HK1203074B - Pyran-spirocyclic piperidine amides as modulators of ion channels - Google Patents

Description

Pyran-spirocyclic piperidine amides as modulators of ion channels

Cross Reference to Related Applications

This application claims the benefit of U.S. provisional patent application No.61/586,875 filed on day 1, 16, 2012, the entire contents of which are incorporated herein by reference.

Technical Field

The present invention relates to compounds useful as inhibitors of ion channels. 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.

Background

Pain is a protective mechanism that allows healthy animals to avoid tissue damage and prevent further damage to injured tissue. However, in many cases, pain persists beyond its usefulness, or the patient will benefit from pain suppression. Voltage-gated sodium channels are thought to play a key role in pain signaling. The belief is based on The known role of these channels in normal physiology, pathological states caused by mutations in The Sodium channel genes, preclinical studies in animal models of disease, and The clinical usefulness of known Sodium channel modulators (Cummins, T.R., sheeps, P.L., and Waxman, S.G., The role of Sodium channels in pathology: Imanicons for mechanisms of pain. Pain131(3), 243(2007), England, S.S., volume-gated Sodium channels: The search for type selectivity. expression approach 17(12), 1849(2008), Kraft, D.S. and Bannon, A.W., colloidal channel expression approach 2008. expression approach 1.2008).

Voltage-gated sodium channels (navs) are key biological mediators of electrical signal transduction. NaV is the main mediator of the rapid upstroke of action potentials of many excitable cell types (e.g. neurons, skeletal muscle cells, cardiac muscle cells) and is therefore critical for the initiation of signal transduction in those cells (Hille, Bertil, Ion Channels of extrinsic electromagnetic fibers, third edition (Sinauer Associates, inc., Sunderland, MA, 2001)). Antagonists that reduce NaV current may prevent or reduce nerve signal conduction due to the role NaV plays in the initiation and propagation of neuronal signals. Thus, NaV channels are likely to be considered Targets in pathological conditions where reduced excitability is predicted to reduce clinical symptoms such as pain, epilepsy and some arrhythmias (channel, m., Chatelier, a., Babich, o., and Krupp, j.j., Voltage-gated sodium channels in neurological disorders drugs 7(2), 144 (2008)).

NaV forms a subfamily of the voltage-gated ion channel superfamily and contains 9 isoforms, designated NaV1.1-NaV1.9. The tissue localization of the 9 isoforms is greatly different. Nav1.4 is the major sodium channel of skeletal muscle, and nav1.5 is the major sodium channel of cardiomyocytes. Nav1.7, 1.8 and 1.9 are located primarily in the peripheral nervous system, while nav1.1, 1.2, 1.3 and 1.6 are neuronal channels found in the central and peripheral nervous systems. The nine isoforms behave functionally similarly, but differ in their characteristics of voltage-dependent and kinetic behavior (Catterall, W.A., Goldin, A.L., and Waxman, S.G., International Union of pharmacology.XLVII. nomenclature and structure-function relationships of voltage-controlled sodium channels. pharmaceutical Rev 57(4), 397 (2005)).

NaV channels have been identified as The primary targets of several clinically useful pain-reducing agents (Cummins, T.R., Sheets, P.L., and Waxman, S.G., The roles of sodium channels in nociception: antibiotics for mechanisms of pain. Pain131(3), 243 (2007)). Local anesthetics such as lidocaine block pain by inhibiting NaV channels. These compounds provide excellent local pain relief, but have the disadvantage of eliminating normal acute pain and sensory input. Systemic administration of these compounds causes dose-limiting side effects, which are generally attributed to blockade of nerve channels in the CNS (nausea, sedation, confusion, ataxia). Cardiac side effects may also occur and in fact these compounds are also used as class 1 antiarrhythmics, presumably due to blockade of the nav1.5 channel in the heart. Other compounds that have been shown to be effective in reducing Pain through sodium channel blockade have also been suggested, including carbamazepine, lamotrigine, and tricyclic antidepressants (Soderpalm, b., antinovusants: aspects of the mechanisms of action. eur J Pain 6 supplement a, 3 (2002); Wang, g.k., Mitchell, J., and Wang, s.y., Block of persistent late Na + currents by anti-inflammatory drug cascade and J.membr Biol 222(2), 79 (2008)). These compounds are also dose-limited due to side effects similar to those seen with the use of local anesthetics. Antagonists that specifically block only isoforms important for nociception are expected to have increased efficacy, as the reduction in side effects caused by blocking off-target channels should enable higher dosing and thus more complete blocking of target channel isoforms.

Four NaV isoforms have been specifically shown, NaV1.3, 1.7, 1.8 and 1.9, may be pain targets. In humans and rodents, nav1.3 is typically found only in the painful sensory neurons of the Dorsal Root Ganglia (DRGs) at an early stage of development and is lost shortly after birth. However, it has been found that damage to damaged nerves leads to the return of nav1.3 channels into DRG neurons, and this can promote abnormal pain signaling in various chronic pain conditions (neuropathic pain) caused by nerve damage. These data suggest that drug blockade of nav1.3 may be an effective treatment for neuropathic pain. Contrary to this view, in a mouse model of neuropathic Pain, a global gene knockout of NaV1.3 in mice does not prevent the development of allodynia (Nassar, m.a. et al, new inner Nerve hubs robustalone and interactive dischargin NaV1.3 null tissue. mol Pain 2, 33 (2006)). Whether compensatory changes in other channels allow normal neuropathic pain in nav1.3 knockout mice is not known, but it has been reported that the knockdown of nav1.1 results in a dramatic upregulation of nav 1.3. These results can be explained by the reaction of the nav1.3 knockout.

Nav1.7, 1.8 and 1.9 are highly expressed in DRG neurons, including neurons whose axons constitute C-fibers and a-fibers (believed to carry the majority of pain signals from the nociceptive terminalia to the central nerve). Similar to nav1.3, expression of nav1.7 increases after nerve injury and can contribute to neuropathic pain conditions. The localization of nav1.7, 1.8 and 1.9 in nociceptors leads to the hypothesis that reducing sodium current through these channels may reduce pain. Indeed, specific interventions that reduce the levels of these channels have proven effective in animal models of pain.

Specific reduction of nav1.7 in rodents by a number of different techniques results in a reduction in observable pain behaviour in model animals. Injection of the viral antisense NaV1.7cDNA construct greatly reduces the normal pain response caused by inflammation or mechanical injury (Yeomans, D.C. et al, Desrea in infllammatory hyperalgesia by human vector-mediated knockdown of NaV1.7 sodium channels in primary enzymes The HumGene Ther 16(2), 271 (2005)). Also, gene knock-out of NaV1.7 in a subset of Nociceptor neurons reduced acute and inflammatory pain in a mouse model (Nassar, m.a. et al, Nociceptor-specific genetic evaluation novalac a major role for NaV1.7 (PN1) in acid and inflamamatoxypain. proc Natl Acad Sci U S101 (34), 12706 (2004)). A full knockout of nav1.7 in mice results in death of the animal on the first day after birth. These mice were unable to feed, which is the presumed cause of death.

Treatment specifically to reduce nav1.8 channels in rodent models effectively reduced pain sensitivity. Knock down of NaV1.8 in rats by intrathecal injection of antisense oligodeoxynucleotides can reduce neuropathic pain behaviour leaving acute pain sensation intact (Lai, J. et al, Inhibition of neuropathic pain by impaired expression of soft-painful sodium channel, NaV1.8. Panel 95(1-2), 143 (2002); Porreca, F. et al, A composition of the cervical role of the tetrodotoxin-inductive channels, PN3/SNS NaN/SNS2, in rate modules of chronicpad.Proc Natl Acad Sci US A96, 7614), (1999)). The global gene knockout of NaV1.8 or specific destruction of neurons expressing NaV1.8 in mice greatly reduces The perception of acute mechanical, inflammatory and visceral pain (Akopian, A.N. et al, The tetrodotoxin-resistant sodium channel death disease associated with pain in pain path. Nat Neurosci 2 (541), (1999), Abrahamsen, B. et al, The cell and molecular basis of mechanical, Cold, and infllamatoxypain. science321(5889), (702), (2008), (Laird, J.M., sousulova, V.Wood, J.N. and Cero, F., Deficits in viral pain related neuron, 2, J.N. and SNS.19), N.N. and N.S. (3532) SNS.19). In contrast to antisense assays performed in rats, knockout mice appear to develop neuropathic pain in general after nerve injury (Lai, J. et al, Inhibition of neuropathic pain by secreted expression of The tetrodotoxin-responsive channels, NaV1.8.Pain95(1-2), 143(2002), Akopian, A.N. et al, The tetrodotoxin-responsive channels, SNS a specific affected function in pain disorders, Naturosci 2(6), 541(1999), Abrahamsen, B. et al, The cell and molecular basis of channels, Cold, and flu, systemic pain 321, 5889, Neurosis, N.19, SNS.19, N.8352, N.23, N.32, J.23, N.23, N.32, J.23, S.23, J.23, N.3, S.3, J.23, S.23, S.3, S.J.3, S.3, S.A. 3, S.3, S.A. 3, S..

NaV1.9 full knockout mice have reduced sensitivity to inflammation-induced pain, but normal acute and neuropathic pain behavior still exists (Amaya, F. et al, The voltage-gated sodium channel Na (v)1.9is effector of a cutaneous inflators paper hypersensitivity. J. Neurosci 26(50), 12852 (2006); Priest, B.T. et al, ligation of The tetrodotoxin-reactive sodium channel NaV1.9to sensory transduction session and nociceptive receptor. Proc Natl Acad Sci U S102A 9382 (932005)). Spinal knockdown NaV1.9 had no apparent effect on the painful behavior of rats (Porreca, F. et al, A composition of the cervical vertebrae-induced pain-sensitive channels, PN3/SNS and NaN/SNS2, in rats of chrono pain. Proc Natl Acad Sci U S A96 (14), 7640 (1999)).

The understanding of the role of NaV channels in human physiology and pathology has been greatly developed by the discovery and analysis of naturally occurring human mutations. The NaV1.1 and NaV1.2 mutations cause different forms of epilepsy (Fujiwara, T., clinical pest of mutations in SCN1A gene: segment myoc epidemic in epidemic and infected epilepsy. Epilepsy Res 70 supplement 1, S223 (2006); George, A.L., Jr., Inheritable disorders of volume-gated sulfur channels. J Clin Invest115(8), (1990); Misra, S.N., Kahlig, K.M. and George, A.L., Jr., J.P.J.M.2008. 2008. and R.2. Impulse infection and receptor epidemic infection, 1539). Mutations in nav1.4 cause muscular disorders like myotonia congenita (vicat, s., Sternberg, d., Fontaine, b., and melia, g., Human skethyl musclesodium channeloppes. neuron Sci 26(4), 194 (2005)). The NaV1.5 mutation causes a heart abnormality like Brugada syndrome and Long QT syndrome (Bennett, P.B., Yazawa, K., Makita, N., and George, A.L., Jr., Molecular mechanism for an associated Cardiac arrhythmia. Nature (6542), 683 (1995); Darbar, D.et al, Cardiac sofa (SCN5A) variant associated with Cardiac arrhythmia.circulation 117(15), 1927(2008), (Wang, Q. et al, SCN5Amutations associated with an associated Cardiac arrhythmia, local QT (5) 805 (1995).

Recent findings have demonstrated that mutations in the gene encoding the nav1.7 channel (SCN9A) cause both enhanced and reduced pain syndromes. Studies by the Waxman group and others have identified at least 15 mutations that result in enhanced current flow through nav1.7 and are associated with major congenital pain syndrome. Mutations that reduce the threshold for nav1.7 activation cause hereditary erythromelalgia (IEM). IEM patients exhibit abnormal burning pain in their hands and feet. Mutations that interfere with the normal inactivating properties of nav1.7 result in prolonged sodium currents and cause paroxysmal megalgia (PEPD). PEPD patients present with periocular, perimandibular (perimandibular) and rectal pain symptoms that progress through one life (Drenth, J.P. et al, SCN9Amutations define primary erythromelal as a neuropathic pain disorders 124(6), 1333 (2005); Estacin, M. et al, NaV1.7 gain-of-functional muscles a connecting um: A1632E display physico-fibrous tissues associated with bone and pathological pain disorders and processes of 11043, 11079).

Recently, several groups have described NaV1.7 deletion mutations in human patients (Ahmad, S. et al, A stopcoden mutation in SCN9A cause lack of disease transmission. hum Mol Genet 16(17), 2114 (2007); Cox, J.J. et al, An SCN9A channel prediction genes mutation gene sheet Nature 444(7121), 894 (2006); Goldberg, Y.P. et al, Loss-of-mutations in the NaV1.7 gene understration gene index to a patent in multiple human protein genes Clin Gene (71) (2007). In all cases, patients show a congenital apathy to pain. These patients reported no pain in any case. Many of these patients suffer dire injuries early in childhood because they do not have protective normal pain that helps prevent tissue damage and produces appropriate protective behavior. These patients appear to be completely normal except for a significant Loss of pain sensation and a reduction or absence of olfaction (Goldberg, y.p. et al, Loss-of-function syndromes in the NaV1.7 gene underscale coherence index. clin genes 71(4), 311 (2007)). Although NaV1.7 shows no sign of abnormal function of sympathetic nerve cells (Toledo-Aral, J.J. et al, Identification of PN1, adrenodominant voltage-dependent nerve channel expressed primary intrinsic nerves. Proc Natl Acad Sci U S A94 (4), 1527(1997) and adrenal chromaffin cells (Klugbauer, N., Lactinova, L., Flockerzi, V. and Hofmann, F., Structure and functional nerve compression of a new cell of the tetrodototoxin-induced nerve cell (EMJ 14), 1084, 1087. patients usually show no sign of loss of function of these sympathetic nerves or of endocrine nerve 1.7. patients.

The acquisition of the pain-causing nav1.7 functional mutation in combination with the loss of the pain-eliminating nav1.7 functional mutation provides strong evidence that nav1.7 plays an important role in human pain signaling. The relatively good health of patients with a loss of nav1.7 indicates that the excision of nav1.7 is well tolerated in these patients.

Unfortunately, the efficacy of currently used sodium channel blockers for the above disease states is largely limited by a number of side effects. These side effects include various CNS disorders such as blurred vision, dizziness, nausea, and sedation, as well as more potentially life-threatening arrhythmias and heart failure. Therefore, there is still a need to develop other Na channel antagonists, preferably with higher efficacy and fewer side effects.

Summary of the invention

It has now been found that the compounds of the present invention and their pharmaceutically acceptable compositions are useful as inhibitors of voltage-gated sodium channels. These compounds have the general formula I:

or a pharmaceutically acceptable salt thereof.

These compounds and pharmaceutically acceptable compositions are useful in the treatment, or lessening the severity of, a variety of diseases, disorders, or conditions, including, but are not limited to, acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy or epilepsy disorders, neurodegenerative diseases, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache or neck pain, severe or refractory pain, nociceptive pain, breakthrough pain, post-operative pain, or cancer pain.

Detailed description of the invention

In one aspect, the invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof,

wherein each occurrence is independently:

R¹is H, C1-C6 hydrocarbyl, C1-C6 fluorinated hydrocarbyl, C3-C8 cyclic hydrocarbyl, CF₃Optionally substituted heterocycloalkyl, aryl, heteroaryl or straight, branched or cyclic (C1-C8) -R⁹In which at most 2 CH₂Units may be substituted by O, CO, S, SO₂、N、CF₂Or NR⁸Replacement;

R²is C1-C6 hydrocarbyl, deuterated C1-C6 hydrocarbyl, C1-C6 hydrocarbyloxy, C1-C6 fluorinated hydrocarbyl, CF₃、CHF₂Or linear, branched or cyclic (C1-C8) -R⁹In which at most 2 CH₂Units may be substituted by O, CO, S, SO₂、N、CF₂Or NR⁸Replacement;

R³is a C1-C6 hydrocarbyl group or halogen;

R⁸is H, C1-C6 hydrocarbyl, C3-C8 cyclic hydrocarbyl, CF₃Or linear, branched or cyclic (C1-C8) -R⁹In which at most 2 CH₂Units may be substituted by O, CO, S, SO₂、N、CF₂Or NR instead, or 2R^{8 and}the atoms to which they are attached together form a ring;

R⁹is H, CF₃、CHF₂、CH₂F、CO₂R, halogen, OH, optionally substituted aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N (R)₂、NRCOR、CON(R)₂CN or SO₂R；

R is H, C1-C6 hydrocarbyl, optionally substituted aryl, heteroaryl, C3-C8 cycloalkyl or heterocycloalkyi;

ring a is an optionally substituted aryl, heteroaryl or heterocyclyl group;

n is an integer from 0 to 4, inclusive; and is

o is an integer from 0 to 4, inclusive.

For the purposes of the present invention, chemical Elements are identified according to the CAS version of the Periodic Table of the Elements of the 75 th edition of the Handbook of Chemistry and Physics (Handbook of Chemistry and Physics). In addition, the general principles of Organic Chemistry are described in "Organic Chemistry", Thomas Sorrell, university science Books, Sausaltito: 1999 and "March's Advanced Organic Chemistry", 5 th edition, eds: smith, m.b. and March, j., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as those set forth generally above or as exemplified by particular classes, subclasses, and species of the invention. The phrase "optionally substituted" may be used interchangeably with the phrase "substituted or unsubstituted". The variable R in formula I as described herein¹-R⁹Specific groups are contemplated, such as, for example, alkyl and aryl groups. Unless otherwise stated, the variable R¹-R⁸Each of the specified groups of (a) may be optionally substituted with one or more of the following substituents: halogen, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. For example, alkyl groups may be optionally substituted with one or more of the following groups: halogen, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As a further example, an aryl group may be optionally substituted with one or more of the following: halogen, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by the present invention are combinations of substituents that result in the formation of stable or chemically feasible compounds. The term "stable" as used herein refers to a compound that does not substantially change when subjected to conditions that allow its preparation, detection, and preferably its recovery, purification, and use for one or more of the purposes disclosed herein. In certain embodiments, a stable compound or chemically feasible compound is a compound that remains substantially unchanged at a temperature of 40 ℃ or less for at least one week in the absence of moisture or other chemically reactive conditions. When two alkoxy groups are bound to the same atom or adjacent atoms, the two alkoxy groups may form a ring together with the atom to which they are bound.

Generally, the term "substituted," whether preceded by the term "optional," refers to the replacement of a hydrogen radical in a given structure with a radical of a specified substituent. Specific substituents are described in the definitions above and in the description of the compounds and examples thereof below. Unless otherwise specified, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position of any given structure may be substituted with more than one substituent selected from a specified group, the substituents at each position may be the same or different. A ring substituent, such as a heterocyclic hydrocarbon group, may be bonded to another ring, such as a cycloalkyl group, to form a spiro-bicyclic ring system, e.g., the two rings share a common atom. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by the present invention are combinations of substituents that result in the formation of stable or chemically feasible compounds.

The phrase "at most" as used herein refers to zero or any integer equal to or less than the number following the phrase. For example, "at most 3" means any of 0,1, 2, and 3. The terms "aliphatic", "aliphatic" or "hydrocarbyl" as used herein mean a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In certain embodiments, the aliphatic group contains 1-10 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in still other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups. The term "alicyclic" or "cyclic hydrocarbon group" refers to a monocyclic, bicyclic or tricyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has one point of attachment to the rest of the molecule. In certain embodiments, "alicyclic" refers to a monocyclic C that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has one point of attachment to the rest of the molecule₃-C₈Of hydrocarbons or of bicyclic rings C₈-C₁₂A hydrocarbon, wherein any individual ring of said bicyclic ring system has 3 to 7 members.

The term "electron withdrawing group" as used herein means an atom or group that is electronegative with respect to hydrogen. See, e.g., "Advanced Organic Chemistry: reactions, Mechanisms, and Structure, "Jerry March, 4 th edition, John Wiley&Sons (1992), e.g., pages 14-16, 18-19, etc. Exemplary such substituents include halogen, e.g., Cl, Br or F, CN, COOH, CF₃And the like.

As used herein, unless otherwise specified, the terms "heterocycle", "heterocyclyl", "heterocycloaliphatic", "heterocycloalkenyl" or "heterocycle" mean a non-aromatic, mono-, bi-or tricyclic ring system in which one or more ring atoms of one or more ring members is an independently selected heteroatom. The heterocyclic ring may be saturated or may contain one or more unsaturated bonds. In certain embodiments, a "heterocycle", "heterocyclyl", "heterocycloaliphatic", "heterocycloalkenyl" or "heterocyclic" group has three to fourteen ring members in which one or more ring members are heteroatoms independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the ring system contains 3 to 7 ring members.

The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus or silicon; quaternized form of any basic nitrogen, or, heterocyclic substitutable nitrogen, such as N (as in 3, 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺(as in N-substituted pyrrolidinyl)).

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

The term "hydrocarbyloxy" or "hydrocarbylthio" as used herein refers to a hydrocarbyl group, as defined herein, which is attached to the main carbon chain through an oxygen ("hydrocarbyloxy") or sulfur ("hydrocarbylthio") atom.

