0r0eth0xy)benz0ic acid F F OXFF F NaOH O\)<F O —’HO MeOH, H20 0 0 To a suspension of methyl 3-methyl(2,2,2- trifluoroethoxy)benzoate (1.7 g, 6.8 mmol) in MeOH (20 mL) and water (10 mL) was added NaOH (1.4 g, 34.2 mmol). The reaction mixture was stirred at rt overnight, turned clear, and concentrated (removing MeOH) under reduced pressure. The residual solution was diluted with water and acidified with 1 N HCl. The resulting precipitate was collected via filtration, washed with water and dried to provide 3-methyl(2,2,2- roethoxy)benzoic acid (1.6 g, 100%) as an off-white solid. ESI-MS m/z calc. 234.2, found 235.2 ; Retention time: 1.73 min (3 min run). ] [(3aR,7aR)—7a-[3-(2-tert-butoxyethoxy)—2-pyridyl]-3a,4,6,7- tetrahydro-[1,3]dioxolo[4,5-c]pyridinyl]-[4-(2-tert—butoxyethoxy)—3-chloro- phenyl]methanone Step 1: [(3aR,7aR)—7a-(3-flu0r0pyridyl)—3a,4,6,7— tetrahydro-[1,3]di0xolo [4,5-c]pyridin-S-yl]-(3-chlor0flu0r0-phenyl)methan0ne >:CI O 0/0., NH F On".

NJKEZCI HATU, TEA, DMF 0 F A 20 mL Vial was d with aR)—7a-(3-fluoro pyridyl)-4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridine (258 mg, 1.15 mmol), 3- chlorofluoro-benzoic acid (201 mg, 1.15 mmol), HATU (481 mg, 1.27 mmol) and DMF (5 mL). To the resulting solution was added triethylamine (640 uL, 4.6 mmol) and the reaction e was stirred at rt for 2 h. Water (50 mL) was added, and the ing mixture was extracted with DCM (3 x 25 mL). The combined extracts were washed with water (25 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (12 g column) using a gradient ofAcOEt (0 to 100%) in hexanes over 12 min affording [(3 aR,7aR)-7a-(3-fluoropyridyl)-3a,4,6,7-tetrahydro-[ 1 ,3]dioxolo[4,5-c]pyridin yl]-(3-chlorofluoro-phenyl)methanone (365 mg, 78 %) as a Viscous colorless oil.

ESI-MS m/z calc. 380.1, found 381.0 (M+1)+; Retention time: 1.09 min (3 min run).

Step 2: [(3aR,7aR)—7a-[3-(2-tert-butoxyethoxy)—2-pyridyl]- 3a,4,6,7—tetrahydr0-[1,3]dioxolo[4,5-c]pyridinyl]-[4-(2-tert—but0xyeth0xy)—3- chloro-phenyl]methan0ne 0/ N O\/\o O\=_ O\/\04< NaH, DMF <on/©:CI In a Vial, 2-tert-butoxyethanol (155 mg, 1.31 mmol) was dissolved in DMF (500 uL). NaH (53 mg, 1.3 mmol) (60% oil dispersion) was added in small portions and the suspension was stirred at rt for 25 min. [(3aR,7aR)—7a-(3- fluoropyridyl)—3 a,4,6,7-tetrahydro-[1 ,3 ] dioxolo [4,5 -c]pyridin-5 -yl] -(3 -chloro fluoro-phenyl)methanone (50 mg, 0.13 mmol) as a on in DMF (100 uL) was added and the reaction mixture was stirred at 80 CC for 1h. The reaction mixture was quenched by the addition of water. The resultant mixture was extracted with DCM (3x). The ed extracts were dried over sodium sulfate and the volatiles were removed under reduced pressure. The crude product was purified by reverse phase HPLC (HCl as a modifier) providing [(3aR,7aR)-7a-[3-(2-tert-butoxyethoxy) pyridyl] -3 7-tetrahydro-[1 ,3 ] dioxolo [4,5 -c]pyridin-5 -yl]- [4-(2-tert-butoxyethoxy)- 3-chloro-phenyl]methanone (38 mg, 47 %) as a colorless solid. ESI-MS m/z calc. 576.3, found 577.0 ; Retention time: 1.48 min (3 min run). 3-(triflu0r0methyl)—4-(3,3,3-triflu0r0pr0p0xy)benz0ic acid Step 1: Methyl 4-hydr0xy(triflu0r0methyl)benzoate OH OH SOCIZ HO F /o F F DMF, MeOH F O F O F 4-hydroxy(trifluoromethyl)benzoic acid (4.9 g, 23.7 mmol) was dissolved in methanol (15 mL) and DMF (18 uL, 0.24 mmol), thionyl chloride (5.2 mL, 71.0 mmol) was added dropwise (over a period of 10 min) to the reaction e, and it was allowed to stir for 18 h at rt. Volatiles were then removed under reduced pressure. The ing solid was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium onate (50 mL). The aqueous layer was further extracted with ethyl acetate (2 X 50 mL). All organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide methyl 4-hydroxy(trifluoromethyl)benzoate (4.9 g, 93 %) as an off-white solid. . 1H NMR (400 MHz, DMSO) 5 11.68 (s, 1H), .10 (m, 2H), 7.20 - 7.07 (m, 1H), 3.83 (s, 3H). ESI-MS m/z calc. 220.0, found 221.0 (M+1)+; Retention time: 1.41 min (3 min run).

Step 2: methyl 3-(triflu0r0methyl)(3,3,3- trifluoropropoxy)benzoate OH M O o F o ijlfFF / CsC03, DMF / F F 0 F o F WO 06280 In a vial, methyl 4-hydroxy(trifluoromethyl)benzoate (1.04 g, 4.73 mmol) was dissolved in DMF (2 mL). Cesium carbonate (4.6 g, 14.2 mmol) was added followed by 3-bromo-1,1,1-trifiuoro-propane (760 uL, 7.1 mmol). The vial was tightly capped and the heterogenous mixture was d at 80 CC for 1 h. The ing thick slurry was diluted with DMF (5 mL) and treated with additional 3- 1,1,1-trifluoro-propane (760 uL, 7.1 mmol). The reaction mixture was stirred at 80 CC for 15 h and treated with additional 3-bromo-1,1,1-trifiuoro-propane (1.5 mL, 14.2 mmol). The reaction mixture was stirred at 80 CC under nitrogen atmosphere for 4 days and treated with additional 3-bromo-1,1,1-trifluoro-propane (1.5 mL, 14.2 mmol). The reaction mixture was heated at 80 0C for 24 h and was cooled and d.

The solids were washed with methanol. The filtrate was concentrated under reduced pressure. Water (50 mL) and ethyl acetate (50 mL) were added and separated. The aqueous phase was fiarther extracted with ethyl acetate (50 mL). The combined extracts were washed with saturated aqueous NaCl, dried over sodium e, filtered, and the volatiles were removed under reduced pressure. ation by flash chromatography on silica gel (24 g column) using a gradient ofAcOEt (0 to 50 % over 20 min) in hexanes provided methyl 3-(trifiuoromethyl)(3,3,3-trifiuoropropoxy)benzoate (387 mg, 26%) as a white solid. 1H NMR (400 MHz, CDClg) 5 8.29 (d, J = 2.0 Hz, 1H), 8.21 (dd, J = 8.7, 2.1 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 4.34 (t, J = 6.5 Hz, 2H), 3.92 (s, 3H), 2.72 (qt, J = 10.4, 6.5 Hz, 2H). ESI-MS m/z calc. 316.1, found 317.0 (M+1)+; Retention time: 1.88 min (3 min run).

Step 3: 3-(triflu0r0methyl)—4-(3,3,3- trifluoropropoxy)benz0ic acid 0WPF o F NaOH WP /0 F F —> HO F F F MeOH, H20 F o F

[00349] A solution of methyl 3-(trifluoromethyl)(3,3,3- trifluoropropoxy)benzoate (380 mg, 1.20 mmol) in methanol (2 mL) was treated with aqueous sodium hydroxide (600 uL of 6 M, 3.6 mmol). The thick suspension was stirred at 60 CC and became a clear solution after 5 min. After stirring at 60 CC for 1.5 h the reaction mixture was diluted with water (25 mL) and was acidified with 6N HCl to pH = 1. The resulting white precipitate was extracted with ethyl acetate (2 x 25 mL).

The combined extracts were dried over sodium sulfate, filtered, and the volatiles were removed under reduced pressure to afford 3-(trifluoromethyl)(3,3,3- trifluoropropoxy)benzoic acid (342 mg, 94%) as a white solid. 1H NMR (400 MHz, DMSO) 5 13.18 (s, 1H), 8.19 (dd, J = 8.7, 2.1 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 4.44 (t, J = 5.6 Hz, 2H), 2.84 (ddq, J = 16.8, 11.2, 5.7 Hz, 2H).

ESI-MS m/z calc. 302.0, found 303.0 (M+1)+; ion time: 1.62 min (3 min run). 3-chlor0(2-flu0ro-Z-methyl-propoxy)benzoic acid Step 1: methyl 3-chloro(2-hydroxy methylpropoxy)benzoate ”(avg okaH /O\'(©:CI W /(kn/(10OH O 0 A 500 ml 3 neck RB flask was fitted with a ical stirrer, a J-Kem temperature probe/controller, an addition funnel, a water cooled reflux condenser and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with methyl 3-chlorohydroxy-benzoate (10 g, 53.6 mmol) and methyl alcohol (40 ml) which provided a clear pale yellow solution. ng was commenced and the pot temperature was ed at 19 0C. The vessel was then charged with potassium carbonate (30 g, 0.21 mol) added as a solid in one portion which resulted in an exotherm to 23 0C. Note: The potassium ate was ground to a fine powder prior to use. The resulting suspension was continued to stir at rt for 15 min and then treated with 1-chloromethyl-propanol (11.6 g, 0.11 mol) added neat dropwise via addition funnel over 10 min. The resulting reaction e/suspension was then heated to 70 0C and stirred for 20 h. The reaction mixture was cooled to rt and diluted with ethyl acetate (250 ml). The mixture was filtered through a glass frit Buchner funnel with a 10 mm layer of Celite. The filter cake was washed with ethyl acetate (2 x 100 ml). The filtrate was transferred to a separatory funnel and partitioned with 1 M s NaOH (250 ml). The organic was removed and washed with 1 M aqueous NaOH (2 x 150 ml), saturated aqueous sodium chloride (150 ml), dried over sodium sulfate (250 g) and filtered through a glass frit r fiJnnel. The te was concentrated under reduced pressure to provide methyl 3-chloro(2-hydroxy methylpropoxy)benzoate (9.0 g, 65%) as a clear pale yellow oil. The material was used without further purification in the next synthetic step. ESl-MS m/z calc. 258.7, found 259.2 (M+1)+; ion time: 1.46 min (3 min run).

Step 2: methyl 3-chlor0(2-flu0r0methyl- propoxy)benzoate FxF' .

/O\n/©::wH(DA/Elmo —>/O\n/E:ECIDCM O 0 A solution of methyl 3-chloro(2-hydroxymethy1- propoxy)benzoate (6.2 g, 24.0 mmol) in DCM (60 mL) was treated slowly with 2- methoxy-N-(2-methoxyethy1)-N-(trifluorosu1fany1)ethanamine (4.9 mL, 26.4 mmol) while a water bath was used to keep the on temperature near rt. The reaction mixture was allowed to stir at rt for 2 h. The reaction mixture was quenched with the addition of ice-cold water (75 mL) and diluted with DCM (50 mL). The phases were ted and the organic phase was washed wtih saturated aqueous NaCl (2>< 75 mL), dried over sodium sulfate, filtered and concentrated under reduced re.

Purification by silica gel column chromatography: 40 gram silica gel column, 0-10% ethyl acetate/hexane gradient over 30 min provided methyl 3-chloro(2-fluoro methyl-propoxy)benzoate (2.4 g, 39%) as a yellow oil. 1H NMR (400 MHz, CDC13) 5 8.07 (d, J = 2.1 Hz, 1H), 7.92 (dd, J = 8.6, 2.1 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 4.06 (t, J = 9.8 Hz, 2H), 3.90 (s, 3H), 1.55 (d, J = 21.5 Hz, 6H). ESI-MS m/z ca1c. 260.1, found 261.2 (M+1)+; Retention time: 1.83 min (3 min run).

[00355] Step 3: 3-chlor0(2-fluoro-Z-methyl-propoxy)benzoic acid 0* 0%F O NaOH HO : H20 MeOH ‘n’ :CI 0 0 A solution of methyl 3-chloro(2-fluoromethy1- propoxy)benzoate (2.4 g, 9.3 mmol) in methanol (5 mL) was treated with a solution of sodium hydroxide (1.1 g, 28.0 mmol) in water (10 mL). The reaction mixture was allowed to stir at 60 CC for 1.5 h. The resulting clear solution was diluted with ethyl e (75 mL) and mixed with aqueous 1 N HC1 (75 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 3-chloro(2-fluoromethyl-propoxy)benzoic acid (2.1 g, 93%) as a white solid. 1H NMR (400 MHz, CDC13)8 8.14 (d, J = 2.1 Hz, 1H), 8.00 (dd, J = 8.6, 2.1 Hz, 1H), 6.97 (d, J = 8.7 Hz, 1H), 4.07 (d, J = 16.1 Hz, 2H), 1.56 (d, J = 21.5 Hz, 6H). ESI-MS m/z calc. 246.0, found 247.2 ; Retention time: 1.5 min (3 min run).

[00357] Methyl 3-meth0xy(3,3,3-triflu0ropropoxy)benzoic acid Step 1: methyl oxy(3,3,3- trifluoropropoxy)benzoate / O/—>NaH,dioxanes ::/\lfll: A on of 3,3,3-trifluoropropanol (1.2 g, 10.9 mmol) in 1,4-dioxane (4.5 mL) was cooled to 0 0C. To the mixture was added a 60% dispersion of sodium hydride in mineral oil (0.4 g, 10.9 mmol) portion wise. A great deal of foaming was observed. After completion of addition (20 min), the reaction mixture was allowed to stir at rt for 1 h. The reaction mixture was treated a solution of methyl 4-fluoromethoxy-benzoate (1.0 g, 5.4 mmol) in 1,4-dioxane (2 mL) and was stirred at rt for 12 h. The reaction mixture was diluted with EtOAc (75 mL) and washed with a pH 14 solution ofNaOH. The aqueous layer was acidified to pH 10 with the addition of 1 N HCl, and was extracted with EtOAc (1 X 75 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. Purification by flash column chromatography (SiOz-24 g, 0-30 % EtOAc-hexanes) afforded methyl 3-methoxy(3,3,3-trifluoropropoxy)benzoate (0.6 g, 39.7%). ESI-MS m/z calc. 278.2 found 279.2 (M+1)+; Retention time: 0.62 min (3 min run).

The following nds were prepared using the ure ed above.

Product Precursor methyl 3-methoxy(3 ,3 ,3 - methyl 4-fluoromethoxy-benzoate tnfluoropropoxy)benzoate. methyl 3-methoxy((4,4,4- methyl 4-fluoromethoxy-benzoate trifluorobutanyl)oxy)benzoate methyl 3-methoxy((1,1,1- methyl 4-fluoromethoxy-benzoate trifluoropropanyl)oxy)benzoate Step 2: methyl 3-meth0xy(3,3,3-trifluoropropoxy)benzoic acid \n/©: WI:0 F NaOH MeO / F MeOH H20 HO\[([:EZ/\/\|EF ediate methyl 3-methoxy(3 ,3 ,3- trifluoropropoxy)benzoate (480 mg, 1.73 mmol) was dissolved in methanol (1.3 mL), and a solution of sodium hydroxide (414 mg, 10.4 mmol) in water (2.6 mL) was added.

The reaction mixture was stirred at 60 CC for 1 h and was diluted with water (50 mL) and acidified to pH 1 with the addition of 1 N HCl. The resulting opaque white suspension was ted with EtOAc (2 X 75 mL). The organic layers were combined, dried over sodium e, filtered and concentrated to provide 3-methoxy- ,3-trifluoropropoxy)benzoic acid (357 mg, 78.4%) as a white solid. 1H NMR (400 MHz, DMSO) 8 12.73 (s, 1H), 7.55 (dd, J = 8.4, 2.0 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 4.27 (t, J = 6.0 Hz, 2H), 3.81 (s, 3H), 2.95 - 2.72 (m, 2H). ESI-MS m/z calc. 264.2, found 265.2 (M+1)+; Retention time: 0.5 min (3 min run).

The following compounds were prepared using the procedure reported above.

Product Precursor 3-methoxy(3 ,3 ,3 - methyl 3-methoxy(3 ,3 ,3 - ropropoxy)benzoic acid trifluoropropoxy)benzoate 3-methoxy((4,4,4-trifluorobutan methyl 3-methoxy((4,4,4- )benzoic acid trifiuorobutanyl)oxy)benzoate 3 xy((1 ,1 1 -trifluoropropan , methyl 3-methoxy((1 ,1 , 1 - yl)oxy)benzoic acid trifluoropropanyl)oxy)benzoate 3-flu0r0meth0xy(3,3,3-triflu0r0pr0p0xy)benzoic acid Step 1: 3-flu0r0meth0xy(3,3,3- trifluor0pr0p0xy)benzaldehyde o/ ch03 DMF In a flask, 3-fluorohydroxymethoxy-benzaldehyde (1.1 g, 6.2 mmol) was dissolved in DMF (7 mL). The mixture was treated with potassium carbonate (2.2 g, 15.9 mmol) and o-1,1,1-trifluoro-propane (1.3 mL, 12.5 mmol) and the reaction mixture was stirred under nitrogen atmosphere at 80 °C for 17 h. Additional 3-bromo-1,1,1-trifiuoro-propane (2.6 mL, 24.9 mmol) was added and the reaction mixture was stirred at 65 0C for 5 h (50% conversion). Another load of 3- bromo-1,1,1-trifiuoro-propane (1.3 mL, 12.5 mmol) was added and the reaction mixture was stirred at 65 0C for 2.5 d. The solids were d and washed with methanol. The filtrate was concentrated under reduced pressure and diluted with water (50 mL) and ethyl acetate (50 mL). The phases were separated after being mixed and the s phase was extracted with ethyl acetate (50 mL). The combined extracts were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered, and the volatiles were d in vacuo. The crude solid was purified by flash chromatography on silica gel (80 g column) using a gradient ofAcOEt (0 to 50 % over 40 min) in hexanes. The t eluted at 15-25% ethyl acetate (13-20 min) to provide 3-fiuoromethoxy(3,3,3-trifiuoropropoxy)benzaldehyde (0.80 g, 48 %) as a colorless liquid. 1H NMR (400 MHZ, CDClg) 5 9.86 (d, J = 1.2 Hz, 1H), 7.29 - 7.25 (m, 2H), 4.38 (td, J = 6.8, 0.5 Hz, 2H), 3.95 (s, 3H), 2.66 (qt, J = 10.6, 6.8 Hz, 2H).

ESI-MS m/z calc. 266.1, found 267.0 (M+1)+; Retention time: 1.63 min (3 min run).

[00367] Step 2: 3-flu0r0meth0xy(3,3,3- 2014/045675 trifluoropropoxy)benz0ic acid NaC|02 2--methy|but—2-ene tBuOH O\v(:[O\/\KF#N21H2PO4/ F 0 :W: H20 CH3CN ] To a solution of 3-fiuoromethoxy(3,3,3- trifiuoropropoxy)benzaldehyde (780 mg, 2.9 mmol) in tBuOH (8 mL), water (5 mL) and acetonitrile (5 mL) was added sodium dihydrogen phosphate (352 mg, 2.9 mmol), ylbutene (1.0 g, 14.7 mmol) and sodium chlorite (265 mg, 2.9 mmol). The reaction mixture was stirred at 25 CC for 21 h and additional sodium dihydrogen phosphate (563 mg, 4.7 mmol), 2-methylbutene (1.5 mL, 14.6 mmol) and NaClOz (795 mg, 8.79 mmol) were added. The reaction mixture was stirred at rt for 7 h, acidified with 1N HC1, and diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2x). The cs were combined, dried with sodium sulfate, filtered and concentrated under reduced pressure to give a waxy solid. The compound was triturated in hexanes, filtered, and dried in a vacuum oven at 40 0C overnight to provide 3-fluoromethoxy(3,3,3- trifiuoropropoxy)benzoic acid (620 mg, 75 %) as an off-white solid. 1H NMR (400 MHz, DMSO) 8 12.97 (s, 1H), 7.43 = 10.5, 1.9 Hz, 1H), - 7.40 (m, 1H), 7.38 (dd, J 4.27 (t, J = 5.9 Hz, 2H), 3.89 (s, 3H), 2.75 (qt, J = 11.4, 5.9 Hz, 2H). ESI-MS m/z calc. 282.1, found 283.0 ; Retention time: 1.49 min (3 min run). 5-chlor0[2-(trifluoromethoxy)ethoxy]pyridine carboxylic acid WEI N, OWXF / ”0 CI 2. NaOH, H20, MeOH / 0 0 Step 1: A solution of methyl 5-chlorooxo-1H-pyridine carboxylate (1.0 g, 5.3 mmol) in DMF and cooled to 0 CC and treated slowly with 60% sodium hydride in mineral oil (213 mg, 5.3 mmol). After ng at rt for 10 min, 2-(trifiuoromethoxy)ethyl trifiuoromethanesulfonate (3.0 g, 5.9 mmol) was added. The reaction e was allowed to stir overnight at rt. It was then diluted with ethyl acetate (75 mL) and washed with saturated aqueous NaCl (2>< 75 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to provide methyl 5-chloro[2-(trifluoromethoxy)ethoxy]pyridinecarboxylate (330 mg) as a brown solid which was dissolved in ol (680 uL). The mixture was treated with a solution of sodium hydroxide (l .3 mL of 2.5 M, 3.3 mmol). The reaction mixture was allowed to stir at 60 CC for 1.5 h. The ing clear on was diluted with ethyl acetate (75 mL) and mixed with aqueous l N HCl. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 5-chloro[2-(trifluoromethoxy)ethoxy] pyridinecarboxylic acid (300 mg, 95.4%) as a white solid. 1H NMR (400 MHz, DMSO) 5 13.32 (s, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 4.78 = - 4.58 (m, 2H), 4.48 (dd, J .1, 3.4 Hz, 2H). ESI-MS m/z calc. 285.0, found 286.03 (M+l)+; Retention time: 1.55 min (3 min run). 5-[(3,3-diflu0r0cyclobutyl)methoxy]methoxy-pyridine carboxylic acid

[00372] Step 1: methyl 6-chlor0[(3,3- difluorocyclobutyl)methoxy]pyridinecarb0xylate \ \ 0% l Mso/\©<FF —> | /O N/ O CI NaH,DMF / N/ CI 0 0 To methyl 6-chlorohydroxy-pyridinecarboxylate (500 mg, 2.7 mmol) in dry DMF (4 mL) was added NaH (1 17 mg, 2.9 mmol) (60% dispersion in oil). The mixture was stirred at rt for 15 min before being treated with (3,3-difluorocyclobutyl)methyl methanesulfonate (865 mg, 4.32 mmol). The ing reaction mixture was stirred at 90 0C for 5 h. The reaction e was cooled down to rt overnight. Water was added and the ing beige precipitate was filtered and washed with water. The wet solid was dissolved in DCM, dried over sodium sulfate, and filtered. The filtrate was concentrated under d pressure and subjected to flash chromatography on silica gel (24 g column) using a gradient of AcOEt (0 to 60 %) in hexanes over 25 min affording methyl 6-chloro[(3,3- difluorocyclobutyl)methoxy]pyridinecarboxylate (384 mg, 49.4%) as a white solid. 1H NMR (400 MHz, CDC13) 8 8.09 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 4.15 (d, J = 5.3 Hz, 2H), 3.98 (s, 3H), 2.86 - 2.68 (m, 3H), 2.68 - 2.52 (m, 2H). ESI-MS m/z calc. 291.0, found 292.0 (M+l)+; Retention time: 1.51 min (3 min run).

The following compounds were prepared using the procedure ed above.

Product Precursor methyl 6-chloro[(3,3- methyl 6-chlorohydroxy- ocyclobutyl)methoxy]pyridine pyridinecarboxylate carboxylate methyl 6-chloro[[1- methyl 6-chlorohydroxy- (trifluoromethyl)cyclopropyl]methoxy]pyridinepyridinecarboxylate 2-carboxylate methyl 6-chloro methyl 6-chlorohydroxy- (cyclobutylmethoxy)pyridinecarboxylate necarboxylate Step 2: 5-[(3,3-diflu0r0cyclobutyl)methoxy]methoxy- pyridine-Z-carboxylic acid F F OfiF O \ fiF l NaOMe, H20 \ O —’ / HO / / N CI N 0M6 1,4-dioxane O 0 A microwave vessel was charged with methyl 6-chloro difluorocyclobutyl)methoxy]pyridinecarboxylate (300 mg, 1.03 mmol), e (4 mL), sodium methoxide (1.4 mL of 25 %w/w, 6.2 mmol) and water (61 uL, 3.40 mmol). The reaction e was stirred under microwave irradiation at 110 CC for 30 min. The resulting reaction mixture was concentrated under reduced pressure.

The remaining white solid was redissolved in water (50 mL) and was washed with ethyl acetate (l X 50 mL). The aqueous layer was acidified to pH 1 with the addition of 6 N HCl solution and extracted with ethyl acetate (2 X 75 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure affording 5-[(3,3-difluorocyclobutyl)methoxy]methoxy-pyridine carboxylic acid (263 mg, 84.6%) as a colorless viscous oil that solidified upon standing. 1H NMR (400 MHz, CDC13)8 7.84 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 4.12 (d, J = 5.8 Hz, 2H), 4.06 (s, 3H), 2.91 - 2.61 (m, 3H), 2.59 - 2.42 (m, 2H).

ESI-MS m/z calc. 2731, found 274.0 (M+l)+; Retention time: 1.29 min (3 min run

[00377] The following compounds were ed using the procedure reported above.

Product Precursor methyl 6-chloro[(3,3- -[(3,3-d1fluorocyclobutyl)methoxy]_ difluorocyclobutyl)methoxy]pyr1d1ne_ _ _ methoxy-pyridinecarboxylic acid carboxylate -[[l- methyl 6-chloro[[l- (trifluoromethyl)cyclopropyl]methoxy] (trifluoromethyl)cyclopropyl]methoxy]pyri hoxy-pyridinecarboxylic acid dinecarboxylate methyl 6-chloro -(cyclobutylmethoxy)methoxy- _ _ necarboxylic ac1d_ _ _ _ (cyclobutylmethoxy)pyr1d1ne ylate 6-methoxy(2,2,2-triflu0r0methyl-eth0xy)pyridine—2- carboxylic acid F 1.

\ NaH, dioxanes I HOE/(NEGOj/k: HO N/ CI 2. NaOMe MeOH H20 0 l,l,l-trifluoropropanol (43 uL, 0.47 mmol) was dissolved in l,4-dioxane (700 uL), and sodium hydride (38 mg, 0.94 mmol) (60 wt % in mineral oil) was added. The e was d at rt for 10 min before 6-chlorofluoropyridinecarboxylic acid (75 mg, 0.43 mmol) was added, and the reaction mixture was stirred at 70 CC overnight. The reaction mixture was treated with sodium methoxide (555 uL of 25 %w/v, 2.56 mmol) (in methanol) and was stirred at 65 CC for 2 h. The reaction mixture was diluted with water (50 mL) and washed with ethyl acetate (1 X 75 mL). The aqueous layer was ed to pH 3 with the addition of 1 N HCl and extracted with DCM (3 X 75 mL). The final organic layers were combined, dried over sodium e, filtered, and concentrated under reduced pressure to provide 6-methoxy(2,2,2-trifluoromethyl-ethoxy)pyridinecarboxylic acid as a ly yellow oil that crystallized upon standing. ESI-MS m/z calc. 265.1, found 266.3 (M+1)+; Retention time: 1.24 min (3 min run).

The following compounds were prepared using the procedure reported above.

Product Precursor 6-methoxy(2,2,2-trifluoromethyl- 6-chlorofluoro-pyridine ethoxy)pyridinecarboxylic acid carboxylic acid oxy(2,2,3,3- 6-chlorofluoro-pyridine tetrafiuoropropoxy)picolinic acid ylic acid

[00381] (5-((6,6-diflu0r0spir0 [3.3] heptan-Z-yl)methoxy)—6- methoxypyridin-Z-yl)((3aR,7aR)—7a-(3-flu0r0phenyl)tetrahydr0-[1,3] di0X010[4,5- c]pyridin-5(6H)-yl)methan0ne ifi F <,.Om :1le0\ M30 <01? 0 082003 DMF o N/ o/

[00382] A solution of 7aR)-7a-(3-fluorophenyl)-3a,4,6,7- tetrahydro- [1 ,3 ] dioxolo [4,5 -c]pyridin-5 -yl] -(5 -hydroxymethoxy pyridyl)methanone (85 mg, 0.23 mmol), (2,2-difluorospiro[3.3]heptanyl)methyl methanesulfonate (109 mg, 0.45 mmol), and powdered potassium carbonate (110 mg, 0.79 mmol) in N,N—dimethylformamide (1.1 mL) was heated at 80 CC for 4 h. The reaction mixture was cooled to rt, filtered and purified by reverse phase HPLC (HCl modifier-l-100% ACN/HZO) to afford (5-((6,6-difluorospiro[3.3]heptan y1)methoxy)—6-methoxypyridiny1)((3aR,7aR)—7a-(3-fluoropheny1)tetrahydro- [1,3]dioxolo[4,5-c]pyridin-5(6H)-y1)methanone (10 mg, 7.8 %). 1H NMR (400 MHz, CDC13) 5 7.44 (d, J = 7.9 Hz, 1H), 7.36 (td, J = 8.0, 5.9 Hz, 1H), 7.20 = 8.0 - 7.12 (m, J Hz, 2H), 7.09 (t, J = 7.0 Hz, 1H), 7.04 = 31.5 Hz, 1H), 4.89 - 6.96 (m, 1H), 5.30 (d, J (d, J = 29.1 Hz, 1H), 4.52 - 4.22 (m, 1H), 4.13 - 4.04 (m, 2H), 4.03 (s, 3H), 4.02 - 3.91 (m, 4H), 3.84 - 3.49 (m, 1H), 2.87 - 2.70 (m, 1H), 2.68 - 2.47 (m, 3H), 2.41 - 2.01 (m, 6H). ESI-MS m/z calc. 518.2, found 519.2 (M+1)+; ion time: 1.621 min (3 min run) .

The following compounds were prepared using the procedure reported above.

Product Mesylate [(3 aR,7aR)-7a-(3-fluoropheny1)-3a,4,6,7- tetrahydro-[1,3]dioxolo[4,5 -c]pyridin-5 -y1]- (2,2-difluorospiro [3 .3]heptan [5-[(2,2-difluorospiro[3 .3]heptan y1)methy1 methanesulfonate hoxy]methoxypyridy1]methanone [(3 aR,7aR)-7a-(3-fluoropheny1)-3a,4,6,7- tetrahydro-[1,3]dioxolo[4,5 idin-5 -y1]- (2,2 ,3 ,3 - [6-methoxy[(2,2,3,3- tetrafluorocyclobuty1)methy1 tetrafluorocyclobuty1)methoxy] methanesulfonate pyridy1]methanone [(3 aR,7aR)-7a-(3-fluoropheny1)-3a,4,6,7- tetrahydro-[1,3]dioxolo[4,5 -c]pyridin-5 -y1]- (3,3-difluorocyclopenty1)methy1 [5-[(3,3-difluorocyclopenty1)methoxy] methanesulfonate methoxypyridy1]methanone [(3 aR,7aR)-7a-(3-fluoropheny1)-3a,4,6,7- tetrahydro-[1,3]dioxolo[4,5 -c]pyridin-5 -y1]- (2,2,3 ,3 -tetrafluoromethy1- hoxy-5 -(2,2 ,3 ,3 -tetrafluoromethy1- ) methanesulfonate propoxy)pyridy1]methanone [(3 aR,7aR)-7a-(3-flu0r0pheny1)-3 a,4,6,7- tetrahydro-[ 1 ,3]di0x010[4,5 -c]pyridin-5 -y1]- ifluorocyclobutyl) [5 -(3 ,3 -difluorocyclobutoxy)—6-methoxy methanesulfonate pyridyl]methanone [(3 aR,7aR)-7a-(3-flu0r0pheny1)-3 a,4,6,7- tetrahydro-[ 1 ,3]di0x010[4,5 -c]pyridin-5 -y1]- cyclopent-3 -eny1methy1 [5 -(cyclopent-3 -eny1methoxy)methoxy- esulfonate 2-pyridy1]methanone [(3 aR,7aR)-7a-(3-flu0r0pheny1)-3 7- tetrahydro-[ 1 ,3]di0x010[4,5 -c]pyridin-5 -y1]- cyclopentenyl (5 -cyclopentenyloxymethoxy methanesulfonate pyridyl)methanone [(3 aR,7aR)-7a-(3-flu0r0pheny1)-3 a,4,6,7- tetrahydro-[ 1 x010[4,5 -c]pyridin-5 -y1](3 ,3 -difluorocyclobutyl)ethyl [5 -[ 1 -(3 ,3 -difluorocyclobuty1)ethoxy] methanesulfonate methoxy-Z-pyridyl]methanone [(3 aR,7aR)-7a-(3-flu0r0pheny1)-3 a,4,6,7- tetrahydro-[ 1 ,3]di0x010[4,5 -c]pyridin-5 -y1]- 2-(3,3-difluorocyclobuty1)ethy1 [5 -[2-(3 ,3 -difluorocyclobuty1)ethoxy] methanesulfonate methoxy-Z-pyridyl]methanone [(3 aR,7aR)-7a-(3-flu0r0pheny1)-3 a,4,6,7- tetrahydro-[ 1 x010[4,5 -c]pyridin-5 -y1]- (3,3-difluoro [5-[(3 uoro bicyclo[3. 1 .0]hexany1)methy1 bicyclo[3. 1 .0]hexany1)methoxy]methoxy- methanesulfonate dy1]methanone 4-[2-(2,2-diflu0r0cyclopr0pyl)eth0xy]meth0xy-benzoic acid Step 1: methyl 4-butenoxymethoxy-benzoate OH 4-bromobut—1-ene ON /O\(©:o/ NaH, DMF /O\n/©:o/ O O

[00385] In a Vial, methyl 4-hydroxymethoxy-benzoate (675 mg, 3.70 mmol) was dissolved in DMF (4 mL) under a nitrogen atmosphere. The mixture was treated with NaH (98 mg, 4.07 mmol) (60% dispersion in mineral oil) in small portions and the reaction mixture was stirred at rt for 20 min before being treated dropwise with 4-bromobutene (1.0 g, 7.4 mmol). The vial was capped, covered with aluminium foil, and was stirred at 80 CC for 21 hours. The reaction mixture was cooled to rt and quenched by the addition of water. The resulting mixture was extracted with ethyl e (2x). The combined extracts were washed with water, dried over sodium sulfate, and concentrated under reduced pressure. ation by flash chromatography on silica gel (40 g column) using a gradient of AcOEt (0 to 40 % over 25 min) in hexanes provided methyl 4-butenoxymethoxy-benzoate (191 mg, 21.6%) as a colorless oil. 1H NMR (400 MHz, CDClg) 8 7.66 (dd, J = 8.4, 2.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 5.91 (ddt, J = 17.1, 10.2, 6.8 Hz, 1H), 5.19 (dq, J =17.2, 1.6 Hz, 1H), 5.13 (ddd,J= .9, 1.2 Hz, 1H), 4.12 (t, J = 7.1 Hz, 2H), 3.92 (s, 3H), 3.89 (s, 3H), 2.63 (qt, J = 7.0, 1.3 Hz, 2H). ESI-MS m/z calc. 236.1, found 237.0 (M+1)+; Retention time: 1.59 min (3 min run).