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

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

Unless otherwise indicated, structures described 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 configuration of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Thus, tautomers of the compounds of formula I are included within the scope of the present invention.

In addition, unless otherwise indicated, structures described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, one of themOr replacement of more hydrogen atoms by deuterium or tritium or replacement of one or more carbon atoms by deuterium or tritium¹³C-or¹⁴C-enriched carbon-substituted compounds of formula I are within the scope of the invention. Such compounds are useful, for example, as analytical tools, probes in bioassays, or sodium channel blockers with improved therapeutic properties.

In the various formulae and figures, the line that intersects the ring and is bonded to the R group, for example in the formula,

meaning that the R group may be bonded to any carbon of the ring, or (if appropriate) a heteroatom such as N, as valency permits.

Under the term such as R¹、R²、R³、R⁴、R⁵Or R⁶In the definition of (1), when CH₂Units or interchangeably, methylene units may be substituted by O, CO, S, SO₂Or NR⁸When substituted, it is meant to include any CH₂Unit including CH in terminal methyl₂. For example, -CH₂CH₂CH₂SH at C₁-C₆Hydrocarbyl radicals of which up to two CH groups₂Units may be replaced by S within the definition, since the CH of the terminal methyl group₂The cell has been replaced by S.

In another embodiment, the invention features compounds of formula I and the attendant definitions, wherein R¹Is an optionally substituted C3-C8 cycloalkyl, aryl, heteroaryl or C1-C6 alkyl. In another embodiment, R¹Is optionally substituted phenyl, pyridyl, thiazole or pyrazole, CH₂CH₃、

In another embodiment, the invention features compounds of formula I and the attendant definitions, wherein R²Is C1-C6 hydrocarbyl, C1-C6 fluorohydrocarbyl, CF₃C1-C6 hydrocarbyloxy or straight, branched or cyclic (C1-C8) -R⁹In which at most 2 CH₂Units may be substituted by O, CO, S, SO₂N or NR⁸And (4) replacing. In another embodiment, R²Is CH₂CH₃、OCH₃、OCH₂CH₃、OCH₂CH₂CH₃、OCH₂CH₂F、OCH₂CH₂OCH₃、OCH₂Ph、Or OCH (CH)₃)₂。

In another embodiment, the invention features compounds of formula I and the attendant definitions, wherein n is 1 or 2. In another embodiment, n is 1. In another embodiment, o is 0 or 1. In another embodiment, o is 0.

In another embodiment, the invention features compounds of formula I and the attendant definitions, wherein R¹And R²Are cis to each other. In another embodiment, R¹And R²Are in trans to each other.

In another embodiment, the invention features compounds of formula I and the attendant definitions, wherein a is

Wherein:

R⁴is H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, CN, OR⁸、SO₂R⁸、SO₂N(R⁸)₂、CHF₂、CF₃，OCF₃、OCHF₂、R⁹Heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl or straight, branched or cyclic (C1-C8) -R⁹In which at most 3 CH₂Units may be substituted by O, CO, S, SO₂、N、CF₂Or NR⁸Replacement;

R⁵is H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, CN, OR⁸、SO₂R⁸、SO₂N(R⁸)₂、CHF₂、CF₃、OCF₃、OCHF₂、R⁹Heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl or straight, branched or cyclic (C1-C8) -R⁹In which at most 3 CH₂Units may be substituted by O, CO, S, SO₂、N、CF₂Or NR⁸Replacement;

R⁶is H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, CN, OR⁸、SO₂R⁸、SO₂N(R⁸)₂、CHF₂、CF₃、OCF₃、OCHF₂、R⁹Heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl or straight, branched or cyclic (C1-C8) -R⁹In which at most 3 CH₂Units may be substituted by O, CO, S, SO₂、N、CF₂Or NR⁸Replacement; or

2 occurrences of R⁴And R⁵Or R⁵And R⁶Together with the carbon to which they are attached form an optionally substituted ring containing up to 2 heteroatoms.

In another embodiment, R⁴Is H, C1-C6 hydrocarbyl, C1-C6 hydrocarbyloxy, heterocyclic hydrocarbyl, halogen, CHF₂、CF₃、OCHF₂Or linear, branched or cyclic (C1-C8) -R⁹In which at most 3 CH₂Units may be substituted by O, CO, S, SO₂、N、CF₂Or NR⁸And (4) replacing. In another embodiment, R⁴Is H, CH₃、OCH₃、OCH₂CH₃、F、Cl、OCHF₂、CHF₂、CF₃、CH₂OCH₃、OCH(CH₃)₂、CH₂OCH₃Or

In another embodiment, R⁵Is H, C1-C6 hydrocarbyl, C1-C6 hydrocarbyloxy, halogen, CF₃、CN、OCHF₂Or linear, branched or cyclic (C1-C8) -R⁹In which at most 3 CH₂Units may be substituted by O, CO, S, SO₂N or NR⁸And (4) replacing. In another embodiment, R⁵Is H, CH₃、OCH₃、OCH(CH₃)₂、F、Cl、CF₃CN or CH₂OH。

In another embodiment, R⁶Is H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, CF₃、SO₂R⁸、SO₂N(R⁸)₂、R⁹Or linear, branched or cyclic (C1-C8) -R⁹In which at most 3 CH₂Units may be substituted by O, S, SO₂N or NR⁸And (4) replacing. In another embodiment, R⁶Is H, F, Cl, CH₃、CF₃、CH₂CH₃、OCH₃、OCH₂CF₃、OCH₂CH₃、OCH₂CH₂CH₃、OCH₂CH₂CH(CH₃)₂、OtBu、tBu、OCH(CH₃)₂、OCH₂CH(CH₃)₂、OCH(CH₃)CH₂CH₃、CH(OH)CH(CH₃)₂、C(OH)(CH₃)CH₂CH₃、OCH₂C(CH₃)₂OH、C(CH₃)₂OH、CH₂C(CH₃)₂OH OCH₂CH₂OCH₃、OCH₂CH₂OH、OCH₂CH₂CH₂OH、SO₂CH₃、SO₂CF₃、SO₂CH(CH₃)₂、SO₂CH₂CH₃、CH₂OCH₂CF₃、CH₂OCH₂CH₂CF₃、OCHF₂、OCH₂CF(CH₃)₂、

In a further embodiment of the process of the present invention,selected from:

in another embodiment, the invention features compounds of formula I and the attendant definitions, wherein a is heteroaryl or heterocyclyl. In another embodiment, a is a monocyclic heteroaryl comprising 1-3 heteroatoms independently selected from N, O or S. In another embodiment, a is a bicyclic heteroaryl comprising 1-3 heteroatoms independently selected from N, O or S.

In another embodiment, A is

Wherein:

R⁴is H, C1-C6 hydrocarbyl, C3-C8 cyclic hydrocarbyl, C1-C6 hydrocarbyloxy, C1-C6 fluorinated hydrocarbyloxy, halogen, CN, OH, OR⁸、N(R⁸)₂、SO₂R⁸、SO₂N(R⁸)₂、CHF₂、CF₃、R⁹Heterocyclic hydrocarbon radicals or straight, branched or cyclic (C1-C8) -R⁹In which at most 3 CH₂Units may be substituted by O, CO, S, SO₂、N、CF₂Or NR⁸Replacement;

R⁵is H, C1-C6 hydrocarbyl, C3-C8 cyclic hydrocarbyl, C1-C6 hydrocarbyloxy, C1-C6 fluorinated hydrocarbyloxy, halogen, CN, OH, OR⁸、N(R⁸)₂、SO₂R⁸、SO₂N(R⁸)₂、CHF₂、CF₃、R⁹Heterocyclic hydrocarbon radicals or straight, branched or cyclic (C1-C8) -R⁹In which at most 3 CH₂Units may be substituted by O, CO, S, SO₂、N、CF₂Or NR⁸Replacement;

R⁶is H, C1-C6 hydrocarbyl, C3-C8 cyclic hydrocarbyl, C1-C6 hydrocarbyloxy, C1-C6 fluorinated hydrocarbyloxy, halogen, CN, OH, OR⁸、N(R⁸)₂、SO₂R⁸、SO₂N(R⁸)₂、CHF₂、CF₃、R⁹Heterocyclic hydrocarbon radicals or straight, branched or cyclic (C1-C8) -R⁹In which at most 3 CH₂Units may be substituted by O, CO, S, SO₂、N、CF₂Or NR⁸Replacement; or

2 occurrences of R⁴And R⁵Or R⁵And R⁶Together with the carbon to which they are attached form an optionally substituted ring containing up to 2 heteroatoms.

In another embodiment, R⁴Is H, C1-C6 hydrocarbyloxy, C1-C6 fluorohydrocarbyloxy, heterocyclic hydrocarbyl or N (R)⁸)₂. In another embodiment, R⁴Is H, OCH₃、OCH₂CH₃、OCH₂CF₃、N(CH₃)₂、NH(CH₂CH(CH₃)₂) Or

In another embodiment, R⁵Is H, C1-C6 hydrocarbyl or C1-C6 hydrocarbyloxy, halogen, heterocycloalkyl or N (R)⁸)₂. In another embodiment, R⁵Is H, CH₃、OCH₃、Cl、tBu、N(CH₃)₂Or

In another embodiment, R⁶Is H, CN, C1-C6 hydrocarbyloxy, C1-C6 fluorinated hydrocarbyloxy, CF₃Or a heterocyclic hydrocarbon group. In another embodiment, R⁶Is H, CN, OCH₃、OCH₂CH₃、OCH(CH₃)₂、CF₃、OCH₂CF₃、Or

In another embodiment, a is selected from the group consisting of:

in another embodiment, the invention features compounds of formula IA:

wherein:

R¹is aryl or heteroaryl;

R²is C1-C6 hydrocarbyloxy or C1-C6 fluorinated hydrocarbyloxy;

R⁵is H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, CN, OR⁸、SO₂R⁸、SO₂N(R⁸)₂、CHF₂、CF₃、OCF₃、OCHF₂、R⁹Heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl or straight, branched or cyclic (C1-C8) -R⁹In which at most 3 CH₂Units may be substituted by O, CO, S, SO₂、N、CF₂Or NR⁸Replacement;

R⁶is H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, CN, OR⁸、SO₂R⁸、SO₂N(R⁸)₂、CHF₂、CF₃、OCF₃、OCHF₂、R⁹Heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl or straight, branched or cyclic (C1-C8) -R⁹In which at most 3 CH₂Units may be substituted by O, CO, S, SO₂、N、CF₂Or NR⁸Replacement; and is

R⁸Is H, C1-C6 hydrocarbyl, C3-C8 cyclic hydrocarbyl, CF₃Or linear, branched or cyclic (C1-C8) -R⁹In which at most 2 CH₂Units may be substituted by O, CO, S, SO₂、N、CF₂Or NR instead, or 2R⁸Form a ring together with the atoms to which they are attached.

In another embodiment, the invention features compounds of formula IA and the attendant definitions, wherein R¹Selected from phenylthiazole, pyridine or pyrazole. In another embodiment, R¹Is that

In another embodiment, the invention features compounds of formula IA and the attendant definitions, wherein R²Is a C1-C6 hydrocarbyloxy group. In another embodiment, R²Is selected from OCH₃、OCH₂CH₃、OCH₂CH₂CH₃、OCH₂CH₂F、OCH₂CH₂OCH₃、Or OCH (CH)₃)₂。

In another embodiment, the invention features compounds of formula IA and the attendant definitions, wherein R⁵Selected from H, C1-C6 alkyl, C1-C6 fluorinated alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, halogen or straight chain, branched chain or cyclic (C1-C8) -R⁹In which at most 3 CH₂Units may be substituted by O, CO, S, SO₂、N、CF₂Or NR⁸And (4) replacing. In another embodiment, R⁵Is H, CH₃、OCH₃、CF₃、OCHF₂F, Cl, CN or CH₂OH。

In another embodiment, the invention features compounds of formula IA and the attendant definitions, wherein R⁶Is H, C1-C6 alkyl, C1-C6 fluorinated alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, halogen, heterocyclic alkyl or straight chain, branched chain or cyclic (C1-C8) -R⁹In which at most 3 CH₂Units may be substituted by O, CO, S, SO₂、N、CF₂Or NR⁸And (4) replacing. In another embodiment, R⁶Is H, Cl CH₂CH₃、tBu、OtBu、OCH₃、OCH(CH₃)₂、OCH₂CH₂(CH₃)₂、OCH₂CH₃、OCH₂CH₂CH₃、OCH₂CH₂CH(CH₃)₂、OCH₂CF(CH₃)₂、CH₂OCH₂CH₂CF₃、OCH₂CH₂OH、CH₂CH₂CH₂OH、OCHF₂、OCH₂CH₂OCH₃、OCH(CH₃)CH₂CH₃、OCH₂C(CH₃)₂OH、C(CH₃)₂OH、CH₂C(CH₃)₂OH、

In a further embodiment of the process of the present invention,moieties are selected from:

in another embodiment, the invention features a compound of formula I and the accompanying definitions, wherein the compound is selected from the following table:

in another aspect, the invention features a pharmaceutical 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 channel in a patient or a biological sample, comprising administering to the patient a compound or composition of the invention, 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 following conditions in a subject: acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy or epilepsy disorders, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorders, myotonia, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache or neck pain, severe or refractory pain, nociceptive pain, penetrating pain, post-operative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, pressure or exercise-induced angina, palpitation, hypertension, migraine or abnormal gastrointestinal motility, the method comprises administering an effective amount of a compound or composition of the invention.

In another embodiment, the method is used to treat or reduce the severity of: femoral cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic lumbago; neuropathic lumbago; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; a pancreas; IBS pain; chronic and acute headache; migraine headache; tension headaches, including cluster headaches; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-related neuropathies; trigeminal neuralgia; Charcot-Marie Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve damage; painful neuroma; ectopic proximal and distal discharges; a radiculopathy; chemotherapy-induced neuropathic pain; radiotherapy-induced neuropathic pain; pain after mastectomy; central pain; pain from spinal cord injury; pain following stroke; thalamic pain; complex regional pain syndrome; phantom limb pain; intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical lumbago; neck pain; tendinitis; injury/athletic pain; acute visceral pain, abdominal pain; pyelonephritis; appendicitis; cholecystitis (cholecystitis); ileus; hernia; chest pain; heartburn; pelvic pain, renal colic; acute labor pain, labor pain; cesarean section pain; acute inflammation; burn and wound pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; oral and facial pain, including sinusitis pain, dental pain; multiple Sclerosis (MS) pain; pain in depression; leprosy pain; behcet's (Behcet) disease pain; painful obesity; pain from phlebitis; Guillain-Barre pain; leg and moving toe pain; haglund syndrome; erythematous limb pain; fabry disease pain; bladder and genitourinary disorders, including urinary incontinence; hyperfunction of bladder; painful bladder syndrome; interstitial Cystitis (IC); prostatitis; complex Regional Pain Syndrome (CRPS), type I and type II; widespread pain, paroxysmal extreme pain, pruritus, tinnitus or pain induced by angina.

The compounds of the present invention can be readily prepared using the following methods. Illustrated below in schemes 1 through 8 are methods for preparing the compounds of the present invention.

Scheme 1

PG ═ protecting group (Boc, CO)₂Bn), LG ═ leaving group (Cl, Br, I, OMs, OTs).

a)1) (1E) -3- [ tert-butyl (dimethyl) silyl]oxy-N, N-dimethyl-but-1, 3-dien-1-amine, 2-butanol; 2) AcCl, Et₂O；b)R¹-MgBr, CuI, HMPA, TMSCl, tetrahydrofuran; c) NaBH₄，CeCl₃，MeOH；d)R²-LG，NaH，DMF；e)PG＝Boc：TFA、CH₂Cl₂；f)R-CO₂H, coupling reagent (HATU, EDCI), base (Et)₃N，Et₂NiPr), solvent (DMF, CH)₂Cl₂)。

Scheme 2

a)SOCl₂、CH₂Cl₂(ii) a b) Piperidine-4-one, NaOH, toluene.

Scheme 3

a)PG＝Boc：TFA，CH₂Cl₂；b)Et₃N，RCOCl，CH₂Cl₂。

Scheme 4

a)1) (1E) -3- [ tert-butyl (dimethyl) silyl]oxy-N, N-dimethyl-but-1, 3-dien-1-amine, 2-butanol; 2) AcCl, Et₂O；b)R¹-MgBr，CuI，HMPA，TMSCl，THF；c)NaBH₄，CeCl₃，MeOH；d)R²-LG，NaH，DMF。

Scheme 5

a)LDA，THF，-78℃-rt；b)PPTS，CH₂Cl₂Microwave, 120 ℃; c) NaBH₄，MeOH，rt；d)H₂，Pd/C，MeOH；e)RX，NaH，DMF。

Scheme 6

a)LDA，THF，-78℃-rt；b)PPTS、CH₂Cl₂Microwave, 120 ℃; c) NaBH₄，MeOH，rt；d)H₂，Pd/C，MeOH；e)RX、NaH，DMF；f)TFA，CH₂Cl₂，rt；g)ArCOCl，NEt₃，CH₂Cl₂Or ArCOOH, EDCI, DIEA, CH₂Cl₂Rt or ArCOOH, DIEA, HATU, DMF, rt.

Scheme 7

a)NaH，THF，rt；b)TBSOTf，TEA，CH₂Cl₂，0℃；c)BF₃·OEt₂，CH₂Cl₂-78 deg.C; d) Dess-Martin reagent (Dess-Martin Periodinane), CH₂Cl₂At 0 ℃ C; e) HOAc, refluxing; f) NaBH₄，MeOH，rt；g)H₂，Pd/C，MeOH，rt；h)RX，NaH，DMF，rt。

Scheme 8

a)DMP，CH₂Cl₂0℃-rt；b)EtMgBr，THF，0℃；c)SOCl₂Pyridine, CH₂Cl₂；d)H₂，Pd/C，EtOH，rt。

Use, formulation and administration

Pharmaceutically acceptable compositions

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

It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, where appropriate, in the form of a pharmaceutically acceptable derivative thereof. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative that upon administration to a subject in need thereof is capable of directly or indirectly providing a compound as otherwise described herein, or a metabolite or residue thereof.

The term "pharmaceutically acceptable salt" as used herein, means a salt, within the scope of sound medical judgment, that is suitable for use in contact with the tissues of human and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. "pharmaceutically acceptable salt" refers to any non-toxic salt of a compound of the present invention, or a salt of an ester thereof, which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present invention, or an inhibitory active metabolite or residue thereof. The term "inhibitory active metabolite or residue thereof" as used herein means that the metabolite or residue thereof is also an inhibitor of voltage-gated sodium ion channels.

Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail in j.pharmaceutical Sciences, 1977, 66, 1-19 to s.m.berge et al, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are amino salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonatesAcid salts, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate (pamoate), pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄And (3) salt. The present invention also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water-soluble or oil-soluble or water-dispersible or oil-dispersible products can be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations, which are formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

As noted above, the pharmaceutically acceptable compositions of the present invention additionally include a pharmaceutically acceptable carrier, adjuvant or excipient, which as used herein includes any and all solvents, diluents or other liquid carriers, dispersing or suspending agents, surfactants, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as appropriate for the particular dosage form desired. Remington's Pharmaceutical Sciences, 16 th edition, e.w. martin (Mack Publishing co., Easton, Pa., 1980) discloses various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation. Unless any conventional carrier medium is incompatible with the compounds of the present invention, e.g., produces any undesirable biological effect or otherwise interacts in a deleterious manner with any other component of a pharmaceutically acceptable composition, the intended use is within the scope of the present invention. Some examples of substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth gum; malt; gelatin; talc powder; 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; a diol; such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethanol and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

Use of compounds and pharmaceutically acceptable compositions

In another aspect, a method of treating or lessening the severity of the following conditions is provided: acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy or epileptic disorders, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, bipolar disorders, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritic pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache or neck pain, severe or refractory pain, nociceptive pain, penetrating pain, post-operative pain, or cancer pain, comprising administering to a subject in need thereof an effective amount of the compound or a pharmaceutically acceptable composition comprising the compound.

In certain embodiments, a method is provided for treating or lessening the severity of: stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, pressure or exercise-induced angina, palpitation, hypertension, migraine or abnormal gastrointestinal motility, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable composition comprising a compound.

In certain embodiments, there is provided a method for treating or reducing the severity of acute, chronic, neuropathic, or inflammatory pain comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable composition. In certain other embodiments, there is provided a method for treating nerve root pain, sciatica, back pain, headache, or neck pain comprising administering an effective amount of a compound or a pharmaceutically acceptable composition to a subject in need thereof. In still other embodiments, there is provided a method for treating or reducing the severity of severe or refractory pain, acute pain, post-operative pain, back pain, tinnitus, or cancer pain comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable composition.

In certain embodiments, a method is provided for treating or lessening the severity of: femoral cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic lumbago; neuropathic lumbago; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, including abdominal pain; a pancreas; IBS pain; chronic and acute headache; migraine headache; tension headaches, including cluster headaches; chronic and acute neuropathic pain, including post-herpetic neuralgia; diabetic neuropathy; HIV-related neuropathies; trigeminal neuralgia; Charcot-Marie Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve damage; painful neuroma; ectopic proximal and distal discharges; a radiculopathy; chemotherapy-induced neuropathic pain; radiotherapy-induced neuropathic pain; pain after mastectomy; central pain; pain from spinal cord injury; pain following stroke; thalamic pain; complex regional pain syndrome; phantom limb pain; intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical lumbago; neck pain; tendinitis; injury/athletic pain; acute visceral pain, including abdominal pain; pyelonephritis; appendicitis; cholecystitis (cholecystitis); ileus; hernia; etc.; chest pain, including heartache; pelvic pain, renal colic; acute labor pain, including labor pain; cesarean section pain; acute inflammation; burn and wound pain; acute intermittent pain, including endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; oral and facial pain, including sinusitis pain, dental pain; multiple Sclerosis (MS) pain; pain in depression; leprosy pain; behcet's disease pain; painful obesity; pain from phlebitis; Guillain-Barre pain; leg and moving toe pain; haglund syndrome; erythematous limb pain; fabry disease pain; bladder and genitourinary disorders, including urinary incontinence; hyperfunction of bladder; painful bladder syndrome; interstitial Cystitis (IC); or prostatitis; complex Regional Pain Syndrome (CRPS), type I and type II; angina-induced pain, the method comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutical composition.

In certain embodiments of the invention, an "effective amount" of a compound or a pharmaceutical composition is an amount effective to treat or reduce the severity of one or more of the following conditions: acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy or epileptic disorders, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache or neck pain, severe or refractory pain, nociceptive pain, breakthrough pain, post-operative pain, tinnitus or cancer pain.

In accordance with the methods of the present invention, the compounds and compositions can be administered in any amount and by any route of administration effective to treat or reduce the severity of one or more of the following conditions: acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy or epileptic disorders, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache or neck pain, severe or refractory pain, nociceptive pain, breakthrough pain, post-operative pain, tinnitus or cancer pain. The precise 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 used, the mode of administration thereof, and the like. The compounds of the present 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 physically discrete units of an agent suitable for the subject to be treated. It will be understood, however, that the total daily amount of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular active agent administered; the specific composition administered; the age, weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the particular active agent administered; the duration of the treatment; drugs used in combination or concomitantly with the specific compound administered, and other factors well known in the medical arts. The term "subject" or "patient" as used herein means an animal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of the present invention may be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), buccally, or as an oral or nasal spray, etc., depending on the severity of the patient to be treated. In certain embodiments, the compounds of the present invention may be administered orally or parenterally, once or more times daily, at dosage levels of from about 0.01mg/kg to about 50mg/kg, and preferably from about 1mg/kg to about 25mg/kg, of the subject's body weight per day to achieve 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, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents, for example, sterile injectable aqueous or oleaginous suspensions. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in1, 3-butanediol. Acceptable carriers or solvents that can be used are water, ringer's solution, u.s.p. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

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

In order to prolong the effect of the compounds of the invention, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material which is poorly water soluble. The rate of absorption of the compound will then depend on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delaying absorption of a parenterally administered compound form is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot dosage forms are prepared by forming microencapsule matrices of the compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injections can also be prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.

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

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants, such as glycerol, d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) dissolution retardants, such as paraffin, f) absorption promoters, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite, 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 forms may also comprise buffering agents.

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

The active compound may also be present in microencapsulated forms with one or more of the above-mentioned excipients. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings, and other coating materials well known in the pharmaceutical formulating art. In these solid dosage forms, the active compound may be mixed with at least one inert diluent (e.g., sucrose, lactose or starch). These dosage forms may also, for example, contain, as is common practice, other substances in addition to inert diluents, such as tableting lubricants and other tableting aids, for example 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 may also be of a composition: they release one or more active ingredients only or preferably in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymers and waxes.

Dosage forms for topical or transdermal administration of the compounds of the invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives or buffers which may be required. Ophthalmic formulations, ear drops and eye drops are also encompassed within the scope of the present invention. Furthermore, the present invention encompasses the use of transdermal patches, which have the additional advantage of controllably delivering the compound to the body. Such dosage forms may be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers may also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

As generally described above, the compounds of the present invention are useful as inhibitors of voltage-gated sodium ion channels. In one embodiment, the compounds and compositions of the invention are inhibitors of one or more of nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav1.9, and thus, without wishing to be bound by any particular theory, are particularly useful for treating or lessening the severity of the following diseases, conditions or disorders: wherein activation or high activity of one or more of nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8, or nav1.9 is associated with the disease, condition, or disorder. When activation or high activity of nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav1.9 is associated with a particular disease, condition or disorder, the disease, condition or disorder may also be referred to as a "nav 1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav 1.9-mediated disease, condition or disorder". Thus, in another aspect, the invention provides a method of treating or lessening the severity of a disease, condition or disorder as follows: wherein activation or high activity of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 or NaV1.9 is associated with the disease state.

The activity of a compound used in the present invention as an inhibitor of nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav1.9 may be determined according to the methods generally described in the examples herein, or according to methods available to one of ordinary skill in the art.

In certain exemplary embodiments, the compounds of the present invention are useful as inhibitors of nav1.7 and/or nav1.8.

It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the present invention may be used in combination therapy, i.e., the compounds and pharmaceutically acceptable compositions may be administered simultaneously with, before or after one or more other desired therapeutic agents or medical procedures. The combination of a particular therapy (therapeutic agent or procedure) for a combination regimen should take into account the compatibility of the therapeutic agent and/or procedure required and the therapeutic effect that is desired to be achieved. It will also be appreciated that the therapy used may achieve the desired effect on the same disease (e.g., the compound of the invention may be administered simultaneously with other agents used to treat the same condition), or it may achieve different effects (e.g., control of any side effects). As used herein, an additional therapeutic agent that is typically administered to treat or prevent a particular disease or condition is referred to as "appropriate for the disease or condition being treated. For example, exemplary additional therapeutic agents include, but are not limited toNon-opioid analgesics (indoles such as etodolac, indomethacin, sulindac, tolmetin, naphthylalkanones such as nabumetone, oxicams such as piroxicam, p-aminophenol derivatives such as paracetamol, propionic acids such as fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen sodium, oxaprozin, salicylates such as aspirin, choline magnesium trisalicylate, diflunisal, fenamates such as meclofenamic acid, mefenamic acid, and pyrazoles such as phenylbutazone); or an opioid (narcotic) agonist (e.g., codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, dextropropoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine). In addition, non-pharmaceutical analgesic methods may be used in conjunction with the administration of one or more compounds of the present invention. For example, anesthesiologic (intraspinal infusion, nerve block), neurosurgical (neurolysis of CNS pathways), neurostimulative (transcutaneous electrical nerve stimulation, spinal stimulation), physiotherapeutic (physical therapy, orthopedic devices, diathermy) or psychological (cognitive methods-hypnosis, biofeedback, or behavioral methods) methods may also be used. Other suitable therapeutic agents or methods are generally described in The Merck Manual, seventeenth edition, MarkH. Beers and Robert Berkow, Merck Research Laboratories,1999, and The U.S. food and drug administration Web sitewww.fda.govThe entire contents of which are incorporated herein by reference.

In another embodiment, the other suitable therapeutic agent is selected from the following:

(1) opioid analgesics, for example morphine, heroin, hydromorphone, oxymorphone, levorphanol, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, dextropropoxyphene, nalmefene, nalprofen, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;

(2) non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac, deflazainal (diflusinal), etodolac, fenbufen, fenoprofen, florfenicol, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitrofluoropyrrolprofen, oxalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, or zomepirac;

(3) barbiturate-type sedatives, such as amobarbital, alprenol, sec-butyl barbital, butabarbital, cresital, methamphetal, methohexital, pentobarbital, phenobarbital (phenobarbital), secobarbital, tabebitul, semital (theomylal), or thiobarbital (thiobarbital);

(4) benzodiazepine with tranquilizing effectClass (iii) e.g. chlorine nitrogenChlorine drawingAcid, diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam;

(5) h1 antagonists with sedative effects, such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine or clorazine;

(6) sedatives such as glutethimide, meprobamate, methaqualone or chloralbyrin;

(7) skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or oxyphennard;

(8) NMDA receptor antagonists, such as dextromethorphan ((+) -3-hydroxy-N-methylmorphinan) or a metabolite thereof, dextromethorphan ((+) -3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4- (phosphonomethyl) -2-piperidinecarboxylic acid, budipine (budipine), EN-3231(MorphiDex (R), a combination dosage form of morphine and dextromethorphan), topiramate, neramexane or Pezinfotel (including NR2B antagonists), such as ifenprodil, troxoprodil or (-) - (R) -6- {2- [4- (3-fluorophenyl) -4-hydroxy-1-piperidinyl ] -1-hydroxyethyl-3, 4-dihydro-2 (1H) -quinolinone;

(9) α -adrenergic agents, such as doxazosin (doxazosin), tamsulosin (tamsulosin), clonidine, guanfacine, dexmetatomidine, modafinil or 4-amino-6, 7-dimethoxy-2- (5-methane-sulfinylamino-1, 2,3, 4-tetrahydroisoquinolin-2-yl) -5- (2-pyridyl) quinazoline;

(10) tricyclic antidepressants, such as desipramine, imipramine, amitriptyline or nortriptyline;

(11) anticonvulsants such as carbamazepine, lamotrigine, topiramate or valproate;

(12) tachykinin (NK) antagonists, in particular NK-3, NK-2 or NK-I antagonists, such as ([ alpha ] R,9R) -7- [3, 5-bis (trifluoromethyl) benzyl ] -8,9,10, 11-tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [ l,4] diazocino [2, l-g ] [ l,7] -naphthyridine-6-13-dione (TAK-637), 5- [ [ (2R,3S) -2- [ (lR) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy-3- (4-fluorophenyl) -4-morpholinyl ] -methyl ] -1, 2-dihydro-3H-1, 2, 4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant, or 3- [ [ 2-methoxy-5- (trifluoromethoxy) phenyl ] -methylamino ] -2-phenylpiperidine (2S, 3S);

(13) muscarinic antagonists such as oxybutynin, tolterodine, propiverine, trospium chloride (tropsiumchloride), darifenacin, solifenacin, tilmicorine, and ipratropium;

(14) COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or romidepoxib (lumiracoxib);

(15) coal tar analgesics, especially paracetamol;

(16) antipsychotics, such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepprazole, blonanserin, iloperidone, peropiropirone, raclopride, zotepine, bifeprunox, asenapine (aseapine), lurasidone (lurasidone), amisulpride, balaperidone, palindore, eletrine, eletrin, osanetant, rimonabant, milnacitan, miraxion (r), or thalizolpidem;

(17) a vanilloid receptor agonist (e.g., resiniferatoxin) or antagonist (e.g., capsaicinoid);

(18) beta-adrenergic agents, such as propranolol;

(19) local anesthetics, such as mexiletine;

(20) corticosteroids, such as dexamethasone;

(21)5-HT receptor agonists or antagonists, particularly 5-HT1B/1D agonists such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

(22)5-HT2A receptor antagonists, such as R (+) - α - (2, 3-dimethoxy-phenyl) -1- [2- (4-fluorophenylethyl) ] -4-piperidinemethanol (MDL-100907);

(23) cholinergic (nicotinic) analgesics such as isopropylidene (isproniline) (TC-1734), (E) -N-methyl-4- (3-pyridyl) -3-buten-1-amine (RJR-2403), (R) -5- (2-azetidinylmethoxy) -2-chloropyridine (ABT-594) or nicotine;

(24) tramadol (r));

(25) PDEV inhibitors, for example 5- [ 2-ethoxy-5- (4-methyl-1-piperazinyl-sulfonyl) phenyl ] -1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one (sildenafil), (6R,12aR) -2,3,6,7,12,12 a-hexahydro-2-methyl-6- (3, 4-methylenedioxyphenyl) -pyrazino [2 ', 1': 6, l ] -pyrido [3,4-b ] indole-1, 4-dione (IC-351 or tadalafil), 2- [ 2-ethoxy-5- (4-ethyl-piperazin-1-yl-1-sul-fon Acyl) -phenyl ] -5-methyl-7-propyl-3H-imidazo [5,1-f ] [1,2,4] triazin-4-one (vardenafil), 5- (5-acetyl-2-butoxy-3-pyridyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one, 5- (5-acetyl-2-propoxy-3-pyridyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one, 5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- [ 2-methoxyethyl ] -2, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one, 4- [ (3-chloro-4-methoxybenzyl) amino ] -2- [ (2S) -2- (hydroxymethyl) pyrrolidin-1-yl ] -N- (pyrimidin-2-ylmethyl) pyrimidine-5-carboxamide, 3- (1-methyl-7-oxo-3-propyl-6, 7-dihydro-1H-pyrazolo [4,3-d ] pyrimidin-5-yl) -N- [2- (1-methylpyrrolidin-2-yl) ethyl ] -4-propoxybenzenesulfonamide;

(26) α -2-ligands, e.g. gabapentin, pregabalin, 3-methyl gabapentin, (1[ α ]],3[α],5[α]) (3-Aminomethylbicyclo [3.2.0 ]]Hept-3-yl) -acetic acid, (3S,5R) -3-aminomethyl-5-methylheptanoic acid, (3S,5R) -3-amino-5-methyl-heptanoic acid, (3S,5R) -3-amino-5-methyloctanoic acid, (2S,4S) -4- (3-chlorophenoxy) proline, (2S,4S) -4- (3-fluorobenzyl) -proline, [ (1R,5R,6S) -6- (aminomethyl) bicyclo [3.2.0]Hept-6-yl]Acetic acid, 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1,2,4]Oxadiazol-5-ones, C- [1- (1H-tetrazol-5-ylmethyl) -cycloheptyl]-methylamine, (3S,4S) - (1-aminomethyl-3, 4-dimethylcyclopentyl) -acetic acid, (3S,5R) -3-aminomethyl-5-methyloctanoic acid, (3S,5R) -3-amino-5-methylnonanoic acid, (3S,5R) -3-amino-5-methyl-octanoic acid, (3R,4R,5R) -3-amino-4, 5-dimethylheptanoic acid and (3R,4R,5R) -3-amino-4, 5-dimethyloctanoic acid;

(27) cannabinoids;

(28) metabotropic glutamate subtype 1 receptor (mglur) antagonists;

(29) 5-hydroxytryptamine reuptake inhibitors, such as sertraline, the sertraline metabolite desmethylsertraline, fluoxetine, norfluoxetine (fluoxetine nor metabolite), fluvoxamine, paroxetine, citalopram, the citalopram metabolite desmethylcitalopram, escitalopram, d, l-fluorophenylpropylamine, femoxetine, efoxetine, cyano dothiepin, ritoxetine, dapoxetine, nefazodone, cilazalone, and trazodone;

(30) norepinephrine (noradrenaline) reuptake inhibitors such as maprotiline, lofepramine, mirtazapine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, the bupropion metabolite hydroxy bupropion, nomifensine, and viloxazine (vivalan (r)), particularly selective norepinephrine reuptake inhibitors such as reboxetine, particularly (S, S) -reboxetine;

(31) dual 5-hydroxytryptamine-norepinephrine reuptake inhibitors such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran, and imipramine;

(32) inducible Nitric Oxide Synthase (iNOS) inhibitors, for example S- [2- [ (1-iminoethyl) amino ] ethyl ] -1-homocysteine, S- [2- [ (1-iminoethyl) -amino ] ethyl ] -4, 4-dioxo-1-cysteine, S- [2- [ (1-iminoethyl) amino ] ethyl ] -2-methyl-1-cysteine, (2S,5Z) -2-amino-2-methyl-7- [ (1-iminoethyl) amino ] -5-heptenoic acid, 2- [ [ (1R,3S) -3-amino-4-hydroxy-1- (5-thiazolyl) -butyl ] thio ] -S-chloro-S -pyridine nitrile; 2- [ [ (1R,3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl ] thio ] -4-chlorobenzonitrile; (2S,4R) -2-amino-4- [ [ 2-chloro-5- (trifluoromethyl) phenyl ] thio ] -5-thiazolobutanol, 2- [ [ (1R,3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl ] thio ] -6- (trifluoromethyl) -3-pyridinecarbonitrile, 2- [ [ (1R,3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl ] thio ] -5-chlorobenzonitrile; n- [4- [2- (3-chlorobenzylamino) ethyl ] phenyl ] thiophene-2-carboxamidine or guanidinoethyl disulfide;

(33) acetylcholinesterase inhibitors such as donepezil;

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

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

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

(37) sodium channel blockers, such as lidocaine;

(38)5-HT3 antagonists, such as ondansetron; and pharmaceutically acceptable salts and solvates thereof.

The amount of additional therapeutic agent present in the compositions of the present invention will not exceed the amount that would normally be administered in a composition containing that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present invention will range from about 50% to 100% of the amount typically present in compositions comprising that agent as the sole therapeutically active agent.

The compounds of the present invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating implantable medical devices, such as prostheses, prosthetic valves, vascular grafts, stents and catheters. Thus, in another aspect, the present invention includes compositions for coating an implantable device comprising a compound of the present invention as generally described above and in classes and subclasses herein, and a carrier suitable for coating the implantable device. In yet another aspect, the invention includes an implantable device coated with a compound of the invention as generally described above and in classes and subclasses herein, and a carrier suitable for coating the implantable device. Suitable coatings and general preparations for coating implantable devices are described in U.S. patent 6,099,562; 5,886,026, respectively; and 5,304,121. The coating is typically a biocompatible polymeric material such as hydrogel polymers, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate copolymers, and mixtures thereof. The coating may optionally be further covered with a suitable outer coating of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart a controlled release characteristic to the composition.

Another aspect of the invention relates to inhibiting the activity of one or more of nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav1.9 in a biological sample or subject, the method comprising administering to the subject a compound of formula I or a composition comprising said compound, or contacting said biological sample with a compound of formula I or a composition comprising said compound. The term "biological sample" as used herein includes, without limitation, cell cultures or extracts thereof; biopsy material obtained from a mammal or an extract thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of the activity of one or more of nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav1.9 in a biological sample is useful for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, the study of sodium ion channels in biological and pathological phenomena; and comparatively evaluating the new sodium ion channel inhibitor.

Examples

A general method.¹H NMR (400MHz or 300MHz) and¹³c NMR (100MHz) spectroscopy in deuterated acetonitrile (CD)₃CN), chloroform-d (CDCl)₃) Deuterated methanol (MeOD-d)₄) Or dimethyl sulfoxide-D₆Mass Spectrometry (MS) was performed using a spectrometer loaded with Phenomenex 50 × 460mm luna-5 μ C18 column obtained from an Applied Biosystems API EXLC/MS system. The LC/MS elution system was H containing 1-99% or 10-99% acetonitrile with 0.035% v/v trifluoroacetic acid, 0.035% v/v formic acid, 5mM HCl or 5mM ammonium formate₂O solution, using a linear gradient of 3 or 15 minutes 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, methylene Chloride (CH)₂Cl₂) Tetrahydrofuran (THF), Dimethylformamide (DMF), Acetonitrile (ACN), methanol (MeOH) and 1, 4-bisThe alkanes were all from Aldrich Sure-Seal bottles kept under dry nitrogen. All reactions were magnetically stirred unless otherwise stated.

[ cis-8-ethoxy-10- (4-fluorophenyl) -11-oxa-3-azaspiro [5.5] undecan-3-yl ] - [ 3-fluoro-4- (1-hydroxy-1-methyl-ethyl) phenyl ] methanone

Step 1: 8-oxo-11-oxa-3-azaspiro [5.5] undec-9-ene-3-carboxylic acid tert-butyl ester

Tert-butyl 4-oxopiperidine-1-carboxylate (19.3g, 96.7mmol) was placed in an oven dried flask. 2-Butanol (140mL) was added. The light yellow solution was purged with argon for 2 minutes. (1E) -3- [ tert-butyl (dimethyl) silyl ] added dropwise at room temperature (water bath) under an argon atmosphere]oxy-N, N-dimethyl-but-1, 3-dien-1-amine (20.0g, 87.9 mmol). The solution turned dark brown. The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo. Anhydrous ether (100mL) was added and removed in vacuo. The residue was dissolved in dry ether (300mL) and cooled to-78 ℃. Acetyl chloride (7.50mL, 106mmol) was added dropwise. The mixture was stirred at-78 ℃ for 15 minutes. The reaction was quenched with saturated sodium bicarbonate (100 mL). Water was added. The mixture was extracted with ether (3 ×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification of the crude dark red oil by column chromatographyAs a yellow oil (20-30% ethyl acetate-hexanes) to give 17.5 g of a yellow-orange oil. This was dissolved in hexane (40mL) at 60 ℃ and the crystalline material was seeded. A white crystalline solid was immediately observed. The mixture was stirred while slowly cooled to room temperature overnight. The crystalline solid was collected by vacuum filtration and washed with hexane to give 8-oxo-11-oxa-3-azaspiro [5.5]]Tert-butyl undec-9-ene-3-carboxylate (12.09g) as a pale yellow crystalline powder.¹H NMR(400MHz，CDCl₃)7.26(d, J ═ 6.1Hz, 1H), 5.42(d, J ═ 6.1Hz, 1H), 3.86(d, J ═ 12.5Hz, 2H), 3.24-3.08(m, 2H), 2.52(s, 2H), 2.12-2.02(m, 2H), 1.60-1.49(m, 2H), 1.46(s, 9H). ESI-MS M/z calculated 267.15, found 268.5(M +1)⁺(ii) a Retention time: 1.13 minutes (run 3 minutes).