Step 2: methyl 4-[2-(2,2-diflu0r0cyclopr0pyl)eth0xy] methoxy-benzoate \ F /O\“/©:O/ ON —Si+F / F Nal, THF, OW F F 1,4-dloxane :O/ O 0 ] To a 15 mL pressure bottle charged with a magnetic stirbar was added methyl 3-enoxy-3 xy-benzoate (191 mg, 0.80 mmol), sodium iodide (30 mg, 0.20 mmol) and anhydrous THF (1.2 mL) under a nitrogen atmosphere. To the mixture was added trimethyl-(trifluoromethyl)silane (414 uL, 2.80 mmol). The reaction vessel was sealed and heated to 65 0C for 21 h. The reaction mixture was cooled to rt and the volatiles were removed by blowing nitrogen over the vessel. The residue was redissolved in dioxane (1.2 mL) before adding sodium iodide (30 mg, 0.20 mmol) and trimethyl-(trifluoromethyl)silane (473 uL, 3.20 mmol) under nitrogen. The pressure vessel was sealed and stirred at 100 0C for 24 h. The vessel was cooled to rt and the volatiles were removed by blowing nitrogen over the reaction mixture. The vessel was charged again with THF (1.2 mL), sodium iodide (30 mg, 0.20 mmol), trimethyl-(trifluoromethyl)silane (414 uL, 2.80 mmol) and stirred at 65 CC for 24 h.

The reaction mixture was cooled and the solvents were removed under reduced pressure. The residue was dissolved in DCM and the organic phase was washed with water, 10% sodium sulfite, saturated sodium bicarbonate and saturated aqueous NaCl.

After drying over sodium sulfate, the solvent was removed by evaporation. The crude material was purified by flash chromatography on silica gel (24 g column) using a gradient t (0 to 40%) in hexanes over 25 min affording methyl 4-[2-(2,2- difluorocyclopropyl)ethoxy]methoxy-benzoate (147 mg, 63.3%) as an ite solid. 1H NMR (400 MHz, CDClg) 5 7.66 (dd, J = 8.4, 2.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 4.21 - 4.10 (m, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 2.15 - 1.91 (m, 2H), 1.76 (ddq, J = 14.9, 11.3, 7.5 Hz, 1H), 1.53 - 1.40 (m, 1H), 1.10 - 0.98 (m, 1H). ESI-MS m/z calc. 286.1, found 287.0 (M+1)+; Retention time: 1.39 min (3 min run).

] Step 3: 4-[2-(2,2-diflu0r0cyclopropyl)ethoxy]methoxy- benzoic acid :VVHNaOH OW 0 ] A solution of methyl 4-[2-(2,2-difluorocyclopropyl)ethoxy] methoxy-benzoate (144 mg, 0.50 mmol) in methanol (1 mL) was treated with sodium hydroxide (250 uL, 1.50 mmol) (6N aqueous solution) and the resulting reaction mixture was stirred at 60 CC. The reaction mixture was diluted with water (50 mL) and was acidified with 6N HCl to pH = 1 inducing formation of a white itate. The precipitate was filtered, washed with water and dried overnight under vacuum vacuum oven at 40 CC affording 4-[2-(2,2-difluorocyclopropyl)ethoxy]-3 xy-benzoic acid (125 mg, 87.8%) as a white solid. 1H NMR (400 MHz, CDClg) 5 7.75 (dd, J = 8.4, 2.0 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 4.18 (t, J = 6.1 Hz, 2H), 3.93 (s, 3H), 2.04 (tdd, J = 14.3, 13.0, 7.0 Hz, 2H), 1.77 (ddq, J = 14.8, 11.2, 7.4 Hz, 1H), 1.54 - 1.40 (m, 1H), 1.11 - 0.94 (m, 1H). ESI-MS m/z calc. 272.1, found 273.0 (M+1)+; Retention time: 1.08 min. (5-(((1R,3r,5S)-6,6-diflu0r0bicyclo[3.1.0]hexan yl)methoxy)methoxypyridin-Z-yl)((3aR,7aR)—7a-(3-flu0r0phenyl)tetrahydr0- ioxolo[4,5-c]pyridin-5(6H)—yl)methan0ne and (5-(((1R,3s,5S)—6,6- difluorobicyclo [3.1.0] hexanyl)meth0xy)—6-methoxypyridin-Z-yl)((3aR,7aR)—7a- (3-flu0r0phenyl)tetrahydr0-[1,3] dioxolo[4,5-c]pyridin-S(6H)—yl)methan0ne To a solution of [(3aR,7aR)—7a-(3-fluorophenyl)-3a,4,6,7- tetrahydro- [l ,3 ] dioxolo [4,5 -c]pyridin-5 -yl] -[5 -(cyclopent-3 -enylmethoxy) methoxypyridyl]methanone (90 mg, 0.20 mmol) in THF (2 mL) was added sodium iodide (59 mg, 0.40 mmol). The mixture was purged with nitrogen for 2 min and hyl-(trifluoromethyl)silane (70 mg, 0.49 mmol) was added. The reaction mixture was sealed and heated at 80 0C for 20 h. The on mixture was cooled to rt and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to dryness. The crude al was purified by column tography to e (5-(((lR,3r,5S)-6,6- difluorobicyclo[3 . l .0]hexanyl)methoxy)methoxypyridinyl)((3aR,7aR)-7a-(3- fluorophenyl)tetrahydro-[l,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanone (3.2 mg, 3.0 %). ESI-MS m/z calc. 504.5, found 505.3 (M+l)+; Retention time: 1.08 min. and (5- ((( l R,3 s,5 S)-6 ,6-difluorobicyclo [3 . l .0]hexan-3 -yl)methoxy)methoxypyridin yl)((3 )-7a-(3-fluorophenyl)tetrahydro-[ l ,3]dioxolo [4,5 -c]pyridin-5(6H)- yl)methanone (2.9 mg, 2.8%). ESI-MS m/z calc. 504.5, found 505.3 (M+l)+; Retention time: 2.01 min (3 min run). [(3aR,7aR)-7a-(3-flu0r0phenyl)—3a,4,6,7—tetrahydr0- [1,3]di0x010[4,5-c]pyridin-S-yl]-[5-(2-cyclopr0pyl-2,2-diflu0r0-eth0xy)—6-meth0xy- 2-pyridyl]methan0ne Step 1: 2-[[6-[(3aR,7aR)—7a-(3-flu0r0phenyl)—3a,4,6,7— tetrahydro-[1,3]dioxolo[4,5-c]pyridine-S-carbonyl]meth0xypyridyl]0xy]-N- methoxy-N-methyl-acetamide o CIQLN,O\ o N\ O\ I N\ O\ I —’ / < l l OH NaH, DMF / o Nxo/ ] To a 25 mL round bottom flask was added [(3aR,7aR)-7a-(3- fluorophenyl)-3a,4,6,7-tetrahydro-[1 ,3 ] dioxolo [4,5 -c]pyridin-5 -yl] -(5 -hydroxy methoxypyridyl)methanone (75 mg, 0.20 mmol) and DMF (2 mL). The reaction mixture was cooled to 0 oC and sodium hydride (8 mg, 0.20 mmol) was added. After 5 min, 2-chloro-N-methoxy-N-methyl-acetamide (28 mg, 0.20 mmol) was added and the on mixture was heated at 45 CC overnight. The on e was filtered and purified Via HPLC (l%-99%) ACN:H20 with a 0.1% HCl modifier affording 2-[[6- [(3 aR,7aR)-7a-(3-fluorophenyl)-3 a,4,6,7-tetrahydro-[1,3]dioxolo[4,5 -c]pyridine-5 - carbonyl]methoxypyridyl]oxy]-N-methoxy-N-methyl-acetamide (28 mg, 28%) as a white solid. ESI-MS m/z calc. 475.2, found 476.3 (M+1)+; Retention time: 1.73 min (3 min run).

Step 2: 1-cyclopropyl((6-(7a-(3-fluorophenyl)hexahydro- [1,3]di0x010[4,5-c]pyridinecarbonyl)—2-methoxypyridinyl)0xy)ethan0ne N\ O\ AMgBr l l <Olu..

/ OWN“ FNKLIRCARA ] To a 10 mL round bottom flask containing 2-[[6-[(3aR,7aR)- 7a-(3-fiuorophenyl)-3a,4,6,7-tetrahydro-[1 ,3]dioxolo[4,5 -c]pyridine-5 -carbonyl] methoxypyridyl]oxy]-N-methoxy-N-methyl-acetamide (23 mg, 0.05 mmol) was added THF (1 mL). The mixture was cooled to 0 oC and treated dropwise with cyclopropyl magnesium bromide (106 uL of 0.5 M in THF, 0.05 mmol). The reaction mixture was d to stir while warming to rt. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated under d pressure. The crude on mixture was purified via reverse phase HPLC (1%-99%) ACN:H20. ESI-MS m/z calc. 475.2, found 476.3 (M+1)+; Retention time: 1.73 min (3 min run).

Step 3: [(3aR,7aR)—7a-(3-flu0r0phenyl)—3a,4,6,7—tetrahydro- [1,3]di0x010[4,5-c]pyridin-S-yl]-[5-(2-cyclopr0pyl—2,2-diflu0r0-eth0xy)—6-meth0xy- 2-pyridyl]methan0ne Nfifllk deoxyfluor, EtOH 0%DCNI <0”... O

[00398] To a 10 mL round bottom flask containing 2-[[6-[(3aR,7aR)- 7a-(3-fluorophenyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5 -c]pyridine-5 -carbonyl] methoxypyridyl]oxy]cyclopropyl-ethanone (16 mg, 0.03 mmol) was added dichoromethane (1 mL). The reaction mixture was cooled to 0 CC and treated with ethanol (0.4 uL, 0.007 mmol) followed by the dropwise addition of deoxy-fluor (16 uL, 0.085 mmol). The reaction e was allowed to stir overnight while warming to rt. Deoxy-fluor (l6 uL, 0.085 mmol) was added again and after 3h the reaction mixture was diluted with dichloroethane (2 mL) and heated at 50 CC oil bath overnight.

The on mixture was quenched with saturated aqueous ammonium chloride and extracted with dichoromethane. The dichoromethane was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified via reverse phase HPLC %) ACN:H20 with a 0.1% HCl modifier to afford [(3aR,7aR)-7a- (3 -fluorophenyl)-3 a,4,6,7-tetrahydro-[1,3]dioxolo[4,5 -c]pyridin-5 -yl]- [5 -(2- cyclopropyl-2,2-difluoro-ethoxy)methoxypyridyl]methanone (8.2 mg, 45.4%).

ESI-MS m/z calc. 478.2, found 479.3 (M+1)+; Retention time: 1.82 min (3 min run).

[00399] 4-[(3,3-diflu0r0cyclobutyl)methylamino]methoxy-benzoic acid H F ”“2 AC)3 Nfi HO 0/ AcOH, (CICH2)2 Hoj‘/©:o/ A solution of 4-aminomethoxy-benzoic acid (200 mg, 1.20 mmol) and 3,3-difluorocyclobutanecarbaldehyde (144 mg, 1.20 mmol) in 1,2- dichloroethane (4 mL) were treated with sodium triacetoxy borohydride (317 mg, 1.68 mmol) and acetic acid (68 uL, 1.20 mmol). A drop of TFA was added and the heterogenous reaction mixture was vigorously stirred at rt for 16 h. To the e was added 1N NaOH (50 mL) and DCM (50 mL) and the two phases were separated.

The aqueous phase was acidified to pH = 6 using 6N HCl and was extracted with DCM:methanol (10: 1) (40 mL). The aqueous phase was further acidified to pH = 1 and then was extracted with with DCM:methanol (10: 1) (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product purified by reverse phase preparative HPLC using HCl as a modifier. ation of the volatiles under d pressure provided 4-[(3,3-difiuorocyclobutyl)methylamino]methoxy-benzoic acid (17 mg, 5.1%) as a white solid. ESI-MS m/z calc. 271.1, found 272.0 (M+1)+; Retention time: 1.3 min (3 min run). 4-[(3,3-diflu0r0cyclobutyl)meth0xy]methoxy-benzoic acid Step 1: methyl 3-chlor0((3,3- diflu0r0cyclobutyl)methoxy)benzoate A 1 L flask equipped with a nitrogen inlet, a condenser and a magnetic stirbar was d with (3,3-difiuorocyclobutyl)methyl methanesulfonate (19.7 g, 88.6 mmol) and anhydrous DMF (400 mL). The mixture was treated with methyl 4-hydroxymethoxy-benzoate (16.1 g, 88.5 mmol) and powdered K2C03 (24.5 g, 177.1 mmol). The on mixture was heated at 80 0C for 30 min. Once the bath reached this temperature, the reaction mixture turned into a very thick gel that rendered magnetic stirring almost inoperative. The on mixture required intermittent manual stirring of the gel with a spatula for 3 h. Progressively, efficient stirring was restored and the reaction was stirred for an onaly 4 h. The reaction mixture was cooled down to rt overnight and poured into ice-cold water under stirring (divided into 2 x 1.4 L ). The resulting suspensions were stirred at rt for 4 h and were filtered on the same buchner filter. The combined white solid was washed with water (2 x 200 mL) and partially dried by suction. The wet solid was dissolved in DCM (200 mL) and the residual water was separated by ation. The organic layer was dried over sodium sulfate, filtered, and the solvents concentrated under reduced pressure to afford a crude pink solid. Purification by flash chromatography on silica gel (330 g column ) using a gradient ofAcOEt (0 to 70% over 30 min) in hexanes provided methyl ro((3,3-difluorocyclobutyl)methoxy)benzoate (22 g, 88% yield) as a white solid. ESI-MS m/z calc. 286.0, found 287.0 (M+1); Retention time: 1.57 min (3 min run).

] The following compounds were prepared using the procedure reported above.

Product Benzoate Mesylate methyl 3-chloro((3,3- (3,3- methyl 3-chloro d1fluorocyclobutyl)methoxy. difluorocyclobutyl)methyl hydroxybenzoate )benzoate methanesulfonate methyl 3-chloro[[1- (1- . methyl 3-chloro (tr1fluoromethyl)cyclopropy (tr1fluoromethyl)cyclopropy. hydroxybenzoate oxy]benzoate yl methanesulfonate methyl4-[(3,3- methyl 3-methoxy- (3 ,3-d1fluorocyclopentyl. difluorocyclopentyl)methox 4'hydlfoxy‘benzoate methanesulfonate ethoxy-benzoate methyl 4-[(3,3- (3,3- methyl 3-methoxyd1fluorocyclobutyl xy. difluorocyclobutyl)methyl 4-hydroxybenzoate ]methoxy-benzoate methanesulfonate methyl 3-methoxy[[1- (1 - (tr1fluoromethyl)cyclopropy. methyl 3-methoxy- oromethyl)cyclopropy. 4-hydroxybenzoate l]methoxy]benzoate l)methyl methanesulfonate methyl 3-methoxy (2’2’3 ’3 ' methyl 3'm6th0Xy- 2,2,3 ,3-tetrafluoropropoxy tetrafluoropropoxy)bbenzoat 4-hydroxybenzoate methanesulfonate Step 2: 4-[(3,3-diflu0r0cyclobutyl)methoxy]methoxy- benzoic acid F F 0VDLF )(©:OM90 NaOH VB“ o —>HO / \n/CEOMe MeOH, H20 O 0 In a 500 mL round bottom flask equipped with a magnetic stirbar, methyl 3-chloro((3,3-difluorocyclobutyl)methoxy)benzoate (22 g, 77 mmol) was suspended in MeOH (100 mL) and was stirred at 60 0C until all solids ved.

NaOH (30 mL of 6 M, 180.0 mmol) (6N aqueous) was added and the mixture was stirred at 60 CC for 1 h. The reaction e was cooled to rt, transferred into a 1 L erlenmeyer flask and diluted with water (500 mL). The solution was neutralized by dropwise addition of aqueous 6N HCl (30 mL) over 20 min, until the solution reached pH = 2. More water was added (200 mL). The ing white precipitate was filtered, washed with water (3 X 100 mL) and dried under vacuum (40 CC) for 3 d ing 4- [(3,3-difluorocyclobutyl)methoxy]—3-methoxy-benzoic acid (20.8 g, 86 %) as a white solid. 1H NMR (400 MHz, CDClg) 8 7.75 (dd, J = 8.4, 2.0 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 4.13 (d, J = 6.2 Hz, 2H), 3.92 (s, 3H), 2.90 - 2.63 (m, 3H), 2.63 - 2.34 (m, 2H). ESI-MS m/z calc. 272.1, found 273.0 (M+1)+; Retention time: 1.26 min (3 min run).

The following compounds were prepared using the procedure reported above.

Product Precursor 2014/045675 3-chloro[(3 ,3- methyl 3-chloro((3,3- ocyclobutyl)methoxy]benzoic acid difluorocyclobutyl)methoxy)benzoate 3-chloro[[1- methyl 3-chloro[[1- oromethyl)cyclopropyl]methoxy]be (trifluoromethyl)cyclopropyl]methoxy] nzoic acid benzoate methyl4-[(3,3- 4-[(3,3-d1fluorocyclopentyl)methoxy]. _ _ difluorocyclopentyl)methoxy] methoxy-benz01c ac1d methoxy-benzoate . methyl 4-[(3,3- 4- [(3 ,3 -d1fluorocyclobutyl)methoxy] -3 - difluorocyclobutyl)methoxy]_ -3 - methoxy-benzoic acid methoxy-benzoate 3 -methoxy[[1- methyl 3-methoxy[[1- (trifluoromethyl)cyclopropyl]methoxy]be (trifluoromethyl)cyclopropyl]methoxy] nzoic acid benzoate 3-methoxy(2,2,3,3- methyl 3-methoxy(2,2,3,3- tetrafluoropropoxy)benzoic acid tetrafluoropropoxy)bbenzoate [(3aR,7aR)—7a-(3-flu0r0phenyl)—3a,4,6,7—tetrahydr0- [1,3]di0x010[4,5-c]pyridin-S-yl]-[4-[(3,3-diflu0r0cyclobutyl)methyl-methyl- amin0]meth0xy-phenyl] one (4-(((3,3-difluorocyclobutyl)methyl)amino) methoxyphenyl)((3aR,7aR)-7a-(3-fiuorophenyl)tetrahydro-[ 1 ,3 ]dioxolo [4,5 -c]pyridin- (6H)-yl)methanone (8.1 mg, 0.017 mmol) was dissolved in DMF (100 uL). K2C03 (7.0 mg, 0.051 mmol) and Mel (5 uL, 0.08 mmol) were added and the reaction e was stirred at rt for 3 days. The reaction mixture was diluted with water (50 uL) and DMF (850 uL), filtered and purified by preparative HPLC using HCl as a modifier.

The pure fraction were collected and the solvents removed by evaporation under 2014/045675 reduced pressure to afford [(3aR,7aR)—7a-(3-fluorophenyl)-3a,4,6,7-tetrahydro- [1 ,3]dioxolo [4,5 -c]pyridin-5 -yl]- [4-[(3 ,3 -difluorocyclobutyl)methyl-methyl-amino] -3 - methoxy-phenyl]methanone (2.5 mg, 30.0%) as a colorless film. ESI-MS m/z calc. 490.5, found 491.4 (M+1)+; ion time: 1.29 min (3 min run). (5-((3,3-diflu0r0bicyclo[3.1.0]hexanyl)methoxy)—6- methoxypyridin-Z-yl)((3aR,7aR)—7a-(3-flu0r0phenyl)tetrahydr0-[1,3]di0x010[4,5- c]pyridin-5(6H)-yl)methan0ne Step 1: (5-((3-((tertbutyldimethylsilyl )0xy)bicyclo [3. 1 .0] 6-yl)meth0xy)meth0xypyridin yl)((3aR,7aR)—7a-(3-flu0r0phenyl)tetrahydr0-[1,3]dioxolo[4,5-c]pyridin-5(6H)— yl)methan0ne M80 <00". N N\ O\ OH TBS | / / N O K2003,DMF OTBS To a solution of [(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7- tetrahydro- [1 ,3 ] dioxolo [4,5 -c]pyridin-5 -yl] -(5 xymethoxy pyridyl)methanone (400 mg, 1.07 mmol) in DMF (5 mL) was added potassium carbonate (221 mg, 1.60 mmol) followed by the addition of (3-((tert- imethylsilyl)oxy)bicyclo[3.1.0]hexanyl)methyl esulfonate (377 mg, 1.18 mmol). The mixture was heated at 80 0C overnight. The reaction mixture was recharged with (3-((tert-butyldimethylsilyl)oxy)bicyclo[3 . 1 .0]hexanyl)methyl methanesulfonate (377 mg, 1.18 mmol) and heated at 140 0C overnight. After cooling to rt, the mixture was repartitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with saturated aqueous NaCl (4x), dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by column chromatography (20-30% EtOAc-Hex) to provide (5- ((3 -((tert-butyldimethylsilyl)oxy)bicyclo[3. 1 .0]hexanyl)methoxy) methoxypyridinyl)((3aR,7aR)—7a-(3-fluorophenyl)tetrahydro- [1 ,3 ]dioxolo [4,5 - c]pyridin-5(6H)-yl)methanone (220 mg, 34.4%). ESI-MS m/z calc. 598.3, found 599.5 (M+1)+; Retention time: 2.65 min (3 min run).

Step 2: ((3aR,7aR)—7a-(3-flu0r0phenyl)tetrahydr0- [1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)(5-((3-hydr0xybicyclo[3.1.0]hexan yl)methoxy)—6-methoxypyridinyl)methanone \ \ | TBAF / < Oh _, OTBS To a solution of (5-((3 -((tert- butyldimethylsilyl)oxy)bicyclo[3 . l .0]hexanyl)methoxy)methoxypyridin yl)((3 aR,7aR)-7a-(3-fluorophenyl)tetrahydro-[ l ,3 ] dioxolo [4,5 -c]pyridin-5 (6H)- yl)methanone (220 mg, 0.37 mmol) in THF (5 mL) was added tetrabutylammonium fluoride (108 uL, 0.37 mmol). The e was heated at 70 0C for l h. The reaction mixture was stirred at 50 0C for 24 h and itioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3x). The combined c layers were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated to dryness. The crude material was purified by column chromatography (80-100% EtOAc-Hex) to provide ((3aR,7aR)-7a-(3-fluorophenyl)tetrahydro-[l,3]dioxolo[4,5- c]pyridin-5(6H)-yl)(5-((3-hydroxybicyclo[3 . 1 .0]hexanyl)methoxy)—6- methoxypyridinyl)methanone (105 mg, 56%). ESI-MS m/z calc. 484.2, found 485.5 (M+l)+; Retention time: 1.71 min (3 min run).

Step 3: [(3aR,7aR)—7a-(3-flu0r0phenyl)—3a,4,6,7— tetrahydro-[1,3]dioxolo[4,5-c]pyridine-S-carbonyl]meth0xy pyridyl]0xymethyl]bicyclo[3.1.0]hexan0ne O 0 On".

N*r/ION\ O\ 01”,. <0 NW1.N\ OH O F F To a solution of 7aR)—7a-(3-fluorophenyl)tetrahydro- [l,3]dioxolo[4,5-c]pyridin-5(6H)—yl)(5-((3-hydroxybicyclo[3 . l .0]hexan yl)methoxy)methoxypyridinyl)methanone (90 mg, 0.19 mmol) in dichloromethane (10 mL) was added Dess Martin periodinane (87 mg, 0.20 mmol).

The reaction mixture was stirred at rt for 30 min, diluted with DCM, washed with ted aqueous Na2S203 (2x), saturated aqueous NaHCOg, saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to dryness. The crude material was d by column chromatography to provide 6-[[6-[(3 )-7a-(3-fluorophenyl)- 3 a,4,6,7-tetrahydro-[1,3]dioxolo[4,5 -c]pyridinecarbonyl]methoxy-3 - l]oxymethyl]bicyclo[3.1.0]hexanone (72 mg, 80%) as a mixture of diastereomers. 1H NMR (400 MHZ, CDClg) 5 7.44 (d, J = 8.0 Hz, 1H), 7.36 (td, J = 8.0, 5.9 Hz, 1H), 7.20 - 7.06 (m, 3H), 7.07 - 6.95 (m, 1H), 5.37 - 5.21 (m, 1H), 4.89 (d, J = 28.4 Hz, 1H), 4.40 (dt, J = 28.2, 4.3 Hz, 1H), 4.12 - 3.90 (m, 8H), 3.82 - 3.52 (m, 1H), 2.65 (dd, J = 20.8, 2.7 Hz, 2H), 2.37 - 2.08 (m, 4H), 1.67 (s, 2H), 1.10 - 0.90 (m, 1H). ESI-MS m/z calc. 482.2, found 483.7 (M+1)+; Retention time: 1.77 min (3 min run).

[00417] Step 4: (5-((3,3-diflu0r0bicyclo[3.1.0]hexanyl)methoxy)— 6-meth0xypyridinyl)((3aR,7aR)—7a-(3-flu0r0phenyl)tetrahydr0- [1,3]dioxolo[4,5-c]pyridin-5(6H)—yl)methan0ne O O 0II".

N N\ O\ OIlh.

N N\ O\ < I deoxy-fluor | / < O / O —> O F F A solution of 6-[[6-[(3aR,7aR)—7a-(3-fiuorophenyl)-3a,4,6,7- tetrahydro- [1 ,3 ] dioxolo [4,5 -c]pyridine-5 -carbonyl]methoxy-3 - pyridyl]oxymethyl]bicyclo[3.1.0]hexanone (23 mg, 0.05 mmol) in DCM (2 mL) and EtOH (0.6 uL, 0.010 mmol) was purged with en for 5 min. Deoxy-fluor (26 mg, 0.12 mmol) was added and the reaction e was heated at 50 0C for 30 min. The reaction mixture was recharged with deoxy-fiuor (26 mg, 0.12 mmol) and heated at 50 0C for 18 h. The reaction was recharged with deoxy-fluor (26 mg, 0.12 mmol) and heated at 50 0C for 60 h. The reaction mixture was quenched with saturated s ammonium chloride and extracted wth DCM. The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (40-60% EtOAc-Hex) afforded (5-((3,3- robicyclo[3 . 1 .0]hexanyl)methoxy)—6-methoxypyridinyl)((3aR,7aR)-7a-(3- fluorophenyl)tetrahydro-[1 ,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanone (5 .5 mg, .6%). 1H NMR (400 MHz,CDC13)5 7.43 (d, J = 8.0 Hz, 1H), 7.36 (td, J = 8.0, 6.0 Hz, 1H), 7.15 (d, J = 7.2 Hz, 2H), 7.13 = 9.7, 7.4 Hz, 1H), - 7.06 (m, 1H), 7.00 (dd, J .30 (t, J = 15.3 Hz, 1H), 4.89 (d, J = 28.6 Hz, 1H), 4.38 (dd, J =18.1, 14.0 Hz,1H), 4.09 - 3.85 (m, 8H), 3.79 = - 3.55 (m, 1H), 2.51 - 2.08 (m, 6H), 1.47 (s, 2H), 1.24 (dt, J 11.4, 6.4 Hz, 1H). ESI-MS m/z calc. 504.2, found 505.5 (M+1)+; Retention time: 1.84 min (3 min run). [(3aR,7aR)—7a-(3,5-diflu0r0phenyl)—3a,4,6,7—tetrahydr0- [1,3]dioxolo[4,5-c]pyridin-S-yl]-[3-meth0xy[2- (trifluoromethoxy)eth0xy]phenyl] methanone Olin, /\/O F NH 0 w<F HATU, TEA, DMF A 20 mL vial was charged with (3aR,7aR)—7a-(3,5- difluorophenyl)-4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridine (215 mg, 0.89 mmol), 3-methoxy[2-(trifluoromethoxy)ethoxy]benzoic acid (250 mg, 0.89 mmol) and HATU (372.8 mg, 0.98 mrnol). Anhydrous DMF (3.5 mL) was added and the e was d until all solids dissolved. Triethyl amine (497uL, 3.56 mmol) was added and the e was stirred at rt for 2.5 h at which time LCMS indicated completion of the reaction. Water and saturated aqueous NaCl were added. The gummy material that formed was separated from the s phase and was dissolved in DCM (50 mL). The organic phase was dried over sodium sulfate and the solvent concentrated under reduced pressure. The product was purified by flash chromatography on silica gel (24 g column ) using a gradient ofAcOEt (0 to 100 % over 15 min) in hexanes. The product eluted at 65-85% ethyl acetate (10-13 min run).

The pure fractions were collected and the solvents removed under reduced pressure. [(3 aR,7aR)-7a-(3 ,5 -difluorophenyl)-3 7-tetrahydro-[1,3]dioxolo[4,5 -c]pyridin-5 - yl]-[3-methoxy[2-(trifluoromethoxy)ethoxy]phenyl]methanone (268 mg, 59.4%) was isolated as a solid off-white foam. 1H NMR (400 MHz, CDC13) 5 7.11 (broad s, 1H), 7.06 (dd, J = 8.2, 1.9 Hz, 1H), 6.96 - 6.87 (m, 3H), 6.76 (tt, J = 8.7, 2.3 Hz, 1H), .31 (s, 1H), 4.85 (s, 1H), 4.42 - 4.25 (m, 4H), 0 (broad d, 2H), 3.90 (s, 3H), 3.72 (broad s, 3H), 2.32 - 1.90 (broad m, 2H).

ESI-MS m/z ca1c. 503.1, found 504.0 (M+1)+; Retention time: 1.91 min (3 min run).

The following compounds were prepared using the procedure reported above.