The following compounds were prepared using the methods reported above:

step 2: 10- (4-fluorophenyl) -8-oxo-11-oxa-3-azaspiro [5.5] undecane-3-carboxylic acid tert-butyl ester

To the dried flask was added cuprous iodide (1.28g, 6.73mmol) under an argon atmosphere followed by anhydrous THF (125 mL). The suspension was cooled to-78 deg.C and then (4-fluorophenyl) magnesium bromide (33.7mL of a 2M solution in ether, 67.3mmol) was added dropwise. The resulting mixture was stirred at-78 ℃ for 20 minutes. HMPA (23.4mL, 135mmol) was added and the reaction mixture was stirred at-78 ℃ for an additional 30 minutes. In a separate flask, TMSCl (17.1mL, 135mmol) was slowly added to 8-oxo-11-oxa-3-azaspiro [5.5]]Tert-butyl undec-9-ene-3-carboxylate (3.00g, 11.2mmol) in THF (10 mL). The solution was then slowly transferred to the reaction mixture at-78 ℃. The resulting thick opaque white color was then mixedThe reaction mixture was slowly warmed to room temperature and stirred overnight, saturated ammonium chloride (75mL) was added to the resulting gray reaction mixture, the mixture was stirred at room temperature for 5 minutes, volatiles were removed under reduced pressure, the remaining 1/3 volumes were combined ethyl acetate (100mL) and water (25mL), the aqueous layer was extracted with ethyl acetate (2 × 50mL), the organic layers were combined, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the resulting yellow oil (20-40% ethyl acetate/hexanes) was purified by column chromatography to give 10- (4-fluorophenyl) -8-oxo-11-oxa-3-azaspiro [ 5.5.5 ]]Tert-butyl undecane-3-carboxylate (3.81 g).¹H NMR(400MHz，CDCl₃)7.41-7.33(m, 2H), 7.11-7.03(m, 2H), 4.83(dd, J-11.2, 3.1Hz, 1H), 3.87-3.72(m, 2H), 3.32(ddd, J-13.4, 11.5, 3.3Hz, 1H), 3.09-2.98(m, 1H), 2.61(ddd, J-14.0, 3.1, 1.7Hz, 1H), 2.57-2.47(m, 2H), 2.39(dd, J-13.9, 1.8Hz, 1H), 2.02-1.95(m, 1H), 1.85(ddd, J-13.4, 5.8, 3.2Hz, 1H), 1.68(ddd, J-13.4, 11.4, 1.5, 1.8, 1H), 1.47(m, 1H), 1.6, 1H), 1.47 (J-13.4, 1H). ESI-MS M/z calculated 363.18, found 364.0(M +1)⁺(ii) a Retention time: 1.81 minutes (run 3 minutes).

The following compounds were prepared using the methods reported above:

and step 3: cis-and trans-10- (4-fluorophenyl) -8-hydroxy-11-oxa-3-azaspiro [5.5] undecane-3-carboxylic acid tert-butyl ester

To 10- (4-fluorophenyl) -8-oxo-11-oxa-3-azaspiro [5.5]]To a solution of tert-butyl undecane-3-carboxylate (2.00g, 5.50mmol) in MeOH (50mL) was added cerium trichloride (1.49g, 6.05 mmol). The mixture was stirred for 5 minutes, then sodium borohydride (250mg, 6.60mmol) was added. Will be provided withThe reaction mixture was stirred at room temperature for 1 hour, saturated ammonium chloride (50mL) was added to quench the reaction, the reaction mixture was stirred for 5 minutes, extracted with ethyl acetate (3 × 75mL), the organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and the crude product (20-40% ethyl acetate/hexane) was purified by column chromatography to give cis- (4-fluorophenyl) -8-hydroxy-11-oxa-3-azaspiro [ 5.5%]Undecane-3-carboxylic acid tert-butyl ester (749mg) and trans-10- (4-fluorophenyl) -8-hydroxy-11-oxa-3-azaspiro [5.5]Tert-butyl undecane-3-carboxylate (644 mg). Cis-isomer:¹H NMR(400MHz，CDCl₃)7.39-7.33(m, 2H), 7.03(ddd, J ═ 8.8, 5.8, 2.5Hz, 2H), 4.94(d, J ═ 11.5Hz, 1H), 4.37(dd, J ═ 6.1, 3.0Hz, 1H), 3.76(d, J ═ 13.9Hz, 2H), 3.27(ddd, J ═ 13.2, 10.2, 4.9Hz, 1H), 3.10-2.98(m, 1H), 2.69(d, J ═ 15.7Hz, 1H), 1.96-1.89(m, 1H), 1.71(d, J ═ 11.9, 11.0, 2.9Hz, 2H), 1.64-1.55(m, 4H), 1.55-1.48(m, 1H), 1.44(m, 44H), 1.9(s). ESI-MSm/z calculated 365.20, found 366.3(M +1)⁺(ii) a Retention time: 1.54 minutes (run 3 minutes). Trans-isomer:¹HNMR(400MHz，CDCl₃)7.38-7.31(m, 2H), 7.03(ddd, J ═ 10.7, 5.9, 2.5Hz, 2H), 4.58-4.50(m, 1H), 4.13(ddd, J ═ 11.3, 6.8, 4.6Hz, 1H), 3.82-3.72(m, 2H), 3.26(ddd, J ═ 13.3, 10.4, 4.6Hz, 1H), 3.07-2.96(m, 1H), 2.23(ddd, J ═ 10.3, 4.4, 2.2Hz, 1H), 2.12(d, J ═ 14.7Hz, 1H), 1.96(ddd, J ═ 12.5, 4.6, 1.8Hz, 1H), 1.70-1.58(m, 2H), 1.55.43H, 1.43(m, 1H), 1.49-2H), 1.49(m, 2H). ESI-MS M/z calculated 365.20, found 366.5(M +1)⁺. Retention time: 1.63 minutes (run 3 minutes).

The following compounds were prepared using the methods reported above:

and 4, step 4: cis-8-ethoxy-10- (4-fluorophenyl) -11-oxa-3-azaspiro [5.5] undecane-3-carboxylic acid tert-butyl ester

To cis- (4-fluorophenyl) -8-hydroxy-11-oxa-3-azaspiro [5.5]To a solution of tert-butyl undecane-3-carboxylate (749mg) in DMF (15mL) was added sodium hydride (410mg, 10.3mmol) (60 wt% in mineral oil.) the mixture was stirred at room temperature for 20 minutes, then iodoethane (5 eq.). the mixture was then stirred at room temperature overnight, the reaction mixture was diluted with ethyl acetate (100mL), washed with water (1 × 75mL), the aqueous layer was extracted with ethyl acetate (2 × 75mL), all organic layers were combined, dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (10-20% ethyl acetate/hexane) to give cis-8-ethoxy-10- (4-fluorophenyl) -11-oxa-3-azaspiro [ 5.5.5%]Tert-butyl undecane-3-carboxylate (510 mg).¹H NMR(400MHz，CDCl₃)7.37-7.31(m, 2H), 7.03(ddd, J ═ 10.8, 5.9, 2.5Hz, 2H), 4.52(dd, J ═ 11.8, 1.7Hz, 1H), 3.76(tt, J ═ 11.1, 4.3Hz, 3H), 3.62-3.47(m, 2H), 3.26(ddd, J ═ 13.3, 10.6, 4.3Hz, 1H), 3.08-2.98(m, 1H), 2.28(ddt, J ═ 12.3, 4.0, 1.9Hz, 1H), 2.13(d, J ═ 13.3Hz, 1H), 1.97(ddd, J ═ 12.6, 4.4, 1.8, 1H), 1.63 (ddd, 10.6, J ═ 4.4, 1.8, 1H), 1.63 (ddd, J ═ 6, 1.5, 1.3H), 1.50H, 1.6 (t, 1H), 3H, 1.50H, 1H). ESI-MS M/z calculated 393.23, found 394.4(M +1)⁺(ii) a Retention time: 2.03 minutes (run 3 minutes).

The following compounds were prepared using the methods reported above:

and 5: cis-8-ethoxy-10- (4-fluorophenyl) -11-oxa-3-azaspiro [5.5] undecane

To cis-8-ethoxy-10- (4-fluorophenyl) -11-oxa-3-azaspiro [5.5]Undecane-3-carboxylic acid tert-butyl ester (510mg, 1.30mmol) in CH₂Cl₂(1mL) to the solution was added 1:1 trifluoroacetic acid (1mL) in CH₂Cl₂(1mL) after 1h, the reaction mixture was diluted with 1N aqueous NaOH (50mL), extracted with ethyl acetate (2 × 50mL), the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give cis-8-ethoxy-10- (4-fluorophenyl) -11-oxa-3-azaspiro [ 5.5%]Undecane (520 mg).¹H NMR(400MHz，CDCl₃)7.46-7.31(m, 2H), 7.10-6.98(m, 2H), 4.54(d, J ═ 11.8Hz, 1H), 3.76(ddd, J ═ 15.7, 11.3, 4.4Hz, 1H), 3.66-3.46(m, 2H), 3.09(dt, J ═ 13.9, 7.0Hz, 1H), 2.99-2.76(m, 3H), 2.69-2.21(m, 2H), 2.17-2.00(m, 2H), 1.79-1.64(m, 1H), 1.64-1.49(m, 1H), 1.50-1.24(m, 2H), 1.24-1.12(m, 3H). ESI-MS M/z calculated 293.18, found 294.5(M +1)⁺(ii) a Retention time: 0.97 min (run 3 min).

The following compounds were prepared using the methods reported above:

step 6: [ cis-8-ethoxy-10- (4-fluorophenyl) -11-oxa-3-azaspiro [5.5] undecan-3-yl ] - [ 3-fluoro-4- (1-hydroxy-1-methyl-ethyl) phenyl ] methanone

To cis-8-ethoxy-10- (4-fluorophenyl) -11-oxa-3-azaspiro [5.5]Undecane (75mg, 0.26mmol) and 3-fluoro-4- (1-hydroxy-1-methyl-ethyl) benzoic acid (56mg, 0.28mmol) in CH₂Cl₂To the solution in (1mL) was added EDCI (54mg, 0.28 mmol). Finally adding twoIsopropylethylamine (134. mu.L, 0.767 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by column chromatography (0-50% EtOAc-Hex) to give [ cis-8-ethoxy-10- (4-fluorophenyl) -11-oxa-3-azaspiro [5.5]]Undec-3-yl]- [ 3-fluoro-4- (1-hydroxy-1-methyl-ethyl) phenyl]Methanone (28.3 mg).¹H NMR(400MHz，CDCl₃)7.60(t, J ═ 8.1Hz, 1H), 7.34(dd, J ═ 8.5, 5.4Hz, 2H), 7.14(dd, J ═ 8.0, 1.6Hz, 1H), 7.11-7.00(m, 3H), 4.60-4.30(m, 2H), 3.77 (brs, 1H), 3.65-3.05(m, 6H), 2.27 (brs, 2H), 2.23-2.07(m, 1H), 1.64(s, 6H), 1.62-1.30(m, 5H), 1.22(dd, J ═ 16.6, 9.6Hz, 3H). ESI-MS M/z calculated 473.24, found 474.5(M +1)⁺(ii) a Retention time: 1.63 minutes (run 3 minutes).

The following compounds were prepared using the methods reported above:

1- (4-Isopropoxy-3-methoxy-benzoyl) piperidin-4-one

Step 1: 4-isopropoxy-3-methoxy-benzoyl chloride

To a stirred solution of 4-isopropoxy-3-methoxy-benzoic acid (40.0g, 190.3mmol) in anhydrous dichloromethane (400mL) was slowly added thionyl chloride (27.8mL, 381mmol) at room temperature. The reaction was then transferred from the room temperature water bath to an oil bath and then warmed to 30 ℃. The solution was stirred at 30 ℃ overnight. The reaction mixture was cooled to room temperature, and thionyl chloride (10.0mL, 137mmol) was then added. The reaction was stirred at 40 ℃ for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure and azeotroped with toluene to give 4-isopropoxy-3-methoxy-benzoyl chloride (44.3g) as a yellow oil. The product was used in the next step without further purification.

The following compounds were prepared using the methods reported above:

product of	Formic acid
		4-isopropoxy-3-methyl-benzoyl chloride	4-isopropoxy-3-methyl-benzoic acid

Step 2: 1- (4-Isopropoxy-3-methoxy-benzoyl) piperidin-4-one

Piperidin-4-one hydrochloride hydrate (29.2g, 190mmol) was dissolved in aqueous sodium hydroxide (95mL of 2.0M, 190 mmol). The resulting clear solution was then stirred in an ice-water bath under a nitrogen atmosphere. 4-Isopropoxy-3-methoxy-benzoyl chloride (43.5g, 190mmol) was dissolved in toluene (90mL) to give a final volume of 100 mL. This solution was added dropwise in 2mL portions, followed by 1mL of aqueous sodium hydroxide (48mL of 4.0M, 192 mmol). This process was repeated until all additions of both reagents were completed. Upon completion, the reaction mixture was stirred at 0 ℃ for an additional 30 minutes. Adding CH to the mixture₂Cl₂(250mL) followed by water (200 mL). The mixture was mixed thoroughly in a separatory funnel and CH was added₂Cl₂The aqueous layer was extracted (2 × 100mL), the organic layers combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a dark brown oil which was purified by column chromatography to give 1- (4-isopropoxy-3-methoxy-benzoyl) piperidin-4-one (16.56g) as a clear light brown oil which crystallized on standing to a light brown white solid.¹H NMR(400MHz，CDCl₃)7.06(d, J ═ 1.9Hz, 1H), 7.02(dd, J ═ 8.2, 2.0Hz, 1H), 6.90(d, J ═ 8.3Hz, 1H), 4.59(dt, J ═ 12.2, 6.1Hz, 1H), 3.90-3.88(br s, 4H), 3.88(s, 3H), 2.51(s, 4H), 1.40(d, J ═ 6.1Hz, 6H). ESI-MS M/z calculated 291.15, found 292.0(M +1)⁺(ii) a Retention time: 0.94 min (run 3 min).

The following compounds were prepared using the methods reported above:

3- (4-Isopropoxy-3-methyl-benzoyl) -11-oxa-3-azaspiro [5.5] undec-9-en-8-one

Step 1: 11-oxa-3-azaspiro [5.5] undec-9-en-8-one

To 8-oxo-11-oxa-3-azaspiro [5.5]]Undeca-9-ene-3-carboxylic acid tert-butyl ester (200mg, 0.748mmol) in CH₂Cl₂To a solution in (2.4mL) was added TFA (0.6mL, 7.8 mmol). The mixture was stirred at room temperature for 15 minutes. The solvent was removed. The crude material was then evaporated from toluene (2X) and dried under high vacuum overnight to give 11-oxa-3-azaspiro [5.5]]Undec-9-en-8-one (300 mg).¹H NMR(400MHz，CDCl₃)7.34(d, J ═ 6.1Hz, 1H), 5.57(d, J ═ 6.1Hz, 1H), 3.45(d, J ═ 11.7Hz, 2H), 3.34(dd, J ═ 24.1, 12.7Hz, 2H), 2.67(s, 2H), 2.38(d, J ═ 14.6Hz, 2H), 1.98(td, J ═ 14.8, 4.8Hz, 2H). ESI-MS M/z calculated 167.09, found 168.2(M +1)⁺(ii) a Retention time: 0.17 min (run 3 min).

Step 2: 3- (4-Isopropoxy-3-methyl-benzoyl) -11-oxa-3-azaspiro [5.5] undec-9-en-8-one

To 11-oxa-3-azaspiro [5.5]]Undec-9-en-8-one; 2,2, 2-trifluoroacetic acid (2.42g, 8.6mmol) in CH₂Cl₂(35mL) to the solution was added triethylamine (10.9mL, 78.2mmol) and then added dropwise to CH₂Cl₂4-Isopropoxy-3-methyl-benzoyl chloride (1.83g, 8.60mmol) in (5 mL). The mixture was stirred at room temperature overnight. By CH₂Cl₂The mixture was diluted, washed with water and MgSO₄Drying, filtering and concentrating to dryness. The crude material was purified by column chromatography (30-50% ethyl acetate-hexanes) to give 3- (4-isopropoxy-3-methyl-benzoyl) -11-oxa-3-azaspiro [5.5]]Undec-9-en-8-one (2.65g) as a pale yellow solid.¹H NMR(400MHz，CDCl₃)7.27(t, J ═ 4.0Hz, 1H), 7.25-7.17(m, 2H), 6.81(d, J ═ 8.1Hz, 1H), 5.43(d, J ═ 6.1Hz, 1H), 4.56(dd, J ═ 12.1, 6.0Hz, 1H), 4.43-3.61 (m, 2H), 3.33(s, 2H), 2.55(s, 2H), 2.20(s, 3H), 2.13(d, J ═ 13.2Hz, 2H), 1.61(s, 2H), 1.35(d, J ═ 6.0Hz, 6H). ESI-MS M/z calculated 343.18, found 344.3(M +1)⁺(ii) a Retention time: 1.50 minutes (run 3 minutes).

10-Ethyl-3- (4-isopropoxy-3-methyl-benzoyl) -11-oxa-3-azaspiro [5.5] undecan-8-one

Step 1: 10-ethyl-11-oxa-3-azaspiro [5.5] undecan-8-one

With N₂Reacting 8-oxo-10-vinyl-11-oxa-3-azaspiro [5.5]]A solution of benzyl undecane-3-carboxylate (380mg, 1.15mmol) in MeOH (30mL) was purged for 2 min. Palladium (10% on carbon) (50mg, 0.047mmol) was added. The mixture was hydrogenated using a hydrogen balloon at room temperature for 24 hours. The catalyst was removed by filtration. Concentration filterLiquid to dry to obtain 10-ethyl-11-oxa-3-azaspiro [ 5.5%]Undecane-8-one (243mg) as a light yellow thick oil, which was used in the next step without further purification. ESI-MS M/z calculated 197.14, found 198.2(M +1)⁺(ii) a Retention time: 0.17 min (run 3 min).

Step 2: 10-Ethyl-3- (4-isopropoxy-3-methyl-benzoyl) -11-oxa-3-azaspiro [5.5] undecan-8-one

To 10-ethyl-11-oxa-3-azaspiro [5.5]]Undecane-8-one (208mg, 1.05mmol) in CH₂Cl₂(5mL) to the solution was added triethylamine (441. mu.L, 3.16mmol) and added dropwise to CH₂Cl₂4-Isopropoxy-3-methyl-benzoyl chloride (247mg, 1.16mmol) in (1 mL). The mixture was stirred at room temperature overnight with CH₂Cl₂Dilute, wash with saturated sodium bicarbonate (2 ×), 10% citric acid (2 ×), brine, MgSO₄Drying, filtering and concentrating to dryness. The crude material was purified by column chromatography (30-40% ethyl acetate-hexanes) to give 10-ethyl-3- (4-isopropoxy-3-methyl-benzoyl) -11-oxa-3-azaspiro [ 5.5%]Undecan-8-one (191 mg).¹H NMR(400MHz，CDCl₃) 7.23-7.17 (m, 2H), 6.81(d, J ═ 8.0Hz, 1H), 4.56(dt, J ═ 12.1, 6.1Hz, 1H), 4.12(d, J ═ 7.1Hz, 2H), 3.69(s, 1H), 3.49(s, 1H), 3.06(s, 1H), 2.37(ddd, J ═ 14.0, 10.5, 8.1Hz, 2H), 2.32-2.23 (m, 2H), 2.20(d, J ═ 4.3Hz, 3H), 1.93(d, J ═ 13.9Hz, 1H), 1.86-1.54 (m, 5H), 1.34(d, J ═ 6.0Hz, 6H), 1.03(t, J ═ 7.4, 3H). ESI-MS M/z calculated 373.23, found 374.5(M +1)⁺(ii) a Retention time: 1.78 minutes (run 3 minutes).