Product propoxymethy1— 4-1sopropoxy_ pheny1)-(6-pheny1 6-pheny1 -benz01c_ azabicyclo[4.1.0]heptan azabicyclo[4.1.0]heptane ac1'd y1)methanone hoxy[2- (trifluoromethoxy)ethoxy]phe 3-methoxy[2- 6-pheny1 ny1]-(6-pheny1 (tr1fluoromethoxy)e_ azabicyclo[4.. 1 .0]heptane azabicyclo[4. 1 .0]heptan thoxy]benzoic acid y1)methanone (4-isopentyloxymethoxy- 4-isopenty10xy pheny1)-(6-pheny1 6-pheny1 methoxy-benz01c_ azabicyclo[4.1.0]heptan azabicyclo[4.1.0]heptane ac1'd y1)methanone [4-( 1-h droxy ymethy1- 4-(1-hydroxy ethy1)methoxy-pheny1] -(6- methyl-ethy1)-3 - 6-pheny1-3 - pheny1 y-benz01c. azabicyclo[4. 1 .0]heptane. azabicyclo [4. 1 .0]heptan-3 - ac1d. y1)methanone WO 06280 [3 -mcthoxy oxy (tctrahydrofuran-Z- (tetrahydrofuran-Z- 6-phcny1—3- ylrncthoxy)phcnyl]-(6-phcny1— ylrncthoxy)bcnzoic azabicyc10[4. 1 .0]hcptanc 3-azabicyc10[4.1.0]hcptan acid yl)rncthanonc [6-mcth0xy[2- 6-mcthoxy[2- (trifluoromcthoxy)cthoxy] (trifluororncthoxy)c 6-phcny1—3- pyridyl]—(6-phcny1—3- thoxy]pyridinc azabicyc10[4. 1 .0]hcptanc azabicyc10[4. 1 .0]hcptan carboxylic acid yl)rncthanonc (5 -isopropoxymcthyl -isopropoxy pyridyl)-(6-phcny1—3- y1—3- methyl-pyridinc azabicyc10[4. 1 .0]hcptan azabicyc10[4. 1 .0]hcptanc carboxylic acid yl)rncthanonc [5 -(2-fluor0rncthyl- -(2-fluor0 propoxy)rncthoxy methyl-propoxy) 6-phcny1—3- pyridyl]—(6-phcny1—3- methoxy-pyridinc- azabicyc10[4. 1 .0]hcptanc azabicyc10[4. 1 tan 2-carb0xy1ic acid yl)rncthanonc [4-(2-fluororncthyl- 4-(2-fluor0 propoxy)—3-rncthoxy-phcnyl]— methyl-propoxy) 6-phcny1—3- (6-phcnyl methoxy-bcnzoic yc10[4. 1 .0]hcptanc azabicyc10[4. 1 .0]hcptan acid yl)rncthanonc [4-(2-hydr0xyrncthyl- 4-(2-hydroxy propoxy)—3-rncthy1—phcnyl]— methyl-propoxy) 6-phcny1—3- (6-phcnyl -benzoic azabicyc10[4. 1 .0]hcptanc azabicyc10[4. 1 .0]hcptan acid yl)rncthanonc [4-(1 -hydr0xy- 1 y1— 4-(1 -hydroxy cthyl)phcny1]-(6-phcny1—3 - 6-phcny1—3- methyl- yclo [4. 1 .0]hcptan azabicyclo [4. 1 .0]hcptanc ethyl)benzoic acid yl)rnethanonc [3 -fluoro(1-hydroxy -cthyl)phcnyl]-(6- 3-flu0ro(1 - 6-phcny1—3- pheny1-3 - hydroxyrncthy1— azabicyclo [4. 1 .0]hcptanc yclo [4. 1 .0]hcptan ethyl)benzoic acid yl)rnethanonc [3 -mcthoxy(3 ,3 ,3 - 3-methoxy trifluoropropoxyrncthyl)phcny (3 ,3 ,3 - 6-phcny1—3- 1] -(6-phcny1—3 - trifluoropropoxyrnc azabicyclo [4. 1 tanc azabicyclo [4. 1 .0]hcptan thyl)benzoic acid yl)rnethanonc [4-(1 -hydr0xyrncthy1— 4-(1-hydroxy cthy1)-3 -rncthy1—phcnyl] -(6- methyl-cthyl)-3 - 6-phcny1—3- methyl-benzoic azabicyclo [4. 1 .0]hcptanc azabicyclo [4. 1 .0]hcptan acid yl)rnethanonc (6-isopropoxy-3 -pyridy1)-(6- phenyl 6-phcny1—3- isopropoxypyridine azabicyclo [4. 1 .0]hcptan azabicyclo [4. 1 .0]hcptanc carboxylic acid yl)rnethanonc [6-mcthyl[2- 6-mcthy1—5-[2— (trifluoromcthoxy)cthoxy] ororncthoxy)c 6-phcny1—3- pyridyl]—(6-phcny1—3- thoxy]pyridinc azabicyclo [4. 1 .0]hcptanc azabicyclo [4. 1 .0]hcptan carboxylic acid yl)rnethanonc WO 06280 2014/045675 (3 rncthoxy-phcny1)- 0 (6-phcny1—3- 6-phcny1—3- methoxy-bcnzoic azabicyclo [4. 1 .0]hcptan azabicyclo [4. 1 .0]hcptanc acid yl)rncthanonc 2,3-dihydr0bcnz0furany1— 2,3 - (6-phcny1—3- y1—3- dihydrobcnzofuranazabicyclo [4. 1 .0]hcptan azabicyclo [4. 1 .0]hcptanc 7-carboxylic acid yl)rncthanonc (6-phcny1—3- quinolinc 6-phcny1—3- azabicyclo[4. 1 .0]hcptanyl) carboxylic acid azabicyclo [4. 1 .0]hcptanc n01y1)rncthanonc [4-(2-hydr0xyrncthyl- 4-(2-hydroxy propoxy)—3-rncthoxy-phcnyl]— methyl-propoxy) 6-phcny1—3- (6-phcny1—3- methoxy-bcnzoic azabicyclo [4. 1 .0]hcptanc azabicyclo [4. 1 .0]hcptan acid yl)rncthanonc 2-isopropoxy(6-phcny1—3- 3-cyano 6-phcny1—3- azabicyclo [4. 1 .0]hcptanc isopropoxy-bcnzoic azabicyclo [4. 1 .0]hcptanc carbonyl)bcnzonitrilc acid (3-fluoroisopropoxy- 3-fluor0 pheny1)-(6-phcnyl 6-phcny1—3- isopropoxy-bcnzoic azabicyclo [4. 1 .0]hcptan azabicyclo [4. 1 .0]hcptanc acid yl)rncthanonc (6-isopropoxyrnethyl _ ropoxy pyr1dy1)-(6-pheny1—3- 6-pheny1—3- methyl-pyr1d1ne. . azabicyclo[4.1.0]heptan azab1cyc10[4.1.0]heptane. carboxyhc a01d. . yl)rnethanone [4-(1- hydroxycyc10buty1)phenyl]- 4-(1- 6-phenyl-3 - (6-pheny1—3 - hydroxycyclobutyl) azablcyclo_ [4. 1 .0]heptane azabicyclo[4.1.0]heptan benzoic acid yl)rnethanone [3 -fluoro(2-hydroxy methyl-propyl)phenyl]-(6- 3-flu0r0(2- 6-pheny1—3- hydroxy-Z-rnethyl- . . azabicyclo [4. 1 .0]heptane azabicyclo [4. 1 .0]heptan propyl)benz01c a01d yl)rnethanone (4-isopr0p0xymethoxy- r0poxy. phenyl)-(6-phenyl 6-pheny1—3- methoxy-benzmc_ azabicyclo[4.1.0]heptan azab1cyc10[4.1.0]heptane_ ac1'd yl)rnethanone N—cyclopropyl(6-phenyl 4- 6-pheny1—3- azabicyclo[4.1.0]heptane (cyclopropylsulfarn azablcyclo. [4. 1 tane carbony1)benzenesulfonarnide oyl)benzoic acid (4-ethylsulfonyl-3 -rnethy1— 4-ethylsulfonyl phenyl)-(6-phenyl methyl-benzmc_ 6-pheny1—3- azabicyclo[4.1.0]heptan azab1cyc10[4.1.0]heptane_ a01'd yl)rnethanone (2-fluoroisopropoxy- 2-fluor0 pheny1)-(6-phcnyl 6-phcny1—3- isopropoxy-bcnzmc_ azabicyclo [4. 1 .0]hcptan yc10[4. 1 .0]hcptanc_ ac1'd yl)rnethanonc [3 -rncth0xy(2,2,2- 3-methoxy trifluorocthoxymcthyl)phcnyl] (2,2,2- 6-phcny1—3- -(6-phcny1—3- trifluorocthoxyrncth azabicyclo [4. 1 .0]hcptanc azabicyclo [4. 1 .0]hcptan yl)benzoic acid yl)rnethanonc (5 -rncthoxyrnethy1—2- -mcthoxy pyridyl)-(6-phcnyl methyl-pyr1d1nc_ _ 6-phcny1—3- azabicyclo [4. 1 tan azab1cyc10[4.. 1 .0]hcptanc carboxylic acid yl)rnethanonc (5-isobutoxypyridy1)-(6- pheny1-3 - y1—3- isobutoxypyridine- azabicyclo [4. 1 .0]hcptan azabicyclo [4. 1 .0]hcptanc 2-carb0xy1ic acid thanonc [5-(2-hydr0xyrncthyl- -(2-hydroxy propoxy)rnethoxy methyl-propoxy) 6-phcny1—3- pyridyl]—(6-phcny1—3- methoxy-pyridinc- azabicyclo [4. 1 tanc yclo [4. 1 .0]hcptan 2-carb0xy1ic acid yl)rnethanonc (4-isopropoxymethyl- 4-isopr0 OXp phenyl)—(6-phcnyloxa y. 6-phcnyloxa methyl-benzmc azabicyclo[4.2.0]octan azab1cyc10[4.2.0]octanc_ acid yl)rnethanonc 2014/045675 (5 -isopropoxymcthyl -isopropoxy pyridyl)—(6-phcny1—7-0Xa 6-phcnyloxa methyl-pyridinc azabicyclo[4.2.0]octan azabicyclo[4.2.0]octanc carboxylic acid yl)rncthanonc [3-mcth0xy[2- (trifluoromcthoxy)cthoxy]phc 3-mcthoxy[2- 6-phcnyloxa nyl]-(6-phcnyloxa ororncthoxy)c azabicyclo[4.2.0]octanc azabicyclo[4.2.0]octan thoxy]bcnzoic acid yl)rncthanonc (6-phcnyloxa quinolinc 6-phcnyloxa azabicyclo[4.2.0]octanyl)- carboxylic acid azabicyclo[4.2.0]octanc (8-quin01y1)rncthanonc [(3 aS,7aS)-7a-phcnyl- 3a,4,6,7-tctrahydr0- (3 aS,7aS)—7a-phcnyl- 3-mcthoxy[2- [1,3]di0X010[4,5-c]pyridin 7-tctrahydr0-3aH- (trifluororncthoxy)c y1]-[3 -rncth0xy[2- [1,3]dioxolo[4,5- thoxy]bcnzoic acid oromcthoxy)cthoxy]phc c]pyridinc nyl]rncthanonc [(3 aS,7aS)-7a-phcnyl- 3a,4,6,7-tctrahydr0- 4-(2-fluor0 (3 aS,7aS)—7a-phcnyl- [1,3]di0X010[4,5-c]pyridin methyl-propoxy) 4,5,6,7-tctrahydr0-3aH- -(2-flu0r0rncthyl- methoxy-bcnzoic [1,3]dioxolo[4,5- propoxy)rncthoxy- acid c]pyridinc phcnyl]rncthanonc [(3 aS,7aS)-7a-phcnyl- 4-(2-hydroxy (3 aS,7aS)—7a-phcnyl- 3a,4,6,7-tctrahydr0- methyl-propoxy) 4,5,6,7-tctrahydr0-3aH- [1,3]di0X010[4,5-c]pyridin methyl-benzoic [1,3]dioxolo[4,5- yl]-[4-(2-hydr0xyrncthyl- acid c]pyridinc propoxy)rncthy1— 2014/045675 ]rncthanonc [(3aS,7aS -7a- hen) p y1- (3aS,7aS)—7a-phcnyl- 3 a,4,6,7-tctrahydro- 4-isopropoxy-3 - 4,5,6,7-tctrahydr0-3aH- [1 ,3]di0X010[4,5 -c]pyridin-5 methyl-benzoic [1,3]dioxolo[4,5- yl] -(4-isopr0poxy-3 -rncthy1— acid d1nc. . phcnyl)rncthanonc [(3 )-7a-phcnyl- 3 a,4,6,7-tctrahydr0- 4-(2-hydroxy (3 aS ,7aS)—7a-phcny1— [1,3]di0x010[4,5 -c]pyridin-5 methyl-propoxy)-3 - 4,5 ,6,7-tctrahydr0-3aH- yl] - [4-(2-hydr0xyrncthyl- methoxy-bcnzoic [1 ,3]di0X010[4,5 - propoxy)rncth0xy- acid c]pyridinc phcnyl]rncthanonc [(3 aS,7aS)-7a-phcnyl- 3 a,4,6,7-tctrahydr0- 4-(1-hydroxy (3 aS ,7aS)—7a-phcny1— [1 ,3]di0x010[4,5 -c]pyridin-5 methyl-cthyl)-3 - 4,5 ,6,7-tctrahydr0-3aH- yl]-[4-(1-hydr0xymcthyl- methyl-benzoic [1 ,3]di0X010[4,5 - cthy1)rncthy1- acid c]pyridinc ]rncthanonc [(3aS,7aS)-7a-phcny1— (3 )—7a-phcnyl- 3a,4,6,7-tctrahydr0- quinolinc-S- 4,5,6,7-tctrahydr0-3aH- [1,3]dioxolo[4,5-c]pyridin-5 carboxylic acid [1,3]dioxolo[4,5- yl]-(8-quinolyl)rncthanonc c]pyridinc [(3 aR,7aR)—7a-phcny1— (3 aR,7aR)-7a-phcny1— 3a,4,6,7-tctrahydr0- 3-mcthoxy[2- 4,5,6,7-tctrahydr0-3aH- [ 1,3 dioxolo 4,5-c] [ ]pyridin-5 (trifluororncthoxy)c [1,3]dioxolo[4,5- yl]-[3-rncthoxy[2- thoxy]bcnzoic acid c]pyr1d1nc. . (trifluoromcthoxy)cthoxy]phc nyl]rncthanonc [(3 aR,7aR)—7a-phcny1— 3a,4,6,7-tctrahydr0- 4-(2-fluor0 (3 aR,7aR)-7a-phcny1— [1,3]di0X010[4,5-c]pyridin methyl-propoxy) 4,5,6,7-tctrahydr0-3aH- y1]-[4-(2-flu0r0rncthyl- y-bcnzoic [1,3]dioxolo[4,5- y)rncthoxy- acid dinc phcnyl]rncthanonc [(3 aR,7aR)—7a-phcny1— 3a,4,6,7-tctrahydr0- 4-(2-hydroxy (3 aR,7aR)-7a-phcny1— i0X010[4,5-c]pyridin methyl-propoxy) 4,5,6,7-tctrahydr0-3aH- yl]-[4-(2-hydr0xyrncthyl- methyl-benzoic [1,3]dioxolo[4,5- propoxy)rncthy1— acid c]pyridinc phcnyl]rncthanonc [(3 aR,7aR)—7a-phcny1— (3 aR,7aR)-7a-phcny1— 3a,4,6,7-tctrahydr0- 4-isopropoxy 4,5,6,7-tctrahydr0-3aH- [1,3]di0X010[4,5-c]pyridin methyl-benzoic [1,3]dioxolo[4,5- yl]—(4-isoprop0xyrncthy1— acid c]pyridinc phcnyl)rncthanonc [(3 aR,7aR)—7a-phcny1— 3a,4,6,7-tctrahydr0- 4-(2-hydroxy (3 aR,7aR)-7a-phcny1— [1,3]di0X010[4,5-c]pyridin methyl-propoxy) 4,5,6,7-tctrahydr0-3aH- yl]-[4-(2-hydr0xyrncthyl- methoxy-bcnzoic [1,3]dioxolo[4,5- propoxy)rncthoxy- acid c]pyridinc phcnyl]rncthanonc [(3 aR,7aR)—7a-phcny1— 3 a,4,6,7-tctrahydr0- 4-(1-hydroxy (3 aR,7aR)-7a-phcny1— [1,3]di0X010[4,5-c]pyridin methyl-cthyl)-3 - 4,5,6,7-tctrahydr0-3aH- yl]-[4-(1-hydr0xymcthyl- methyl-benzoic [1,3]dioxolo[4,5- cthy1)-3 -rncthy1— acid c]pyridinc phcnyl]rncthanonc [(3 )—7a-phcny1— (3 aR,7aR)-7a-phcny1— 3a,4,6,7-tctrahydr0- quinolinc 4,5,6,7-tctrahydr0-3aH- [1,3]di0X010[4,5-c]pyridin carboxylic acid [1,3]dioxolo[4,5- yl] -(8-quin01y1)rncthanonc c]pyridinc [5-cyclopropy1 5-cyclopropyl (trifluoromcthyl)-4,5,6,7- (trifluoromcthyl)- tctrahydropyrazolo [1 ,5 - 4,5 ,6 ,7- 6-phcny1—3- rnidiny1]—(6-phcny1— tctrahydropyrazolo[ azabicyc10[4. 1 tanc 3-azabicyc10[4.1.0]hcptan 1,5-a]pyrirnidinc yl)rncthanonc carboxylic acid [6-(4-fluorophcnyl) 4-(2-hydroxy yc10[4. 1 .0]hcptany1]— methyl-propoxy) 6-(4-fluorophcnyl)—3- [4-(2-hydr0xyrncthyl- methyl-benzoic azabicyc10[4. 1 .0]hcptanc propoxy)rncthy1— acid phcnyl]rncthanonc [4-(2-hydr0xyrncthyl- 4-(2-hydroxy propoxy)—3-rncthy1—phcny1]— methyl-propoxy) (1R,6S)—6-phcny1—3- [(1R,6S)phcnyl-3 - methyl-benzoic azabicyc10[4. 1 .0]hcptanc azabicyc10[4. 1 tan acid yl]rncthanonc hydr0xyrncthyl- 4-(2-hydroxy propoxy)—3-rncthy1—phcny1]— methyl-propoxy) (1 S,6R)—6-phcny1—3- [(1 S ,6R)—6-phcny1—3 - methyl-benzoic azabicyc10[4. 1 .0]hcptanc azabicyc10[4. 1 .0]hcptan acid yl]rncthanonc [(3 aS,7aS)-7a-phcnyl- 3a,4,6,7-tctrahydr0- 2- (3 aS,7aS)—7a-phcnyl- [1,3]di0X010[4,5-c]pyridin (trifluoromcthoxym 4,5,6,7-tctrahydr0-3aH- y11-[2- cthyl)-2,3-dihydro- ioxolo[4,5- (trifluoromcthoxymcthy1)-2,3- 1 ,4-bcnz0dioxinc- c]pyridinc dihydro- 1 ,4-bcnzodi0xin 6-carboxylic acid yl]rncthanonc [(3 aS,7aS)-7a-phcnyl- 3a,4,6,7-tctrahydr0- 4-(2-fluor0 (3 aS,7aS)—7a-phcnyl- [1,3]di0X010[4,5-c]pyridin methyl-propoxy) 4,5,6,7-tctrahydr0-3aH- y1]-[4-(2-flu0r0rncthyl- methyl-benzoic ioxolo[4,5- propoxy)rncthy1— acid c]pyridinc phenyl]rncthanonc [(3 aR,7aR)—7a-phcny1— 3a,4,6,7-tctrahydr0- 2- (3 aR,7aR)-7a-phcny1— [1,3]di0X010[4,5-c]pyridin (trifluoromcthoxym 4,5,6,7-tctrahydr0-3aH- y11-[2- cthyl)-2,3-dihydro- [1,3]dioxolo[4,5- (trifluoromcthoxymcthy1)-2,3- 1 ,4-bcnz0dioxinc- c]pyridinc dihydro- 1 zodi0xin 6-carboxylic acid yl]rncthanonc [(3 aR,7aR)—7a-phcny1— 3a,4,6,7-tctrahydr0- 4-(2-fluor0 (3 aR,7aR)-7a-phcny1— [1,3]di0X010[4,5-c]pyridin methyl-propoxy) 4,5,6,7-tctrahydr0-3aH- y1]-[4-(2-flu0r0rncthyl- methyl-benzoic [1,3]dioxolo[4,5- propoxy)rncthy1— acid c]pyridinc phenyl]rncthanonc [(3aS,7aS)-7a-(4- (3aS,7aS)-7a-(4- fluorophcnyl)-3a,4,6,7- oxy[2- hcnyl)—4,5,6,7- tctrahydro-[ 1 ,3 ] dioxolo [4,5 - (trifluororncthoxy)c tetrahydro-3aH- c]pyridin-5 -y1]-[3-rncthoxy bcnzoic acid [1,3]dioxolo[4,5- dinc (trifluoromcthoxy)cthoxy]phc nyl]rncthanonc [(3 aR,7aR)—7a-(4- hcnyl)-3a,4,6,7- (3 aR,7aR)—7a-(4- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - 3-rncthoxy[2- fluorophcnyl)—4,5,6,7- c]pyridin-5 -y1]-[3-rncthoxy (trifluororncthoxy)c tetrahydro-3aH- [2- thoxy]benzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridine nyl]rncthanonc [(3 aR,7aR)-7a-pyrirnidin y1-3 a,4,6,7-tctrahydr0- (3 aR,7aR)-7a-pyrirnidin- 3-rncthoxy[2- [1,3]di0X010[4,5-c]pyridin 2-y1—4,5,6,7-tctrahydro- (trifluororncthoxy)c y1]-[3 -rncth0xy[2- 3aH-[1,3]dioxolo[4,5- thoxy]benzoic acid (trifluoromcthoxy)cthoxy]phc dine nyl]rncthanonc [(3aS,7aS)-7a-(1- methylpyrazoly1)-3a,4,6,7- (3aS,7aS)-7a-(1- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - hoxy[2- pyrazoly1)— c]pyridin-5 -y1]-[3-rncthoxy (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- [2- thoxy]benzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridine nyl]rncthanonc [(3 aS,7aR)-7a-thiaz01—2-y1— 3a,4,6,7-tctrahydr0- 4-(2-hydroxy (3 aS,7aR)—7a-thiaz01—2-y1— [1,3]di0X010[4,5-c]pyridin methyl-propoxy) 4,5,6,7-tctrahydr0-3aH- -(2-hydr0xyrncthyl- methyl-benzoic [1,3]dioxolo[4,5- y)rnethy1— acid c]pyridine phenyl]rncthanonc [(3 )-7a-thiaz01—2-y1— 3a,4,6,7-tctrahydr0- 4-(2-fluor0 (3 aS,7aR)—7a-thiaz01—2-y1— [1,3]di0X010[4,5-c]pyridin methyl-propoxy) 4,5,6,7-tctrahydr0-3aH- y1]-[4-(2-flu0r0rncthyl- methyl-benzoic [1,3]dioxolo[4,5- propoxy)rncthy1— acid c]pyridinc phcnyl]rncthanonc [(3 )-7a-thiaz01—2-y1— 3a,4,6,7-tctrahydr0- uor0 (3 aS,7aR)—7a-thiaz01—2-y1— [1,3]di0X010[4,5-c]pyridin methyl-propoxy) 7-tctrahydr0-3aH- y1]-[4-(2-flu0r0rncthyl- methoxy-bcnzoic [1,3]dioxolo[4,5- propoxy)rncthoxy- acid c]pyridinc phcnyl]rncthanonc [(3 aS,7aR)-7a-thiaz01—2-y1— ,7-tctrahydr0- (3 aS,7aR)—7a-thiaz01—2-y1— 3-mcthoxy[2- [1,3]di0X010[4,5-c]pyridin 4,5,6,7-tctrahydr0-3aH- (trifluororncthoxy)c y1]-[3 -rncth0xy[2- [1,3]dioxolo[4,5- thoxy]bcnzoic acid (trifluoromcthoxy)cthoxy]phc c]pyridinc nyl]rncthanonc [(3 aR,7aS)-7a-thiaz01—2-y1— 3a,4,6,7-tctrahydr0- 4-(2-hydroxy (3 aR,7aS)—7a-thiaz01—2-y1— [1,3]di0X010[4,5-c]pyridin methyl-propoxy) 4,5,6,7-tctrahydr0-3aH- -(2-hydr0xyrncthyl- methyl-benzoic [1,3]dioxolo[4,5- propoxy)rncthy1— acid c]pyridinc phcnyl]rncthanonc [(3 aR,7aS)-7a-thiaz01—2-y1— 3a,4,6,7-tctrahydr0- 4-(2-fluor0 (3 aR,7aS)—7a-thiaz01—2-y1— [1,3]di0X010[4,5-c]pyridin methyl-propoxy) 4,5,6,7-tctrahydr0-3aH- y1]-[4-(2-flu0r0rncthyl- methyl-benzoic [1,3]dioxolo[4,5- propoxy)rncthy1— acid c]pyridinc phcnyl]rncthanonc [(3aR,7aS)-7a-thiaz01—2-y1— ,7-tctrahydr0- 4-(2-fluor0 (3aR,7aS)—7a-thiaz01—2-y1— [1 ,3]di0x010[4,5-c]pyridin methyl-propoxy) 4,5 ,6,7-tctrahydr0-3aH- y1]- [4-(2-fluororncthyl- methoxy-bcnzoic [1 ,3 ] dioxolo [4,5 - propoxy)rncthoxy- acid c]pyridinc phcnyl]rncthanonc [(3aR,7aS)-7a-thiaz01—2-y1— 3a,4,6,7-tctrahydr0- (3aR,7aS)—7a-thiaz01—2-y1— oxy[2- [1,3]dioxolo[4,5-c]pyridin 4,5 ,6,7-tctrahydro-3aH- (trifluoromcthoxy)c_ y1]-[3 -rncthoxy[2- 10xolo[4,5-. thoxy]bcnz01c ac1d_ _ (trifluoromcthoxy)cthoxy]phc c]pyr1d1nc_ _ nyl]rncthanonc [(3aS,7aS)-7a-(4- (3aS,7aS)-7a-(4- fluorophcny1)-3 a,4,6,7- 4-(2-hydroxy fluorophcny1)-4,5,6,7- tctrahydr0-[ 1 ,3]diox010[4,5- methyl-propoxy) ydro-3aH- c]pyridin-5 -y1]-[4-(2-hydroxy- methyl-benzoic [1,3]dioxolo[4,5- 2-rncthy1—propoxy)-3 y1— acid c]pyr1d1nc. . phcnyl]rncthanonc [(3aS,7aS)-7a-(4- aS)-7a-(4- fluorophcny1)-3a,4,6,7- 4-(2-fluor0 fluorophcny1)-4,5,6,7- tctrahydr0-[ 1 ,3]diox010[4,5- methyl-propoxy) tctrahydro-3aH- c]pyridin-5 -y1]-[4-(2-flu0r0 methyl-benzoic [1,3]dioxolo[4,5- methyl-propoxy)rncthy1— acid c]pyr1d1nc. . phcnyl]rncthanonc [(3aS,7aS)-7a-(4- (3aS,7aS)-7a-(4- fluorophcny1)-3a,4,6,7- uor0 fluorophcny1)-4,5,6,7- tctrahydr0-[ 1 ,3]diox010[4,5- methyl-propoxy) tctrahydr0-3aH- c]pyridiny1]-[4-(2-flu0r0 methoxy-bcnzoic [1,3]d10xolo[4,5-. methyl-propoxy)rncth0xy- ac1d_ c]pyr1d1nc. . phcnyl]rncthanonc [(3aS,7aS)-7a-(4- fluorophcny1)-3a,4,6,7- (3aS,7aS)-7a-(4- 3-methoxy tetrahydro-[ 1 ,3 ] dioxolo [4,5 - fluorophcny1)-4,5,6,7- (3 ,3 ,3 - c]pyridin-5 -y1]-[3-rncthoxy tetrahydro-3aH- trifluoropropoxyrnc (3 ,3 ,3 - [1,3]dioxolo[4,5- thyl)benzoic acid ropropoxyrncthyl)phcny c]pyridine 1]rnethanonc [(3 aR,7aR)—7a-(4- (3 aR,7aR)—7a-(4- fluorophcny1)-3a,4,6,7- 4-(2-hydroxy fluorophcny1)-4,5,6,7- tetrahydro-[ 1 ,3 ] o [4,5 - methyl-propoxy) tetrahydro-3aH- c]pyridin-5 -y1]-[4-(2-hydroxy- methyl-benzoic [1,3]dioxolo[4,5- 2-rncthy1—propoxy)-3 -rncthy1— acid c]pyridine phenyl]rncthanonc [(3 aR,7aR)—7a-(4- (3 aR,7aR)—7a-(4- fluorophcny1)-3a,4,6,7- 4-(2-fluor0 fluorophcny1)-4,5,6,7- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - methyl-propoxy) tetrahydro-3aH- c]pyridin-5 -y1]-[4-(2-flu0r0 methyl-benzoic [1,3]dioxolo[4,5- methyl-propoxy)rncthy1— acid c]pyridine phenyl]rncthanonc [(3 aR,7aR)—7a-(4- (3 aR,7aR)—7a-(4- fluorophcny1)-3a,4,6,7- 4-(2-fluor0 fluorophcny1)-4,5,6,7- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - methyl-propoxy) tetrahydro-3aH- c]pyridin-5 4-(2-flu0r0 y-bcnzoic ioxolo[4,5- methyl-propoxy)rncth0xy- acid dine ]rncthanonc [(3 aR,7aR)—7a-(4- fluorophcny1)-3a,4,6,7- (3 aR,7aR)—7a-(4- 3-methoxy tetrahydro-[ 1 ,3 ] o [4,5 - fluorophcny1)-4,5,6,7- (3 ,3 ,3 - c]pyridin-5 -y1]-[3-rncthoxy tetrahydro-3aH- trifluoropropoxyrnc (3 ,3 ,3 - [1,3]dioxolo[4,5- thyl)benzoic acid trifluoropropoxyrncthyl)phcny c]pyridine 1]rnethanonc [(3 )-7a-pyrirnidin y1-3 a,4,6,7-tctrahydr0- 4-(2-fluor0 (3 aR,7aR)-7a-pyrirnidin- [1,3]di0X010[4,5-c]pyridin methyl-propoxy) ,5,6,7-tctrahydro- y1]-[4-(2-flu0r0rncthyl- methyl-benzoic 3aH-[1,3]dioxolo[4,5- propoxy)rncthy1— acid c]pyridinc phcnyl]rncthanonc [(3 aR,7aR)-7a-pyrirnidin y1-3 a,4,6,7-tctrahydr0- 4-(2-fluor0 (3 aR,7aR)-7a-pyrirnidin- [1,3]di0X010[4,5-c]pyridin methyl-propoxy) 2-y1—4,5,6,7-tctrahydro- y1]-[4-(2-flu0r0rncthyl- methoxy-bcnzoic 3aH-[1,3]dioxolo[4,5- propoxy)rncthoxy- acid c]pyridinc phcnyl]rncthanonc [(3 aR,7aR)-7a-pyrirnidin (3 aR,7aR)-7a-pyrirnidin- y1-3 a,4,6,7-tctrahydr0- 4-isopropoxy 2-y1—4,5,6,7-tctrahydro- [1,3]di0X010[4,5-c]pyridin methyl-benzoic 3aH-[1,3]dioxolo[4,5- yl]—(4-isoprop0xyrncthy1— acid c]pyridinc )rncthanonc [(3 aS,7aR)-7a-thiaz01—2-y1— 3a,4,6,7-tctrahydr0- (3 aS,7aR)—7a-thiaz01—2-y1— 3-rncthy1—4-[2— [1,3]di0X010[4,5-c]pyridin 4,5,6,7-tctrahydr0-3aH- (trifluororncthoxy)c y1]-[3 -rncthy1—4-[2- [1,3]dioxolo[4,5- thoxy]bcnzoic acid oromcthoxy)cthoxy]phc c]pyridinc nyl]rncthanonc [(3 aS,7aR)-7a-thiaz01—2-y1— 3a,4,6,7-tctrahydr0- 6-mcthoxy[2- (3 aS,7aR)—7a-thiaz01—2-y1— [1,3]di0X010[4,5-c]pyridin (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- yl]—[6-rncthoxy[2- thoxy]pyridinc [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy] carboxylic acid dinc pyridyl]rncthanonc [(3 aR,7aS)-7a-thiaz01—2-y1— 3a,4,6,7-tctrahydr0- (3 aR,7aS)—7a-thiaz01—2-y1— 3-mcthy1—4-[2— [1,3]d10xolo[4,5-c]pyridin. 4,5 ,6,7-tetrahydro-3aH- (trifluororncthoxy)c_ y1]-[3 -rnethy1—4-[2- [1,3]d10xolo[4,5-. thoxy]benz01c acid_ (trifluoromcthoxy)cthoxy]phc_ c]pyridinc nyl]rncthanonc [(3 aR,7aS)-7a-thiaz01—2-y1— 3a,4,6,7-tctrahydr0- 6-mcthoxy[2- (3 aR,7aS)—7a-thiaz01—2-y1— [1,3]dioxolo[4,5-c]pyridin (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- yl]—[6-rncthoxy[2- thoxy]pyridinc [1,3]di0x010[4,5- (trifluoromcthoxy)cthoxy] carboxylic acid dinc l]rncthanonc [(3 aR,7aR)-7a-thiaz01—4-y1— 3a,4,6,7-tctrahydr0- (3 aR,7aR)-7a-thiaz01—4- . . . 3-mcthoxy[2- [1,3]d10X010[4,5-c]pyr1d1n y1-4,5,6,7-tctrahydro-3aH- (trifluororncthoxy)c. y1]-[3 -rncth0xy[2- [1,3]di0X010[4,5- _ benzoic acid (trifluoromcthoxy)cthoxy]phc c]pyr1d1nc_ _ nyl]rncthanonc [(3 aR,7aR)-7a-thiaz01—4-y1— 3a,4,6,7-tctrahydr0- (3 aR,7aR)-7a-thiaz01—4- [1,3 ] dioxolo [4,5 1d1n-5 -. . . 3-mcthy1—4-[2— y1-4,5 ,6,7-tctrahydr0-3aH- (trifluororncthoxy)c. y1]-[3 -rnethy1—4-[2- [1 ,3]di0X010[4,5- thoxy]benzoic acid oromcthoxy)cthoxy]phc_ c]pyridinc nyl]rncthanonc [(3 aR,7aR)-7a-thiaz01—4-y1— 3a,4,6,7-tctrahydr0- 4-(2-fluor0 (3 aR,7aR)-7a-thiaz01—4- [1,3]di0xolo[4,5-c]pyridin methyl-propoxy) ,6,7-tctrahydro-3aH- y1]-[4-(2-flu0r0rncthyl- methyl-benzoic [1,3]di0X010[4,5- propoxy)rncthy1— acid c]pyridinc phenyl]rncthanonc [7a-(2-pyridy1)—3a,4,6,7- tctrahydr0-[ 1 ,3]di0x010[4,5 - 7a-(2-pyridy1)—4,5 ,6,7- 3-mcthoxy[2- din-5 -y1]-[3-rncthoxy tctrahydro-3aH- (trifluororncthoxy)c [2- [1,3]d10xolo[4,5-. thoxy]bcnz01c ac1d_ _ (trifluoromcthoxy)cthoxy]phc c]pyr1d1nc_ _ nyl]rncthanonc [(3aR,7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0- (3aR,7aR)-7a-(2-pyridy1)- 3-mcthoxy[2- [1,3 ] dioxolo [4,5 -c]pyridin-5 - 4,5 ,6,7-tctrahydro-3aH- (trifluoromcthoxy)c_ y1]-[3 -rncthoxy[2- [1,3]d10xolo[4,5-. thoxy]bcnz01c ac1d_ _ (trifluoromcthoxy)cthoxy]phc c]pyr1d1nc_ _ cthanonc [(3aR,7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0- 4-(2-fluor0 (3aR,7aR)-7a-(2-pyridy1)- [1 ,3]di0x010[4,5-c]pyridin methyl-propoxy) 4,5 ctrahydr0-3aH- y1]- [4-(2-fluororncthyl- methoxy-bcnzoic [1 ,3]di0X010[4,5 - propoxy)rncthoxy- acid dinc phcnyl]rncthanonc [(3aR,7aR)-7a-(2-pyridy1)- ,7-tctrahydr0- uor0 (3aR,7aR)-7a-(2-pyridy1)- [1 ,3]di0x010[4,5-c]pyridin methyl-propoxy) 4,5 ,6,7-tctrahydr0-3aH- y1]- [4-(2-fluororncthyl- methyl-benzoic [1,3]di0X010[4,5 - propoxy)rncthy1— acid c]pyridinc phcnyl]rncthanonc [(3aR,7aR)—7a-(6-brorno (3 aR,7aR)-7a-(6-brorno pyridy1)-3a,4,6,7-tctrahydr0- 3-mcthoxy[2- pyridyl)—4,5 ,6,7- i0X010[4,5-c]pyridin (trifluoromcthoxy)c. tctrahydro-3aH- y1]-[3 -rncth0xy[2- thoxy]bcnzoic acid [1,3]di0X010[4,5- (trifluoromcthoxy)cthoxy]phc c]pyr1d1nc. . nyl]rncthanonc WO 06280 [(3aR,7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0- 4-(2-hydroxy (3 aR,7aR)-7a-(2-pyridyl)- i0xolo[4,5-c]pyridin methyl-propoxy) 4,5,6,7-tctrahydr0-3aH- yl]-[4-(2-hydr0xyrncthyl- methyl-benzoic [1,3]dioxolo[4,5- propoxy)rncthy1— acid c]pyridinc phcnyl]rncthanonc [(3 aR,7aR)—7a-(3 -ch10r0 (3 aR,7aR)-7a-(3-chlor0 pyridy1)-3a,4,6,7-tctrahydr0- 3-mcthoxy[2- pyridyl)—4,5 ,6,7- [1,3]di0X010[4,5-c]pyridin (trifluororncthoxy)c. tctrahydro-3aH- y1]-[3 -rncth0xy[2- thoxy]bcnzoic acid [1 X010 [4,5- oromcthoxy)cthoxy]phc c]pyr1d1nc. . nyl]rncthanonc [(3 aR,7aR)—7a-(3 -ch10r0 (3 aR,7aR)-7a-(3-chlor0 pyridy1)-3a,4,6,7-tctrahydr0- 3-mcthy1—4-[2— pyridyl)—4,5 ,6,7- [1,3]di0X010[4,5-c]pyridin (trifluororncthoxy)c. tctrahydro-3aH- y1]-[3 -rncthy1—4-[2- thoxy]bcnzoic acid [1 ,3]di0X010 [4,5- (trifluoromcthoxy)cthoxy]phc. d1nc. . nyl]rncthanonc [(3 aR,7aR)—7a-(3 -ch10r0 (3 aR,7aR)-7a-(3-chlor0 pyridy1)-3a,4,6,7-tctrahydr0- 4-(2-fluor0 pyridyl)—4,5 ,6,7- [1,3]di0xolo[4,5-c]pyridin methyl-propoxy) tctrahydro-3aH- y1]-[4-(2-flu0r0rncthyl- methyl-benzoic [1,3]dioxolo[4,5- propoxy)rncthy1— acid c]pyr1d1nc. . phcnyl]rncthanonc [(3 aR,7aR)—7a-(3 -ch10r0 (3 aR,7aR)-7a-(3-chlor0 pyridy1)-3a,4,6,7-tctrahydro- ropoxy l)—4,5,6,7- [1,3]di0xolo[4,5-c]pyridin methyl-pyridinc tctrahydro-3aH- yl]-(5-isopr0poxyrncthyl carboxylic acid [1,3]di0X010[4,5- pyridyl)rncthanonc c]pyridinc [(3 aS,7aR)-7a-thiaz01—2-y1— ,7-tctrahydr0- (3 aS,7aR)—7a-thiaz01—2-y1— 3-mcthy1—4-(2,2,2- [1,3]di0X010[4,5-c]pyridin 4,5,6,7-tctrahydr0-3aH- trifluoroethoxy)bcn y1]-[3-nicthyl(2,2,2- [1,3]dioxolo[4,5- zoic acid trifluorocthoxy)phcnyl]nictha c]pyridine none [(3 aS,7aR)-7a-thiaz01—2-y1— 3a,4,6,7-tctrahydr0- 3-ch10r0(2- (3 aS,7aR)—7a-thiaz01—2-y1— [1,3]di0X010[4,5-c]pyridin hydroxy-Z-nicthyl- 4,5,6,7-tctrahydr0-3aH- y1]-[3-ch10r0(2-hydr0xy propoxy)bcnzoic [1,3]dioxolo[4,5- methyl- acid c]pyridine y)phcnyl]mcthanonc [(3 aR,7aS)-7a-thiaz01—2-y1— 3a,4,6,7-tctrahydr0- (3 aR,7aS)—7a-thiaz01—2-y1— 3-mcthy1—4-(2,2,2- [1,3]di0X010[4,5-c]pyridin 4,5,6,7-tctrahydr0-3aH- trifluoroethoxy)bcn y1]-[3-nicthyl(2,2,2- [1,3]dioxolo[4,5- zoic acid trifluorocthoxy)phcnyl]nictha c]pyridine none [(3 aR,7aS)-7a-thiaz01—2-y1— ,7-tctrahydr0- 3-ch10r0(2- (3 aR,7aS)—7a-thiaz01—2-y1— i0X010[4,5-c]pyridin hydroxy-Z-nicthyl- 7-tctrahydr0-3aH- -ch10r0(2-hydr0xy propoxy)bcnzoic [1,3]dioxolo[4,5- methyl- acid c]pyridine propoxy)phcnyl]mcthanonc [(3 aR,7aR)-7a-(3-mcthoxy-2— (3 aR,7aR)—7a-(3- pyridy1)-3a,4,6,7-tctrahydr0- 3-mcthoxy[2- methoxypyridyl)- [1,3]di0X010[4,5-c]pyridin (trifluoromcthoxy)c 4,5,6,7-tctrahydr0-3aH- y1]-[3 -mcth0xy[2- thoxy]benzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridine ny1]nicthanonc [(3 aR,7aR)-7a-(3-mcthoxy-2— (3 aR,7aR)—7a-(3- pyridy1)-3a,4,6,7-tctrahydr0- 3-mcthy1—4-[2— methoxypyridyl)- [1,3]di0X010[4,5-c]pyridin (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- y1]-[3 -rnethy1—4-[2- thoxy]benzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridine nyl]rncthanonc [(3 )-7a-(3-mcthoxy-2— (3 aR,7aR)—7a-(3- pyridy1)-3a,4,6,7-tctrahydr0- 3-ch10r0[2- methoxypyridyl)- [1,3]di0X010[4,5-c]pyridin (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- y1]-[3-ch10r0[2- thoxy]benzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridine nyl]rncthanonc [(3 aR,7aR)-7a-(3-mcthoxy-2— (3 aR,7aR)—7a-(3- pyridy1)-3a,4,6,7-tctrahydr0- 4-(2-fluor0 methoxypyridyl)- i0X010[4,5-c]pyridin methyl-propoxy) 4,5,6,7-tctrahydr0-3aH- -(2-flu0r0rncthyl- methyl-benzoic [1,3]dioxolo[4,5- propoxy)rnethy1— acid c]pyridine phenyl]rncthanonc [(3 aR,7aR)—7a-(3-fluoro (3 aR,7aR)-7a-(3-fluoro pyridy1)-3a,4,6,7-tctrahydr0- oxy[2- pyridy1)-4,5 ,6,7- i0X010[4,5-c]pyridin (trifluororncthoxy)c tctrahydro-3aH- y1]-[3 -rncth0xy[2- thoxy]benzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridine nyl]rncthanonc [(3 )—7a-(3-fluoro (3 aR,7aR)-7a-(3-fluoro pyridy1)-3a,4,6,7-tctrahydr0- 3-mcthy1—4-[2— pyridy1)-4,5 ,6,7- i0X010[4,5-c]pyridin (trifluororncthoxy)c tctrahydro-3aH- y1]-[3 -rnethy1—4-[2- thoxy]benzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridine nyl]rncthanonc [(3 aR,7aR)—7a-(3-fluoro (3 aR,7aR)-7a-(3-fluoro pyridy1)-3a,4,6,7-tctrahydr0- 4-(2-fluor0 pyridy1)-4,5 ,6,7- i0X010[4,5-c]pyridin methyl-propoxy) tctrahydro-3aH- y1]-[4-(2-flu0r0rncthyl- methyl-benzoic [1,3]dioxolo[4,5- propoxy)rncthy1— acid c]pyr1d1nc. . phcnyl]rncthanonc [(3 aR,7aR)—7a-(3-fluoro (3 aR,7aR)-7a-(3-fluoro 1)-3a,4,6,7-tctrahydr0- 3-ch10r0[2- pyridyl)—4,5 ,6,7- [1,3]di0X010[4,5-c]pyridin (trifluororncthoxy)c tctrahydro-3aH- y1]-[3-ch10r0[2- thoxy]bcnzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridinc nyl]rncthanonc [(3 aR,7aR)—7a-(3-fluoro (3 aR,7aR)-7a-(3-fluoro pyridy1)-3a,4,6,7-tctrahydr0- 6-mcthoxy[2- pyridy1)-4,5 ,6,7- [1,3]di0X010[4,5-c]pyridin (trifluororncthoxy)c tctrahydro-3aH- yl]—[6-rncthoxy[2- thoxy]pyridinc [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy] carboxylic acid d1nc. . pyridyl]rncthanonc [(3 aR,7aR)—7a-(2- methylthiazolyl)-3a,4,6,7- (3 )—7a-(2- ydro-[ 1 ,3 ] dioxolo [4,5 - 3-mcthoxy[2- methylthiazolyl)- c]pyridin-5 -y1]-[3-rncthoxy (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- [2- thoxy]bcnzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridinc nyl]rncthanonc [(3 aR,7aR)—7a-(2- methylthiazolyl)-3a,4,6,7- (3 )—7a-(2- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - 3-mcthy1—4-[2— methylthiazolyl)- c]pyridiny1]-[3-rncthy1—4- (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- [2- thoxy]bcnzoic acid [1 ,3]di0X010 [4,5- (trifluoromcthoxy)cthoxy]phc c]pyridinc nyl]rncthanonc [(3 aR,7aR)—7a-(2- (3 aR,7aR)—7a-(2- methylthiazolyl)-3a,4,6,7- 4-(2-fluor0 methylthiazolyl)- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - methyl-propoxy) 4,5,6,7-tctrahydr0-3aH- c]pyridin-5 -y1]-[4-(2-flu0r0 methyl-benzoic [1,3]dioxolo[4,5- methyl-propoxy)rncthy1— acid c]pyr1d1nc. . phcnyl]rncthanonc [(3 aR,7aR)—7a-(2- methylthiazolyl)-3a,4,6,7- (3 aR,7aR)—7a-(2- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - 3-ch10r0[2- methylthiazolyl)- diny1]-[3-chloro (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- [2- thoxy]bcnzoic acid [1,3]di0X010[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridinc nyl]rncthanonc [(3 aR,7aR)—7a-(2- (3 )—7a-(2- methylthiazolyl)-3a,4,6,7- 6-mcthoxy[2- methylthiazo1y1)- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- c]pyridin-5 -y1]-[6-rncthoxy thoxy]pyridinc ioxolo[4,5- [2-(triflu0rorncthoxy)cthoxy] - carboxylic acid c]pyr1d1nc. . 