(4-Isopropoxy-3-methoxy-phenyl) - [ cis-8-methoxy-10-phenyl-11-oxa-3-azaspiro [5.5] undecan-3-yl ] methanone

Step 1: 3- (4-Isopropoxy-3-methoxy-benzoyl) -11-oxa-3-azaspiro [5.5] undec-9-en-8-one

A suspension of 1- (4-isopropoxy-3-methoxy-benzoyl) piperidin-4-one (12.8g, 44.0mmol) in 2-butanol (100mL) was purged with argon for 5 minutes. (1E) -3- [ tert-butyl (dimethyl) silyl ] added dropwise at room temperature under an argon atmosphere]oxy-N, N-dimethyl-but-1, 3-dien-1-amine (10.0g, 4.0 mmol). The reaction mixture was stirred at room temperature overnight. The mixture became a dark brown clear solution. The solvent was removed. The residue was redissolved in THF (200mL) and cooled to-78 ℃. Acetyl chloride (3.75mL, 52.8mmol) was added dropwise. The mixture was stirred at-78 ℃ for 30 minutes. The reaction was quenched with saturated sodium bicarbonate (25 mL). The organic layer was separated. The aqueous layer was extracted with ether (3 ×). The combined organic layers were washed with brine, MgSO₄Drying, filtering and concentrating. The crude material was purified by column chromatography (40-60% ethyl acetate-hexanes) to give 3- (4-isopropoxy-3-methoxy-benzoyl) -11-oxa-3-azaspiro [5.5]]Undec-9-en-8-one (8.5g) as a light yellow thick oil.¹H NMR(400MHz，CDCl₃)7.28(d, J ═ 6.1Hz, 1H), 6.99(d, J ═ 1.9Hz, 1H), 6.94(dd, J ═ 8.2, 1.9Hz, 1H), 6.87(d, J ═ 8.3Hz, 1H), 5.44(d, J ═ 6.1Hz, 1H), 4.57(dt, J ═ 12.2, 6.1Hz, 1H), 4.25-4.00(m, 2H), 3.87(s, 3H), 3.34(s, 2H), 2.56(s, 2H), 2.15(d, J ═ 14.1Hz, 2H), 1.62(s, 2H), 1.39(t, J ═ 5.3Hz, 6H). ESI-MS M/z calculated 359.17, found 360.3(M +1)⁺(ii) a Retention time: 1.18 minutes (run 3 minutes).

Step 2: 3- (4-Isopropoxy-3-methoxy-benzoyl) -10-phenyl-11-oxa-3-azaspiro [5.5] undecan-8-one

The round bottom flask was heated in vacuo with a heat gun and then charged with Ar. This process was repeated 3 times. To the flask was placed cuprous iodide (2.32g, 12.2mmol) followed by addition of THF (5 mL). The suspension was purged with argon for 2 minutes and then cooled to-78 ℃. Phenylmagnesium bromide in THF (122mL of 1M, 122mmol) was added dropwise at-78 deg.C under an argon atmosphere. The mixture was stirred at-78 ℃ for 20 minutes. HMPA (44.0g, 244mmol) was added. The mixture was stirred at-78 ℃ for 30 minutes. TMSCl (26.5g, 244mmol) was added to 3- (4-isopropoxy-3-methoxy-benzoyl) -11-oxa-3-azaspiro [5.5]]Undec-9-en-8-one (7.30g, 20.3mmol) in THF (25 mL). The above solution was added dropwise to the reaction mixture. The mixture was slowly warmed to room temperature and stirred at room temperature overnight. With saturated NH₄The reaction was quenched with Cl solution and redistributed between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2 ×). The combined organic layers were washed with brine, MgSO₄Drying, filtering and concentrating to dryness. The crude material was purified by column chromatography (40-60% ethyl acetate-hexanes) to give 3- (4-isopropoxy-3-methoxy-benzoyl) -10-phenyl-11-oxa-3-azaspiro [ 5.5%]Undecan-8-one (6 g). ESI-MSm/z calculated 437.22, found 438.0(M +1)⁺(ii) a Retention time: 1.69 minutes (run 3 minutes).

The following compounds were prepared using the methods reported above:

and step 3: cis-and trans- [ 8-hydroxy-10-phenyl-11-oxa-3-azaspiro [5.5] undecan-3-yl ] - (4-isopropoxy-3-methoxy-phenyl) methanone

To 3- (4-isopropoxy-3-methoxy-benzoyl) -10-phenyl-11-oxa-3-nitrogenHetero spiro [5.5]]To a solution of undecane-8-one (4.50g, 10.3mmol) in MeOH (110mL) was added cerium trichloride (2.79g, 11.3 mmol). The mixture was stirred at room temperature for 5 minutes. Sodium borohydride (467mg, 12.4mmol) was added. The mixture was stirred at room temperature for 20 minutes. The reaction was quenched with water and extracted with ethyl acetate (2 ×). The combined organic layers were washed with brine, MgSO₄Drying, filtering and concentrating to dryness. The crude material was purified by column chromatography (40-60% ethyl acetate-hexane) to give [ cis-8-hydroxy-10-phenyl-11-oxa-3-azaspiro [5.5]]Undec-3-yl]- (4-isopropoxy-3-methoxy-phenyl) methanone (1.5g) and [ trans-8-hydroxy-10-phenyl-11-oxa-3-azaspiro [5.5]]Undec-3-yl]- (4-isopropoxy-3-methoxy-phenyl) methanone (1.3 g). Cis-isomer:¹H NMR(400MHz，CDCl₃)7.43-7.33(m, 4H), 7.33-7.27(m, 1H), 6.96(d, J ═ 1.6Hz, 1H), 6.95-6.90(m, 1H), 6.86(d, J ═ 8.2Hz, 1H), 4.65-4.48(m, 2H), 4.23-4.05(m, 2H), 3.95-3.75(m, 1H), 3.85(s, 3H), 3.49(s, 1H), 3.20(s, 1H), 2.25(dd, J ═ 20.6, 8.4Hz, 2H), 1.98(dd, J ═ 12.5, 2.9Hz, 1H), 1.73(s, 2H), 1.62-1.40(m, 3H), 1.37(t, 6.0, 6H). ESI-MSm/z calc.439.24, found 440.4(M +1)⁺(ii) a Retention time: 1.49 minutes (run 3 minutes). Trans-isomer¹H NMR(400MHz，CDCl₃)7.43-7.38(m, 2H), 7.39-7.33(m, 2H), 7.31-7.24(m, 1H), 6.96(d, J ═ 1.7Hz, 1H), 6.92(dd, J ═ 8.2, 1.8Hz, 1H), 6.85(d, J ═ 8.2Hz, 1H), 4.97(d, J ═ 11.2Hz, 1H), 4.55(dt, J ═ 12.2, 6.1Hz, 1H), 4.44-4.32(m, 1H), 4.05-3.75(m, 2H), 3.85(s, 3H), 3.49(s, 1H), 3.24(s, 1H), 2.77(dd, J ═ 25.2, 13.7, 1H), 1.96(d, 1.84 (d, 1.70H), 1.54 (d, 1H), 1.54H), 1H, 1. ESI-MS M/z calculated 439.24, found 440.2(M +1)⁺(ii) a Retention time: 1.61 min (run 3 min).

The following compounds were prepared using the methods reported above:

and 4, step 4: (4-Isopropoxy-3-methoxy-phenyl) - [ cis-8-methoxy-10-phenyl-11-oxa-3-azaspiro [5.5] undecan-3-yl ] methanone

To [ cis-8-hydroxy-10-phenyl-11-oxa-3-azaspiro [5.5]]Undec-3-yl]To a solution of (4-isopropoxy-3-methoxy-phenyl) methanone (139mg, 0.3mmol) in DMF (4mL) was added sodium hydride (34mg, 1.5 mmol). The mixture was stirred at room temperature for 30 minutes. Methyl iodide (187. mu.L, 3.00mmol) was heated. The mixture was stirred at room temperature overnight and then redistributed between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2 ×), the combined organic layers were washed with water (3 ×), brine, and MgSO₄Drying, filtering and concentrating to dryness. The crude material was purified by column chromatography (50-60% ethyl acetate-hexanes) to give (4-isopropoxy-3-methoxy-phenyl) - [ cis-8-methoxy-10-phenyl-11-oxa-3-azaspiro [ 5.5%]Undec-3-yl]Methanone (102 mg).¹H NMR(400MHz，CDCl₃)7.48-7.33(m, 4H), 7.33-7.28(m, 1H), 7.01-6.90(m, 2H), 6.86(d, J ═ 8.2Hz, 1H), 4.66-4.46(m, 2H), 4.12-3.90(m, 2H), 3.86(s, 3H), 3.76-3.61(m, 1H), 3.48(s, 1H), 3.37(d, J ═ 4.5Hz, 3H), 3.21(t, J ═ 11.8Hz, 1H), 2.28(dd, J ═ 39.8, 13.2Hz, 2H), 2.00(dd, J ═ 12.6, 2.7Hz, 1H), 1.85-1.62(m, 3H), 1.59-1.44(m, 1H), 1.42-1H (m, 33H). ESI-MS M/z calculated 453.25, found 454.5(M +1)⁺(ii) a Retention time: 1.65 minutes (run 3 minutes).

The following compounds were prepared using the methods reported above:

cis-4-ethoxy-2- (pyridin-2-yl) -1-oxa-9-azaspiro [5.5] undecan-9-yl) (4-isopropoxy-3-methylphenyl) methanone step 1: 4-Oxospiro [ chroman-2, 4 '-piperidine ] -1' -carboxylic acid tert-butyl ester

Step 1: 1- (3-pyridinyl) butane-1, 3-diones

The method A comprises the following steps:

to a solution of 1- (3-pyridyl) ethanone (15.0g, 124mmol) in DMF (100mL) at 0 deg.C was added sodium hydride (5.9g, 149 mmol). The reaction mixture was then stirred at room temperature for 10 minutes. After cooling to 0 deg.C, methyl acetate (11.8mL, 149mmol) was slowly added dropwise. The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was quenched by the addition of saturated ammonium chloride (100mL) and acidified to pH 5 by the addition of 1N HCl. The mixture was then extracted with ethyl acetate (2X 75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The 16 g of crude product was filtered through a pad of silica gel. The filtrate was concentrated under reduced pressure. The residue was dissolved in a 1:9 ethyl acetate/hexane solution (300mL) at 65 ℃. The resulting solution was slowly cooled to warm temperature while stirring, and the precipitate was collected by vacuum filtration to give 1- (3-pyridyl) butane-1, 3-dione (7.7g) as a yellow solid.

The method B comprises the following steps:

to a solution of pyridine-3-carboxylic acid methyl ester (20.0g, 146mmol) in THF (200mL) was added acetone (50mL, 681.0 mmol). At room temperature under N₂Sodium methoxide (32.7mL of 25% w/w, 146.0mmol) was added dropwise under an atmosphere. The mixture was stirred at room temperature for 72 hours with saturated NH₄Quenched with Cl and acidified to pH 5 with 1N HCl. The aqueous layer was extracted with EtOAc (3 ×). The combined organic layers were washed with brine, MgSO₄Drying, filtering and concentrating to dryness. The crude material was purified by column chromatography (0-10% EtOAc-Hex) to give 1- (3-pyridyl) butane-1, 3-dione (7g) as a pale yellow crystalline solid.¹H NMR(400MHz，CDCl₃)15.98(s, 1H), 9.19-8.99(m, 1H), 8.74(dd, J ═ 4.8, 1.7Hz, 1H), 8.34-8.04(m, 1H), 7.41(ddd, J ═ 8.0, 4.8, 0.8Hz, 1H), 6.20(s, 1H), 2.24(s, 3H). ESI-MS M/z calculated 163.06, found 164.3(M +1)⁺(ii) a Retention time: 0.32 min (run 3 min).

The following compounds were prepared using the methods reported above:

esters	Product of
		1- (2-pyridinyl) ethanones	1- (2-pyridinyl) butane-1, 3-diones
1- (4-pyridinyl) ethanones	1- (4-pyridinyl) butane-1, 3-diones

Step 2: 4- [ 4-hydroxy-1- (4-isopropoxy-3-methyl-benzoyl) -4-piperidinyl ] -1- (3-pyridinyl) butane-1, 3-dione

To an oven dried round bottom flask was added diisopropylamine (6.4mL, 46mmol) and THF (125mL), cooled to-78 deg.C, added a solution of nBuLi in hexanes (18mL of 2.5M, 46mmol), stirred at 0 deg.C for 30 minutes, cooled to-78 deg.C, added dropwise a solution of 1- (3-pyridyl) butane-1, 3-dione (3.40g, 21.0mmol) in THF (25mL), after 30 minutes at-78 deg.C, 1- (4-isopropoxy-3-methyl-benzoyl) piperidin-4-one (5.74g, 20.8mmol) in THF (25mL) was added dropwise the reaction mixture was slowly warmed to room temperature, stirred overnight, quenched with saturated ammonium chloride (100mL), the reaction was quenched, removed volatiles under reduced pressure to a third volume, extracted with ethyl acetate (2 × 75mL), combined organic layers were dried, filtered, concentrated under reduced pressure, purified by column chromatography to give a crude oil of ethyl 4- [ 4% hydroxypropoxy-3-4-methyl-benzoyl) -4-piperidinyl ] -1- (3-4-one-half of ethyl acetate]-1- (3-pyridinyl) butane-1, 3-dione (5.85g) as a yellow foamy solid.¹HNMR(400MHz，CDCl₃)15.81(s, 1H), 9.08(d, J ═ 1.9Hz, 1H), 8.76(dd, J ═ 4.8, 1.5Hz, 1H), 8.19(dd, J ═ 8.0, 1.6Hz, 1H), 7.49-7.42(m, 1H), 7.24-7.17(m, 2H), 6.80(d, J ═ 8.2Hz, 1H), 6.20(s, 1H), 4.55(m, 1H), 4.51-4.25(br s, 1H), 3.52-3.26(m, 4H), 2.68(s, 2H), 2.20(s, 3H), 1.75-1.51(m, 4H), 1.34(d, J ═ 6.0Hz, 6H). ESI-MS M/z calculated 438.22, found 439.5(M +1)⁺(ii) a Retention time: 1.37 minutes (run 3 minutes).

The following compounds were prepared using the methods reported above:

and step 3: 3- (4-Isopropoxy-3-methyl-benzoyl) -10- (3-pyridyl) -11-oxa-3-azaspiro [5.5] undec-9-en-8-one

The method A comprises the following steps:

4- [ 4-hydroxy-1- (4-isopropoxy-3-methyl-benzoyl) -4-piperidyl]-1- (3-pyridyl) butane-1, 3-dione (4.5g, 10.3mmol) was dissolved in glacial acetic acid (45mL, 791mmol), and stirred under reflux for 2 hours. The acetic acid was removed under reduced pressure. The crude residue was purified by column chromatography (40 g silica gel column, 40-80% ethyl acetate/hexanes) to give 3- (4-isopropoxy-3-methyl-benzoyl) -10- (3-pyridyl) -11-oxa-3-azaspiro [ 5.5%]Undec-9-en-8-one (3.75g) as a yellow viscous foam.¹H NMR(400MHz，CDCl₃) 9.04(d, J ═ 1.9, 1H), 8.74(dd, J ═ 4.8, 1.5, 1H), 8.08-8.02 (m, 1H), 7.44(dd, J ═ 8.0, 4.9, 1H), 7.26-7.21 (m, 2H), 6.82(d, J ═ 8.6, 1H), 6.07(s, 1H), 4.57(dt, J ═ 12.1, 6.0, 1H), 4.5-3.75(m, 2H), 3.44(br s, 2H), 2.65(s, 2H), 2.23(br s, 2H), 2.22(s, 3H), 1.74(br s, 2H), 1.35(d, J ═ 6.0, 6H). ESI-MS M/z calculated 420.20, found 420.8(M +1)⁺(ii) a Retention time: 1.45 minutes (run 3 minutes).

The method B comprises the following steps:

to 4- [ 4-hydroxy-1- (4-isopropoxy-3-methyl-benzoyl) -4-piperidinyl]To a solution of-1- (3-pyridyl) butane-1, 3-dione (1mmol) in dichloromethane (5mL) was added PPTS (251mg, 1.00 mmol). The mixture was heated in a microwave at 120 ℃ for 45 minutes. Water was added. The aqueous layer was extracted with dichloromethane (2 ×). The combined organic layers were washed with brine, MgSO₄Drying, filtering and concentrating to dryness. The residue was purified by column chromatography (40-50% ethyl acetate-hexanes) to give 3- (4-isopropoxy-3-methyl-benzoyl) -10- (3-pyridyl) -11-oxa-3-aza-3Spiro [5.5]Undec-9-en-8-one.

The following compounds were prepared using the methods reported above:

and 4, step 4: (4-hydroxy-2- (pyridin-3-yl) -1-oxa-9-azaspiro [5.5] undec-2-en-9-yl) (4-isopropoxy-3-methylphenyl) methanone

To 3- (4-isopropoxy-3-methyl-benzoyl) -10- (3-pyridyl) -11-oxa-3-azaspiro [5.5]Slowly adding sodium borohydride (328mg, 8.68mmol) to a solution of undec-9-en-8-one (3.65g, 8.68mmol) in methanol (35mL) after 2 hours, adding saturated ammonium chloride (75mL), stirring the mixture for 15 minutes, concentrating the mixture to half volume under reduced pressure, extracting the remaining suspension with ethyl acetate (3 × 75mL), combining the organic layers, drying over sodium sulfate, filtering, concentrating under reduced pressure, purifying the crude product (70-100% ethyl acetate/hexane) by column chromatography to give (4-hydroxy-2- (pyridin-3-yl) -1-oxa-9-azaspiro [ 5.5.5%]Undec-2-en-9-yl) (4-isopropoxy-3-methylphenyl) methanone (3.32 g).¹H NMR (400MHz, CDCl3)8.90(d, J ═ 1.8Hz, 1H), 8.57(dd, J ═ 4.7, 1.3Hz, 1H), 7.91(d, J ═ 8.0Hz, 1H), 7.31(dd, J ═ 8.0, 4.8Hz, 1H), 7.23(dd, J ═ 13.9, 5.8Hz, 2H), 6.81(d, J ═ 8.1Hz, 1H), 5.56(d, J ═ 3.5Hz, 1H), 4.56(dt, J ═ 12.0, 6.0Hz, 2H), 4.51-4.22 (m, 1H), 3.82(br, 1H), 3.39(br, 2H), 2.21(s, 3H), 2.17-4.6H (m, 1H), 6.55H (d, 6H). ESI-MS M/z calculation 422.2, measurement 423(M +1)⁺(ii) a Retention time: 1.23 minutes (run 3 minutes).

The following compounds were prepared using the methods reported above:

and 5: cis-8-hydroxy-10- (3-pyridyl) -11-oxa-3-azaspiro [5.5] undecan-3-yl ] - (4-isopropoxy-3-methyl-phenyl) methanone

Reacting [ 8-hydroxy-10- (3-pyridyl) -11-oxa-3-azaspiro [5.5]]Undec-9-en-3-yl]- (4-isopropoxy-3-methyl-phenyl) methanone (1.20g, 2.84mmol) was dissolved in ethanol. Under a nitrogen atmosphere, palladium (90.7mg, 0.09mmol) (10 wt% on carbon, wet) was added. The reaction was charged with hydrogen and the mixture was stirred in a hydrogen balloon overnight. The reaction mixture was filtered through a pad of celite. Purifying the concentrated filtrate (70-100% ethyl acetate/hexane) by column chromatography to obtain cis-8-hydroxy-10- (3-pyridyl) -11-oxa-3-azaspiro [5.5]]Undec-3-yl]- (4-isopropoxy-3-methyl-phenyl) methanone (520mg) as a white foamy solid.¹H NMR(400MHz，CDCl₃)8.65(s, 1H), 8.57(d, J ═ 4.2Hz, 1H), 7.80(d, J ═ 7.5Hz, 1H), 7.37(s, 1H), 7.19(d, J ═ 8.5Hz, 2H), 6.80(d, J ═ 8.1Hz, 1H), 4.65 (brs, 1H), 4.55(dt, J ═ 12.1, 6.0Hz, 1H), 4.40 (brs, 1H), 4.17(brs, 1H), 3.75-3.01(m, 3H), 2.27-2.12(m, 2H), 2.19(s, 3H), 2.13-1.93(m, 2H), 1.84-1.39(m, 4H), 1.34(d, J ═ 6.0, 6H). ESI-MS M/z calculation 424.24, found 425.4(M +1)⁺(ii) a Retention time: 1.13 minutes (run 3 minutes).