2-pyridy1]rncthanonc [(3 aS,7aR)-7a-thiaz01—2-y1— 3a,4,6,7-tctrahydr0- (3 aS,7aR)—7a-thiaz01—2-y1— 3-ch10r0[2- [1,3]di0X010[4,5-c]pyridin 4,5,6,7-tctrahydr0-3aH- (trifluororncthoxy)c y1]-[3-ch10r0[2- [1,3]dioxolo[4,5- bcnzoic acid (trifluoromcthoxy)cthoxy]phc c]pyr1d1nc_ _ nyl]rncthanonc [(3 aR,7aS)-7a-thiaz01—2-y1— 3a,4,6,7-tctrahydr0- (3 aR,7aS)—7a-thiaz01—2-y1— r0[2- [1,3]di0X010[4,5-c]pyridin 7-tctrahydr0-3aH- ororncthoxy)c y1]-[3-ch10r0[2- [1,3]dioxolo[4,5- thoxy]bcnzoic acid (trifluoromcthoxy)cthoxy]phc c]pyr1d1nc_ _ nyl]rncthanonc [(3aR,7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0- 6-mcthoxy[2- (3aR,7aR)-7a-(2-pyridy1)- [1 ,3]di0X010[4,5 -c]pyridin-5 - (trifluororncthoxy)c 4,5 ,6,7-tctrahydr0-3aH- yl] - [6-mcthoxy-5 - [2- thoxy]pyridinc i0x010[4,5 - oromcthoxy)cthoxy] carboxylic acid c]pyridinc pyridyl]rncthanonc [(3aR,7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0- (3aR,7aR -7a- 2-) ( pyridy)1 - 3-mcthy1—4-[2— [1,3]d10xolo[4,5 -c]pyridin-5 -. 4,5 ,6,7-tctrahydro-3aH- (trifluoromcthoxy)c_ yl]-[3 -rncthy1—4-[2- [1 ,3]di0X010[4,5- bcnzoic acid (trifluoromcthoxy)cthoxy]phc_ c]pyridinc nyl]rncthanonc [(3aR,7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0- (3aR,7aR)-7a-(2-pyridy1)- 3-ch10r0[2- [1,3]d10xolo[4,5-c]pyr1d1n. . . 4,5 ,6,7-tctrahydro-3aH- (trifluoromcthoxy)c_ yl]-[3-ch10r0[2- [1,3]di0X010[4,5- bcnz01c ac1d. . (trifluoromcthoxy)cthoxy]phc_ c]pyr1d1nc_ _ nyl]rncthanonc [4-(2-hydr0xy-1 , 1 -dirncthy1— 4-(2-hydr0xy-1 ,1- cthy1)-3 -mcthoxy-phcnyl]—(6- dimcthyl-cthyl) 6-phcny1—3- pheny1-3 - methoxy-bcnzoic yclo [4. 1 .0]hcptanc azab1cyc10[4.1.0]hcptan. ac1d. yl)rncthanonc [(3 aS,7aR)-7a-thiaz01—2-y1— 3a,4,6,7-tctrahydr0- 6-cth0xy[2- (3 )—7a-thiaz01—2-y1— [1,3]dioxolo[4,5-c]pyridin (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- yl]-[6-cthoxy[2- thoxy]pyridinc [1,3]di0x010[4,5- (trifluoromcthoxy)cthoxy] carboxylic acid c]pyridinc pyridyl]rncthanonc [(3 aR,7aS)-7a-thiaz01—2-y1— 3a,4,6,7-tctrahydr0- 6-cth0xy[2- (3 aR,7aS)—7a-thiaz01—2-y1— [1,3]dioxolo[4,5-c]pyridin (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- y1]-[6-cthoxy[2- thoxy]pyridinc [1,3]di0x010[4,5- (trifluoromcthoxy)cthoxy] carboxylic acid c]pyridinc pyridyl]rncthanonc [(3 aR,7aR)—7a-(2- (3 )—7a-(2- methylth1az01—4-yl)-3a,4,6,7-. 6-cth0xy[2- methylthiazolyl)- tctrahydr0-[ 1 ,3]diox010[4,5- (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- c]pyridiny1]-[6-cthoxy thoxy]pyridinc ioxolo[4,5- [2-(trifluororncthoxy)cthoxy]- carboxylic acid c]pyr1d1nc. . 2-pyr1dy1]rncthanonc. [(3 aR,7aS)-7a-thiaz01—2-y1— ,7-tctrahydr0- (3 aR,7aS)—7a-thiaz01—2-y1— 3-flu0r0[2- [1,3]d10xolo[4,5 -c]pyr1d1n-5 -. . . 4,5 ,6,7-tctrahydro-3aH- (trifluororncthoxy)c_ -flu0r0[2- i0X010[4,5- _ thoxy]bcnzoic acid (trifluoromcthoxy)cthoxy]phc c]pyridinc nyl]rncthanonc [(3 aS,7aR)-7a-thiaz01—2-y1— 3a,4,6,7-tctrahydr0- (3 aS,7aR)—7a-thiaz01—2-y1— 3-flu0r0[2- [1,3]d10xolo[4,5 -c]pyr1d1n-5 -. . . 4,5 ,6,7-tctrahydro-3aH- (trifluororncthoxy)c_ y1]-[3-flu0r0[2- [1,3]di0X010[4,5- thoxy]bcnz01c ac1d. . (trifluoromcthoxy)cthoxy]phc_ c]pyridinc nyl]rncthanonc [(3aR,7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0- (3 aR,7aR)-7a-(2-pyridyl)- 3-ch10r0(2,2- [1,3]d10xolo[4,5 -c]pyridin-5 -. 4,5 ,6,7-tctrahydro-3aH- d1rncthy1propoxy)b_ y1]-[3-ch10r0(2,2- [1,3]di0X010[4,5- . . enz01c ac1d dimcthy1pr0p0xy)phcnyl]rncth_ dinc 8.110116 2014/045675 [(3aR,7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0- 3-ch10r0[2- (3 aR,7aR)-7a-(2-pyridy1)- [1,3]di0X010[4,5-c]pyridin (2,2,2- 7-tctrahydr0-3aH- yl]—[3-ch10r0[2-(2,2,2- trifluorocthoxy)cth [1,3]dioxolo[4,5- trifluorocthoxy)cthoxy]phcny1 oxy]bcnzoic acid c]pyridine ]rnethanonc 7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0- 3-ch10r0(4,4,4- (3 aR,7aR)-7a-(2-pyridy1)- [1,3]di0X010[4,5-c]pyridin trifluoro-Z-mcthyl- 4,5,6,7-tctrahydr0-3aH- yl]—[3-chlor0(4,4,4- butoxy)bcnzoic [1,3]dioxolo[4,5- trifluoro-Z-mcthyl- acid dine butoxy)phcnyl]mcthanonc [(3aR,7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0- 3-chloro[(3,3- (3 aR,7aR)-7a-(2-pyridy1)- [1,3]di0X010[4,5-c]pyridin difluorocyclobutyl) 4,5,6,7-tctrahydr0-3aH- y1]-[3-chloro[(3,3- methoxy]bcnzoic [1,3]dioxolo[4,5- ocyclobutyl)rnethoxy]p acid c]pyridine hcny1]rncthanonc [(3aR,7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0- (3 aR,7aR)-7a-(2-pyridy1)- 3-ch10ro(2,2,3,3- [1,3]di0X010[4,5-c]pyridin 4,5,6,7-tctrahydr0-3aH- tetrafluoropropoxy) y1]-[3-ch10r0(2,2,3,3- [1,3]dioxolo[4,5- benzoic acid tetrafluoropropoxy)phcnyl]Inc c]pyridine thanonc [(3aR,7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0- 6-mcthy1—5-[2— (3 aR,7aR)-7a-(2-pyridy1)- [1,3]di0X010[4,5-c]pyridin ororncthoxy)c 4,5,6,7-tctrahydr0-3aH- yl]—[6-rncthy1—5-[2— thoxy]pyridinc [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy] carboxylic acid c]pyridine pyridyl]rncthanonc [(3aR,7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0- 3-(trifluor0rncthyl)- (3 aR,7aR)-7a-(2-pyridy1)- [1,3]di0X010[4,5-c]pyridin 4-(3,3,3- 4,5,6,7-tctrahydr0-3aH- -(triflu0r0rncthyl) trifluoropropoxy)bc [1 ,3 ] dioxolo [4,5 - (3 ,3 ,3 - nzoic acid c]pyridinc trifluoropropoxy)phcnyl]mcth anonc [(3aR,7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0- 4-(2-fluor0 (3 aR,7aR)-7a-(2-pyridyl)- [1,3]di0X010[4,5-c]pyridin -propoxy) 4,5,6,7-tctrahydr0-3aH- y1]-[4-(2-flu0r0rncthyl- (trifluoromcthyl)bc [1,3]di0X010[4,5- propoxy) nzoic acid c]pyridinc (trifluoromcthyl)phcnyl]metha none [(3aR,7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0- 3-ch10r0(2- (3 aR,7aR)-7a-(2-pyridyl)- [1,3]di0X010[4,5-c]pyridin fluoro-Z-mcthyl- 4,5,6,7-tctrahydr0-3aH- yl]-[3-ch10r0(2-fluor0 propoxy)bcnzoic [1,3 ] dioxolo [4,5 - methyl- acid c]pyridinc propoxy)phcnyl]rncthanonc [(3aR,7aR)-7a-(2-pyridy1)- (3 aR,7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0ch10r0 4,5,6,7-tctrahydr0-3aH- [1,3]di0X010[4,5-c]pyridin y-bcnzoic [1,3]dioxolo[4,5- y1]-(3 0hydr0xy- acid c]pyr1d1nc. . phcnyl)rncthanonc [(3aR,7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0- (3 aR,7aR)-7a-(2-pyridy1)- 3-ch10r0(2,2- [1,3]di0X010[4,5-c]pyridin 4,5,6,7-tctrahydr0-3aH- difluoropropoxy)bc y1]-[3-ch10r0(2,2- [1,3]dioxolo[4,5- nzoic acid opropoxy)phcnyl]mcth c]pyr1d1nc_ _ 8.110116 [(3aR,7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0- (3 aR,7aR)-7a-(2-pyridyl)- 3-ch10r0(2,2,2- [1,3]di0X010[4,5-c]pyridin 4,5,6,7-tctrahydr0-3aH- trifluoromcthy1— yl]—[3-chlor0(2,2,2- [1,3]dioxolo[4,5- ethoxy)benzoic acid trifluororncthy1— c]pyridine cthoxy)phcny1]rncthanonc [(3aR,7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0- 3-ch10r0[(2,2- (3 aR,7aR)-7a-(2-pyridyl)- [1,3]di0X010[4,5-c]pyridin ocyclopropyl 4,5,6,7-tetrahydro-3aH- y1]-[3-ch10r0[(2,2- xy]bcnzoic [1,3 ] o [4,5 - difluorocyclopropyl)rnethoxy] acid c]pyridine phenyl]rncthanonc [(3aR,7aR)-7a-(2-pyridy1)- (3 aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tctrahydr0- 4-(2-tcrt- 4,5,6,7-tctrahydr0-3aH- [1,3]di0X010[4,5-c]pyridin butoxycthoxy)—3- [1,3]dioxolo[4,5- y1]-[4-(2-tcrt—butoxycthoxy)- chloro-bcnzoic acid dine r0-phcny1]rncthanonc [7a-(2-pyridy1)-2,3,3a,4,6,7- hexahydrofur0[3,2-c]pyridin- 3-mcthoxy[2- 7a-(2-pyridy1)- -y1]—[3-rncth0xy[2- (trifluorornethoxy)e 3 ,3 a,4,5 ,6,7-hcxahydro- (trifluoromcthoxy)cthoxy]phc bcnzoic acid 2H-fi1r0[3,2-c]pyridinc nyl]rncthanonc [(3 aR,7aR)-7a-(6-rncthy1—2- (3 aR,7aR)-7a-(6-rncthy1— pyridy1)-3a,4,6,7-tctrahydr0- 3-mcthoxy[2- 2-pyridy1)-4,5 ,6,7- [1,3]di0X010[4,5-c]pyridin (trifluororncthoxy)c tetrahydro-3aH- y1]-[3 -rncth0xy[2- thoxy]bcnzoic acid [1,3]di0X010[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridine nyl]rncthanonc WO 06280 [(3 aR,7aR)-7a-(6-rncthy1—2- (3 aR,7aR)-7a-(6-rncthy1— pyridy1)-3a,4,6,7-tctrahydr0- 3-mcthy1—4-[2— dy1)-4,5,6,7- [1,3]di0X010[4,5-c]pyridin (trifluororncthoxy)c tetrahydro-3aH- y1]-[3 y1—4-[2- thoxy]benzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridine nyl]rncthanonc [(3 aR,7aR)-7a-(6-rncthoxy (3 aR,7aR)—7a-(6- pyridy1)-3a,4,6,7-tctrahydr0- 3-mcthoxy[2- methoxypyridyl)- [1,3]di0X010[4,5-c]pyridin (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- y1]-[3 -rncth0xy[2- thoxy]benzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridine nyl]rncthanonc [(3 aR,7aR)-7a-(6-rncthoxy (3 aR,7aR)—7a-(6- pyridy1)-3a,4,6,7-tctrahydr0- 3-mcthy1—4-[2— methoxypyridyl)- [1,3]di0X010[4,5-c]pyridin (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- y1]-[3 -rnethy1—4-[2- thoxy]benzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridine nyl]rncthanonc [(3 aR,7aR)-7a-(6-isobutoxy- 2-pyridy1)-3a,4,6,7- (3 aR,7aR)—7a-(6- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - 3-mcthoxy[2- isobutoxy-Z-pyridyl)- c]pyridin-5 -y1]-[3-rncthoxy (trifluororncthoxy)c 7-tctrahydr0-3aH- [2- thoxy]benzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc dine nyl]rncthanonc [(3 aR,7aR)-7a-(6-isobutoxy- 2-pyridy1)-3a,4,6,7- (3 aR,7aR)—7a-(6- ydro-[ 1 ,3 ] dioxolo [4,5 - 3-mcthy1—4-[2— isobutoxy-Z-pyridyl)- c]pyridiny1]-[3-rncthy1—4- (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- [2- benzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridine nyl]rncthanonc [(3aS,7aS)—7a-(2- [(3aR,7aR)-7a-(2-pyridy1)- pyridyl)- 1,3,3a,4,6,7- 1,3,3a,4,6,7- hexahydrofur0[3,4-c]pyridin- drofilro[3,4- -y1]—[3-rncth0xy[2- c]pyridin-S-y]1 - 3-[ (trifluoromcthoxy)cthoxy]phc (3aR,7aR)-7a-(2-pyridy1)- methoxy[2- nyl]rncthanonc;[(3aS,7aS)-7a- 3,3a,4,5,6,7-hcxahydr0- (trifluororncthoxy)c (2-pyridy1)-1,3,3a,4,6,7- o[3 ,4-c]pyridinc thoxy]phcnyl]rncth drofur0[3,4-c]pyridin- anonc;3-rncth0xy- -y1]—[3-rncth0xy[2- 4-[2- (trifluoromcthoxy)cthoxy]phc (trifluororncthoxy)c nyl]rncthanonc thoxy]benzoic acid [(3 aR,7aR)—7a-phcny1— 3 a,4,6,7-tctrahydr0- 3-mcthoxy (3 aR,7aR)-7a-phcny1— [1,3]di0X010[4,5-c]pyridin (2,2,2-trifluor0 4,5,6,7-tctrahydr0-3aH- yl]— [3 -rncthoxy(2,2,2- l- [1,3]dioxolo[4,5- trifluororncthy1— cthoxy)bcnzoic acid c]pyridinc cthoxy)phcny1]rncthanonc [(3 aR,7aR)—7a-phcny1— 3 a,4,6,7-tctrahydr0- (3 aR,7aR)-7a-phcny1— difluorocyclobutyl) [1,3]di0X010[4,5-c]pyridin 4,5,6,7-tctrahydr0-3aH- mcthoxy]—3- yl]-[4-[(3,3- [1,3]d10xolo[4,5-. methoxy-bcnzoic difluorocyclobutyl)rnethoxy]- c]pyridine acid 3-rncthoxy-phcnyl]mcthanonc [(3aR,7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0- 3-mcthoxy (3 aR,7aR)-7a-(2-pyridyl)- [1,3]di0X010[4,5-c]pyridin (2,2,2-trifluor0 4,5,6,7-tctrahydr0-3aH- y1]-[3 oxy(2,2,2- rnethyl- [1,3]dioxolo[4,5- trifluoro- 1 y1— cthoxy)bcnzoic acid c]pyridinc cthoxy)phcny1]rncthanonc [(3 aR,7aR)-7a-(2-pyridyl)- 4-[(3,3- 3a,4,6,7-tetrahydro- (3 )-7a-(2-pyr1dy1)-. difluorocyclobutyl) [1,3]dioxolo[4,5-c]pyridin 4,5,6,7-tetrahydro-3aH- y]—3- y1]-[4-[(3,3- [1,3]d10xolo[4,5-. methoxy-benzoic difluorocyclobutyl)rnethoxy]- _ c]pyridine a01d 3-rnethoxy-phenyl]methanone [(3 aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro- 3-fluor0 (3 aR,7aR)-7a-(2-pyridyl)- [1,3]dioxolo[4,5-c]pyridin methoxy(3,3,3- 4,5,6,7-tetrahydro-3aH- -fluor0rnethoxy trifluoropropoxy)be [1 ,3 ] dioxolo [4,5 - (3 ,3 ,3 - nzoic acid c]pyridine trifluoropropoxy)phenyl]meth anone [(3 aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro- 4-[(2,2- [1,3]dioxolo[4,5-c]pyridin (3 aR,7aR)-7a-(2-pyridy1)- difluorocyclopropyl y11-[4-[(2,2- 4,5,6,7-tetrahydro-3aH- )methoxy]—3- difluorocyclopropyl)rnethoxy] [1,3]dioxolo[4,5- (trifluoromethyl)be -3 _ c]pyridine _ _ nzo1c a01d (trifluoromethyl)phenyl]metha none [(3 )-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro- 4-(2,2,3,3- (3 aR,7aR)-7a-(2-pyr1dy1)-_ [1,3]dioxolo[4,5-c]pyridin tetrafluoropropoxy) 4,5,6,7-tetrahydro-3aH- y1]-[4-(2,2,3,3- [1,3]dioxolo[4,5- uoropropoxy)—3- (trifluoromethyl)be c]pyridine (trifluoromethyl)phenyl]metha _ _ nzo1c a01d 110116 [(3 aR,7aR)-7a-(2-pyridyl)- 3 a,4 6,7-tctrahydr0- ro , (3 aR,7aR)-7a-(2-pyridy1)- [1,3]di0X010[4,5-c]pyridin y[2- 4,5,6,7-tctrahydr0-3aH- yl] -[3 -chlor0-5 -mcthoxy [2- (trifluororncthoxy)c [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc thoxy]benzoic acid c]pyridine nyl]rncthanonc [(4aR, 8aR)—8a-phcnyl- 2,3 ,4a,5 ,7,8-hcxahydr0- (4aR,8aR)-8a-phcny1— 3-mcthoxy[2- [1,4] dioxino [2,3 -c]pyridin 3,4a,5,6,7,8-hcxahydr0- (trifluororncthoxy)c yl] - [3 -rncth0xy [2- 2H-[1,4]di0xin0[2,3- thoxy]benzoic acid (trifluoromcthoxy)cthoxy]phc dine nyl]rncthanonc [(3 )—7a-phcny1— 3 a,4 6,7-tctrahydr0- , 3-methoxy (3 aR,7aR)-7a-phcny1— [1,3]di0X010[4,5-c]pyridin (3 ,3 ,3 - 4,5,6,7-tctrahydr0-3aH- y1]- [3 0xy(3 ,3 ,3 - trifluoropropoxy)bc [1,3]dioxolo[4,5- trifluoropropoxy)phcnyl]mcth nzoic acid c]pyridine anonc [(3 aR,7aR)-7a-(2-pyridyl)- 3 a,4 6,7-tctrahydr0- , 3-methoxy (3 aR,7aR)-7a-(2-pyridy1)- [1,3]di0X010[4,5-c]pyridin (3 ,3 ,3 - 7-tctrahydr0-3aH- y1]- [3 -rncth0xy(3 ,3 ,3 - trifluoropropoxy)bc [1,3]dioxolo[4,5- trifluoropropoxy)phcnyl]mcth nzoic acid c]pyridine anonc [(3 aR,7aR)-7a-(2-pyridyl)- 3-methoxy 3 a,4 6,7-tctrahydr0- , (3 aR,7aR)-7a-(2-pyridy1)- (3,3,3-triflu0r0 [1,3]di0X010[4,5-c]pyridin 4,5,6,7-tctrahydr0-3aH- methyl- y1]- [3 -rncth0xy(3 ,3 ,3 - [1,3]dioxolo[4,5- propoxy)bcnzoic trifluororncthy1— c]pyridine acid propoxy)phcnyl]rncthanonc [(3aR,7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0- 4-(2,2- (3 aR,7aR)-7a-(2-pyridyl)- [1,3]di0X010[4,5-c]pyridin difluoropropoxy) 4,5,6,7-tctrahydro-3aH- yl]-[4-(2,2-difluoropropoxy)— (trifluoromcthyl)bc [1,3]di0X010[4,5- nzoic acid c]pyridinc (trifluoromcthy1)phcnyl]metha none [(3aR,7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0- 4-[(3,3- i0X010[4,5-c]pyridin (3 aR,7aR)-7a-(2-pyr1dy1)-. difluorocyclobutyl) y1]-[4-[(3,3- 4,5,6,7-tctrahydr0-3aH- methoxy]—3- difluorocyclobutyl)mcthoxy]- [1,3]d10xolo[4,5-. (trifluoromcthyl)bc 3 _ dinc _ _ nz01c ac1d (trifluoromcthy1)phcnyl]metha none [(3aR,7aR)-7a-(2-pyridy1)- 3a,4,6,7-tctrahydr0- fluor0nicthyl)- (3 aR,7aR)-7a-(2-pyridy1)- [1,3]di0X010[4,5-c]pyridin 4-(2,2,2-triflu0ro 4,5 ctrahydr0-3aH- yl]-[3-(triflu0r0nicthyl) methyl- [1,3]dioxolo[4,5- (2,2,2-trifluor0nicthy1- cthoxy)bcnz0ic acid c]pyridinc )phcny1]mcthanonc [(3 aR,7aR)—2,2-didcutcrio-7a- (3,5-difluorophcnyl)-3 a,4,6,7- (3 aR,7aR)-2,2-didcutcrio- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - 3-mcthoxy[2- 7a-(3,5-diflu0r0phcnyl)- c]pyridin-5 -y1]-[3-nicthoxy (trifluoromcthoxy)c 4,5,6,7-tctrahydr0-3aH- [2- thoxy]bcnzoic acid [1,3]di0X010[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridinc ny1]nicthanonc [(3 aR,7aR)—2,2-didcutcrio-7a- (3 aR,7aR)-2,2-dideutcrio- ifluorophcnyl)-3 a,4,6,7- 3-methoxy 7a-(3,5-diflu0r0phcnyl)- tetrahydr0-[ 1 ,3 ] dioxolo [4,5 - -trifluor0 4,5,6,7-tctrahydr0-3aH- c]pyridin-5 -y1]-[3-rncthoxy methyl- [1,3]dioxolo[4,5- (2,2,2-trifluoromethyl- ethoxy)benzoic acid c]pyr1d1nc_ _ cthoxy)phcny1]rncthanonc [(3 aR,7aR)—2,2-didcutcrio-7a- 4-[(3,3- (3 aR,7aR)-2,2-didcutcri0- ifluorophcnyl)-3 a,4,6,7- difluorocyclobutyl) 5-difluorophenyl)- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - methoxy]—3- 4,5,6,7-tctrahydr0-3aH- c]pyridiny1]—[4-[(3 ,3- methoxy-bcnzoic [1,3]di0X010[4,5- difluorocyclobutyl)rnethoxy]-. ac1d_ d1ne_ _ 3-rncthoxy-phcnyl]mcthanonc [(3 aR,7aR)—2,2-didcutcrio-7a- (3 aR,7aR)-2,2-dideutcrio- (3,5-difluorophcnyl)-3 a,4,6,7- 6-methoxy[2- 7a-(3,5-diflu0r0phcnyl)- tetrahydr0-[ 1 ,3]diox010[4,5- (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- c]pyridiny1]-[6-rncth0xy thoxy]pyridinc [1,3]dioxolo[4,5- [2-(trifluororncthoxy)cthoxy]- carboxylic acid c]pyr1d1nc. . dy1]rncthanonc [(3aR,7aR)—2,2-didcutcrio-7a- (3 aR,7aR)-2,2-dideutcrio- (3 ,5-difluorophcnyl)-3 7- 6-methyl[2- 7a-(3,5-diflu0r0phcnyl)- tetrahydr0-[ 1 ,3 ] dioxolo [4,5 - (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- c]pyridiny1]-[6-rncthy1—5- thoxy]pyridinc [1,3]dioxolo[4,5- [2-(trifluororncthoxy)cthoxy]- carboxylic acid c]pyr1d1nc. . 2-pyridy1]rncthanonc [(3aR,7aR)—2,2-didcutcrio-7a- (3 -fluorophcny1)—3a,4,6,7- aR)-2,2-dideuteriotetrahydr0- [ 1 ,3]diox010[4,5- 3-mcthoxy[2- 7a-(3-fluor0phcnyl)- c]pyridin-5 -y1]-[3-rncthoxy (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- [2- thoxy]bcnzoic acid [1,3]di0X010[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridinc nyl]rncthanonc [(3 aR,7aR)—2,2-didcutcrio-7a- (3 aR,7aR)-2,2-dideutcrio- (3 -fluorophcnyl)—3 a,4,6,7- 3-methoxy 7a-(3-fluor0phcnyl)- ydro-[ 1 ,3 ] dioxolo [4,5 - (2,2,2-triflu0r0 4,5,6,7-tctrahydr0-3aH- c]pyridin-5 -y1] -[3 -rncth0xy methyl- [1,3]dioxolo[4,5- (2,2,2-triflu0r0rncthy1— ethoxy)benzoic acid c]pyr1d1nc_ _ cthoxy)phcny1]rncthanonc [(3 aR,7aR)—2,2-didcutcrio-7a- 4-[(3,3- (3 )-2,2-didcutcri0- (3 -fluorophcnyl)—3 a,4,6,7- difluorocyclobutyl) 7a-(3-fluoropheny1)- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - methoxy]—3- 4,5,6,7-tctrahydr0-3aH- din-5 -y1] - [4- [(3 ,3 - rncthoxy-bcnzoic [1,3]di0X010[4,5- difluorocyclobuty1)rnethoxy]- acid c]pyridine 3-rncthoxy-phcnyl]mcthanonc [(3 aR,7aR)—2,2-didcutcrio-7a- (3 aR,7aR)-2,2-dideutcrio- (3 -fluorophcnyl)—3 a,4,6,7- 6-mcthoxy[2- 7a-(3-fluor0phcnyl)- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- c]pyridin-5 -y1] thoxy-5 - pyridinc [1,3]dioxolo[4,5- [2-(triflu0rorncthoxy)cthoxy] - carboxylic acid d1nc. . 2-pyridy1]rncthanonc [(3 )—2,2-didcutcrio-7a- (3 aR,7aR)-2,2-dideutcrio- (3 -fluorophcnyl)—3 a,4,6,7- 6-mcthy1—5-[2— 7a-(3-fluor0phcnyl)- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- c]pyridin-5 -y1]-[6-rncthy1—5 - thoxy]pyridinc [1,3]dioxolo[4,5- [2-(triflu0rorncthoxy)cthoxy] - carboxylic acid c]pyr1d1nc. . 2-pyridy1]rncthanonc [(3 aR,7aR)—2,2-didcutcrio-7a- (2-pyridy1)—3 a,4,6,7- (3 )-2,2-dideutcriotetrahydro- [ 1 ,3 ] dioxolo [4,5 - 3-mcthoxy[2- 7a-(2-pyridy1)—4,5,6,7- c]pyridin-5 -y1] -[3 -rncth0xy ororncthoxy)c tetrahydro-3aH- [2- thoxy]bcnzoic acid [1,3]di0X010[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridine nyl]rncthanonc [(3 aR,7aR)—2,2-didcutcrio-7a- (2-pyridy1)—3a,4,6,7- (3 aR,7aR)-2,2-dideutcrio- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - 3-ch10r0[2- 7a-(2-pyridy1)—4,5,6,7- c]pyridiny1]-[3-chloro (trifluororncthoxy)c tetrahydro-3aH- [2- thoxy]benzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridine nyl]rncthanonc [(3 aR,7aR)—2,2-didcutcrio-7a- (3 aR,7aR)-2,2-dideutcrio- idy1)—3a,4,6,7- 6-mcthy1—5-[2— 7a-(2-pyridy1)—4,5,6,7- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - (trifluororncthoxy)c tetrahydro-3aH- c]pyridiny1]-[6-rncthy1—5- thoxy]pyridinc [1,3]dioxolo[4,5- [2-(triflu0rorncthoxy)cthoxy] - carboxylic acid c]pyridine 2-pyridy1]rncthanonc [(3 aR,7aR)—2,2-didcutcrio-7a- (3 aR,7aR)-2,2-dideutcrio- pheny1-3a,4,6,7-tctrahydr0- 3-mcthoxy[2- ny1—4,5,6,7- [1,3]di0X010[4,5-c]pyridin (trifluororncthoxy)c tetrahydro-3aH- y1]-[3 -rncth0xy[2- benzoic acid [1,3]dioxolo[4,5- oromcthoxy)cthoxy]phc c]pyridine nyl]rncthanonc [3-chlor0[2- (trifluoromcthoxy)cthoxy]phc 3-ch10r0[2- uorophenyl)—3- nyl]-[6-(4-fluorophcnyl) (trifluororncthoxy)c azabicyclo [4. 1 tanc azabicyclo [4. 1 .0]hcptan thoxy]benzoic acid yl]rnethanonc [6-(4-fluorophenyl) azabicyclo [4. 1 .0]hcptany1]— 3-mcthoxy[2- uorophenyl)—3- [3-mcth0xy[2- (trifluororncthoxy)c azabicyclo [4. 1 .0]hcptanc (trifluoromcthoxy)cthoxy]phc thoxy]benzoic acid nyl]rncthanonc [6-(4-flu0rophcny1) 6-mcthoxy[2- azabicyclo [4. 1 .0]hcptany1]— (trifluororncthoxy)c 6-(4-fluorophcnyl)—3- [6-mcth0xy[2- pyridinc azabicyclo [4. 1 .0]hcptanc (trifluoromcthoxy)cthoxy] carboxylic acid pyridyl]rncthanonc 4-[(3,3- difluorocyclobutyl)rncthoxy]- difluorocyclobutyl) 3-mcth0xy-phcny1]—[6-(4- 6-(4-fluorophcnyl)—3- methoxy]—3- fluorophcny1) azabicyclo [4. 1 .0]hcptanc. methoxy-bcnzmc. azabicyclo [4. 1 tan acid yl]rncthanonc [6-(4-flu0rophcny1) 3-mcthoxy azabicyclo [4. 1 .0]hcptany1]— (2,2,2-trifluoro 6-(4-fluorophcnyl)—3- [3-rncthoxy(2,2,2-triflu0r0- methyl- azabicyclo [4. 1 .0]hcptanc 1 -rncthy1— cthoxy)bcnzoic acid )phcny1]rncthanonc [5-chloro[2- -chloro[2- (trifluoromcthoxy)cthoxy] -3 - (trifluororncthoxy)c 6-(4-fluorophcnyl)—3- pyridyl]-[6-(4-flu0r0phcnyl)- thoxy]pyridinc azabicyclo [4. 1 .0]hcptanc 3-azabicyc10[4.1.0]hcptan carboxylic acid thanonc [(3 aR,7aR)—7a-phcny1— 3a,4,6,7-tctrahydr0- 5-ch10r0[2- (3 aR,7aR)-7a-phcny1— [1,3]di0X010[4,5-c]pyridin (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- y1]-[5-chloro[2- thoxy]pyridinc [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy] -3 - carboxylic acid c]pyridinc pyridyl]rncthanonc [(3 aR,7aR)-7a-(2-pyridyl)- -chloro[2- (3 aR,7aR)-7a-(2-pyridyl)- ,7-tctrahydr0- (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- i0X010[4,5-c]pyridin thoxy]pyridinc [1,3]dioxolo[4,5- y1]-[5-chloro[2- carboxylic acid c]pyridinc (trifluoromcthoxy)cthoxy] -3 - pyridyl]rnethanone [(3 aR,7aR)—2,2-dideuterio-7a- (3 aR,7aR)-2,2-dideuterio- pheny1-3a,4,6,7-tetrahydr0- 6-methoxy[2- 7a-pheny1—4,5 ,6,7- ioxolo[4,5-c]pyridin (trifluoromethoxy)e tetrahydro-3aH- yl]—[6-rnethoxy[2- thoxy]pyridine [1,3]dioxolo[4,5- (trifluoromethoxy)ethoxy] carboxylic acid c pyrl me] 'd' pyridyl]rnethanone 3-[(3 aR,7aR)[3-rnethoxy- 3-[(3aR,7aR)—4,5,6,7- 4 [2 . 3-rnethoxy[2- tetrahydr0-3aH- (trlfluoromethoxy)ethoxy]ben (tnfluorornethoxy)e. [1 ,3 ] dloxolo [4,5 -. zoyl]-3a,4,6,7-tetrahydr0- thoxy]benz01c a01d. . c]pyr1d1n-7a-. . loxolo[4,5-c]pyr1d1n-7a-. . . yl]benz0n1trlle_ _ yl]benz0nitrile 3-[(3 aR,7aR)[6-rnethoxy- 3-[(3aR,7aR)—4,5,6,7- -[2— 6-methoxy[2- tetrahydro-3aH- (trifluorornethoxy)ethoxy]pyri (trifluoromethoxy)e [1,3]dioxolo[4,5- dine-Z-carbonyl]-3a,4,6,7- thoxy]pyridine _ _ _ d1n-7a-. tetrahydro-[l,3]d10x010[4,5- yllc ac1d z0n1trlle. . c]pyridin-7a-yl]benzonitrile 3-[(3aR,7aR)—5-[4-[(3,3- 4-[(3,3- 3-[(3aR,7aR)—4,5,6,7- difluorocyclobutyl)rnethoxy]- difluorocyclobutyl) tetrahydro-3aHrnethoxy-benzoy1]—3 7- methoxy]—3 - [1,3 ] dioxolo [4,5 - tetrahydr0-[ 1 ,3 ] dioxolo [4,5 - methoxy-benzoic c]pyridin-7a- c]pyridin-7a-yl]benzonitrile acid yl]benz0nitrile 3-[(3 )[3-rnethoxy- R,7aR)—4,5,6,7- 3-rnethoxy 4-(2 ,2,2-triflu0r0rncthy1— tetrahydro-3aH- (2,2,2-triflu0r0 cthoxy)bcnzoy1]—3 a,4,6,7- [1,3]dioxolo[4,5- methyl- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - c]pyridin-7aethoxy )benzoic acid c]pyridin-7a-yl]benzonitrilc yl]bcnz0nitrilc [(3aR,7aR)-7a-(2,5- difluorophcnyl)-3a,4,6,7- (3aR,7aR)—7a-(2,5- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - 3-rncthoxy[2- difluorophcnyl)-4,5,6,7- c]pyridin-5 -y1]-[3-rncthoxy ororncthoxy)c ydro-3aH- [2- thoxy]benzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridine nyl]rncthanonc [(3aR,7aR)-7a-(2,5- (3aR,7aR)—7a-(2,5- difluorophcnyl)-3a,4,6,7- 6-mcthoxy[2- difluorophcnyl)-4,5,6,7- tetrahydro-[ 1 ,3 ] o [4,5 - (trifluororncthoxy)c tetrahydro-3aH- c]pyridin-5 -y1]-[6-rncthoxy thoxy]pyridinc [1,3]dioxolo[4,5- [2-(triflu0rorncthoxy)cthoxy] - carboxylic acid c]pyridine 2-pyridy1]rncthanonc [(3aR,7aR)-7a-(2,5- 4-[(3 ,3 - (3aR,7aR)—7a-(2,5- difluorophcnyl)-3a,4,6,7- difluorocyclobutyl) difluorophcnyl)-4,5,6,7- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - methoxy]-3 - tetrahydro-3aH- c]pyridiny1]—[4-[(3,3- y-bcnzoic [1,3]dioxolo[4,5- difluorocyclobutyl)rnethoxy]- acid c]pyridine 3-rncthoxy-phcnyl]mcthanonc [(3aR,7aR)-7a-(2,5- ophcnyl)-3a,4,6,7- (3aR,7aR)—7a-(2,5- 3-rnethoxy tetrahydro-[ 1 ,3 ] dioxolo [4,5 - difluorophcnyl)-4,5,6,7- (3 ,3 ,3 - c]pyridin-5 -y1]-[3-rncthoxy tetrahydro-3aH- ropropoxy)bc (3 ,3 ,3 - [1,3]dioxolo[4,5- nzoic acid trifluoropropoxy)phcnyl]mcth c]pyridine 8.110116 [(3 aR,7aR)-7a-(2,5 - (3aR,7aR)—7a-(2,5- difluorophcnyl)-3 a,4,6,7- 3-methoxy difluorophcnyl)-4,5,6,7- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - (2,2,2-triflu0r0 tetrahydro-3aH- c]pyridin-5 -y1] -[3 -rncth0xy - [1,3]dioxolo[4,5- (2,2,2-triflu0r0rncthy1— ethoxy)benzoic acid c]pyridine cthoxy)phcny1]rncthanonc [3 -rncth0xy [2- (trifluoromcthoxy)cthoxy]phc oxy[2- 6-(2-pyridy1) nyl]-[6-(2-pyridy1)-3 - (trifluororncthoxy)c azabicyclo [4. 1 tanc yclo [4. 1 .0]hcptan thoxy]benzoic acid thanonc [(3 aR,7aR)—2,2-didcutcrio-7a- - (3 aR,7aR)-2,2-dideutcrio- (3 -fluorophcnyl)—3 a,4,6,7- (cyclobutylrnethoxy 7a-(3-fluor0phcnyl)- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - )rnethoxy- 4,5,6,7-tctrahydr0-3aH- c]pyridin-5 -y1]- [5 - ne [1,3]dioxolo[4,5- (cyclobutylrnethoxy) carboxylic acid c]pyridine methoxy-Z-pyridy1]rncthanonc [(3 aR,7aR)—7a-(3- 4-[(3 ,3 - (3 aR,7aR)—7a-(3- chlorophcnyl)-3a,4,6,7- difluorocyclobutyl) chlorophcnyl)-4,5,6,7- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - methoxy]-3 - tetrahydro-3aH- c]pyridiny1]—[4-[(3,3- methoxy-bcnzoic [1,3]dioxolo[4,5- difluorocyclobutyl)rnethoxy]- acid c]pyridine 3-rncthoxy-phcnyl]mcthanonc [(3 aR,7aR)—7a-(3- chlorophcnyl)-3a,4,6,7- (3 )—7a-(3- ydro-[ 1 ,3 ] dioxolo [4,5 - 3-mcthoxy[2- chlorophcnyl)-4,5,6,7- c]pyridin-5 -y1]-[3-rncthoxy (trifluororncthoxy)c tetrahydro-3aH- [2- thoxy]benzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridine nyl]rncthanonc [(3 aR,7aR)—7a-(3- chlorophcnyl)-3a,4,6,7- (3 aR,7aR)—7a-(3- 3-methoxy tetrahydro-[ 1 ,3 ] dioxolo [4,5 - chlorophcnyl)-4,5,6,7- (3 ,3 ,3 - c]pyridin-5 -y1]-[3-rncthoxy tetrahydro-3aH- trifluoropropoxy)bc (3 ,3 ,3 - ioxolo[4,5- nzoic acid trifluoropropoxy)phcnyl]mcth c]pyridine anonc [(3 aR,7aR)—7a-(3- (3 aR,7aR)—7a-(3- chlorophcnyl)-3a,4,6,7- oxy chlorophcnyl)-4,5,6,7- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - -triflu0r0 tetrahydro-3aH- c]pyridin-5 -y1]-[3-rncthoxy methyl- [1,3]dioxolo[4,5- (2,2,2-trifluor0rncthy1— ethoxy)benzoic acid c]pyridine cthoxy)phcny1]rncthanonc [(3aR,7aR)-7a-(2,3- 4-[(3 ,3 - (3aR,7aR)—7a-(2,3- difluorophcnyl)-3a,4,6,7- difluorocyclobutyl) difluorophcnyl)-4,5,6,7- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - methoxy]-3 - tetrahydro-3aH- c]pyridiny1]—[4-[(3,3- methoxy-bcnzoic [1,3]dioxolo[4,5- difluorocyclobutyl)rnethoxy]- acid dine 3-rncthoxy-phcnyl]mcthanonc [(3aR,7aR)-7a-(2,3- difluorophcnyl)-3a,4,6,7- (3aR,7aR)—7a-(2,3- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - 3-mcthoxy[2- difluorophcnyl)-4,5,6,7- c]pyridin-5 -y1]-[3-rncthoxy (trifluororncthoxy)c tetrahydro-3aH- [2- thoxy]benzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridine nyl]rncthanonc [(3aR,7aR)-7a-(2,3- (3aR,7aR)—7a-(2,3- difluorophcnyl)-3a,4,6,7- 3-methoxy difluorophcnyl)-4,5,6,7- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - (3 ,3 ,3 - tetrahydro-3aH- din-5 -y1]-[3-rncthoxy trifluoropropoxy)bc ioxolo[4,5- (3 ,3 ,3 - nzoic acid dine trifluoropropoxy)phcnyl]mcth WO 06280 [(3aR,7aR)-7a-(2,3- (3aR,7aR)—7a-(2,3- difluorophenyl)-3a,4,6,7- 3-methoxy difluorophcnyl)-4,5,6,7- tetrahydr0-[ 1 ,3 ] dioxolo [4,5 - (2,2,2-trifluor0 ydro-3aH- c]pyridiny1]-[3-rncth0xy methyl- [1,3]dioxolo[4,5- (2,2,2-trifluoromethyl- ethoxy)benzoic acid c]pyr1d1nc_ _ cthoxy)phcny1]rncthanonc [(3 aR,7aR)—7a-(3- (3 aR,7aR)—7a-(3- chlorophcnyl)-3a,4,6,7- oxy[2- chlorophcnyl)-4,5,6,7- tetrahydr0-[ 1 x010[4,5- (trifluororncthoxy)c tetrahydro-3aH- c]pyridiny1]-[6-rncth0xy pyridinc [1,3]dioxolo[4,5- [2-(trifluororncthoxy)cthoxy]- carboxylic acid c]pyr1d1nc. . 2-pyridy1]rncthanonc 7aR)-7a-(2,3- (3aR,7aR)—7a-(2,3- difluorophenyl)-3a,4,6,7- 6-methoxy[2- difluorophcnyl)-4,5,6,7- tetrahydr0-[ 1 ,3]diox010[4,5- (trifluororncthoxy)c tetrahydro-3aH- c]pyridin-5 -y1]-[6-rncthoxy thoxy]pyridinc [1,3]dioxolo[4,5- [2-(trifluororncthoxy)cthoxy]- carboxylic acid c]pyr1d1nc. . 2-pyridy1]rncthanonc [(3aR,7aR)-7a-(2,3- difluorophcnyl)-3a,4,6,7- 5-[(3,3- (3aR,7aR)—7a-(2,3- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - difluorocyclobutyl) difluorophcny1)-4,5 ,6,7- c]pyridiny1]—[5-[(3,3- methoxy]—6- tetrahydr0-3aH- difluorocyclobutyl)mcthoxy]- methoxy-pyridinc- [ 1 ,3 ] dioxolo [4,5 - 6-mcthoxy 2-carb0xy1ic acid c]pyridinc pyridyl]rncthanonc [(3 aR,7aR)—7a-(3- chlorophcny1)-3 a,4,6,7- 5-[(3,3- (3 aR,7aR)—7a-(3- tetrahydro-[ 1 ,3]dioxolo[4,5- difluorocyclobutyl) chlorophcny1)-4,5,6,7- c]pyridiny1]—[5-[(3 ,3- methoxy]—6- tctrahydro-3aH- difluorocyclobutyl)mcthoxy]- methoxy-pyridinc- [1,3]di0x010[4,5- oxy 2-carb0xy1ic acid c]pyridinc pyridyl]rncthanonc [(3 aR,7aR)—2,2-didcutcrio-7a- (3,5-difluorophcnyl)-3 a,4,6,7- 5-[(3,3- (3 aR,7aR)-2,2-didcutcrio- ydro-[ 1 ,3]dioxolo[4,5- difluorocyclobutyl) 7a-(3 ,5-difluorophcny1)- c]pyridiny1]—[5-[(3,3- y]—6- 4,5,6,7-tctrahydro-3aH- difluorocyclobutyl)mcthoxy]- methoxy-pyridinc- [1,3]di0x010[4,5- 6-mcthoxy 2-carb0xy1ic acid c]pyridinc pyridyl]rncthanonc [(3 aR,7aR)—2,2-didcutcrio-7a- (3 phcny1)—3a,4,6,7- 5-[(3,3- (3 aR,7aR)-2,2-didcutcriotetrahydro- [ 1 ,3]dioxolo[4,5- difluorocyclobutyl) 7a-(3-fluorophcny1)- c]pyridiny1]—[5-[(3,3- methoxy]—6- 4,5,6,7-tctrahydro-3aH- ocyclobutyl)mcthoxy]- methoxy-pyridinc- [1 ,3]diox010[4,5- 6-mcthoxy 2-carb0xy1ic acid c]pyridinc pyridyl]rncthanonc [(3aR,7aR)-7a-(2-pyridy1)- 1’3’3a’4’6’7' 3 -rnct oxy-h 4- [2- (3 R7 R) 7a a - a- , (2-pyr1 y'd 1) - hcxahydrofur0[3,4-c]pyridin- (trifluororncthoxy)c 3 ,3 a,4,5 ,6,7-hcxahydro- -y1]—[3-rncth0xy[2- bcnzoic acid 1H-fi1r0[3,4-c]pyridinc (trifluoromcthoxy)cthoxy]phc. nyl]rncthanonc (3aS,7aS)[3-rncthoxy[2- (3 )-7a-(2-pyr1dyl)-. (trifluoromcthoxy)cthoxy]bcn 3-mcthoxy[2- 3,3a,4,5,6,7- zoyl]-7a-(2-pyridy1)-3a,4,6,7- ororncthoxy)c hexahydrofur0[3,4- tctrahydro-3H-fiaro[3,4- thoxy]bcnzoic acid c]pyr1d1n0nc. . c]pyridin0nc [(3 aR,7aR)—7a-(3- 4-[(3 ,3 - (3 aR,7aR)—7a-(3 - fluorophcny1)-3a,4,6,7- difluorocyclobutyl) fluorophcnyl)—4,5,6,7- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - methoxy]-3 - tctrahydro-3aH- c]pyridiny1]—[4-[(3,3- methoxy-bcnzoic [1,3]dioxolo[4,5- difluorocyclobutyl)rncthoxy]- acid c]pyridinc 3-rncthoxy-phcnyl]mcthanonc [(3 aR,7aR)—7a-(3- (3 aR,7aR)—7a-(3- fluorophcny1)-3a,4,6,7- 6-mcthoxy[2- fluorophcnyl)—4,5,6,7- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - (trifluororncthoxy)c ydro-3aH- din-5 6-rncthoxy thoxy]pyridinc [1,3]dioxolo[4,5- [2-(triflu0rorncthoxy)cthoxy] - carboxylic acid c]pyridinc 2-pyridy1]rncthanonc [(3aS,7aS)-7a-(2-pyridy1)— 1,3,3a,4,6,7- 3-mcthoxy[2- (3 aS,7aS)-7a-(2—pyridyl)- hcxahydrofur0[3,4-c]pyridin- (trifluororncthoxy)c 3,3a,4,5,6,7-hcxahydr0- -y1]—[3-rncth0xy[2- thoxy]bcnzoic acid 1H-furo[3 ,4-c]pyridinc (trifluoromcthoxy)cthoxy]phc cthanonc [(3aR,7aR)-7a-[6- (3aR,7aR)-7a-[6- (trifluororncthyl)—2-pyridy1] - (trifluororncthyl) ,7-tctrahydr0- oxy[2- pyridy1]-4,5,6,7- [1,3]di0X010[4,5-c]pyridin (trifluororncthoxy)c tctrahydro-3aH- y1]-[3 0xy[2- thoxy]bcnzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridinc nyl]rncthanonc [(3aR,7aR)-7a-[6- (3aR,7aR)-7a-[6- (trifluororncthyl)—2-pyridy1] - 4-[(3 ,3 - (trifluororncthyl) 3a,4,6,7-tctrahydr0- difluorocyclobutyl) pyridy1]-4,5,6,7- [1,3]di0X010[4,5-c]pyridin methoxy]-3 - tctrahydro-3aH- y1]-[4-[(3,3- methoxy-bcnzoic [1,3]dioxolo[4,5- difluorocyclobutyl)rncthoxy]- acid c]pyridinc 3-rncthoxy-phcnyl]mcthanonc [(3aR,7aR)-7a-[6- (3 R7 R) 7a a - a- , [6- (trifluororncthyl)—2-pyridy1]- 3-mcthoxy (tr1fluororncthyl). ,7-tctrahydro- (3,3,3- pyr1dy1]—4,5,6,7-. [1,3]di0X010[4,5-c]pyridin trifluoropropoxy)bc. tctrahydro-3aH- yl]—[3 -rncthoxy(3,3,3- nzoic acid [1,3]dioxolo[4,5- trifluoropropoxy)phcnyl]mcth c]pyr1d1nc. . anonc 7aR)-7a-[6- (3 R7 R) 7a a - a- , [6- (trifluororncthyl)—2-pyridy1]- 3-mcthoxy (tr1fluororncthyl). 3a,4,6,7-tctrahydro- (2,2,2-trifluor0 pyridy1]-4,5,6,7- [1,3]di0X010[4,5-c]pyridin methyl- tctrahydro-3aH- yl]— [3 -rncthoxy(2,2,2- cthoxy)bcnz01c ac1d. . [1,3]d10xolo[4,5-. trifluororncthy1— c]pyr1d1nc. . cthoxy)phcny1]rncthanonc [(3 R7 R -7a a - 6- , ) a[ (3aR,7aR)-7a-[6- (trifluororncthy)1pylidy1]- oxy[2- (trifluororncthyl) 3a,4,6,7-tctrahydro- ororncthoxy)c pyr1dy1]—4,5,6,7-. [1,3]di0X010[4,5-c]pyridin thoxy]pyridinc tctrahydro-3aH- yl]—[6-rncthoxy[2- carboxylic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy] c]pyr1d1nc. . pyridyl]rncthanonc [(3aR,7aR)-7a-(2,3- difluorophcnyl)-3a,4,6,7- 6-mcth0xy[[1- (3aR,7aR)—7a-(2,3- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - (trifluororncthyl)cy difluorophcnyl)-4,5,6,7- din-5 -y1]-[6-rncthoxy clopropyl]rncthoxy] tctrahydro-3aH- [[ 1 - ne-Z- [1,3]dioxolo[4,5- (trifluororncthyl)cyclopropyl] carboxylic acid c]pyridinc methoxy] pyridyl]rncthanonc [(3 aR,7aR)—7a-(3- chlorophcnyl)-3a,4,6,7- 6-mcthoxy[[1- (3 aR,7aR)—7a-(3- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - (trifluoromcthyl)cy chlorophcnyl)-4,5,6,7- c]pyridin-5 -y1]-[6-rncthoxy clopropy1]rncthoxy] tctrahydro-3aH- [[ 1 - pyridine ioxolo[4,5- (trifluororncthyl)cyclopropyl] carboxylic acid c]pyridinc methoxy] pyridy1]rncthanonc [(3 aR,7aR)—2,2-didcutcrio-7a- (3,5-difluorophcnyl)-3 a,4,6,7- 6-mcthoxy[[1- (3 aR,7aR)-2,2-didcutcrio- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - (trifluoromcthyl)cy 7a-(3,5-diflu0r0phcnyl)- c]pyridin-5 -y1]-[6-rncthoxy clopropy1]rncthoxy] 4,5,6,7-tctrahydr0-3aH- [[ 1 - ne [1,3]dioxolo[4,5- (trifluororncthyl)cyclopropyl] carboxylic acid c]pyridinc methoxy] pyridy1]rncthanonc [(3 aR,7aR)—7a-(3- fluorophcny1)-3a,4,6,7- oxy[[1- (3 aR,7aR)—7a-(3- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - (trifluoromcthyl)cy hcny1)-4,5,6,7- c]pyridin-5 -y1]-[6-rncthoxy clopropy1]rncthoxy] tctrahydro-3aH- [[ 1 - pyridine [1,3]dioxolo[4,5- (trifluororncthyl)cyclopropyl] carboxylic acid dinc methoxy] pyridy1]rncthanonc [(3aR,7aR)-7a-[6- (trifluororncthyl)—2-pyridy1] - (3aR,7aR)-7a-[6 [(3 ,3 - 3a,4,6,7-tctrahydr0- ororncthyl) difluorocyclobutyl) [1,3]di0X010[4,5-c]pyridin pyridy1]-4,5,6,7- methoxy]—6- y1]-[5-[(3,3- tctrahydro-3aH- methoxy-pyridinc- difluorocyclobutyl)rncthoxy] [1,3]dioxolo[4,5- 2-carb0xy1ic acid oxy c]pyridinc pyridy1]rncthanonc [3 -rncth0xy [2- (trifluoromcthoxy)cthoxy]phc 3-mcthoxy[2- (1 S,6R)—6-(2-pyridy1)—3- nyl] - [(1 S ,6R)—6-(2-pyridy1)—3 - (trifluororncthoxy)c azabicyclo [4. 1 .0]hcptanc azabicyclo [4. 1 tan thoxy]benzoic acid yl]rnethanonc [3 -rncth0xy [2- (trifluoromcthoxy)cthoxy]phc 3-mcthoxy[2- (1R,6S)—6-(2-pyridyl) (1R,6S)—6-(2-pyridyl)—3 - (trifluororncthoxy)c azabicyclo [4. 1 .0]hcptanc azabicyclo [4. 1 tan thoxy]benzoic acid yl]rnethanonc [(3 aR,7aR)—7a-phcny1— 3 a,4 6,7-tctrahydr0- , 6-mcthoxy[[1- (3 aR,7aR)-7a-phcny1— [1,3]di0X010[4,5-c]pyridin (trifluoromcthyl)cy 4,5,6,7-tctrahydr0-3aH- yl] -[6-mcthoxy-5 -[[1- clopropy1]rnethoxy] ioxolo[4,5- (trifluoromcthyl)cyclopropyl] pyridine c]pyridine methoxy] carboxylic acid pyridyl]rncthanonc [(3 aR,7aR)—7a-(3 - 6-mcthoxy (3 aR,7aR)—7a-(3- fluorophcnyl)-3 a,4,6,7- (2,2,2-triflu0r0 fluorophcnyl)—4,5,6,7- ydro-[ 1 ,3 ] dioxolo [4,5 - methyl- ydro-3aH- c]pyridin-5 -y1] -[6-mcthoxy-5 - cthoxy)pyridinc [1,3]dioxolo[4,5- (2,2,2-triflu0r0rncthy1— ylic acid c]pyridine cthoxy)—2-pyridy1]rncthanonc [(3 aR,7aR)—7a-(3 - 6-mcthoxy (3 )—7a-(3- fluorophcnyl)-3 a,4,6,7- (2,2,3 ,3 - fluorophcnyl)—4,5,6,7- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - tetrafluoropropoxy) tetrahydro-3aH- c]pyridin-5 -y1]-[6-rncthoxy pyridine [1,3]dioxolo[4,5- (2,2,3,3-tetrafluoropropoxy)— carboxylic acid c]pyridine 2-pyridy1]rncthanonc [(3 )-7a-(2,3- oxy (3 aR,7aR)—7a-(2,3- difluorophcnyl)-3 a,4,6,7- (2,2,2-trifluoro difluorophcnyl)-4,5,6,7- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - methyl- tctrahydro-3aH- c]pyridin-5 -y1] -[6-mcthoxy-5 - cthoxy)pyridinc [1,3]di0X010[4,5- (2,2,2-trifluor0rncthy1— ylic acid c]pyridinc cthoxy)—2-pyridy1]rncthanonc [(3 aR,7aR)-7a-(2,3- 6-mcthoxy (3 aR,7aR)—7a-(2,3- difluorophcnyl)-3 a,4,6,7- (2,2,3,3- difluorophcnyl)-4,5,6,7- ydro-[ 1 ,3 ] dioxolo [4,5 - tctrafluoropropoxy) ydro-3aH- c]pyridin-5 -y1] -[6-mcthoxy-5 - pyridinc-Z- [1,3]dioxolo[4,5- (2,2,3 ,3 -tctrafluoropropoxy)— ylic acid c]pyridinc 2-pyridy1]rncthanonc [(3 aR,7aR)-7a-(2-pyridyl)- 3 a,4,6,7-tctrahydr0- 6-mcthoxy[[1- (3 aR,7aR)-7a-(2-pyr1dyl)-_ [1,3]di0X010[4,5-c]pyridin (trifluoromcthyl)cy 4,5,6,7-tctrahydr0-3aH- yl]—[6-rncthoxy[[ 1 - clopropy1]rncthoxy] [1,3]dioxolo[4,5- (trifluororncthyl)cyclopropyl] pyridine dinc methoxy] carboxylic acid pyridyl]rncthanonc [(3 aR,7aR)—7a-(3 - (3 aR,7aR)—7a-(3- fluorophcnyl)-3 a,4,6,7- 4- fluorophcny1)-4,5,6,7- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - (difluororncthylsulf ydro-3aH- c]pyridin-5 -y1]- [4- onyl)bcnzoic acid [1,3]dioxolo[4,5- (difluoromcthylsulfony1)phcn c]pyridinc yl]rncthanonc [7,7-difluoro(2-pyridy1) azabicyclo [4. 1 .0]hcptany1]— 3-mcthoxy[2- 7,7-diflu0r0(2-pyridy1)— [3-mcth0xy[2- (trifluororncthoxy)c 3- (trifluoromcthoxy)cthoxy]phc thoxy]bcnzoic acid azabicyc10[4. 1 .0]hcptanc nyl]rncthanonc [4-[(3,3- 4-[(3 ,3 - difluorocyclobutyl)rnethoxy]- difluorocyclobutyl)_ fluoro(2-pyr1dy1)—_ _ 3-mcthoxy-phcnyl]—[7,7- d1fluoro(2-pyr1dyl). . methoxy]—3- methoxy-bcnzmc_ azab1cyc10[4. 1 .0]hcptanc_ azabicyc10[4. 1 .0]hcptan ac1d. yl]rnethanonc 7aR)-7a-(2,3- difluorophcnyl)-3a,4,6,7- (3 aR,7aR)—7a-(2,3- 3-mcthoxy[(1 S)— tetrahydro-[ 1 ,3 ] dioxolo [4,5 - d1fluorophcny1)-4,5 ,6,7-. 2,2,2-trifluoro c]pyridin-5 -y1] -[3 -rncth0xy tetrahydro-3aH- [(IS)-2,2,2-trifluoro [1,3]d10xolo[4,5-. ethoxy]benz01c ac1d_ _ methyl- c]pyr1d1nc_ _ cthoxy]phcny1]mcthanonc 7aR)-7a-(2,3- difluorophcnyl)-3a,4,6,7- (3 aR,7aR)—7a-(2,3- 3-mcthoxy[(1R)- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - ophcny1)-4,5 ,6,7- 2,2,2-triflu0ro c]pyridin-5 -y1] -[3 -rncth0xy tetrahydro-3aH- [(1R)-2,2,2-triflu0ro [1,3]di0X010[4,5- ethoxy]benzoic acid methyl- c]pyr1d1nc_ _ cthoxy]phcny1]mcthanonc [(3 aR,7aR)—7a-(3- (3 aR,7aR)—7a-(3- fluorophcny1)-3a,4,6,7- 4-(2-fluor0 fluorophcny1)-4,5,6,7- tetrahydr0-[ 1 ,3]diox010[4,5- methyl-propoxy) tetrahydro-3aH- c]pyridiny][1 - 4- 2-fluor0( mcthy1-bcnzoic [1,3]dioxolo[4,5- methyl-propoxy)rncthy1— acid c]pyr1d1nc. . ]rncthanonc [(3 aR,7aR)—7a-(3- 3- (3aR,7aR)—7a-(3- fluorophcny1)-3a,4,6,7- difluorocyclobutyl) fluorophcny1)-4,5,6,7- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - methoxy]—6- tetrahydro-3aH- c]pyridiny1]—[5-[(3 ,3- methoxy-pyridinc- [1,3]di0X010[4,5- difluorocyclobutyl)rnethoxy]- 2-carb0xy1ic acid c]pyridinc 6-methoxy pyridyl]rncthanonc [(3 aR,7aR)—7a-(3- fluorophcny1)-3a,4,6,7- (3 aR,7aR)—7a-(3- tetrahydro-[ 1 ,3]dioxolo[4,5- 3-chloro[2- fluorophcnyl)—4,5 ,6,7- c]pyridin-5 -y1]- [3 -ch10r0 (trifluororncthoxy)c tctrahydro-3aH- [2- thoxy]bcnzoic acid [1 ,3]di0X010 [4,5- (trifluoromcthoxy)cthoxy]phc c]pyridinc nyl]rncthanonc [3-chlor0[2- (trifluoromcthoxy)cthoxy]phc 3 -ch10r0[2- (1 S -(2-pyridy1)—8- nyl] - [(1 S ,6R)—6-(2-pyridy1)—8- (trifluororncthoxy)c oxa-3 - oxaazabicyclo[4.2.0]octan- thoxy]bcnzoic acid azabicyclo[4.2.0]octanc 3-y1]rncthanonc [3-chlor0[2- (trifluoromcthoxy)cthoxy]phc 3-ch10r0[2- )(2-pyridy1)—8- nyl]-[(1R,6R)(2-pyridyl) (trifluororncthoxy)c oxa oxaazabicyclo[4.2.0]octan- thoxy]bcnzoic acid azabicyclo[4.2.0]octanc 3-y1]rncthanonc [(3aR,7aR)—7a-(3- 4-[2-(2,2- (3aR,7aR)—7a-(3- fluorophcnyl)-3a,4,6,7- difluorocyclopropyl fluorophcnyl)—4,5,6,7- ydro-[ 1 ,3 ] dioxolo [4,5 - )cthoxy]—3- tctrahydro-3aH- c]pyridiny1]-[4-[2-(2,2- rncthoxy-bcnzoic [1,3]dioxolo[4,5- ocyclopropyl)cthoxy]- ac1d_ c]pyr1d1nc_ _ 3-rncthoxy-phcnyl]mcthanonc 2014/045675 [(3aR,7aR)-7a-[4- (3aR,7aR)-7a-[4- (trifluororncthyl)—2-pyridy1] - oxy[2- (trifluororncthyl) 3a,4,6,7-tctrahydr0- (trifluororncthoxy)c pyridyl]—4,5,6,7- [1,3]di0X010[4,5-c]pyridin thoxy]pyridinc tctrahydro-3aH- yl]—[6-rncthoxy[2- carboxylic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy] c]pyridinc pyridyl]rncthanonc [(3aR,7aR)-7a-[4- (3aR,7aR)-7a-[4- (trifluororncthyl)—2-pyridy1] - 3-mcthoxy (trifluororncthyl) 3a,4,6,7-tctrahydr0- (3 ,3 ,3 - pyridy1]-4,5,6,7- [1,3]di0X010[4,5-c]pyridin trifluoropropoxy)bc tctrahydro-3aH- y1]-[3 -rncthoxy(3,3,3- nzoic acid [1,3]dioxolo[4,5- trifluoropropoxy)phcnyl]mcth c]pyridinc anonc [(3aR,7aR)-7a-[4- (trifluororncthyl)—2-pyridy1] - (3aR,7aR)-7a-[4 [(3 ,3 - 3a,4,6,7-tctrahydr0- (trifluororncthyl) difluorocyclobutyl) [1,3]di0X010[4,5-c]pyridin pyridy1]-4,5,6,7- methoxy]—6- y1]-[5-[(3,3- tctrahydro-3aH- methoxy-pyridinc- difluorocyclobutyl)rncthoxy]- [1,3]dioxolo[4,5- 0xy1ic acid 6-mcthoxy c]pyridinc pyridyl]rncthanonc [(3 aR,7aR)—7a-(3- (3 )—7a-(3- fluorophcny1)-3a,4,6,7- 6-cthoxy[2- fluorophcnyl)—4,5,6,7- tetrahydro-[ 1 ,3 ] o [4,5 - (trifluororncthoxy)c tctrahydro-3aH- c]pyridiny1]-[6-cthoxy pyridinc [1,3]dioxolo[4,5- [2-(trifluororncthoxy)cthoxy]- carboxylic acid c]pyridinc 2-pyridy1]rncthanonc 7aR)-7a-[4- (3aR,7aR)-7a-[4- (trifluororncthyl)—2-pyridy1] - (trifluororncthyl) 3a,4,6,7-tctrahydr0- 3-ch10r0[2- pyridy1]-4,5,6,7- [1,3]di0X010[4,5-c]pyridin (trifluororncthoxy)c tetrahydro-3aH- y1]-[3-ch10r0[2- thoxy]benzoic acid [1,3]dioxolo[4,5- oromcthoxy)cthoxy]phc dine nyl]rncthanonc [(3aR,7aR)-7a-[4- (3aR,7aR)-7a-[4- (trifluororncthyl)—2-pyridy1] - (trifluororncthyl) 3a,4,6,7-tctrahydr0- 3-mcthoxy[2- pyridy1]-4,5,6,7- i0X010[4,5-c]pyridin (trifluororncthoxy)c ydro-3aH- y1]-[3 -rncth0xy[2- thoxy]benzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridine nyl]rncthanonc [3-ch10r0[2- (trifluoromcthoxy)cthoxy]phc 3-ch10r0[2- 7,7-diflu0r0(2-pyridy1)— nyl]-[7,7-difluoro(2- (trifluororncthoxy)c 3- pyridy1)-3 - thoxy]bcnzoic acid azabicyc10[4. 1 .0]hcptanc azabicyclo [4. 1 tan yl]rnethanonc [(3 aR,7aR)-7a-(4-rncthoxy-2 pyridy1)-3a,4,6,7-tctrahydr0- 5-[(3,3- (3aR,7aR)—7a-(4- [1,3]di0X010[4,5-c]pyridin difluorocyclobutyl) methoxy-Z-pyridyl)- y1]-[5-[(3,3- y]—6- 4,5,6,7-tctrahydr0-3aH- difluorocyclobutyl)rnethoxy]- rncthoxy-pyridinc- [1,3]dioxolo[4,5- 6-methoxy 2-carb0xy1ic acid c]pyridinc pyridyl]rncthanonc [(3 aR,7aR)-7a-(4-rncthoxy-2 (3 aR,7aR)—7a-(4- pyridy1)-3a,4,6,7-tctrahydr0- 3-mcthoxy[2- methoxypyridyl)- [1,3]di0X010[4,5-c]pyridin (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH- y1]-[3 -rncth0xy[2- thoxy]bcnzoic acid [1 ,3]di0X010 [4,5- (trifluoromcthoxy)cthoxy]phc c]pyridine nyl]rncthanonc [(3 aR,7aR)-7a-(4-rncthoxy (3 aR,7aR)—7a-(4- pyridy1)-3 7-tctrahydr0- 3-ch10r0[2- methoxypyridyl)- [1,3]di0X010[4,5-c]pyridin (trifluororncthoxy)c 4,5,6,7-tctrahydr0-3aH yl] - [3 -chlor0[2- thoxy]benzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridine nyl]rncthanonc [(3 aR,7aR)—7a-(3 - chlorophcnyl)-3 a,4,6,7- (3 aR,7aR)—7a-(3- 3-mcthoxy[(1 S)- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - chlorophcnyl)-4,5,6,7- 2,2,2-trifluoro c]pyridin-5 -y1] -[3 0xy ydro-3aH- methyl- [(1 S)-2,2,2-triflu0ro ioxolo[4,5- ethoxy]benzoic acid methyl- c]pyridine cthoxy]phcny1]mcthanonc [(3 aR,7aR)—7a-(3 - chlorophcnyl)-3 a,4,6,7- (3 aR,7aR)—7a-(3- 3-mcthoxy[(1R)- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - phcnyl)-4,5,6,7- 2,2,2-triflu0ro c]pyridin-5 -y1] -[3 -rncth0xy tetrahydro-3aH- methyl- [(1R)-2,2,2-trifluoro [1,3]dioxolo[4,5- ethoxy]benzoic acid methyl- dine cthoxy]phcny1]mcthanonc [(3 aR,7aR)—7a-(3- (3 aR,7aR)—7a-(3- fluorophcny1)-3a,4,6,7- 4-fluoro fluorophcny1)-4,5,6,7- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - methoxy-bcnzoic tetrahydro-3aH- c]pyridiny1]-(4-fluoro acid [1,3]dioxolo[4,5- methoxy-phcnyl)mcthanonc c]pyridine [(3 aR,7aR)—7a-(3 - (3 aR,7aR)—7a-(3 - fluorophcnyl)-3 a,4,6,7- 4- fluorophcny1)-4,5,6,7- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - butylrnethoxy tetrahydro-3aH- c]pyridin-5 -y1]- [4- )rnethoxy- [1,3]dioxolo[4,5- (cyclobutylrnethoxy)-3 - benzoic acid c]pyridine methoxy-phcnyl]mcthanonc [(3 aR,7aR)—7a-(3 - (3 )—7a-(3 - fluorophcnyl)-3 a,4,6,7- 4-[(3- fluorophcny1)-4,5,6,7- tetrahydro-[ 1 ,3 ] o [4,5 - fluorocyclobutyl)rn tetrahydro-3aH- din-5 -y1] - [4- [(3 - cthoxy]rncth0xy- [1,3]dioxolo[4,5- fluorocyclobutyl)rnethoxy] -3 - benzoic acid c]pyridine methoxy-phcnyl]mcthanonc [(3 aR,7aR)—7a-(3 - 3-methoxy (3 aR,7aR)—7a-(3- fluorophcnyl)-3 a,4,6,7- ,3-tetrafluoro- fluorophcny1)-4,5,6,7- tetrahydro-[ 1 ,3 ] dioxolo [4,5 mcthy1— tetrahydro-3aH- c]pyridin-5 -y1] -[3 -rncth0xy propoxy)bcnzoic [1,3]dioxolo[4,5- (2,2,3 ,3 -tctrafluor0rncthy1— acid c]pyridine propoxy)phcnyl]rncthanonc [3 -chlor0[2- (trifluoromcthoxy)cthoxy]phc 3-ch10r0[2- (1 S,6R)—6-(2-pyridy1)—3- nyl] - [(1 S ,6R)—6-(2-pyridy1)—3 - (trifluororncthoxy)c yclo [4. 1 .0]hcptanc azabicyclo [4. 1 .0]hcptan thoxy]benzoic acid yl]rnethanonc [(3 aR,7aR)—7a-(3 - hcnyl)-3 a,4,6,7- (3 aR,7aR)—7a-(3- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - oxy[2- fluorophcny1)-4,5,6,7- c]pyridin-5 -y1]-[3-rncthoxy (trifluororncthoxy)c tetrahydro-3aH- [2- thoxy]benzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridine nyl]rncthanonc [(3aR,7aR)-7a-[4- (3aR,7aR)-7a-[4- (trifluororncthyl)—2-pyridy1] - 4-[(3 ,3 - (trifluororncthyl) 3a,4,6,7-tctrahydr0- difluorocyclobutyl) pyridy1]-4,5,6,7- [1,3]di0X010[4,5-c]pyridin methoxy]-3 - tctrahydro-3aH- yl]-[4-[(3,3- methoxy-bcnzoic [1,3]dioxolo[4,5- difluorocyclobutyl)rncthoxy]- acid c]pyridinc 3-rncthoxy-phcnyl]mcthanonc [(3aR,7aR)-7a-(3,5- 4-[(3 ,3 - (3aR,7aR)—7a-(3,5- difluorophcnyl)-3a,4,6,7- difluorocyclobutyl) difluorophcnyl)-4,5,6,7- tetrahydro-[ 1 ,3 ] o [4,5 - methoxy]-3 - tctrahydro-3aH- c]pyridiny1]—[4-[(3,3- y-bcnzoic [1,3]dioxolo[4,5- difluorocyclobutyl)rncthoxy]- acid c]pyridinc 3-rncthoxy-phcnyl]mcthanonc [(3aR,7aR)-7a-[4- (3aR,7aR)-7a-[4- (trifluororncthyl)—2-pyridy1] - 4-[2-(2,2- (trifluororncthyl) 3a,4,6,7-tctrahydr0- difluorocyclopropyl pyridy1]-4,5,6,7- [1,3]di0X010[4,5-c]pyridin )cthoxy]-3 - tctrahydro-3aH- y11-[4-[2-(2,2- y-bcnzoic [1,3]dioxolo[4,5- difluorocyclopropyl)cthoxy]- acid c]pyridinc 3-rncthoxy-phcnyl]mcthanonc [(3 )—7a-(6-ch10r0 methoxy-Z-pyridyl)-3a,4,6,7- (3 aR,7aR)-7a-(6-chloro-4_ tetrahydro-[ 1 ,3 ] dioxolo [4,5 - 3-mcthoxy[2- methoxypyridyl)- c]pyridin-5 -y1]-[3-rncthoxy ororncthoxy)c 4,5,6,7-tctrahydr0-3aH- [2- thoxy]bcnzoic acid [1,3]dioxolo[4,5- oromcthoxy)cthoxy]phc c]pyridinc nyl]rncthanonc [(3aS,7aS)-7a-(3- (3aS,7aS)-7a-(3- fluorophcny1)-3a,4,6,7- 3-flu0r0[2- fluorophcny1)-4,5,6,7- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - (trifluororncthoxy)c tctrahydro-3aH- c]pyridiny1]—[3-fluor0[2- thoxy]bcnzoic acid ioxolo[4,5- oromcthoxy)cthoxy]phc c]pyridinc nyl]rncthanonc [(3aS,7aS)-7a-(3- fluorophcny1)-3a,4,6,7- (3aS,7aS)-7a-(3- 4-(2-fluor0 tetrahydro-[ 1 ,3 ] dioxolo [4,5 - fluorophcny1)-4,5,6,7- methyl-propoxy) c]pyridin-5 -y1]-[4-(2-flu0r0 tetrahydro-3aH- (trifluoromcthyl)bc methyl-propoxy)—3- [1,3]dioxolo[4,5- nzoic acid (trifluoromcthyl)phcnyl]metha c]pyridine none [(3aS,7aS)-7a-(3- fluorophcny1)-3a,4,6,7- (3aS,7aS)-7a-(3(trifluor0rncthyl)- ydro-[ 1 ,3 ] dioxolo [4,5 - fluorophcny1)-4,5,6,7- 4-(3 ,3 ,3 - c]pyridiny1]—[3- tetrahydro-3aH- trifluoropropoxy)bc (trifluororncthyl)(3,3,3- [1,3]dioxolo[4,5- nzoic acid trifluoropropoxy)phcnyl]mcth c]pyridine anonc [(3aS,7aS)-7a-(3- (3aS,7aS)-7a-(3- fluorophcny1)-3a,4,6,7- 3-ch10r0(2- fluorophcny1)-4,5,6,7- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - fluoro-Z-mcthyltetrahydro-3aH- diny1]-[3-chloro propoxy)bcnzoic ioxolo[4,5- (2-flu0r0rncthy1— acid c]pyridine propoxy)phcnyl]rncthanonc [(3aS,7aS)-7a-(3- fluorophcny1)-3a,4,6,7- (3aS,7aS)-7a-(3- tetrahydro-[ 1 ,3 ] o [4,5 - 3-ch10r0[2- fluorophcny1)-4,5,6,7- c]pyridiny1]-[3-chloro (trifluororncthoxy)c ydro-3aH- [2- thoxy]benzoic acid [1,3]dioxolo[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridine nyl]rncthanonc 7aS)-7a-(3- 4-[(3,3- (3aS,7aS)-7a-(3- fluorophcny1)-3a,4,6,7- difluorocyclobutyl) fluorophcny1)-4,5,6,7- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - methoxy]—3- tctrahydr0-3aH- c]pyridiny1]—[4-[(3 ,3- methoxy-bcnzoic [1 ,3]di0X010[4,5 - difluorocyclobutyl)rncthoxy]- ac1d_ c]pyr1d1nc_ _ 3-rncthoxy-phcnyl]rncthanonc [(3aS,7aS)-7a-(3- fluorophcnyl)-3a,4,6,7- (3aS,7aS)-7a-(3- tetrahydro-[ 1 ,3 ] dioxolo [4,5 rncthoxy [2- fluorophcny1)-4,5 ,6,7- diny1]-[3-rncth0xy (trifluororncthoxy)c tctrahydr0-3aH- [2- thoxy]bcnzoic acid [1,3]di0X010[4,5- (trifluoromcthoxy)cthoxy]phc c]pyridinc nyl]rncthanonc [(3aS,7aS)-7a-(3- fluorophcny1)-3a,4,6,7- 6-methoxy[[1- (3aS,7aS)-7a-(3- tetrahydro-[ 1 ,3 ] dioxolo [4,5 - (trifluororncthyl)cy fluorophcny1)-4,5,6,7- c]pyridin-5 -y1]-[6-rncthoxy clopropyl]rncthoxy] ydro-3aH- [[ 1 - pyridinc-Z- [1,3]dioxolo[4,5- (trifluororncthyl)cyclopropyl] carboxylic acid c]pyridinc methoxy] pyridyl]rncthanonc [(3 aS ,7a )7a(S - - 3- (3as,7aS)-7a-(3- hcny1)-3 a,4,6,7rncthoxy fluorophcny1)-4,5,6,7- ydr0-[ 1 ,3]di0x010[4,5 - (2,2,2-trifluor0 tctrahydro-3aH- c]pyridin-5 -y1] -[3 -rncth0xy methyl- [1,3]dioxolo[4,5- (2,2,2-trifluoromcthyl- cthoxy)bcnzoic acid c]pyr1d1nc_ _ )phcny1]rncthanonc [(3aR,7aR)—7a-(3- 3- (3aR,7aR)—7a-(3- fluorophcny1)-3 a,4,6,7- difluorocyclobutyl) fluorophcny1)-4,5 ,6,7- tctrahydr0-[ 1 ,3]di0x010[4,5 - arnino] -3 - tctrahydro-3aH- c]pyridin-5 -y1] - [4- [(3 ,3 - methoxy-bcnzoic [1,3 ] dioxolo [4,5 - difluorocyc10buty1)rncthylarni acid c]pyridinc no]—3-rncthoxy- phcnyl]rncthanonc [4- [(3 ,3 - 4-[(3 ,3 - difluorocyclobuty1)rncthoxy]- difluorocyclobutyl) (1R,6R)(2-pyridyl) 3-mcth0xy-phcny1] - [( 1 R,6R)- methoxy]-3 - oxa 6-(2-pyridy1)—8-0xa-3 - methoxy-bcnzoic azabicyclo[4.2.0]octanc azabicyclo [4 .2 . 0]octan-3 - acid yl]rncthanonc [6-mcthoxy-5 -(2,2,3 ,3 - 6-mcthoxy tctrafluoropropoxy)—2- (2,2,3 ,3 - (1R,6R)(2-pyridyl) pyridy1]-[(1 R,6R)—6-(2- tetrafluoropropoxy) oxa pyridyl)—8-oxa-3 - pyridine azabicyclo[4.2.0]octanc azabicyclo [4 .2 . 0]octan-3 - carboxylic acid yl]rncthanonc [3-ch10ro[(3,3- difluorocyclobutyl)rncthoxy]p ro[(3,3- )(2-pyridyl) heny1]-[(1R,6R)(2- ocyclobutyl) oxa pyridyl)—8-oxa-3 - y]bcnzoic azabicyclo[4.2.0]octanc azabicyclo [4 .2 . 0]octan-3 - acid yl]rncthanonc [3 -ch10r0[[1- oromcthyl)cyclopropyl] 3-chloro[[1- (1R,6R)(2-pyridyl) methoxy]phcnyl]—[(1R,6R) (trifluoromcthyl)cy oxa (2-pyridy1)—8-0xa-3 - clopropy1]rncthoxy] azabicyclo[4.2.0]octanc azabicyclo [4 .2 . 0]octan-3 - benzoic acid yl]rncthanonc [3 -rncthy1—4- [2- (trifluoromcthoxy)cthoxy]phc 3-mcthy1—4-[2— (1R,6R)(2-pyridyl) ny1]-[(1R,6R)(2-pyridy1) (trifluororncthoxy)c oxa oxaazabicyclo [4 .2 . 0]octan- thoxy]benzoic acid azabicyclo[4.2.0]octanc 3 -y1]rncthanonc [4-(2-fluor0rncthyl- propoxy)-3 - 4-(2-fluor0 (1R,6R)(2-pyridyl) (trifluororncthyl)phcnyl] - methyl-propoxy) oxa [(1 R,6R)(2-pyridyl)oxa- oromcthyl)bc azabicyclo[4.2.0]octanc 3 -azabicyclo [4 .2 . 0]octan-3 - nzoic acid yl]rnethanonc [(3 )-7a- [4- (trifluororncthyl)—2-pyridy1] - (3aR,7aR)-7a-[4- 4-[(3 ,3 - 3 a,4 6,7-tctrahydr0- , (trifluororncthyl) difluorocyclopentyl [1,3]di0X010[4,5-c]pyridin pyridy1]-4,5,6,7- )rncthoxy] -3 - yam-[(3,3- tetrahydro-3aH- methoxy-bcnzoic difluorocyclopentyl)rnethoxy] [1,3]dioxolo[4,5- acid -3 -rnethoxy- c]pyridine phenyl]rncthanonc [(3 aR,7aR)-7a-(4-mcthoxy-2— 4-[(3 ,3 - (3 aR,7aR)—7a-(4- pyridy1)-3 a,4 ,6 ,7-tctrahydr0- difluorocyclobutyl) methoxypyridyl)- [1,3]di0X010[4,5-c]pyridin methoxy]-3 - 4,5,6,7-tctrahydr0-3aH- y1]-[4-[(3,3- methoxy-bcnzoic ioxolo[4,5- difluorocyclobuty1)rnethoxy]- acid c]pyridine 3-rncthoxy-phcnyl]mcthanonc [3 -chlor0[2- oromcthoxy)cthoxy]phc 3-ch10r0[2- (1R,6R)(2-pyridyl) ny1]-[(1R,6R)(2-pyridy1) (trifluororncthoxy)c oxa oxaazabicyclo[4.2.0]octan- thoxy]benzoic acid yclo[4.2.0]octanc 3-y1]rncthanonc 2014/045675 [3-ch10r0[2- (trifluoromcthoxy)cthoxy]phc 3 -ch10r0[2- (1 S ,6S)(2-pyridyl) ny1]-[(1S,6S)(2-pyridyl) (trifluororncthoxy)c oxa azabicyclo[4.2.0]octan- thoxy]bcnzoic acid azabicyclo[4.2.0]octanc 3-y1]rncthanonc [(3aR,7aR)-7a-[4- (3aR,7aR)-7a-[4- (trifluororncthyl)—2-pyridy1]rncthoxy[[ 1 - (tr1fluororncthyl). ,7-tctrahydr0- (m'fluorornct yh 1)cy pyri y'd 1] 4 5 6 7- - , , , i0X010[4,5-c]pyridin clopropyl]rncthoxy] tetrahydr0-3aH- yl]—[3-rncthoxy[[1- benzoic acid [1,3]dioxolo[4,5- (trifluororncthyl)cyclopropyl] c]pyr1d1nc. . methoxy]phcnyl]mcthanonc [(3aR,7aR)-7a-[4- (3 R7 R) 7a a - a- , [4- (trifluororncthyl)—2-pyridy1]- 3-mcthoxy (trifluororncthyl) 3a,4,6,7-tctrahydr0- (2,2,3,3- pyr1dy1]—4,5,6,7-. [1,3]di0X010[4,5-c]pyridin tctrafluoropropoxy) tetrahydro-3aH- yl]—[3-rncthoxy(2,2,3,3- bcnzoic acid [1,3]dioxolo[4,5- tctrafluoropropoxy)phcnyl]mc c]pyridinc thanonc 7aR)-7a-(3,5- difluorophcnyl)-3a,4,6,7- (3 aR,7aR)—7a-(3,5- tetrahydro-[ 1 ,3 ] o [4,5 rncthoxy [2- difluorophcny1)-4,5 ,6,7- c]pyridin-5 -y1]-[3-rncthoxy (trifluororncthoxy)c tetrahydro-3aH- [2- thoxy]bcnzoic acid [1 ,3]di0X010 [4,5- (trifluoromcthoxy)cthoxy]phc c]pyridinc nyl]rncthanonc [(3 aR,7aR)-7a-(4-rncthoxy (3 aR,7aR)—7a-(4- pyridy1)-3a,4,6,7-tctrahydr0- 3-mcthoxy methoxypyridyl)- [1,3]dioxolo[4,5-c]pyridin (2,2,3 ,3- 4,5,6,7-tctrahydr0-3aH- yl]—[3-mcthoxy(2,2,3,3- tetrafluoropropoxy) [1,3]d10xolo[4,5-_ tetrafluoropropoxy)phcny1]inc bcnz01c ac1d_ _ c]pyr1d1nc_ _ thanonc [(3aR,7aR)-7a-[4- (3aR,7aR)-7a-[4- (trifluoromethyl)pyridyl] - 4-(2-fluoro (trifluoromethyl) 3a,4,6,7-tetrahydromethyl-propoxy ) pyridyl]-4,5,6,7- ioxolo[4,5-c]pyridin methyl-benzoic ydro-3aH- yl]-[4-(2-fluoromethyl- acid [1,3]dioxolo[4,5- propoxy)methylc ]pyr1d1ne_ _ phenyl]methanone [(3 aR,7aR)—7a-(3-fluoro 3- (3aR,7aR)-7a-(3-fluoro pyridyl)-3a,4,6,7-tetrahydrodifluorocyclobutyl ) pyridyl)—4,5,6,7- ioxolo[4,5-c]pyridin methoxy] ydro-3aH- yum-[(3,3- methoxy-benzoic [l,3]dioxolo[4,5- difluorocyclobutyl)methoxy]- acid c]pyridine 3-methoxy-phenyl]methanone (3-chlor0((3,3- difluorocyclobutyl)meth0xy)phenyl)((3aR,7aR)—7a-(pyridinyl)tetrahydro- [1,3]dioxolo[4,5-c]pyridin-5(6H)—yl)methan0ne Step 1: [(3aR,7aR)—7a-(2-pyridyl)—3a,4,6,7—tetrahydr0- [1,3]dioxolo[4,5-c]pyridin-S-yl]-(3-chlor0flu0r0-phenyl)methan0ne NH F A solution of 3-chlorofluoro-benzoic acid (440 mg, 2.52 mmol) in DMF (7.2 mL) was treated with HATU (960 mg, 2.5 mmol) and the reaction mixture was allowed to stir for 5 min. A solution of (3aR,7aR)-7a-(pyridin yl)hexahydro-[1,3]dioxolo[4,5-c]pyridine (500 mg, 2.4 mmol) and triethylamine (2.5 mL, 14.5 mmol) in DMF (7.1 mL) was added to the mixture and the reaction mixture was stirred at rt for 2 h. The product was diluted with water and extracted with EtOAc (3x). The combined organics were washed with water, saturated aqueous NaCl, dried (NaZSO4), filtered and concentrated. ation by flash chromatography (ethyl acetate-hexanes 10-50%) afforded [(3aR,7aR)-7a-(2-pyridyl)—3a,4,6,7-tetrahydro- [l,3]dioxolo[4,5-c]pyridinyl]-(3-chlorofluoro-phenyl)methanone (643 mg, 73%) which was used directly in the ing on. ESI-MS m/z calc. 362.8, found 363.13 (M+l)+; Retention time: 1.27 min (3 min run).