The following compounds were prepared using the methods reported above:

step 6: cis-4- (cyclopropylmethoxy) -2- (pyridin-3-yl) -1-oxa-9-azaspiro [5.5] undecan-9-yl) (4-isopropoxy-3-methylphenyl) methanone

[ cis-8-hydroxy-10- (3-pyridyl) -11-oxa-3-azaspiro [5.5] in DMF at 0 deg.C]Undec-3-yl]To (4-isopropoxy-3-methyl-phenyl) methanone (80mg) was added sodium hydride (5eq., 60 wt% in mineral oil). After stirring at room temperature for 5 minutes, cyclopropylmethyl bromide (5eq.) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was stirred with saturated sodium bicarbonate solution (20 mL). The mixture was redistributed between water (50mL) and ethyl acetate (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography to give cis-4- (cyclopropylmethoxy) -2- (pyridin-3-yl) -1-oxa-9-azaspiro [ 5.5%]Undecan-9-yl) (4-isopropoxy-3-methylphenyl) methanone.¹H NMR(400MHz，CDCl₃)8.62(s，1H)，8.55(d，J＝3.9Hz，1H)，7.74(d，J＝7.8Hz，1H)，7.30(dd，J＝7.8，4.8Hz，1H)，7.23-7.11(m，2H)，6.80(d，J＝8.2Hz，1H)，4.70-4.51(m，1H)，4.56(dq，J＝12.1，6.1Hz，1H)，4.37(br s，1H)，3.82-3.00(m，5H)，3.34(d，J＝6.8Hz，1H)，2.40-2.10(m，2H)，2.19(s，3H)，2.09-1.92(m，2H)，1.88-1.39(m，4H)，1.42-1.26(m，6H)，1.04(td，J＝7.0，3.5Hz，1H)，0.64-0.47(m，2H)，0.30-0.12(m，2H)。

The following compounds were prepared using the methods reported above:

cis-4-isopropoxy-2- (pyridin-3-yl) -1-oxa-9-azaspiro [5.5] undecan-9-yl) (4-isopropoxy-3-methylphenyl) methanone

Step 1: (4-isopropoxy-3-methyl-phenyl) - [ 8-isopropoxy-10- (3-pyridyl) -11-oxa-3-azaspiro [5.5] undec-9-en-3-yl ] methanone

Reacting [ 8-hydroxy-10- (3-pyridyl) -11-oxa-3-azaspiro [5.5]]Undec-9-en-3-yl]- (4-isopropoxy-3-methyl-phenyl) methanone (300mg, 0.71mmol) was dissolved in isopropanol (6.0mL, 78 mmol). Adding pyridine p-toluenesulfonate(178mg, 0.71mmol), the reaction mixture was stirred at 50 ℃ for 1 hour, the reaction mixture was diluted with water (50mL), extracted with ethyl acetate (2 × 50mL), the organic layers were combined, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography (50-75% ethyl acetate/hexanes) to give (4-isopropoxy-3-methyl-phenyl) - [ 8-isopropoxy-10- (3-pyridyl) -11-oxa-3-azaspiro [5.5]]Undec-9-en-3-yl]Methanone (173mg) as a clear oil.¹HNMR(400MHz，CDCl₃)8.90(d, J ═ 1.5Hz, 1H), 8.55(d, J ═ 3.6Hz, 1H), 7.90(dt, J ═ 8.0, 1.9Hz, 1H), 7.28(dd, J ═ 7.6, 4.5Hz, 1H), 7.26-7.17(m, 2H), 6.82(d, J ═ 8.2Hz, 1H), 5.55(d, J ═ 3.9Hz, 1H), 4.71-4.27(m, 2H), 4.19(dd, J ═ 9.4, 5.3Hz, 1H), 3.97-3.59(m, 2H), 3.39(br s, 2H), 2.40-2.10(m, 1H), 2.21(s, 3H), 2.05-1.84(m, 3H), 3.83 (t, 1H), 3.49 (t, 8.6H), 1H), 8.8, 8(dd, 8H, 1H). ESI-MS M/z calculated 464.27, found 465.5(M +1)⁺(ii) a Retention time: 1.56 minutes (run 3 minutes).

Step 2: cis- (4-isopropoxy-3-methyl-phenyl) -8-isopropoxy-10- (3-pyridyl) -11-oxa-3-azaspiro [5.5] undecan-3-yl ] methanone

To (4-isopropoxy-3-methyl-phenyl) - [ 8-isopropoxy-10- (3-pyridyl) -11-oxa-3-azaspiro [5.5] in a nitrogen atmosphere]Undec-9-en-3-yl]To a solution of methanone (163mg, 0.35mmol) in ethanol (10mL) was added palladium (37mg, 0.035mmol) (10 wt% on carbon, wet). The reaction was purged with hydrogen and stirred overnight in a hydrogen balloon. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The reaction mixture was purified by column chromatography (50-100% ethyl acetate/hexane) to give (4-isopropoxy-3-methyl-phenyl) - [ cis-8-isopropoxy-10- (3-pyridyl) -11-oxa-3-azaspiro [ 5.5%]Undec-3-yl]Methanone (28.7mg) as a clear colorless oil.¹H NMR(400MHz，CDCl₃)8.62(s, 1H), 8.54(d, J ═ 3.9Hz, 1H), 7.73(d, J ═ 7.8Hz, 1H), 7.37-7.24(m, 1H), 7.22-7.13(m, 2H), 6.80(d, J ═ 8.1Hz, 1H), 4.65-4.50(m.1H), 4.55(dp, J ═ 12.2, 6.1Hz, 1H), 4.36(br s, 1H), 3.85(s, 1H), 3.76(dt, J ═ 12.1, 6.1Hz, 1H), 3.70-3.01(m, 3H), 2.25(m, 2H), 2.19(s, 3H), 1.95(dd, J ═ 12.8, 2.9, 1H), 1.84(m, 3H), 1.5 (dd, 6H), 6.6.6H, 6H), 1H, 6.6.19 (dd, 6H), 6.6.6.6H). ESI-MS M/z calculated 466.28, found 467.6(M +1)⁺(ii) a Retention time: 1.41 minutes (run 3 minutes).

Cis-8-ethoxy-10- (2-pyridyl) -11-oxa-3-azaspiro [5.5] undecan-3-yl ] - (4-isopropoxy-3-methyl-phenyl) methanone

Step 1: cis-8-ethoxy-10- (2-pyridyl) -11-oxa-3-azaspiro [5.5] undecane; 2,2, 2-trifluoroacetic acid

To cis-8-ethoxy-10- (2-pyridyl) -11-oxa-3-azaspiro [5.5]To a solution of tert-butyl undecane-3-carboxylate (38mg, 0.1mmol) in dichloromethane (1mL) was added TFA (400. mu.L, 5.2 mmol). The mixture was stirred at room temperature for 1 hour. The solvent and excess TFA were removed. Crude cis-8-ethoxy-10- (2-pyridyl) -11-oxa-3-azaspiro [5.5]Undecane; 2,2, 2-trifluoroacetic acid was used in the next step without further purification. ESI-MS M/z calculated 276.0, found 277.0(M +1)⁺(ii) a Retention time: 0.83 min (run 3 min).

The following compounds were prepared using the methods reported above:

step 2: cis-8-ethoxy-10- (2-pyridyl) -11-oxa-3-azaspiro [5.5] undecan-3-yl ] - (4-isopropoxy-3-methyl-phenyl) methanone

To cis-8-ethoxy-10- (2-pyridyl) -11-oxa-3-azaspiro [5.5]Undecane; to a solution of 2,2, 2-trifluoroacetic acid (42mg, 0.11mmol) in dichloromethane (1mL) was added triethylamine (75. mu.L, 0.54 mmol). 4-Isopropoxy-3-methyl-benzoyl chloride (46mg, 0.21mmol) (-50% pure) was added. The mixture was stirred at room temperature for 15 minutes. Water was added. The aqueous layer was extracted with dichloromethane (2 ×). The combined organic layers were washed with water and MgSO₄Drying, filtering and concentrating to dryness. The crude material was purified by column chromatography (40-60% ethyl acetate-hexane) to give cis-8-ethoxy-10- (2-pyridyl) -11-oxa-3-azaspiro [ 5.5%]Undec-3-yl]- (4-isopropoxy-3-methyl-phenyl) methanone (37 mg). ESI-MSm/z calculated 452.27, found 453.3(M +1)⁺(ii) a Retention time: 1.38 minutes (run 3 minutes).

The following compounds were prepared using the methods reported above:

cis-8-ethoxy-10- (2-pyridyl) -11-oxa-3-azaspiro [5.5] undecan-3-yl) (3-fluoro-2-methoxyphenyl) methanone

Combined cis-8-ethoxy-10- (2-pyridyl) -11-oxa-3-azaspiro [5.5]Undecane (25mg) and benzoic acid (1.2eq) dissolved in DMF (300 μ L). HATU (1.2eq) was added followed by DIPEA (3.0 eq). The reaction mixture was stirred at 50 ℃ for 1 hour. The reaction mixture was filtered and purified by reverse phase HPLC: 10-99% acetonitrile/water gradient, 15 min.¹H NMR(400MHz，CDCl₃)8.58-8.47(m，1H)，7.81-7.65(m，1H)，7.62-7.46(m，1H)，7.23-7.16(m，1H)，7.03(m，3H)，4.64(dd，J＝43.1，11.9Hz，1H)，4.55-4.36(m，1H)，4.04-3.70(m，4H)，3.69-3.56(m，1H)，3.55-3.33(m，2H)，3.32-3.00(m，2H)，2.58(t，J＝13.8Hz，1H)，2.22(dd，J＝74.2，14.3Hz，1H)，2.05-1.92(m，1H)，1.90-1.51(m，3H)，1.50-1.24(m，2H)，1.24-1.12(m，3H)。

The following compounds were prepared using the methods reported above:

cis-8-ethoxy-10- (2-pyridyl) -11-oxa-3-azaspiro [5.5] undecan-3-yl) (4-isopropoxy-3-methyl-phenyl) methanone

Treatment of cis-8-ethoxy-10- (4-pyridyl) -11-oxa-3-azaspiro [5.5] with DIPEA (94. mu.L, 0.54mmol)]A solution of undecane (50mg, 0.18mmol), EDCI (38mg, 0.20mmol) and 4-isopropoxy-3-methyl-benzoic acid (35mg, 0.18mmol) in dichloromethane (0.9mL) was stirred for 16 h. The reaction mixture was filtered and purified by reverse phase HPLC (1-100% ACN/water) to give cis-8-ethoxy-10- (2-pyridyl) -11-oxa-3-azaspiro [5.5]]Undecan-3-yl) (4-isopropoxy-3-methyl-phenyl) methanone (47mg, 57.58%). ESI-MS M/z calculated 452.27, found 453.2(M +1)⁺(ii) a Retention time: 1.059 min (run 3 min).

The following compounds were prepared using the methods reported above:

cis-4-ethoxy-2- (5-fluoropyridin-3-yl) -1-oxa-9-azaspiro [5.5] undecan-9-yl) (4-isopropoxy-3-methylphenyl) methanone

Step 1: 1- (1- (4-isopropoxy-3-methylbenzoyl) piperidin-4-ylidene) propan-2-one

To an oven dried flask was placed mineral oil containing 60% sodium hydride (1.5g, 36 mmol). tetrahydrofuran (90mL) was added to the flask under nitrogen atmosphere, the mixture was cooled to 0 deg.C, and a solution of 1-diethoxyphosphorylpropan-2-one (7.1mL, 37mmol) in tetrahydrofuran (20mL) was added dropwise, the mixture was stirred at 25 deg.C for 30 minutes, treated with 1- (4-isopropoxy-3-methyl-benzoyl) piperidin-4-one (10g, 36mmol) in tetrahydrofuran (90mL), the mixture was stirred at 25 deg.C for 24 hours, the reaction was quenched with saturated aqueous sodium bicarbonate, extracted with ethyl acetate (3 × 200mL), the combined organic layers were washed with brine, dried over magnesium sulfate, evaporated, the crude product was purified with silica gel using a gradient of 0-30% ethyl acetate in hexane to give 1- [1- (4-isopropoxy-3-methyl-benzoyl) -4-piperidylidene]Propan-2-one (10.2g)¹HNMR(400MHz，CDCl₃)7.25-7.17(m, 2H), 6.81(d, J ═ 8.2Hz, 1H), 6.12(s, 1H), 4.60-4.51(m, 1H), 3.66(br d, 4H), 2.95(br s, 2H), 2.50-2.33(m, 2H), 2.19(s, 6H), 1.34(d, J ═ 6.0Hz, 6H). ESI-MS M/z calculated 315.18, found 316.0(M +1)⁺(ii) a Retention time: 2.2 minutes (run 3 minutes).

Step 2: 4- (5-Fluoropyridin-3-yl) -4-hydroxy-1- (1- (4-Isopropoxy-3-methylbenzoyl) piperidin-4-ylidene) butan-2-one

Step 1: a solution of 1- [1- (4-isopropoxy-3-methyl-benzoyl) -4-piperidylidene ] propan-2-one (130mg, 0.41mmol) in dichloromethane (1.7mL) was treated with diisopropylethylamine (93. mu.L, 0.53mmol) at 0 ℃ followed by the addition of trifluoromethanesulfonic acid (tert-butyl (dimethyl) silyl) ester (114mg, 99. mu.L, 0.43 mmol). The mixture was stirred at 0 ℃ for 30 minutes.

Step 2. cooling a solution of 5-fluoronicotinaldehyde (51mg, 0.41mmol) in dichloromethane (1.7mL) to-78 ℃, adding diethyl etherate boron trifluoride (164 μ L, 0.82mmol), stirring the mixture at-78 ℃ for 5 minutes, adding the solution from step 1. stirring the mixture at-78 ℃ for 5 minutes, quenching with a buffer solution of pH 7, extracting the aqueous layer with dichloromethane (3 × 50mL), drying the combined organic layers with magnesium sulfate, filtering, concentrating to dryness, purifying the crude product with silica gel, gradient with 60-100% ethyl acetate in hexane to give 4- (5-fluoro-3-pyridinyl) -4-hydroxy-1- [1- (4-isopropoxy-3-methyl-benzoyl) -4-piperidylidene]Butan-2-one (105 mg).¹H NMR(400MHz，CDCl₃) 8.46-8.31 (m, 2H), 7.53-7.49 (m, 1H), 7.24-7.22(m, 2H), 6.83(d, J ═ 8.1Hz, 1H), 6.09(s, 1H), 5.26(dd, J ═ 8.9, 5.9Hz, 1H), 4.62-4.53(m, 1H), 4.13-4.12(m, 1H), 3.69(br d, 4H), 3.00(br s, 2H), 2.88(d, J ═ 6.2Hz, 2H), 2.37(br s, 2H), 2.21(s, 3H), 1.36(d, J ═ 6.0Hz, 6H). ESI-MS M/z calculated 440.21, found 441.4(M +1)⁺(ii) a Retention time: 1.65 minutes (run 3 minutes).

And step 3: 1- (5-Fluoropyridin-3-yl) -4- (1- (4-Isopropoxy-3-methylbenzoyl) piperidin-4-ylidene) butane-1, 3-dione

Mixing 4- (5-fluoro-3-pyridyl) -4-hydroxy-1- [1- (4-isopropoxy-3-methyl-benzoyl) -4-piperidylidene]A solution of butan-2-one (475mg, 1.08mmol) in dichloromethane (15mL) was cooled to 0 deg.C and treated with dess-martin reagent (457mg, 1.08mmol) the reaction mixture was stirred for 30 minutes and treated with dess-martin reagent (150mg, 0.35mmol) the reaction mixture was stirred for 30 minutes, quenched by addition of saturated aqueous sodium sulfite solution, the mixture was extracted with dichloromethane (3 × 50mL), the combined organic layers were washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered, concentrated under reduced pressure, silica gelPurifying the crude product with a gradient of 60-100% ethyl acetate in hexane to give 1- (5-fluoro-3-pyridyl) -4- [1- (4-isopropoxy-3-methyl-benzoyl) -4-piperidylidene]Butane-1, 3-dione (317 mg).¹H NMR(400MHz，CDCl₃)16.25(br s, OH), 8.81(t, J ═ 1.5Hz, 1H), 8.52(d, J ═ 2.8Hz, 1H), 7.82(ddd, J ═ 9.0, 2.7, 1.8Hz, 1H), 7.18(dd, J ═ 11.4, 3.0Hz, 2H), 6.76(d, J ═ 8.1Hz, 1H), 6.08(s, 1H), 5.86(s, 1H), 4.50(m, 1H), 3.65(br s, 4H), 3.02(br s, 2H), 2.36(br s, 2H), 2.14(s, 3H), 1.28(d, J ═ 6.0Hz, 6H). ESI-MS M/z calculated 438.20, found 439.5(M +1)⁺(ii) a Retention time: 2.15 min as a colorless oil (run 3 min).

And 4, step 4: 2- (5-Fluoropyridin-3-yl) -9- (4-isopropoxy-3-methylbenzoyl) -1-oxa-9-azaspiro [5.5] undec-2-en-4-one

1- (5-fluoro-3-pyridyl) -4- [1- (4-isopropoxy-3-methyl-benzoyl) -4-piperidylidene]A mixture of butane-1, 3-dione (100mg, 0.23mmol) in acetic acid (1.7mL, 30mmol) was heated at 120 ℃ for 1 hour, the reaction mixture was cooled to 25 ℃, redistributed between ethyl acetate and water, the aqueous layer was separated, extracted with ethyl acetate (3 × 50mL), the combined organic layers were washed with brine, dried over magnesium sulfate, concentrated to dryness and the crude product was purified by gradient on silica gel using 60-100% ethyl acetate in hexane to give 10- (5-fluoro-3-pyridyl) -3- (4-isopropoxy-3-methyl-benzoyl) -11-oxa-3-azaspiro [ 5.5.5 ]]Undec-9-en-8-one (92 mg).¹H NMR(400MHz，CDCl₃)8.86(s, 1H), 8.61(d, J ═ 2.7Hz, 1H), 7.74(ddd, J ═ 9.0, 2.7, 1.9Hz, 1H), 7.28-7.24(m, 2H), 6.84(d, J ═ 9.0Hz, 1H), 6.09(s, 1H), 4.58(dt, J ═ 12.1, 6.1Hz, 1H), 3.42(br s, 2H), 2.68(s, 2H), 2.27-2.22(m, 6H), 1.75(m, 3H), 1.36(d, J ═ 6.0Hz, 6H). ESI-MS M/z calculated 438.20, found 439.3(M +1)⁺(ii) a Retention time: 1.78 minutes (run 3 minutes).

And 5: (2- (5-Fluoropyridin-3-yl) -4-hydroxy-1-oxa-9-azaspiro [5.5] undec-2-en-9-yl) (4-isopropoxy-3-methylphenyl) methanone

To 10- (5-fluoro-3-pyridyl) -3- (4-isopropoxy-3-methyl-benzoyl) -11-oxa-3-azaspiro [5.5]To a solution of undec-9-en-8-one (273mg, 0.62mmol) in methanol (7.8mL) was slowly added sodium borohydride (25mg, 0.65 mmol.) the reaction mixture was stirred for 30 minutes, saturated aqueous ammonium chloride (50mL) was added, after brief stirring, the mixture was concentrated to half volume, extracted with dichloromethane (3 × 75mL), the organic layers were combined, dried over sodium sulfate, filtered, concentrated under reduced pressure, the crude product was purified by silica gel gradient with 60-100% ethyl acetate in hexane to give [10- (5-fluoro-3-pyridyl) -8-hydroxy-11-oxa-3-azaspiro [ 5.5.5%]Undec-9-en-3-yl]- (4-isopropoxy-3-methyl-phenyl) methanone (256mg) as a colourless oil. ESI-MS M/z calculated 440.2, found 441.3(M +1)⁺(ii) a Retention time: 1.73 minutes (run 3 minutes).

Step 6: cis-4-ethoxy-2- (5-fluoropyridin-3-yl) -1-oxa-9-azaspiro [5.5] undecan-9-yl) (4-isopropoxy-3-methylphenyl) methanone

Reacting [10- (5-fluoro-3-pyridyl) -8-hydroxy-11-oxa-3-azaspiro [5.5] with nitrogen]Undec-9-en-3-yl]A solution of (4-isopropoxy-3-methyl-phenyl) methanone (56mg, 0.13mmol) in ethanol (4.4mL) was purified for 5 minutes and treated with 10% palladium on carbon (13mg, 0.012 mmol). The mixture was evacuated and placed in a hydrogen atmosphere (balloon). The reaction mixture was stirred at 25 ℃ for 12 hours. Mixing the reactionThe reaction mixture was evacuated, placed in an inert gas atmosphere, then 10% palladium on carbon (54mg, 0.05mmol) was added, the mixture was evacuated, placed in a hydrogen atmosphere (balloon), stirred for 4 hours, the reaction mixture was evacuated, placed in an inert gas atmosphere, the Pd-catalyst was removed by filtration, washed with ethyl acetate, the filtrate was concentrated to dryness, dissolved in DMF (2.4mL), the mixture was cooled to 0 ℃, treated with 60% NaH (28mg, 1.19mmol) and iodoethane (95 μ L, 1.2mmol), the reaction mixture was warmed to 25 ℃, stirred for 2 hours, the reaction mixture was quenched by addition of methanol, partitioned between water and ethyl acetate, the layers were separated, the aqueous layer was extracted with ethyl acetate (3 × 50mL), the combined organic layer was washed with saturated aqueous sodium chloride solution, dried with sodium sulfate, filtered, concentrated under reduced pressure, purified by reverse phase HPLC (1-100% aqueous acetonitrile without modifier) to give cis-4-ethoxy-2- (5-oxa-pyridine-1-5-oxaspiro) -5.5-5-azaspiro [ 5.5-5-oxa-5-spirol ] (1.5-5-ethyl acetate)]Undecan-9-yl) (4-isopropoxy-3-methylphenyl) methanone (68mg) ESI-MS M/z calculated 470.26, found 471.2(M +1)⁺(ii) a Retention time: 1.453 minutes (run 3 minutes).