[00425] The following compounds were prepared using the procedure ed above.

Product Benzoic Acid (3-chloro [dimethylaminofluorophenyl )((3aR,7aR)—7a- (triazolo[5,4- 3-chlorofluoro- (pyridinyl)tetrahydro- b]pyridin benzoic acid [1 ,3 ] dloxolo [4,5 -c]pyr1d1n-_ _ _ yloxy)methylene] - (6H)—yl)methanone dimethyl-ammonium (4-fluoro [dimethylamino- (trifluoromethyl)phenyl)((3aR,7a (triazolo[5,4- 4-fluoro R)-7a-(pyridinyl)tetrahydro- b]pyridin (trifluoromethyl)be [l,3]dioxolo[4,5-c]pyridin- yloxy)methylene]— nzoic acid (6H)—yl)methanone dimethyl-ammonium (3 -chloro (3 aR,7aR)-7a-(3- fluorophenyl)((3aR,7aR)—7a-(3- fluorophenyl)hexahy 3-chlorofluoro- henyl)tetrahydro- ,3]dioxolo[4,5- c acid [l,3]dioxolo[4,5-c]pyridin- c]pyridine (6H)—yl)methanone Step 2: (3-chlor0((3,3- difluorocyclobutyl)meth0xy)phenyl)((3aR,7aR)—7a-(pyridinyl)tetrahydr0- lO [1,3]dioxolo[4,5-c]pyridin-5(6H)—yl)methan0ne A solution of ifluorocyclobutyl)methanol (l 18 mg, 0.96 mmol) in DMF (1 mL) was treated with sodium e (42 mg, 1.06 mmol) and the reaction mixture was allowed to stir for 5 min. [(3 aR,7aR)-7a-(2-pyridyl)-3a,4,6,7- ydro- [1 ,3 ] dioxolo [4,5 -c]pyridin-5 -yl] -(3 -chlorofluoro-phenyl)methanone (175 mg, 0.48 mmol) was added as a solution in DMF (1 mL). The reaction mixture was allowed to stir at rt for 1 h, diluted with ethyl acetate (75 mL) and washed with saturated aqueous NaCl (l X 75 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was d by silica gel column chromatography: 4 gram silica gel column, 25-75% ethyl acetate/hexane gradient over 15 min to provide [(3aR,7aR)-7a-(2-pyridyl)-3a,4,6,7- ydro-[l ,3]dioxolo[4,5-c]pyridin-5 -yl]-[3-chloro[(3 ,3- difluorocyclobutyl)methoxy] ]methanone (130 mg, 58%) as a thick oil. 1H NMR (400 MHz, CDClg) 8 8.58 (s, 1H), 7.75 (s, 1H), 7.62 (d, J = 25.5 Hz, 2H), 7.44 (s, 1H), 7.26 (s, 1H), 6.93 (d, J = 8.2 Hz, 1H), 5.32 (s, 1H), 4.85 (s, 1H), 4.40 (s, 1H), 4.09 (d, J = 5.2 Hz, 2H), 3.87 (t, J = 53.2 Hz, 4H), 2.69 (dd, J = 45.1, 10.2 Hz, 5H), 2.35 (s, 1H), 2.09 (d, J = 63.9 Hz, 1H). ESI-MS m/z calc. 464.1, found 465.3 (M+1)+; Retention time: 1.57 min (3 min run).

The following compounds were prepared using the procedure reported above.

Product Precursor (3-chloro ntyloxy)phenyl)((3aR,7aR)-7a- (3 -chlorofluorophenyl)((3aR,7aR)-7a- (pyridinyl)tetrahydro- (pyridinyl)tetrahydro- [1 ,3 ] dioxolo [4,5 - [1,3]dioxolo[4,5-c]pyridin-5(6H)- c]pyridin-5(6H)-yl)methanone yl)methanone (3 -chloro(4,4,4-trifluoro methylbutoxy)phenyl)((3aR,7aR)-7a- (3 -chlorofluorophenyl)((3aR,7aR)-7a- (pyridinyl)tetrahydro- (pyridinyl)tetrahydro- [1 ,3 ] dioxolo [4,5 - [1,3]dioxolo[4,5-c]pyridin-5(6H)- c]pyridin-5(6H)-yl)methanone yl)methanone (3-ch10ro((3,3- difluorocyclobuty1)rnethoxy)pheny1)((3a (3 -ch10rofluoropheny1)((3aR,7aR)-7a- R,721R)-7a-(pyridin-Z-y1)tetrahydr0- (pyridin-Z-yl)tetrahydro- [1 X010[4,5 - [1 ,3]dioxolo[4,5-c]pyridin-5(6H)- c]pyridin-5(6H)-y1)rnethanone y1)rnethanone (3-ch10r0((2,2- difluorocyc10propy1)rnethoxy)pheny1)((3 (3 -ch10rofluoropheny1)((3aR,7aR)-7aaR ,721R)-7a-(pyridiny1)tetrahydr0- (pyridin-Z-yl)tetrahydro- [1 ,3]di0X010[4,5 - [1 xolo[4,5-c]pyridin-5(6H)- c]pyridin-5(6H)-y1)rnethanone y1)rnethanone (4-(2-(tert-butoxy)ethoxy)—3- (3 -ch10rofluoropheny1)((3aR,7aR)-7a- ch10r0pheny1)((3aR,7aR)-7a-(pyridin in-Z-yl)tetrahydro- [1 ,3]di0X010[4,5 - y1)tetrahydr0-[1 ,3]di0x010[4,5 -c]pyridin- c]pyridin-5(6H)-y1)rnethanone (6H)-y1)rnethanone (4-((2,2-difluor0cyc10pr0py1)rnethoxy)—3- (4-fluoro (trifluoromethy1)pheny1)((3aR,7aR)—7a- (trifluorornethyl)pheny1)((3aR,7aR)-7a- (pyridin-Z-y1)tetrahydro- (pyridin-Z-yl)tetrahydro- [1 ,3]di0X010 [4,5 - [1 ,3]dioxolo[4,5-c]pyridin-5(6H)- c]pyridin-5(6H)—y1)rnethanone y1)rnethanone (4-(2,2-difluoropropoxy) ro (trifluoromethy1)pheny1)((3aR,7aR)—7a- (trifluorornethyl)pheny1)((3aR,7aR)-7a- (pyridin-Z-y1)tetrahydro- (pyridin-Z-yl)tetrahydro- [1 ,3]di0X010 [4,5 - [1 ,3]dioxolo[4,5-c]pyridin-5(6H)- c]pyridin-5(6H)—y1)rnethanone y1)rnethanone (4-((3,3-difluorocyclobuty1)rnethoxy) (4-fluoro oromethy1)pheny1)((3aR,7aR)—7a- (trifluorornethyl)pheny1)((3aR,7aR)-7a- (pyridin-Z-y1)tetrahydro- (pyridin-Z-yl)tetrahydro- [1 ,3]di0X010 [4,5 - [1 xolo[4,5-c]pyridin-5(6H)- c]pyridin-5(6H)—y1)rnethanone y1)rnethanone ((3 aR,721R)-7a-(pyridiny1)tetrahydr0- (4-fluoro [1 ,3]dioxolo[4,5-c]pyridin-5(6H)—y1)(3- (trifluorornethyl)pheny1)((3aR,7aR)-7a- (trifluoromethy1)((1 ,1 , 1 - (pyridin-Z-yl)tetrahydro- [1 ,3]di0X010 [4,5 - trifluoropropan-Z- c]pyridin-5(6H)-y1)rnethanone y1)0xy)pheny1)rnethanone c10buty1methoxy)-3 - methoxypheny1)((3aR,7aR)-7a-(3 - (3 -ch10roflu0ropheny1)((3aR,7aR)-7a-(3- fluoropheny1)tetrahydro- fluoropheny1)tetrahydro- [1 ,3]di0X010 [4,5 - [1 ,3]di0X010[4,5 -c]pyridin-5 (6H)- c]pyridin-5(6H)-y1)rnethanone y1)rnethanone (4-(((1r,3R)—3 - fluorocyclobuty1)rnethoxy)-3 - (3 -ch10roflu0ropheny1)((3aR,7aR)-7a-(3- methoxypheny1)((3aR,7aR)-7a-(3 - fluoropheny1)tetrahydro- [1 ,3]di0X010 [4,5 - heny1)tetrahydro- c]pyridin-5(6H)-y1)rnethanone [1 ,3]di0X010[4,5 -c]pyridin-5 (6H)- y1)rnethanone (3 -ch10r0(2-(2,2,2- trifluoroethoxy)ethoxy)pheny1)((3 aR,7aR (3 -ch10rofluoropheny1)((3aR,7aR)-7a- )-7a-(pyridiny1)tetrahydr0- (pyridin-Z-y1)tetrahydro- [1 ,3]diox010[4,5 - [1 ,3]di0X010[4,5 -c]pyridin-5 (6H)- c]pyridin-5(6H)-y1)rnethanone y1)rnethanone (3 -ch10ro(2,2,3 ,3 - tetrafluoropropoxy)pheny1)((3aR,721R)- (3 ofluoropheny1)((3aR,7aR)-7a- 7a-(pyridin-Z-y1)tetrahydro- (pyridin-Z-y1)tetrahydro- [1 ,3]diox010[4,5 - [1 ,3]di0X010[4,5 -c]pyridin-5 (6H)- c]pyridin-5(6H)-y1)rnethanone y1)rnethanone (3 o(2,2- difluoropropoxy)pheny1)((3aR,7aR)-7a- (3 -ch10rofluoropheny1)((3aR,7aR)-7a- (pyridin-Z-y1)tetrahydro- (pyridin-Z-y1)tetrahydro- [1 ,3]diox010[4,5 - [1 X010[4,5 -c]pyridin-5 (6H)- c]pyridin-5(6H)-y1)rnethanone y1)rnethanone (3 o((1 ,1 , 1 -trifluor0pr0pan (3 -ch10rofluoropheny1)((3aR,7aR)-7a- y1)0xy)pheny1)((3aR,7aR)-7a-(pyridin-Z- (pyridin-Z-y1)tetrahydro- [1 ,3]diox010[4,5 - y1)tetrahydr0-[1 ,3]di0x010[4,5 -c]pyridin- c]pyridin-5(6H)-y1)rnethanone 2014/045675 (6H)-yl)rnethanone Table 3 below recites the analytical data for the compounds of Table 1.

Table 3. --_Cmpd.LC/MS LC/RT H NMR (400 MHz, CDClg) 8 8.41 (d, J = 4.3 Hz, 1H), 7.57 = 8.4, 4.2 Hz, 1H), 7.19 - 7.44 (m, 1H), 7.35 (dt, J = 8.2 Hz, 1H), 5.34 (broad s, - 6.98 (m, 2H), 6.89 (d, J 1H), 4.93 (broad s, 1H), 4.68 (broad s, 1H), 4.38 (broad 4—-47900 m, 1H), 4.08 (d, J = 6.4 Hz, 2H), 4.02 (broad s, 1H), 3.88 (s, 3H), 3.77 (broad s, 1H), 3.49 (broad m, 1H), 2.91 - 2.62 (m, 3H), 2.60 - 2.42 (m, 2H), 2.33 (broad _——— 501.10 H NMR (400 MHz, CDClg) 8 7.11 (broad s, 1H), 7.06 (dd, J = 8.2, 1.9 Hz, 1H), 6.96 - 6.87 (m, 3H), 6.76 (tt, J 504.50 ——8.7, 2.3 Hz, 1H), 5.31 (s, 1H), 4.85 (s, 1H), 4.42 - 4.25 (m, 4H), 4.2-4.0 (broad d,2H), 3.90 (s, 3H), 3.72 _——— WO 06280 Cmpd. LC/MS LC/RT No. M+1 min 432.50 1.54 1.46 1.89 11 1.82 1H NMR (400 MHz, MCOD) 8 9.11 — 8.93 (m, 2H), 7.80 — 7.60 (m, 1H), 7.19 — 7.00 (m, 3H), 5.38 (s, 1H), 12 470.40 1.60 4.96 (s, 1H), 4.54 (s, 1H), 4.40 — 4.35 (m, 2H), 4.30 (d, J = 4.0 Hz, 2H), 4.09 (d, J = 14.4 Hz, 1H), 3.88 (s, 3H), 3.87 — 3.76 (m, 2H), 3.70 (s, 1H), 2.67 _ 2.16 (m, 2H). 1H NMR (400 MHz, MCOD) 8 7.47 — 7.22 (m, 7H), 6.99 (t, J = 9.1 Hz, 1H), 4.72 _ 4.54 (m, 2H), 4.46 _ 4.03 13 366.50 1.95 (m, 2H), 3.99 = 25.7, — 3.74 (m, 2H), 3.66 (dd, J 12.9 Hz, 1H), 3.09 (t, J = 15.9 Hz, 1H), 2.57 _ 2.25 (m, 1H), 14 1.54 1.69 16 2.00 17 1.39 18 351.18 2.07 _--— _--— _--— _--— WO 06280 Cmpd. LC/MS LC/RT No. M+1 min 23 431.23 1.30 24 437.25 1.52 413-10 1-15— 26 397.12 1.68 27-— 28-— 29-— -— 31--— 32-— 33-— 34-— -— 36 --— 37 368. 16 1 .71 _38-— _--— _--— 2014/045675 Cmpd. LC/MS LC/RT No. M+1 min 41 499.50 1.09 1H NMR (400 MHz, CDC13) 8 7.28 — 7.19 (m, 4H), 7.02 — 6.94 (m, 2H), 6.81 (d, J = 8.0 Hz, 1H), 3.89 (s, 44 398.40 1.79 2H), 3.82 (s, 2H), 3.45 (s, 1H), 2.28 (s, 3H), 2.14 (s, 2H), 1.74 (s, 2H), 1.38 (s, 6H), 1.04 (s, 1H), 0.88 (t, J = 45 1.51 46 1.45 47 1.76 48 1.88 49 1.50 50 1.32 51 1.87 52 421.20 1.80 53 --— 54 --— 55 --— 56 --— 57 --— 58 --— 59 --— 6°“— 61 467.40 1.41 -- 1H NMR (400 MHz, MCOD) 5 7.82 (d, J = 3.3 Hz, 1H), 62 463.00 1.24 7.58 (d, J = 3.3 Hz, 1H), 7.29—7.34 (m, 2H), 7.20 (t, J = 8.4 Hz, 1H 5.34 s, 1H 4.99 , s, 1H 4.54 - 4.25 , , m, Cmpd. LC/MS LC/RT ,4.07 - 3.53 (m, 4H), 2.55 - 2.02 (m, 2H). 429-40_— 1H NMR (400 MHz, C6D6) 5 8.53 (s, 1H), 7.21 — 7.04 (m, 3H), 6.78 = 7.7 Hz, 2H), 6.57 — 6.65 (m, J (d, J = 8.1 Hz, 1H), 4.15 _ 3.91 (m, 4H), 3.86 64 467.20 (d, J = 8.2 Hz, 1H), 3.81 — 3.70 (m, 4H), 3.68 — 3.58 (m, 2H), 3.37 (s, 3H), 3.18 = 29.0, 16.9 Hz, 2H), 2.27 — 2.95 (m, J — 1.98 m, J = 538,188 Hz, 2H. 65-— 67 418.30 1.63 1H NMR (400 MHz, DMSO) 5 8.59 (d, J = 4.2 Hz, 1H), 7.85 (td, J = 7.8, 1.7 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.40 — 7.26 (m, 1H), 7.06 (d, J = 23.8 Hz, 3H), .31 (s, 1H), 4.73 (s, 1H), 4.41 (dd, J = 5.3, 3.0 Hz, 469.10 1.40 2H), 4.33 (s, 1H), 4.29 — 4.25 (m, 2H), 3.96 — 3.83 (m, 1H), 3.80 (s, 3H), 3.73 (d, J = 13.9 Hz, 1H), 3.62 (dd, J = 6.8, 4.7 Hz, 1H), 3.55 — 3.45 (m, 1H), 2.30 (d, J = 1H NMR (400 MHz, CDC13) 8 7.44 — 7.36 (m, 4H), 7.36 — 7.28 (m, 1H), 7.11 (s, 1H), 7.07 (dd, J = 8.2, 1.9 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 5.30 (s, 1H), 4.87 (s, 71 430.28 1.74 1H), 4.27 (s, 1H), 4.03 (t, J = 14.4 Hz, 2H), 3.90 (d, J = 8.6 Hz, 3H), 3.70 (s, 3H), 2.13 (s, 2H), 1.62 (s, 1H), _--— _--— _--— _--— _--— WO 06280 Cmpd. LC/MS LC/RT No. M+1 min 77 382.40 1.96 1H NMR (400 MHz, CDC13) 5 7.27 (d, J = 9.7 Hz, 1H), 7.13 (s, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 8.2 78 489.20 1.60 Hz, 1H), 5.32 (s, 1H), 4.98 (s, 1H), 4.40 (s, 1H), 4.36 — 4.24 (m, 4H), 4.01 (s, 2H), 3.90 (s, 4H), 3.71 (s, 2H), 79 2.27 2.22 81 1.96 82 1.67 83 2.03 84 1.24 85 1.56 475.23 1.56 87 577.00 1.48 _--— Cmpd. LC/MS LC/RT 1H NMR (400 MHz, DMSO) 5 8.64 — 8.55 (m, 1H), 7.86 (td, J = 7.8, 1.7 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.35 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.10 (s, 1H), 7.04 — 4.69 (m, 1H), 4.42 (dd, J 92 469'“) 1'37 (s, 2H), 5.32 (s, 1H), 4.87 .3, 3.1 Hz, 2H), 4.34 (bs, 1H), 4.31 _ 4.23 (m, 2H), 4.17 — 3.85 (m, 1H), 3.81 (s, 3H), 3.74 (d, J = 13.5 Hz, 1H), 368 357 (m, 1H), 3.—57 3.45 (m, 1H), 2.37 — H NMR (400 MHz, CDClg) 8 860 (s, 1H), 769 (s, 1H), 753 (s, 1H), 712 (s, 1H), 708 (d, J—— 82 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 5.39 (s, 1H), 5.05 (s, 487 30' 153' 1H), 4.67 (s, 2H), 4.32 (tt, J = 8.8, 2.7 Hz, 4H), 4.08 (s, 1H), 3.96 = 60.2 — 3.69 (m, 5H), 3.62 (s, 1H), 2.25 (d, J H NMR (400 MHz, DMSO) 8 8.60 (d, J = 4.0 Hz, 1H), 7.86 (td, J = 7.7, 1.7 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.35 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.30 (s, 2H), 7.05 — 6.94 (m, 1H), 5.30 (s, 1H), 4.73 (bs, 1H), 4.31 41520 (bs, 1H), 4.05 (d, J = 19.6 Hz, 2H), 3.95 — 3.81 (m, 1H), 3.74 (d, J = 13.1 Hz, 1H), 3.67 — 3.42 (m, 2H), 2.38 _ 223 (m, 1H), 222 (s 3H), 214— 189 (m J: 171, 42125i- Cmpd.