The following compounds were prepared using the methods reported above:

(4-hydroxy-2- (pyridin-3-yl) -1-oxa-9-azaspiro [5.5] undecan-9-yl) (4-isopropoxy-3-methylphenyl) methanone was prepared according to scheme 3 (steps 1-6)

Step 1: 9- (4-Isopropoxy-3-methylbenzoyl) -2- (pyridin-3-yl) -1-oxa-9-azaspiro [5.5] undecan-4-one

Reacting [ 8-hydroxy-10- (3-pyridyl) -11-oxa-3-azaspiro [5.5]]Undec-3-yl]A solution of- (4-isopropoxy-3-methyl-phenyl) methanone (100mg, 0.24mmol) in dichloromethane (3.4mL) was cooled to 0 deg.C and treated with Dess-Martin reagent (100mg, 0.24 mmol.) the reaction mixture was stirred for 2 hours and quenched by addition of saturated aqueous sodium sulfite solution, the mixture was extracted with dichloromethane (3 × 25mL), the combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure, the crude product was purified on silica gel with a gradient of 50-100% ethyl acetate in hexane to give 3- (4-isopropoxy-3-methyl-benzoyl) -10- (3-pyridyl) -11-oxa-3-azaspiro [ 5.5.5%]Undecane-8-one (84mg) ESI-MS M/z calculated 422.22, found 423.3(M +1)⁺(ii) a Retention time: 1.41 minutes (run 3 minutes).

Step 2: (4-Ethyl-2- (pyridin-3-yl) -1-oxa-9-azaspiro [5.5] undec-4-en-9-yl) (4-isopropoxy-3-methylphenyl) methanone

Reacting 3- (4-isopropoxy-3-methyl-benzoyl) -10- (3-pyridyl) -11-oxa-3-azaspiro [5.5]]A solution of undecane-8-one (148mg, 0.35mmol) in THF (1.8mL) was cooled to 0 deg.C and treated with ethyl-magnesium bromide (42. mu.L of 1M, 0.42 mmol). The reaction mixture was stirred for 2 hours, quenched by addition of saturated aqueous ammonium chloride solution, the mixture was extracted with ethyl acetate (3 × 100mL), the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated under reduced pressure, the resulting oil was diluted with dichloromethane (2mL), treated with pyridine (34. mu.L, 0.42mmol), the reaction mixture was cooled to 0 deg.C and treated with dropwise thionyl chloride (28. mu.L, 0.39 mmol). The reaction mixture was stirred for 90 minutes, quenched with ice-cold water (5mL), quenched with CH₂Cl₂Diluted (80mL) the solution was washed with dilute HCl (5%, 2 × 15mL), water (2 × 20mL) and sodium bicarbonate (5%, 15mL)And (3) mixing. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by gradient on silica gel using 50-100% ethyl acetate in hexane to give [ 8-ethyl-10- (3-pyridyl) -11-oxa-3-azaspiro [5.5]]Undec-7-en-3-yl]- (4-Isopropoxy-3-methyl-phenyl) methanone (90mg) ESI-MS M/z calculated 434.26, found 435.3(M +1)⁺(ii) a Retention time: 1.74 minutes (run 3 minutes).

(cis-4-ethyl-2- (pyridin-3-yl) -1-oxa-9-azaspiro [5.5] undecan-9-yl) (4-isopropoxy-3-methylphenyl) methanone

Reacting [ 8-ethyl-10- (3-pyridyl) -11-oxa-3-azaspiro [5.5] with nitrogen]Undec-7-en-3-yl]A solution of (4-isopropoxy-3-methyl-phenyl) methanone (90mg, 0.21mmol) in EtOH (14mL) was purified for 5 minutes and then treated with 10% palladium on carbon (220mg, 0.21 mmol). The mixture was evacuated and placed in a hydrogen atmosphere (balloon). The reaction mixture was stirred at 25 ℃ for 4 hours. The reaction mixture was evacuated and placed under an inert gas atmosphere. The Pd-catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated to dryness. The crude mixture was purified on silica gel using a gradient of 50-100% ethyl acetate and hexane to give (cis-4-ethyl-2- (pyridin-3-yl) -1-oxa-9-azaspiro [ 5.5%]Undecan-9-yl) (4-isopropoxy-3-methylphenyl) methanone (17mg) ESI-MS M/z calculated 436.27, found 437.5(M +1)⁺(ii) a Retention time: 1.68 minutes (run 3 minutes).

4- (1-hydroxy-1-methyl-ethyl) -3-methyl-benzoic acid

4-bromo-3-methyl-benzoic acid (3.96g, 18.4mmol) was dissolved in tetrahydrofuran (100mL) and the solution was cooled to-78 ℃. In 20 minutesA solution of n-butyllithium in hexane (16.2mL of 2.5M, 41mmol) was added dropwise. The reaction mixture was stirred at-78 ℃ for 30 minutes, then acetone (1.35mL, 18.4mmol) was added dropwise. The reaction mixture was stirred at-78 ℃ for 30 minutes and then warmed to room temperature. The reaction mixture was then diluted with 100mL of 1M aqueous sodium hydroxide. The organic layer was discarded, and then the aqueous layer was made acidic with 4M aqueous hydrochloric acid. The aqueous layer was then extracted 3 times with ethyl acetate. The combined organic extracts were dried over sodium sulfate and then evaporated to dryness. The crude material was further purified on silica gel with a gradient of 0-10% methanol in dichloromethane to give 4- (1-hydroxy-1-methyl-ethyl) -3-methyl-benzoic acid (1.51g, 42%).¹H NMR(400MHz，DMSO)12.74(s，1H)，7.68(dd，J＝3.9，2.5Hz，2H)，7.55(d，J＝8.7Hz，1H)，5.06(s，1H)，2.56(s，3H)，1.51(s，6H)。

5-isopropoxy-6-methylpyridinecarboxylic acid

Step 1: 4, 6-dibromo-2-methylpyridin-3-ol

2-methyl-3-pyridinol (8.3g, 76.1mmol) was suspended in acetonitrile (125 mL). A solution of NBS (27.7g, 155.6mmol, 2.05 equiv.) in acetonitrile (275mL) was added dropwise to the suspension over 1 hour. The mixture was heated at reflux for 1.5 hours. The mixture was concentrated and the residue was purified by column chromatography (DCM) to give 4, 6-dibromo-2-methylpyridin-3-ol (15.8g, 78%) as a yellow solid.¹H NMR(300MHz，DMSO)2.41(s，3H)，7.70(s，1H)，9.98(s，1H)。

Step 2: 6-bromo-2-methylpyridin-3-ol

4, 6-dibromo-2-methylpyridin-3-ol (15.8g, 59.4 mmol)) Dissolved in THF (200 mL). The solution was cooled to-78 deg.C and n-BuLi (50mL, 125mmol, 2.5M in hexanes) was added dropwise, maintaining the temperature below-78 deg.C. The mixture was stirred at this temperature for 2 hours. The mixture was quenched with water (50mL) and neutralized with 2N HCl. The aqueous mixture was extracted with dichloromethane (2 ×). The combined organic layers were dried (Na)₂SO₄) Concentrate to 6-bromo-2-methylpyridin-3-ol (10.5g, 95%) as a yellow oil.¹H-NMR(300MHz，DMSO)2.29(s，3H)，7.08(d，1H)，7.26(d，1H)，10.08(s，1H)。

And step 3: 6-bromo-3-isopropoxy-2-methylpyridine

6-bromo-2-methylpyridin-3-ol (10.5g, 55.9mmol) was dissolved in DMF (100 mL). Will K₂CO₃(19.3g, 139.6mmol) and 2-bromopropane (13.1ml, 139.6mmol) were added to the solution and the mixture was heated at 100 ℃ overnight. The mixture was poured into a mixture of water and EtOAc (200 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 ×). The combined organic layers were dried (Na)₂SO₄) And (4) concentrating. The crude oil was purified by column chromatography (0-20% ethyl acetate/heptane) to give 6-bromo-3-isopropoxy-2-methylpyridine (10.9g, 85) as a yellow oil.¹H-NMR(300MHz，CDCl₃)1.42(d，6H)，2.48(s，3H)，4.65(m，1H)，7.20(d，1H)，8.04(d，1H)。

And 4, step 4: 5-Isopropoxy-6-methylpyridinecarboxylic acid methyl ester

In a Berghoff reactor 6-bromo-3-isopropoxy-2-methylpyridine (2.00g, 8.70mmol), PdCl₂(PPh₃)₂(0.18g, 0.26mmol) and Et₃N (1.8ml, 13.04mmol) was added to MeOH (5.2mL) and acetonitrile (20 mL). 10 bar CO (g) was added to the reactor and heated at 60 ℃ overnight. The mixture was concentrated and the residue partitioned between DCM and water. The layers were separated and the organic layer was washed with brine and dried (Na)₂SO₄). The mixture was concentrated and purified by column chromatography to give methyl 5-isopropoxy-6-methylpyridinecarboxylate (1.3g, 71%) as a yellow oil.¹H-NMR(300MHz，CDCl₃)1.40(d，6H)，2.53(s，3H)，3.98(s，3H)，4.62(m，1H)，7.12(d，1H)，7.98(d，1H)。

And 5: 5-isopropoxy-6-methylpyridinecarboxylic acid

Methyl 5-isopropoxy-6-methylpyridinecarboxylate (1.3g, 6.22mmol) was dissolved in THF/water 2:1(9 mL). Adding LiOH H₂O (0.26g, 6.22mmol), and the mixture was stirred at room temperature overnight. The mixture was poured into a mixture of water and EtOAc, the layers were separated, the aqueous layer was acidified to pH 4 with 2N HCl, and extracted with EtOAc (2 ×). The combined organic layers were dried (Na)₂SO₄) And concentrated to give 5-isopropoxy-6-methylpyridinecarboxylic acid (860mg, 74%) as a pale brown solid.¹H-NMR(300MHz，DMSO)1.31(d，6H)，4.73(m，1H)，7.44(d，1H)，7.86(d，1H)。

4- (2-hydroxypropan-2-yl) -3-methoxybenzoic acid

4-bromo-3-methoxy-benzoic acid (2.00g, 8.67mmol) was dissolved in THF (50mL) and the solution was cooled to-78 ℃. A solution of n-BuLi in hexane (7.6mL of 2.5M, 19mmol) was added dropwise over 15 minutes. The reaction mixture was stirred at-78 ℃ for 30 minutes, then acetone (640. mu.L, 8.9mmol) was added dropwise. The reaction mixture was stirred at-78 ℃ for 30 minutes and then warmedAnd (4) cooling to room temperature. The reaction mixture was then diluted with 100mL of 1M aqueous sodium hydroxide. The organic layer was discarded, and the aqueous layer was made acidic with 4M aqueous hydrochloric acid. The aqueous layer was then extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate and then evaporated to dryness. The crude material was purified by column chromatography using a gradient of 0-5% methanol in dichloromethane to give 4- (2-hydroxypropan-2-yl) -3-methoxybenzoic acid (618mg, 34%). ESI-MS M/z calculated 210.1, found 209.1(M-1)^-(ii) a Retention time: 0.68 min (run 3 min).

4- (isopropylsulfonyl) -3-methylbenzoic acid

Step 1: 4- (isopropylsulfanyl) -3-methylbenzoic acid

Butyllithium (16mL of 1.6M, 26mmol) was added dropwise to a mixture of 4-bromo-3-methyl-benzoic acid (2.5g, 12mmol) and THF (63mL) at-78 deg.C. The mixture was stirred at-78 ℃ for 30 minutes, then a solution of 2-isopropyldithioalkyl propane (1.7g, 12mmol) in THF (2mL) was added dropwise. The mixture was stirred at-78 ℃ for 30 minutes and then at room temperature for 30 minutes. The mixture was then diluted with 100mL of 1M aqueous sodium hydroxide. The organic layer was discarded, and the aqueous layer was made acidic with 4M aqueous hydrochloric acid. The aqueous layer was then extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate and then evaporated to dryness. The crude material was purified by column chromatography using a gradient of 0-5% MeOH in dichloromethane to give 4- (isopropylsulfanyl) -3-methylbenzoic acid (870mg, 18%). MS M/z calcd 210.3, found 211.2(M +1)⁺. Retention time: 2.32 minutes (run 3 minutes).

Step 2: 4- (isopropylsulfonyl) -3-methylbenzoic acid

3-Chlorobenzeneperoxyformic acid (930mg, 4.2mmol) was added to a mixture of 4- (isopropylsulfanyl) -3-methylbenzoic acid (250mg, 1.2mmol) and dichloromethane (5.0mL) at 25 ℃. The mixture was stirred at 25 ℃ for 2 hours and then concentrated in vacuo. The white solid was dissolved in dichloromethane and column chromatography (0-2% MeOH/dichloromethane) afforded 4-isopropylsulfonyl-3-methyl-benzoic acid (90mg, 31%) as a white solid. ESI-MS M/z calculation 242.3, measurement 243.2(M +1)⁺. Retention time: 1.57 minutes (run 3 minutes).¹H NMR(400MHz，DMSO)13.50(s，1H)，8.50–7.66(m，3H)，3.50-3.47(m，1H)，2.67(s，3H)，1.19(d，J＝1.16Hz，6H)。

3-formyl-4-isopropoxybenzoic acid

Step 1: 3-formyl-4-isopropoxybenzoic acid methyl ester

To methyl 3-formyl-4-hydroxy-benzoate (10.0g, 55.5mmol), potassium carbonate (30.7g, 222mmol) and N, N-dimethylformamide (63mL) was added 2-iodopropane (11.1mL, 111 mmol). The mixture was heated at 60 ℃ for 18 hours. The mixture was filtered using ethyl acetate (200mL) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (150mL) and washed with water (3x75mL) and saturated aqueous sodium chloride (1x75 mL). The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 3-formyl-4-isopropoxy-benzoic acid methyl ester (98%) as a yellow viscous liquid. ESI-MS M/z calculated 222.2, found 223.3(M +1) +; retention time: 1.51 minutes (run 3 minutes).¹H NMR(400MHz，DMSO)10.35(s，1H)，8.23(d，J＝2.3Hz，1H)，8.17(dd，J＝8.8，2.3Hz，1H)，7.39(d，J＝8.9Hz，1H)，4.98–4.83(m，1H)，3.85(s，3H)，1.38(d，J＝6.0Hz，6H)。

Step 2: 3-formyl-4-isopropoxybenzoic acid

To the ester (from the previous step) in twoTo the solution in alkane (4mL) was added 2mL of sodium hydroxide solution (5N). The reaction mixture was heated at 65 ℃ for 4 hours. The reaction mixture was cooled to room temperature and diluted with 20mL of water. The aqueous layer was extracted with 20mL portions of ethyl acetate (2X). The organic extracts were discarded and the aqueous layer was made acidic with 1M HCl. The product obtained is then extracted into ethyl acetate over MgSO₄Drying, filtration and evaporation to dryness gave 3-formyl-4-isopropoxy-benzoic acid (320mg, 55%, 2 steps) as a white solid.¹H NMR(400MHz，DMSO)10.36(s，1H)，8.23(d，J＝2.5Hz，1H)，8.15(dd，J＝2.5，8.9Hz，1H)，7.37(d，J＝8.9Hz，1H)，4.96-4.87(m，1H)，1.37(d，J＝5.6Hz，6H)。

3- (hydroxymethyl) -4-isopropoxy-benzoic acid

Step 1: 3-formyl-4-isopropoxy-benzoic acid methyl ester

3-formyl-4-isopropoxy-benzoic acid methyl ester (180mg, 0.81mmol) was dissolved in tetrahydrofuran (4.8mL) and LiBH was added₄(35mg, 1.6 mmol). The reaction was stirred at room temperature for 30 minutes, then quenched with methanol (3 mL). The reaction was neutralized by addition of saturated aqueous sodium bicarbonate (3mL) and then extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with saturated aqueous sodium chloride (1 × 10mL), dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 3- (hydroxymethyl) -4-isopropoxy-benzoic acid methyl ester (99%) as a viscous liquid. ESI-MS M/z calculated 224.3, found 225.3(M +1) +; retention time: 1.26 minutes (run 3 minutes))。¹H NMR(400MHz，DMSO)8.09(s，1H)，7.89(d，J＝8.6Hz，1H)，7.13(d，J＝8.6Hz，1H)，5.25(t，J＝5.6Hz，1H)，4.86–4.68(m，1H)，4.54(d，J＝5.6Hz，2H)，3.87(s，3H)，1.35(d，J＝6.0Hz，6H)。

Step 2: 3- (hydroxymethyl) -4-isopropoxy-benzoic acid

To a mixture of 3- (hydroxymethyl) -4-isopropoxy-benzoic acid methyl ester (180mg, 0.80mmol) and 1, 4-bisTo the alkane (1.895mL) was added sodium hydroxide (2.1mL of 1.0M, 2.1mmol) and the mixture was heated at 80 ℃ for 50 minutes. The solvent was evaporated under reduced pressure and the crude mixture was dissolved in water (10mL), washed with ethyl acetate (3 × 10mL) and discarded. The aqueous layer was acidified with hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 3- (hydroxymethyl) -4-isopropoxy-benzoic acid (89%) as a white solid. ESI-MS M/z calculated 210.2, found 211.3(M +1)⁺(ii) a Retention time: 1.01 minutes (run 3 minutes).

3-cyano-4-isopropylsulfonyl-benzoic acid

Step 1: 3-cyano-4-fluoro-benzoic acid methyl ester

To 100mL rbf was added 3-cyano-4-fluoro-benzoic acid (2.6g, 15.9mmol), potassium carbonate (6.6g, 47.6mmol), and DMF (30mL), and the reaction was stirred for 10 min. Methyl iodide (1.1mL, 17.5mmol) was added dropwise and the reaction stirred for 1 hour. Reaction completion was indicated by lcms. The reaction was quenched with brine and extracted with EtOAC. The organic layer was washed 3 times with brine,the organic layer was dried over sodium sulfate and evaporated. Methyl 3-cyano-4-fluoro-benzoate (2.5g, 62%) was isolated as a white solid. ESI-MS M/z calculated 179.0, found 180.0(M +1)⁺(ii) a Retention time: 1.15 minutes (run 3 minutes).

Step 2: 3-cyano-4-isopropylsulfonyl-benzoic acid

To 100mL rbf was added 3-cyano-4-fluoro-benzoic acid methyl ester (2.5g, 14.0mmol) followed by DMF (20 mL). Sodium isopropyl thioalkyl (3.8g, 39.7mmol) was added and the reaction was placed in a preheated oil bath at 65 ℃ and stirred overnight. Reaction completion was indicated by lcms. The reaction was quenched with brine and extracted 3 times with EtOAc. The aqueous layer was then treated with bleach (100mL) and the reaction was stirred for 10 minutes. 1N HCl was then added to pH 1. The reaction was then extracted with EtOAc, and the organic layer was washed 3 times with brine. The organic layer was then dried over sodium sulfate and the solvent was removed. 3-cyano-4-isopropylsulfonyl-benzoic acid (2.24g) was isolated as a white solid.¹H NMR(400MHz，CDCl₃)8.59(d，J＝1.4Hz，1H)，8.47(dd，J＝8.2，1.7Hz，1H)，8.28(d，J＝8.2Hz，1H)，3.64(s，1H)，1.39(d，J＝6.8Hz，6H)。

Preparation of 3-fluoro-4-isopropoxy-benzoic acid

Step 1:

to methyl 3-fluoro-4-hydroxy-benzoate (2.0g, 11.8mmol) in DMF (12mL) was added K₂CO₃(6.50g, 47.04mmol) followed by 2-iodopropane (2.35mL, 23.5 mmol). The reaction mixture was stirred at 60 ℃ for 1.5 hours. The reaction mixture was cooled, diluted with EtOAc, filtered and the solvent evaporated in vacuo. Dissolving the obtained residue in waterWashed with water (3 × 10mL) and brine solution (1 × 10mL) in succession in EtOAc. Separating the organic layer with Na₂SO₄Drying, filtration, and concentration in vacuo afforded the desired ester. ESI-MS M/z calculated 212.2, found 213.3(M +1)⁺(ii) a Retention time: 1.7 minutes (run 3 minutes).¹H NMR(400MHz，DMSO)7.76(ddd，J＝8.6，2.1，1.2Hz，1H)，7.69(dd，J＝11.9，2.1Hz，1H)，7.31(t，J＝8.6Hz，1H)，4.79(dt，J＝12.1，6.0Hz，1H)，3.82(s，3H)，1.32(d，J＝6.5Hz，6H)。

Step 2:

addition of di to the ester from the previous stepAlkane (31mL) and NaOH solution (31.2mL of 1M, 31.2mmol), the reaction was heated at 80 ℃ for 20 min and then concentrated in vacuo. The crude mixture was dissolved in water and washed with EtOAc (3 × 10 mL). The layers were separated and the aqueous layer was acidified with 1M HCl solution. The aqueous layer was extracted with EtOAc (3 × 10 mL). With Na₂SO₄The organic layer was dried, filtered, and concentrated in vacuo to give 3-fluoro-4-isopropoxy-benzoic acid (1.7g, 72%) as a white solid. ESI-MS M/z calculated 198.1, found 199.1(M +1)⁺(ii) a Retention time: 1.7 minutes (run 3 minutes).¹H NMR(400MHz，DMSO)12.90(br s，1H)，7.73(ddd，J＝8.6，2.0，1.1Hz，1H)，7.65(dd，J＝11.9，2.1Hz，1H)，7.28(t，J＝8.6Hz，1H)，4.77(hept，J＝6.1Hz，1H)，1.32(d，J＝6.0Hz，6H)。