LM/M+)_A LC/IRT 197 (—400 H NMR MHz, CDC13) 8 7.36 (dd, J = 8.5, 5.3 Hz, 2H), 7.09 (dd, J = 16.0, 7.5 Hz, 4H), 6.92 (d, J = 486.30 . 7.9 Hz, 1H), 5.30 (s, 1H), 4.85 (s, 1H), 4.32 (dd, J = 77, 49 Hz, 4H), 407 (s, 1H), 3.90 (s, 3H), 3.71 (s, H NMR (400 MHz, CDC13) 8 8.39 (d, J: 4.6 Hz,1H), 7.47 (ddd, J: 10.9 8.3,1.,2Hz1H),7.3-9 7.27 (m, 3H), 6.80 (d, J = 8.9 Hz, 1H), 5.31 (broad s, 1H), 4.91 (broad s, 1H), 4.66 (broad s, 1H), 4'43._ 4.02 (m, 1H), 100 43340 - 3.96 (d, J = 16.4 Hz, 3H, overlapped w1th broad s, 1H), 3.79 (broad m, 1H), 3.50 (broad s, 1H), 2.28 (s, 3H, overlapped with broad m, 2H), 1.55 (s, 3H), 1.50 (s, H NMR (400 MHz, ) 8 845 (d, J: 44 Hz, 1H), 771 (td J= 77,19,Hz1H),73,4(d J= 81,Hz 1H), 7.16 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.05 — 7.00 (m, 2H), 6.95 (dd, J = 8.1, 1.9 Hz, 1H), 4.45 — 4.38 (m, 101 43120 ' 2H), 4.31 — 4.24 (m, 2H), 3.90 (br s, 1H), 3.79 (s, 3H), 3.74 (br s, 1H), 3.46 (br s, 1H), 3.28 (br s, 1H), 2.59 (br s, 1H), 2.10 (s, 1H), 170 (s, 1H), 1.28 (dd, J = 9.1, 4.4 H NMR (400 MHz, CDC13) 8 744 736 (m, 4H), 7.-36 7.28(rn, 1H), 713 (s 1H), 70,9(dd J= 82,18 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 5.31 (s, 1H), 4.87 (s, 102 45210 ' 1H), 4.28 (t, J = 6.9 Hz, 3H), 4.07 (s, 1H), 3.90 (s, 3H), 3.77 (d, J = 49.0 Hz, 3H), 2.70 (qt, J = 10.6, 7.0 Hz, 2H 2.21 , d, J = 29.3 Hz, 2H . 103 169 104 163 106 143 107 136 108 149 109 190 WO 06280 LC/IRT 1.47 H NMR (400 MHz, CDClg) 8 8.64 (d, J = 6.4 Hz, 1H), 7.47 (s, 1H), 7.21 (d, J = 5.9 Hz, 1H), 7.15 (s, 1H), 7.13 — 7.07 (m, 1H), 6.91 (d, J = 8.1 Hz, 1H), 5.39 (s, 1H), 4.99 (s, 1H), 4.71 (s, 1H), 4.62 (d, J = 15.1 Hz, 1H), 4.38 = 15.1, 2.1 _ 4.21 (m, 4H), 4.14 (s, 3H), 3.97 (dd, J Hz, 1H), 3.90 (s, 3H), 3.84 — 3.79 (m, 1H), 3.08 — 2.86 m, 1H ,221 d, J=146Hz, 1H,169 161 m, 1H. 113 169— 114 178— 115 189— 116 154— _4-——117 184— _——— 1H NMR (400 MHz, CDClg) 8 7.44 — 7.36 (m, 4H), 7.36 — 7.28 (m, 3H), 6.84 — 6.78 (m, 1H), 5.30 (s, 1H), 41450 4.87 (s, 1H), 4.25 (s, 1H), 3.98 (t, J = 15.7 Hz, 3H), 375 (s, 3H), 228 (s, 3H), 2.16 (d, J = 36.8 Hz, 2H), _——— WO 06280 Crnpd. LC/MS LC/RT 1H NMR (400 MHz, CDC13) 8 7.36 (dd, J = 8.5, 5.2 Hz, 2H), 7.09 (dd, J = 16.0, 7.5 Hz, 4H), 6.92 (d, J = 122 486.50 1.85 7.7 Hz, 1H), 5.30 (s, 1H), 4.85 (s, 1H), 4.38 — 4.27 (rn, 5H), 4.07 (s, 1H), 3.90 (s, 3H), 3.71 (s, 3H), 2.09 (s, 1H), 1.61 (s, 2H). _--— _--— 471.40 H NMR (400 MHz, CDC13) 2 conformers observed (ca. 30:70) 8 8.60 (br s, 1H), 7.87 - 7.72 (rn, 1H), 7.66 (dd, J = 22.8, 7.5 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.26 (br rn, 1H), 7.13 (d, J = 8.0 Hz, 1H), 5.36 (s, 30% of 1H), 5.29 (s, 70% of 1H), 4.95 48000 (s, 30% of 1H), 4.84 ' (s, 70% of 1H), 4.60 (br rn, 30% of 1H), 4.51 (br rn, 70% of 1H), 4.33-4.28 (rn, 1H), 4.23 _ 4.05 (rn, 3H), 4.02 (s, 70% of 3H), 3.97 (s, 30% of 3H), 3.94 — 3.69 (rn, 2H), 244 (brrn, 1H), 2.24 _ 1.96 (rn, 1H), 1.21 _ H NMR (400 MHz, CDClg) 8 740 (s,1H), 737 727 (H1, 2H), 724 (dd J=52, 36,Hz 1H), 712 (s 1H), 7.08 (dd, J = 8.2, 1.7 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 48623 ' 5.31 (s, 1H), 4.85 (s, 1H), 4.28 (t, J = 6.9 Hz, 2H), 4.25 — 393 (,rn 2H), 390 (s, 3H), 385 354 (rn, 3H), 2.70 HNMR (400 M,Hz CDC13) 8 752 (d, J: 74Hz, 2H), 7.=4,1(tJ 76,Hz 2H),7.,32(tJ— 7..3,,Hz1H)711- 132 48220 ' 683 (rn, 3H), 4.-59 390 (rn, 8H), 3.88 (s, 3H), 3.81 - H NMR (400 MHz, CDC13) 8 735 — 722 (rn, 6H), 722 71,7(rn 1H), 681 (d J=81,Hz 1H), 39,2(s 133 38040 . 1H), 3.82 (s, 2H), 3.49 (s, 2H), 2.28 (s, 3H), 2.14 (d, J ——41.4 Hz, 2H), 1.57 (d, J = 27.3 Hz, 2H), 1.38 (s, 6H), N0. M+1 mm _--— _--— !I!_HNMR(400MHz,CDC13)87.41-7.37 (m, 4H), 7.36- 7.28 (m, 1H), 7.11 (broad s, 1H), 7.08 (dd, J = 8.2, 1.8Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 5.30 (broad s, 1H),460.40 4.87 (s, 1H), 4.27 (broad m, 1H), 4.08 (d, J = 6.3 Hz, 2H, overlapped with broad s, 1H), 3.88 (s, 3H), 3.70 (broad s, 3H), 2.89- 2.61 (m, 3H), 2.61 - 2.35 (m, 2H), _——— H NMR (400 MHz, DMSO) 5 7.83 (t, J: 7.8 Hz, 1H), 7.64 (dd, J = 10.5, 7.7 Hz, 2H), 7.09 (s, 1H), 7.04 (s, 2H), 5.31 (s, 1H), 4.75 (s, 1H), 4.42 (dd, J = 5.3, 3.1 54710 Hz, 2H), 4.37 _ 4.22 (m, 3H), 4.04 — 3.85 (m, 1H), 3.81 (s, 3H), 3,—75 n 2H), 3,—55 34,3(rn1H),237- _———141i- 32912 _--— _--— 1H NMR (400 MHz, CDC13) 5 8.58 (s, 1H), 7.75 (s, 1H), 7.62 (d, J = 25.5 Hz, 2H), 7.44 (s, 1H), 7.26 (s, 1H), 6.93 (d, J = 8.2 Hz, 1H), 5.32 (s, 1H), 4.85 (s, 146 46520 1'56 1H), 4.40 (s, 1H), 4.09 (d, J = 5.2 Hz, 2H), 3.87 (t, J = 53.2 Hz, 4H), 2.69 (dd, J = 45.1, 10.2 Hz, 5H), 2.35 (s, 1H), 2.09 (d, J = 63.9 Hz, 1H), 1.58 (s, 3H). _--— _--— _--— --_Cmpd.LC/MS LC/RT H NMR (400 MHz, CDClg) 5 7.40 (dd, J = 7.6, 5.7 Hz, 4H), 7.36 _ 7.28 (m, 1H), 7.13 (s, 1H), 7.08 (dd, J = 8.2, 1.6 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 5.30 (s, 1H), 150‘-46826 4.87 (s, 1H), 4.37 — 4.26 (m, 4H), 4.08 (s, 1H), 3.90 (s, 3H), 371 (s, 2H), 220 (d, J=356Hz, 2H), 160 (s, _——H— _--— 53840 _--— _--— _——— H NMR (400 MHz, DMSO) 8 8.61 (d, J = 4.1 Hz, 1H), 7.89 (td, J = 7.8, 1.7 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.57 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.38 (dd, J ——7.0, 5.3 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 5.31 (s, 473 10 1H), 4.73 (s, 1H), 4.46 (dd, J = 5.5, 2.6 Hz, 2H), 4.40 (d, J = 4.6 Hz, 2H), 4.37 — 4.29 (m, 1H), 3.89 — 3.71 (m, 2H), 355 346 (m, 2H), 2.36 — 2.21 (m, 1H), 2.08 — _——— H NMR (400 MHz, CDClg) 5 7.46 7.36 (m, 5H), 7.31 (ddd, J = 6.7, 5.5, 2.4 Hz, 1H), 7.20 — 7.13 (m, 1H), 4.50 = 5.3, 3.1 Hz, 2H), — 4.32 (m, 3H), 4.30 (dd, J 471 40 4.05 (d, J = 4.4 Hz, 4H), 3.98 (s, 1H), 3.96 — 3.88 (m, 1H), 384 361 (m 1H), d, J=203, 121, 45 l45440I- 1H NMR (400 MHz, CDC13)8 7.39 (t, J: 4.5 Hz, 4H), 161 414.40 1.91 7.37 — 7.28 (m, 3H), 6.83 — 6.78 (m, 1H), 5.30 (s, 1H), Cmpd. LC/MS LC/RT 3.74 (s, 3H), 2.28 (s, 3H), 2.12 (s, 2H), 1.52 (d, J = 21.4 Hz, 7H . 1H NMR (400 MHz, CDC13) 5 7.42 (d, J = 7.5 Hz, 2H), 7.20 (t, J = 21.1 Hz, 3H), 5.30 (d, J = 28.2 Hz, 1H), 162 505.20 1.80 4.81 (d, J = 35.5 Hz, 1H), 4.39 (t, J = 39.8 Hz, 5H), 4.17 = 82.8, 67.7 Hz, 2H), — 3.60 (m, 7H), 2.18 (dd, J 1.63 s, 1H . 1H NMR (400 MHz, CDClg) 5 7.37 — 7.30 m, 1H), 7.11 (s, 1H), 7.10 — 6.95 (m, 3H), 6.92 (d, J = 8.2 Hz, 1H), 163 504.30 1.87 5.30 (br s, 1H), 4.79 (br s, 1H), 4.35 _ 4.20 (m, 5H), 4.05 — 3.92 (m, 1H), 3.89 (s, 3H), 3.82 — n, 3H), 164 48510 1.70— 165 453.10 1.53 166 475.10 1.51 1H NMR (400 MHz, CDC13) 5 7.81 (d, J = 3.2 Hz, 1H), 7.41 — 7.28 (m, 3H), 6.85 — 6.75 (m, 1H), 5.35 (s, 1H), 167 45930 1'76 .06(s,1H),4.33(dd,J=5.8,3.3Hz,3H),4.26-4.19 168 459.30 1.76 169 537.23 1.87 170 486.23 1.99 171 380.40 1.77 _--— _--— Cmpd. LC/MS LC/RT 1H NMR (400 MHz, CDC13) 5 7.11 (s, 1H), 7.06 (dd, J = 8.2, 1.9 Hz, 1H), 6.92 (d, J = 8.2 Hz, 3H), 6.80 — 6.72 174 506.30 1.91 (m, 1H), 5.29 (s, 0H), 4.83 (s, 0H), 4.38 _ 4.26 (m, 4H), 4.26 _ 4.13 (m, 1H), 4.05 (s, 1H), 3.90 (s, 3H), 3.72 (s, 3H), 2.10 (s, 2H). _-—— 176 494-23 193— 177 187 178 437.40 H NMR (400 MHz, CDC13) 5 8.76 (d, J: 5.0 Hz, 1H), 7.87 (s, 1H), 7.55 — 7.41 (m, 1H), 7.22 — 7.03 (m, 2H), 179 537.40 . 6.92 (d, J = 8.1 Hz, 1H), 5.36 (s, 1H), 4.88 (s, 1H), 4.54 -424 (m SH), 419 396 (m 1H),3.90(s,3H),3.90- H NMR (400 MHz, CDC13) 5 744 (d, J: 80 Hz, 1H), 7.4-.-0730 (m, 1H), 7.-.,20710(rn 3H), 7.04- 6.,95(rn 4.93 and 180 479 00 1H), 5.34 and 5.26 (2 s, 30%:70%, total 1H), 4.85 (2 s, 30%:70%, total 1H) 4.44 and 4.36 (2 , t, J = 4 1 Hz, 30%70%, total 1H), 4 17 351 (m, 9H), 287- H NMR (400 MHz, CDC13) 5 737 (td, J: 8 1, 59 Hz, 1H), 7.—20 710(rn, 3H), d J= 82,19Hz,1H), 181 488.40 . 7.01 (td, J = 8.0, 2.2 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 4.49 — 4.17 (m, 5H), 4.08 (s, 1H), 3.90 (s, 3H), 3.71 (s, 182 200 183 194 H NMR (400 MHz, CDC13) 8 7.38 (t, J = 7.0 Hz, 1H), 7.21 = 8.2, 1.9 Hz, 1H), 6.89 - 7.09 (m, 3H), 7.07 (dd, J (d, J = 8.2 Hz, 1H), 5.30 (broad s, 1H), 4.78 (broad s, 496.31 1H), 4.28 (broad s, 1H), 4.07 (d, J = 6.3 Hz, 2H), 3.99 (broad s, 1H), 3.88 (s, 3H), 3.77 (broad s, 3H), 2.88 - 2.58 (m, 3H), 2.58 - 2.42 (m, 2H), 2.36 (broad s, 1H), 2.11 (broad s, 1H). 2014/045675 Cmpd. LC/MS LC/RT 1H NMR (400 MHz, CDClg) 5 7.47 — 7.32 (m, 2H), 7.29 = 9.4, 7.7 Hz, 1H), 6.30 — 7.10 (m, 3H), 7.01 (dd, J = 29.8 Hz, 1H), 4.88 (d, J = — 5.92 (m, 1H), 5.30 (d, J 185 48940 1'84 27.8 Hz, 1H), 4.51 _ 4.30 (m, 3H), 4.14 — 3.88 (m, 6H), 3.82 — 3.57 (m, 1H), 2.18 (ddd, J: 23.1, 15.1, 9.9 Hz, 2H). _--— _--— 1H NMR (400 MHz, CDClg) 5 7.44 (d, J = 7.9 Hz, 1H), 7.36 (td, J = 8.0, 5.9 Hz, 1H), 7.16 (dd, J = 10.5, 7.3 Hz, 3H), 7.05 = 30.4 Hz, 1H), — 6.97 (m, 1H), 5.30 (d, J 188 48730 1'86 4.89 (d, J = 28.6 Hz, 1H), 4.47 — 4.25 (m, 5H), 4.04 (s, 4H), 3.96 (d, J = 14.8 Hz, 2H), 3.82 — 3.57 (m, 1H), 3.49 (s, 0H), 2.33 — 2.08 (m, 2H), 1.59 (s, 1H). 48940 H NMR (400 MHz, DMSO) 5 7.80 — 7.71 (m, 1H), 7.30 (d, J = 7.2 Hz, 2H), 7.16 (d, J = 7.2 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 5.29 (s, 1H), 4.76 (s, 1H), 4.49 — 4.42 (m, 2H), 4.33 — 4.26 (m, 48320 2H), 4.23 (dt, J = 9.7, 4.1 Hz, 1H), 3.86 (s, 3H), 3.82 — 3.70 (m, 1H), 3.70 — 3.59 (m, 1H), 3.59 — 3.45 (m, 1H), 340 334 (m 1H), 240—224 (m 1H), 219 (s 3H), _——— _--— 1H NMR (400 MHz, CDClg) 5 7.37 (td, J = 8.1, 5.9 Hz, 1H), 7.13 (dd, J = 12.9, 5.5 Hz, 3H), 7.07 (dd, J = 8.2, 1.8 Hz, 1H), 7.01 (td, J = 8.3, 2.4 Hz, 1H), 6.89 (d, J = 193 478.30 . 8.2 Hz, 1H), 5.31 (s, 1H), 4.86 (s, 1H), 4.24 (s, 1H), 4.08 (d, J = 6.3 Hz, 3H), 3.88 (s, 3H), 3.72 (d, J = 14.5 Hz, 2H), 349 (s, 0H), 285 262 (m, 3H), 258 —2.40 H NMR (400 MHz, DMSO) 5 774 (t, J: 77 Hz, 1H), 740 (d J=77,Hz 1H), 730 (s, 2H), 721 (d, J=77 194 467.20 . Hz, 1H), 7.01 (d, J = 9.0 Hz, 1H), 5.28 (s, 1H), 4.72 (s, 1H), 4.50 _ 4.39 (m, 2H), 4.39 — 4.20 (m, 3H), 4.20 — -_Cmpd.LC/MS LC/RT ---3.—56 346 (m, 1H), 248 (s, 3H), 2.36 -2.22(rn,1H),_--— _--— _--— _--— 491200!-00HNMR(400MHz, CDClg) 5 7.45 (d, J = 8.0 Hz, 1H),7.43 — 7.32 (m, 1H), 7.15 (d, J = 7.1 Hz, 2H), 7.09 (t, J——7.0 Hz, 1H), 7.05 — 6.95 (m, 1H), 5.30 (d, J = 31.1 Hz, 1H), 4.89 49330 (d, J = 28.8 Hz, 1H), 4.40 (dt, J = 28.2, 4.1 Hz, 1H), 4.08 (t, J = 7.0 Hz, 2H), 4.03 (s, 3H), 4.00 — 3.90 (m, 3H), 3.86 — 3.48 (m, J 16.2, 13.5, 5.4 Hz, 1H), 286 265 (m 2H), 2..48-210(rn, 5H), J _--— _--— _--— _--— _--— 46750'- _--— _--— WO 06280 Cmpd. LC/MS LC/RT No. M+1 min 210 445.50 0.92 211 477.00 1.79 212--— 213 --— 214 486.50 2.01 215 478.50 2.02 216-— LC/IRT 221 170 H NMR (400 MHz, CDClg) 8 7.44 (d, J = 7.9 Hz, 1H), 7.36 (td, J = 8.0, 5.9 Hz, 1H), 7.20 = 8.0 — 7.12 (m, J Hz, 2H), 7.09 (t, J = 7.0 Hz, 1H), 7.04 — 6.96 (m, 1H), 519.20 5.30 (d, J = 31.5 Hz, 1H), 4.89 (d, J = 29.1 Hz, 1H), 4.52 _ 4.22 (m, 1H), 4.13 _ 4.04 (m, 2H), 4.03 (s, 3H), 402 391 (m, 4H), 384 349 (m, 1H), 287 2.70 H NMR (400 MHz, CDClg) 8 742 (d, J: 77 Hz, 1H), 736 (dd, J: 140, 80 Hz, 1H), 723 711 (m, 3H), 7.08 = 29.9 Hz, 1H), 4.89 (d, — 6.95 (m, 1H), 5.30 (d, J 49320 J = 28.3 Hz, 1H), 4.40 (d, J = 27.3 Hz, 2H), 4.07 (s, 1H), 4.02 (s, 3H), 3.96 (s, 2H), 3.86 — 3.53 (m, 1H), 281 _ 235 (m, 5H), 2.35 — 2.07 (m, 2H), 1.28 (d, J = H NMR (400 MHz, CDClg) 8 713 — 700 (m, 2H), 6.—96 n 3H), 67,6(tt J: 87, 23,Hz 1H), 531 496.40 (s, 1H), 4.85 (s, 1H), 4.37 — 4.13 (m, 1H), 4.12 — 3.95 (m, 3H), 389 (s, 3H), 384 354 (m, 3H), 2.—86 2.59 H NMR (400 MHz, CDC13)8 876 (d, J: 50 Hz, 1H), 787 (s 1H), 7.—57 740 (m 1H), 718 701 (m, 2H), 6.89 (d, J = 8.1 Hz, 1H), 5.36 (s, 1H), 4.89 (s, 1H), 4.55 529.40 = 6.3 Hz, — 4.18 (m, 1H), 4.16 — 4.09 (m, 1H), 4.08 (d, J 2H), 3.95 — 3.89 (m, 1H), 3.89 (s, 3H), 3.88 — 3.60 (m, 2H, 2.87 — 2.60 m, 3H, 2.60 — 2.40 m, 2H, 2.40 — WO 06280 Cmpd. LC/MS LC/RT _--— 227--— 1H NMR (400 MHz, CDClg) 5 7.37 (td, J = 8.1, 6.0 Hz, 1H), 7.13 (d, J = 3.4 Hz, 3H), 7.08 (d, J = 8.2 Hz, 1H), 228 486.50 1.77 7.05 — 6.97 (m, 1H), 6.92 (d, J = 8.2 Hz, 1H), 5.31 (s, 1H), 4.86 (s, 1H), 4.29 (tt, J = 90.1, 45.2 Hz, 6H), 3.90 229 1.88 230 1.92 231 1.99 232 2.15 1H NMR (400 MHz, CDClg) 5 7.43 (d, J = 7.8 Hz, 1H), 7.36 (dd, J = 14.0, 7.9 Hz, 1H), 7.15 (d, J = 7.4 Hz, 2H), 6.99 (dt, J = 14.4, 7.5 Hz, 2H), 5.30 (d, J = 29.9 233 465.20 1.41 Hz, 1H), 4.89 (d, J = 28.3 Hz, 1H), 4.69 (s, 1H), 4.39 (dt, J = 6.8, 3.7 Hz, 1H), 4.05 (s, 3H), 4.11 — 3.89 (m, 3H), 3.83 — 3.54 (m, 1H), 3.21 — 3.05 (m, 2H), 2.95 — 2.76 m, 2H . . . 1H NMR (400 MHz, CDClg) 5 7.50 — 7.30 (m, 2H), 7.30 = 7.5 Hz, 2H), 7.01 (dd, — 7.21 (m, 1H), 7.15 (d, J J = 9.6, 7.7 Hz, 1H), 6.38 — 5.94 (m, 1H), 5.30 (d, J = 28.7 Hz, 1H), 4.88 (d, J = 27.5 Hz, 1H), 4.81 — 4.65 (m, 234 503.20 1.52 1H), 4.39 (dt, J = 33.8, 4.0 Hz, 1H), 4.10 _ 4.04 (m, 1H), 4.04 (s, 3H), 4.00 — 3.87 (m, 2H), 3.82 — 3.51 (m, 1H), 2.19 (ddd, J = 23.4, 15.0, 10.0 Hz, 2H), 1.48 (d, J 1H NMR (400 MHz, CDClg) 5 7.44 (d, J = 8.0 Hz, 1H), 7.36 (td, J = 8.0, 5.8 Hz, 1H), 7.23 — 7.08 (m, 3H), 7.00 (td, J = 7.8, 7.3, 2.1 Hz, 1H), 5.30 (d, J = 31.2 Hz, 1H), 235 493.10 1.64 4.89 (d, J = 28.9 Hz, 1H), 4.53 _ 4.26 (m, 1H), 4.13 _ 3.88 (m, 7H), 3.83 — 3.51 (m, 1H), 2.82 _ 2.64 (m, 1H), 2.37 (dd, J = 22.7, 11.8 Hz, 1H), 2.32 _ 1.89 (m, 5H), 237 505.30 1.98 WO 06280 Cmpd. LC/MS LC/RT No. M+1 min 238 441.30 1.43 239 502.00 7.17 240-— 241 442.00 7.13 242-— 1H NMR (400 MHz, CDClg) 5 7.40 (s, 1H), 7.37 — 7.21 (m, 3H), 7.13 (s, 1H), 7.03 (s, 2H), 5.30 (s, 1H), 4.85 (s, 1H), 4.61 (dt, J = 12.7, 6.3 Hz, 1H), 4.48 — 3.98 (m, 2H), 3.90 (s, 3H), 3.87 — 3.39 (m, 3H), 2.35 — 1.88 (m, 2H), 1.52 (d, J = 6.5 Hz, 3H). 1H NMR (400 MHz, CDClg) 5 7.40 (s, 1H), 7.36 — 7.27 (m, 2H), 7.27 _ 7.21 (m, 1H), 7.13 (s, 1H), 7.03 (s, 2H), .30 (s, 1H), 4.84 (s, 1H), 4.60 (hept, J = 6.4 Hz, 1H), 4.42 — 3.96 (m, 2H), 3.90 (s, 3H), 3.84 — 3.48 (m, 3H), 246——— 247——— WO 06280 Cmpd. LC/MS No. M+1 LC/IRT I-54140I-n0150-— 1H NMR (400 MHz, CDC13) 8 8.77 (d, J = 5.0 Hz, 1H), 7.87 (s, 1H), 7.46 (dd, J = 5.0, 1.0 Hz, 1H), 7.31 — 6.98 521 40 (m, 2H), 6.91 (d, J = 8.2 Hz, 1H), 5.36 (s, 1H), 4.89 (s, 252i-1H), 4.56 _ 4.33 (m, 1H), 4.28 (t, J = 6.9 Hz, 2H), 4.17— 4.01 (m, 1H), 3.90 (s, 3H), 4.02 — 3.50 (m, 3H), 2.70(qt, J: 106, 69,Hz 2H), 225 (d J=439,Hz 2H)47800——45750 _--— _--— 1H NMR (400 MHz, CDC13) 8 7.45 — 7.26 (m, 3H), 7.22 - 7.06 (m, 2H), 7.08 - 6.93 (m, 1H), 6.87 - 6.72 (m, 1H), 5.31 (broad s, 1H), 4.86 (broad s, 1H), 4.22 256 43250 1'88 (broad s, 1H), 3.96 (d, J = 16.4 Hz, 2H, overlapped with broad s,1H), 3.72 (broad s, 3H), 2.28 (s, 3H), 2.25 H NMR (400 MHz, CDC13) 8 7.38 (t, J: 6. 9 Hz, 1H), 7.21 -7.09 (m, 3H), 7.02 (d, J=8.4Hz, 2H), 5.30 (s, 257 48810 1'63 1H), 4.77 (bs, 1H), 4.61 (dt, J = 12.7, 6.3 Hz, 1H), 4.28 (bs, 1H), 4.04 - 3.92 (m, 1H), 3.89 (s, 3H), 3.87 - 3.67 (m, 3H), 2.45 - 2.26 (m, 1H), 2.24 - 2.08 (m, 1H), 1.51 2014/045675 --_Cmpd.LC/MS LC/RT H NMR (400 MHz, CDClg) 5 7.38 (t, J = 7.0 Hz, 1H), 7.20 — 7.08 (m, 3H), 7.07 — 6.95 (m, 2H), 5.30 (s, 1H), 4.77 (s, 1H), 4.60 (dt, J = 12.8, 6.4 Hz, 1H), 4.28 (bs, 488 10 1H), 4.03 — 3.92 (m, 1H), 3.89 (s, 3H), 3.86 — 3.63 (m, 3H), 244 22,8(111 1H), 22.,7-208(rn 1H), 15,2(d J _——— _--— _--— _--— _--— _--— _--— 1H NMR (400 MHz, DMSO-d6) 5 8.45 (d, J = 3.5 Hz, 1H), 7.71 (td, J = 7.8, 1.9 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.16 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.05 — 7.00 (m, 2H), 6.95 (dd, J = 8.2, 1.9 Hz, 1H), 4.46 — 4.37 (m, 266 43720 0'83 2H), 4.31 - 4.23 (m, 2H), 3.89 (br s, 1H), 3.79 (s, 3H), 3.61 (br s, 1H), 3.53 (br s, 1H), 3.28 (br s, 1H), 2.59 (br s, 1H), 2.10 (br s, 1H), 1.70 (br s, 1H), 1.28 (dd, J = 8.9, 4.4 Hz, 1H 1.05 , brs, 1H 1.95 — 1.55 , m, 1H. 530.00I- 49700'- _--— _--— _--— WO 06280 Cmpd. LC/MS LC/RT No. M+1 min 272 538.24 1.85 273-— 274 521.24 1.85 275 529.30 1.91 276--— 277--— 278 467.20 0.98 1H NMR (400 MHz, MeOD) 5 7.45 — 7.37 (m, 1H), 7.33 — 7.21 (m, 4H), 7.07 — 6.98 (m, 1H), 4.45 — 4.30 284 445.00 1.50 (m, 1H), 4.25 _ 4.15 (m, 1H), 4.07 — 3.92 (m, 6H), 3.92 — 3.79 (m, 1H), 3.71 (dd, J = 8.3, 3.0 Hz, 1H), 2.91 _ WO 06280 Cmpd. LC/MS LC/RT No. M+1 min 285 437.20 0.85 286--— 287--— 288 --— 289--— 290--— 291--— 292--— 293 --— 294--— 295 473.10 1.90 296--— 297--— 298 446.20 1.96 299-— 2014/045675 Cmpd. LC/MS LC/RT No. M+1 min 300 454.10 1.94 301 458-10 2-08— 1H NMR (400 MHz, CDClg) 5 7.40 (dd, J = 7.7, 5.8 Hz, 4H), 7.36 _ 7.28 (m, 1H), 7.13 (s, 1H), 7.08 (dd, J = 302 470.40 1.81 8.2, 1.8 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 4.55 — 3.96 (m, 6H), 3.90 (s, 3H), 3.71 (s, 3H), 2.09 (d, J = 38.5 Hz, 2H 1.60 , s, 2H ,0.05——0.05 m, 3H. 303 456-40 1-32— 304 475.10 1.56 1H NMR (400 MHz, CDClg) 5 8.60 (d, J = 3.9 Hz, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.29 (s, 1H), 7.14 (s, 1H), 305 471.40 1.37 7.10 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 4.45 (s, 1H), 4.38 _ 4.21 (m, 4H), 4.08 (s, 1H), 3.90 (s, 4H), 3.76 s, 2H ,2.28 d,J=91.8 Hz, 2H . 306 1.82 307 1.93 308 1.89 309 1.94 310 1.19 311 491.00 1.27 312-— Cmpd. LC/MS LC/RT No. M+1 min 313 473.00 1.22 1H NMR (400 MHz, DMSO) 5 7.73 (dd, J = 8.0, 7.6 Hz, 1H), 7.20 — 6.93 (m, 4H), 6.77 — 6.65 (m, 1H), 5.30 (s, 1H), 4.76 (s, 1H), 4.42 (dd, J = 5.3, 3.0 Hz, 2H), 314 541.30 2.06 4.33 = — 4.15 (m, 3H), 4.10 — 3.97 (m, 2H), 3.90 (dd, J 7.2, 5.3 Hz, 1H), 3.80 (s, 3H), 3.76 — 3.67 (m, 1H), 3.66 — 3.48 (m, 2H), 2.40 _ 2.11 (m, 1H), 2.11 _ 1.82 (m, ASSA YS FOR DETECTING AND MEASURING NaVINHIBITIONPROPERTIES OF COMPOUND E-VIPR o tical membrane otential assa method with ical stimulation

[00430] Sodium channels are e-dependent proteins that can be activated by inducing membrane voltage changes by applying ic fields. The electrical ation ment and methods of use are described in Ion Channel Assay Methods PCT/USO 1/2 1 652, herein incorporated by reference and are referred to as E-VIPR. The instrument comprises a microtiter plate handler, an optical system for exciting the in dye while simultaneously recording the coumarin and oxonol emissions, a waveform tor, a current- or voltage-controlled amplifier, and a device for inserting electrodes in well. Under integrated computer control, this instrument passes user-programmed electrical stimulus protocols to cells within the wells of the microtiter plate.

[00431] 24 hours before the assay on E-VIPR, HEK cells expressing human NaV subtype, like NaV 1.7, are seeded in 384-well poly-lysine coated plates at ,000-20,000 cells per well. Other subtypes are performed in an analogous mode in a cell line expressing the NaV of interest. HEK cells are grown in media (exact composition is specific to each cell type and NaV subtype) supplemented with 10% FBS (Fetal Bovine Serum, qualified; GibcoBRL #16140-071) and 1% Pen-Strep (Penicillin-Streptomycin; GibcoBRL #15140-122). Cells are grown in vented cap flasks, in 90% humidity and 10% C02, to 100% confluence. They are usually split by trypsinization 1:10 or 1:20, depending on scheduling needs, and grown for 2-3 days before the next split.

Reagents and Solutions: 100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO Compound Plates: 384-well round bottom plate, e.g. Corning 384-well Polypropylene Round Bottom #3656 ] Cell Plates: 384-well tissue culture treated plate, e.g. Greiner #781091-1B 10 mM DiSBAC6(3) (Aurora #00010) in dry DMSO 10 mM CC2-DMPE (Aurora #00008) in dry DMSO 200 mM ABSC1 in H20 Bathl buffer. Glucose 10mM (1.8g/L), Magnesium Chloride (Anhydrous), 1mM (0.095g/L), Calcium Chloride, 2mM (0.222g/L), HEPES 10mM /L), Potassium de, 4.5mM (0.335g/L), Sodium Chloride 160mM (9.35 g/L).

] Hexyl Dye Solution: Bathl Buffer + 0.5% odextrin (make this prior to use, Sigma #C4767), 8 uM CC2-DMPE + 2.5 uM DiSBAC6(3). To make the solution Add volume of 10% ic F127 stock equal to volumes of CC2- DMPE + 6(3). The order of preparation is first mix Pluronic and CC2-DMPE, then add DiSBAC6(3) while vortexing, then add Bathl + B-Cyclodextrin.

Assay Protocol.' 1) ot compounds (in neat DMSO) into compound plates.

Vehicle control (neat DMSO), the positive control (20mM DMSO stock tetracaine, 125 uM final in assay) and test compounds are added to each well at 160x desired final concentration in neat DMSO. Final compound plate volume will be 80 ML (80- fold intermediate on from 1 uL DMSO spot; 160-fold final dilution after transfer to cell plate). Final DMSO concentration for all wells in assay is 0.625%. 2) Prepare Hexyl Dye Solution. 3) Prepare cell plates. On the day of the assay, medium is ted and cells are washed three times with 100 uL of Bathl Solution, maintaining uL residual volume in each well. 4) se 25 uL per well of Hexyl Dye Solution into cell plates. Incubate for 20-35 minutes at room temp or ambient conditions. 5) Dispense 80 uL per well of Bathl into compound plates.

Acid Yellow-l7 (1 mM) is added and Potassium Chloride can be altered from 4.5 to 20 mM depending on the NaV subtype and assay sensitivity.

[00445] 6) Wash cell plates three times with 100 uL per well of Bathl, leaving 25 uL of residual volume. Then transfer 25uL per well from Compound Plates to Cell . Incubate for 20-35 minutes at room temp/ambient ion 7) Read Plate on E-VIPR. Use the current-controlled amplifier to deliver stimulation wave pulses for typically 9 seconds and a scan rate of 400Hz. A imulus recording is performed for 0.5seconds to obtain the un-stimulated intensities baseline. The stimulatory waveform is applied for 9 seconds followed by 0.5 seconds of post-stimulation ing to e the relaxation to the resting state.

The stimulatory waveform of the electrical stimulation is specific for each cell type and can vary the magnitude, duration and frequency of the applied current to provide an optimal assay signal.

Data Analysis Data are analyzed and ed as normalized ratios of background-subtracted emission ities measured in the 460 nm and 580 nm channels. Background intensities are then subtracted from each assay channel.

Background intensities are obtained by measuring the emission intensities during the same time periods from cally treated assay wells in which there are no cells.

The response as a function of time is then reported as the ratios ed using the following formula: (intensity 460 nm - background 460 11m) R(t) = --------------------------------------------- (intensity 580 nm - background 580 nm) The data is r reduced by calculating the initial (R) and final (Rf) ratios. These are the average ratio values during part or all of the pre- stimulation period, and during sample points during the stimulation period. The response to the stimulus R = Rf/Ri is then calculated and reported as a function of time.

Control responses are obtained by performing assays in the presence of a compound with the desired properties (positive control), such as tetracaine, and in the absence of pharmacological agents (negative control). Responses to the ve (N) and positive (P) controls are calculated as above. The compound antagonist activity A is defined as: A _fl* 100 N — P where R is the ratio response of the test compound ELECTROPHYSIOLOGYASSAYSFOR IVITYAND INHIBITION OF TEST COMPOUNDS

[00450] Patch clamp electrophysiology was used to assess the efficacy and selectivity of sodium channel blockers in dorsal root ganglion neurons. Rat s were isolated from the dorsal root ganglions and maintained in culture for 2 to days in the presence ofNGF (50 ng/ml) (culture media consisted ofNeurobasalA supplemented with B27, glutamine and antibiotics). Small diameter neurons (nociceptors, 8-12 um in diameter) have been visually identified and probed with fine tip glass electrodes connected to an amplifier (Axon Instruments). The “voltage clamp” mode has been used to assess the compound’s ICSO g the cells at — 60 mV. In on, the “current clamp” mode has been employed to test the efficacy of the compounds in blocking action potential generation in response to current injections. The results of these experiments have contributed to the ion of the efficacy profile of the compounds. ks .

Sodium ts were recorded using the automated patch clamp system, IonWorks (Molecular Devices Corporation, Inc.). Cells expressing Nav subtypes are harvested from tissue culture and placed in suspension at 0.5-4 million cells per mL Bathl. The IonWorks instrument measures s in sodium ts in response to applied voltage clamp similarly to the traditional patch clamp assay, except in a 384-well format. Using the ks, dose-response relationships were determined in voltage clamp mode by depolarizing the cell from the experiment specific holding ial to a test potential of about 0 mV before and following addition of the test compound. The influence of the compound on currents are measured at the test potential. azepin-Z-one binding assay

[00452] The sodium channel inhibiting properties of the compounds of the ion can also be determined by assay methods described in Williams, B. S. et al., “Characterization of a New Class of Potent Inhibitors of the Voltage-Gated Sodium Channel NaV 1.7,” Biochemistry, 2007, 46, 14693-14703, the entire contents of which are incorporated herein by reference.

[00453] The exemplified compounds of Table 1 herein are active against one or more sodium channels as measured using the assays described herein above as presented in Table 4.

Table 4.

IC50: +++ <2 2.0 uM< ++ <2 5.0 uM IC50: +++ <2 2.0 uM< ++ <2 5.0 uM < + < + Cmpd. Binned Activity Cmpd. Binned Activity No. Data No. Data +++ 15 ++ +++ 16 ++ +++ 17 ++ ++ 18 ++ 19 ++ ++ 21 ++ 22 ++ 23 ++ 24 ++ ++ 26 ++ ++ 28 WO 06280 ICSO: +++ <2 2.0 MM< ++ <2 5.0 MM ICSO: +++ <2 2.0 uM< ++ <2 5.0 MM < + < + O5%9- IIBinned Activity O5%9- IIBinned Activity SE,9: 53’,9: +++ +++ +++ \]N +++ +++ +++ +++ —\]J; +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ —\]O +++ +++ +++ I ++ —J;N + — -_ + —##J> GUI-h II+ —U:N ++ —\oJ; + m- —O\] —O\N — —O\J> -_ — —O\ \l — m. — —\lO — WO 06280 ICSO: +++ <2 2.0 MM< ++ <2 5.0 MM ICSO: +++ <2 2.0 uM< ++ <2 5.0 MM < + < + Binned Activity Binned Activity I:0 IISE,9: I:0 II53’,a: —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ —+++ — +++ 2014/045675 ICSO: +++ <2 2.0 MM< ++ <2 5.0 MM ICSO: +++ <2 2.0 uM< ++ <2 5.0 MM < + < + Binned Activity Binned Activity Z0 IISE,9: Z0 II53’,9: —+++ — +++ —+++ — +++ —+++ — ++ —+++ — —+++ — —+++ — —+++ — —+++ — —II — —+ — — ++ — — + — + — ++ — + —+ — + — —+ — —II+ — —I ICSO: +++ <2 2.0 nM< ++ <= 5.0 MM ICSO: +++ <2 2.0 nM< ++ <2 5.0 MM < + < + Binned Activity w:FL Binned Activity I:o I)ata I:o I)ata —+++ +++ —+++ +++ —+++ +++ —+++ +++ —+++ +++ +++ +++ — +++ ||||||||||||||||||||||||||||||||||||||||||||||||||||||%i — +++ —+++ +++ —+++ +++ — +++ — +++ — +++ — +++ — +++ — +++ —II++ ++ 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 specific embodiments described herein are d by way of example only.

Claims (19)

We claim :

1. A compound of formula I: 5 or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence, O O O O O O ring A is O , O , , , O , O , , D F O D, F or ; ring B is ed from a pyridyl, thiazole, pyrimidine, pyrazole, furan, 10 thiophene, pyrrole, e, imidazole, isoxazole, isothiazole, pyridazine, pyrazine F F F Cl F CN ring, , , , , , , , F CF3 Br N N S N N N N N F O , , , , , , , O O Cl CF3 S S N N N N N N N , , , , , , , O O O N N N N N F O , , , , or ; O F3C O O O O O F ring C is ed from CF3 , F , , OH, O O O Cl O Cl O CF3 CF3 , , F F , CF3 , OH , OH , , Cl Cl O O O O O 5 , CF3 , , HO , , OH , OH , O Cl O O O O O O F F O O F F F F , , CF3 , CF3 , CF3, F F , O O O CF3 O O O O S O F HO O F OH , , , , F F , , F F3C CF3 O O O O O F F F F OH , , F3C , CF3 , F F , O CF3 O NC O O CF3 , F , F3C , F F , , O O F O O F O 5 F F3C , F , F , OH , CF3 , F F , Cl Cl F O O O S O F NH O S O F Cl O O CF3 , , , F , OH , , , Cl O CF3 O O O O O O O F F , F , , F F , F , O O Cl O O O F F , , CF3 , or ; R1 is C1-C6 alkyl, C1-C6 alkoxy, halo, fluoro-C1-C6 alkyl, -C1-C6 5 alkoxy, or oxo; R3 is C1-C6 alkyl, C1-C6 alkoxy, halo, CN, fluoro-C1-C6 alkyl, or -C1- C6 alkoxy; and n and p are integers from 0 to 4 inclusive.

2. The compound of claim 1, wherein R1 is C1-C6 alkyl, halo, or oxo. 10

3. The compound of claim 1, wherein R1 is CH3, F, or oxo.

4. The compound of any one of claims 1 to 3, wherein R3 is C1-C6 alkyl.

5. The compound of any one of claims 1 to 4, wherein R3 is CH3.

6. The compound of claim 1, wherein ring C is .

7. The compound of claim 1, wherein ring C is CF3 .

8. The compound of claim 1, wherein the compound has formula IA: 5 or a pharmaceutically able salt thereof, wherein, O F3C O O R5 O F R6 is selected from CF3 , F , , O O O O Cl OH, CF3 , , F F , CF3 , OH , Cl Cl O O O F CF3 O OH , , , CF3 , , HO , , O O O O O F F O O OH , OH , F F , , CF3 , CF3 , O O O O O O O O F F F HO O CF3 , F F , OH , , , , CF3 CF3 O O O O O S O O F F F 5 F F , , OH , , F3C , CF3 , O O CF3 F F O F F , CF3 , F , F3C , F F , O O NC F , F, F F , OH , CF3 , F Cl Cl O O O S O F NH O S O F Cl O CF3 , , , F , OH , , F F , O CF3 O O O O O O F , F F F , , F F , , or 5 CF3 .

9. The compound of claim 1, wherein the compound has formula IB: (R2)o O N or a pharmaceutically acceptable salt f, 5 wherein, independently for each occurrence, F F F Cl is selected from , , , , , F CN F F F , , or ; O F3C O O O O O F is ed from CF3 , F , , OH, O O O Cl O Cl O CF3 CF3 , , F F , CF3 , OH , OH , , Cl Cl O O O O O , CF3 , , HO , , OH , OH , O Cl O O O O O O F F O O F F F F , , CF3 , CF3 , CF3, F F , O O O CF3 O O O O S O F HO O F 5 OH , , , , F F , , F F3C CF3 O O O O O F F F F OH , , F3C , CF3 , F F , O CF3 O NC O O CF3 , F , F3C , F F , , O O Cl F O S O F , F , F OH , CF3 , F CF3 , , Cl Cl O O O O S O F Cl O , F , OH , , F F , F , , O O Cl O F F 5 F F , F , , or CF3 .

10. A nd selected from: 335335 337337 340340 342342 343343 345345 350350 352352 353353 355355

11. A nd selected from: 360360 361361 362362 364364 367367 369369 370370 372372 373373 375375 377377 378378 379379 380380 381381 382382

12. A pharmaceutical ition comprising the compound of any one of claims 1 to 11 and a pharmaceutically acceptable carrier.

13. An in vitro method of inhibiting a voltage-gated sodium ion channel in a 5 biological sample; comprising contacting the biological sample, with the compound or composition of any one of claims 1 to 12.

14. The in vitro method of claim 13, wherein the voltage-gated sodium ion channel is NaV 1.7.

15. Use of the compound of any one of claims 1 to 11 in the manufacture of a 10 medicament for inhibiting a voltage gated sodium ion channel in a human patient.

16. The use of claim 15, n the voltage-gated sodium ion channel is NaV 1.7

17. Use of the compound according to any one of claims 1 to 11 in the manufacture of a medicament for treating or lessening the severity of the pain in a human t afflicted with acute, c, neuropathic, or inflammatory pain, 15 arthritis, migraine, r headaches, trigeminal neuralgia, herpatic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, dipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine ers, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, 20 diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or table pain, nociceptive pain, breakthrough pain, postsurgical pain, cancer pain, , cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stressor exercise induced angina, palpitations, hypertension, migraine, or abormal intestinal motility.

18. The use according to claim 17, wherein the medicament is for treating or lessening the severity of the pain in a subject afflicted with femur cancer pain; nonmalignant chronic bone pain; rheumatoid arthritis; rthritis; spinal stenosis; neuropathic low back pain; athic low back pain; myofascial pain syndrome; 5 fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic; IBS pain; chronic and acute headache pain; migraine; tension headache, cluster headaches; chronic and acute neuropathic pain, post-herpatic neuralgia; diabetic athy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie Tooth neuropathy; tary sensory neuropathies; peripheral nerve injury; painful 10 neuromas; ectopic proximal and distal discharges; radiculopathy; herapy induced neuropathic pain; radiotherapy-induced neuropathic pain; post-mastectomy pain; l pain; spinal cord injury pain; post-stroke pain; ic pain; x regional pain syndrome; phantom pain; intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; 15 neck pain; tendonitis; injury/exercise pain; acute visceral pain, nal pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory, burn and trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; 20 breakthrough pain; orofacial pain, sinusitis pain, dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; l legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; r and urogenital disease, urinary incontinence; hyperactivity bladder; painful r syndrome; interstitial cyctitis 25 (IC); prostatitis; complex regional pain syndrome (CRPS), type I and type II; widespread pain, paroxysmal extreme pain, is, tinnitis, or angina-induced pain.

19. The compound according to any one of claims 1, 10 or 11, substantially as herein described with reference to any one of the Examples thereof.