The following compounds were also prepared according to the above method: 4-Isopropoxy-3-methylbenzoic acid

Preparation of 4-isopropoxy-3-methoxy-benzoic acid

Step 1:

2-Bromopropane (3.39) at room temperaturemL, 36.2mmol) was added to 4-bromo-2-methoxy-phenol (5g, 24.1mmol), K₂CO₃(6.67g, 48.3mmol) and DMSO (71 mL). The heterogeneous mixture was stirred at 55 ℃ for 2 hours, then cooled to room temperature and diluted with water. With Et₂The reaction mixture was extracted O, the extract was washed successively with 10% aqueous NaOH solution, water, then brine solution, the organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-bromo-1-isopropoxy-2-methoxy-benzene (5.83g, 94%) as a light yellow oil. ESI-MS M/z calculated 244.0, found 245.0(M +1)⁺(ii) a Retention time: 1.93 minutes (run 3 minutes).¹H NMR(400MHz，CDCl₃)7.03-6.95(m，2H)，6.76(dd，J＝7.7，1.1Hz，1H)，4.47(dt，J＝12.2，6.1Hz，1H)，3.84(s，3H)，1.35(d，J＝6.1Hz，6H)。

Step 2:

tert-butyllithium (2.14mL of a 1.6M solution in toluene, 3.42mmol) was added dropwise to a solution of 4-bromo-1-isopropoxy-2-methoxy-benzene (400mg, 1.63mmol) in THF (6mL) at-78 deg.C under a nitrogen atmosphere. The reaction mixture was stirred at-78 ℃ for 1 hour, then added dropwise to CO contained in THF (2mL)₂(1.8g, 40.8mmol) (solid, dry ice) in a flask. The reaction mixture was stirred for 30 minutes and warmed to room temperature. Water (20mL) was added to the reaction mixture and volatiles were removed in vacuo. The resulting aqueous layer was acidified to pH 1 with 1N HCl solution and extracted with ethyl acetate (3 × 15 mL). The organic layer was separated and the combined organic layers were washed with brine solution, dried over sodium sulfate, filtered and concentrated in vacuo to give 4-isopropoxy-3-methoxy-benzoic acid (310mg, 85%) as a white solid. ESI-MS M/z calculated 210.1, found 211.1(M +1)⁺(ii) a Retention time: 1.23 minutes (run 3 minutes).¹H NMR(400MHz，DMSO)12.63(s，1H)，7.53(dd，J＝8.4，2.0Hz，1H)，7.44(d，J＝2.0Hz，1H)，7.04(d，J＝8.7Hz，1H)，4.67(dt，J＝12.1，6.0Hz，1H)，3.78(s，3H)，1.28(d，J＝6.0Hz，6H)。

Preparation of 4- (2-hydroxy-2-methyl-propoxy) benzoic acid

Step 1:

1-chloro-2-methyl-propan-2-ol (10mL), 4-hydroxybenzonitrile (2g, 16.8mmol), K₂CO₃A mixture of (9.3g, 67.3mmol) in water (6mL) and ethanol (60mL) was heated at 80 ℃ for 16 h. The reaction mixture was cooled and the solvent was concentrated in vacuo. The residue was diluted with ether (200mL), filtered, and the filtrate was washed with water (50mL) and brine solution (50mL) in that order. Separating the organic layer with MgSO₄Drying and removal of the solvent in vacuo gave a residue which was purified by silica gel column chromatography using (0-100%) EtOAc/DCM as eluent to give 4- (2-hydroxy-2-methyl-propoxy) benzonitrile (3.0g, 94%) as a yellow solid. ESI-MS M/z calculated 191.1, found 192.3(M +1)⁺(ii) a Retention time: 1.05 min (run 3 min).

Step 2:

to 4- (2-hydroxy-2-methyl-propoxy) benzonitrile (1.0g, 5.2mmol) in ethanol (15mL) was added NaOH solution (5mL 5M, 25mmol), and the reaction mixture was heated at 85 deg.C for 1h, concentrated in vacuo, and diluted with ethyl acetate (50 mL). To the organic layer was added a mixture of aqueous salt solution (10mL) and 6N HCl (3mL, adjusted to pH 6). Separating the organic layer with MgSO₄Drying and concentration in vacuo afforded a yellow solid which was triturated with ether to afford 4- (2-hydroxy-2-methyl-propoxy) benzoic acid (0.8g, 76%) as a white solid. ESI-MS M/z calculated 195.1, found 196.1(M +1)⁺(ii) a Retention time: 0.62 min (run 3 min).¹H NMR(400MHz，DMSO)12.59(s，1H)，7.98-7.66(m，2H)，7.09-6.81(m，2H)，4.66(d，J＝9.3Hz，1H)，3.77(d，J＝7.9Hz，2H)，1.30-1.00(s，6H)。

Preparation of 4- (1-hydroxycyclopentyl) benzoic acid

A solution of 4-bromobenzoic acid (4.02g, 20.0mmol) in tetrahydrofuran (100mL) was purged with argon for 5 minutes. N-butyllithium (16.0mL of a 2.5M solution in hexane, 40mmol) was added dropwise at-78 deg.C to give a yellow thick syrup. The mixture was stirred at-78 ℃ for 30 minutes. Cyclopentanone (3.89mL, 44.0mmol) was added dropwise. Immediately use saturated NH₄The reaction was quenched with Cl, warmed to room temperature, the mixture was acidified to pH 3 with 1N HCl, extracted with ethyl acetate (3 × 50mL), the combined organic layers were washed with brine, and MgSO₄Drying and vacuum concentrating. The solid residue was suspended in hexane, filtered and the solid was washed with hexane. The solid was resuspended in dichloromethane and then in hexane. The resulting precipitate was filtered, washed with hexane and air dried to give 4- (1-hydroxycyclopentyl) benzoic acid (1.25g, 30%) as a white solid.¹H NMR(400MHz，DMSO)12.78(s，1H)，7.88(d，J＝8.5Hz，2H)，7.58(d，J＝8.5Hz，2H)，4.93(s，1H)，1.93–1.71(m，8H)。

The following compounds were prepared by the general procedure described above:

4- (1-hydroxycyclobutyl) benzoic acid

4- (2-hydroxybut-2-yl) benzoic acid

3-fluoro-4- (2-hydroxypropan-2-yl) benzoic acid

4-tert-butoxy-3-methoxybenzoic acid

Step 1: 4-tert-butoxy-3-methoxybenzaldehyde

Combine 4-hydroxy-3-methoxy-benzaldehyde (500mg, 3.29mmol), Boc in dichloromethane (5mL)₂O (1.74g, 7.97mmol) and Sc (OTf)₃(0.080g, 0.16 mmol). The reaction mixture was warmed to room temperature for 24 hours. Water (5mL) and methylene chloride (5mL) were added and the two phases separated. The aqueous layer was extracted with dichloromethane (3x5mL) and the combined organic layers were stirred with 10% aqueous potassium hydroxide until no total residual starting material was observed in the organic phase (TLC, 40% ethyl acetate in hexane). The two phases were separated, and the dichloromethane layer was washed 2 times with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and evaporated to dryness to give 4-tert-butoxy-3-methoxybenzaldehyde (130mg, 19%) as a yellow oil. Rf 0.66 (SiO)₂40% ethyl acetate in hexane); ESI-MS M/z calculated 208.1, found 209.2(M +1)⁺. Retention time: 0.96 min (run 6 min).

Step 2: 4-tert-butoxy-3-methoxybenzoic acid

4-tert-butoxy-3-methoxybenzaldehyde (130mg, 0.62mmol) was suspended in bis (tert-butoxy-3-methoxybenzaldehyde)Alkane (520. mu.L) and potassium hydroxide (6.5mL of 0.20M, 1.3 mmol). Adding KMnO₄(150mg, 0.93mmol) and the reaction mixture stirred vigorously for 16 h. The reaction mixture was filtered and then concentrated to 3 mL. Hydrochloric acid (1M, 4mL) was added and the resulting precipitate was filtered (after standing for 15 minutes) and washed with 1M HCl and a small amount of water to give 4-tert-butoxy-3-methoxy-benzoic acid (68mg, 49%) as a white solid. Rf 0.23 (SiO)₂40% ethyl acetate in hexane); ESI-MS M/z calculated 224.1, found 225.2(M +1)⁺. Retention time: 1.66 minutes (run 3 minutes).¹H NMR(400MHz，DMSO)12.80(s，1H)，7.66–7.41(m，2H)，7.09(d，J＝8.8Hz，1H)，3.78(s，3H)，1.32(s，9H)。

Table 2 below describes the analytical data for the compounds of table 1.

Table 2.

Assay for detecting and measuring NaV inhibitory properties of compounds

E-VIPR optical membrane potential measurement using electric stimulation

Sodium channels are voltage-dependent proteins that can be activated by applying an electric field to induce changes in membrane voltage. Electrical stimulation apparatus and Methods of use thereof are described in Ion Channel Assay Methods PCT/US01/21652, which is incorporated herein by reference, and is referred to as E-VIPR. The instrument comprises a microtiter plate processor, an optical system for exciting coumarin dyes while recording coumarin and oxonol emissions, a waveform generator, a current or voltage controlled amplifier and means for inserting electrodes into the wells. Under integrated computer control, the instrument delivers a user-programmed electrical stimulation protocol to the cells in the wells of the microtiter plate.

HEK cells expressing human NaV subtypes (e.g., NaV1.7) were seeded at 15,000 and 20,000 cells/well in polylysine-coated 384-well plates 24 hours prior to assay on E-VIPR. Other subtypes proceed in a similar pattern in cell lines expressing NaV of interest. HEK cells were allowed to qualify in cells supplemented with 10% FBS (fetal bovine serum)Of (1); GibcoBRL # 16140-; GibcoBRL #15140-122) in culture medium (precise composition specific for each cell type and NaV subtype). Cells were placed in vented capped flasks at 90% humidity and 10% CO₂Growth down to 100% confluence. It is usually split by trypsinization 1:10 or 1:20, depending on the time course needs, and grown for 2-3 days, before splitting again.

Reagents and solutions：

Pluronic (Pluronic) F-127(Sigma # P2443) at 100mg/mL in anhydrous DMSO

Compound plate 384-well round bottom plate, e.g. Corning 384-well Polypropylene round bottom #3656

384-well tissue culture treatment plates, e.g. Greiner #781091-1B

10mM DiSBAC in anhydrous DMSO₆(3)(Aurora#00-100-010)

10mM CC2-DMPE in anhydrous DMSO (Aurora #00-100-

H₂200mM ABSC1 in O

Bath 1 buffer: glucose 10mM (1.8g/L), magnesium chloride (anhydrous) 1mM (0.095g/L), calcium chloride 2mM (0.222g/L), HEPES 10mM (2.38g/L), potassium chloride 4.5mM (0.335g/L), sodium chloride 160mM (9.35 g/L).

Hexyl dye solution bath 1 buffer + 0.5% β -Cyclodextrin (prepared before use, Sigma # C4767), 8. mu. MCC2-DMPE + 2.5. mu.M DiSBAC₆(3). To prepare this solution, a volume equal to CC2-DMPE + DiSBAC was added₆(3) Volume 10% pluronic F127 stock. The preparation sequence was that Pluronic and CC2-DMPE were mixed first, and then DiSBAC was added₆(3) Vortexing was performed simultaneously, followed by addition of warm bath solution 1+ β -cyclodextrin.

Assay protocol：

1) Compounds (in pure DMSO) were pre-spotted into compound plates, vehicle control (pure DMSO), positive control (20mM tetracaine in DMSO stock, final 125 μ M in the assay), and test compounds were added to each well at 160x the desired final concentration in pure DMSO. The final compound plate volume will be 80 μ L (80-fold intermediate dilution from 1 μ L DMSO spotting; 160-fold final dilution after transfer to the cell plate). The final DMSO concentration for all wells in the assay was 0.625%.

2) A hexyl dye solution was prepared.

3) A cell plate was prepared. On the day of assay, the medium was aspirated and the cells were washed three times with 100 μ Ι of warm bath 1 solution, maintaining a residual volume of 25 μ Ι per well.

4) 25 μ L of hexyl dye solution per well was dispensed into the cell plate. Incubate at room temperature or ambient conditions for 20-35 minutes.

5) 80 μ L of warm bath solution 1 per well was dispensed into the compound plate. Acid yellow-17 (1mM) was added and potassium chloride was changed from 4.5 to 20mM depending on NaV subtype and assay sensitivity.

6) The cell plate was washed three times with 100. mu.L of warm bath 1 per well, leaving a residual volume of 25. mu.L. Next, 25 μ Ι _ per well from the compound plate was transferred to the cell plate. Incubate at room temperature/ambient conditions for 20-35 minutes.

7) The plate was read on an E-VIPR. A current-controlled amplifier is used to deliver the stimulus pulses, typically 9 seconds, at a scan rate of 400 Hz. Pre-stimulation recordings were made for 0.5 seconds to obtain an unstimulated intensity baseline. The stimulus waveform was applied for 9 seconds, followed by 0.5 seconds of recording after the stimulus to check for relaxation to a resting state. The stimulation waveform of the electrical stimulation is specific to each cell type, and the magnitude, duration, and frequency of the applied current can be varied to provide the optimal measurement signal.

Data analysis

The data were analyzed and reported as normalized ratios of the emission intensities measured in the 460nm and 580nm channels minus the background value. Next, the background intensity was subtracted from each measurement channel. Background intensity was obtained by measuring the emission intensity from the same treated assay well in the absence of cells during the same time period. Next, the reaction as a function of time is reported using the ratio obtained by the following formula:

by calculating the initial (R)_i) And finally (R)_f) Ratios to further simplify the data. These ratios are the average ratio values over part or all of the pre-stimulation period and over the sampling points during the stimulation period. Then, the response to the stimulus R ═ R was calculated_f/R_iAnd reported as a function of time.

A control reaction is obtained by performing the assay in the presence of a compound having the desired properties (positive control), such as tetracaine, and in the absence of a pharmacological agent (negative control). The reactions of the negative (N) and positive (P) controls were calculated as above. Compound antagonist activity a is defined as:

where R is the ratio response of the test compounds.

Electrophysiological assay for NaV activity and test compound inhibition

Patch-clamp electrophysiology was used to evaluate the efficacy and selectivity of sodium channel blockers in dorsal root ganglion neurons. Rat neurons were isolated from dorsal root ganglia and maintained in the presence of NGF (50ng/mL) in a medium consisting of Neurobasal a supplemented with B27, glutamine and antibiotics for 2 to 10 days. Small diameter neurons (nociceptors, 8-12 μm in diameter) have been identified visually and probed using tiny tip glass electrodes connected to amplifiers (Axon Instruments). The cells were maintained at-60 mV and the IC50 of the compound was evaluated using a "voltage clamp" mode. In addition, compounds have been tested for their efficacy in blocking the action potential generated by current injection using the "current clamp" model. The results of these experiments help to define the efficacy profile of the compounds.

IonWorks assay

Sodium current was recorded using an automatic patch clamp system, IonWorks (Molecular Devices Corporation, Inc.). Cells expressing a subset of Nav were collected from tissue culture and placed in suspension at 50 ten thousand to 4 million cells per ml bath 1. The IonWorks instrument measures changes in sodium current in response to application of a voltage clamp similar to a conventional patch clamp assay (except using a 384-well format). Dose-response relationships were determined in a voltage clamp mode using IonWorks by depolarizing cells from the experiment-specific holding potential to a test potential of about 0mV before and after addition of the test compound. The effect of the compound on the current was measured at the test potential.

1-benzazepine -2-keto binding assay

The sodium Channel inhibiting properties of the compounds of the present invention may also be measured by the "Characterization of a New Class of content Inhibitors of the Voltage-gated sodium Channel NaV1.7" in Williams, B.S. et al "Biochemistry2007,46,14693-14703, the entire contents of which are incorporated herein by reference.

As presented in table 3, the exemplified compounds in table 1 herein were active on one or more sodium channels as measured using the assays described above.

Table 3.

It will be apparent to those skilled in the art that many modifications and variations can be made to the embodiments described herein without departing from the scope thereof. The specific embodiments described herein are provided by way of example only.

Claims (17)

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

R¹is CH₂CH₃、

R²Is CH₂CH₃、OCH₃、OCH₂CH₃、OCH₂CH₂CH₃、OCH₂CH₂F、OCH₂CH₂OCH₃、Or OCH (CH)₃)₂；

R³Is C1-C6 alkyl or halogen;

ring a is:

wherein

R⁴Is H, CH₃、OCH₃、OCH₂CH₃、F、Cl、OCHF₂、CHF₂、CF₃、CH₂OCH₃、OCH(CH₃)₂、CH₂OCH₃Or

R⁵Is H, CH₃、OCH₃、OCH(CH₃)₂、F、Cl、CF₃CN or CH₂OH; and is

R⁶Is H, F, Cl, CH₃、CF₃、CH₂CH₃、OCH₃、OCH₂CF₃、OCH₂CH₃、OCH₂CH₂CH₃、OCH₂CH₂CH(CH₃)₂、OtBu、tBu、OCH(CH₃)₂、OCH₂CH(CH₃)₂、OCH(CH₃)CH₂CH₃、CH(OH)CH(CH₃)₂、C(OH)(CH₃)CH₂CH₃、OCH₂C(CH₃)₂OH、C(CH₃)₂OH、CH₂C(CH₃)₂OH 、OCH₂CH₂OCH₃、OCH₂CH₂OH、OCH₂CH₂CH₂OH、SO₂CH₃、SO₂CF₃、SO₂CH(CH₃)₂、SO₂CH₂CH₃、CH₂OCH₂CF₃、CH₂OCH₂CH₂CF₃、OCHF₂、OCH₂CF(CH₃)₂、Or

Ring a is:

wherein:

R⁴is H, OCH₃、OCH₂CH₃、OCH₂CF₃、N(CH₃)₂、NH(CH₂CH(CH₃)₂) Or

R⁵Is H, CH₃、OCH₃、Cl、tBu、N(CH₃)₂OrAnd is

R⁶Is H, CN, OCH₃、OCH₂CH₃、OCH(CH₃)₂、CF₃、OCH₂CF₃、

n is 1 or 2; and is

o is 0.

2. The compound of claim 1, wherein ring a is

3. The compound of claim 2, whereinSelected from:

4. the compound of claim 1, wherein ring a is

5. The compound of claim 4, wherein ring a is selected from the group consisting of:

6. the compound of claim 1, wherein the compound has formula IA:

wherein:

R¹is that

R²Is OCH₃、OCH₂CH₃、OCH₂CH₂CH₃、OCH₂CH₂F、OCH₂CH₂OCH₃、Or OCH (CH)₃)₂；

R⁵Is H, CH₃、OCH₃、CF₃、OCHF₂F, Cl, CN or CH₂OH；

R⁶Is H, Cl CH₂CH₃、tBu、OtBu、OCH₃、OCH(CH₃)₂、OCH₂CH₂(CH₃)₂、OCH₂CH₃、OCH₂CH₂CH₃、OCH₂CH₂CH(CH₃)₂、OCH₂CF(CH₃)₂、CH₂OCH₂CH₂CF₃、OCH₂CH₂OH、CH₂CH₂CH₂OH、OCHF₂、OCH₂CH₂OCH₃、OCH(CH₃)CH₂CH₃、OCH₂C(CH₃)₂OH、C(CH₃)₂OH、CH₂C(CH₃)₂OH、

7. The compound of claim 6, whereinMoieties are selected from:

8. a compound selected from the following table

9. A pharmaceutical composition comprising a compound of any one of claims 1-8 and a pharmaceutically acceptable carrier.

10. Use of a compound according to any one of claims 1 to 8 in the manufacture of a medicament for inhibiting a voltage-gated sodium ion channel in a biological sample.

11. The use of claim 10, wherein the voltage-gated sodium ion channel is NaV1.7.

12. Use of a compound according to any one of claims 1 to 8 in the manufacture of a medicament for inhibiting a voltage-gated sodium ion channel in a patient.

13. The use of claim 12, wherein the voltage-gated sodium ion channel is NaV1.7.

14. Use of a compound according to any one of claims 1 to 8 in the manufacture of a medicament for treating or lessening the severity of: acute, chronic, neuropathic, or inflammatory pain, arthritis, epilepsy, neurodegenerative disorders, psychiatric disorders, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, palpitation, hypertension, or abnormal gastrointestinal motility.

15. The use of claim 14, wherein the neuropathic pain is trigeminal neuralgia, herpetic neuralgia, general neuralgia, post-herpetic neuralgia, or sciatica.

16. Use of a compound according to any one of claims 1 to 8 in the manufacture of a medicament for treating or lessening the severity of: epilepsy, anxiety, depression, bipolar disorder, visceral pain, osteoarthritis pain, diabetic neuropathy, radicular pain, back pain, headache or neck pain, severe or refractory pain, nociceptive pain, penetrating pain, post-operative pain, cancer pain, or pressure or exercise induced angina.

17. The use of claim 16, wherein the headache is migraine or cluster headache.